WO2026030512A1 - Pharmaceutical compounds for the treatment of complement mediated disorders - Google Patents

Abstract

This disclosure provides compounds, compositions, and methods to treat medical disorders, such as complement-mediated disorders, including complement C1s-mediated disorders.

Description

PHARMACEUTICAL COMPOUNDS FOR THE TREATMENT OF COMPLEMENT MEDIATED DISORDERS Field of the Disclosure Herein are provided pharmaceutical compounds to treat medical disorders, such as complement- mediated disorders, including complement C1-mediated disorders. Background of the Disclosure The complement system is a part of the innate immune system which does not adapt to changes over the course of the subject’s life but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells), and agglutination (clustering and binding of pathogens together). The complement system has three pathways: classical, alternative, and lectin. The classical pathway is triggered by antibody-antigen complexes with the antibody isotypes IgG and IgM. The antibody-antigen complex binds to C1 and this initiates the cleavage of C4 and C2 to generate C3 convertase that then splits C3 into C3a and C3b. C3a interacts with its C3a receptor to recruit leukocytes, while C3b binds to C3 convertase to form C5 convertase. C5 convertase cleaves C5 into C5a and C5b. Similar to C3a, C5a interacts with its C5a receptor to recruit leukocytes, but C5b interacts with C6, C7, C8, and C8 and together these proteins form the cylindrical membrane attack complex (MAC) that causes the cell to swell and burst. These immune responses can be inhibited by preventing C1 from being able to bind the antibody-antigen complex. Given the range of serious diseases mediated by a disfunction of the complement system, there is a clear medical need to provide pharmaceutically acceptable compounds, methods, compositions, and methods of manufacture to inhibit the complement system in a patient in need thereof. Therefore, the present disclosure provides compounds and their uses and compositions to treat disorders arising from or amplified by a disfunction of the complement system. The present disclosure also provides compounds, uses, compositions, combinations, and processes of manufacture that inhibit C1s (complement C1 esterase) and thus can treat disorders mediated by C1s. Summary The present disclosure provides compounds, compositions, and methods for treating a disorder mediated by the complement cascade (including a dysfunctional cascade), a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity including for example, the classical complement pathway, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other allogenic tissue or fluid administration. In some embodiments, the active compound may act as an inhibitor of the complement classical pathway by inhibiting complement C1s. Without wishing to be bound by theory, the present disclosure is based, in part, on the unexpected discovery that compounds of the disclosure exhibit advantageous properties over other C1s inhibitors (e.g., the compounds described in WO2020/198062, WO2022/066774, WO2023/183405, WO2024/035686, and WO2024/044098), such as improved C1s inhibiting activity, improved classical pathway hemolysis inhibiting activity, improved Caco-2 permeability, improved oral bioavailability, improved C1s selectivity (e.g., over other proteases, such as trypsin, thrombin, tryptase, and/or MASP-2), improved physiochemical properties, improved metabolic stability, reduced cytotoxicity, and/or reduced cardiotoxicity as determined by the assays described in, e.g., Examples 3-12 In one aspect, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, in which all variables are as defined herein. In another aspect, the present disclosure provides a pharmaceutical composition including a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another aspect, the present disclosure provides a method of treating a complement C1 esterase (C1s) mediated disorder. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method of inhibiting C1s activity in a subject. The method includes administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof, for use in the treatment of a C1s mediated disorder. In another aspect, the present disclosure provides a use of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof in the preparation a medicament for use in the treatment of a C1s mediated disorder. Definitions Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the present disclosure belongs. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term “or” means “and/or.” Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely as illustration, and does not pose a limitation on the scope of the invention. The term “absent,” as used herein in reference to a structural variable, refers to the lack of a substituent due to the valency of the atom to which the structural variable is attached. For example, for an =C(R2)- group, one of the R2 is a substituent (e.g., H), while the other is absent due to the valency of the carbon atom. The term “alkoxy,” as used herein, refers to a -OR radical, in which R is alkyl, as defined herein. The term “alkoxyalkyl,” as used herein, refers to a -ROR’ radical, in which R is alkylene and R’ is alkyl, as defined herein. The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted. The monovalency of an alkyl group does not include the optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group may contain, e.g., 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-methylpropyl, and 2,2- dimethylpropyl. The term “alkylene,” as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalency of an alkylene group does not include the optional substituents on the alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene. The term “amino,” as used herein, refers to a monovalent radical of formula -NH₂. An “optionally substituted amino,” as used herein, refers to an amino group in which one or both hydrogen atoms are independently replaced with a substituent as defined herein. The term “aryl,” as used herein, refers to any monocyclic or fused ring bicyclic or multicyclic system containing only carbon atoms in the ring(s), which has the characteristics of aromaticity in terms of electron distribution throughout the entire ring system, e.g., phenyl, naphthyl, or phenanthryl. An aryl group may have, e.g., 6-16, 6-14, or 6-10 carbon ring atoms (e.g., C6-C16, C6-C14, C6-C10, C6, C10, C14, or C16). The term “arylalkyl,” as used herein, refers to a -RR’ radical, in which R’ is aryl, as defined herein, and R is alkylene, as defined herein. The term “aryloxy,” as used herein, refers to an -OR radical, in which R is aryl, as defined herein. The term “carbocyclyl,” as used herein, refers to a monovalent, saturated (i.e., cycloalkyl) or unsaturated, non-aromatic group (e.g., cycloalkenyl, which contains at least one carbon-carbon double bond and no carbon-carbon triple bonds) containing only C and H when unsubstituted, which may be monocyclic, bicyclic, or multicyclic (e.g., tricyclic). A carbocyclyl may have, e.g., 3-14 carbons (e.g., a C3- C4, C3-C5, C3-C6, C3-C7, C3-C8, or C3-C14 carbocyclyl). Examples of carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cycloheptenyl, and fluorenyl. The term “carbocyclyl” also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1]heptyl. The term “cycloalkylalkyl,” as used herein, refers to an -RR’ radical, in which R’ is cycloalkyl, as defined herein, and R is alkylene, as defined herein. The term “cycloalkyloxy,” as used herein, refers to an -OR radical, in which R is cycloalkyl, as defined herein. The term “halo,” as used herein, refers to a fluorine (fluoro; F), chlorine (chloro; Cl), bromine (bromo; Br), or iodine (iodo; I) radical. The term “haloalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more H is replaced with halo, as defined herein. Examples of haloalkyl include, but are not limited to, CF3, CHF2, and CH2F. The term “haloalkoxy,” as used herein, refers to an -OR radical, in which R is haloalkyl, as defined herein. The term “heteroaryl,” as used herein, refers to a monocyclic, bicyclic, or multicyclic aromatic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, B, and P (e.g., 1-4, 1-3, or 1 or 2 heteroatoms selected from N, O, and S) as ring atoms, with the remaining ring atoms being carbon. In some embodiments, a heteroaryl group is a bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1, 2, 3, or 4 heteroatoms selected from N, O, S, B, and P (e.g., 1-4, 1-3, or 1 or 2 heteroatoms selected from N, O, and S) as ring atoms, with the remaining ring atoms being carbon. In some embodiments, a heteroaryl group is a monocyclic aromatic ring having 5 or 6 ring atoms (i.e., 5- or 6-membered heteroaryl). In some embodiments, is a bicyclic aromatic ring system having 8 to 10 ring atoms (i.e., 8- to 10-membered bicyclic heteroaryl). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. The term “heterocyclyl,” as used herein, refers to saturated or unsaturated, non-aromatic, monocyclic, bicyclic, or multicyclic group containing 1, 2, 3, or 4 heteroatoms selected from N, O, S, B, and P (e.g., 1-4, 1-3, or 1 or 2 heteroatoms selected from N, O, and S) as ring atoms, with the remaining ring atoms being carbon. The term “heterocyclyl” includes, e.g., monocyclic 3-to 12-membered rings, bicyclic 5- to 16-membered ring systems, multicyclic (e.g., tricyclic) 10- to 18-membered ring systems, which may include bridged ring systems when bicyclic or multicyclic. In some embodiments, a heterocyclyl group contains 3-16 ring atoms (i.e., 3- to 16-membered heterocyclyl), e.g., 3-12 ring atoms (i.e., 3- to 12-membered heterocyclyl) or 4-10 ring atoms (i.e., 4-to 10-membered heterocyclyl). Examples of saturated heterocyclyl groups include saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl); saturated 4 to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl); saturated 3 to 6-membered monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of unsaturated, non-aromatic heterocyclyl radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Other examples of heterocyclyl radicals include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4- a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ- benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl. “Bicyclic heterocyclyl” includes groups in which a saturated or unsaturated, non-aromatic ring containing 1, 2, 3, or 4 heteroatoms as ring atoms is fused with an aryl group (e.g., phenyl) or a cycloalkyl group. “Bicyclic heterocyclyl” also includes groups in which a heteroaryl group, as defined herein, is fused to a saturated or unsaturated, non- aromatic ring containing 0, 1, 2, 3, or 4 heteroatoms as ring atoms. The term “heterocyclyloxy,” as used herein, refers to a monovalent radical of formula -OR, in which R is heterocyclyl, as defined herein. The term “hydroxyalkyl,” as used herein, refers to a monovalent radical of formula -ROH, in which R is alkylene, as defined herein. The term “oxo,” as used herein, refers to a =O radial. The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety as defined herein or selected from an indicated group of moieties, provided that the designated atom's normal valence is not exceeded, and the resulting compound is stable. For example, when the substituent is oxo (i.e., =O), then two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. The phrase “optionally substituted X,” as used herein, is intended to be equivalent to “X, in which X is optionally substituted” (e.g., “alkyl, in which said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. The term “optionally substituted,” as used herein, refers to having 0, 1, or more substituents (e.g., 0-10 substituents, 0-5 substituents, or 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents). Alkyl, alkylene, alkoxy, amino, carbocyclyl, aryl, arylene, aryloxy, heteroaryl, and heterocyclyl groups may be substituted with carbocyclyl (e.g., cycloalkyl); aryl; heteroaryl; heterocyclyl; halo; OR, in which R is H, alkyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, or heterocyclyl; SR, in which R is H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; CN; NO2; N3; NRR^’; in which each of R and R’ is, independently, H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; SO2R, in which R is H, alkyl, or aryl; SO₂NRR’, in which each of R and R’ is, independently, H, alkyl, or aryl; SOR, in which R is H, alkyl, or aryl; or P(O)(OR)₂, in which each R is, independently, H or alkyl. Amino, aryl, carbocyclyl, heteroaryl, and heterocyclyl groups may also be substituted with alkyl. Alkyl, alkylene, carbocyclyl, and heterocyclyl groups may also be substituted with oxo or =NR, in which R is H or alkyl. Alkyl and alkylene groups may also be substituted with spirocyclic carbocycle (e.g., spirocyclic cycloalkyl) or spirocyclic heterocyclyl. In some embodiments, a substituent is further substituted with one or more substituents as described herein. For example, a C1 alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group and further substituted with OH or NR2 to form a carboxyl group or an amido group. The term “complement-mediated disorder,” as used herein, refers to a disorder in which the amount or activity of complement is such as to cause disorder in an individual. As used herein, a compound having “complement C1 esterase (C1s) inhibiting activity” refers to a compound exhibiting an IC50 of less than 1 µM against as determined with a human complement C1s enzyme assay as described in Example 3 herein. The term “pharmaceutical composition,” as used herein, refers to one or more active compounds, formulated together with one or more pharmaceutically acceptable excipients. In some embodiments, a compound of the disclosure (e.g., is present in a unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In certain embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, or capsules; and parenteral administration, for example, by subcutaneous, intramuscular, or intravenous injection. As used herein, the term “pharmaceutically acceptable salt” represents those salts of the compounds described that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid. The term “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) that is biocompatible and suitable for administration to a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. The term “subject,” as used herein, can be a human, non-human primate, or other non-human mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human. As used herein, and as well understood in the art, “to treat” a condition or “treatment” of various diseases and disorders is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilizing (i.e., not worsening) of the state of disease, disorder, or condition; delay or slowing in the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. “Palliating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or the time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. A “therapeutically effective amount” or an “effective amount” of an active compound pharmaceutical composition of the present disclosure refers an amount effective, when administered to a subject, to provide a therapeutic benefit, such as an amelioration of symptoms or reduction or diminution of the disease itself. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent a significant increase, or will significantly reduce, the detectable level of hemolysis in the patient’s blood, serum, or tissues. Detailed Description Active Compounds The present disclosure provides compounds and salts useful for the treatment of a disorder mediated by the complement cascade (e.g., a disorder mediated by C1s). In some embodiments, a compound of the present disclosure is a compound described by Formula (I): or a pharmaceutically acceptable salt thereof, in which: X⁴ X⁵ R³ X³ X² A is R⁴ X¹ , in which X¹ is O, S, C(R^a)₂, or NR^a, in which each R^a is independently selected from absent, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl; X² is N or CR^b, in which R^b is absent or H; each of X³, X⁴, and X⁵ is independently selected from NR^c and C(R^c)2, in which each R^c is independently selected from absent, H, halo, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, and C1-C6 alkyl, and only one of X³ and X⁵ can be NR^c when X⁴ is NR^c; R³ is H or halo; R⁴ is H, halo, NH2, NH(C1-C6 alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; and each is independently selected from a single bond and a double bond; each of R¹ and R¹ is independently selected from H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and (C1-C6 alkoxy)(C1-C6 alkyl); each of R², R^2’, R⁵, and R^5’ is independently selected from H; halo; OH; C₁-C₆ alkyl; C₁-C₆ haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 hydroxyalkyl; (C1-C6 alkoxy)(C1-C6 alkyl); OCH2P(O)(OR^f)2, in which each R^f is independently selected from H and C1-C6 alkyl; and (4- to 10- membered heterocyclyl)oxy containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with oxo; or R² and R^2’, together with the carbon atom to which they are attached, form spirocyclic C3-C8 cycloalkyl or 4- to 6-membered spirocyclic heterocycloalkyl containing 1 or 2 oxygen ring atoms; or R² and R⁵ or R^2’ and R^5’, together with the carbon atoms to which each is attached, form cyclopropyl; R⁶ is H or C1-C6 alkyl; each of X and X’ is independently selected from N and CR^d, in which R^d is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or cyclopropyl; L¹ is a bond, NH, NHC(O), NHC(O)O, NHC(O)NH, or NHS(O)₂; L² is a bond or C1-C6 alkylene optionally substituted with one or more substituents independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, (C₁-C₆ alkoxy)(C₁-C₆ alkyl), and oxo; L³ is a bond, NH, NHC(O), C(O), O, or S(O)₂CH₂; and B is C6-C14 aryl; C3-C14 carbocyclyl; 5- to 14-membered heterocyclyl containing 1, 2, or 3 ring atoms independently selected from N, O, and S; or 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; in which B is optionally substituted with one or more substituents independently selected from halo; cyano; COOR^e, in which R^e is H or C₁-C₆ alkyl; S(O)2(C1-C6 alkyl); C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; C6-C14 aryl optionally substituted with one or more substituents independently selected from halo, COOH, SF5, S(O)2NH2, S(O)₂(C₁-C₆ alkyl), S(O)(NH)CH₃, P(O)(OH)₂, P(O)(OH)CH₃, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₃-C₆ carbocyclyl; C₆-C₁₄ aryloxy optionally substituted with one or more halo; C₃- C6 cycloalkyl optionally substituted with one or more halo; C3-C6 cycloalkyloxy optionally substituted with one or more halo; (C3-C8 cycloalkyl)(C1-C6 alkyl); (C6-C14 aryl)(C1-C6 alkyl); 5- to 8-membered heterocyclyl containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents independently selected from C₁-C₆ alkyl, OH, C₁-C₆ hydroxyalkyl, and oxetanyl; 6-membered heteroaryloxy containing 1 or 2 nitrogen ring atoms and optionally substituted with C1-C6 alkyl; and 5- or 6-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents selected from halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. Exemplary Embodiments of Compounds of the Present Disclosure In some embodiments, when A is , at least one of the following is true: (i) L¹ is a bond, NHC(O), NHC(O)O, NHC(O)NH, or NHS(O)2; (ii) L² is a bond or C2-C6 alkylene optionally substituted with one or more substituents independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, (C₁-C₆ alkoxy)(C₁-C₆ alkyl), and oxo; (iii) L³ is NH, NHC(O), C(O), O, or S(O)2CH2; (iii) at least one of R², R^2’, R⁵, and R^5’ is not H; (iv) at least one of R¹ and R^1’ is not H; (v) X’ is N; and (vi) B is not . In some embodiments, the compound is of Formula (I’): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (I”): or a pharmaceutically acceptable salt thereof. In some embodiments, the A group provides improved potency, metabolic stability, permeability, pharmacokinetics, and/or oral bioavailability. In some embodiments, A is . In some embodiments, X³ is N. In some embodiments, X³ is CR^c. In some embodiments, X³ is CH. In some embodiments, X³ is CNH2. In some embodiments, X⁵ is N. In some embodiments, X⁵ is CR^c. In some embodiments, X⁵ is CH. In some embodiments, X⁵ is C(C1-C6 alkyl). In some embodiments, X⁵ is C(CH3). In some embodiments, X⁵ is CNH2. In some embodiments, X⁴ is N. In some embodiments, X¹ is S. In some embodiments, X¹ is O. In some embodiments, X¹ is NR^a. In some embodiments, X¹ is NH. In some embodiments, X¹ is N(C1-C6 alkyl). In some embodiments, X¹ is NCH3. In some embodiments, X¹ is NCH2CH3. In some embodiments, X¹ is N(C1-C6 haloalkyl). In some embodiments, X¹ is NCHF2. In some embodiments, X¹ is N(C3-C6 cycloalkyl). In some embodiments, X¹ is N(cyclopropyl). In some embodiments, A is . In some embodiments, X³ is N. In some embodiments, X⁴ is C(R^c)2. In some embodiments, X⁴ is CH2. In some embodiments, X⁴ is N. In some embodiments, X³ is C(R^c)2. In some embodiments, X³ is CH2. In some embodiments, X¹ is S. In some embodiments, X¹ is O. In some embodiments, X¹ is NR^a. In some embodiments, X¹ is NH. In some embodiments, X¹ is N(C₁-C₆ alkyl). In some embodiments, X¹ is NCH₃. In some embodiments, X¹ is NCH₂CH₃. In some embodiments, X¹ is N(C1-C6 haloalkyl). In some embodiments, X¹ is NCHF2. In some embodiments, X¹ is N(C3-C6 cycloalkyl). In some embodiments, X¹ is N(cyclopropyl). In some embodiments, A is . In some embodiments, X¹ is CR^a. In some embodiments, X¹ is C(C₁-C₆ alkyl). In some embodiments, X¹ is CCH₃. In some embodiments, X¹ is CH. In some embodiments, X² is N. In some embodiments, X³ is CH. In some embodiments, X⁴ is CH. In some embodiments, R³ is H. In some embodiments, R³ is halo. In some embodiments, R³ is F. In some embodiments, R⁴ is H. In some embodiments, R⁴ is NH₂. In some embodiments, R⁴ is halo. In some embodiments, R⁴ is Cl. In some embodiments, R⁴ is C₁-C₆ alkyl. In some embodiments, R⁴ is methyl. In some embodiments, R⁴ is C3-C6 cycloalkyl. In some embodiments, R⁴ is cyclopropyl. In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is N N . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . , . In some embodiments, embodiments, A is . In some embodiments, A is . In some embodiments, A is . , . In some embodiments, A is In some embodiments, In some embodiments, R¹ is H. In some embodiments, R^1’ is H. In some embodiments, the bicyclic core (including variables R², R^2’, R⁵, R^5’, R⁶, X, and X’) provides improved potency, improved pharmacokinetics, and/or reduced hERG inhibition. In some embodiments, R² is H. In some embodiments, R² is halo. In some embodiments, R² is F. In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is methyl. In some embodiments, R² is C1-C6 alkoxy. In some embodiments, R² is methoxy. In some embodiments, R² is OH. In some embodiments, R² is (C1-C6 alkoxy)(C1-C6 alkyl). In some embodiments, R² is methoxymethyl. In some embodiments, R^2’ is H. In some embodiments, R^2’ is halo. In some embodiments, R^2’ is F. In some embodiments, R^2’ is C₁-C₆ alkyl. In some embodiments, R^2’ is methyl. In some embodiments, R^2’ is C₁-C₆ alkoxy. In some embodiments, R^2’ is methoxy. In some embodiments, R^2’ is OH. In some embodiments, R^2’ is (C1-C6 alkoxy)(C1-C6 alkyl). In some embodiments, R^2’ is methoxymethyl. In some embodiments, R^2’ is OCH₂P(O)(OR^f)₂. In some embodiments, R^2’ is OCH₂P(O)(OH)₂. In some embodiments, R^2’ is OCH₂P(O)(OH)(OCH₂CH₃). In some embodiments, R^2’ is OCH₂P(O)(OCH₂CH₃)₂. In some embodiments, R² and R^2’, together with the carbon atom to which they are attached, form spirocyclic C₃-C₈ cycloalkyl. In some embodiments, R² and R^2’, together with the carbon atom to which they are attached, form spirocyclic cyclopropyl. In some embodiments, R² and R^2’, together with the carbon atom to which they are attached, form spirocyclic cyclopentyl. In some embodiments, R² and R⁵, together with the carbon atoms to which they are attached, form cyclopropyl. In some embodiments, R^2’ and R^5’, together with the carbon atoms to which they are attached, form cyclopropyl. In some embodiments, R⁵ is H. In some embodiments, R^5’ is H. In some embodiments, R⁶ is H. In some embodiments, R⁶ is CH3 In some embodiments, X is N. In some embodiments, X is CR^d. In some embodiments, X is CCH₃. In some embodiments, X is CH. In some embodiments, X is CCl. In some embodiments, X is C(C1-C6 haloalkyl). In some embodiments, X is CCF3. In some embodiments, X is C(C1-C6 haloalkoxy). In some embodiments, X is C(OCF3). In some embodiments, X’ is N. In some embodiments, X’ is CR^d. In some embodiments, X’ is CCH₃. In some embodiments, X’ is CH. In some embodiments, only one of X and X’ is N. In some embodiments, the -L¹-L²-L³-B fragment provides improved potency, metabolic stability, permeability, pharmacokinetics, and/or protease selectivity. In some embodiments, L¹ is NH. In some embodiments, L¹ is NHC(O). In some embodiments, L² is a bond. In some embodiments, L² is C₁-C₆ alkylene optionally substituted with C1-C6 alkyl or C1-C6 hydroxyalkyl. In some embodiments, L² is -CH2-. In some embodiments, L² is -(CH2)2-. In some embodiments, L² is -(CH2)3-. In some embodiments, L² is - CH(CH₃)-. In some embodiments, L² is -CH(CH₃)CH₂-. In some embodiments, L² is -CH(CH₂OH)-. In some embodiments, L³ is a bond. In some embodiments, L³ is O. In some embodiments, L³ is C(O). H H N N In some embodiments, -L¹-L²-L³- is . In some embodiments, -L¹-L²-L³- is . In H H N N some embodiments, -L¹-L²-L³- is . In some embodiments, -L¹-L²-L³- is . In H H N N some embodiments, -L¹-L²-L³- is . In some embodiments, -L¹-L²-L³- is . In some H H N N embodiments, -L¹-L²-L³- is . In some embodiments, -L¹-L²-L³- is . In some H H N N embodiments, -L¹-L²-L³- is ^O . In some embodiments, -L¹-L²-L³- is ^O . In some H N _O H 1-L²-L³ _{N O} embodiments, -L - is ^O . In some embodiments, -L¹-L²-L³- is . In some H H N N embodiments, -L¹-L²-L³- is ^O . In some embodiments, -L¹-L²-L³- is ^OH . In some embodiments, B is phenyl optionally substituted with one or more substituents independently selected from halo; cyano; COOR^e, in which R^e is C₁-C₆ alkyl; S(O)₂(C₁-C₆ alkyl); C₁-C₆ alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; phenyl optionally substituted with one or more halo; phenoxy; C3-C6 cycloalkyl; C3-C6 cycloalkyloxy optionally substituted with 1 or 2 halo; 5- to 8-membered heterocyclyl containing 1 or 2 ring atoms independently selected from N and O and optionally substituted with hydroxymethyl or oxetanyl; 5- or 6-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, and cyclopropyl; and -O(pyridyl). In some embodiments, B is F F . In some embodiments, B is . In some embodiments, B is . In some O F N embodiments, B is . In some embodiments, B is ^F . In some embodiments, B is O F S O Cl . In some embodiments, B is . In some embodiments, B is . In some O Cl O embodiments, B is . In some embodiments, B is . In some embodiments, B is S CF₃ CN N . In some embodiments, B is . In some embodiments, B is . In some O embodiments, B is . In some embodiments, B is . In some embodiments, B is N ^N S N N . In some embodiments, B is . In some embodiments, B is . In some N S N N C^F embodiments, B is ³ . In some embodiments, B is . In some embodiments, B is F F S N N N F . In some embodiments, B is . In some embodiments, B is . In N N N F some embodiments, B is . In some embodiments, B is . In some embodiments, N N S N N F B is . In some embodiments, B is . In some embodiments, B is . F N N F In some embodiments, B is . In some embodiments, B is . In some O N N embodiments, B is . In some embodiments, B is . In some embodiments, B is S S N N N . In some embodiments, B is . In some embodiments, B is . In O _N ^O N N some embodiments, B is . In some embodiments, B is and . In some O O embodiments, B is . In some embodiments, B is . In some embodiments, B F F O O is . In some embodiments, B is ^F . In some embodiments, B is ^F . In some embodiments, B is . In some embodiments, B is . In some embodiments, B is O _F O O F N . In some embodiments, B is . In some embodiments, B is ^N . O O In some embodiments, B is . In some embodiments, B is . In some OH O N F embodiments, B is . In some embodiments, B is F . In some F _F O O embodiments, B is . In some embodiments, B is ^{F F} . In some embodiments, B O N N is . In some embodiments, B is naphthyl optionally substituted with one or more substituents selected from halo and C1-C6 alkoxy. In some embodiments, B is . In some embodiments, B is O Cl . In some embodiments, B is . In some embodiments, B is C₃-C₁₄ carbocyclyl optionally substituted with phenyl.In some embodiments, B is . In some embodiments, B is C₃-C₆ cycloalkyl optionally substituted with phenyl optionally substituted with one or more halo; benzoxazolyl optionally substituted with one or more halo or C₁-C₆ alkyl, -O(pyridyl) optionally substituted with C1-C6 alkyl, thiazolopyridinyl, oxazolopyridinyl optionally substituted with C₁-C₆ alkyl, or benzothiazolyl, or phenoxy optionally substituted with one or more halo. In some embodiments, B is cyclohexyl. In some embodiments, B is . In some F embodiments, B is . In some embodiments, B is . In some embodiments, B is N N N O O O . In some embodiments, B is . In some embodiments, B is . In N S O N some embodiments, B is . In some embodiments, B is . In some S S N N N embodiments, B is . In some embodiments, B is ^N . In some O S N N N embodiments, B is . In some embodiments, B is ^N . In some O O N N N N embodiments, B is . In some embodiments, B is . In some O O N N N N embodiments, B is . In some embodiments, B is . In some embodiments, O O N N B is . In some embodiments, B is . In some embodiments, B is O O N O N N . In some embodiments, B is . In some embodiments, B is . O O N N In some embodiments, B is ^F . In some embodiments, B is ^F . In some O _{O F} N F N embodiments, B is . In some embodiments, B is . In some embodiments, F F O B is . In some embodiments, B is . In some embodiments, B is 5- to 14-membered heterocyclyl containing 1 or 2 ring atoms independently selected from O and N and optionally substituted with C₁-C₆ alkyl and further optionally substituted with pyridyl or phenyl optionally substituted with one or more halo. In some embodiments, B is O O O . In some embodiments, B is . In some embodiments, B is . In O ^N O some embodiments, B is ^O . In some embodiments, B is . In some F N N embodiments, B is ^N . In some embodiments, B is . In some embodiments, B is N F . In some embodiments, B is 5- to 10-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S; in which B is optionally substituted with one or more substituents independently selected from halo; C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; phenoxy; phenyl optionally substituted with one or more substituents selected from halo, COOH, S(O)₂NH₂, S(O)₂(C₁- C₆alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₃-C₆ cycloalkyl; C₃-C₆ carbocyclyl optionally substituted with C1-C6 alkyl or halo; (C3-C6 cycloalkyl)(C1-C6 alkyl); phenyl(C1-C6 alkyl); 5- to 8-membered heterocyclyl containing 1 or 2 ring atoms independently selected from N and O and optionally substituted with halo, OH, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, and oxetanyl; and 5- or 6- membered heteroaryl containing 1 or 2 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halo. In some embodiments, B is 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms and optionally substituted with C₁-C₆ alkyl; C₁-C₆ alkoxy; phenoxy; C₃-C₆ cycloalkyl optionally substituted with one or more substituents independently selected from C₁-C₆ alkyl and halo; 5- to 8-membered heterocyclyl containing one or two nitrogen ring atoms and optionally substituted with one or more substituents independently selected from halo, OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, and oxetanyl; and 5- membered heteroaryl containing 1 or 2 ring atoms independently selected from N and S. In some N N _S N embodiments, B is . In some embodiments, B is . In some embodiments, B is N N N N N . In some embodiments, B is . In some embodiments, B is . In some O O N N embodiments, B is . In some embodiments, B is . In some embodiments, B is O O O N N N . In some embodiments, B is . In some embodiments, B is . In N _{O N O} some embodiments, B is . In some embodiments, B is . In some N _{O N O} F embodiments, B is . In some embodiments, B is F . In some embodiments, B is _{N O N O} O N . In some embodiments, B is . In some embodiments, B is ^N . In N _O N some embodiments, B is ^O . In some embodiments, B is ^N . In some embodiments, OH N _{N N N} B is ^N . In some embodiments, B is ^N . In some embodiments, B is OH OH N _{N N N} O N . In some embodiments, B is . In some embodiments, B is ^{N N} . F _F O O N F In some embodiments, B is ^N . In some embodiments, B is F . In some N _{O N O} F F embodiments, B is ^N F . In some embodiments, B is ^N F . In some embodiments, B is OH N _{O N N OH N N} N F F . In some embodiments, B is ^N . In some embodiments, B is ^N . In N _{N N N} OH N N some embodiments, B is . In some embodiments, B is ^HO . In some embodiments, OH N _N OH _{N N} B is ^N . In some embodiments, B is ^N . In some embodiments, B is F O F N N _{N N N} O N N . In some embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is 5-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S (e.g., furan, thiophene, oxazole, isooxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyrazole, or triazole) and optionally substituted with one or more substituents independently selected from halo; C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; phenyl optionally substituted with one or more substituents selected from halo, COOH, S(O)₂NH₂, S(O)₂(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, and C₃-C₆ cycloalkyl; C₃-C₆ carbocyclyl; (C₃-C₆ cycloalkyl)(C₁-C₆ alkyl); phenyl(C₁-C₆ alkyl); 5- or 6-membered heterocyclyl containing 1 or 2 ring atoms independently selected from N and O and optionally substituted with OH; and 5- or 6-membered heteroaryl containing 1 or 2 ring atoms independently selected from N and O and optionally substituted with one or more substituents independently selected from halo and C₁-C₆ alkyl. In some embodiments, B is 5-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N and O and substituted with phenyl optionally substituted with one or more substituents independently selected from halo and C₁-C₆ haloalkoxy. In some embodiments, B is isoxazolyl, thiadiazolyl, or oxadiazole, in which B is substituted with phenyl or pyridyl, each of which is optionally substituted one or more substituents independently selected from halo and C1-C6 alkyl. N O O N In some embodiments, B is . In some embodiments, B is . In some N ^N N _N ^N N embodiments, B is ^F . In some embodiments, B is . In some embodiments, B is F _O ^N O ^N F O ^N F F . In so ^Cl O me embodiments, B is . In some embodiments, B is . F F N ^N N N N In some embodiments, B is . In some embodiments, B is F . In some F N S N embodiments, B is . In some embodiments, B is . In some embodiments, B is Cl N N _{N F} N N N . In some embodiments, B is . In some embodiments, B is . In some N N N N embodiments, B is . In some embodiments, B is . In some embodiments, B is Cl N N N N N N . In some embodiments, B is . In some embodiments, B is . In some N _{N Cl} N N embodiments, B is . In some embodiments, B is . In some embodiments, B is N N N N _F N N . In some embodiments, B is . In some embodiments, B is . In some N N O S S N embodiments, B is . In some embodiments, B is _{. In some embodiments, B is} ^N . O S S N _{In some embodiments, B is} ^N . In some embodiments, B is . In some embodiments, B _O ^N O S N N is . In some embodiments, B is . In some embodiments, B is . In S S N some embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, S O _{O F} N B is ^N . In some embodiments, B is . In some embodiments, B is . In some S S N N S N embodiments, B is ^N . In some embodiments, B is . In some embodiments, B is ^N . S O N N In some embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B S N S N is ^N . In some embodiments, B is ^N . In some embodiments, B is . In some O O O N embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is . In F S _O ^N some embodiments, B is ^N . In some embodiments, B is . In some embodiments, B is S _F S S N N N N . In some embodiments, B is ^N . In some embodiments, B is ^N . In some F S S N N embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is N S N N N N O N . In some embodiments, B is ^O . In some embodiments, B is ^N . In some N _CF3 S _S N embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is F Cl S S S N N N N . In some embodiments, B is ^N . In some embodiments, B is ^N . In some N N S N S N embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is N CF O _{3 S Cl} S S N N N N . In some embodiments, B is . In some embodiments, B is ^N . In some F N _F N O O embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is N N O S S S N N N N . In some embodiments, B is ^N . In some embodiments, B is ^N . In some N O S _{N F} N embodiments, B is ^N . In some embodiments, B is ^O . In some embodiments, B is N F F O S S N N N . In some embodiments, B is . In some embodiments, B is ^O . In some S S N N embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is O O S S N N _{S F} N N . In some embodiments, B is ^N . In some embodiments, B is . In some F S _{S F} N embodiments, B is . In some embodiments, B is ^N . In some embodiments, B is F F N N S S O N . In some embodiments, B is ^N . In some embodiments, B is ^N . In some N F N S N N embodiments, B is ^N O . In some embodiments, B is ^N . In some embodiments, B is N N N N N N N N N O . In some embodiments, B is ^O . In some embodiments, B is ^O . In some N N N S O N embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is N N N S S S N N . In some embodiments, B is . In some embodiments, B is ^N . In some O N S N _{S S} N _{O O} embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is N N S _O S N N N O N . In some embodiments, B is . In some embodiments, B is ^N . In some F F N N S S N N embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is F O N S _S N _{N F} N _{O NH2} N O N . In some embodiments, B is ^O . In some embodiments, B is ^N . In some F N S O N embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is F N S _{S COOH S F} N N N N . In some embodiments, B is ^N . In some embodiments, B is ^N . In some S S F N F O embodiments, B is ^N . In some embodiments, B is ^N . In some embodiments, B is ^N . O _{F N N F} In some embodiments, B is ^N . In some embodiments, B is . In some embodiments, B N N O S O is ^F . In some embodiments, B is ^N . In some embodiments, B is ^N . In some N N S _{N F} N embodiments, B is ^N . In some embodiments, B is ^O . In some embodiments, B is F H_{N N N N} N N O . In some embodiments, B is ^F . In some embodiments, B is ^F . In OH O N S N S N N N some embodiments, B is . In some embodiments, B is . In some embodiments, B is F S _{S N} N S N N N . In some embodiments, B is . In some embodiments, B is ^F . In some _{N S} N N embodiments, B is ^F . In some embodiments, B is ^F . In some embodiments, B is F N Cl Cl S N _{N O N O} N N N . In some embodiments, B is . In some embodiments, B is . In some O _{N O N} embodiments, B is ^{N N} . In some embodiments, B is ^N . In some embodiments, B is Cl N _{O N O N O} N N N . In some embodiments, B is . In some embodiments, B is . Cl N Cl O _{O N} N N In some embodiments, B is . In some embodiments, B is . In some O _{N O N} N N N embodiments, B is . In some embodiments, B is . In some embodiments, B is O _{N O N O N} N N N . In some embodiments, B is . In some embodiments, B is . In O _N N O _N N N some embodiments, B is . In some embodiments, B is . In some O _{N O N} F N N embodiments, B is . In some embodiments, B is . In some O _{N O N} N embodiments, B is ^F . In some embodiments, B is ^F . In some embodiments, B is O _{N O N O N} N N F . In some embodiments, B is ^F . In some embodiments, B is ^{F F} . In some O _{N N O} embodiments, B is ^F . In some embodiments, B is ^F . In some embodiments, B is O _{N O N O N} N . In some embodiments, B is . In some embodiments, B is . In N _{O N O} some embodiments, B is ^F . In some embodiments, B is . In some embodiments, F O _{N O N} N B is . In some embodiments, B is . In some embodiments, B is O _{N O N N O N} N N N F . In some embodiments, B is ^F . In some embodiments, B is H . In _{O N} N _{O N} O N N some embodiments, B is . In some embodiments, B is . In some embodiments, Cl Cl N _{O N O N O} N N N B is . In some embodiments, B is . In some embodiments, B is . In N _{O N O} N N some embodiments, B is . In some embodiments, B is ^F . In some embodiments, N _{O N O N O} N N B is ^F . In some embodiments, B is ^F . In some embodiments, B is ^N . N _{O N O} N F N In some embodiments, B is . In some embodiments, B is . In some N _{O N O} N N embodiments, B is . In some embodiments, B is . In some embodiments, B is F N _{O N O N O} N N . In some embodiments, B is . In some embodiments, B is ^F . In F N _{O N O} some embodiments, B is ^F . In some embodiments, B is ^F . In some embodiments, B C^l _N ^Cl _N N N S O N N N O N is . In some embodiments, B is . In some embodiments, B is . In some Cl C^l _N N N S N S N S N N N N embodiments, B is . In some embodiments, B is . In some embodiments, B is . F N S N S N N N In some embodiments, B is . In some embodiments, B is . In some embodiments, B is N ^N _N ^N _N ^N N F . In some embodiments, B is ^F . In some embodiments, B is ^F . In some N ^Cl _N O N O N N N embodiments, B is . In some embodiments, B is . In some embodiments, B is pyridyl optionally substituted with one or more substituents independently selected from halo, C1-C6 alkoxy, and C3-C6 cycloalkyl. In some embodiments, B is N _Cl N Cl N . In some embodiments, B is . In some embodiments, B is . In some O N N embodiments, B is ^N . In some embodiments, B is . In some embodiments, B is ^F . In N some embodiments, B is . In some embodiments, B is 9-membered bicyclic heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with one or more halo. In some Cl S S embodiments, B is . In some embodiments, B is . In some embodiments, B is S O _{O Cl} N . In some embodiments, B is . In some embodiments, B is ^N . In some S _Cl S embodiments, B is . In some embodiments, B is . In some embodiments, B is F F S O _{S N} . In some embodiments, B is . In some embodiments, B is . In some O _{O Cl} embodiments, B is ^N . In some embodiments, B is . In some embodiments, B is F O _{F S F} O N . In some embodiments, B is ^N . In some embodiments, B is ^N . In some N _{F S N} embodiments, B is ^S . In some embodiments, B is ^N . In some embodiments, B is N S N . O H O OH H ^S _{O N} In some embodiments, B is N . In some embodiments, the compound is of Formula (II): N H O N ⁶ O H₂N R S L¹ L³ N L² B X' R2 X R^2' (II), or a pharmaceutically acceptable salt thereof, in which all variables are as defined herein. In some embodiments, the compound is of Formula (III): H O N O A _R ⁶ H 1' _{N B R1 R} N X' O 2 X R _R ^2' (III), or a pharmaceutically acceptable salt thereof, in which all variables are as defined herein. In some embodiments, the compound is of Formula (IV): or a pharmaceutically acceptable salt thereof, in which R^2’ is C1-C6 alkyl or C1-C6 alkoxy, and all other variables are as defined herein. In some embodiments, R^2’ is CH3. In some embodiments, R^2’ is OCH3. In some embodiments, the compound is of Formula (V): or a pharmaceutically acceptable salt thereof, in which R^2’ is H or C₁-C₆ alkyl, and all other variables are as defined herein. In some embodiments, R^2’ is H. In some embodiments, R^2’ is CH3. In some embodiments, the compound is of Formula (VI): or a pharmaceutically acceptable salt thereof, in which R² is C₁-C₆ alkyl, and all other variables are as defined herein. In some embodiments, R² is CH3. In some embodiments, the compound is of Formula (VII): or a pharmaceutically acceptable salt thereof, in which variables are as defined herein. In some embodiments, a compound of the disclosure is a compound of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of the disclosure is a compound having C1 esterase (C1s) inhibiting activity. Pharmaceutical Compositions A pharmaceutical composition of the disclosure contains one or more of the compounds disclosed herein (e.g., one or more of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) as the therapeutic compound. In addition to a therapeutically effective amount of the compound, the pharmaceutical compositions also contain a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art. In some embodiments, the pharmaceutical compositions for treating cancer contain one or more of the compounds disclosed herein (e.g., one or more of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) may be formulated and/or administered with or without other therapeutics for a particular condition. Examples of such therapeutics (second therapeutic agents) are described herein. The compounds disclosed herein (e.g., the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) may be used in the form of free base or in the form of salts. All forms are within the scope of the disclosure. Exemplary routes of administration of the pharmaceutical compositions (or the compounds of the composition) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) is formulated for oral administration. Formulations for Oral Administration The pharmaceutical compositions of the present disclosure include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers; granulating and disintegrating agents; binding agents; and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like. Pharmaceutical compositions for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment. The liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, as well as elixirs and similar pharmaceutical vehicles. Formulations for Parenteral Administration The pharmaceutical compositions of the present disclosure can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous, intramuscular, subcutaneous or the like) formulation as described herein. The pharmaceutical composition may also be administered parenterally in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the present disclosure may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water; water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer; 1,3-butanediol; Ringer’s solution; and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference in its entirety. The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration: (1) “Drug Injection:” a liquid preparation that is a drug substance (e.g., a compound of the present disclosure), or a solution thereof; (2) “Drug for Injection:” the drug substance (e.g., a compound of the present disclosure) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection; (3) “Drug Injectable Emulsion:” a liquid preparation of the drug substance (e.g., a compound of the present disclosure) that is dissolved or dispersed in a suitable emulsion medium; (4) “Drug Injectable Suspension:” a liquid preparation of the drug substance (e.g., a compound of the present disclosure) suspended in a suitable liquid medium; and (5) “Drug for Injectable Suspension:” the drug substance (e.g., a compound of the present disclosure) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension. Exemplary formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 23^rd Ed., Adejare, Ed., Academic Press (2020) and in The United States Pharmacopeia and National Formulary (USP-NF 2021 Issues 1-3), published in 2021. Formulations for parenteral administration may, for example, contain sterile water, saline, polyalkylene glycols (e.g., polyethylene glycol), oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. The dosage of the compounds described herein (e.g., the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1), and/or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form). For example, the dose range may be 10-1000 mg (e.g., 50-800 mg). Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may be 0.1-100 mg/kg. A dosage form containing a compound disclosed herein (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) can be administered, for example, once a day (QD), twice a day (BID), three times a day (TID), four times a day (QID), once every other day (Q2D), once every third day (Q3D), or any dosing schedule as needed, Uses of Active Compounds for Treatment of Selected Disorders In one aspect, an effective amount of an active compound described herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1), or a pharmaceutically acceptable salt thereof) is used to treat a medical disorder which is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade) including a complement-related disorder or alternative complement pathway-related disorder, a disorder or abnormality of a cell that adversely affects the ability of the cell to engage in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure or a pharmaceutical or biopharmaceutical drug administration, a blood transfusion, or other allogenic tissue or fluid administration. In some embodiments, the disorder is an autoimmune disease. In some embodiments, the disorder is cancer. In some embodiments, the disorder is an infectious disease. In some embodiments, the disorder is an inflammatory disease. In some embodiments, the disorder is a hematological disease. In some embodiments, the disorder is an ischemia-reperfusion injury. In some embodiments, the disorder is an ocular disease. In some embodiments, the disorder is a renal disease. In some embodiments, the disorder is transplant rejection. In some embodiments, the disorder is antibody-mediated transplant rejection, e.g., acute antibody-mediated rejection. In some embodiments, the disorder is a vascular disease. In some embodiments, the disorder is a vasculitis disorder. In some embodiments, the disorder is a neurodegenerative disorder, e.g., a tauopathy. In some embodiments, the disorder is a medical disorder of the central nervous system (CNS) or peripheral nervous system disorders involving complement activation. In some embodiments, the disorder is an acquired brain or spinal cord injury. In some embodiments, the disorder is ischemic- reperfusion injury. In some embodiments, the disorder is stroke. In some embodiments, the disorder is traumatic brain injury (TBI). In some embodiments, the disorder is spinal cord injury (SCI). In some embodiments, the disorder is a neuroinflammatory disorder. In some embodiments, the neuroinflammatory disorder is cranial arteritis. In some embodiments, the neuroinflammatory disorder is giant cell arteritis. In some embodiments, the neuroinflammatory disorder is Holmes-Adie syndrome. In some embodiments, the neuroinflammatory disorder is inclusion body myositis (IBM). In some embodiments, the neuroinflammatory disorder is meningitis. In some embodiments, the neuroinflammatory disorder is a neurologic paraneoplastic syndrome, e.g., Lambert- Eaton myasthenic syndrome, stiff-person syndrome, encephalomyelitis (inflammation of the brain and spinal cord), myasthenia gravis, cerebellar degeneration, limbic and/or brainstem encephalitis, neuromyotonia, opsoclonus (involving eye movement), or sensory neuropathy. In some embodiments, the neuroinflammatory disorder is polymyositis. In some embodiments, the neuroinflammatory disorder is transverse myelitis. In some embodiments, the neuroinflammatory disorder is vasculitis, e.g., temporal arteritis. In some embodiments, the neuroinflammatory disorder is arachnoiditis. In some embodiments, the neuroinflammatory disorder is Kinsbourne syndrome. In some embodiments, the neuroinflammatory disorder is opsoclonus myoclonus syndrome (OMS). In some embodiments, the neuroinflammatory disorder is Saint Vitus Dance or Sydenham’s chorea (SD) disease. In some embodiments, the disorder is Alzheimer's disease (AD). AD is characterized by two hallmark pathologies; amyloid-β (Aβ) plaques and neurofibrillary tangles comprising hyperphosphorylated tau. Recent studies have implicated complement in AD pathogenesis, including genome-wide association studies identifying single nucleotide polymorphisms (SNPs) associated with risk of late-onset AD in genes encoding complement proteins clusterin (CLU) and CR1 (CR1). See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019. Biomarker studies have also identified complement proteins and activation products in plasma and/or CSF that distinguish AD from controls and predict risk of progression to AD. In some embodiments, the disorder is frontotemporal dementia. In some embodiments, the disorder is Pick's disease. In some embodiments, the disorder is sporadic frontotemporal dementia, e.g., frontotemporal dementia with Parkinsonism linked to chromosome 17. In some embodiments, progressive supranuclear palsy (PSP). In some embodiments, corticobasal degeneration (CBD). In some embodiments, the disorder is subacute sclerosing panencephalitis. In some embodiments, the disorder is amyotrophic lateral sclerosis (ALS). ALS is caused by progressive loss of upper and lower (α) motor neurons resulting in denervation of neuromuscular junctions in the peripheral nervous system, progressive muscle weakness, atrophy, spasticity, respiratory failure, and ultimately paralysis and death. Recent studies have shown increased C1q protein in motor cortex and spinal cord of ALS post-mortem tissue; C3 activation fragments and TCC in areas of pathology; C4d and TCC staining of degenerating neurons and glia in ALS motor cortex and spinal cord, and C5aR1 upregulation in areas of pathology. C3d and C4d have been found on oligodendroglia and degenerating neurites, surrounded by CR4-positive microglia, in spinal cord and motor cortex, and C1q, C3, and TCC have been shown to be present on motor endplates in intercostal muscles in ALS donors even early in the disease process. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019. In some embodiments, the disorder is Parkinson's disease (PD). PD is characterized by loss of dopaminergic neurons in the substantia nigra and deposits of the protein α-synuclein that form the pathological hallmarks of the disease, Lewy bodies. Patients present with resting tremor, bradykinesia, and rigidity. Complement activation has been associated with α-synuclein and Lewy bodies in Parkinson's disease; in vitro studies have demonstrated that the disease-associated splice variant α- synuclein 112, but not the full-length protein, cause activation of complement. In vivo, C3d, C4d, C7 and C9 localization in Lewy bodies has been reported. More recently, deposition of iC3b and C9 in Lewy bodies and melanized neurons has been reported, and iC3b immunoreactivity has been shown to be increased with normal ageing and was further elevated in PD vs. age-matched controls. Furthermore, correlation between the ratios of C3/Aβ42 or FH/Aβ42 in CSF and severity of Parkinson's disease motor and cognitive symptoms has been shown. See Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019. In some embodiments, the subject to be treated suffers from Parkinson’s Disease with dementia (PDD). In some embodiments, the disorder is Huntington's disease (HD). HD is an autosomal dominant, inherited neurodegenerative disease characterized by progressive motor symptoms, psychiatric disturbances, and dementia. It is caused by expansion of a three-base-pair (CAG) repeat (39–121 repeats vs. normal range 8–39 repeats) in exon 1 of the HTT gene that translates into a polyglutamine tract at the N-terminus of the protein. This results in a polyglutamine length-dependent misfolding and accumulation of huntingtin protein in the striatum and cortex (layers 3, 5, and 6) followed by neuronal loss in these areas which spreads to the hippocampus. It has been shown that neurons, astrocytes, and myelin sheaths in the HD caudate and striatum were immunoreactive for C1q, C4, C3 and neo-epitopes in iC3b and TCC. Expression of mRNA encoding early complement components C1q (c-chain), C1r, C3, and C4, complement regulators C1INH, Clusterin, MCP, DAF and CD59, and complement receptors C3a and C5a, have been shown to be upregulated in the HD striatum, see Carpanini et al., Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System, Front. Immunol., 04 March 2019. In some embodiments, the disorder is argyrophilic grain dementia. In some embodiments, the disorder is British type amyloid angiopathy. In some embodiments, the disorder is cerebral amyloid angiopathy. In some embodiments, the disorder is Creutzfeldt-Jakob disease. In some embodiments, the disorder is dementia pugilistica. In some embodiments, the disorder is diffuse neurofibrillary tangles with calcification. In some embodiments, the disorder is Down's syndrome. In some embodiments, the disorder is frontotemporal lobar degeneration. In some embodiments, the disorder is Gerstmann- Straussler-Scheinker disease. In some embodiments, the disorder is Hallervorden-Spatz disease. In some embodiments, the disorder is inclusion body myositis. In some embodiments, the disorder is multiple system atrophy (MSA). In some embodiments, the disorder is myotonic dystrophy. In some embodiments, the disorder is Niemann-Pick disease type C. In some embodiments, the disorder is non- Guamanian motor neuron disease with neurofibrillary tangles. In some embodiments, the disorder is postencephalitic parkinsonism. In some embodiments, the disorder is prion protein cerebral amyloid angiopathy. In some embodiments, the disorder is progressive subcortical gliosis. In some embodiments, the disorder is progressive supranuclear palsy. In some embodiments, the disorder is subacute sclerosing panencephalitis. In some embodiments, the disorder is Tangle only dementia. In some embodiments, the disorder is multi-infarct dementia. In some embodiments, the disorder is ischemic stroke. In some embodiments, the disorder is chronic traumatic encephalopathy (CTE). In some embodiments, the disorder is a hereditary motor and sensory neuropathy (HMSN). In some embodiments, the HMSN is Charcot-Marie-Tooth (CMT) disease. In some embodiments, the HSMN is Charcot–Marie–Tooth disease type 1A or type 1B. In some embodiments, the HSMN is Charcot–Marie–Tooth disease type 2. In some embodiments, the HSMN is Dejerine–Sottas disease (Charcot–Marie–Tooth type 3). In some embodiments, the HSMN is Refsum disease. In some embodiments, the HSMN is Charcot–Marie–Tooth with pyramidal features. In some embodiments, the HSMN is Charcot–Marie–Tooth type 6. In some embodiments, the HSMN is HMSN+retinitis pigmentosa. In some embodiments, the disorder is Churg-Strauss syndrome. In some embodiments, the disorder is peripheral artery disease (PAD). In some embodiments, the disorder is myasthenia gravis, e.g., myasthenia gravis with CNS involvement. In some embodiments, the disorder is dementia with Lewy bodies. In some embodiments, the disorder is prion disease. In some embodiments, the disorder is Behcet's Disease. In some embodiments, the disorder is congenital myasthenia. In some embodiments, the disorder is subacute sclerosing panencephalitis (SSPE). In some embodiments, the disorder is a demyelinating disease. In some embodiments, the disorder is demyelinating myelinoclastic disease. In some embodiments, the disorder is demyelinating leukodystrophic disease. In some embodiments, the demyelinating myelinoclastic disease is multiple sclerosis (MS). Multiple sclerosis (MS) is the most common cause of neurological disability in young adults in northern European-Caucasian populations, with an approximate lifetime risk of one in 400. C3 has been shown to be deposited in the brains of MS patients. T-cell clone (TCC) has been shown to be in association with capillary endothelial cells, predominantly within plaques and adjacent white matter. Localization of C activation to areas of active myelin destruction has also been shown, with TCC deposited exclusively in such areas. C3d has been shown to be deposited in association with short segments of disrupted myelin in plaques with low-grade active demyelination and provides evidence for a C contribution to disease progression as well as acute inflammation. See Ingram et al., Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol.2009 Feb;155(2):128-39. In some embodiments, the demyelinating myelinoclastic disease is neuromyelitis optica (NMO). Neuromyelitis optica (NMO) is an inflammatory demyelinating disease affecting predominantly the optic nerves and spinal cord. Traditionally seen as a variant of MS, it has been redefined recently according to new criteria using a combination of phenotypic subtyping along with a newly developed biomarker of disease, NMO-immunoglobulin G (IgG) (reported sensitivity of 58–76% and specificity of 85–99% for NMO). NMO patients have higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels correlated with disease activity, neurological disability and aquaporin-4 IgG. Nytrova et al. J Neuroimmunol.2014 Sep 15;274(1-2):185-91. In some embodiments, the demyelinating myelinoclastic disease is idiopathic inflammatory demyelinating diseases (IIDD). In some embodiments, the demyelinating myelinoclastic disease is anti- NMDA receptor encephalitis. In some embodiments, the demyelinating myelinoclastic disease is acute disseminated encephalomyelitis. In some embodiments, the demyelinating myelinoclastic disease is anti- MOG autoimmune encephalomyelitis. In some embodiments, the demyelinating myelinoclastic disease is chronic relapsing inflammatory optic neuritis (CRION). In some embodiments, the demyelinating myelinoclastic disease is acute disseminated encephalomyelitis (ADEM). In some embodiments, the demyelinating myelinoclastic disease is immune-mediated encephalomyelitis. In some embodiments, the demyelinating myelinoclastic disease is progressive multifocal leukoencephalopathy (PML). In some embodiments, the demyelinating myelinoclastic disease is McDonalds-positive multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is acute hemorrhagic leukoencephalitis. In some embodiments, the demyelinating myelinoclastic disease is Rasmussen's Encephalitis. In some embodiments, the demyelinating myelinoclastic disease is Marburg multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is pseudotumefactive or tumefactive multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is Balo concentric sclerosis. In some embodiments, the demyelinating myelinoclastic disease is diffuse myelinoclastic sclerosis. In some embodiments, the demyelinating myelinoclastic disease is solitary sclerosis. In some embodiments, the demyelinating myelinoclastic disease is multiple sclerosis with cavitary lesions. In some embodiments, the demyelinating myelinoclastic disease is myelocortical multiple sclerosis (MCMS). In some embodiments, the demyelinating myelinoclastic disease is atypical optic-spinal multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is pure spinal multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is HLA DRB3*02:02 multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is autoimmune GFAP astrocytopathy. In some embodiments, the demyelinating myelinoclastic disease is chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the demyelinating myelinoclastic disease is Guillain– Barré syndrome (acute or chronic). In some embodiments, the demyelinating myelinoclastic disease is progressive inflammatory neuropathy. In some embodiments, the demyelinating myelinoclastic disease is Lewis-Sumner Syndrome. In some embodiments, the demyelinating myelinoclastic disease is combined central and peripheral demyelination (CCPD). In some embodiments, the demyelinating myelinoclastic disease is Bickerstaff brainstem encephalitis. In some embodiments, the demyelinating myelinoclastic disease is Fisher syndrome. In some embodiments, the demyelinating myelinoclastic disease is trigeminal neuralgia. In some embodiments, the demyelinating myelinoclastic disease is NMDAR anti- NMDA receptor encephalitis. In some embodiments, the demyelinating myelinoclastic disease is primary progressive MS (PPMS). In some embodiments, the demyelinating myelinoclastic disease is OPA1 variant multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is KIR4.1 multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is aquaporin-related multiple sclerosis. In some embodiments, the demyelinating myelinoclastic disease is chronic cerebrospinal venous insufficiency (CCSVI or CCVI). In some embodiments, the demyelinating myelinoclastic disease is diffuse sclerosis. In some embodiments, the demyelinating myelinoclastic disease is Schilder's disease. In certain aspects, the disorder to be treated is a demyelinating leukodystrophic disease. In some embodiments, the demyelinating leukodystrophic disease is myelitis. In some embodiments, the demyelinating leukodystrophic disease is central pontine myelinolysis (CPM). In some embodiments, the demyelinating leukodystrophic disease is extrapontine myelinolysis. In some embodiments, the demyelinating leukodystrophic disease is tabes dorsalis. In some embodiments, the demyelinating leukodystrophic disease is progressive multifocal leukoencephalopathy. In some embodiments, the demyelinating leukodystrophic disease is leukoencephalopathy with vanishing white matter. In some embodiments, the demyelinating leukodystrophic disease is leukoencephalopathy with neuroaxonal spheroids. In some embodiments, the demyelinating leukodystrophic disease is reversible posterior leukoencephalopathy syndrome. In some embodiments, the demyelinating leukodystrophic disease is megalencephalic leukoencephalopathy with subcortical cysts. In some embodiments, the demyelinating leukodystrophic disease is megalencephalic leukoencephalopathy with subcortical cysts 1. In some embodiments, the demyelinating leukodystrophic disease is hypertensive leukoencephalopathy. In some embodiments, the demyelinating leukodystrophic disease is metachromatic leukodystrophy. In some embodiments, the demyelinating leukodystrophic disease is Krabbe disease. In some embodiments, the demyelinating leukodystrophic disease is Canavan disease. In some embodiments, the demyelinating leukodystrophic disease is X-linked adrenoleukodystrophy. In some embodiments, the demyelinating leukodystrophic disease is Alexander disease. In some embodiments, the demyelinating leukodystrophic disease is cerebrotendinous xanthomatosis. In some embodiments, the demyelinating leukodystrophic disease is Pelizaeus–Merzbacher disease. In some embodiments, the demyelinating leukodystrophic disease is Refsum disease. In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat Buerger's disease, also known as thromboangiitis obliterans. In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat giant cell arteritis. In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat Raynaud's disease. In certain aspects, the disorder to be treated is a demyelinating disease of the peripheral nervous system. In some embodiments, the demyelinating disease of the peripheral nervous system is anti-MAG peripheral neuropathy. In some embodiments, the demyelinating disease of the peripheral nervous system is hereditary neuropathy with liability to pressure palsy. In some embodiments, the demyelinating disease of the peripheral nervous system is a copper deficiency-associated condition (e.g., peripheral neuropathy, myelopathy, or rarely optic neuropathy). In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat transverse myelitis. In certain aspects, the disorder to be treated is a peripheral neuropathy. In some embodiments, the peripheral neuropathy is a mononeuropathy. In some embodiments, the neuropathy is a polyneuropathy. In some embodiments, the polyneuropathy is distal axonopathy, diabetic neuropathy, a demyelinating polyneuropathy, small fiber peripheral neuropathy, mononeuritis multiplex, polyneuritis multiplex, autonomic neuropathy, or neuritis. In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat multifocal motor neuropathy. In some embodiments, an effective amount of an active compound described herein, or a pharmaceutically acceptable salt thereof, is used to treat an autoimmune vascular disease. In some embodiments, the autoimmune vascular disease is vasculitis. In some embodiments, the vasculitis includes, but is not limited to, autoimmune inflammatory vasculitis, Cutaneous small-vessel vasculitis, Granulomatosis with polyangiitis , Eosinophilic granulomatosis with polyangiitis, Behçet's disease, Kawasaki disease, Buerger's disease, and "Limited" granulomatosis with polyangiitis vasculitis. In some embodiments, an active compound (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or its salt or composition as described herein is used to treat an arteritis. In some embodiments, the arteritis is giant cell arteritis. In some embodiments, the arteritis is Takayasu arteritis. In some embodiments, the arteritis is temporal arteritis. In some embodiments, the arteritis is polyarteritis nodosa. In some embodiments, a method for the treatment of a glomerulonephritis is provided. In some embodiment, the glomerulonephritis is membranoproliferative glomerulonephritis (MPGN). In some embodiments, the MPGN is MPGN Type I. In some embodiments, the MPGN is MPGN Type II. In some embodiments, the MPGN is MPGN Type III. In some embodiments, the MPGN is C3 glomerulonephritis (C3G). In some embodiments, the MPGN is dense deposit disease (DDD). In some embodiments, the MPGN is a C4 deposition disorder. In some embodiments, the glomerulonephritis is IC-MPGN. In some embodiments, the glomerulonephritis is a membranous glomerulonephritis. In some embodiments, the glomerulonephritis is IgA nephropathy. In some embodiments, the glomerulonephritis is post-infectious glomerulonephritis. In some embodiments, the glomerulonephritis is a rapidly progressive glomerulonephritis, for example Type I (Goodpasture syndrome), Type II, or Type III rapidly progressive glomerulonephritis. In some embodiments, a method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is provided that includes the administration of an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof to a subject, optionally in a pharmaceutically acceptable composition. In some embodiments, a method for the treatment of hereditary angioedema (HAE) is provided that includes the administration of an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof to a subject, optionally in a pharmaceutically acceptable composition. Mutations in the SERPING1 gene cause hereditary angioedema type I and type II. Hereditary angioedema is a disorder characterized by recurrent episodes of severe swelling (angioedema). The most common areas of the body to develop swelling are the limbs, face, intestinal tract, and airway. The SERPING1 gene provides instructions for making the C1 inhibitor protein, which is important for controlling inflammation. C1 inhibitor blocks the activity of certain proteins that promote inflammation. Mutations that cause hereditary angioedema type I lead to reduced levels of C1 inhibitor in the blood, while mutations that cause type II result in the production of a C1 inhibitor that functions abnormally. Without the proper levels of functional C1 inhibitor, excessive amounts of a protein fragment (peptide) called bradykinin are generated. Bradykinin promotes inflammation by increasing the leakage of fluid through the walls of blood vessels into body tissues. Excessive accumulation of fluids in body tissues causes the episodes of swelling seen in individuals with hereditary angioedema type I and type II. In some embodiments, a method for the treatment of cold agglutinin disease (CAD) is provided that includes the administration of an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof to a subject, optionally in a pharmaceutically acceptable composition. CAD is a rare autoimmune hemolytic condition with potentially serious acute and chronic consequences that are driven by C1 activation of the classical complement pathway. In some embodiments, a method for the treatment of atypical hemolytic uremic syndrome (aHUS) is provided that includes the administration of an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof to a subject, optionally in a pharmaceutically acceptable composition. Atypical hemolytic-uremic syndrome is a disease that primarily affects kidney function. Atypical hemolytic uremic syndrome, which can occur at any age, causes abnormal blood clots (thrombi) to form in small blood vessels in the kidneys. These clots can cause serious medical problems if they restrict or block blood flow. Atypical hemolytic-uremic syndrome is characterized by three major features related to abnormal clotting: hemolytic anemia, thrombocytopenia, and kidney failure. In another embodiment, a method for the treatment of wet or dry age-related macular degeneration (AMD) in a subject is provided that includes the administration of an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof to a subject, optionally in a pharmaceutically acceptable composition. In another embodiment, a method for the treatment of rheumatoid arthritis in a subject is provided that includes the administration of an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof to a subject, optionally in a pharmaceutically acceptable composition. In another embodiment, a method for the treatment of multiple sclerosis in a subject is provided that includes the administration of an effective amount of a compound disclosed herein (e.g., any one of the compounds of Formulas (I), (I’), (I”), (II), (III), (IV), (V), (VI), and (VII), and Table 1) or a pharmaceutically acceptable salt thereof to a subject, optionally in a pharmaceutically acceptable composition. The active compounds or pharmaceutically acceptable salts thereof disclosed herein, are also useful for administration in combination (in the same or a different dosage form) or alternation with a second pharmaceutical agent for use in ameliorating or reducing a side effect of the second pharmaceutical agent. For example, in some embodiments, the active compound may be used in combination with an adoptive cell-transfer therapy to reduce an inflammatory response associated with such therapy, for example, a cytokine mediated response such as cytokine response syndrome. In some embodiments, the adoptive cell-transfer therapy is a chimeric antigen receptor T-Cell (CAR T), or a dendritic cell used to treat a hematologic or solid tumor, for example, a B-cell related hematologic cancer. In some embodiments, the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a cancer that expresses CD19. In some embodiments, the adoptive cell-transfer therapy is a non-engineered T-cell therapy, in which the T-cells have been activated and/or expanded to one or more viral or tumor antigens. In some embodiments, the associated inflammatory response is a cytokine mediated response. In some embodiments, the second pharmaceutical agent is a cell that has been transformed to express a protein, in which the protein in the subject is mutated or otherwise has impaired function. In some embodiments, the transformed cell includes a CRISPR gene. Another embodiment is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition to a subject to treat an ocular, pulmonary, gastrointestinal, or other disorder. In other embodiments of the disclosure, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) provided herein can be used to treat or prevent a disorder in a subject mediated by complement. As examples, the disclosure includes methods to treat or prevent complement associated disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder or by ischemic injury. The disclosure also provides methods to decrease inflammation or an immune response, including an autoimmune response, where mediated or affected by the classical complement pathway. In some embodiments, the disorder is selected from fatty liver and conditions stemming from fatty liver, such as nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, and liver failure. In some embodiments of the present disclosure, a method is provided for treating fatty liver disease in a subject by administering an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In another embodiment, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein is used to modulate an immune response prior to or during surgery or other medical procedure. One non-limiting example is use in connection with acute or chronic graft versus subject disease, which is a common complication as a result of organ transplantation, allogeneic tissue transplant, and can also occur as a result of a blood transfusion. In some embodiments, the present disclosure provides a method of treating dermatomyositis by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating amyotrophic lateral sclerosis by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In another embodiment, a method is provided for the treatment or prevention of cytokine or inflammatory reactions in response to the administration of pharmaceutical or biotherapeutic (e.g., CAR T- cell therapy or monoclonal antibody therapy) in a subject by administering an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. Various types of cytokine or inflammatory reactions may occur in response to a number of factors, such as the administrations of biotherapeutics. In some embodiments, the cytokine or inflammatory reaction is cytokine release syndrome. In some embodiments, the cytokine or inflammatory reaction is tumor lysis syndrome (which also leads to cytokine release). Symptoms of cytokine release syndrome range from fever, headache, and skin rashes to bronchospasm, hypotension, and even cardiac arrest. Severe cytokine release syndrome is described as a cytokine storm and can be fatal. Fatal cytokine storms have been observed in response to infusion with several monoclonal antibody therapeutics. See, Abramowicz D, et al. “Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients” Transplantation (1989) 47(4):606-8; Chatenoud L, et al. “In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids” Transplantation (1990) 49(4):697-702; and Lim LC, Koh LP, and Tan P. “Fatal cytokine release syndrome with chimeric anti- CD20 monoclonal antibody rituximab in a 71-year-old patient with chronic lymphocytic leukemia” J. Clin Oncol. (1999) 17(6):1962-3. Also contemplated herein, is the use of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to mediate an adverse immune response in patients receiving bi-specific T-cell engagers (BiTE). A bi-specific T-cell engager directs T-cells to target and bind with a specific antigen on the surface of a cancer cell. For example, Blinatumomab (Amgen), a BiTE has recently been approved as a second line therapy in Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. Blinatumomab is given by continuous intravenous infusion in 4-week cycles. The use of BiTE agents has been associated with adverse immune responses, including cytokine release syndrome. The most significantly elevated cytokines in the CRS associated with ACT include IL-10, IL-6, and IFN-γ (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood (2012) 119:6226– 6233). In another embodiment, the disorder is episcleritis, idiopathic episcleritis, anterior episcleritis, or posterior episcleritis. In some embodiments, the disorder is idiopathic anterior uveitis, HLA-B27 related uveitis, herpetic keratouveitis, Posner Schlossman syndrome, Fuch’s heterochromic iridocyclitis, or cytomegalovirus anterior uveitis. In some embodiments, the present disclosure provides a method of treating an IC-MPGN by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating a paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating a hereditary angioedema (HAE) by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating cold agglutinin disease (CAD) by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating atypical hemolytic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating myasthenia gravis by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the present disclosure provides a method of treating atypical hemolytic uremic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In another embodiment, the present disclosure provides a method of treating a disorder as described below by administering to a subject in need thereof an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein, including: vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease; retinal vasculitis, Eales disease, tuberculosis, syphilis, or toxoplasmosis; neuroretinitis, viral retinitis, or acute retinal necrosis; varicella zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or Dengue-associated disease (e.g., hemorrhagic Dengue Fever); Masquerade syndrome, contact dermatitis, trauma induced inflammation, UVB induced inflammation, eczema, granuloma annulare, or acne. In an additional embodiment, the disorder is selected from: acute myocardial infarction, aneurysm, cardiopulmonary bypass, dilated cardiomyopathy, complement activation during cardiopulmonary bypass operations, coronary artery disease, restenosis following stent placement, or percutaneous transluminal coronary angioplasty (PTCA); antibody-mediated transplant rejection, anaphylactic shock, anaphylaxis, allogenic transplant, humoral and vascular transplant rejection, graft dysfunction, graft-versus-subject disease, Graves' disease, adverse drug reactions, or chronic graft vasculopathy; allergic bronchopulmonary aspergillosis, allergic neuritis, drug allergy, radiation- induced lung injury, eosinophilic pneumonia, radiographic contrast media allergy, bronchiolitis obliterans, or interstitial pneumonia; parkinsonism-dementia complex, sporadic frontotemporal dementia, frontotemporal dementia with Parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, tangle only dementia, cerebral amyloid angiopathy, cerebrovascular disorder, certain forms of frontotemporal dementia, argyrophilic grain dementia, dementia pugilistica, dementia with Lewy Bodies (DLB), or multi- infarct dementia; Creutzfeldt-Jakob disease, multifocal motor neuropathy (MMN), prion protein cerebral amyloid angiopathy, polymyositis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, non-Guamanian motor neuron disease with neurofibrillary tangles, neural regeneration, and diffuse neurofibrillary tangles with calcification. In some embodiments, the disorder is selected from: atopic dermatitis, dermatitis, dermatomyositis bullous pemphigoid, scleroderma, sclerodermatomyositis, psoriatic arthritis, pemphigus vulgaris, Discoid lupus erythematosus, cutaneous lupus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome; cryoglobulinemic vasculitis, mesenteric/enteric vascular disorder, peripheral vascular disorder, antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), IL-2 induced vascular leakage syndrome, immune complex vasculitis, angioedema, low platelets (HELLP) syndrome, sickle cell disease, platelet refractoriness, red cell casts, or typical or infectious hemolytic uremic syndrome (tHUS); hematuria, hemorrhagic shock, drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA), azotemia, blood vessel and/or lymph vessel inflammation, rotational atherectomy, or delayed hemolytic transfusion reaction; British type amyloid angiopathy, Buerger's disease, bullous pemphigoid, C1q nephropathy, cancer, and catastrophic antiphospholipid syndrome. In some embodiments, the disorder is autoimmune hemolytic anemia, e.g., warm autoimmune hemolytic anemia. In another embodiment, the disorder is selected from: wet (exudative) AMD, dry (non-exudative) AMD, chorioretinal degeneration, choroidal neovascularization (CNV), choroiditis, loss of RPE function, loss of vision (including loss of visual acuity or visual field), loss of vision from AMD, retinal damage in response to light exposure, retinal degeneration, retinal detachment, retinal dysfunction, retinal neovascularization (RNV), retinopathy of prematurity, pathological myopia, or RPE degeneration; pseudophakic bullous keratopathy, symptomatic macular degeneration related disorder, optic nerve degeneration, photoreceptor degeneration, cone degeneration, loss of photoreceptor cells, pars planitis, scleritis, proliferative vitreoretinopathy, or formation of ocular drusen; chronic urticaria, Churg-Strauss syndrome, cold agglutinin disease (CAD), corticobasal degeneration (CBD), cryoglobulinemia, cyclitis, damage of the Bruch's membrane, Degos disease, diabetic angiopathy, elevated liver enzymes, endotoxemia, epidermolysis bullosa, or epidermolysis bullosa acquisita; essential mixed cryoglobulinemia, excessive blood urea nitrogen-BUN, focal segmental glomerulosclerosis, Gerstmann-Straussler- Scheinker disease, giant cell arteritis, gout, Hallervorden-Spatz disease, Hashimoto's thyroiditis, Henoch- Schonlein purpura nephritis, or abnormal urinary sediments; hepatitis, hepatitis A, hepatitis B, hepatitis C or human immunodeficiency virus (HIV), a viral infection more generally, for example selected from Flaviviridae, Retroviruses, Coronaviridae, Poxviridae, Adenoviridae, Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae, Togaviridae, Orthomyxoviridae, Rhabdoviridae, or Hepadnaviridae; Neisseria meningitidis, Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS), hemolytic uremic syndrome (HUS); Streptococcus, and poststreptococcal glomerulonephritis. In a further embodiment, the disorder is selected from: hyperlipidemia, hypertension, hypoalbuminemia, hypovolemic shock, hypocomplementemic urticarial vasculitis syndrome, hypophosphastasis, hypovolemic shock, idiopathic pneumonia syndrome, or idiopathic pulmonary fibrosis; inclusion body myositis, intestinal ischemia, iridocyclitis, iritis, juvenile chronic arthritis, Kawasaki's disease (arteritis), or lipiduria; membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed cryoglobulinemia, molybdenum cofactor deficiency (MoCD) type A, pancreatitis, panniculitis, Pick's disease, polyarteritis nodosa (PAN), progressive subcortical gliosis, proteinuria, reduced glomerular filtration rate (GFR), or renovascular disorder; multiple organ failure, multiple system atrophy (MSA), myotonic dystrophy, Niemann-Pick disease type C, chronic demyelinating diseases, or progressive supranuclear palsy; spinal cord injury, spinal muscular atrophy, spondyloarthropathies, Reiter's syndrome, spontaneous fetal loss, recurrent fetal loss, pre-eclampsia, synucleinopathy, Takayasu's arteritis, post-partum thyroiditis, thyroiditis, Type I cryoglobulinemia, Type II mixed cryoglobulinemia, Type III mixed cryoglobulinemia, ulcerative colitis, uremia, urticaria, venous gas embolus (VGE), or Wegener's granulomatosis; von Hippel-Lindau disease, histoplasmosis of the eye, hard drusen, soft drusen, pigment clumping, and photoreceptor and/or retinal pigmented epithelia (RPE) loss. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein is useful for treating a disorder selected from autoimmune oophoritis, endometriosis, autoimmune orchitis, Ord’s thyroiditis, autoimmune enteropathy, coeliac disease, Hashimoto’s encephalopathy, antiphospholipid syndrome (APLS) (Hughes syndrome), aplastic anemia, autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adipose dolorosa (Dercum’s disease), adult onset Still’s disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, eosinophilic fasciitis (Shulman’s syndrome), Felty syndrome, IgG4-related disease, mixed connective tissue disease (MCTD), palindromic rheumatism (Hench-Rosenberg syndrome), Parry-Romberg syndrome, Parsonage-Turner syndrome, relapsing polychondritis (Meyenburg-Altherr-Uehlinger syndrome), retroperitonial fibrosis, rheumatic fever, Schnitzler syndrome, fibromyalgia, neuromyotonia (Isaac’s disease), paraneoplastic degeneration, autoimmune inner ear disease, Meniere’s disease, interstitial cystitis, autoimmune pancreatitis, zika virus- related disorders, chikungunya virus-related disorders, subacute bacterial endocarditis (SBE), IgA nephropathy, IgA vasculitis, polymyalgia rheumatic, rheumatoid vasculitis, alopecia areata, autoimmune progesterone dermatitis, dermatitis herpetiformis, erythema nodosum, gestational pemphigoid, hidradenitis suppurativa, lichen sclerosus, linear IgA disease (LAD), morphea, myositis, pityriasis lichenoides et varioliformis acuta, vitiligo post-myocardial infarction syndrome (Dressler’s syndrome), post-pericardiotomy syndrome, autoimmune retinopathy, Cogan syndrome, Graves opthalmopathy, ligneous conjunctivitis, Mooren’s ulcer, opsoclonus myoclonus syndrome, optic neuritis, retinocochleocerebral vasculopathy (Susac’s syndrome), sympathetic ophthalmia, Tolosa-Hunt syndrome, interstitial lung disease, antisynthetase syndrome, Addison’s disease, autoimmune polyendocrine syndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II, autoimmune polyendocrine syndrome (APS) type III, disseminated sclerosis (multiple sclerosis, pattern II), rapidly progressing glomerulonephritis (RPGN), juvenile rheumatoid arthritis, enthesitis-related arthritis, reactive arthritis (Reiter’s syndrome), autoimmune hepatitis or lupoid hepatitis, primary biliary cirrhosis (PBS), primary sclerosing cholangitis, microscopic colitis, latent lupus (undifferentiated connective tissue disease (UCTD)), acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-(R)-N- methyl-D-aspartate receptor encephalitis, Balo concentric sclerosis (Schilders disease), Bickerstaff’s encephalitis, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton mysathenic syndrome, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS), progressive inflammatory neuropathy, restless leg syndrome, stiff person syndrome, Sydenhem syndrome, transverse myelitis, lupus vasculitis, leukocytoclastic vasculitis, Microscopic Polyangiitis, polymyositis, and ischemic- reperfusion injury of the eye. Examples of eye disorders that may be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchocercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases, environmental dry eye diseases, corneal neovascularization diseases, post-corneal transplant rejection prophylaxis and treatment, autoimmune uveitis, infectious uveitis, posterior uveitis (including toxoplasmosis), pan-uveitis, an inflammatory disease of the vitreous or retina, endophthalmitis prophylaxis and treatment, macular edema, macular degeneration, age related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, an autoimmune disease of the retina, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open angle glaucoma, closed angle glaucoma, pigmentary glaucoma, and combinations thereof. In a further embodiment, the disorder is selected from glaucoma, diabetic retinopathy, blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatricial pemphigoid, uveitis, adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, diabetic macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, birdshot retinochorioditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, and retinal vein occlusion, and central retinal vein occlusion (CVRO). In some embodiments, a method for the treatment of an autoimmune blistering disease in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, a method for the treatment of bullous pemphigoid in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, the complement mediated disorder is an ophthalmic disease (e.g., early or neovascular age-related macular degeneration and geographic atrophy), an autoimmune disease (e.g., arthritis or rheumatoid arthritis), a respiratory diseases, or a cardiovascular disease. In other embodiments, the compounds of the disclosure are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders. In some embodiments, a method for the treatment of geographic atrophy in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. Disorders that may be treated or prevented by an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein also include, but are not limited to: hereditary angioedema, capillary leak syndrome, hemolytic uremic syndrome (HUS), neurological disorders, Guillain-Barré Syndrome, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including membrane proliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and neural regeneration, or Barraquer-Simons Syndrome; inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), disorders of inappropriate or undesirable complement activation, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, systemic lupus erythematosus (SLE), lupus nephritis, arthritis, immune complex disorders and autoimmune diseases, systemic lupus, or lupus erythematosus; ischemia/ reperfusion injury (I/R injury), myocardial infarction, myocarditis, post-ischemic reperfusion conditions, balloon angioplasty, atherosclerosis, post-pump syndrome in cardiopulmonary bypass or renal bypass, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, antiphospholipid syndrome, autoimmune heart disease, ischemia-reperfusion injuries, obesity, or diabetes; Alzheimer’s dementia, stroke, schizophrenia, traumatic brain injury, trauma, Parkinson's disease, epilepsy, transplant rejection, prevention of fetal loss, biomaterial reactions (e.g. in hemodialysis, implants), hyperacute allograft rejection, xenograft rejection, transplantation, psoriasis, burn injury, thermal injury including burns or frostbite, or crush injury; asthma, allergy, acute respiratory distress syndrome (ARDS), cystic fibrosis, adult respiratory distress syndrome, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome (anti-glomerular basement membrane nephritis), pulmonary vasculitis, Pauci-immune vasculitis, and immune complex- associated inflammation. In some embodiments, a method for the treatment of sickle cell disease in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, a method for the treatment of immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (ITP) in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), or (I”), Table 1) or its salt or composition as described herein. In some embodiments, a method for the treatment of immune thrombocytopenic purpura (ITP). In some embodiments, a method for the treatment of ANCA-vasculitis in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, a method for the treatment of IgA nephropathy in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), or (I”), Table 1) or its salt or composition as described herein. In some embodiments, a method for the treatment of rapidly progressing glomerulonephritis (RPGN), in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, a method for the treatment of lupus nephritis, in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In some embodiments, a method for the treatment of hemorrhagic dengue fever, in a subject is provided that includes the administration of an effective amount of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein. In an additional alternative embodiment, an active compound (e.g., a compound of Formula (I), (I’), or (I”), Table 1) or its salt or composition as described herein is used in the treatment of an autoimmune disorder. The complement pathway enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body. It is part of the innate immune system and in healthy individuals is an essential process. Inhibiting the complement pathway will decrease the body’s immune system response. Therefore, it is an object of the present disclosure to treat autoimmune disorders by administering an effective does of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to a subject in need thereof. In some embodiments, the autoimmune disorder is caused by activity of the complement system. In some embodiments the autoimmune disorder is caused by activity of the alternative complement pathway. In some embodiments the autoimmune disorder is caused by activity of the classical complement pathway. In another embodiment the autoimmune disorder is caused by a mechanism of action that is not directly related to the complement system, such as the over-proliferation of T- lymphocytes or the over-production of cytokines. Non-limiting examples of autoimmune disorders include: lupus, allograft rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel diseases (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis, and scleroderma. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein is used in the treatment of lupus. Non-limiting examples of lupus include lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, chilblain lupus erythematosus, and lupus erythematosus-lichen planus overlap syndrome. Lupus erythematosus is a general category of disease that includes both systemic and cutaneous disorders. The systemic form of the disease can have cutaneous as well as systemic manifestations. However, there are also forms of the disease that are only cutaneous without systemic involvement. For example, SLE is an inflammatory disorder of unknown etiology that occurs predominantly in women, and is characterized by articular symptoms, butterfly erythema, recurrent pleurisy, pericarditis, generalized adenopathy, splenomegaly, as well as CNS involvement and progressive renal failure. The sera of most patients (over 98%) contain antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific for SLE. Conventional treatment for this disease has been the administration of corticosteroids or immunosuppressants. There are three forms of cutaneous lupus: chronic cutaneous lupus (also known as discoid lupus erythematosus or DLE), subacute cutaneous lupus, and acute cutaneous lupus. DLE is a disfiguring chronic disorder primarily affecting the skin with sharply circumscribed macules and plaques that display erythema, follicular plugging, scales, telangiectasia, and atrophy. The condition is often precipitated by sun exposure, and the early lesions are erythematous, round scaling papules that are 5 to 10 mm in diameter and display follicular plugging. DLE lesions appear most commonly on the cheeks, nose, scalp, and ears, but they may also be generalized over the upper portion of the trunk, extensor surfaces of the extremities, and on the mucous membranes of the mouth. If left untreated, the central lesion atrophies and leaves a scar. Unlike SLE, antibodies against double-stranded DNA (e.g., DNA-binding test) are almost invariably absent in DLE. Diabetes can refer to either type 1 or type 2 diabetes. In some embodiments an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein is provided at an effective dose to treat a patient with type 1 diabetes. In some embodiments an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein is provided at an effective dose to treat a patient with type 2 diabetes. Type 1 diabetes is an autoimmune disease. An autoimmune disease results when the body's system for fighting infection (the immune system) attacks a part of the body. In the case of diabetes type 1, the pancreas then produces little or no insulin. In some embodiments, the complement-mediated disease or disorder comprises transplant rejection. In some embodiments, the complement-mediated disease or disorder is antibody-mediated transplant rejection. In certain aspects, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein is used to treat a proliferative disorder, including, but not limited to, cancer. Targeted cancers suitable for administration of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt described herein include, but are not limited to, estrogen-receptor positive cancer, HER2-negative advanced breast cancer, late-line metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers, adenocarcinoma of the colon, adenocarcinoma of the rectum, central nervous system germ cell tumors, teratomas, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, familial testicular germ cell tumors, HER2-negative breast cancer, HER2-positive breast cancer, male breast cancer, ovarian immature teratomas, ovarian mature teratoma, ovarian monodermal and highly specialized teratomas, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, recurrent colon cancer, recurrent extragonadal germ cell tumors, recurrent extragonadal non-seminomatous germ cell tumor, recurrent extragonadal seminomas, recurrent malignant testicular germ cell tumors, recurrent melanomas, recurrent ovarian germ cell tumors, recurrent rectal cancer, stage III extragonadal non-seminomatous germ cell tumors, stage III extragonadal seminomas, stage III malignant testicular germ cell tumors, stage III ovarian germ cell tumors, stage IV breast cancers, stage IV colon cancers, stage IV extragonadal non-seminomatous germ cell tumors, stage IV extragonadal seminoma, stage IV melanomas, stage IV ovarian germ cell tumors, stage IV rectal cancers, testicular immature teratomas, testicular mature teratomas. In particular embodiments, the targeted cancers included estrogen-receptor positive, HER2-negative advanced breast cancer, late-line metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumors, retinoblastoma positive breast cancer as well as retinoblastoma positive endometrial, vaginal and ovarian cancers and lung and bronchial cancers, metastatic colorectal cancer, metastatic melanoma with CDK4 mutation or amplification, or cisplatin-refractory, unresectable germ cell tumors, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrous histiocytoma, hemangiosarcoma, angiosarcoma, lymphangiosarcoma, Mesothelioma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma; epidermoid carcinoma, malignant skin adnexal tumors, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, hypernephroma, cholangiocarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma, glioma anaplastic; glioblastoma multiforme, neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary carcinoma of thyroid, bronchial carcinoid, pheochromocytoma, Islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, Merkel cell neoplasm, cystosarcoma phyllodes, salivary cancers, thymic carcinomas, bladder cancer, and Wilms tumor, a blood disorder or a hematologic malignancy, including, but not limited to, myeloid disorder, lymphoid disorder, leukemia, lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), mast cell disorder, and myeloma (e.g., multiple myeloma), among others, T-cell or NK-cell lymphoma, for example, but not limited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma, for example anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small/medium CD4+ T- cell lymphoma, and lymphomatoid papulosis; Adult T-cell Leukemia/Lymphoma (ATLL); blastic NK-cell lymphoma; enteropathy-type T-cell lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic Lymphoma; nasal NK/T-cell lymphomas; treatment-related T-cell lymphomas; for example lymphomas that appear after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; chronic lymphoproliferative disorder of NK-cells; aggressive NK cell leukemia; systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection); hydroa vacciniforme-like lymphoma; adult T-cell leukemia/ lymphoma; Enteropathy- associated T-cell lymphoma; Hepatosplenic T-cell lymphoma; or Subcutaneous panniculitis-like T-cell lymphoma. In some embodiments, the methods described herein can be used to treat a subject, for example a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality. For example, the methods as described herein can be administered to a subject with a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma. For example, the subject can have a Non-Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt’s Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment- Related T-Cell Lymphomas; or Waldenstrom's Macroglobulinemia, a Hodgkin Lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin’s Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL, a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma; Mediastinal large B cell lymphoma; Nodal marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis; B- cell prolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia, unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairy cell leukemia-variant; Lymphoplasmacytic lymphoma; Heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; Primary cutaneous follicle center lymphoma; T cell/histiocyte rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; plasmablastic lymphoma; Large B-cell lymphoma arising in HHV8-associated multicentric; Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B- cell lymphoma; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, a leukemia, for example, an acute or chronic leukemia of a lymphocytic or myelogenous origin, such as, but not limited to: acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or adult T-cell chronic leukemia. In some embodiments, the patient has an acute myelogenous leukemia, for example an undifferentiated AML (M0); myeloblastic leukemia (M1; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7), small cell lung cancer, retinoblastoma, HPV positive malignancies like cervical cancer and certain head and neck cancers, MYC amplified tumors such as Burkitts’ Lymphoma, and triple negative breast cancer; certain classes of sarcoma, certain classes of non-small cell lung carcinoma, certain classes of melanoma, certain classes of pancreatic cancer, certain classes of leukemia, certain classes of lymphoma, certain classes of brain cancer, certain classes of colon cancer, certain classes of prostate cancer, certain classes of ovarian cancer, certain classes of uterine cancer, certain classes of thyroid and other endocrine tissue cancers, certain classes of salivary cancers, certain classes of thymic carcinomas, certain classes of kidney cancers, certain classes of bladder cancers, and certain classes of testicular cancers. In certain aspects, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt as described herein can be used to preserve or prevent damage to an organ or blood product. For example, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt described herein can be used to prevent damage to an organ, tissue, cell product, or blood product, that has been harvested for transplantation. In some embodiments, the organ is the heart, kidney, pancreas, lung, liver, or intestine. In some embodiments, the tissue is derived from the cornea, bone, tendon, muscle, heart valve, nerve, artery or vein, or the skin. In some embodiments, the blood product is whole blood, plasma, red blood cells or reticulocytes. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein prevents or delays the onset of at least one symptom of a complement-mediated disease or disorder in an individual. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein reduces or eliminates at least one symptom of a complement-mediated disease or disorder in an individual. Examples of symptoms include, but are not limited to, symptoms associated with autoimmune disease, cancer, hematological disease, infectious disease, inflammatory disease, ischemia-reperfusion injury, neurodegenerative disease, neurodegenerative disorder, renal disease, transplant rejection, ocular disease, vascular disease, or a vasculitis disorder. The symptom can be a neurological symptom, for example, impaired cognitive function, memory impairment, loss of motor function, etc. The symptom can also be the activity of C1s protein in a cell, tissue, or fluid of an individual. The symptom can also be the extent of complement activation in a cell, tissue, or fluid of an individual. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual modulates complement activation in a cell, tissue, or fluid of an individual. In some embodiments, administration of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual inhibits complement activation in a cell, tissue, or fluid of an individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein, when administered in one or more doses as monotherapy or in combination therapy to an individual having a complement-mediated disease or disorder, inhibits complement activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to complement activation in the individual before treatment with the compounds described herein. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein reduces C3 deposition onto red blood cells; for example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein reduces deposition of C3b, iC3b, etc., onto RBCs. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein inhibits complement-mediated red blood cell lysis. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein reduces C3 deposition onto platelets; for example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein reduces deposition of C3b, iC3b, etc., onto platelets. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), or (I”), Table 1) or its salt or composition as described herein results in an outcome selected from the group consisting of: (a) a reduction in complement activation; (b) an improvement in cognitive function; (c) a reduction in neuron loss; (d) a reduction in phospho-Tau levels in neurons; (e) a reduction in glial cell activation; (f) a reduction in lymphocyte infiltration; (g) a reduction in macrophage infiltration; (h) a reduction in antibody deposition, (i) a reduction in glial cell loss; (j) a reduction in oligodendrocyte loss; (k) a reduction in dendritic cell infiltration; (l) a reduction in neutrophil infiltration; (m) a reduction in red blood cell lysis; (n) a reduction in red blood cell phagocytosis; (o) a reduction in platelet phagocytosis; (p) a reduction in platelet lysis; (q) an improvement in transplant graft survival; (r) a reduction in macrophage mediated phagocytosis; (s) an improvement in vision; (t) an improvement in motor control; (u) an improvement in thrombus formation; (v) an improvement in clotting; (w) an improvement in kidney function; (x) a reduction in antibody mediated complement activation; (y) a reduction in autoantibody mediated complement activation; (z) an improvement in anemia; (aa) reduction of demyelination; (ab) reduction of eosinophilia; (ac) a reduction of C3 deposition on red blood cells (e.g., a reduction of deposition of C3b, iC3b, etc., onto RBCs); and (ad) a reduction in C3 deposition on platelets (e.g., a reduction of deposition of C3b, iC3b, etc., onto platelets); and (ae) a reduction of anaphylatoxin toxin production; (af) a reduction in autoantibody mediated blister formation; (ag) a reduction in autoantibody induced pruritis; (ah) a reduction in autoantibody induced erythematosus; (ai) a reduction in autoantibody mediated skin erosion; (aj) a reduction in red blood cell destruction due to transfusion reactions; (ak) a reduction in red blood cell lysis due to alloantibodies; (al) a reduction in hemolysis due to transfusion reactions; (am) a reduction in allo-antibody mediated platelet lysis; (an) a reduction in platelet lysis due to transfusion reactions; (ao) a reduction in mast cell activation; (ap) a reduction in mast cell histamine release; (aq) a reduction in vascular permeability; (ar) a reduction in edema; (as) a reduction in complement deposition on transplant graft endothelium; (at) a reduction of anaphylatoxin generation in transplant graft endothelium; (au) a reduction in the separation of the dermal-epidermal junction; (av) a reduction in the generation of anaphylatoxins in the dermal-epidermal junction; (aw) a reduction in alloantibody mediated complement activation in transplant graft endothelium; (ax) a reduction in antibody mediated loss of the neuromuscular junction; (ay) a reduction in complement activation at the neuromuscular junction; (az) a reduction in anaphylatoxin generation at the neuromuscular junction; (ba) a reduction in complement deposition at the neuromuscular junction; (bb) a reduction in paralysis; (bc) a reduction in numbness; (bd) increased bladder control; (be) increased bowel control; (bf) a reduction in mortality associated with autoantibodies; and (bg) a reduction in morbidity associated with autoantibodies. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein, when administered in one or more doses to an individual having a complement-mediated disease or disorder, is effective to achieve a reduction of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, of one or more of the following outcomes: (a) complement activation; (b) decline in cognitive function; (c) neuron loss; (d) phospho-Tau levels in neurons; (e) glial cell activation; (f) lymphocyte infiltration; (g) macrophage infiltration; (h) antibody deposition, (i) glial cell loss; (j) oligodendrocyte loss; (k) dendritic cell infiltration; (l) neutrophil infiltration; (m) red blood cell lysis; (n) red blood cell phagocytosis; (o) platelet phagocytosis; (p) platelet lysis; (q) transplant graft rejection; I macrophage mediated phagocytosis; (s) vision loss; (t) antibody mediated complement activation; (u) autoantibody mediated complement activation; (v) demyelination; (w) eosinophilia; compared to the level or degree of the outcome in the individual before treatment with the active compound or its salt. In some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein, when administered in one or more doses to an individual having a complement-mediated disease or disorder, is effective to achieve an improvement of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, of one or more of the following outcomes: a) cognitive function; b) transplant graft survival; c) vision; d) motor control; e) thrombus formation; f) clotting; g) kidney function; and h) hematocrit (red blood cell count), compared to the level or degree of the outcome in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual reduces complement activation in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces complement activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to complement activation in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein improves cognitive function in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) described herein, when administered in one or more doses to an individual having a complement-mediated disease or disorder, improves cognitive function in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the cognitive function in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein reduces the rate of decline in cognitive function in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces the rate of decline of cognitive function in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the rate of decline in cognitive function in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual reduces neuron loss in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces neuron loss in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to neuron loss in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual reduces phospho-Tau levels in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces phospho-Tau in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the phospho- Tau level in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual reduces glial cell activation in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces glial activation in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to glial cell activation in the individual before treatment with the active compound or its salt. In some embodiments, the glial cells are astrocytes or microglia. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual reduces lymphocyte infiltration in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces lymphocyte infiltration in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to lymphocyte infiltration in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual reduces macrophage infiltration in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces macrophage infiltration in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to macrophage infiltration in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual reduces antibody deposition in the individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces antibody deposition in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to antibody deposition in the individual before treatment with the active compound or its salt. In some embodiments, administering an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt or composition as described herein to an individual reduces anaphylatoxin (e.g., C3a, C4a, C5a) production in an individual. For example, in some embodiments, an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt, when administered in one or more doses to an individual having a complement-mediated disease or disorder, reduces anaphylatoxin production in the individual by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, compared to the level of anaphylatoxin production in the individual before treatment with the active compound or its salt. The present disclosure provides a use of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt of the present disclosure or a pharmaceutical composition comprising an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt of the present disclosure and a pharmaceutically acceptable excipient to treat an individual having a complement-mediated disease or disorder. In some embodiments, the present disclosure provides a use of an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt of the present disclosure to treat an individual having a complement-mediated disease or disorder. In some embodiments, the present disclosure provides a use of a pharmaceutical composition comprising an active compound (e.g., a compound of Formula (I), (I’), (I”), (II), (III), (IV), (V), (VI), or (VII), or Table 1) or its salt of the present disclosure and a pharmaceutically acceptable excipient to treat an individual having a complement-mediated disease or disorder. Examples The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, patents, and patent applications cited throughout this application are expressly incorporated herein by reference. Example 1. Non-Limiting Synthetic Examples of Compounds of the Present Disclosure The below schemes are non-limiting examples of methods to make compounds of the present disclosure. The skilled artisan will recognize that there are various modifications that can be performed to make analogs or prepare compounds in other ways. Abbreviations

GENERAL METHODS All nonaqueous reactions were performed under an atmosphere of dry argon or nitrogen gas using anhydrous solvents. The progress of reactions and the purity of target compounds were determined using one of the two liquid chromatography (LC) methods A or B disclosed herein. The structure of starting materials, intermediates, and final products was confirmed by standard analytical techniques, including NMR spectroscopy and mass spectrometry. LC Method A Instrument: Waters Acquity Ultra Performance LC Column: ACQUITY UPLC BEH C182.1 ´ 50 mm, 1.7 mm Column Temperature: 40 °C Mobile Phase: Solvent A: H2O + 0.05% FA; Solvent B: CH3CN + 0.05% FA Flow Rate: 0.8 mL/min Gradient: 0.24 min @ 15% B, 3.5 min gradient (15-85% B), then 0.5 min @ 85% B. Detection: UV (210-410 nm) and MS (SQ in ES+ mode) Scheme 1. Synthesis of (6S)-3-(dibenzofuran-2-ylmethylamino)-4-oxo-N-(1H-pyrrolo[3,2-c]pyridin- 2-ylmethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 1) A 250 mL round bottom flask was charged with tert-butyl (S)-5-oxopyrrolidine-2-carboxylate (4000 mg, 21.60 mmol), toluene (120 mL), and Lawesson's Reagent (4000 mg, 11.61 mmol) and heated to 70 ˚C for 30 minutes. Afterwards, the mixture was allowed to cool to room temperature, concentrated in vacuo, and adsorbed onto Celite. Flash chromatography (RediSep Rf Gold silica, 120g, 0-10% MeOH in dichloromethane) afforded the title compound (3.422 g, 17.00 mmol, 78.72% yield) as a white solid. LC/MS: (ESI+) m/z = 202 [M+H]⁺. Step 2: tert-Butyl (2S)-5-methylsulfanyl-3,4-dihydro-2H-pyrrole-2-carboxylate A 250 mL round bottom flask was charged with tert-butyl (2S)-5-thioxopyrrolidine-2-carboxylate (3.422g, 17.00 mmol), 2-methyltetrahydrofuran (60 mL), and iodomethane (4.2 mL, 67 mmol) at room temperature, and the mixture was stirred for 4 hours. Afterwards, the mixture was concentrated in vacuo. The crude oil was then taken up in DCM (100 mL) and washed with saturated NaHCO₃ solution (100 mL). The aqueous layer was then extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the title compound (3.335 g, 15.49 mmol, 91.11% yield) as an orange oil. LC/MS: (ESI+) m/z = 216 [M+H]⁺. Step 3: tert-Butyl (2S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate A 100 mL round bottom was charged with tert-butyl (2S)-5-methylsulfanyl-3,4-dihydro-2H-pyrrole- 2-carboxylate (4.20 g, 19.5 mmol), MeOH (40 mL), and NH₄Cl (1300 mg, 24.30 mmol) at room temperature, and the mixture was heated to reflux for 2 hours. Afterwards, the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was taken up in DCM (75 mL), filtered, and concentrated in vacuo. The crude product was then triturated with hexanes and filtered. The resulting light-yellow solid was then added to a solution of saturated K₂CO₃ (100 mL) and DCM (100 mL). The aqueous layer was then further extracted with DCM (3 x 25 mL). The combined organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (2.45 g, 13.3 mmol, 68.2% yield) that was carried forward without further purification. LC/MS: (ESI+) m/z = 185 [M+H]⁺. Step 4: 6-(tert-Butyl) 3-methyl (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-3,6-dicarboxylate A 150 mL round bottom flask was charged with dimethyl 2-(methoxymethylene)propanedioate (2.50 g, 14.4 mmol) and MeOH (30 mL) and cooled to -10 ˚C in an acetone/ice bath. Tert-butyl (2S)-5- amino-3,4-dihydro-2H-pyrrole-2-carboxylate (2.65 g, 14.4 mmol) in MeOH (30 mL) was then added dropwise, and the resulting solution was allowed to warm to room temperature and stir overnight. Afterwards, the mixture was concentrated in vacuo and subjected to flash chromatography (RediSep Rf Gold silica, 40g, 0-5% MeOH in DCM) to afford the title compound (2205 mg, 7.492 mmol, 52.1% yield) as an orange solid.¹H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 5.01 (dd, J = 9.8, 2.7 Hz, 1H), 3.88 (s, 3H), 3.35 – 3.21 (m, 1H), 3.19 – 3.07 (m, 1H), 2.60 – 2.49 (m, 1H), 2.35 – 2.24 (m, 1H), 1.48 (s, 9H). LC/MS: (ESI+) m/z = 295 [M+H]⁺. Step 5: (6S)-6-tert-Butoxycarbonyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-3-carboxylic acid A 100 mL round bottom was charged with 6-(tert-butyl) 3-methyl (S)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-3,6-dicarboxylate (2205 mg, 7.492 mmol) and MeOH (40 mL), followed by cooling to 0 ˚C in a brine/ice bath. LiOH.H₂O (325 mg, 7.563 mmol) in water (8 mL) was added dropwise, and the resulting solution was allowed to slowly warm to room temperature and stir overnight. Afterwards, the mixture was concentrated in vacuo and diluted in water (15 mL). The aqueous mixture was washed with MTBE (10 mL), and the organic layer was discarded. The pH of the aqueous layer was then adjusted to pH 2 with 1M HCl. The aqueous layer was then extracted with DCM (3 x 50 mL). The organic layer was then dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (1425 mg, 5.084 mmol, 67.85% yield) as a light-orange solid. LC/MS: (ESI+) m/z = 281 [M+H]⁺. Step 6: tert-Butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate A 100 mL round bottom flask was charged with (6S)-6-tert-butoxycarbonyl-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-3-carboxylic acid (750 mg, 2.676 mmol), 1,4-dioxane (15 mL), TEA (0.400 mL, 2.87 mmol), and DPPA (0.600 mL, 2.78 mmol), and the mixture was heated to reflux for 1 hour. Water (0.150 mL, 8.33 mmol) was then added, and the resulting mixture was refluxed for an additional 30 minutes. Afterwards, the mixture was allowed to cool to room temperature and concentrated in vacuo. Flash chromatography (Redisep Rf Gold silica, 40g, 0-10% MeOH in DCM) afforded the title compound (352 mg, 1.4008 mmol, 52.35% yield) as a light-yellow solid.¹H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 4.96 (dd, J = 9.6, 2.9 Hz, 1H), 3.83 (s, 2H), 3.22 – 3.05 (m, 1H), 3.04 – 2.84 (m, 1H), 2.65 – 2.43 (m, 1H), 2.38 – 2.18 (m, 1H), 1.48 (s, 9H). LC/MS: (ESI+) m/z = 252 [M+H]⁺. Step 7: tert-Butyl (6S)-3-(dibenzofuran-2-ylmethylamino)-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylate A 100 mL round bottom flask was charged with tert-butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylate (345 mg, 1.3730 mmol), dibenzofuran-2-carbaldehyde (275 mg, 1.402 mmol), DCE (5 mL), and AcOH (0.080 mL, 1.4 mmol) at room temperature under nitrogen. The mixture was allowed to stir for 30 minutes, and sodium triacetoxyborohydride (450 mg, 2.1232 mmol) was added to the mixture. The reaction mixture was allowed to stir overnight at room temperature. Afterwards, the mixture was diluted with DCM (25 mL), washed with saturated NaHCO₃ solution (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-10% MeOH in DCM) afforded the title compound (472 mg, 1.094 mmol, 79.67% yield) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 7.96 – 7.88 (m, 2H), 7.59 – 7.49 (m, 2H), 7.47 – 7.39 (m, 2H), 7.37 – 7.30 (m, 1H), 7.05 (s, 1H), 4.96 (td, J = 9.2, 4.2 Hz, 2H), 4.43 (d, J = 5.3 Hz, 2H), 3.08 (dt, J = 17.0, 9.4 Hz, 1H), 2.93 (ddd, J = 17.1, 9.4, 3.4 Hz, 1H), 2.50 (dq, J = 13.4, 9.5 Hz, 1H), 2.33 – 2.21 (m, 1H), 1.49 (s, 9H). LC/MS: (ESI+) m/z = 432 [M+H]⁺. Step 8: (6S)-3-(Dibenzofuran-2-ylmethylamino)-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylic acid A 20 mL vial was charged with tert-butyl (6S)-3-(dibenzofuran-2-ylmethylamino)-4-oxo-7,8- dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate (460 mg, 1.066 mmol) and DCM (3 mL), and the mixture was cooled to 0 ˚C in a brine/ice bath. Trifluoroacetic acid (2.5 mL, 33 mmol) was added dropwise, and the resulting mixture was allowed to warm to room temperature and stir for 3 hours. Afterwards, the mixture was concentrated in vacuo to afford the title compound as a brown solid, which was directly carried forward to the next reaction. LC/MS: (ESI+) m/z = 376 [M+H]⁺. Step 9: (6S)-3-(Dibenzofuran-2-ylmethylamino)-4-oxo-N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-7,8-dihydro- 6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 1) A 20 mL vial was charged with 1H-pyrrolo[3,2-c]pyridin-2-ylmethanamine;dihydrochloride (75 mg, 0.34075 mmol), (6S)-3-(dibenzofuran-2-ylmethylamino)-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylic acid (100 mg, 0.2664 mmol), DMF (3 mL), and TEa (0.200 mL, 1.51 mmol), and the mixture was cooled to 0 ˚C in a brine/ice bath. [Dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium;hexafluorophosphate (150 mg, 0.39450 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was diluted in EtOAc (25 mL), washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-50% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 1 (16 mg, 0.03171 mmol, 11.91% yield) as a white solid.¹H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.80 (s, 1H), 8.22 (d, J = 5.9 Hz, 1H), 8.02 – 7.88 (m, 3H), 7.55 (dd, J = 12.8, 8.3 Hz, 2H), 7.51 – 7.39 (m, 2H), 7.39 – 7.31 (m, 1H), 7.21 (d, J = 5.8 Hz, 1H), 7.13 (s, 1H), 6.39 (s, 1H), 5.10 (d, J = 8.8 Hz, 1H), 4.89 (s, 1H), 4.63 (dd, J = 15.4, 6.5 Hz, 1H), 4.50 (dd, J = 15.4, 5.3 Hz, 1H), 4.42 (s, 2H), 3.32 – 3.18 (m, 1H), 3.04 – 2.89 (m, 1H), 2.82 – 2.69 (m, 1H), 2.46 – 2.33 (m, 1H). LC/MS: (ESI+) m/z = 505 [M+H]⁺. RT (Method A): 1.31 min. Compound 2 was prepared according to the procedures set forth above, using tert-butyl (R)-5- oxopyrrolidine-2-carboxylate as the starting material in Step 1.¹H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.48 (s, 1H), 8.17 (d, J = 6.3 Hz, 1H), 8.03 (s, 1H), 8.00 – 7.90 (m, 1H), 7.65 (d, J = 6.3 Hz, 1H), 7.62 – 7.43 (m, 5H), 7.33 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.79 (s, 1H), 5.13 (dd, J = 9.2, 3.7 Hz, 1H), 4.76 (s, 1H), 4.59 (d, J = 16.1 Hz, 1H), 4.52 (s, 2H), 3.18 – 3.07 (m, 1H), 3.02 – 2.91 (m, 1H), 2.66 – 2.53 (m, 1H), 2.34 – 2.22 (m, 1H). LC/MS: (ESI+) m/z = 505 [M+H]⁺. RT (Method A): 1.21 min. Scheme 2. Synthesis of (R)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-6-((1-(dibenzo[b,d]furan-2- yl)ethyl)amino)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxamide (Compound 3) To a pre-heated phosphoric acid solution (10 g, 102.0 mmol) (115% H₃PO₄) at 100 °C was added methyl 2-aminothiazole-4-carboxylate (500 mg, 3.16 mmol). To this viscous solution was added methyl 3,3-dimethoxypropanoate (0.9 mL, 6 mmol) in two equal portions, 3 hours apart. The reaction was stirred for 72 hours at 100 °C to give a dark-brown solution. The mixture was diluted with water and basified with 1N NaOH to pH 9. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to give the title compound (49 mg, 8% yield) as a light-yellow oil. LC/MS (ESI) m/z: 211 (M+H)⁺. Step 2: Methyl 6-bromo-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate To a solution of methyl 5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate (180 mg, 0.6 mmol) in MeCN (5 mL) was added NBS (160 mg, 0.9 mmol) at room temperature. The reaction mixture was stirred for 1 hour and concentrated. The mixture was then diluted with saturated Na₂S₂O₃ and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified on silica gel column chromatography (0 to 60% EtOAc in hexanes) to give the title compound (208 mg, >100% yield) as a yellow solid. LC/MS (ESI) m/z: 289, 291 (M+H)⁺. Step 3: Methyl (R)-6-((1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3- carboxylate A mixture of methyl 6-bromo-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylate (80 mg, 0.28 mmol), (1R)-1-dibenzofuran-2-ylethanamine (120 mg, 0.57 mmol), Cs₂CO₃(200 mg, 0.62 mmol), Pd2(dba)3 (26 mg, 0.028 mmol), and XantPhos (48 mg, 0.083 mmol) in 1,4-dioxane (4 mL) (pre-sparged with nitrogen for 20 minutes before use) was sparged with nitrogen for 5 minutes. The mixture was heated to 105 °C for 2 hours. The mixture was diluted with EtOAc (10 mL) and filtered over a Celite pad. The filtrate was concentrated and diluted with water/MTBE. The solid was removed. The filtrate was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The reside was purified on silica gel column chromatography (0 to 80% EtOAc in hexanes) to give the title compound (17 mg, 12% yield) as a yellow foamy solid. LC/MS (ESI) m/z: 420 (M+H)⁺. Step 4: (R)-6-((1-(Dibenzo[b,d]furan-2-yl)ethyl)amino)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-carboxylic acid To a solution of methyl (R)-6-((1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-5-oxo-5H-thiazolo[3,2- a]pyrimidine-3-carboxylate (12 mg, 0.029 mmol) in MeOH (0.5 mL, 10 mmol), water (0.5 mL, 30 mmol), and THF (0.5 mL, 6 mmol) was added LiOH.H₂O (1.5 mg, 0.063 mmol) at room temperature, and the reaction mixture was stirred for 1 hour. The mixture was basified with 1N NaOH (0.2 mL) and extracted with EtOAc (10 mL). The organic layer was discarded, and the aqueous layer was acidified to pH 3-4 with 1N HCl and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give (the title compound (10 mg, 60% yield) as a yellow wax. LC/MS (ESI) m/z: 406 (M+H)⁺. Step 5: (R)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-6-((1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-5-oxo-5H- thiazolo[3,2-a]pyrimidine-3-carboxamide (Compound 3) A suspension of (R)-6-((1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-5-oxo-5H-thiazolo[3,2- a]pyrimidine-3-carboxylic acid (10 mg, 0.017 mmol), (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride (4 mg, 0.018 mmol), and 50% T3P in EtOAc (0.022 mL, 0.074 mmol) in DMF (2 mL) was cooled with ice bath. After 5 minutes, DIPEA (0.01 mL, 0.06 mmol) was added. After stirring for 40 minutes. Saturated aq. NaHCO₃ (1 mL) was added, and the resulting mixture was diluted with DMSO (2 mL). After filtration through a Celite pad, the filtrate was purified by ACCQ prep-HPLC (0 to 100% MeCN in H2O (with 0.05% HCOOH)) to give Compound 3 (3.2 mg, 35% yield) as an off-white solid. ¹H-NMR (400 MHz, MeOD) δ 8.92 (s, 1H), 8.31 (s, 2H), 8.20 (s, 1H), 8.04 – 7.73 (m, 3H), 7.61 – 7.32 (m, 4H), 7.22 (t, J = 7.5 Hz, 1H), 7.02 (s, 1H), 6.97 (s, 1H), 4.58 (d, J = 6.7 Hz, 1H), 1.57 (d, J = 6.7 Hz, 3H). LC/MS (ESI) m/z: 535 (M+H)⁺. RT (Method A): 1.61 min. Scheme 3. Synthesis of (6S)-4-oxo-3-[(5-phenylthiophene-2-carbonyl)amino]-N-(1H-pyrrolo[3,2- c]pyridin-2-ylmethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide formic acid salt (Compound 4) Step 1: tert-Butyl (6S)-4-oxo-3-[(5-phenylthiophene-2-carbonyl)amino]-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylate A 20 mL vial was charged with tert-butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylate (50 mg, 0.2 mmol), 5-phenylthiophene-2-carboxylic acid (150 mg, 0.73 mmol), DMF (2.0 mL), and 1-methylimidazole (0.125 mL, 1.57 mmol) at room temperature. [Chloro(dimethylamino)methylene]-dimethyl-ammonium hexafluorophosphate (200 mg, 0.7 mmol) was then added, and the resulting mixture was stirred at room temperature for 4 hours. Afterwards, the mixture was diluted in EtOAc (25 mL) and washed with saturated NaHCO₃ solution (50 mL). The organic layer was then washed with brine (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 24g, 0-100% EtOAc in hexanes) afforded the title compound (90 mg, 0.2057 mmol, 103.4% yield) as a white solid.¹H NMR (400 MHz, DMSO) δ 8.44 (d, J = 3.9 Hz, 1H), 8.07 (d, J = 4.0 Hz, 1H), 7.95 (s, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 3.9 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 4.99 (dd, J = 9.9, 3.2 Hz, 1H), 3.16 – 3.01 (m, 2H), 2.62 (dd, J = 13.1, 9.5 Hz, 1H), 2.22 – 2.10 (m, 1H), 1.44 (s, 9H). LC/MS: (ESI+) m/z = 438 [M+H]⁺ Step 2: (6S)-4-Oxo-3-[(5-phenylthiophene-2-carbonyl)amino]-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylic acid A 20 mL vial was charged with tert-butyl (6S)-4-oxo-3-[(5-phenylthiophene-2-carbonyl)amino]-7,8- dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate (87 mg, 0.20 mmol) and DCM (2.5 mL) and cooled to 0 ˚C in a brine/ice bath. TFA (2 mL) was added dropwise, and the resulting mixture was allowed to warm to room temperature and stir for 3 hours. Afterwards, the mixture was concentrated in vacuo to afford the title compound (80 mg, 0.2098 mmol, 105.5% yield) as a white solid, which was directly carried forward to the next reaction. LC/MS: (ESI+) m/z = 382 [M+H]⁺. Step 3: (6S)-4-Oxo-3-[(5-phenylthiophene-2-carbonyl)amino]-N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-7,8- dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 4) (formic acid salt) A 20 mL vial was charged with 1H-pyrrolo[3,2-c]pyridin-2-ylmethanamine;dihydrochloride (60 mg, 0.27260 mmol), (6S)-4-oxo-3-[(5-phenylthiophene-2-carbonyl)amino]-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (80 mg, 0.2 mmol), DMF (5 mL), and TEA (0.500 mL, 3.77 mmol) and cooled to 0 ˚C in a brine/ice bath. T3P (0.300 mL, 0.504 mmol) was then added dropwise, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was diluted with EtOAc (50 mL), washed with saturated NaHCO₃ (100 mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-50% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 4 as its formic acid salt (37 mg, 0.06648 mmol, 31.69% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 9.62 (s, 1H), 9.04 (t, J = 5.6 Hz, 1H), 8.75 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.06 (d, J = 4.0 Hz, 1H), 7.75 (dd, J = 7.2, 1.7 Hz, 2H), 7.62 (d, J = 4.0 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.33 (d, J = 5.6 Hz, 1H), 6.47 (s, 1H), 5.12 (dd, J = 9.4, 3.0 Hz, 1H), 4.49 (qd, J = 15.8, 5.5 Hz, 2H), 3.19 – 3.00 (m, 2H), 2.63 – 2.53 (m, 1H), 2.35 – 2.15 (m, 1H). LC/MS: (ESI+) m/z = 511 [M+H]⁺. RT (Method A): 1.15 min. The following compounds were isolated as their formic acid salts based on the procedures set forth above.

^a Step 3 was performed with HATU and DIPEA instead of T3P and TEA. ^b Step 2 was performed with HCl/1,4-dioxane under N₂ at 60 °C in 2 hours. ^c Step 2 was performed with HCl/1,4-dioxane in DCM in 2 hours. ^d Step 1 was performed in MeCN. Scheme 4. Synthesis of (6S)-4-Oxo-3-(3-phenylpropylamino)-N-(1H-pyrrolo[3,2-c]pyridin-2- ylmethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 6) Step 1: tert-Butyl (6S)-4-oxo-3-(3-phenylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylate A 250 mL round bottom flask was charged with tert-butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylate (100 mg, 0.4 mmol), 3-phenylpropanal (55 mg, 0.41 mmol), DCE (5 mL), and AcOH (0.023 mL, 0.40 mmol) at room temperature under nitrogen. The mixture was allowed to stir for 30 minutes, and sodium triacetoxyborohydride (120 mg, 0.56620 mmol) was added to the mixture. The reaction mixture was allowed to stir overnight at room temperature. Afterwards, the mixture was diluted in DCM (25 mL), washed with saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over NA₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 0-10% MeOH in DCM) afforded the title compound (56 mg, 0.15 mmol, 38% yield) as a yellow solid.¹H NMR (400 MHz, DMSO) δ 7.32 – 7.25 (m, 2H), 7.25 – 7.12 (m, 3H), 6.92 (s, 1H), 5.23 (s, 1H), 4.88 (dd, J = 9.7, 3.2 Hz, 1H), 3.00 (t, J = 6.8 Hz, 2H), 2.96 – 2.86 (m, 2H), 2.68 – 2.60 (m, 2H), 2.57 – 2.51 (m, 1H), 2.15 – 2.03 (m, 1H), 1.84 (p, J = 7.4 Hz, 2H), 1.42 (s, 9H). LC/MS: (ESI+) m/z = 370 [M+H]⁺. Step 2: (6S)-4-Oxo-3-(3-phenylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid A 20 mL vial was charged with tert-butyl (6S)-4-oxo-3-(3-phenylpropylamino)-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylate (53 mg, 0.14 mmol) and DCM (1.5 mL), and the solution was cooled to 0 ˚C in a brine/ice bath. TFA (1 mL) was added dropwise, and the resulting mixture was allowed to warm to room temperature and stir for 3 hours. Afterwards, the mixture was concentrated in vacuo to the title compound (45 mg, 0.14 mmol, 100.1% yield) as a white solid that was directly carried forward to the next reaction. LC/MS: (ESI+) m/z = 314 [M+H]⁺. Step 3: (6S)-4-Oxo-3-(3-phenylpropylamino)-N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 6) A 20 mL vial was charged with 1H-pyrrolo[3,2-c]pyridin-2-ylmethanamine;dihydrochloride (40 mg, 0.18 mmol), (6S)-4-oxo-3-(3-phenylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (44 mg, 0.14 mmol), DMF (2 mL), and TEA (0.200 mL, 1.51 mmol), and the mixture was cooled to 0 ˚C in a brine/ice bath. T3P (0.160 mL, 0.269 mmol) was then added dropwise, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was diluted with EtOAc (50 mL), washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep- HPLC (C18, 150 x 21 mm, 5 μM, 5-50% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 6 (22.3 mg, 0.0504 mmol, 35.9% yield) as a white solid.¹H NMR (400 MHz, MeOD) δ 8.84 (s, 1H), 8.51 (s, 1H), 8.18 (d, J = 6.2 Hz, 1H), 7.62 (d, J = 6.1 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.23 – 7.11 (m, 3H), 6.99 (s, 1H), 6.76 (s, 1H), 5.11 (dd, J = 9.2, 3.6 Hz, 1H), 4.75 (d, J = 16.0 Hz, 1H), 4.58 (d, J = 16.0 Hz, 1H), 3.20 – 3.12 (m, 1H), 3.11 (t, J = 7.0 Hz, 2H), 3.05 – 2.95 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.65 – 2.54 (m, 1H), 2.35 – 2.23 (m, 1H), 1.95 (p, J = 7.3 Hz, 2H). LC/MS: (ESI+) m/z = 443 [M+H]⁺. RT (Method A): 0.94 min. The following compounds were prepared based on the procedures set forth above.

^a HATU was used in place of T3P in Step 3. Scheme 5. Synthesis of (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(dibenzo-[b,d]furan- 2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 8) To a solution of bicyclo[2.2.1]hepta-2,5-diene (10.0 g, 109 mmol) in DCM (100 mL) was added sulfurisocyanatidic chloride (16.7 g, 118 mmol) dropwise at -15 °C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aq. Na2S2O3 solution, adjusted to pH 9 with 1N aq. NaOH solution, and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (1.1 g, yield 7.5%) as a yellow solid. Step 2: Methyl (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of 3-azatricyclo[4.2.1.02,5]non-7-en-4-one (1.0 g, 7.41 mmol) in ethylbenzene (2 mL) was added methyl (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (2.9 g, 18.47 mmol), and the mixture was stirred under N₂ atmosphere at 130 °C overnight. The mixture was concentrated under reduced pressure to remove ethylbenzene, and the mixture was stirred at 150 °C for another 8 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (752 mg, yield 52.3%) as a yellow oil. LC/MS (ESI) m/z: 195 (M+H)⁺. Step 3: Methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (750 mg, 3.87 mmol) in CHCl₃ (7 mL) was added Br₂ (623 mg, 3.89 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 4 hours. The mixture was quenched with saturated aq. Na2S2O3 solution and extracted wit EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (280 mg, yield 26.6%) as a yellow solid. LC/MS (ESI) m/z: 273 (M+H)⁺. Step 4: Methyl (S)-3-(((R)-1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylate (280 mg, 1.03 mmol) and (R)-1-(dibenzo[b,d]furan-2-yl)-ethan-1-amine (294 mg, 1.39 mmol) in toluene (6 mL) was added Cs₂CO₃ (670 mg, 2.06mmol), BINAP (128 mg, 0.21 mmol), and Pd₂(dba)₃ (23 mg, 0.10 mmol) under N₂ atmosphere, and the reaction mixture was degassed under N₂ atmosphere for three times and stirred under N2 atmosphere at 100 °C for 5 hours. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (150 mg, yield 36.1%) as a yellow oil. LC/MS (ESI) m/z: 404 (M+H)⁺. Step 5: (S)-3-(((R)-1-(Dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (S)-3-(((R)-1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (150 mg, 0.37 mmol) in MeOH/water (5.0 mL, v/v= 2/1) was added LiOH (35.7 mg, 1.49 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (120 mg, yield 82.9%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 390 (M+H)⁺. Step 6: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(dibenzo[b,d]furan-2-yl)-ethyl)amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 8) To a mixture of (S)-3-(((R)-1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (120 mg, 0.31 mmol) and (1H-pyrrolo[3,2-c]pyridin-2- yl)methanamine hydrochloride (66 mg, 0.45 mmol) in DMF (2 mL) was added DIPEA (198 mg, 1.53 mmol) and HATU (176 mg, 0.46 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) and further purified by prep-HPLC to give Compound 8 (26.1 mg, yield 16.4%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ: 11.37 (s, 1H), 8.95 (t, J = 5.5 Hz, 1H), 8.75 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.11 (m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 5.7 Hz, 1H), 6.79 (s, 1H), 6.46 (s, 1H), 5.55 (d, J = 6.8 Hz, 1H), 5.05 - 4.98 (m, 1H), 4.61 - 4.54 (m, 1H), 4.52 - 4.43 (m, 2H), 2.97 - 2.87 (m, 1H), 2.77 - 2.67 (m, 1H), 2.45 - 2.35 (m, 1H), 2.12 - 2.04 (m, 1H), 1.57 (d, J = 6.7 Hz, 3H). LC/MS (ESI) m/z: 519 (M+H)⁺. RT (Method A): 1.42 min. Scheme 6. Synthesis of (R)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(dibenzo-[b,d]furan- 2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 10) A mixture of methyl (R)-5-oxopyrrolidine-2-carboxylate (7.0 g, 48.95 mmol) and dimethyl sulfate (8.12 g, 64.44 mmol) was stirred under N₂ atmosphere at 60 °C for 22 hours. The mixture was cooled to room temperature and added dropwise to a solution of TEA (10 mL) in MTBE (100 mL) at 0 °C. The reaction mixture was quenched with saturated aq. Na2CO3 solution and extracted with MTBE twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.1 g, yield 14.3%) as a colorless oil. LC/MS (ESI) m/z: 158 (M+H)⁺. Step 2: Methyl (R)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of 3-azatricyclo[4.2.1.0^2,5]non-7-en-4-one (380 mg, 2.81 mmol) in ethylbenzene (4 mL) was added methyl (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (1.1 g, 7.0 mmol), and the mixture was stirred under N2 atmosphere at 120 °C overnight. The mixture was concentrated under reduced pressure to remove ethylbenzene, and the mixture was stirred at 150 °C for another 8 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (370 mg, yield 78.8%) as a yellow oil. LC/MS (ESI) m/z: 195 (M+H)⁺. Step 3: Methyl (R)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (R)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (370 mg, 1.91 mmol) in chloroform (4 mL) was added Br₂ (305 mg, 1.91 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 4 hours. The mixture was quenched with saturated aq. Na₂S₂O₃ solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (80 mg, yield 15.4%) as a yellow solid. LC/MS (ESI) m/z: 273 (M+H)⁺. Step 4: Methyl (R)-3-(((R)-1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (R)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (80 mg, 0.29 mmol) and (R)-1-(dibenzo[b,d]furan-2-yl)ethan-1-amine hydrochloride (124 mg, 0.59 mmol) in toluene (1 mL) was added Cs2CO3 (191 mg, 0.59 mmol), BINAP (37 mg, 0.06 mmol), and Pd₂(dba)₃ (7 mg, 0.03 mmol) under N₂ atmosphere, and the reaction mixture was degassed under N₂ atmosphere for three times and stirred under N2 atmosphere at 100 °C for 5 hours. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (67 mg, yield 56.5%) as a yellow oil. LC/MS (ESI) m/z: 404 (M+H)⁺. Step 5: (R)-3-(((R)-1-(Dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (R)-3-(((R)-1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (67 mg, 0.17 mmol) in MeOH/water (3.0 mL, v/v = 2/1) was added LiOH (16 mg, 0.67 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (64 mg, yield 99.0%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 390 (M+H)⁺. Step 6: (R)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 10) To a mixture of (R)-3-(((R)-1-(dibenzo[b,d]furan-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (64 mg, 0.16 mmol) and (1H-pyrrolo[3,2-c]pyridin-2- yl)methanamine hydrochloride (46 mg, 0.25 mmol) in DMF (1 mL) was added DIPEA (108 mg, 0.84 mmol) and HATU (95 mg, 0.25 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) and further purified by prep-HPLC to give Compound 10 (5.1 mg, yield 5.9%) as a white solid.¹ H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 8.94 (t, J = 5.5 Hz, 1H), 8.76 (s, 1H), 8.16 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.59 - 7.56 (m, 1H), 7.52 - 7.48 (m, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 5.6 Hz, 1H), 6.82 (s, 1H), 6.46 (s, 1H), 5.56 (d, J = 7.1 Hz, 1H), 5.04 - 4.99 (m, 1H), 4.57 (t, J = 6.9 Hz, 1H), 4.50 - 4.40 (m, 2H), 2.92 - 2.79 (m, 2H), 2.46 - 2.39 (m, 1H), 2.10 - 2.05 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H). LC/MS (ESI) m/z: 519 (M+H)⁺. RT (Method A): 1.36 min. The following compounds were prepared based on Steps 4-6 shown in Scheme 6. Scheme 7. Synthesis of (S)-N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((S)-2,3-dihydro-1H-inden- 1-yl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 12) Step 1: Ethyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate A round bottom flask was charged with ethyl (2S)-5-oxopyrrolidine-2-carboxylate (1.00 g, 6.36 mmol), dichloromethane (30 mL, 468.0 mmol), and cooled to 0 ˚C in a brine/ice bath. Trimethyloxonium;tetrafluoroborate (1.050 g, 7.099 mmol) was added portionwise, and the resulting mixture was allowed to warm to room temperature and stir for 3 hours. Afterwards, the mixture was cooled to 0 ˚C and quenched with saturated NaHCO3 solution (100 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford the title compound (960 mg, 5.6 mmol,79% yield) as a light-yellow oil.¹H NMR (400 MHz, CDCl₃) δ 4.51 (dd, J = 8.6, 5.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.65 – 2.55 (m, 1H), 2.55 – 2.42 (m, 1H), 2.40 – 2.25 (m, 1H), 2.25 – 2.06 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). LC/MS: (ESI)+ m/z = 171.76 [M+H]⁺. Step 2: Ethyl (6S)-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate A 100 mL round bottom was charged with ethyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2- carboxylate (950 mg, 5.5494 mmol), 3-azatricyclo[4.2.1.02,5]non-7-en-4-one (1.10 g, 8.14 mmol), and toluene (1.0 mL, 9.5 mmol) at room temperature, and the mixture was heated to 110 ˚C overnight. Afterwards, the mixture was allowed to cool to room temperature and subjected to flash chromatography (RediSep Rf Gold silica, 40g, 0-100% EtOAc in hexanes) to afford ethyl (1S)-9-oxo-1,2,3,4a,5,8,8a,9- octahydro-5,8-methanopyrrolo[2,1-b]quinazoline-1-carboxylate as a black oil. (LC/MS: (ESI)+ m/z = 274.76 [M+H]⁺). The oil was then heated to 150 ˚C for 1 hour and allowed to cool to room temperature to afford the title compound (650 mg, 3.1 mmol, 56% Yield) as a black oil, which was carried forward without further purification. LC/MS: (ESI)+ m/z = 208.86 [M+H]⁺. Step 3: Ethyl (6S)-3-bromo-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate A 100 mL round bottom flask was charged with ethyl (6S)-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylate (600 mg, 2.88 mmol), DMF (5 mL), and 1-bromopyrrolidine-2,5-dione (600 mg, 3.37 mmol) at room temperature. The mixture was then heated to 50 ˚C for 30 minutes. Afterwards, the mixture was allowed to cool to room temperature and diluted in water (100 mL). The mixture was then extracted with EtOAc (3 x 25 mL). The layers were separated, and the combined organic extracts were then washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 0-10% MeOH in DCM) afforded the title compound (550 mg, 1.9 mmol, 66.5% yield) as an orange oil.¹H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 5.10 (dd, J = 9.7, 3.0 Hz, 1H), 4.34 – 4.20 (m, 2H), 3.30 – 3.14 (m, 1H), 3.14 – 3.03 (m, 1H), 2.68 – 2.52 (m, 1H), 2.40 – 2.28 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H). LC/MS: (ESI)+ m/z = 286.92 [M+H]⁺. Step 4: ethyl (S)-3-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate A 20 mL microwave vial was charged with (1S)-indan-1-amine (65 mg, 0.49 mmol), ethyl (6S)-3- bromo-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate (100 mg, 0.35 mmol), Cs2CO3 (230 mg, 0.71 mmol), Pd(OAc)₂ (6 mg, 0.027 mmol), and [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]- diphenyl-phosphane (34 mg, 0.055 mmol), and was subsequently crimp sealed and placed under nitrogen.1,4-Dioxane (5.0 mL) was added, and the resulting mixture was sparged with nitrogen for 10 minutes. The vessel was then heated to 110 °C for 18 hours. Afterwards, the mixture was allowed to cool to room temperature, filtered over Celite, washed with EtOAc, adsorbed onto Celite, and concentrated in vacuo. Reverse-phase flash chromatography (RediSep Rf Gold C18, 15.5g, 10-100% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded the title compound (50 mg, 0.15 mmol, 42% yield) as a brown solid.¹H NMR (400 MHz, CDCl3) δ 7.97 – 7.69 (m, 1H), 7.64 – 7.06 (m, 3H), 6.94 – 6.66 (m, 1H), 5.06 (d, J = 9.6 Hz, 1H), 4.88 (s, 1H), 4.73 (s, 1H), 4.40 – 4.11 (m, 2H), 3.29 – 2.84 (m, 4H), 2.63 – 2.48 (m, 2H), 2.41 – 2.16 (m, 1H), 2.10 – 1.83 (m, 1H), 1.30 (td, J = 7.1, 3.2 Hz, 3H). LC/MS: (ESI+) m/z = 340 [M+H]⁺. Step 5: (S)-3-(((S)-2,3-Dihydro-1H-inden-1-yl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid A 20 mL vial was charged with ethyl (6S)-3-[[(1S)-indan-1-yl]amino]-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.1473 mmol), THF (2.5 mL) and MeOH (0.50 mL). Sodium hydroxide (1M, 0.450 mL) was added, and the resulting solution was stirred at room temperature for 60 minutes. The pH of the solution was then adjusted to pH 2 with 1M HCl, then the solution was diluted with brine (10 mL). The aqueous layer was then extracted with EtOAc (3 x 20 mL). The layers were separated, and the combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (45 mg, 0.14 mmol, 98% Yield) as a yellow residue, which was directly carried forward to the next reaction. LC/MS: (ESI+) m/z = 312 [M+H]⁺. Step 6: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 12) A 20 mL vial was charged with 1H-pyrrolo[3,2-c]pyridin-2-ylmethanamine;dihydrochloride (35 mg, 0.16 mmol), (6S)-3-[[(1S)-indan-1-yl]amino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (45 mg, 0.1446 mmol), DMF (2 mL), and TEA (0.100 mL, 0.753 mmol) and cooled to 0 ˚C in a brine/ice bath. T3P (0.260 mL, 0.437 mmol) was then added dropwise, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was diluted with EtOAc (50 mL), washed with saturated NaHCO₃ (100 mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-50% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 12 (4.5 mg, 0.010 mmol, 7.1% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H), 9.02 (t, J = 5.3 Hz, 1H), 8.73 (s, 1H), 8.40 (s, 2H), 8.11 (d, J = 5.3 Hz, 1H), 7.37 – 7.11 (m, 6H), 6.44 (s, 1H), 5.11 – 5.00 (m, 2H), 5.00 – 4.90 (m, 1H), 4.57 – 4.38 (m, 2H), 3.03 – 2.92 (m, 2H), 2.91 – 2.78 (m, 2H), 2.20 – 2.03 (m, 1H), 1.98 – 1.83 (m, 1H). LC/MS: (ESI+) m/z = 441 [M+H]⁺. RT (Method A): 0.84 min. Scheme 8. Synthesis of (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(2- phenyloxazol-4-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 13) To a solution of benzamide (8.0 g, 66 mmol) in 1,4-dioxane/EtOH (80 mL, v/v= 1/1) was added 1- bromobutane-2,3-dione (10.9 g, 66.1 mmol), and the reaction mixture was stirred at 90 °C overnight. The mixture was concentrated under reduced pressure to half volume and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% EtOAc in PE) to give the title compound (1.8 g, yield 14.6%) as a yellow solid. LC/MS (ESI) m/z: 188 (M+H)⁺. Step 2: (R,Z)-2-Methyl-N-(1-(2-phenyloxazol-4-yl)ethylidene)propane-2-sulfinamide To a mixture of 1-(2-phenyloxazol-4-yl)ethan-1-one (1.8 g, 9.61 mmol) and (R)-2-methylpropane- 2-sulfinamide (4.67 g, 38.7 mmol) in THF (20 mL) was added Ti(OEt)4 (8.77 g, 38.5 mmol) under N2 atmosphere, and the reaction mixture was stirred at 70 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1 g, yield 35.8%) as a brown oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 291 (M+H)⁺. Step 3: (R)-2-Methyl-N-((R)-1-(2-phenyloxazol-4-yl)ethyl)propane-2-sulfinamide To a solution of ((R,Z)-2-methyl-N-(1-(2-phenyloxazol-4-yl)ethylidene)propane-2-sulfinamide (1 g, 3.44 mmol) in THF (10 mL) was added DIBAL-H (13 mL, 20.0 mmol, 1.5 M in THF) dropwise at -78 °C under N2 atmosphere, and the mixture was stirred under N2 atmosphere at -78 °C for 30 minutes. The mixture was quenched with saturated aq. potassium sodium tartrate solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure then purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (625 mg, yield 62.0%) as a yellow solid. LC/MS (ESI) m/z: 293 (M+H)⁺. Step 4: (R)-1-(2-Phenyloxazol-4-yl)ethan-1-amine hydrochloride To a solution of (R)-2-methyl-N-((R)-1-(2-phenyloxazol-4-yl)ethyl)propane-2-sulfinamide (620 mg, 2.12 mmol) in DCM (4 mL) was added HCl/1,4-dioxane (2 mL, 4 M), and the reaction mixture was stirred under N₂ atmosphere at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (450 mg, yield 94.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 189 (M+H)⁺. Step 5: Methyl (S)-4-oxo-3-(((R)-1-(2-phenyloxazol-4-yl)ethyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of (R)-1-(2-phenyloxazol-4-yl)ethan-1-amine hydrochloride (130 mg, 0.51 mmol) and methyl (S)-6-bromo-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylate (100 mg, 0.36 mmol) in toluene (5 mL) was added Cs2CO3 (359 mg, 1.10 mmol), BINAP (45 mg, 0.072 mmol), Pd(OAc)2 (8 mg, 0.035 mmol) under N2 atmosphere, and the reaction mixture was degassed under N2 atmosphere for three times and stirred at 100 °C overnight. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the title compound (20 mg, yield 14.3%) as a yellow solid. LC/MS (ESI) m/z: 381 (M+H)⁺. Step 6: (S)-4-Oxo-3-(((R)-1-(2-phenyloxazol-4-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine- 6-carboxylic acid To a solution of methyl (S)-4-oxo-3-(((R)-1-(2-phenyloxazol-4-yl)ethyl)amino)-4,6,7,8-tetra- hydropyrrolo[1,2-a]pyrimidine-6-carboxylate (20 mg, 0.052 mmol) in MeOH/water (2.0 mL, v/v = 4/1) was added LiOH·H2O (5 mg, 0.12 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (18 mg, yield 93.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 367 (M+H)⁺. Step 7: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(2-phenyloxazol-4-yl)ethyl)amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 13) To a mixture of (S)-4-oxo-3-(((R)-1-(2-phenyloxazol-4-yl)ethyl)amino)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (18 mg, 0.049 mmol) and (1H-pyrrolo[3,2-c]pyridin-2- yl)methanamine hydrochloride (15 mg, 0.081 mmol) in DMF (2 mL) was added DIPEA (32 mg, 0.24 mmol) and HATU (22 mg, 0.057 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC and further purified by prep-SFC (Chiral Cel OJ, 250×21.2mm I.D., 5µm, A for CO₂ and B for MeOH (0.1% 7mol/L NH3 in MeOH)) to give Compound 13 (2.9 mg, yield 11.9%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.38 (d, J = 4.3 Hz, 1H), 8.10 - 8.06 (m, 3H), 7.57 - 7.46 (m, 4H), 7.34 (d, J = 5.8 Hz, 1H), 6.60 (s, 1H), 5.22 (dd, J = 9.6, 3.3 Hz, 1H), 4.66 - 4.59 (m, 2H), 4.47 - 4.39 (m, 1H), 3.39 - 3.34 (m, 1H), 3.25 - 3.19 (m, 1H), 2.71 - 2.64 (m, 1H), 2.39 - 2.32 (m, 1H), 1.51 - 1.48 (m, 3H). LC/MS (ESI) m/z: 496 (M+H)⁺. RT (Method A): 0.37 min. Scheme 9. Synthesis of (S)-N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-((3-(4- fluorophenyl)propyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide A 20 mL microwave vial was charged with 3-(4-fluorophenyl)propan-1-amine (75 mg, 0.49 mmol), ethyl (6S)-3-bromo-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate (90 mg, 0.31 mmol), Cs2CO3 (230 mg, 0.71 mmol), Pd(OAc)2 (8 mg, 0.04 mmol), and BINAP (40 mg, 0.06 mmol), and was subsequently crimp sealed and placed under nitrogen. Toluene (5.0 mL) was added, and the resulting solution was sparged with nitrogen for 10 minutes. The vessel was then heated to 110 °C for 18 hours. Afterwards, the mixture was allowed to cool to room temperature, filtered over Celite, washed with EtOAc, adsorbed onto Celite, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 10- 100% EtOAc in hexanes) afforded the title compound (23 mg, 0.064 mmol, 20.4% yield) as a brown solid. LC/MS: (ESI+) m/z = 360 [M+H]⁺. Step 2: (S)-3-((3-(4-Fluorophenyl)propyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid A 20 mL vial was charged with ethyl (S)-3-((3-(4-fluorophenyl)propyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (23 mg, 0.064 mmol), THF (2.5 mL, 31 mmol) and MeOH (0.50 mL). NaOH (1M, 0.20 mL) was added, and the resulting solution was stirred at room temperature for 60 minutes. The pH of the solution was then adjusted to pH 2 with 1M HCl and diluted with brine (10 mL). The aqueous layer was then extracted with EtOAc (3 x 20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (25 mg, 0.075 mmol, 117% Yield) as a yellow residue, which was directly carried forward to the next reaction. LC/MS: (ESI+) m/z = 312 [M+H]⁺. Step 3: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-((3-(4-fluorophenyl)propyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 21) A 20 mL vial was charged with 1H-pyrrolo[3,2-c]pyridin-2-ylmethanamine;dihydrochloride (20 mg, 0.09 mmol), (S)-3-((3-(4-fluorophenyl)propyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (25 mg, 0.075 mmol), DMF (1.0 mL), and TEA (0.100 mL, 0.753 mmol), and the mixture was cooled to 0 ˚C in a brine/ice bath. HATU (40 mg, 0.11 mmol) was then added dropwise, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was diluted with EtOAc (50 mL), washed with saturated NaHCO₃ (50 mL), LiOH (0.5% w/v in water, 2 x 25 mL), and brine (50 mL), then dried over Na₂SO₄, filtered, and concentrated in vacuo. Prep-HPLC (RediSep C18Aq, 150 x 21 mm, 5 μM, 10-50% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 21 (6 mg, 0.013 mmol, 17% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H), 8.95 (t, J = 5.7 Hz, 1H), 8.73 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 1H), 7.30 – 7.22 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 6.93 (s, 1H), 6.44 (s, 1H), 5.17 (t, J = 5.8 Hz, 1H), 5.01 (dd, J = 9.2, 2.9 Hz, 1H), 4.55 – 4.41 (m, 2H), 3.04 – 2.93 (m, 3H), 2.91 – 2.81 (m, 1H), 2.68 – 2.64 (m, 1H), 2.63 (t, J = 7.7 Hz, 2H), 2.48 – 2.42 (m, 1H), 2.19 – 2.05 (m, 1H), 1.84 (p, J = 7.3 Hz, 2H). LC/MS: (ESI+) m/z = 461 [M+H]⁺. RT (Method A): 1.10 min. Scheme 10. Synthesis of (S)-N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((6- fluorobenzo[b]thiophen-2-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 41) A 100 mL Schlenk flask was charged with 6-fluorobenzothiophene (550 mg, 3.6 mmol) and THF (6.0 mL) and cooled to -78 ˚C in a dry ice/acetone bath. N-BuLi (2.3M in cyclohexane/hexanes) (1.76 mL, 4.0 mmol) was then added dropwise, and the resulting mixture was stirred for 1 hour at -78 ˚C. DMF (0.300 mL) was then added dropwise at -78 ˚C. After stirring for 1 hour, the mixture was quenched while at -78 ˚C with saturated NH4Cl solution (25 mL). The mixture was then allowed to warm to room temperature then extracted with EtOAc (2 x 50 mL). The combined organic extracts were then washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. To the resulting solid was added minimal DCM (~ 1 mL) and heptanes (10 mL), and the suspension was sonicated for 5 minutes. The precipitate was then filtered, washed with heptanes, and dried to afford the title compound (362 mg, 2.01 mmol, 55.6% Yield) as a white solid.¹H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.00 (s, 1H), 7.91 (dd, J = 8.8, 5.2 Hz, 1H), 7.58 (d, J = 10.3 Hz, 1H), 7.21 (td, J = 8.8, 2.0 Hz, 1H). Step 2: tert-Butyl (S)-3-(((6-fluorobenzo[b]thiophen-2-yl)methyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate A 100 mL round bottom flask was charged with tert-butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylate (60 mg, 0.24 mmol), 6-fluorobenzothiophene-2-carbaldehyde (50 mg, 0.28 mmol), DCE (2 mL), and AcOH (0.014 mL, 0.24 mmol) at room temperature under nitrogen. The mixture was allowed to stir for 30 minutes, and sodium triacetoxyborohydride (75 mg, 0.33 mmol) was added to the mixture. The reaction mixture was allowed to stir overnight at room temperature. Afterwards, EtOH (3 mL) and NaBH₄ (50 mg) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with DCM (25 mL), washed with saturated NaHCO3 solution (50 mL) and brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 0-10% MeOH in DCM) afforded the title compound (50 mg, 0.12 mmol, 50.4% Yield) as a yellow solid. LC/MS: (ESI+) m/z = 416 [M+H]⁺. Step 3: (S)-3-(((6-Fluorobenzo[b]thiophen-2-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid A 100 mL round bottom flask was charged with tert-butyl (6S)-3-[(6-fluorobenzothiophen-2- yl)methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.12 mmol) and DCM (2.0 mL), and the solution was cooled to 0 ˚C in a brine/ice bath. TFA (2.0 mL, 26 mmol) was added dropwise, and the resulting mixture was allowed to warm to room temperature and stir for 3 hours. Afterwards, the mixture was concentrated in vacuo to afford the title compound (43 mg, 0.12 mmol, 99% Yield) as a white solid, which was directly carried forward to the next reaction. LC/MS: (ESI+) m/z = 360 [M+H]⁺. Step 4: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((6-fluorobenzo[b]thiophen-2-yl)methyl)amino)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 41) A 20 mL vial was charged with 1H-pyrrolo[3,2-c]pyridin-2-ylmethanamine;dihydrochloride (30 mg, 0.14 mmol), (6S)-3-[(6-fluorobenzothiophen-2-yl)methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (40 mg, 0.11 mmol), DMF (2 mL), and TEA (0.100 mL, 0.753 mmol) and cooled to 0 ˚C in a brine/ice bath. HATU (65 mg, 0.17 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was diluted in EtOAc (50 mL), washed with saturated NaHCO3 (50 mL), LiOH (0.5% in water) (2 x 10 mL) and brine (50 mL), dried over NaSO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 4g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-50% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 41 (10 mg, 0.020 mmol, 18.4% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H), 8.97 (t, J = 5.6 Hz, 1H), 8.74 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.40 – 7.33 (m, 2H), 7.20 (td, J = 9.1, 2.3 Hz, 1H), 7.03 (s, 1H), 6.46 (s, 1H), 6.06 (t, J = 6.2 Hz, 1H), 5.02 (dd, J = 9.2, 2.6 Hz, 1H), 4.56 (d, J = 6.2 Hz, 2H), 4.49 (d, J = 5.5 Hz, 2H), 3.02 – 2.89 (m, 1H), 2.89 – 2.77 (m, 1H), 2.47 – 2.41 (m, 1H), 2.17 – 2.05 (m, 1H). LC/MS: (ESI+) m/z = 489 [M+H]⁺. RT (Method A): 0.93 min. Compound 43 was prepared according to the procedures set forth above, using 6- chlorobenzothiophene in place of 6-fluorobenzothiophene as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H), 8.97 (t, J = 5.5 Hz, 1H), 8.74 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.03 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.41 – 7.32 (m, 3H), 7.02 (s, 1H), 6.46 (s, 1H), 6.09 (t, J = 6.2 Hz, 1H), 5.02 (dd, J = 9.3, 2.7 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.49 (d, J = 5.5 Hz, 2H), 3.01 – 2.87 (m, 1H), 2.87 – 2.75 (m, 1H), 2.48 – 2.39 (m, 1H), 2.18 – 2.02 (m, 1H). LC/MS: (ESI+) m/z = 505 [M+H]⁺. RT (Method A): 1.29 min. Scheme 11. Synthesis of (S)-N-(5-Chloro-2-(1H-tetrazol-1-yl)benzyl)-4-oxo-3-(5-phenyl-thiophene- 2-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 44) To a mixture of methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (500 mg, 1.84 mmol) and tert-butyl carbamate (236 mg, 2.02 mmol) in toluene (25 mL) was added Cs2CO3 (600 mg, 1.84 mmol), BrettPhos (197 mg, 0.37 mmol), and Pd2(dba)3 (336 mg, 0.37 mmol) under N2 atmosphere, the reaction mixture was degassed under N2 atmosphere for three times and stirred at 120 °C for 5 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure and then purified by prep-TLC (DCM: MeOH= 20: 1) to give the title compound (130 mg, yield 22.9%) as a cream-colored solid. LC/MS (ESI) m/z: 310 (M+H)⁺. Step 2: Methyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxylate (50 mg, 0.16 mmol) in DCM (1 mL) was added TFA (1 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (30 mg, yield 88.8%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 210 (M+H)⁺. Step 3: Methyl (S)-4-oxo-3-(5-phenylthiophene-2-carboxamido)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (30 mg, 0.14 mmol) and 5-phenylthiophene-2-carboxylic acid (29 mg, 0.14 mmol) in MeCN (1 mL) was added TCFH (120 mg, 0.43 mmol) and NMI (35 mg, 0.43 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep- TLC (DCM: MeOH= 20: 1) to give the title compound (25 mg, yield 44.1%) as a yellow solid. LC/MS (ESI) (m/z): 396 (M+H)⁺. Step 4: (S)-4-Oxo-3-(5-phenylthiophene-2-carboxamido)-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carboxylic acid To a solution of methyl (S)-4-oxo-3-(5-phenylthiophene-2-carboxamido)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylate (25 mg, 0.06 mmol) in MeOH (1 mL) and water (0.5 mL) was added LiOH (6 mg, 0.25 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (24 mg, yield 99.5%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 382 (M+H)⁺. Step 5: (S)-N-(5-Chloro-2-(1H-tetrazol-1-yl)benzyl)-4-oxo-3-(5-phenylthiophene-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 44) To a mixture of (S)-4-oxo-3-(5-phenylthiophene-2-carboxamido)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxylic acid (24 mg, 0.06 mmol) and (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine (25 mg, 0.12 mmol) in DMF (1 mL) was added DIPEA (51 mg, 0.40 mmol) and HATU (45 mg, 0.12 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (C₁₈, 40-98% MeCN in water with 0.1% NH_3.H₂O) to give Compound 44 (5.7 mg, yield 15.8%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 9.57 (s, 1H), 8.79 (s, 1H), 7.85 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.60 - 7.55 (m, 1H), 7.52 - 7.43 (m, 4H), 7.38 (t, J = 7.3 Hz, 1H), 5.12 - 5.09 (m, 1H), 4.39 - 4.24 (m, 2H), 3.26 - 3.18 (m, 1H), 3.14 - 3.08 (m, 1H), 2.62 - 2.53 (m, 1H), 2.29 - 2.19 (m, 1H). LC/MS (ESI) (m/z): 573 (M+H)⁺. RT (Method A): 2.10 min. Scheme 12. Synthesis of (3S,6R,8aS)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-5-oxo-6-(5-phenyl- thiophene-2-carboxamido)octahydroindolizine-3-carboxamide (Compound 45) To a solution of 1-(tert-butyl) 2-methyl (R)-5-oxopyrrolidine-1,2-dicarboxylate (8.5 g, 34.9 mmol) in THF (150 mL) was added vinylmagnesium bromide (42 mL, 42.0 mmol) dropwise at -40 °C under N₂ atmosphere and the mixture was stirred under N₂ atmosphere at -40 °C for 3 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30 - 60% EtOAc in PE) to give the title compound (7.0 g, yield 73.9%) as a colorless oil. LC/MS (ESI) m/z: 272 (M+H)⁺. Step 2: 9-(tert-Butyl) 1-methyl (2R)-2-((tert-butoxycarbonyl)amino)-8-((diphenyl-methylene)amino)-5- oxononanedioate To a mixture of methyl (R)-2-((tert-butoxycarbonyl)amino)-5-oxohept-6-enoate (5 g, 18.4 mmol) and tert-butyl 2-((diphenylmethylene)amino)acetate (6 g, 20.3 mmol) in THF (110 mL) was added Cs2CO3 (6 g, 18.4 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30 - 70% EtOAc in PE) to give the title compound (1.7 g, yield 16.3%) as a colorless oil. LC/MS (ESI) m/z: 567 (M+H)⁺. Step 3: tert-Butyl (3S,6R,8aS)-6-((tert-butoxycarbonyl)amino)-5-oxooctahydroindolizine-3-carboxylate To a solution of 9-(tert-butyl) 1-methyl (2R)-2-((tert-butoxycarbonyl)amino)-8-((diphenyl- methylene)amino)-5-oxononanedioate (880 mg, 1.6 mmol) in EtOH (16 mL) and AcOH (2 mL) was added Pd/C (100 mg, 10% w.t.). The mixture was degassed under N2 atmosphere for three times and stirred under a H₂ balloon at room temperature overnight. The mixture was basified with aq. NaHCO₃ to pH 8 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40 - 70% EtOAc in PE) to give the title compound (200 mg, yield 36.3%) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ 5.25 (s, 1H), 4.30 (d, J = 9.6 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.63 - 3.55 (m, 1H), 2.48 (s, 1H), 2.14 - 2.06 (m, 2H), 2.01 - 1.92 (m, 2H), 1.86 - 1.78 (m, 1H), 1.73 - 1.64 (m, 2H), 1.44 (s, 9H), 1.42 (s, 9H). LC/MS (ESI) m/z: 355 (M+H)⁺. Step 4: tert-Butyl (3S,6R,8aS)-6-amino-5-oxooctahydroindolizine-3-carboxylate To a solution of tert-butyl (3S,6R,8aS)-6-((tert-butoxycarbonyl)amino)-5-oxooctahydro-indolizine- 3-carboxylate (180 mg, 0.5 mmol) in DCM (2 mL) was added TFA (0.5 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was basified with aq. NaHCO₃ to pH 8 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (110 mg, yield 85.2%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 255 (M+H)⁺. Step 5: tert-Butyl (3S,6R,8aS)-5-oxo-6-(5-phenylthiophene-2-carboxamido)octahydro-indolizine-3- carboxylate To a mixture of tert-butyl (3S,6R,8aS)-6-amino-5-oxooctahydroindolizine-3-carboxylate (90 mg, 0.4 mmol) and 5-phenylthiophene-2-carboxylic acid (90 mg, 0.4 mmol) in MeCN (5 mL) was added NMI (88 mg, 1.1 mmol) and TCFH (298 mg, 1.1 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (110 mg, yield 70.6%) as a white solid. LC/MS (ESI) m/z: 441 (M+H)⁺. Step 6: (3S,6R,8aS)-5-Oxo-6-(5-phenylthiophene-2-carboxamido)octahydroindolizine-3-carboxylic acid A solution of tert-butyl (3S,6R,8aS)-5-oxo-6-(5-phenylthiophene-2-carboxamido)octahydro- indolizine-3-carboxylate (110 mg, 0.25 mmol) in HCl/1,4-dioxane (3 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give the title compound (80 mg, yield 83.3%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 385 (M+H)⁺. Step 7: (3S,6R,8aS)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-5-oxo-6-(5-phenylthiophene-2- carboxamido)octahydroindolizine-3-carboxamide (Compound 45) To a mixture of (3S,6R,8aS)-5-oxo-6-(5-phenylthiophene-2-carboxamido)octahydro-indolizine-3- carboxylic acid (80 mg, 0.2 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)-methanamine hydrochloride (55 mg, 0.3 mmol) in DMF (4 mL) was added HBTU (103 mg, 0.3 mmol) and DIPEA (135 mg, 1.0 mmol), and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (C₁₈, 10% - 95% MeCN in water with 0.1% FA) to give Compound 45 (3.6 mg, yield 3.37%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 8.21 (d, J = 6.3 Hz, 1H), 7.78 (d, J = 6.4 Hz, 1H), 7.69 (d, J = 5.6 Hz, 3H), 7.46 - 7.41 (m, 3H), 7.38 - 7.34 (m, 1H), 6.90 (s, 1H), 4.81 (s, 1H), 4.53 - 4.44 (m, 3H), 3.79 (t, J = 7.0 Hz, 1H), 2.29 - 2.20 (m, 3H), 2.15 - 2.08 (m, 2H), 2.06 - 2.02 (m, 1H), 1.88 - 1.79 (m, 2H). LC/MS (ESI) m/z: 514 (M+H)⁺. RT (Method A): 1.35 min. Compound 46 was prepared according to the procedures set forth above using 1-(tert-butyl) 2- methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate as the starting material.¹H NMR (400 MHz, CD3OD) δ 8.87 (s, 1H), 8.02 (d, J = 6.4 Hz, 1H), 7.61 (d, J = 6.5 Hz, 1H), 7.60 - 7.58 (m, 1H), 7.58 - 7.56 (m, 2H), 7.43 - 7.40 (m, 2H), 7.38 - 7.35 (m, 1H), 7.26 (d, J = 4.0 Hz, 1H), 6.89 (s, 1H), 4.77 - 4.68 (m, 2H), 4.57 - 4.54 (m, 1H), 4.52 (d, J = 9.2 Hz, 1H), 3.82 - 3.76 (m, 1H), 2.32 - 2.21 (m, 3H), 2.16 - 2.10 (m, 2H), 2.07 - 2.02 (m, 1H), 2.00 - 1.83 (m, 2H). LC/MS (ESI) m/z: 514 (M+H)⁺. RT (Method A): 1.35 min. Scheme 13. Synthesis of (6S)-3-[(2-Fluoro-3-methoxy-phenyl)methylamino]-4-oxo-N-(1H- pyrrolo[3,2-c]pyridin-2-ylmethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide) (Compound 47) To a solution of tert-butyl (2S)-5-oxopyrrolidine-2-carboxylate (10 g, 54 mmol) in DCM (100 mL) was added trimethyloxonium tetrafluoroborate (8 g, 54 mmol). The resulting suspension was stirred for 2 hrs. The reaction was quenched by the addition of saturated aqueous NaHCO₃ at 0 ˚C. The organic layer was removed, and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the title compound (8.5 g, 79% yield). LC/MS: (ESI)+ m/z = 185 [M+H]+. Step 2: tert-Butyl (2S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate Tert-butyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (10.5 g, 52.7 mmol) was dissolved in MeOH. NH₄Cl (3.4 g, 63.2 mmol) was added into the reaction mixture, and it was refluxed for 7 hours. The solvent was evaporated, and the crude mass was dissolved in DCM and filtered. The filtrate was evaporated, and the solid was washed with hexanes. The salt thus obtained was extracted with DCM and washed with saturated Na2CO3 solution to give the title compound (8.9 g, 84%yield) as a white solid, which was used in next step without further purification. Step 3: 6-tert-Butyl-3-methyl (6S)-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-3,6-dicarboxylate A 250 mL round bottom flask was charged with dimethyl 2-(methoxymethylene)propanedioate (10.1 g, 58.0 mmol) and MeOH (100 mL), and the mixture was cooled to -10 ˚C in an acetone/ice bath. Tert-butyl (2S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate (8.8 g, 48 mmol) in MeOH (100 mL) was then added dropwise, and the resulting mixture was allowed to warm to room temperature over 4 hr. Afterwards, the mixture was concentrated in vacuo and subjected to flash chromatography (RediSep Rf Gold silica, 40g, 0-5% MeOH in DCM) to afford the title compound as a yellow solid. LC/MS: (ESI+) m/z = 295 [M+H]+. Step 4: (6S)-6-tert-Butoxycarbonyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-3-carboxylic acid A 250 mL round bottom was charged with 6-tert-butyl 3-methyl (6S)-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-3,6-dicarboxylate (7.6 g, 26 mmol) and MeOH (150 ml), and the mixture was cooled to 0 ˚C in a brine/ice bath. LiOH (1.6 g, 39 mmol) in water (30 mL) was added dropwise, and the resulting mixture was warmed to room temperature and stirred overnight. Afterwards, the mixture was concentrated in vacuo and diluted with water. The aqueous mixture was washed with MTBE, and the organic layer was discarded. The pH of the aqueous layer was then adjusted to pH 2 with 1M HCl and extracted with DCM. The organic extract was then dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (4.7 g, 65% yield) as a light-orange solid. LC/MS: (ESI+) m/z = 281 [M+H]+. Step 5: tert-Butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate A 250 mL round bottom flask was charged with (6S)-6-tert-butoxycarbonyl-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-3-carboxylic acid (4.7 g, 16.77 mmol), TEA (2.34 mL, 16.77 mmol), DPPA (3.80 mL, 17.61 mmol), and dioxane, and the mixture was heated to reflux for 4 hours. Water (0.9 mL) was then added, and the resulting mixture was refluxed for an additional 30 minutes. Afterwards, the mixture was cooled to room temperature and concentrated in vacuo. Flash chromatography (Redisep Rf Gold silica, 80g, 0-10% MeOH in DCM) afforded the title compound (1.7 g, 40% yield) as a light-yellow solid. LC/MS: (ESI+) m/z = 252 [M+H]+. Step 6: tert-Butyl (6S)-3-[(2-fluoro-3-methoxy-phenyl)methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylate A vial was charged with tert-butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylate (0.03 g, 0.12 mmol), 2-fluoro-3-methoxy-benzaldehyde (0.03 g, 0.18 mmol), DCE, and AcOH (0.007 mL, 0.12 mmol) at room temperature under nitrogen. The mixture was stirred for 30 minutes, and sodium triacetoxyborohydride (0.038 g, 0.18 mmol) was added to the mixture. The reaction mixture was stirred overnight at room temperature. Afterwards, the mixture was diluted in DCM (25 mL), washed with saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (50-70 % EtOAc in hexanes) afforded the title compound (25 mg, 53.8% yield). LC/MS: (ESI+) m/z = 390 [M+H]+. Step 7: (6S)-3-[(2-Fluoro-3-methoxy-phenyl)methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine- 6-carboxylic acid Tert-Butyl (6S)-3-[(2-fluoro-3-methoxy-phenyl)methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylate (0.03 g, 0.064 mmol) was dissolved in DCM (2 mL). TFA (1 mL) was added, and the mixture was allowed to stir at room temperature for 3 hrs. The mixture was evaporated to complete dryness to give the title compound (21 mg, 98% yield), which was used in next step without further purification. LC/MS: (ESI+) m/z = 334 [M+H]+. Step 8: (6S)-3-[(2-Fluoro-3-methoxy-phenyl)methylamino]-4-oxo-N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)- 7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 47) (6S)-3-[(2-fluoro-3-methoxy-phenyl)methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine- 6-carboxylic acid (0.021 g, 0.063 mmol), 1H-pyrrolo[3,2-c]pyridin-2-ylmethanamine;dihydrochloride (0.015 g, 0.07 mmol), and DIPEA (0.055 mL, 0.32 mmol) were dissolved in DCM, and the mixture was allowed to cool at 0 ˚C. HATU (0.037 g, 0.095 mmol) was added, and the reaction was stirred at 0 ˚C for 30 minutes. The reaction mixture was washed with saturated NaHCO₃, and the layers were separated. The organic layer was dried over Na₂SO₄ and concentrated. The crude mixture was purified using column chromatography (10-20 % MeOH in DCM) to give Compound 47 (15 mg, 52% yield).¹H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.42 (t, J = 5.8 Hz, 1H), 8.16 (d, J = 5.7 Hz, 1H), 7.17 (d, J = 5.9 Hz, 1H), 7.10 – 6.95 (m, 2H), 6.96 – 6.77 (m, 2H), 6.32 (s, 1H), 5.05 (dd, J = 8.8, 2.9 Hz, 1H), 4.82 (s, 1H), 4.63 (dd, J = 15.4, 6.5 Hz, 1H), 4.44 (dd, J = 15.4, 4.9 Hz, 1H), 4.39 – 4.20 (m, 2H), 3.87 (s, 3H), 3.21 (dt, J = 17.0, 9.3 Hz, 1H), 2.90 (ddd, J = 17.4, 9.5, 3.6 Hz, 1H), 2.57 (ddt, J = 12.5, 9.0, 3.2 Hz, 1H), 2.40 – 2.25 (m, 1H). LC/MS: (ESI+) m/z = 463 [M+H]⁺. RT (Method A): 0.70 min. The following compounds were prepared according to the procedures set forth above, using the appropriate aldehyde in Step 6 and amine in Step 8.

Compound 194 was also synthesized in according to the procedures set forth above using 1- methylpiperidin-4-one in step 6 and 2-(aminomethyl)thieno[3,2-c]pyridin-6-amine dihydrochloride in step 8 (0.5 mg, 8 %Yield).¹H NMR (400 MHz, MeOD) δ 8.37 (s, 1H), 7.13 (d, J = 4.4 Hz, 2H), 6.96 (s, 1H), 5.09 (dd, J = 9.4, 2.9 Hz, 1H), 4.69 – 4.52 (m, 2H), 4.37 (s, 1H), 4.25 (s, 1H), 3.19 (dt, J = 18.2, 9.3 Hz, 1H), 2.99 (ddd, J = 17.1, 9.5, 3.4 Hz, 2H), 2.73 (s, 3H), 2.58 (dq, J = 13.2, 9.4 Hz, 1H), 2.35 – 2.25 (m, 1H), 2.20 (d, J = 14.3 Hz, 2H), 1.73 (s, 1H). LC/MS: (ESI+) m/z = 454 [M+H]⁺. RT (Method A): 0.26 min. Scheme 14. Synthesis of (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((2-phenyloxazol-4- yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 52) Step 1: Methyl (S)-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (200 mg, 0.73 mmol) and (2-phenyloxazol-4-yl)methanamine (123 mg, 0.88 mmol) in toluene (5mL) was added Cs2CO3 (717 mg, 2.20 mmol), BrettPhos (40 mg, 0.07 mmol), and Pd2(dba)3 (67 mg, 0.07 mmol) under N₂ atmosphere, and the reaction mixture was degassed under N₂ atmosphere for three times and stirred at 80 °C for 4 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) and further purified by Chiral SFC (ChiralPak IC, 250 × 20 mm I.D., 5 µm, 40 mL/min, 40% MeOH + 0.1% 7 mol/L NH3 in CO2) to give the title compound (retention time: 3.05 min, 41 mg, yield 15.3%) as a white solid. LC/MS (ESI) m/z: 367 (M+H)⁺. Step 2: (S)-4-Oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carboxylic acid To a solution of methyl (S)-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylate (41.0 mg, 0.111 mmol) in MeOH (3.0 mL) and water (0.5 mL) was added LiOH.H₂O (14.0 mg, 0.33 mmol), and the mixture was stirred at 25 °C for 3 hours. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (31.0 mg, yield 56.3%) as a white solid. LC/MS (ESI) (m/z): 353 (M+H)⁺. Step 3: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((2-phenyloxazol-4-yl)-methyl)amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 52) To a mixture of (S)-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxylic acid (31 mg, 0.09 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (31 mg, 0.17 mmol) in DMF (3 mL) was added DIPEA (68 mg, 0.52 mmol) and HATU (40 mg, 0.10 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM: MeOH= 5: 1) and further purified by prep- HPLC (C18, 30% - 70% MeCN in water with 0.1% NH3.H2O) to give Compound 52 (10 mg, yield 23.8%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 8.30 (d, J = 6.6 Hz, 1H), 8.07 - 7.96 (m, 2H), 7.93 (d, J = 6.1 Hz, 2H), 7.55 - 7.48 (m, 3H), 7.26 (s, 1H), 7.01 (s, 1H), 5.27 - 5.20 (m, 1H), 4.80 (s, 1H), 4.67 - 4.58 (m, 1H), 4.37 (s, 2H), 3.23 - 3.11 (m, 2H), 2.81 - 2.64 (m, 1H), 2.51 - 2.33 (m, 1H). LC/MS (ESI) (m/z): 482 (M+H)⁺. RT (Method A): 0.97 min. The following compounds were prepared in accordance with the procedures set forth above.

^a Step 1 was performed with Pd-175 in place of Pd₂(dba)₃ and BrettPhos. ^b T3P was used in place of HATU in Step 3. ^c Step 1 was performed with RuPhos Pd G2 in place of Pd2(dba)3. ^d Step 2 was performed with TBD in MeCN/H₂O. ^d Step 2 was performed in THF/H₂O. ^e BINAP was used in place of BrettPhos in Step 1. ^f Step3 was performed with TCFH and NMI in MeCN. ^g Step 1 was performed with Pd₂(dba)₃ and XantPhos in the presence of Cs2CO3 in 1,4-dioxane. Scheme 15. Synthesis of (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(4-fluorophen-ethyl)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 53) To a mixture of methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (500 mg, 1.83 mmol) and (E)-2-(4-fluorostyryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (680 mg, 2.74 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was added K₃PO₄ (1.21 g, 5.49 mmol) and Pd(dtbpf)Cl2 (118 mg, 0.18 mmol) under N2 atmosphere, and the reaction mixture was degassed under N2 atmosphere for three times and stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (300 mg, yield 51.8%) as a white solid. LC/MS (ESI) m/z: 315 (M+H)⁺. Step 2: Methyl (S)-3-(4-fluorophenethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (S,E)-3-(4-fluorostyryl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (300 mg, 0.95 mmol) in MeOH (3 mL) was added Pd/C (30 mg, 10% w.t.). The reaction mixture was degassed under N2 atmosphere for three times and stirred under a H2 balloon at room temperature for 4 hours. The mixture was filtered, and the filtrate was concentrated to give the title compound (250 mg, yield 83.0%) as a yellow oil, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 317 (M+H)⁺. Step 3: (S)-3-(4-Fluorophenethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (S)-3-(4-fluorophenethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxylate (250 mg, 0.78 mmol) in MeOH (4 mL) and water (2 mL) was added LiOH (49 mg, 1.18 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (200 mg, yield 84.0%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 303 (M+H)⁺. Step 4: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(4-fluorophenethyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 53) To a mixture of (S)-3-(4-fluorophenethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (50 mg, 0.17 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (45 mg, 0.25 mmol) in DMF (3 mL) was added DIPEA (380 mg, 1.02 mmol) and HATU (33 mg, 0.25 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (C18, 40% - 98% MeCN in water with 0.1% NH4HCO3) and further purified by Chiral SFC (ChiralPak C-IG, 250 × 30 mm I.D., 5 µm, 60 mL/min, 0.01MEA +40% MeOH in CO₂) to give Compound 53 (4.2 mg, yield 5.8%) as a yellow solid.¹H NMR (400 MHz, CD3OD) δ 9.04 (s, 1H), 8.29 (d, J = 6.7 Hz, 1H), 7.88 (d, J = 6.7 Hz, 1H), 7.65 (s, 1H), 7.18 - 7.13 (m, 2H), 7.03 (s, 1H), 7.00 - 6.93 (m, 2H), 5.21 - 5.12 (m, 1H), 4.83 - 4.81 (m, 1H), 4.68 - 4.58 (m, 1H), 3.25 - 3.20 (m, 1H), 3.16 - 3.10 (m, 1H), 2.89 - 2.82 (m, 2H), 2.79 - 2.70 (m, 2H), 2.68 - 2.61 (m, 1H), 2.36 - 2.25 (m, 1H). LC/MS (ESI) m/z: 432 (M+H)⁺. RT (Method A): 0.94 min. Scheme 16. Synthesis of (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-(pyrrolo[1,2-a]pyrazin-7- ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 54) To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylic acid (35 mg, 0.11 mmol) and pyrrolo[1,2-a]pyrazin-7-ylmethanamine (20 mg, 0.13 mmol) in MeCN (3 mL) was added NMI (55 mg, 0.66 mmol) and TCFH (94 mg, 0.33 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) and further purified by prep-HPLC (C18, 40% - 98% MeCN in water with 0.1% NH3.H2O) to give Compound 54 (8.0 mg, yield 16.3%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.09 (d, J = 4.9 Hz, 1H), 7.68 (s, 1H), 7.36 (d, J = 4.9 Hz, 1H), 7.28 - 7.24 (m, 2H), 7.20 (d, J = 7.1 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 6.96 (s, 1H), 6.89 (s, 1H), 5.10 - 5.06 (m, 1H), 4.63 - 4.58 (m, 1H), 4.52 - 4.48 (m, 1H), 3.19 - 3.12 (m, 1H), 3.11 - 3.07 (m, 2H), 3.00 - 2.93 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.61 - 2.53 (m, 1H), 2.29 - 2.22 (m, 1H), 1.98 - 1.92 (m, 2H). LC/MS (ESI) (m/z): 443 (M+H)⁺. RT (Method A): 1.10 min. The following compounds were prepared according to the procedures set forth above. ^a The coupling reaction was performed in the presence of NATU and TEA in DMF. Scheme 17. Synthesis of (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-((4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrazin-2-yl)methyl)-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxamide (Compound 55) To a solution of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (250 mg, 1.63 mmol) in THF (10 mL) was added (Boc)₂O (710 mg, 3.26 mmol) and saturated aq. NaHCO₃ solution (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (400 mg, yield 96.9%) as a light-yellow oil, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 254 (M+H)⁺. Step 2: tert-Butyl 2-(azidomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate To a solution of tert-butyl 2-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (400 mg, 1.58 mmol) in toluene (8 mL) was added DBU (960 mg, 6.32 mmol) and DPPA (1.30 g, 4.74 mmol) at room temperature under N2 atmosphere, and the reaction mixture was stirred at 110 °C for 6 hours. The mixture was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (170 mg, yield 38.7%) as a light-yellow oil.¹H NMR (400 MHz, CDCl3) δ 5.96 (s, 1H), 4.53 (s, 2H), 4.20 (s, 2H), 4.05 (t, J = 5.4 Hz, 2H), 3.78 (t, J = 5.4 Hz, 2H), 1.38 (s, 9H). Step 3: tert-Butyl 2-(aminomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate To a solution of tert-butyl 2-(azidomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (170 mg, 0.61 mmol) in THF (4 mL) and water (4 mL) was added PPh₃ (320 mg, 1.22 mmol) at room temperature under N₂ atmosphere, and the reaction mixture was stirred at 40 °C for 3 hours. The mixture was diluted with water and washed with EtOAc twice. The organic layer was concentrated under reduced pressure to give the title compound (110 mg, yield 71.4%) as a light-yellow oil, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 253 (M+H)⁺. Step 4: tert-Butyl (S)-2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)-6,7-dihydropyrazolo [1,5-a]pyrazine-5(4H)-carboxylate To a mixture of tert-butyl 2-(aminomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (40 mg, 0.16 mmol) and (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine- 6-carboxylic acid (35 mg, 0.11 mmol) in DMF (2 mL) was added DIPEA (60 mg, 0.47 mmol) and HATU (51 mg, 0.13 mmol), and the reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (50 mg, yield 81.8%) as a light-yellow oil. LC/MS (ESI) m/z: 548 (M+H)⁺. Step 5: (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 55) To a solution of tert-butyl (S)-2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (50 mg, 0.091 mmol) in DCM (4 mL) was added HCl/1,4-dioxane (1.0 mL, 4 M), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (C18, 20% - 98% MeCN in water with 0.1% NH3.H2O) to give Compound 55 (5.1 mg, yield 12.5%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 7.29 - 7.24 (m, 2H), 7.22 - 7.16 (m, 3H), 6.95 (s, 1H), 6.14 (s, 1H), 5.06 (dd, J = 9.2, 9.2 Hz, 1H), 4.37 (s, 2H), 4.18 - 4.14 (m, 4H), 3.44 - 3.40 (m, 2H), 3.12 - 3.06 (m, 3H), 2.99 -2.91 (m, 1H), 2.74 - 2.70 (m, 2H), 2.61 - 2.51 (m, 1H), 2.28 - 2.21 (m, 1H), 1.97 - 1.91 (m, 2H). LC/MS (ESI) m/z: 448 (M+H)⁺. RT (Method A): 1.02 min. Scheme 18. Synthesis of (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-(thieno[3,2-c]pyridin-2-ylmethyl)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 56) To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylic acid (35 mg, 0.11 mmol) and thieno[3,2-c]pyridin-2-ylmethanamine (25 mg, 0.15 mmol) in DMF (1 mL) was added DIPEA (72 mg, 0.56 mmol) and HATU (64 mg, 0.17 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (C₁₈, 20% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 56 (4.2 mg, yield 8.2%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.31 (d, J = 5.7 Hz, 1H), 7.92 (d, J = 5.4 Hz, 1H), 7.49 (s, 1H), 7.29 - 7.23 (m, 2H), 7.22 - 7.14 (m, 3H), 6.96 (s, 1H), 5.14 - 5.06 (m, 1H), 4.75 - 4.72 (m, 2H), 3.14 - 3.07 (m, 3H), 3.02 - 2.94 (m, 1H), 2.74 - 2.69 (m, 2H), 2.64 - 2.54 (m, 1H), 2.32 - 2.23 (m, 1H), 1.99 - 1.91 (m, 2H). LC/MS (ESI) (m/z): 460 (M+H)⁺. RT (Method A): 1.21 min. The following compounds were prepared based on the procedures set forth above. Scheme 19. Synthesis of (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-((4,5,6,7-tetrahydro-thieno[3,2- c]pyridin-2-yl)methyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 57) To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxylic acid (35 mg, 0.11 mmol) and tert-butyl 2-(aminomethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxylate (45 mg, 0.17 mmol) in DMF (3 mL) was added DIPEA (87 mg, 0.67 mmol) and HATU (47 mg, 0.12 mmol) under N2 atmosphere, and the mixture was stirred at room temperature for an hour. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (50 mg, yield 79.4%) as a white solid. LC/MS (ESI) m/z: 564 (M+H)⁺. Step 2: (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-((4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methyl)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 57) To a solution of tert-butyl (S)-2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (50 mg, 0.089 mmol) in DCM (2 mL) was added HCl/1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (C18, 40 - 90% MeCN in water with 0.1% NH3.H2O) to give Compound 57 (5.0 mg, yield 12.1%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 7.26 (t, J = 7.4 Hz, 2H), 7.20 (d, J = 7.1 Hz, 2H), 7.16 (t, J = 7.1 Hz, 1H), 6.95 (s, 1H), 6.72 (s, 1H), 5.07 - 5.01 (m, 1H), 4.56 - 4.44 (m, 2H), 3.93 (s, 2H), 3.25 - 3.20 (m, 2H), 3.13 - 3.06 (m, 3H), 2.98 - 2.91 (m, 1H), 2.88 (t, J = 5.1 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.59 - 2.49 (m, 1H), 2.25 - 2.17 (m, 1H), 1.98 - 1.91 (m, 2H). LC/MS (ESI) m/z: 464 (M+H)⁺. RT (Method A): 1.18 min. Compound 58 was prepared according to the procedures set forth above using (S)-4-oxo-3-((3- phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid as the starting material. ¹H NMR (400 MHz, CD3OD) δ 7.27 - 7.14 (m, 5H), 6.95 (s, 1H), 6.71 (s, 1H), 5.03 (dd, J = 9.4, 2.9 Hz, 1H), 4.56 - 4.43 (m, 2H), 3.96 (s, 2H), 3.11 - 3.05 (m, 5H), 2.98 - 2.91 (m, 1H), 2.74 - 2.69 (m, 2H), 2.68 - 2.63 (m, 2H), 2.59 - 2.48 (m, 1H), 2.25 - 2.16 (m, 1H), 1.98 - 1.90 (m, 2H). LC/MS (ESI) m/z: 464 (M+H)⁺. RT (Method A): 1.16 min. Compound 371 was prepared based on the procedures set forth above using tert-butyl (2- (aminomethyl)thieno[2,3-d]pyridazin-4-yl)carbamate as the starting material and T3P in place of HATU in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 9.60 (t, J = 5.9 Hz, 1H), 9.12 (s, 1H), 9.00 (s, 1H), 8.80 (s, 1H), 8.12 - 8.10 (m, 2H), 8.03 (s, 1H), 7.68 - 7.59 (m, 4H), 5.21 - 5.18 (m, 1H), 4.92 - 4.88 (m, 1H), 4.75 - 4.73 (m, 2H), 3.56 (s, 3H), 2.62 - 2.58 (m, 1H), 2.47 - 2.43 (m, 1H). LC/MS (ESI) m/z: 576 (M+H)⁺. RT (Method A): 1.36 min. Scheme 20. Synthesis of (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-((4,5,6,7-tetrahydro-pyrazolo[1,5- c]pyrimidin-2-yl)methyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 65) To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxylic acid (45 mg, 0.14 mmol) in MeCN (0.8 mL) was added tert-butyl 2-(aminomethyl)-4,5- dihydropyrazolo[1,5-c]pyrimidine-6(7H)-carboxylate (40 mg, 0.16 mmol), NMI (34 mg, 0.42 mmol), and TCFH (78 mg, 0.28 mmol), and the mixture was stirred at room temperature for 20 minutes. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 9% MeOH in DCM) to give the title compound (30 mg, yield 39.2%) as a white solid. Step 2: (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-((4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidin-2-yl)methyl)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 65) A solution of tert-butyl (S)-2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)-4,5-dihydropyrazolo[1,5-c]pyrimidine-6(7H)-carboxylate (30 mg, 0.055 mmol) in HCl/1,4-dioxane (2 mL, 4 M) was stirred under N₂ atmosphere at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep- HPLC (C18, 20% - 100% MeCN in water with 0.1% NH3.H2O) to give Compound 65 (8 mg, yield 32.5%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 7.28 - 7.24 (m, 2H), 7.20 (d, J = 6.9 Hz, 2H), 7.16 (t, J = 6.9 Hz, 1H), 6.95 (s, 1H), 6.06 (s, 1H), 5.08 - 5.04 (m, 1H), 4.90 (s, 2H), 4.36 (d, J = 1.5 Hz, 2H), 3.18 - 3.12 (m, 1H), 3.10 (d, J = 2.3 Hz, 2H), 3.08 (d, J = 5.8 Hz, 2H), 2.98 - 2.92 (m, 1H), 2.82 (d, J = 6.0 Hz, 2H), 2.71 (d, J = 7.7 Hz, 2H), 2.58 - 2.52 (m, 1H), 2.26 - 2.21 (m, 1H), 1.94 (d, J = 7.2 Hz, 2H). LC/MS (ESI) m/z: 448 (M+H)⁺. RT (Method A): 1.15 min. The following compounds were prepared based on the procedures set forth above. ^a Step 2 was performed with TFA in DCM. Scheme 21. Synthesis of (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-(pyrazolo[1,5-a]pyrazin-2- ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 73) To a solution of ethyl 1H-pyrazole-3-carboxylate (15 g, 107.14 mmol) in MeCN (120 mL) was added Cs2CO3 (52.36 g, 160.71 mmol), followed by a solution of 2-bromo-1,1-diethoxyethane (22.16 g, 112.50 mmol) in MeCN (40 mL), and the reaction mixture was stirred at 82 °C overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 17% EtOAc in PE) to give the title compound (18.7 g, yield 65.8%) as a light-yellow oil.¹H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.3 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 4.75 (t, J = 5.5 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.24 (d, J = 5.5 Hz, 2H), 3.71 - 3.63 (m, 2H), 3.42 - 3.34 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.0 Hz, 6H). LC/MS (ESI) m/z: 257 (M+H)⁺. Step 2: Ethyl 1-(2,2-diethoxyethyl)-5-formyl-1H-pyrazole-3-carboxylate To a solution of ethyl 1-(2,2-diethoxyethyl)-1H-pyrazole-3-carboxylate (18.70 g, 73.05 mmol) in THF (150 mL) was added LDA (54.80 mL, 109.58 mmol, 2.0 M in hexane) dropwise at -78 °C under N₂ atmosphere, and the mixture was stirred under N₂ atmosphere at -78 °C for 30 minutes. Subsequently, a solution of DMF (9.60 g, 131.49 mmol) in THF (20 mL) was added dropwise to the above mixture at -78 °C, and the resulting mixture was stirred under N2 atmosphere at room temperature overnight. The mixture was quenched with saturated aq. NH₄Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 14% EtOAc in PE) to give the title compound (1.25 g, yield 6.0%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 9.92 (s, 1H), 7.39 (s, 1H), 4.85 (t, J = 5.7 Hz, 1H), 4.72 (d, J = 5.7 Hz, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.73 - 3.66 (m, 2H), 3.48 - 3.41 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.0 Hz, 6H). Step 3: Ethyl pyrazolo[1,5-a]pyrazine-2-carboxylate A solution of ethyl 1-(2,2-diethoxyethyl)-5-formyl-1H-pyrazole-3-carboxylate (1.25 g, 4.40 mmol) in 2-methyltetrahydrofuran (2.5 mL), TFA (5 mL) and water (2.5 mL) was added stirred at 40 °C for 3 hours. The mixture was concentrated under reduced pressure and evaporated with toluene three times. The residue was dissolved in EtOH (10 mL) and AcOH (798 mg, 13.30 mmol), then NH4OAc (1.02 g, 13.30 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in 2-methyltetrahydrofuran (24 mL) and water (24 mL), and the mixture was stirred at room temperature for 0.5 hour. The mixture was neutralized with K2CO3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 45% EtOAc in PE) to give the title compound (800 mg, yield 95.2%) as a yellow solid.¹H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 4.1 Hz, 1H), 8.31 (t, J = 4.4 Hz, 1H), 7.84 (t, J = 5.1 Hz, 1H), 7.20 (d, J = 4.7 Hz, 1H), 4.37 - 4.28 (m, 2H), 1.34 - 1.26 (m, 3H). LC/MS (ESI) m/z: 192 (M+H)⁺. Step 4: Pyrazolo[1,5-a]pyrazine-2-carboxylic acid To a solution of ethyl pyrazolo[1,5-a]pyrazine-2-carboxylate (800 mg, 4.19 mmol) in MeCN (16 mL) and water (8 mL) was added TBD (1.16 g, 8.37 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (680 mg, yield 99.6%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 164 (M+H)⁺. Step 5: N-Methoxy-N-methylpyrazolo[1,5-a]pyrazine-2-carboxamide To a mixture of pyrazolo[1,5-a]pyrazine-2-carboxylic acid (680 mg, 4.17 mmol) and N,O- dimethylhydroxylamine hydrochloride (808 mg, 8.34 mmol) in DMF (10 mL) was added DIPEA (2.15 g, 16.67 mmol) and HATU (2.06g, 5.42 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 2% MeOH in DCM) to give the title compound (300 mg, yield 34.9%) as a light-yellow oil.¹H NMR (400 MHz, CDCl₃) δ 9.12 (d, J = 1.3 Hz, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.95 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 0.6 Hz, 1H), 3.80 (s, 3H), 3.49 (s, 3H).LC/MS (ESI) m/z: 207 (M+H)⁺. Step 6: Pyrazolo[1,5-a]pyrazine-2-carbaldehyde To a solution of N-methoxy-N-methylpyrazolo[1,5-a]pyrazine-2-carboxamide (300 mg, 1.45 mmol) in THF (6 mL) was added DIBAL-H (1.6 mL, 2.40 mmol, 1.5 M in THF) dropwise at -60 °C under N₂ atmosphere, and the mixture was stirred under N2 atmosphere at -60 °C for 4 hours. The mixture was quenched with saturated aq. potassium sodium tartrate solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (100 mg, yield 46.7%) as a white solid.¹H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 9.19 (d, J = 1.3 Hz, 1H), 8.45 - 8.39 (m, 1H), 8.03 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 0.7 Hz, 1H). Step 7: (R,Z)-2-Methyl-N-(pyrazolo[1,5-a]pyrazin-2-ylmethylene)propane-2-sulfinamide To a mixture of pyrazolo[1,5-a]pyrazine-2-carbaldehyde (100 mg, 0.68 mmol) and (R)-2- methylpropane-2-sulfinamide (166 mg, 1.37 mmol) in THF (4 mL) was added Ti(OEt)₄ (465 g, 2.04 mmol) under N₂ atmosphere, and the reaction mixture was stirred at 60 °C for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (138 mg, yield 81.2%) as a yellow oil. LC/MS (ESI) m/z: 251 (M+H)⁺. Step 8: (R)-2-Methyl-N-(pyrazolo[1,5-a]pyrazin-2-ylmethyl)propane-2-sulfinamide (9) To a solution of (R,Z)-2-methyl-N-(pyrazolo[1,5-a]pyrazin-2-ylmethylene)propane-2-sulfinamide (100 mg, 0.40 mmol) in THF (6 mL) was added DIBAL-H (0.44 mL, 0.60 mmol, 1.5 M in THF) dropwise under N₂ atmosphere at -60 °C, and the mixture was stirred under N₂ atmosphere at -60 °C for 1 hour. The mixture was quenched with saturated aq. potassium sodium tartrate solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure and then purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (50 mg, yield 49.6%) as a yellow oil. LC/MS (ESI) m/z: 253 (M+H)⁺. Step 9: Pyrazolo[1,5-a]pyrazin-2-ylmethanamine hydrochloride (10) To a solution of (R)-2-methyl-N-(pyrazolo[1,5-a]pyrazin-2-ylmethyl)propane-2-sulfinamide (50 mg, 0.20 mmol) in DCM (3 mL) was added HCl/1,4-dioxane (1 mL, 4 M), and the reaction mixture was stirred under N2 atmosphere at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (36 mg, yield 98.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 149 (M+H)⁺. Step 10: (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-(pyrazolo[1,5-a]pyrazin-2-ylmethyl) -4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 73) To a mixture of pyrazolo[1,5-a]pyrazin-2-ylmethanamine hydrochloride (18 mg, 0.098 mmol) and (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (15 mg, 0.048 mmol) in MeCN (1 mL) was added NMI (12 mg, 0.15 mmol) and TCFH (40 mg, 0.14 mmol) at 0 °C, and the mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated, and the residue was purified by prep-HPLC (C₁₈, 20% - 98% MeCN in water with 0.1% NH₃.H₂O) to give Compound 73 (3.2 mg, yield 15.2%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 9.04 (d, J = 1.4 Hz, 1H), 8.53 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 4.8 Hz, 1H), 7.28 - 7.23 (m, 2H), 7.21 - 7.15 (m, 3H), 6.96 (d, J = 5.7 Hz, 2H), 5.14 - 5.09 (m, 1H), 4.68 (d, J = 6.2 Hz, 2H), 3.17 - 3.12 (m, 1H), 3.09 (t, J = 6.9 Hz, 2H), 3.01 - 2.93 (m, 1H), 2.71 (t, J = 7.6 Hz, 2H), 2.62 - 2.55 (m, 1H), 2.33 - 2.26 (m, 1H), 1.96 - 1.92 (m, 2H). LC/MS (ESI) (m/z): 444 (M+H)⁺. RT (Method A): 1.44 min. Scheme 22. Synthesis of (S)-4-Oxo-3-(5-phenylthiophene-2-carboxamido)-N-(thieno[3,2-c]pyridin- 2-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 82) To a mixture of methyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.23 mmol) and 5-phenylthiophene-2-carboxylic acid (97 mg, 0.48 mmol) in MeCN (2 mL) was added was added TCFH (200 mg, 0.72 mmol) and NMI (58 mg, 0.72 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30 - 60% EtOAc in PE) to give the title compound (25 mg, yield 26.4%) as a white solid. LC/MS (ESI) m/z: 396 (M+H)⁺. Step 2: (S)-4-Oxo-3-(5-phenylthiophene-2-carboxamido)-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxylic acid To a mixture of methyl (S)-4-oxo-3-(5-phenylthiophene-2-carboxamido)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylate (25 mg, 0.06 mmol) in MeCN/water (2 mL, v/v= 1/1) was added TBD (26 mg, 0.19 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (20 mg, yield 83.3%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 382 (M+H)⁺. Step 3: (S)-4-Oxo-3-(5-phenylthiophene-2-carboxamido)-N-(thieno[3,2-c]pyridin-2-yl-methyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 82) To a solution of (S)-4-oxo-3-(5-phenylthiophene-2-carboxamido)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxylic acid (20 mg, 0.05 mmol) in DMF (1 mL) was added thieno[3,2-c]pyridin-2- ylmethanamine (17 mg, 0.1 mmol), HATU (23 mg, 0.06 mmol), and DIPEA (20 mg, 0.15 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (C₁₈, 40% - 60% MeCN in water with 0.1% NH3.H2O) to give Compound 82 (8 mg, yield 28.9%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.98 (s, 1H), 8.79 (s, 1H), 8.31 (d, J = 5.7 Hz, 1H), 7.93 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.73 - 7.70 (m, 2H), 7.50 (s, 1H), 7.47 - 7.42 (m, 3H), 7.39 - 7.35 (m, 1H), 5.20 - 5.16 (m, 1H), 4.76 - 4.74 (m, 2H), 3.27 - 3.23 (m, 1H), 3.16 - 3.10 (m, 1H), 2.72 - 2.63 (m, 1H), 2.37 - 2.30 (m, 1H). LC/MS (ESI) m/z: 528 (M+H)⁺. RT (Method A): 1.38 min. The following compounds were prepared according to the methods set forth above.

^a Step 2 was performed with LiOH in THF/H2O. ^b Step 2 was performed with LiOH in MeOH/H2O. ^c T3P was used in place of HATU in Step 3. Scheme 23. Synthesis of (S)-4-Oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-N-(thieno[3,2-c]pyridin- 2-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 84) To a mixture of methyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.24 mmol) and 2-phenyloxazole-5-carbaldehyde (125 mg, 0.72 mmol) in MeOH (5 mL) was added MgSO₄ (287 mg, 2.38 mmol) and NaBH₃CN (44 mg, 0.71 mmol) under N₂ atmosphere, and the reaction mixture was stirred under N2 atmosphere at 50 °C for 2 hours. The mixture was filtered, and the filtrate was diluted with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (70 mg, yield 79.9%) as a colorless oil. LC/MS (ESI) m/z: 367 (M+H)⁺. Step 2: (S)-4-Oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carboxylic acid To a solution of methyl (S)-4-oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylate (70 mg, 0.19 mmol) in MeOH/water (2 mL, v/v= 4/1) was added LiOH (14 mg, 0.58 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (60 mg, yield 89.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 353 (M+H)⁺. Step 3: (S)-4-Oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-N-(thieno[3,2-c]pyridin-2-yl-methyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 84) To a mixture of (S)-4-oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxylic acid (40 mg, 0.11 mmol) and thieno[3,2-c]pyridin-2-ylmethanamine hydrochloride (28 mg, 0.17 mmol) in DMF (2 mL) was added DIPEA (71 mg, 0.55 mmol) and HATU (50 mg, 0.13 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (C18, 40 - 60% MeCN in water with 0.1% NH_3.H₂O) to give the Compound 84 (5.6 mg, yield 9.8%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.15 (t, J = 5.8 Hz, 1H), 9.04 (d, J = 0.8 Hz, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.94 - 7.91 (m, 2H), 7.53 - 7.50 (m, 3H), 7.47 (s, 1H), 7.21 (d, J = 3.6 Hz, 2H), 5.79 (t, J = 6.4 Hz, 1H), 5.01 - 4.98 (m, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.43 (d, J = 6.3 Hz, 2H), 3.00 - 2.92 (m, 1H), 2.89 - 2.84 (m, 1H), 2.49 - 2.43 (m, 1H), 2.10 - 2.04 (m, 1H). LC/MS (ESI) m/z: 499 (M+H)⁺. RT (Method A): 0.93 min. The following compounds were prepared according to the methods set forth above.

^a Step 2 was performed with TBD in MeCN/H2O. Scheme 24. Synthesis of (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluoro-phenyl)-1H- pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 91) Step 1: (E)-N-((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methylene)-2-methylpropane-2-sulfinamide To a mixture of 1-(2-fluorophenyl)-1H-pyrazole-4-carbaldehyde (450 mg, 2.37 mmol) and 2- methylpropane-2-sulfinamide (717 mg, 5.92 mmol) in THF (10 mL) was added Ti(OEt)4 (2.16 g, 9.48 mmol) under N2 atmosphere at room temperature, the reaction solution was stirred at 90 °C overnight. The mixture was quenched with saturated aq. NH₄Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 50 - 100% EtOAc in PE) to give the title compound (600 mg, yield 86.3%) as a colorless oil. LC/MS (ESI) m/z: 294 (M+H)⁺. Step 2: N-((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)-2-methylpropane-2-sulfinamide To a mixture of (E)-N-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methylene)-2-methylpropane-2- sulfinamide (250 mg, 0.85 mmol) in MeOH (5.0 mL) was added NaBH4 (76 mg, 2.0 mmol) under N2 atmosphere at room temperature, the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 50 - 100% EtOAc in PE) to give the title compound (211 mg, yield 84.0%) as a colorless oil. LC/MS (ESI) m/z: 296 (M+H)⁺. Step 3: (1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methanamine hydrochloride To a solution of N-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2-methylpropane-2-sulfinamide (211 mg, 0.71 mmol) in DCM (2.5 mL) was added HCl/1,4-dioxane (0.5 mL, 4 M) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered. The solid was dried under vacuum to give the title compound (130 mg, yield 80.4%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 192 (M+H)⁺. Step 4: 1-(tert-Butyl) 2-methyl (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (5.0 g, 20.55 mmol) in THF (50 mL) was added lithium triethylborohydride (41 mL, 41.0 mmol, 1M in THF) dropwise at -78 °C under N2 atmosphere and the mixture was stirred under N2 atmosphere at -78 °C for 3 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 20 - 60% EtOAc in PE) to give the title compound (3.2 g, yield 63.5%) as a colorless oil. Step 5: 1-(tert-Butyl) 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-methyl (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate (3.2 g, 13.05 mmol) in MeOH (32.0 mL) was added PTSA (2.25 g, 13.05 mmol) under N2 atmosphere at room temperature, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with saturated aq. NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (2.5 g, yield 73.9%) as a colorless oil. Step 6: 1-(tert-Butyl) 2-methyl (2S)-5-cyanopyrrolidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate (1.5 g, 5.78 mmol) and TMSCN (1.15 g, 11.56 mmol) in DCM (15 mL) was added BF3.Et2O (7.7 mL, 11.56 mmol) dropwise under N₂ atmosphere at -10 °C, the reaction solution was stirred at this temperature for 3 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 20 - 50% EtOAc in PE) to give the title compound (1.08 g, yield 73.5%) as a colorless oil. Step 7: Methyl (2S)-5-cyanopyrrolidine-2-carboxylate 2,2,2-trifluoroacetate To a solution of 1-(tert-butyl) 2-methyl (2S)-5-cyanopyrrolidine-1,2-dicarboxylate (900 mg, 3.54 mmol) in DCM (9 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give the title compound (938 mg, yield 98.8%) as a white solid, which was used directly in the next reaction without further purification. Step 8: Methyl (S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a mixture of methyl (2S)-5-cyanopyrrolidine-2-carboxylate 2,2,2-trifluoroacetate (900 mg, 3.36 mmol) in toluene (10 mL) was added oxalyl chloride (640 mg, 5.04 mmol) dropwise under N₂ atmosphere at room temperature, and the mixture was stirred at 85 °C for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40 - 100% EtOAc in PE) to give the title compound (280 mg, yield 31.7%) as a white solid. LC/MS (ESI) m/z: 263 (M+H)⁺. Step 9: Methyl (S)-1-chloro-3-(((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a mixture of methyl (S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxylate (200 mg, 0.76 mmol) and (1-(2-fluorophenyl)-1H-pyrazol-4-yl)methanamine hydrochloride (130 mg, 0.57 mmol) in DMF (2.0 mL) was added K2CO3 (210 mg, 1.52 mmol) under N2 atmosphere at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the title compound (150 mg, yield 47.2%) as a white solid. LC/MS (ESI) m/z: 418 (M+H)⁺. Step 10: Methyl (S)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a mixture of methyl (S)-1-chloro-3-(((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (130 mg, 0.31 mmol) in EtOH (2.0 mL) was added Pd/C (13 mg, 10% wt.). The mixture was degassed under N₂ atmosphere for three times and stirred under a H2 balloon at room temperature overnight. The mixture was filtered, and concentrated under reduced pressure to give the title compound (87 mg, yield 73.2%) as a yellow solid. LC/MS (ESI) m/z: 384 (M+H)⁺. Step 11: (S)-3-(((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetra-hydropyrrolo[1,2- a]pyrazine-6-carboxylic acid To a mixture of methyl (S)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (85 mg, 0.22 mmol) in MeOH (0.5 mL) and water (0.5 mL) was added LiOH.H2O (28 mg, 0.67 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was acidified with 1N aq. HCl to pH 4 and extracted with EtOAc twice. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (75 mg, yield 92.3%) as a white solid. LC/MS (ESI) m/z: 370 (M+H)⁺. Step 12: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4- yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Compound 91) To a mixture of (S)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid (25 mg, 0.068 mmol) and (1H-pyrrolo-[3,2-c]pyridin-2- yl)methanamine hydrochloride (30 mg, 0.14 mmol) in DMF (1 mL) was added HATU (27 mg, 0.07 mmol) and DIPEA (26 mg, 0.2 mmol) under N₂ atmosphere, and the mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) and further purified by prep-HPLC (C18, 40 - 98% MeCN in water with 0.1% NH3.H2O) to give Compound 91 (5.1 mg, yield 15.3%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H), 8.09 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.41 - 7.35 (m, 2H), 7.35 - 7.28 (m, 2H), 6.89 (s, 1H), 6.56 (s, 1H), 5.06 - 5.03 (m, 1H), 4.72 - 4.67 (m, 1H), 4.58 - 4.54 (m, 1H), 4.54 - 4.51 (m, 2H), 3.16 - 3.08 (m, 1H), 3.05 - 2.97 (m, 1H), 2.56 - 2.46 (m, 1H), 2.33 - 2.26 (m, 1H). LC/MS (ESI) m/z: 499 (M+H)⁺. RT (Method A): 0.98 min. Scheme 25. Synthesis of (S)-N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H- pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Comp Step 1: 1-Ethylpyrrolo[3,2-c]pyridine 1H-Pyrrolo[3,2-c]pyridine (1000 mg, 8.46 mmol) and 2-methyltetrahydrofuran (20 mL) were combined and cooled to 0 °C in a brine/ice bath. NaH (500 mg, 12.5011 mmol) was added, and the resulting mixture was stirred for 30 minutes at 0 °C. Iodoethane (0.800 mL, 9.98 mmol) was then added. After 2 hours at 0 °C, the mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 0-20% MeOH in DCM) afforded the title compound (500 mg, 3.42 mmol, 40% yield) as a brown solid. LC/MS: (ESI+) m/z = 147 [M+H]⁺. Step 2: 1-Ethylpyrrolo[3,2-c]pyridine-2-carbaldehyde 1-Ethylpyrrolo[3,2-c]pyridine (500 mg, 3.42 mmol), THF (15 mL), and TMEDA (0.550 mL, 3.67 mmol) were combined and cooled to -78 ˚C in a dry ice/acetone bath. LDA (2.0M in THF/heptane/ethylbenzene; 2.1 mL, 4.2 mmol) was then added dropwise, and the resulting mixture was stirred for 1 hour at -78 °C. DMF (0.600 mL) was then added dropwise at -78 °C, and the mixture was warmed to 0 °C in a brine/ice bath. After stirring for 1 hour at 0 °C, the mixture was quenched with water (~10 mL). The mixture was then extracted with EtOAc (2 x 50 mL). The combined organic extracts were then washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (468 mg, 2.69 mmol, 79% yield) as a red oil. LC/MS: (ESI+) m/z = 175 [M+H]⁺. Step 3: (NE,R)-N-[(1-Ethylpyrrolo[3,2-c]pyridin-2-yl)methylene]-2-methyl-propane-2-sulfinamide 1-Ethylpyrrolo[3,2-c]pyridine-2-carbaldehyde (468 mg, 2.69 mmol), THF (10 mL), (R)-2- methylpropane-2-sulfinamide (650 mg, 5.36 mmol), and Ti(OEt)₄ (1.35 mL, 5.43 mmol) were combined and heated to 70 °C for 18 hours. Afterwards, the mixture was cooled to room temperature, decanted into brine, and filtered. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica 24g, 0-30% methanol in DCM) afforded the title compound (750 mg, 2.7 mmol, 100% Yield) as an orange oil. LC/MS: (ESI+) m/z = 278 [M+H]⁺. Step 4: (R)-N-[(1-Ethylpyrrolo[3,2-c]pyridin-2-yl)methyl]-2-methyl-propane-2-sulfinamide (NE,R)-N-[(1-Ethylpyrrolo[3,2-c]pyridin-2-yl)methylene]-2-methyl-propane-2-sulfinamide (430 mg, 1.550 mmol), MeOH (10 mL), and NaBH4 (150 mg, 3.96 mmol) were combined at 0 °C, and the mixture was allowed to warm to room temperature and stir for 1 hour. Afterwards, the mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (275 mg, 0.98 mmol, 37% yield) as an orange oil, which was used without further purification. LC/MS: (ESI+) m/z = 280 [M+H]⁺. Step 5. (1-Ethylpyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride (R)-N-[(1-Ethylpyrrolo[3,2-c]pyridin-2-yl)methyl]-2-methyl-propane-2-sulfinamide (275 mg, 0.98 mmol) and HCl (4.0M in dioxane; 3 mL, 12 mmol) were combined at room temperature, and the mixture was stirred for 1 hour. Afterwards, the mixture was concentrated in vacuo. The white solid was triturated with hexanes (3 x 5 mL) to afford the title compound (211 mg, 0.85 mmol, 86% yield) as a white solid. LC/MS: (ESI+) m/z = 176 [M+H]⁺. Step 6: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4- yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 98) A 20 mL vial was charged with (1-methylpyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride (44 mg, 0.132 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (50 mg, 0.135 mmol), DMF (2 mL), and TEA (0.100 mL, 0.753 mmol) and cooled to 0 °C in a brine/ice bath. HATU (75 mg, 0.19725 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was diluted in EtOAc (50 mL), washed with saturated NaHCO3 (20 mL), followed by LiOH solution (0.5% w/v, 2 x 15 mL) and brine (50 mL). The organic layer was then dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 98 (32 mg, 46% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (t, J = 5.4 Hz, 1H), 8.76 (s, 1H), 8.21 – 8.14 (m, 2H), 7.80 (d, J = 6.6 Hz, 1H), 7.76 (s, 1H), 7.47 (d, J = 6.3 Hz, 2H), 7.42 – 7.30 (m, 2H), 7.10 (s, 1H), 6.54 (s, 1H), 5.56 (t, J = 6.3 Hz, 1H), 5.01 (dd, J = 9.4, 2.5 Hz, 1H), 4.54 (qd, J = 15.9, 5.5 Hz, 2H), 4.25 – 4.12 (m, 4H), 3.02 – 2.90 (m, 1H), 2.89 – 2.78 (m, 1H), 2.48 – 2.41 (m, 1H), 2.13 – 1.99 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H). LC/MS: (ESI+) m/z = 527 [M+H]⁺. RT (Method A): 0.69 min. Scheme 26. Synthesis of (S)-3-(((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-N-((5-methyl- 5H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 99) Step 1: tert-Butyl ((5-methyl-5H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate Tert-Butyl ((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate (1000 mg, 4.05 mmol) and MeTHF (25 mL) were cooled to 4 °C in an ice bath. NaH (60% dispersion in mineral oil;250 mg, 6.08 mmol) was added followed by iodomethane (0.375 mL, 6 mmol), and the mixture was stirred for 2 hours at 4 °C. Afterwards, the reaction was slowly quenched by adding saturated NH4Cl solution (50 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 0-25% MeOH in DCM) afforded the title compound (350 mg, 32% yield) as a white solid. LC/MS: (ESI+) m/z = 262 [M+H]⁺. Step 2: (5-Methyl-5H-pyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride Tert-Butyl ((5-methyl-5H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate (350 mg, 1.3 mmol) was combined with HCl (4.0M in dioxane) and the mixture was stirred at room temperature for 1 hour. Afterwards, the mixture was concentrated in vacuo to afford the title compound as an off-white solid (250 mg, quant), which was carried forward without further purification. LC/MS: (ESI+) m/z = 162 [M+H]⁺. Step 3: (S)-3-(((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-N-((5-methyl-5H-pyrrolo[3,2-c]pyridin-2- yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 99) A 20 mL vial was charged with (5-methylpyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride (50 mg, 0.215 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (50 mg, 0.135 mmol), DMF (2 mL), and TEA (0.100 mL, 0.753 mmol) and cooled to 0 °C in a brine/ice bath. HATU (75 mg, 0.20 mmol) was then added, and the resulting mixture was stirred at 0 °C for 30 minutes. Afterwards, the mixture was diluted with EtOAc (50 mL), washed with saturated NaHCO₃ (20 mL) followed by LiOH solution (0.5% w/v, 2 x 15 mL) and brine (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 99 (36 mg, 52 % yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (t, J = 5.5 Hz, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 8.22 – 8.14 (m, 2H), 7.78 (d, J = 9.1 Hz, 2H), 7.49 – 7.36 (m, 2H), 7.36 – 7.29 (m, 1H), 7.11 (s, 1H), 6.75 (s, 1H), 5.51 (t, J = 6.2 Hz, 1H), 5.04 (dd, J = 9.4, 2.8 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 4.24 (s, 3H), 4.20 (d, J = 6.2 Hz, 2H), 2.99 – 2.89 (m, 1H), 2.88 – 2.77 (m, 1H), 2.48 – 2.40 (m, 1H), 2.09 (s, 1H). LC/MS: (ESI+) m/z = 513 [M+H]⁺. RT (Method A): 0.74 min. Scheme 27. Synthesis of (S)-4-Oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-N-(pyrrolo[1,2- a]pyrazin-7-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 101) To a mixture of methyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.24 mmol) and 2-phenyloxazole-5-carbaldehyde (82 mg, 0.48 mmol) in MeOH (3 mL) was added NaBH₃CN (75 mg, 1.20 mmol) and MgSO₄ (287 mg, 2.40 mmol) under N₂ atmosphere, and the reaction mixture was stirred at 50 °C for 2 hours. The mixture was filtered, and the filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 92% EtOAc in PE) to give the title compound (50 mg, yield 57.1%) as a white solid. LC/MS (ESI) m/z: 367 (M+H)⁺. Step 2: (S)-4-Oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxylic acid To a solution of methyl (S)-4-oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.14 mmol) in MeCN (3 mL) and water (1 mL) was added TBD (28 mg, 0.21 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give the title compound (45 mg, yield 83.3%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 353 (M+H)⁺. Step 3: (S)-4-Oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-N-(pyrrolo[1,2-a]pyrazin-7-yl-methyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 101) To a mixture of (S)-4-oxo-3-(((2-phenyloxazol-5-yl)methyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (45 mg, 0.13 mmol) and pyrrolo[1,2-a]pyrazin-7-ylmethanamine (23 mg, 0.17 mmol) in MeCN (3 mL) was added NMI (63 mg, 0.78 mmol) and TCFH (107 mg, 0.39 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (C₁₈, 10~95% MeCN in water with 0.1% NH3.H2O) to give Compound 101 (10 mg, yield 16.4%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.84 (t, J = 5.8 Hz, 1H), 8.75 (s, 1H), 8.22 - 8.20 (m, 1H), 7.94 - 7.91 (m, 2H), 7.67 (s, 1H), 7.53 - 7.50 (m, 3H), 7.43 (d, J = 4.8 Hz, 1H), 7.21 (d, J = 4.8 Hz, 2H), 6.73 (s, 1H), 5.77 (t, J = 6.4 Hz, 1H), 5.00 - 4.96 (m, 1H), 4.44 - 4.39 (m, 4H), 3.01 - 2.92 (m, 1H), 2.87 - 2.80 (m, 1H), 2.47 - 2.42 (m, 1H), 2.09 - 2.03 (m, 1H). LC/MS (ESI) m/z: 482 (M+H)⁺. RT (Method A): 0.83 min. Compound 103 was prepared according to the methods set forth above, using 1-(2- fluorophenyl)-1H-pyrazole-4-carbaldehyde as the aldehyde in Step 1.¹H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.12 - 8.06 (m, 2H), 7.76 (s, 1H), 7.75 - 7.72 (m, 1H), 7.69 (s, 1H), 7.45 - 7.37 (m, 1H), 7.37 - 7.30 (m, 3H), 7.14 (s, 1H), 6.89 (s, 1H), 5.16 - 5.03 (m, 1H), 4.61 - 4.48 (m, 2H), 4.32 (s, 2H), 3.17 - 3.10 (m, 1H), 2.99 - 2.92 (m, 1H), 2.63 - 2.53 (m, 1H), 2.28 - 2.21 (m, 1H). LC/MS (ESI) m/z: 499 (M+H)⁺. RT (Method A): 0.85 min. Scheme 28. Synthesis of (6S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-8-methoxy-4-oxo-3-(((2- phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 104) and (6S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-8-hydroxy-4-oxo-3-(((2- phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide To a mixture of methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (1.08 g, 3.95 mmol) in DMF (11 mL) was added Selectfluor (1.68 g, 4.75 mmol), and the mixture was stirred under N2 atmosphere at 90 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10 - 50% EtOAc in PE) to give the title compound (750 mg, yield 65.2%) as a light-yellow oil. LC/MS (ESI) m/z: 291 (M+H)⁺. Step 2: (6S)-3-Bromo-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (6S)-3-bromo-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylate (720 mg, 2.47 mmol) in MeCN/water (8 mL, v/v= 3/1) was added TBD (516 mg, 3.71 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (400 mg, yield 58.5%) as a yellow solid, which was used in the next step without further purification. LC/MS (ESI) m/z: 277 (M+H)⁺. Step 3: tert-Butyl (6S)-3-bromo-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of (6S)-3-bromo-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (300 mg, 1.08 mmol) and TEA (327 mg, 3.24 mmol) in DCM (3 mL) was added (Boc)₂O (706 mg, 3.24 mmol) under N₂ atmosphere, and the reaction mixture was stirred under N₂ atmosphere at room temperature overnight. The mixture was diluted water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10 - 50% EtOAc in PE) to give the title compound (60 mg, yield 16.7%) as a yellow solid. LC/MS (ESI) m/z: 333 (M+H)⁺. Step 4: tert-Butyl (6S)-8-fluoro-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of tert-butyl (6S)-3-bromo-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine- 6-carboxylate (60 mg, 0.18 mmol) and (2-phenyloxazol-4-yl)methanamine (42 mg, 0.24 mmol) in 1,4- dioxane (2 mL) was added K₂CO₃ (74 mg, 0.54 mmol), Brettphos (21 mg, 0.04 mmol), and Pd(OAc)₂ (5 mg, 0.02 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at 100 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30 - 75% EtOAc in PE) to give the title compound (10 mg, yield 13.0%) as a yellow oil. LC/MS (ESI) m/z: 427 (M+H)⁺. Step 5: (6S)-8-Methoxy-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid and (6S)-8-Hydroxy-4-oxo-3-(((2-phenyl-oxazol-4-yl)methyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of tert-butyl (6S)-8-fluoro-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (10 mg, 0.023 mmol) in MeOH/water (0.4 mL, v/v = 1/1) was added LiOH (4 mg, 0.1 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the mixture of (6S)-8-Methoxy-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid and (6S)-8-Hydroxy-4-oxo-3-(((2-phenyl-oxazol-4-yl)methyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (5 mg, yield 59.0%) as a white solid, which was used without further purification. LC/MS (ESI) m/z for (6S)-8-Methoxy-4-oxo-3-(((2-phenyloxazol-4- yl)methyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid: 383 (M+H)⁺, LC/MS (ESI) m/z for (6S)-8-Hydroxy-4-oxo-3-(((2-phenyl-oxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid: 369 (M+H)⁺. Step 6: (6S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-8-methoxy-4-oxo-3-(((2-phenyl-oxazol-4- yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 104) and (6S)-N- ((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-8-hydroxy-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8- tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamide (Compound 105) To a mixture of compound (6S)-8-Methoxy-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8- tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid and compound (6S)-8-Hydroxy-4-oxo-3-(((2-phenyl- oxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (5 mg, 0.013 mmol) and (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (17 mg, 0.026 mmol) in DMF (0.1 mL) was added DIPEA (13 mg, 0.1 mmol) and HATU (7 mg, 0.02 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (C₁₈, 5 - 95% MeCN in water with 0.01% NH_3.H₂O) to give Compound 104 (0.2 mg, yield 3.0%) and Compound 105 (0.7 mg, yield 10.8%) as white solids. Compound 104: ¹H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 8.15 (d, J = 6.2 Hz, 1H), 8.03 - 7.99 (m, 2H), 7.91 (s, 1H), 7.59 (d, J = 6.6 Hz, 1H), 7.52 - 7.49 (m, 3H), 7.30 (s, 1H), 6.73 (s, 1H), 5.36 - 5.33 (m, 1H), 5.14 - 5.11 (m, 2H), 4.77 - 4.76 (m, 2H), 3.50 (s, 3H), 3.49 - 3.48 (m, 1H), 2.65 - 2.57 (m, 1H), 2.57 - 2.42 (m, 1H). LC/MS (ESI) m/z: 512 (M+H)⁺. RT (Method A): 1.09 min. Compound 105: ¹H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.79 (s, 1H), 7.65 - 7.61 (m, 1H), 7.57 - 7.53 (m, 2H), 7.45 (d, J = 5.9 Hz, 1H), 6.57 (s, 1H), 5.17 - 5.14 (m, 1H), 4.78 (s, 2H), 4.58 (s, 2H), 4.55 - 4.50 (m, 1H), 2.70 - 2.62 (m, 1H), 2.39 - 2.30 (m, 1H). LC/MS (ESI) m/z: 498 (M+H)⁺. RT (Method A): 0.42 min. Scheme 29. Synthesis of (S)-3-(((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)amino)-4-oxo-N- (pyrrolo-[1,2-a]pyrazin-7-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound Step 1: Ethyl To a mixture of cyclopropanecarbohydrazide (3 g, 29.98 mmol) and TEA (9.1 g, 89.95 mmol) in DCM (50 mL) was added ethyl 2-chloro-2-oxoacetate (4.1 g, 29.98 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and then purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (5.3 g, yield 88.4%) as a colorless oil. LC/MS (ESI) m/z: 201 (M+H)⁺. Step 2: Ethyl 5-cyclopropyl-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 2-(2-(cyclopropanecarbonyl)hydrazineyl)-2-oxoacetate (5.3 g, 26.49 mmol) in THF (50 mL) was added Lawesson's Reagent (10.7 g, 26.49 mmol), and the reaction mixture was degassed under N2 atmosphere for three times and stirred at room temperature overnight. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (3.8 g, yield 72.4%) as a yellow oil. LC/MS (ESI) m/z: 199 (M+H)⁺. Step 3: (5-Cyclopropyl-1,3,4-thiadiazol-2-yl)methanol To a solution of ethyl 5-cyclopropyl-1,3,4-thiadiazole-2-carboxylate (3.8 g, 19.19 mmol) in EtOH (40 mL) was added NaBH4 (1.5 g, 38.37 mmol) in portions at 0 °C, and the reaction mixture was stirred under N₂ atmosphere at room temperature for 4 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (2.4 g, yield 80.2%) as a yellow oil, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 157 (M+H)⁺. Step 4: 5-Cyclopropyl-1,3,4-thiadiazole-2-carbaldehyde To a solution of (5-cyclopropyl-1,3,4-thiadiazol-2-yl)methanol (2.2 g, 14.10 mmol) in DCM (30 mL) was added DMP (9 g, 21.15 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with saturated aq. Na₂S₂O₃ solution, and the mixture was basified with saturated aq. NaHCO3 solution to pH 8 and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1 g, yield 46.1%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 2.52 - 2.46 (m, 1H), 1.41 - 1.36 (m, 2H), 1.31 - 1.28 (m, 2H). LC/MS (ESI) m/z: 155 (M+H)⁺. The 5-cyclopropyl-1,3,4-thiadiazole-2-carbaldehyde was used to prepare Compound 106 based on the procedures set forth in, e.g., Scheme 27.¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.09 (d, J = 4.9 Hz, 1H), 7.69 (s, 1H), 7.36 (d, J = 4.9 Hz, 1H), 7.09 (s, 1H), 6.89 (s, 1H), 5.10 - 5.06 (m, 1H), 4.70 (s, 2H), 4.63 - 4.58 (m, 1H), 4.52 - 4.48 (m, 1H), 3.18 - 3.09 (m, 1H), 3.00 - 2.92 (m, 1H), 2.61 - 2.53 (m, 1H), 2.42 - 2.37 (m, 1H), 2.28 - 2.21 (m, 1H), 1.25 - 1.21 (m, 2H), 1.03 - 1.00 (m, 2H). LC/MS (ESI) m/z: 463 (M+H)⁺. RT (Method A): 0.30 min. Scheme 30. Synthesis of (S)-3-(((5-Methyl-1,3,4-thiadiazol-2-yl)methyl)amino)-4-oxo-N-(thieno[3,2- c]pyridin-2-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 108) To a solution of ethyl 5-methyl-1,3,4-thiadiazole-2-carboxylate (400 mg, 2.32 mmol) in THF (5 mL) was added DIBAL-H (4.6 mL, 6.97 mmol, 1.5M) at -40 °C under N₂ atmosphere, and the reaction mixture was stirred at -40 °C for 2 hours. The mixture was quenched with saturated aq. NH4Cl solution and filtered. The filtrate was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by prep-TLC (PE: EtOAc= 1: 1) to give the title compound (70 mg, yield 23.6%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 10.16 (s, 1H), 2.89 (s, 3H). The 5-methyl-1,3,4-thiadiazole-2-carbaldehyde was used to prepare Compound 108 based on the procedures set forth in, e.g., Scheme 27.¹H NMR (400 MHz, CD3OD) δ 8.97 (d, J = 2.8 Hz, 1H), 8.34 - 8.30 (m, 1H), 7.95 - 7.91 (m, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 3.4 Hz, 1H), 5.11 (s, 1H), 4.73 (s, 2H), 4.61 - 4.56 (m, 2H), 3.15 - 3.09 (m, 1H), 3.00 - 2.97 (m, 1H), 2.72 (s, 3H), 2.62 - 2.56 (m, 1H), 2.30 - 2.24 (m, 1H). LC/MS (ESI) m/z: 454 (M+H)⁺. RT (Method A): 0.24 min. Compound 120 was prepared according to the procedures set forth above starting from Step 2, using 5-phenyl-1,3,4-thiadiazole-2-carbaldehyde as the starting material.¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.11 - 8.08 (m, 1H), 7.93 - 7.88 (m, 2H), 7.69 (s, 1H), 7.51 (t, J = 7.3 Hz, 3H), 7.36 (d, J = 4.9 Hz, 1H), 7.18 (s, 1H), 6.89 (s, 1H), 5.11 - 5.08 (m, 1H), 4.62 - 4.49 (m, 4H), 3.16 - 3.09 (m, 1H), 3.01 - 2.94 (m, 1H), 2.60 - 2.54 (m, 1H), 2.27 - 2.21 (m, 1H). LC/MS (ESI) m/z: 499 (M+H)⁺. RT (Method A): 0.78 min. Scheme 31. Synthesis of (S)-3-(((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-N-((1-methyl- 1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 109) Step 1: tert-Butyl ((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate Tert-Butyl N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)carbamate (500 mg, 2.02 mmol), 1,4-dioxane (10 mL), sodium tert-butoxide (250 mg, 2.6 mmol), and methyl p-toluenesulfonate (0.400 mL, 2.56 mmol) were combined at room temperature, and the mixture was stirred for 2 hours. Afterwards, the mixture was diluted in water (~50 mL) and extracted with EtOAc (3 x10 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 24g, 0-30% MeOH in DCM) afforded the title compound (65 mg, 12% Yield) as a colorless residue. LC/MS: (ESI+) m/z = 262 [M+H]⁺. Step 2: (1-Methylpyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride Tert-Butyl N-[(1-methylpyrrolo[3,2-c]pyridin-2-yl)methyl]carbamate (65 mg, 0.249 mmol) and HCl (4.0M in dioxane) were combined at room temperature, and the mixture was stirred for 1 hour. Afterwards, the mixture was concentrated in vacuo to afford the title compound (58 mg, 99% yield) as a white solid, which was used without further purification. LC/MS: (ESI+) m/z = 162 [M+H]⁺. Step 3: (S)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-N-((1-methyl-1H-pyrrolo[3,2-c]pyridin-2- yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 109) A 20 mL vial was charged with (1-methylpyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride (50 mg, 0.149 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (50 mg, 0.135 mmol), DMF (2 mL), and TEA (0.100 mL, 0.753 mmol) and cooled to 0 ˚C in a brine/ice bath. HATU (75 mg, 0.197 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was concentrated in vacuo at 55 °C to remove DMF. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 109 (34 mg, 49% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (t, J = 5.4 Hz, 1H), 8.76 (s, 1H), 8.19 (d, J = 5.9 Hz, 2H), 7.82 – 7.75 (m, 2H), 7.46 (d, J = 5.9 Hz, 2H), 7.44 – 7.29 (m, 2H), 7.11 (s, 1H), 6.56 (s, 1H), 5.55 (t, J = 6.2 Hz, 1H), 4.99 (dd, J = 9.3, 2.6 Hz, 1H), 4.62 (dd, J = 15.8, 5.9 Hz, 1H), 4.48 (dd, J = 15.8, 4.9 Hz, 1H), 4.20 (d, J = 6.2 Hz, 2H), 3.70 (s, 3H), 3.02 – 2.90 (m, 1H), 2.86 – 2.76 (m, 1H), 2.48 – 2.39 (m, 1H), 2.13 – 2.01 (m, 1H). LC/MS: (ESI+) m/z = 513 [M+H]⁺. RT (Method A): 0.61 min. Scheme 32. Synthesis of (S)-N-(Imidazo[1,2-c]pyrimidin-2-ylmethyl)-4-oxo-3-((3-phenyl- propyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 110) C^{ompound 110} Step 1: 2-(Chloromethyl)-5-(methylthio)imidazo[1,2-c]pyrimidine To a solution of 2-(methylthio)pyrimidin-4-amine (5.0 g, 35.5 mmol) in AcOH (8 mL) was added 1,3-dichloropropan-2-one (6.8 g, 53.2 mmol) and the reaction mixture was stirred under N2 atmosphere at 110 °C overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (230 mg, yield 3.0%) as a yellow oil. LC/MS (ESI) m/z: 214 (M+H)⁺. Step 2: 2-(Azidomethyl)-5-(methylthio)imidazo[1,2-c]pyrimidine To a solution of 2-(chloromethyl)-5-(methylthio)imidazo[1,2-c]pyrimidine (230 mg, 1.08 mmol) in DMF (2 mL) was added NaN3 (70 mg, 1.08 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (180 mg, yield 75.6%) as a yellow oil. LC/MS (ESI) m/z: 221 (M+H)⁺. Step 3: Imidazo[1,2-c]pyrimidin-2-ylmethanamine To a solution of 2-(azidomethyl)-5-(methylthio)imidazo[1,2-c]pyrimidine (150 mg, 0.68 mmol) in THF (2 mL) was added Pd/C ( 15 mg, 10% wt.) and triethylsilane (237 mg, 2.05 mmol), and the reaction mixture was stirred under N2 atmosphere at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (80 mg, yield 79.2%) as a colorless oil. LC/MS (ESI) m/z: 149 (M+H)⁺. Step 4: (S)-N-(Imidazo[1,2-c]pyrimidin-2-ylmethyl)-4-oxo-3-((3-phenylpropyl) amino) -4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 110) To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylic acid (10 mg, 0.03 mmol) and imidazo[1,2-c]pyrimidin-2-yl-methanamine (5.0 mg, 0.03 mmol) in MeCN (1 mL) was added TCFH (27 mg, 0.09 mmol) and NMI (7 mg, 0.08 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C18250 x 21 mm, 10 - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 110 (2.3 mg, yield 16.4%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 7.97 (s, 1H), 7.94 (d, J = 6.5 Hz, 1H), 7.48 (d, J = 6.5 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.21 - 7.14 (m, 3H), 6.97 (s, 1H), 5.13 - 5.09 (m, 1H), 4.67 - 4.62 (m, 1H), 4.58 - 4.52 (m, 1H), 3.20 - 3.13 (m, 1H), 3.11 - 3.08 (m, 2H), 3.02 - 2.94 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.63 - 2.55 (m, 1H), 2.35 - 2.28 (m, 1H), 1.98 - 1.93 (m, 2H). LC/MS (ESI) m/z: 444 (M+H)⁺. RT (Method A): 1.30 min. Scheme 33. Synthesis of (S)-3-(((5-Cyclopentyl-1,3,4-thiadiazol-2-yl)methyl)amino)-4-oxo-N- (thieno[3,2-c]pyridin-2-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide To a solution of ethyl cyclopentanecarboxylate (2 g, 14 mmol) in EtOH (20 mL) was added N₂H₄.H₂O (30 mg, 0.16 mmol) under N₂ atmosphere and the reaction mixture was stirred at 50 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 6% MeOH in DCM) to give the title compound (1.75 g, yield 97.2%) as a yellow oil. LC/MS (ESI) m/z: 129 (M+H)⁺. Step 2: Ethyl 2-(2-(cyclopentanecarbonyl)hydrazineyl)-2-oxoacetate To a solution of cyclopentanecarbohydrazide (1.7 g, 13.3 mmol) and ethyl 2-chloro-2-oxoacetate (1.77 g, 13.3 mmol) in DCM (30 mL) was added TEA (8 mL, 26.7 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (2.2 g, yield 72.6%) as a white solid. LC/MS (ESI) m/z: 229 (M+H)⁺. Step 3: Ethyl 5-cyclopentyl-1,3,4-thiadiazole-2-carboxylate To a mixture of ethyl 2-(2-(cyclopentanecarbonyl)hydrazineyl)-2-oxoacetate (900 mg, 3.94 mmol) in toluene (20 mL) was added Lawesson’s Reagent (3.19 g, 7.88 mmol) under N₂ atmosphere and the reaction mixture was stirred at 80 °C for 6 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (300 mg, yield 33.6%) as a white oil. LC/MS (ESI) m/z: 227 (M+H)⁺. Step 4: (5-Cyclopentyl-1,3,4-thiadiazol-2-yl)methanol To a solution of ethyl 5-cyclopentyl-1,3,4-thiadiazole-2-carboxylate (300 mg, 1.33 mmol) in MeOH (8 mL) was added NaBH4 (100 mg, 2.66 mmol) in portions at 0 °C, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by purified by prep-HPLC (YMC-Actus Triart C₁₈, 20~95 % MeOH in water with 0.1% NH_3.H₂O) to give the title compound (60 mg, yield 24.6%) as a yellow oil. LC/MS (ESI) m/z: 185 (M+H)⁺. Step 5: 5-Cyclopentyl-1,3,4-thiadiazole-2-carbaldehyde To a solution of (5-cyclopentyl-1,3,4-thiadiazol-2-yl)methanol (60 mg, 0.32 mmol) in DCM (3 mL) was added DMP (275 mg, 0.64 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aq. Na2S2O3 solution and extracted with EtOAc twice. The combined organic layers were washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (30 mg, yield 42.5%) as a colorless oil. LC/MS (ESI) m/z: 183 (M+H)⁺. The 5-cyclopentyl-1,3,4-thiadiazole-2-carbaldehyde was used to prepare Compound 111 based on the procedure set forth in, e.g., Scheme 27.¹H NMR (400 MHz, CD₃OD) δ 8.98 (s, 1H), 8.32 (d, J = 5.7 Hz, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.50 (s, 1H), 7.10 (s, 1H), 5.12 - 5.08 (m, 1H), 4.73 (s, 4H), 3.54 - 3.48 (m, 1H), 3.16 - 3.09 (m, 1H), 3.01 - 2.93 (m, 1H), 2.64 - 2.54 (m, 1H), 2.30 - 2.23 (m, 1H), 2.23 - 2.15 (m, 2H), 1.83 - 1.70 (m, 6H). LC/MS (ESI) m/z: 508 (M+H)⁺. RT (Method A): 0.86 min. Scheme 34. Synthesis of (S)-4-Oxo-3-(((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)amino)-N-(pyrrolo [1,2-a]pyrazin-7-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 113) Step1: Ethyl 2-(2-benzoylhydrazineyl)-2-oxoacetate To a mixture of benzohydrazide (1.0 g, 7.34 mmol) and TEA (1.4 g, 7.32 mmol) in DCM (10 mL) was added ethyl 2-chloro-2-oxoacetate (1.0 g, 7.34 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (1.48 g, yield 85.3%) as a yellow oil. LC/MS (ESI) m/z: 237 (M+H)⁺. Step 2: Ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate A solution of ethyl 2-(2-benzoylhydrazineyl)-2-oxoacetate (850 mg, 3.59 mmol) in POCl3 (10 mL) was stirred under N2 atmosphere at 70 °C overnight. The reaction the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (730 mg, yield 92.9%) as a yellow oil. LC/MS (ESI) m/z: 219 (M+H)⁺. Step 3: (5-Phenyl-1,3,4-oxadiazol-2-yl)methanol To a solution of ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (700 mg, 3.2 mmol) in MeOH (10 mL) was added NaBH4 (237 mg, 6.2 mmol) in portions at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (450 mg, yield 79.6 %) as a white solid. LC/MS (ESI) m/z: 177 (M+H)⁺. Step 4: 5-Phenyl-1,3,4-oxadiazole-2-carbaldehyde To a solution of (5-phenyl-1,3,4-oxadiazol-2-yl)methanol (450 mg, 2.5 mmol) in DCM (8 mL) was added DMP (2.1 g, 5.1 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2.5 hours. The mixture was filtered, and the filtrate was diluted with EtOAc, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 38% EtOAc in PE) to give the title compound (450 mg, yield 67.4 %) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 8.14 - 8.11 (m, 2H), 7.69 - 7.60 (m, 3H). The 5-phenyl-1,3,4-oxadiazole-2-carbaldehyde was used to prepare Compound 113 based on the procedures set forth in, e.g., Scheme 27.¹H NMR (400 MHz, CD₃OD) δ 8.68 - 8.65 (m, 1H), 8.10 - 8.06 (m, 1H), 8.03 - 7.97 (m, 2H), 7.71 - 7.67 (m, 1H), 7.59 - 7.51 (m, 3H), 7.35 (d, J = 4.9 Hz, 1H), 7.30 (s, 1H), 6.88 (s, 1H), 5.11 - 5.07 (m, 1H), 4.72 (s, 2H), 4.62 - 4.57 (m, 1H), 4.52 - 4.47 (m, 1H), 3.15 - 3.10 (m, 1H), 3.00 - 2.96 (m, 1H), 2.62 - 2.54 (m, 1H), 2.28 - 2.22 (m, 1H). LC/MS (ESI) m/z: 483 (M+H)⁺. RT (Method A): 0.62 min. Scheme 35. Synthesis of (S)-3-(((5-Methyl-1,3,4-thiadiazol-2-yl)methyl)amino)-4-oxo-N-(pyrrolo [1,2-a]pyrazin-7-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 114) Step 1: (5-Methyl-1,3,4-thiadiazol-2-yl)methanol To a solution of ethyl 5-methyl-1,3,4-thiadiazole-2-carboxylate (500 mg, 2.90 mmol) in MeOH (5 mL) was added NaBH₄ (440 mg, 11.57 mmol) in portions at 0 °C, and the reaction mixture was stirred under N₂ atmosphere at room temperature for 4 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (270 mg, yield 71.0%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 5.04 (s, 2H), 2.78 (s, 3H). LC/MS (ESI) m/z: 131 (M+H)⁺. Step 2: 5-methyl-1,3,4-thiadiazole-2-carbaldehyde To a solution of (5-methyl-1,3,4-thiadiazol-2-yl)methanol (200 mg, 1.53 mmol) in DCM (3 mL) was added DMP (978 mg, 2.3 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with saturated aq. Na2S2O3 solution, basified with saturated aq. NaHCO3 solution to pH 8 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (90.0 mg, yield 45.1%) as a yellow oil.¹H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 3.04 - 2.77 (m, 3H). The 5-methyl-1,3,4-thiadiazole-2-carbaldehyde was used to prepare Compound 114 based on the procedure set forth in, e.g., Scheme 27.¹H NMR (400 MHz, CH₃OD) δ 8.68 (s, 1H), 8.11 (d, J = 4.9 Hz, 1H), 7.70 (s, 1H), 7.37 (d, J = 4.9 Hz, 1H), 7.11 (s, 1H), 6.90 (s, 1H), 5.23 -5.02 (m, 1H), 4.74 (s, 2H), 4.63 - 4.42 (m, 2H), 3.21 - 3.05 (m, 1H), 3.02 - 2.91 (m, 1H), 2.72 (s, 3H), 2.65 - 2.50 (m, 1H), 2.36 - 2.15 (m, 1H). LC/MS (ESI) (m/z): 437 (M+H)⁺. RT (Method A): 0.21 min. Scheme 36. Synthesis of (S)-3-(((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)amino)-N-((1-methyl- 1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxamide (Compound 116) Step 1: tert-Butyl (S)-(6-(((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl) carbamate To a mixture of (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]- pyrimidine-6-carboxylic acid (40 mg, 0.14 mmol) and (1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (29 mg, 0.18 mmol) in DMF (10 mL) was added HATU (68 mg, 0.18 mmol), DIPEA (90 mg, 0.70 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was filtered, the filtrate was concentrated under reduced pressure then purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (20 mg, yield 32.6%) as a yellow solid. LC/MS (ESI) m/z: 439 (M+H)⁺. Step 2: (S)-3-Amino-N-((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-4,6,7, 8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide hydrochloride A solution of tert-butyl (S)-(6-(((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamate (20 mg, 0.046 mmol) in HCl/1,4-dioxane (1 mL, 4 M) was stirred at room temperature for 10 minutes. The mixture was filtered, and the solid was dried under vacuum to give the title compound (14 mg, yield 93.7%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 339 (M+H)⁺. Step 3: (S)-3-(((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)amino)-N-((1-methyl-1H-pyrrolo[3,2-c]pyridin-2- yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamide (Compound 116) To a mixture of (S)-3-amino-N-((1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide hydrochloride (16 mg, 0.043 mmol) and 5-cyclopropyl- 1,3,4-thiadiazole-2-carbaldehyde (14 mg, 0.089 mmol) in MeOH (1 mL) was added MgSO4 (10 mg, 0.089 mmol), NaBH3CN (5 mg, 0.067 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 116 (4 mg, yield 18.9%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.17 (d, J = 5.9 Hz, 1H), 7.44 (d, J = 6.0 Hz, 1H), 7.09 (s, 1H), 6.69 (s, 1H), 5.09 – 5.05 (m, 1H), 4.70 (s, 2H), 4.63 – 4.57 (d, m, 2H), 3.79 (s, 3H), 3.16 – 3.10 (m, 1H), 3.01 – 2.93 (m, 1H), 2.61 – 2.53 (m, 1H), 2.43 – 2.36 (m, 1H), 2.29 – 2.22 (m, 1H), 1.26 – 1.22 (m, 2H), 1.04 – 0.99 (m, 2H). LC/MS (ESI) m/z: 477 (M+H)⁺. RT (Method A): 0.34 min. Compound 119 was prepared according to the procedures set forth above, using thieno[3,2- c]pyridin-2-yl-methanamine as the amine in Step 1 and 3-(4-fluorophenoxy)propanal as the aldehyde in Step 3.¹H NMR (400 MHz, CD3OD) δ 8.96 (d, J = 0.6 Hz, 1H), 8.31 (d, J = 5.7 Hz, 1H), 7.91 (d, J = 5.7 Hz, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 6.98 – 6.94 (m, 2H), 6.93 – 6.90 (m, 2H), 5.11 – 5.08 (m, 1H), 4.73 (s, 2H), 4.58 (s, 2H), 4.08 – 4.05 (m, 2H), 3.18 – 3.10 (m, 1H), 3.01 – 2.94 (m, 1H), 2.63 – 2.54 (m, 1H), 2.31 – 2.24 (m, 1H), 2.11 – 2.06 (m, 2H). LC/MS (ESI) m/z: 494 (M+H)⁺. RT (Method A): 1.19 min. Scheme 37. Synthesis of (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-(thiazolo[4,5-c]pyridin-2- ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 117) Step 1: tert-Butyl (thiazolo[4,5-c]pyridin-2-ylmethyl)carbamate To a mixture of 4-iodopyridin-3-amine (1.6 g, 7.27 mmol) and tert-butyl (2-amino-2- thioxoethyl)carbamate (1.66 g, 8.72 mmol) in MeCN (15 mL) was added CaO (610 mg, 10.8 mmol), dppf (402 mg, 0.72 mmol), and Pd2(dba)3 (133 mg, 0.14 mmol) under N2 atmosphere, and the reaction mixture was degassed under N2 atmosphere for three times and stirred at 60 °C overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (780 mg, yield 40.4%) as a yellow oil. LC/MS (ESI) m/z: 266(M+H)⁺. Step 2: Thiazolo[4,5-c]pyridin-2-ylmethanamine hydrochloride To a solution of tert-butyl (thiazolo[4,5-c]pyridin-2-ylmethyl)carbamate (200 mg, 0.75 mmol) in DCM (2 mL) was added HCl/1,4-dioxane (1 mL, 4 M), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (150 mg, yield 98.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 166(M+H)⁺. Step 3: (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-(thiazolo[4,5-c]pyridin-2-ylmethyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 117) To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylic acid (15 mg, 0.048 mmol) and thiazolo[4,5-c]pyridin-2-yl-methanamine hydrochloride (15 mg, 0.074 mmol) in DMF (2 mL) was added DIPEA (31 mg, 0.24 mmol) and HATU (22 mg, 0.057 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20mm, 30-80% MeCN in water with 0.1% NH3.H2O) to give Compound 117 (5.1 mg, yield 23.1%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 9.15 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.08 - 8.05 (m, 1H), 7.27 - 7.23 (m, 2H), 7.21 - 7.14 (m, 3H), 6.96 (s, 1H), 5.18 - 5.14 (m, 1H), 4.89-4.87 (d, m 2H), 3.19 - 3.12 (m, 1H), 3.10 - 3.07 (m, 2H), 3.02 - 2.95 (m, 1H), 2.73 - 2.69 (m, 2H), 2.66 - 2.58 (m, 1H), 2.39 - 2.33 (m, 1H), 1.97 - 1.91 (m, 2H). LC/MS (ESI) m/z: 461 (M+H)⁺. RT (Method A): 1.39 min. Scheme 38. Synthesis of (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-4'-oxo-3'-(((2-phenyloxazol- 4-yl)methyl)amino)-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]-6'- carboxamide (Compound 121) and (R)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)-methyl)-4'-oxo-3'-(((2- phenyloxazol-4-yl)methyl)amino)-6',7'-dihydro-4'H-spiro-[cyclopropane-1,8'-pyrrolo[1,2- a]pyrimidine]-6'-carboxamide (Compound 122) Step 1: 6- Benzyl 5-(tert-butyl) (S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (5 g, 20.72 mmol) in DMF (50 mL) was added K₂CO₃ (5.52 g, 40.00 mmol) and benzyl bromide (3.54 g, 20.72 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (5 g, yield 73.0%) as a colorless oil. LC/MS (ESI) m/z: 332 (M+H)⁺. Step 2: 6-Benzyl 5-(tert-butyl) (S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate To a mixture of NaIO₄ (8.72 g, 40.76 mmol) and RuO₂ (250 mg, 1.88 mmol) in EtOAc (30 mL) and water (27 mL) was added a solution of 6-benzyl 5-(tert-butyl) (S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5 g, 15.10 mmol) dropwise at 0 °C. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0- 30% EtOAc in PE) to give the title compound (2.7 g, yield 51.7%) as a colorless oil. LC/MS (ESI) m/z: 346 (M+H)⁺. Step 3: Benzyl (S)-4-oxo-5-azaspiro[2.4]heptane-6-carboxylate To a solution of 6-benzyl 5-(tert-butyl) (S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.7 g, 7.80 mmol) in DCM (27 mL) was added HCl/1,4-dioxane (10 mL, 4 M) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (1.76 g, yield 91.7%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 246 (M+H)⁺. Step 4: Benzyl (S)-4-methoxy-5-azaspiro[2.4]hept-4-ene-6-carboxylate A solution of benzyl (S)-4-oxo-5-azaspiro[2.4]heptane-6-carboxylate (1.4 g, 5.69 mmol) in dimethyl sulfate (14 mL) was stirred at 60 °C overnight. After cooling down to room temperature, to the reaction was added TEA (2 mL) dropwise. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (520 mg, yield 35.2%) as a yellow oil. LC/MS (ESI) m/z: 260 (M+H)⁺. Step 5: Benzyl (S)-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a] pyrimidine]-6'- carboxylate To a solution of benzyl (S)-4-methoxy-5-azaspiro[2.4]hept-4-ene-6-carboxylate (480 mg, 1.85 mmol) in ethylbenzene (2 mL) was added 3-azatricyclo[4.2.1.0^2,5]non-7-en-4-one (625 mg, 4.63 mmol) and the mixture was stirred at 120 °C under N₂ atmosphere overnight. The reaction mixture was concentrated under reduced pressure. The residue was stirred at 150 °C under N₂ atmosphere for 8 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (500 mg, yield 91.1%) as a yellow oil. LC/MS (ESI) m/z: 297 (M+H)⁺. Step 6: Benzyl (S)-3'-bromo-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo [1,2-a]pyrimidine]-6'- carboxylate To a solution of benzyl (S)-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]- pyrimidine]-6'-carboxylate (460 mg, 1.55 mmol) in DMF (5 mL) was added NBS (331 mg, 1.86 mmol), and the mixture was stirred at 50 °C under N₂ atmosphere for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (85 mg, yield 14.6%) as a yellow oil. LC/MS (ESI) m/z: 375 (M+H)⁺. Step 7: Benzyl 4'-oxo-3'-(((2-phenyloxazol-4-yl)methyl)amino)-6',7'-dihydro-4'H-spiro-[cyclopropane-1,8'- pyrrolo[1,2-a]pyrimidine]-6'-carboxylate To a mixture of benzyl (S)-3'-bromo-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2- a]pyrimidine]-6'-carboxylate (85 mg, 0.23 mmol) and (2-phenyloxazol-4-yl)methanamine (59 mg, 0.34 mmol) in toluene (2 mL) was added Cs2CO3 (112 mg, 0.35 mmol), BrettPhos (24 mg, 0.043 mmol), and Pd2(dba)3 (39 mg, 0.043 mmol) under N2 atmosphere, and the reaction mixture was degassed under N2 atmosphere for three times and stirred at 90 °C for 3 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (38 mg, yield 35.2%) as a yellow oil. LC/MS (ESI) m/z: 469 (M+H)⁺. Step 8: 4'-Oxo-3'-(((2-phenyloxazol-4-yl)methyl)amino)-6',7'-dihydro-4'H-spiro-[cyclopropane-1,8'- pyrrolo[1,2-a]pyrimidine]-6'-carboxylic acid To a solution of benzyl 4'-oxo-3'-(((2-phenyloxazol-4-yl)methyl)amino)-6',7'-dihydro-4'H- spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]-6'-carboxylate (38 mg, 0.077 mmol) in MeOH/water (2 mL, 4/1) was added LiOH (4 mg, 0.15 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (25 mg, yield 86.2%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 379 (M+H)⁺. Step 9: (S)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-4'-oxo-3'-(((2-phenyloxazol-4-yl)-methyl)amino)-6',7'- dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a] pyrimidine]-6'-carboxamide (Compound 120) and (R)- N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-4'-oxo-3'-(((2-phenyloxazol-4-yl)methyl)amino)-6',7'-dihydro-4'H- spiro [cyclopropane-1,8'-pyrrolo-[1,2-a]pyrimidine]-6'-carboxamide (Compound 122) To a mixture of 4'-oxo-3'-(((2-phenyloxazol-4-yl)methyl)amino)-6',7'-dihydro-4'H- spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]-6'-carboxylic acid (20 mg, 0.053 mmol) and (1H- pyrrolo[3,2-c]pyridin-2-yl)methanamine hydrochloride (12 mg, 0.079 mmol) in DMF (1 mL) was added DIPEA (34 mg, 0.27 mmol) and HATU (15 mg, 0.069 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (C18250*20mm*5um, 15-95% MeCN in water with 0.1% NH₃.H₂O) and further purified by SFC (ChiralPakAS, 250×20mm I.D., 5µm, 35% IPA in CO2 with 0.01% DEA, 40mL/min) to give Compound 121 (2.8 mg, retention time: 9.017, yield 10.4%) and Compound 122 (1.2 mg, retention time: 6.412, yield 4.3%) as white solids. Compound 121: ¹H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.11 (d, J = 5.7 Hz, 1H), 8.03 - 7.98 (m, 2H), 7.88 (s, 1H), 7.51 - 7.47 (m, 4H), 7.15 (s, 1H), 6.63 (s, 1H), 5.16 - 5.12 (m, 1H), 4.74 - 4.72 (m, 1H), 4.57 - 4.52 (m, 1H), 4.33 (s, 2H), 2.77 - 2.71 (m, 1H), 2.28 - 2.24 (m, 1H), 1.29 - 1.19 (m, 4H). LC/MS (ESI) m/z: 508 (M+H)⁺. RT (Method A): 1.17 min. Compound 122: ¹H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.11 (d, J = 5.9 Hz, 1H), 8.01 (d, J = 3.9 Hz, 2H), 7.88 (s, 1H), 7.51 - 7.46 (m, 4H), 7.15 (s, 1H), 6.62 (s, 1H), 5.18 - 5.13 (m, 1H), 4.77 - 4.73 (m, 1H), 4.58 - 4.53 (m, 1H), 4.33 (s, 2H), 2.78 - 2.71 (m, 1H), 2.29 - 2.24 (m, 1H), 1.34 - 1.18 (m, 4H). LC/MS (ESI) m/z: 508 (M+H)⁺. RT (Method A): 1.17 min. Scheme 39. Synthesis of (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-(thiazolo[5,4-c]pyridin-2-yl- methyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 125) Step 1: tert-Butyl (thiazolo[5,4-c]pyridin-2-ylmethyl)carbamate To a mixture of 3-iodopyridin-4-amine (2.0 g, 9.09 mmol) and tert-butyl (2-amino-2- thioxoethyl)carbamate (2.1 g, 11.04 mmol) in MeCN (15 mL) was added CaO (765 mg, 13.64 mmol), dppf (505 mg, 0.91 mmol), and Pd2(dba)3 (166 mg, 0.18 mmol) under N2 atmosphere, and the reaction mixture was degassed under N2 atmosphere for three times and stirred at 60 °C overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (1.8 g, yield 70.3%) as a yellow oil. LC/MS (ESI) m/z: 266 (M+H)⁺. Step 2: Thiazolo[5,4-c]pyridin-2-ylmethanamine hydrochloride To a solution of tert-butyl (thiazolo[5,4-c]pyridin-2-ylmethyl)carbamate (300 mg, 1.13 mmol) in DCM (2 mL) was added HCl/1,4-dioxane (2 mL, 4 M), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (150 mg, yield 65.7%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 166 (M+H)⁺. Step 3: tert-Butyl (S)-(4-oxo-6-((thiazolo[5,4-c]pyridin-2-ylmethyl)carbamoyl)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidin-3-yl)carbamate To a mixture of ((S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxylic acid (100 mg, 0.34 mmol) and thiazolo[5,4-c]pyridin-2-yl-methanamine hydrochloride (150 mg, 0.91 mmol) in DMF (2 mL) was added DIPEA (219 mg, 1.69 mmol) and HATU (155 mg, 0.40 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (140 mg, yield 93.4%) as a yellow oil. LC/MS (ESI) m/z: 443 (M+H)⁺. Step 4: (S)-3-Amino-4-oxo-N-(thiazolo[5,4-c]pyridin-2-ylmethyl)-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamide hydrochloride To a solution of tert-butyl (S)-(4-oxo-6-((thiazolo[5,4-c]pyridin-2-ylmethyl)carbamoyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamate (140 mg, 0.32 mmol) in DCM (2 mL) was added HCl/1,4- dioxane (2 mL, 4 M), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (60 mg, yield 50.0%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 343 (M+H)⁺. Step 5: (S)-4-Oxo-3-((3-phenylpropyl)amino)-N-(thiazolo[5,4-c]pyridin-2-ylmethyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 125) To a mixture of (S)-3-amino-4-oxo-N-(thiazolo[5,4-c]pyridin-2-ylmethyl)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxamide hydrochloride (50 mg, 0.13 mmol) and 3-phenyl-propanal (20 mg, 0.15 mmol) in MeOH (3 mL) was added MgSO4 (50 mg, 0.42 mmol) and NaBH3CN (45 mg, 0.72 mmol) under N₂ atmosphere and the reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep- HPLC (YMC-Actus Triart C18250*20mm, 20 - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 125 (3.5 mg, yield 5.7%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 9.21 (d, J = 0.8 Hz, 1H), 8.57 (d, J = 5.7 Hz, 1H), 7.96 - 7.93 (m, 1H), 7.27 - 7.23 (m, 2H), 7.21-7.14 (m, 3H), 6.96 (s, 1H), 5.19 - 5.15 (m, 1H), 4.92 - 4.89 (m, 2H), 3.20 - 3.13 (m, 1H), 3.11 - 3.07 (m, 2H), 3.03 - 2.95 (m, 1H), 2.73 - 2.69 (m, 2H), 2.68 - 2.59 (m, 1H), 2.41 - 2.34 (m, 1H), 1.98 - 1.91 (m, 2H). LC/MS (ESI) m/z: 461 (M+H)⁺. RT (Method A): 1.38 min. Scheme 40. Synthesis of (S)-N-((6-Methylpyrrolo[1,2-a]pyrazin-7-yl)methyl)-4-oxo-3-((3-phenyl- propyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 126) C^{ompound 126} Step 1: Ethyl 6-bromo-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate To a solution of ethyl 1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate (500 mg, 2.12 mmol) in MeCN (25 mL) was added NBS (420 mg, 2.36 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 18% EtOAc in PE) to give the title compound (440 mg, yield 66.2%) as a white solid.¹H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 5.0 Hz, 1H), 7.48 (d, J = 5.0 Hz, 1H), 7.24 (s, 1H), 4.35 - 4.30 (m, 2H), 2.58 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). LC/MS (ESI) m/z: 315/317 (M+H)⁺. Step 2: Ethyl 6-methyl-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate To a mixture of ethyl 6-bromo-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate (440 mg, 1.40 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.9 mL, 5.00 mmol) in 1,4-dioxane (16 mL) and water (1.6 mL) was added K2CO3 (700 mg, 5.07 mmol) and Pd(PPh3)4 (160 mg, 0.14 mmol) under N2 atmosphere, and the reaction mixture was stirred at 105 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (210 mg, yield 60.1%) as a white solid.¹H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 5.0 Hz, 1H), 7.33 (d, J = 5.0 Hz, 1H), 7.11 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.65 (s, 3H), 2.57 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). LC/MS (ESI) m/z: 251 (M+H)⁺. Step 3: (6-Methyl-1-(methylthio)pyrrolo[1,2-a]pyrazin-7-yl)methanol To a solution of ethyl 6-methyl-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate (200 mg, 0.80 mmol) in DCM (5 mL) was added DIBAL-H (2.4 mL, 2.40 mmol, 1M) dropwise at 0 °C under N2 atmosphere, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated potassium sodium tartrate solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 6% MeOH in DCM) to give the title compound (80 mg, yield 48.2%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J = 4.9 Hz, 1H), 7.37 (s, 1H), 6.76 (s, 1H), 4.75 (s, 2H), 2.63 (s, 3H), 2.44 (s, 3H). LC/MS (ESI) m/z: 209 (M+H)⁺. Step 4: 7-(Azidomethyl)-6-methyl-1-(methylthio)pyrrolo[1,2-a]pyrazine To a solution of (6-methyl-1-(methylthio)pyrrolo[1,2-a]pyrazin-7-yl)methanol (70 mg, 0.34 mmol) in toluene (4 mL) was added DBU (255 mg, 1.68 mmol) and DPPA (270 mg, 0.98 mmol), and the reaction mixture was stirred under N2 atmosphere at 100 °C overnight. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0- 4% MeOH) to give the title compound (60 mg, yield 76.5%) as a yellow oil. Step 5: (6-Methylpyrrolo[1,2-a]pyrazin-7-yl)methanamine To a solution of 7-(azidomethyl)-6-methyl-1-(methylthio)pyrrolo[1,2-a]pyrazine (60 mg, 0.26 mmol) in THF (3 mL) was added triethylsilane (120 mg, 1.03 mmol) and Pd/C (25 mg, 10% wt.) under N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified prep-HPLC (YMC-Actus Triart C₁₈, 18-60% MeCN in water 0.1% NH₃.H₂O) to give the title compound (10 mg, yield 23.9%) as a light-yellow oil. LC/MS (ESI) m/z: 162 (M+H)⁺. Step 6: (S)-N-((6-Methylpyrrolo[1,2-a]pyrazin-7-yl)methyl)-4-oxo-3-((3-phenylpropyl) amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 126) To a mixture of (6-methylpyrrolo[1,2-a]pyrazin-7-yl)methanamine (10 mg, 0.062 mmol) and (S)-4- oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (20 mg, 0.064 mmol) in MeCN (1.0 mL) was added NMI (15 mg, 0.18 mmol) and TCFH (50 mg, 0.18 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 16 - 90% MeCN in water 0.1% NH₃.H₂O) to give Compound 126 (1.7 mg, yield 6.1%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.64 (d, J = 1.2 Hz, 1H), 7.89 (d, J = 5.0 Hz, 1H), 7.41 (d, J = 5.0 Hz, 1H), 7.28 - 7.24 (m, 2H), 7.21 - 7.16 (m, 3H), 6.95 (s, 2H), 5.05 (dd, J = 9.4, 3.1 Hz, 1H), 4.56 - 4.52 (m, 2H), 3.12 - 3.06 (m, 3H), 2.99 - 2.94 (m, 1H), 2.74 - 2.70 (m, 2H), 2.58 - 2.53 (m, 1H), 2.49 (s, 3H), 2.25 - 2.19 (m, 1H), 1.97 - 1.92 (m, 2H). LC/MS (ESI) m/z: 457 (M+H)⁺. RT (Method A): 1.16 min. Scheme 41. Synthesis of (S)-3-(((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-N-(furo[3,2- c]pyridin-2-ylmethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 127) A 20 mL vial was charged with furo[3,2-c]pyridin-2-ylmethanamine dihydrochloride (50 mg, 0.226 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (50 mg, 0.135 mmol), DMF (2 mL), and TEA (0.100 mL, 0.753 mmol) and cooled to 0 ˚C in a brine/ice bath. HATU (75 mg, 0.197 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was concentrated in vacuo at 55 °C to remove DMF. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 127 (20 mg, 30% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (t, J = 5.6 Hz, 1H), 8.89 (s, 1H), 8.43 (d, J = 5.7 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.63 (d, J = 5.7 Hz, 1H), 7.50 – 7.29 (m, 3H), 7.11 (s, 1H), 6.89 (s, 1H), 5.55 (t, J = 6.4 Hz, 1H), 5.00 (dd, J = 9.3, 2.8 Hz, 1H), 4.55 – 4.47 (m, 2H), 4.20 (d, J = 6.3 Hz, 2H), 3.02 – 2.88 (m, 1H), 2.88 – 2.79 (m, 1H), 2.48 – 2.41 (m, 1H), 2.12 – 1.96 (m, 1H). LC/MS: (ESI+) m/z = 500 [M+H]⁺. RT (Method A): 0.79 min. Scheme 42. Synthesis of (S)-N-((1-Cyclopropyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2- fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 129) Step 1: 1-Cyclopropylpyrrolo[3,2-c]pyridine Copper(II) acetate (1750 mg, 9.63 mmol), 2-(2-pyridyl)pyridine (1500 mg, 9.60 mmol), and DCE (50 mL) were combined and heated to 70 °C.1H-Pyrrolo[3,2-c]pyridine (1500 mg, 12.7 mmol), cyclopropylboronic acid (2000 mg, 23.28 mmol), Na2CO3 (3000 mg, 28.3 mmol) were then added, and the resulting mixture was stirred at 70 °C for 20 hours. Afterwards, the mixture was cooled to room temperature. The mixture was then diluted with water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 0- 20% MeOH in DCM) afforded the title compound (387 mg, 19% yield) as a brown solid.¹H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.33 (d, J = 5.7 Hz, 1H), 7.45 (d, J = 5.7 Hz, 1H), 7.15 (d, J = 3.3 Hz, 1H), 6.52 (d, J = 3.2 Hz, 1H), 3.44 – 3.27 (m, 1H), 1.17 – 1.07 (m, 3H), 1.07 – 0.96 (m, 2H). LC/MS: (ESI+) m/z = 159 [M+H]⁺. Step 2: Cyclopropylpyrrolo[3,2-c]pyridine-2-carbaldehyde 1-Cyclopropylpyrrolo[3,2-c]pyridine (600 mg, 3.79 mmol), THF (15 mL), and TMEDA (0.650 mL, 4.34 mmol) were combined and cooled to -78 ˚C in a dry ice/acetone bath. LDA (2.5 mL, 5.0 mmol) was then added dropwise, and the resulting mixture was stirred for 1 hour at -78 ˚C. DMF (0.600 mL, 7.75 mmol) was then added dropwise at -78 ˚C, and the mixture was warmed to 0 °C in a brine/ice bath. After stirring for 1 hour at 0 °C, the mixture was quenched with water (~10 mL). The mixture was then extracted with EtOAc (2 x 50 mL). The combined organic extracts were then washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (510 mg, 72% yield) as a red oil, which was carried forward without further purification. LC/MS: (ESI+) m/z = 187 [M+H]⁺. Step 3: (NE,R)-N-[(1-Cyclopropylpyrrolo[3,2-c]pyridin-2-yl)methylene]-2-methyl-propane-2-sulfinamide 1-Cyclopropylpyrrolo[3,2-c]pyridine-2-carbaldehyde (513 mg, 2.76 mmol), THF (10 mL), (R)-2- methylpropane-2-sulfinamide (650 mg, 5.36 mmol), and Ti(OEt)₄ (1.35 mL, 5.43 mmol) were combined and heated to 70 °C for 4 hours. Afterwards, the mixture was cooled to room temperature. The mixture was then decanted into brine (50 mL), filtered, and washed with EtOAc. The aqueous layer was then extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 24g, 0- 25% MeOH in DCM) afforded the title compound (340 mg, 43% yield) as an orange oil. LC/MS: (ESI+) m/z = 290 [M+H]⁺. Step 4: (R)-N-[(1-Cyclopropylpyrrolo[3,2-c]pyridin-2-yl)methyl]-2-methyl-propane-2-sulfinamide (NE,R)-N-[(1-Cyclopropylpyrrolo[3,2-c]pyridin-2-yl)methylene]-2-methyl-propane-2-sulfinamide (340 mg, 1.175 mmol), MeOH, and NaBH4 (150 mg, 3.96 mmol) were combined at room temperature, and the mixture was allowed to stir for 1 hour. Afterwards, the mixture was quenched with water (20 mL) and diluted with EtOAc (75 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 24g, 0-25% MeOH in DCM) afforded the title compound (271 mg, 34% yield) as an orange oil. LC/MS: (ESI+) m/z = 292 [M+H]⁺. Step 5: (1-Cyclopropylpyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride (R)-N-[(1-Cyclopropylpyrrolo[3,2-c]pyridin-2-yl)methyl]-2-methyl-propane-2-sulfinamide (271 mg, 0.93 mmol) and HCl (4N in dioxane; 2.00 mL, 8.00 mmol) were combined at room temperature, and stirred for 1.5 hours. Afterwards, the mixture was concentrated in vacuo. The brown solid was then triturated with hexanes (3 x 10 mL) to afford the title compound (215 mg, 89% yield) as a brown solid, which was used without further purification. LC/MS: (ESI+) m/z = 188 [M+H]⁺. Step 6: (S)-N-((1-Cyclopropyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4- yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 129) A 20 mL vial was charged with (1-cyclopropylpyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride (50 mg, 0.192 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8- dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (50 mg, 0.135 mmol), DMF (2 mL), and TEA (0.100 mL, 0.753 mmol) and cooled to 0 ˚C in a brine/ice bath. HATU (75 mg, 0.197 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was concentrated in vacuo at 55 °C to remove DMF. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 129 (8 mg, 11% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.05 – 8.97 (m, 2H), 8.34 (d, J = 6.3 Hz, 1H), 8.19 (d, J = 2.9 Hz, 1H), 7.83 – 7.77 (m, 2H), 7.76 (s, 1H), 7.49 – 7.29 (m, 3H), 7.11 (s, 1H), 6.76 (s, 1H), 5.52 (t, J = 6.3 Hz, 1H), 5.05 (dd, J = 9.4, 2.8 Hz, 1H), 4.77 – 4.58 (m, 2H), 4.20 (d, J = 6.3 Hz, 2H), 3.46 – 3.39 (m, 1H), 3.02 – 2.90 (m, 1H), 2.89 – 2.78 (m, 1H), 2.48 – 2.42 (m, 1H), 2.14 – 2.03 (m, 1H), 1.28 – 1.17 (m, 2H), 1.12 – 0.98 (m, 2H). LC/MS: (ESI+) m/z = 539 [M+H]⁺. RT (Method A): 0.93 min. Scheme 43. Synthesis of (S)-N-((3-Fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2- fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 130) Tert-Butyl N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)carbamate (500 mg, 2.022 mmol), MeCN (20 mL), AcOH (2 mL), and SelectFluor (1150 mg, 3.08 mmol) were combined at room temperature, and the mixture was heated to 50 °C for 2 hours. Afterwards, the mixture was cooled and slowly quenched with saturated NaHCO₃ solution. The mixture was extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 24g, 0-30% MeOH in DCM) afforded the title compound (65 mg, 12% yield) as an orange oil. LC/MS: (ESI+) m/z = 239 [M+H]⁺. Step 2: (3-Fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride Tert-butyl N-[(3-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl]carbamate (65 mg, 0.245 mmol) and HCl (4.0M in dioxane, 2.0 mL, 8.0 mmol) were combined at room temperature, and the mixture was stirred for 2 hours. Concentration in vacuo afforded the title compound (45 mg, 77% yield) as a brown solid, which was used without further purification. LC/MS: (ESI+) m/z = 166 [M+H]⁺. Step 3: (S)-N-((3-Fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4- yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 130) A 20 mL vial was charged with (3-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine dihydrochloride (40 mg, 0.168 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8- dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (50 mg, 0.14 mmol), DMF (2 mL), and TEA (0.100 mL, 0.75 mmol) and cooled to 0 ˚C in a brine/ice bath. HATU (75 mg, 0.197 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was concentrated in vacuo at 55 °C to remove DMF. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 130 (7 mg, 10% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H), 8.93 (t, J = 5.4 Hz, 1H), 8.79 (s, 1H), 8.19 (d, J = 5.3 Hz, 2H), 7.80 (d, J = 6.4 Hz, 1H), 7.76 (s, 1H), 7.51 – 7.27 (m, 4H), 7.11 (s, 1H), 5.55 (t, J = 6.4 Hz, 1H), 4.96 (dd, J = 9.2, 2.7 Hz, 1H), 4.57 – 4.37 (m, 2H), 4.20 (d, J = 6.3 Hz, 2H), 3.02 – 2.89 (m, 1H), 2.87 – 2.75 (m, 1H), 2.46 – 2.35 (m, 1H), 2.13 – 2.03 (m, 1H). LC/MS: (ESI+) m/z = 517 [M+H]⁺. RT (Method A): 0.90 min. Scheme 44. Synthesis of (S)-4-Oxo-3-(((5-phenylthiazol-2-yl)methyl)amino)-N-(thieno[3,2-c]pyridin- 2-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 131) Step 1: 5-Phenylthiazole-2-carbaldehyde To a mixture of 5-bromothiazole-2-carbaldehyde (500 mg, 2.62 mmol) and phenylboronic acid (352 mg, 2.88 mmol) in DMSO (5 mL) was added Pd(PPh3)4 (151 mg, 0.13 mmol) and K2CO3 (543 mg, 3.93 mmol) under N2 atmosphere. The reaction mixture was degassed with N2 three times and stirred under N₂ atmosphere at 120 °C for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (250 mg, yield 50.7%) as a yellow solid. LC/MS (ESI) m/z: 190 (M+H)⁺. The 5-phenylthiazole-2-carbaldehyde was used to prepare Compound 131 based on the procedures set forth in, e.g., Scheme 23.¹H NMR (400 MHz, DMSO) δ 9.20 - 9.14 (m, 1H), 9.05 (s, 1H), 8.39 - 8.34 (m, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 4.7 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.48 (s, 1H), 7.42 - 7.37 (m, 2H), 7.35 - 7.31 (m, 1H), 6.99 (d, J = 1.6 Hz, 1H), 6.24 - 6.19 (m, 1H), 5.02 (d, J = 9.2 Hz, 1H), 4.62 (s, 2H), 4.57 (d, J = 4.6 Hz, 2H), 3.03 - 2.79 (m, 3H), 2.10 - 2.04 (m, 1H). LC/MS (ESI) m/z: 515 (M+H)⁺. RT (Method A): 1.18 min. Scheme 45. Synthesis of (S)-N-(imidazo[1,2-a]pyrazin-2-ylmethyl)-4-oxo-3-((3-phenylpropyl) amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 133) To a solution of pyrazin-2-amine (3.8 g, 39.68 mmol) in EtOH (50 mL) was added 1,3- dichloropropan-2-one (5 g, 39.68 mmol). The reaction mixture was stirred under N2 atmosphere at 80 °C overnight. The mixture was basified with aq.NaHCO3 to pH~8 and extracted with DCM twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the title compound (130 mg, yield 1.9%) as a yellow solid. LC/MS (ESI) m/z: 168 (M+H)⁺. Step 2: 2-(Azidomethyl)imidazo[1,2-a]pyrazine To a solution of 2-(chloromethyl)imidazo[1,2-a]pyrazine (130 mg, 0.78 mmol) in DMF (3 mL) was added NaN3 (61 mg, 0.93 mmol) and the reaction mixture was stirred under N2 atmosphere at room temperature overnight. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 25% MeOH in DCM) to give the title compound (30 mg, yield 22.2%) as a yellow solid. LC/MS (ESI) m/z: 175 (M+H)⁺. Step 3: Imidazo[1,2-a]pyrazin-2-ylmethanamine hydrochloride To a solution of 2-(azidomethyl)imidazo[1,2-a]pyrazine (30 mg, 0.17 mmol) in THF (3 mL) and water (1 mL) was added PPh3 (5 mg, 0.02 mmol) and the reaction mixture was stirred under N2 atmosphere at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (20 mg, yield 78.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 149 (M+H)⁺. Step 4: (S)-N-(imidazo[1,2-a]pyrazin-2-ylmethyl)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 133) To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (34 mg, 0.11 mmol) and imidazo[1,2-a]pyrazin-2-ylmethanamine hydrochloride (20 mg, 0.11 mmol) in MeCN (3 mL) were added TCFH (91 mg, 0.32 mmol) and NMI (27 mg, 0.32 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 30%-95% MeCN in water with 0.1% NH3.H2O) to give Compound 133 (2.6 mg, yield 4.3%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, 1H), 8.49 - 8.46 (m, 1H), 8.06 (s, 1H), 7.86 (d, J = 4.6 Hz, 1H), 7.25 (d, J = 7.3 Hz, 2H), 7.21 - 7.15 (m, 3H), 6.97 (s, 1H), 5.13 - 5.09 (m, 1H), 4.70 (d, J = 15.9 Hz, 1H), 4.59 (s, 1H), 4.59 (d, J = 4.3 Hz, 2H), 3.14 - 3.07 (m, 3H), 3.03 - 2.97 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.63 - 2.57 (m, 1H), 2.34 - 2.28 (m, 1H), 1.97 - 1.92 (m, 2H). LC/MS (ESI) m/z: 444 (M+H). Scheme 46. Synthesis of (S)-N-((6-Chlorothieno[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)- 1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 140) 6-Chlorothieno[3,2-c]pyridine (1000 mg, 5.89 mmol) and THF (30 mL) were combined and cooled to -78 ˚C in a dry ice/acetone bath. n-Butyllithium (2.3M in cyclohexane/hexanes) (3.2 mL, 7.4 mmol) was then added dropwise, and the resulting mixture was stirred for 1 hour at -78 ˚C. DMF (1.0 mL, 13 mmol) was then added dropwise at -78 ˚C. After stirring for 1 hour, the mixture was quenched while at -78 ˚C with saturated NH4Cl solution (25 mL). The mixture was then allowed to warm to room temperature and extracted with EtOAc (2 x 50 mL). The combined organic extracts were then washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford a 65:35 mixture of starting material and the title compound (1165 mg, 35% yield) as a yellow solid. The product was directly carried forward without further purification. LC/MS: (ESI+) m/z = 198 [M+H]⁺ Step 2: (NE,R)-N-[(6-Chlorothieno[3,2-c]pyridin-2-yl)methylene]-2-methyl-propane-2-sulfinamide 6-Chlorothieno[3,2-c]pyridine-2-carbaldehyde (407 mg, 2.06 mmol), THF (10 mL), (R)-2- methylpropane-2-sulfinamide (375 mg, 3.09 mmol), and Ti(OEt)4 (1.45 mL, 5.84 mmol) were combined and heated to 70 °C for 18 hours. Afterwards, the mixture was cooled to room temperature, decanted into brine, filtered, and washed with EtOAc. The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica 24g, 0-30% MeOH in DCM) afforded the title compound (419 mg, 67% yield) as an orange oil. LC/MS: (ESI+) m/z = 301 [M+H]⁺ Step 3: (R)-N-[(6-Chlorothieno[3,2-c]pyridin-2-yl)methyl]-2-methyl-propane-2-sulfinamide (NE,R)-N-[(6-Chlorothieno[3,2-c]pyridin-2-yl)methylene]-2-methyl-propane-2-sulfinamide (419 mg, 1.39 mmol), MeOH (10 mL), and NaBH₄ (155 mg, 4.1 mmol) were combined at 0 °C, and the mixture was allowed to warm to room temperature and stir for 1 hour. Afterwards, the mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (620 mg, 99% yield) as an orange oil that was used without further purification. LC/MS: (ESI+) m/z = 303 [M+H]⁺ Step 4: (6-Chlorothieno[3,2-c]pyridin-2-yl)methanamine dihydrochloride (R)-N-[(6-Chlorothieno[3,2-c]pyridin-2-yl)methyl]-2-methyl-propane-2-sulfinamide (620 mg, 2.05 mmol) and HCl (4.0M in dioxane, 3 mL, 12 mmol) were combined at room temperature, and the mixture was stirred for 1 hour. Afterwards, the mixture was concentrated in vacuo. The white solid was triturated with hexanes (3 x 5 mL) to afford the title compound (400 mg, 72% yield) as a white solid. LC/MS: (ESI+) m/z = 199 [M+H]⁺ Step 5: (S)-N-((6-Chlorothieno[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4- yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 140) A 20 mL vial was charged with (6-chlorothieno[3,2-c]pyridin-2-yl)methanamine dihydrochloride (50 mg, 0.18 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (50 mg, 0.14 mmol), DMF (2 mL), and TEA (0.15 mL, 1.1 mmol) and cooled to 0 ˚C in a brine/ice bath. HATU (75 mg, 0.19725 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was concentrated in vacuo at 55 °C to remove DMF. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 140 (32 mg, 43% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (t, J = 5.9 Hz, 1H), 8.87 (s, 1H), 8.19 (s, 2H), 7.84 – 7.73 (m, 2H), 7.51 – 7.29 (m, 4H), 7.10 (s, 1H), 5.56 (t, J = 6.4 Hz, 1H), 4.98 (dd, J = 9.3, 2.6 Hz, 1H), 4.60 (d, J = 3.1 Hz, 1H), 4.20 (d, J = 6.3 Hz, 2H), 3.01 – 2.88 (m, 1H), 2.88 – 2.75 (m, 1H), 2.48 – 2.40 (m, 1H), 2.13 – 1.99 (m, 1H). LC/MS: (ESI+) m/z = 550 [M+H]⁺. RT (Method A): 1.69 min. Scheme 47. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)- 1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 141) p Step 1: tert-Butyl N-[(6-chlorothieno[3,2-c]pyridin-2-yl)methyl]carbamate 6-Chlorothieno[3,2-c]pyridin-2-yl)methanamine dihydrochloride (300 mg, 1.11 mmol), THF (4 mL), water (4 mL), and sodium bicarbonate (400 mg, 4.76 mmol) were combined at room temperature. Boc2O (350 mg, 1.60 mmol) was added portionwise, and the resulting mixture was stirred for 2 hours. Afterwards, the mixture was extracted with EtOAc (3 x 50 mL). The organic layer was then washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (434 mg, >100% yield) as a light-brown solid. LC/MS: (ESI+) m/z = 299 [M+H]⁺ Step 2: tert-Butyl N-[[6-[(2,4-dimethoxyphenyl)methylamino]thieno[3,2-c]pyridin-2-yl]methyl]carbamate A 20 mL microwave vial was charged with (2,4-dimethoxyphenyl)methanamine (0.350 mL, 2.33 mmol), tert-butyl N-[(6-chlorothieno[3,2-c]pyridin-2-yl)methyl]carbamate (330 mg, 1.104 mmol), Cs2CO3 (750 mg, 2.3 mmol), Pd(OAc)2 (13 mg, 0.058 mmol), [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]- diphenyl-phosphane (70 mg, 0.112 mmol) and was subsequently crimp sealed and placed under nitrogen. Dioxane (1 mL) was added, and the resulting solution was sparged with nitrogen for 10 minutes. The vessel was then heated to 110 °C for 4 hours. Afterwards, the mixture was diluted in saturated NH4Cl solution (10 mL) and EtOAc (25 mL). The organic layer was then washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 24g, 10-75% EtOAc in hexanes) afforded the title compound (102 mg, 22% yield) as a light-yellow solid. LC/MS: (ESI+) m/z = 430 [M+H]⁺ Step 3: 2-(Aminomethyl)thieno[3,2-c]pyridin-6-amine dihydrochloride Tert-Butyl N-[[6-[(2,4-dimethoxyphenyl)methylamino]thieno[3,2-c]pyridin-2-yl]methyl]carbamate (102 mg, 0.24 mmol), MeOH (1.0 mL), and HCl (4.0M in dioxane, 3.0 mL, 12 mmol) were combined at room temperature. After 1 hour, the mixture was concentrated in vacuo. The crude material was then triturated with MTBE (3 x 2 mL) to afford the title compound (71 mg, >100% yield) as a yellow solid. LC/MS: (ESI+) m/z = 180 [M+H]⁺ Step 4: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4- yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 141) A 20 mL vial was charged with 2-(aminomethyl)thieno[3,2-c]pyridin-6-amine dihydrochloride (71 mg, 0.28 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (50 mg, 0.14 mmol), DMF (2 mL), and TEA (0.10 mL, 0.75 mmol), and cooled to 0 °C in a brine/ice bath. HATU (65 mg, 0.17 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was concentrated in vacuo at 55 °C to remove DMF. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 141 (15 mg, 21% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (t, J = 5.8 Hz, 1H), 8.49 (s, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.51 – 7.28 (m, 3H), 7.20 – 7.08 (m, 3H), 6.53 (brs, 2H), 5.55 (s, 1H), 4.97 (dd, J = 9.3, 2.2 Hz, 1H), 4.54 – 4.40 (m, 2H), 4.20 (d, J = 4.1 Hz, 2H), 3.00 – 2.87 (m, 1H), 2.87 – 2.77 (m, 1H), 2.48 – 2.40 (m, 1H), 2.11 – 1.97 (m, 1H). LC/MS: (ESI+) m/z = 531 [M+H]⁺. RT (Method A): 0.93 min. Scheme 48. Synthesis of (6S)-4-Oxo-3-(3-thiazol-2-ylpropylamino)-N-(thieno[3,2-c]pyridin-2- ylmethyl)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 143) Thiazole-2-carbaldehyde (1 g, 8.8 mmol), 3-ethoxy-3-oxo-propanoic acid (1.75 g, 13.3 mmol), and piperidine (0.09 mL, 0.9 mmol) were dissolved in pyridine and stirred at 100 ˚C for 1 hour. The mixture was acidified with 1N HCl and extracted with EtOAc. The layers were separated, and the organic layer was dried over Na₂SO₄ and evaporated to dryness to give the title compound (1.4 g, 86% yield), which was used in the next step without further purification. LC/MS: (ESI+) m/z = 184 [M+H]⁺. Step 2: Ethyl 3-thiazol-2-ylpropanoate Ethyl (E)-3-thiazol-2-ylprop-2-enoate (1.4 g, 7.6 mmol) was dissolved in MeOH, and Pd(OH)₂/C (0.11 g, 0.76 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature under hydrogen for 2 hours. Palladium was filtered off over Celite, and the filtrate was evaporated to dryness to give the title compound (1.4 g, 99% yield), which was used in the next step without further purification. LC/MS: (ESI+) m/z = 186 [M+H]⁺. Step 3: 3-Thiazol-2-ylpropan-1-ol A solution of ethyl 3-thiazol-2-ylpropanoate (0.5 g, 2.7 mmol) in THF was added dropwise and under vigorous stirring to a 0 °C suspension of LAH (0.13 g, 3.24 mmol) in THF. The solution was stirred at room temperature until TLC showed complete consumption of the starting material (30-40 minute). The reaction mixture was carefully quenched with saturated aq. Na₂SO₄, stirred at room temperature for 15 minutes and diluted with EtOAc. The layers were separated, and the organic layer was dried over Na2SO4, and concentrated to afford the title compound (175 mg, 45% yield) which was used in the next step without further purification. LC/MS: (ESI+) m/z = 144 [M+H]⁺. Step 4: 3-Thiazol-2-ylpropanal To a solution of oxalyl chloride (2 mol/L) in DCM (0.7 mL, 1.3 mmol) in dry DCM was added DMSO (0.2 mL, 2.7 mmol) dropwise at -78 °C under nitrogen. The reaction mixture was stirred for 20 min, and a solution of 3-thiazol-2-ylpropan-1-ol (0.18 g, 1.2 mmol) in DCM was then added dropwise at -78 °C. After an additional 40 min of stirring at that temperature, dry TEA (0.6 mL, 4.0 mmol) was added dropwise, and the reaction mixture was stirred for 15 minutes and warmed to room temperature. Water was then added, and the biphasic mixture was transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine (20 mL), dried with Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography eluting with 10 % EtOAc/hexanes to give the title compound (152 mg, 88% yield) as a colorless oil. LC/MS: (ESI+) m/z = 142 [M+H]⁺. Step 5: tert-Butyl (6S)-4-oxo-3-(3-thiazol-2-ylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylate A vial was charged with tert-butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylate (0.05 g, 0.2 mmol), 3-thiazol-2-ylpropanal (0.04 g, 0.3 mmol), DCE, and AcOH (0.01 mL, 0.2 mmol) at room temperature under nitrogen. The mixture was allowed to stir for 30 minutes, and sodium triacetoxy borohydride (0.06 g, 0.3 mmol) was then added to the mixture. The reaction mixture was stirred overnight at room temperature. Afterwards, the mixture was diluted with DCM (25 mL), washed with saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 0-10% MeOH in DCM) afforded the title compound (46 mg, 76% yield). LC/MS: (ESI+) m/z = 377 [M+H]⁺. Step 6: (6S)-4-oxo-3-(3-thiazol-2-ylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid Tert-butyl-(6S)-4-oxo-3-(3-thiazol-2-ylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylate (0.05 g, 0.12 mmol) was dissolved in DCM (2 mL). TFA (1 mL) was added, and the mixture was allowed to stir at room temperature for 3 hours. The mixture was evaporated to complete dryness to give the title compound (39 mg, 100% yield), which was used in next step without further purification. LC/MS: (ESI+) m/z = 320 [M+H]⁺. Step 7: (6S)-4-Oxo-3-(3-thiazol-2-ylpropylamino)-N-(thieno[3,2-c]pyridin-2-ylmethyl)-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 143) (6S)-4-oxo-3-(3-thiazol-2-ylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (0.04 g, 0.12 mmol), thieno[3,2-c]pyridin-2-ylmethanamine dihydrochloride (0.032 g, 0.14 mmol) and DIPEA (0.11 mL, 0.61 mmol) were dissolved in DCM, and the mixture was allowed to cool at 0 °C. HATU (0.071 g, 0.18 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was washed with saturated NaHCO3, and the organic layer was separated, dried over Na2SO4, and concentrated. The crude mixture was purified using column chromatography (10-20 % MEOH in DCM) to give Compound 143 (42 mg, 74% yield).¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (t, J = 6.0 Hz, 1H), 9.04 (s, 1H), 8.40 – 8.30 (m, 1H), 7.97 (dd, J = 13.0, 5.5 Hz, 1H), 7.69 (d, J = 3.4 Hz, 1H), 7.57 (d, J = 3.3 Hz, 1H), 7.47 (s, 1H), 6.98 (s, 1H), 5.27 (t, J = 6.1 Hz, 1H), 5.00 (dd, J = 9.4, 2.7 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 3.08 (dt, J = 23.2, 7.1 Hz, 4H), 2.96 (dt, J = 18.3, 9.4 Hz, 1H), 2.85 (ddd, J = 16.7, 9.4, 3.2 Hz, 1H), 2.13 – 1.94 (m, 3H). LC/MS: (ESI+) m/z = 467 [M+H]⁺. RT (Method A): 0.51 min. The following compounds were prepared according to the procedures set forth above, using the appropriate aldehyde in Step 1 and amine in Step 7. Scheme 49. Synthesis of (6S,8S*)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-8-hydroxy-4-oxo-3-(((2- phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxamide (Compound 144) and (6S,8R*)-N-((1H-Pyrrolo[3,2-c] pyridin-2-yl)methyl)-8-hydroxy-4-oxo-3-(((2- phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 145) Step 1: Methyl (6S)-3,8-dibromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (5.0 g, 18.3 mmol) in MeCN (20 mL) and AcOH (30 mL) was added NBS (3.3 g, 18.3 mmol) under N2 atmosphere, and the reaction mixture was stirred at 50 °C overnight. The mixture was filtered, and the filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (1.0 g, yield 15.6%) as a yellow solid. LC/MS (ESI) m/z: 351 (M+H)⁺. Step 2: Methyl (6S)-8-acetoxy-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (6S)-3,8-dibromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (1.0 g, 2.84 mmol) in DMA (10 mL) was added AgOAc (856 mg, 5.13 mmol) and the reaction mixture was stirred under N₂ atmosphere at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (940 mg, yield 99.8%) as a yellow oil. LC/MS (ESI) m/z: 331 (M+H)⁺. Step 3: Methyl (6S)-8-acetoxy-3-((tert-butoxycarbonyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (6S)-8-acetoxy-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine- 6-carboxylate (200 mg, 0.61 mmol) and tert-butyl carbamate (141 mg, 1.21 mmol) in toluene (5 mL) was added K2CO3 (167 mg, 1.21 mmol), BrettPhos (32 mg, 0.06 mmol), and Pd2(dba)3 (56 mg, 0.06 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at 100 °C for 6 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure and then purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (70 mg, yield 31.5%) as a yellow solid. LC/MS (ESI) m/z: 368 (M+H)⁺. Step 4: Methyl (6S)-8-acetoxy-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylate hydrochloride A solution of methyl (6S)-8-acetoxy-3-((tert-butoxycarbonyl)amino)-4-oxo-4,6,7,8-tetra- hydropyrrolo[1,2-a]pyrimidine-6-carboxylate (70 mg, 0.19 mmol) in HCl/1,4-dioxane (2 mL, 4M) was stirred under N₂ atmosphere at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (50 mg, yield 86.2%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 268 (M+H)⁺. Step 5: Methyl (6S)-8-acetoxy-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetra- hydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of methyl (6S)-8-acetoxy-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine- 6-carboxylate hydrochloride (50.0 mg, 0.16 mmol) and 2-phenyloxazole-4-carbaldehyde (65 mg, 0.37 mmol) in MeOH (3 mL) was added MgSO4 (50 mg) and NaBH3CN (59 mg, 0.94 mmol) at 0 °C, and the reaction mixture was stirred under N2 atmosphere at 50 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (65 mg, yield 92.9%) as a colorless oil. LC/MS (ESI) m/z: 425 (M+H)⁺. Step 6: (6S)-8-Hydroxy-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (6S)-8-acetoxy-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (60 mg, 0.14 mmol) in MeOH (3.0 mL) and water (1 mL) was added LiOH.H₂O (9 mg, 0.37 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the title compound (50.0 mg, yield 96.2%) as a white solid. LC/MS (ESI) (m/z): 369 (M+H)⁺. Step 7: (6S,8S*)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-8-hydroxy-4-oxo-3-(((2-phenyloxazol-4- yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 144) and (6S,8R*)-N-((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)-8-hydroxy-4-oxo-3-(((2-phenyloxazol-4- yl)methyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 145) To a mixture of (6S)-8-hydroxy-4-oxo-3-(((2-phenyloxazol-4-yl)methyl)amino)-4,6,7,8-tetra- hydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (50 mg, 0.14 mmol) and (1H-pyrrolo[3,2-c]pyridin-2- yl)methanamine hydrochloride (37 mg, 0.20 mmol) in DMF (2 mL) was added DIPEA (68 mg, 0.29 mmol) and HATU (48 mg, 0.58 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC and further purified by prep-SFC (ChiralPak IB, 250×30mm I.D., 5µm, A for CO2 and B for MeOH (0.1% DEA)) to give Compound 144 (peak 1, retention time: 3.58 min) (4.2 mg, yield 6.2%) and Compound 145 (peak 2, retention time: 4.78) (3.1 mg, yield 4.6%) as white solids. Compound 144: ¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.11 - 8.07 (m, 1H), 8.03 - 7.98 (m, 2H), 7.89 (s, 1H), 7.52 - 7.47 (m, 3H), 7.41 (d, J = 5.9 Hz, 1H), 7.30 (s, 1H), 6.59 (s, 1H), 5.16 - 5.11 (m, 2H), 4.71 (d, J = 15.6 Hz, 1H), 4.55 (d, J = 15.9 Hz, 1H), 4.37 (s, 2H), 2.66 - 2.59 (m, 1H), 2.42 - 2.33 (m, 1H). LC/MS (ESI) (m/z): 498 (M+H)⁺. RT (Method A): 0.86 min. Compound 145: ¹H NMR (400 MHz, CD₃OD) δ 8.73 (s, 1H), 8.10 (d, J = 5.9 Hz, 1H), 8.02 - 7.99 (m, 2H), 7.90 (s, 1H), 7.52 - 7.48 (m, 3H), 7.46 (d, J = 5.8 Hz, 1H), 7.30 (s, 1H), 6.63 (s, 1H), 4.99 - 4.92 (m, 2H), 4.74 (s, 1H), 4.56 (d, J = 15.8 Hz, 1H), 4.38 (s, 2H), 2.92 - 2.84 (m, 1H), 2.21 - 2.15 (m, 1H). LC/MS (ESI) (m/z): 498 (M+H)⁺. RT (Method A): 0.88 min. Scheme 50. Synthesis of (S)-N-((1-(Difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2- fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 147) _F Step 1: tert-Butyl N-[[1-(difluoromethyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]carbamate Tert-Butyl N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)carbamate (500 mg, 2.02 mmol), MeCN (5 mL), ethyl 2-bromo-2,2-difluoro-acetate (0.350 mL, 2.73 mmol), and potassium tert-butoxide (350 mg, 3.09 mmol) were combined in a crimp-sealed vial at room temperature and heated to 100 °C for 1 hour. Afterwards, the mixture was cooled to room temperature, carefully vented, and filtered. The filtrate was concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 24g, 0-25% MeOH in DCM) afforded the title compound (180 mg, 30% yield) as an orange solid. LC/MS: (ESI+) m/z = 298 [M+H]⁺. Step 2: [1-(Difluoromethyl)pyrrolo[3,2-c]pyridin-2-yl]methanamine dihydrochloride Tert-Butyl N-[[1-(difluoromethyl)pyrrolo[3,2-c]pyridin-2-yl]methyl]carbamate (180 mg, 0.605 mmol) and HCl (4.0M in dioxane, 3.0 mL, 12 mmol) were combined at room temperature, and the mixture was stirred for 30 minutes. Afterwards, the mixture was concentrated in vacuo, triturated with MTBE (3 x 5 mL), and again dried to afford the title compound (156 mg, 95% yield) as an orange solid. LC/MS: (ESI+) m/z = 198 [M+H]⁺. Step 3: (S)-N-((1-(Difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol- 4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 147) A 20 mL vial was charged with [1-(difluoromethyl)pyrrolo[3,2-c]pyridin-2-yl]methanamine dihydrochloride (60 mg, 0.22 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8- dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (55 mg, 0.15 mmol), DMF (2 mL), and TEA (0.10 mL, 0.75 mmol) and cooled to 0 °C in a brine/ice bath. HATU (80 mg, 0.21 mmol) was then added, and the resulting mixture was stirred at 0 °C for 30 minutes. Afterwards, the mixture was diluted with EtOAc (25 mL), washed with saturated NaHCO3 solution (25 mL), 0.1% LiOH solution (2 x 10 mL), and brine (50 mL). The organic layer was then dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 5-60% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 147 (26 mg, 32% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (t, J = 5.7 Hz, 1H), 8.88 (s, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.98 (t, JF-H = 57.9 Hz, 1H), 7.82 – 7.78 (m, 1H), 7.76 (s, 1H), 7.65 (d, J = 5.7 Hz, 1H), 7.49 – 7.28 (m, 3H), 7.11 (s, 1H), 6.76 (s, 1H), 5.57 (t, J = 6.3 Hz, 1H), 5.01 (dd, J = 9.3, 2.9 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 6.3 Hz, 2H), 3.02 – 2.89 (m, 1H), 2.89 – 2.79 (m, 1H), 2.49 – 2.42 (m, 1H), 2.12 – 2.02 (m, 1H). LC/MS: (ESI+) m/z = 549 [M+H]⁺. RT (Method A): 0.72 min. Scheme 51. Synthesis of (S)-N-(4-Oxo-6-((thieno[3,2-c]pyridin-2-ylmethyl)carbamoyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyloxazole-2-carboxamide (Compound 150) Step 1: 5-Phenyloxazole-2-carboxylic acid To a solution of ethyl 5-phenyloxazole-2-carboxylate (30 mg, 0.14 mmol) in MeCN (3.0 mL) and water (0.5 mL) was added TBD (35 mg, 0.42 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (25 mg, yield 94.5%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 190 (M+H)⁺. Step 2: (S)-N-(4-Oxo-6-((thieno[3,2-c]pyridin-2-ylmethyl)carbamoyl)-4,6,7,8-tetra-hydropyrrolo[1,2- a]pyrimidin-3-yl)-5-phenyloxazole-2-carboxamide (Compound 150) To a mixture of 5-phenyloxazole-2-carboxylic acid (25 mg, 0.13 mmol) and (S)-3-amino-4-oxo-N- (thieno[3,2-c]pyridin-2-ylmethyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (35 mg, 0.10 mmol) in MeCN (1.0 mL) was added TCFH (87 mg, 0.31 mmol) and NMI (25 mg, 0.31 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (C₁₈, 20 - 95% MeCN in water with 0.01% FA) to give Compound 150 (3.2 mg, yield 6.3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 9.26 (t, J = 5.7 Hz, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.03 - 7.99 (m, 2H), 7.86 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.48 (d, J = 6.7 Hz, 2H), 5.15 - 5.10 (m, 1H), 4.68 - 4.62 (m, 2H), 3.13 - 3.05 (m, 2H), 2.62 - 2.56 (m, 1H), 2.18 - 2.12 (m, 1H). LC/MS (ESI) m/z: 513 (M+H)⁺. RT (Method A): 1.13 min. The following compounds were prepared following Step 2 shown above. Scheme 52. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((3- phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 157) To a solution of 4,6-dichloronicotinaldehyde (4.81 g, 27.3 mmol) in DCM (50 mL) was added TEA (7.6 mL, 54.6 mmol) and ethyl 2-mercaptoacetate (3.93 g, 32.7 mmol) at 0 °C under N2 atmosphere, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (3.11 g, yield 47.3%) as a yellow solid. LC/MS (ESI) m/z: 242 (M+H)⁺. Step 2: Ethyl 6-(tert-butoxycarbonylamino)thieno[3,2-c]pyridine-2-carboxylate To a mixture of ethyl 6-chlorothieno[3,2-c]pyridine-2-carboxylate (1.80 g, 7.47 mmol) and tert- butyl carbamate (1.75 g, 14.9 mmol) in 1,4-dioxane (20 mL) were added Cs₂CO₃ (7.35 g, 22.4 mmol), X- Phos (358 mg, 0.75 mmol), and Pd(OAc)₂ (206 mg, 0.75 mmol). The mixture was degassed under N₂ atmosphere three times and stirred at 100 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (1.10 g, yield 45.8%) as a yellow solid. LC/MS (ESI) m/z: 323 (M+H)⁺. Step 3: tert-Butyl 2-(hydroxymethyl)thieno[3,2-c]pyridin-6-ylcarbamate To a solution of ethyl 6-(tert-butoxycarbonylamino)thieno[3,2-c]pyridine-2-carboxylate (1.10 g, 3.42 mmol) in THF (15 mL) was added LAH (177 mg, 5.12 mmol) at 0 °C under N₂ atmosphere and the reaction mixture was stirred at 0 °C for 1 hour. The reaction was quenched with Na2SO4.10H2O (1.10 g) and diluted with EtOAc (50 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (610 mg, yield 63.7%) as a yellow solid. LC/MS (ESI) m/z: 281 (M+H)⁺. Step 4: tert-Butyl (2-(azidomethyl)thieno[3,2-c]pyridin-6-yl)carbamate To a solution of tert-butyl (2-(hydroxymethyl)thieno[3,2-c]pyridin-6-yl)carbamate (580 mg, 2.07 mmol) in toluene (7 mL) was added DBU (630 g, 4.14 mmol) and DPPA (1.13 mg, 4.14 mmol) at 25 °C under N2 atmosphere, the reaction mixture was degassed under N2 atmosphere three times and stirred at 90 °C for 6 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (600 mg, yield 95.07%) as a yellow solid. LC/MS (ESI) m/z: 306 (M+H)⁺. Step 5: tert-Butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate To a solution of tert-butyl (2-(azidomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (600 mg, 1.97 mmol) in THF (5 mL) and water (5 mL) was added PPh3 (1.29 g, 4.92 mmol). The mixture was stirred under N₂ atmosphere at room temperature overnight. The mixture was acidified with 1N aq. HCl to pH 3 and washed with EtOAc twice. The aqueous phase was basified to pH 8 with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (300 mg, yield 54.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 280 (M+H)⁺. Step 6: tert-Butyl (S)-(2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate To a mixture of tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (60 mg, 0.22 mmol) and (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine-6-carboxylic acid (67 mg, 0.22 mmol) in DMF (2 mL) was added DIPEA (85 mg, 0.66 mmol) and HATU (100 mg, 0.26 mmol). The mixture was stirred at room temperature 30 minutes. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (76 mg, yield 60%) as a yellow solid. LC/MS (ESI) m/z: 575 (M+H)⁺. Step 7: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((3-phenylpropyl) amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 157) To a solution of tert-butyl (S)-(2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl) carbamate (70 mg, 0.12 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (C₁₈, 20 - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 157 (25 mg, yield 44%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.81 (t, J = 5.9 Hz, 1H), 9.22 (s, 1H), 8.12 - 8.07 (m, 2H), 8.05 - 7.98 (m, 3H), 7.92 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 6.66 (s, 2H), 5.95 (t, J = 5.9 Hz, 1H), 5.79 (dd, J = 9.3, 2.6 Hz, 1H), 5.31 - 5.23 (m, 2H), 3.85 - 3.80 (m, 2H), 3.79 - 3.71 (m, 1H), 3.69 - 3.61 (m, 1H), 3.48 - 3.43 (m, 2H), 3.28 - 3.22 (m, 1H), 2.91 - 2.84 (m, 1H), 2.71 - 2.64 (m, 2H). LC/MS (ESI) (m/z): 475 (M+H)⁺. RT (Method A): 1.20 min. Scheme 53. Synthesis of (6S)-4-Oxo-N-[(5-oxothieno[3,2-c]pyridin-2-yl)methyl]-3-(3- phenylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 158) Thieno[3,2-c]pyridin-2-ylmethanamine (0.1 g, 0.61 mmol) and TEA (0.17 mL, 1.22 mmol) were dissolved in DCM, and the mixture was cooled to 0 °C. Boc₂O (0.15 g, 0.7 mmol) was added, and the mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was washed with saturated NaHCO3 solution. The organic layer was isolated, dried, and evaporated to give the title compound (140 mg, 90% yield), which was used in next step without further purification. LC/MS: (ESI+) m/z = 265 [M+H]⁺. Step 2: (5-Oxothieno[3,2-c]pyridin-2-yl)methanamine dihydrochloride Tert-Butyl N-(thieno[3,2-c]pyridin-2-ylmethyl)carbamate (0.05 g, 0.19 mmol) was dissolved in DCM. m-CPBA (0.04 g, 0.21 mmol) was added, and the mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was washed with saturated NaHCO3 solution. The organic layer was isolated, dried over Na2SO4, and evaporated to reduce the volume to ~2 mL. TFA (1 mL) was added, and the mixture was allowed to stir at room temperature for 2 hours. Excess reagent and solvent were evaporated, and the crude residue was dissolved in DCM and treated with 0.5 mL 4M HCL in dioxane, then evaporated to dryness to give the title compound (30 mg, 63% yield). LC/MS: (ESI+) m/z = 217 [M+H]⁺. Step 3: (6S)-4-Oxo-N-[(5-oxothieno[3,2-c]pyridin-2-yl)methyl]-3-(3-phenylpropylamino)-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 158) (6S)-4-Oxo-3-(3-phenylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (0.04 g, 0.13 mmol), (5-oxothieno[3,2-c]pyridin-2-yl)methanamine hydrochloride (0.03 g, 0.14 mmol) and DIPEA (0.11 mL, 0.64 mmol) were dissolved in DCM, and the mixture was allowed to cool at 0 °C. HATU (0.075 g, 0.2 mmol) was added, and the reaction was stirred at 0 °C for 30 minutes. The reaction mixture was washed with saturated NaHCO₃, and the layers were separated. The organic layer was separated, dried over Na₂SO₄, and concentrated. The crude mixture was purified using column chromatography (10- 20 % MEOH in DCM) to give Compound 158 (18 mg, 59% yield).¹H NMR (400 MHz, MeOD) δ 8.83 (d, J = 1.8 Hz, 1H), 8.16 (dd, J = 7.0, 1.8 Hz, 1H), 7.99 (d, J = 7.0 Hz, 1H), 7.44 (d, J = 4.1 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.17 (dd, J = 15.7, 7.5 Hz, 3H), 6.95 (s, 1H), 5.10 (dd, J = 9.4, 3.1 Hz, 1H), 4.81 – 4.61 (m, 2H), 3.20 – 3.05 (m, 3H), 2.98 (ddd, J = 17.0, 9.5, 3.6 Hz, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.59 (dq, J = 13.2, 9.4 Hz, 1H), 2.30 (ddt, J = 12.9, 9.4, 3.4 Hz, 1H), 1.96 (p, J = 7.3 Hz, 2H). LC/MS: (ESI+) m/z = 476 [M+H]⁺. RT (Method A): 1.30 min. Scheme 54. Synthesis of (S)-N-((7-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((3- phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 160) Compound 160 Step 1: 5-Bromo-4-chloronicotinaldehyde To a mixture of 3-bromo-4-chloropyridine (7.5 g, 0.039 mol) in THF (80 mL) was added LDA (18.5 mL, 0.047 mol) dropwise under N2 atmosphere at -78 °C, and the mixture was stirred at -78 °C for 2 hours. DMF (5 mL) was added dropwise to the mixture at -78 °C, and the resulting mixture was stirred at - 78 °C to room temperature for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (2.3 g, yield 26.8%) as a yellow oil. LC/MS (ESI) (m/z): 221 (M+H)⁺. Step 2: Ethyl 7-bromothieno[3,2-c]pyridine-2-carboxylate To a mixture of 5-bromo-4-chloronicotinaldehyde (2.0 g, 9.1 mmol) and K2CO3 (2.5 g, 18.2 mmol) in DMF (30 mL) was added ethyl 2-mercaptoacetate (1.09 g, 9.1 mmol) under N₂ atmosphere at room temperature and the mixture was stirred at 60 °C for 0.5 hour. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (0.62 g, yield 23.9%) as a white solid. LC/MS (ESI) (m/z): 287 (M+H)⁺. Step 3: Ethyl 7-((tert-butoxycarbonyl)amino)thieno[3,2-c]pyridine-2-carboxylate To a mixture of 5-bromo-4-chloronicotinaldehyde (600 mg, 2.1 mmol), Pd₂(dba)₃ (192 mg, 0.21 mmol), X-Phos (200 mg, 0.42 mmol) and K₃PO₄ (1.34 g, 6.3 mmol) in 1,4-dioxane (10 mL) was added tert-butyl carbamate (614 mg, 5.24 mmol) under N2 atmosphere at room temperature and the mixture was stirred at 100 °C overnight. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (400 mg, yield 59.2%) as a yellow oil. LC/MS (ESI) (m/z): 323 (M+H)⁺. Step 4: tert-Butyl (2-(hydroxymethyl)thieno[3,2-c]pyridin-7-yl)carbamate To a mixture of ethyl 7-((tert-butoxycarbonyl)amino)thieno[3,2-c]pyridine-2-carboxylate (350 mg, 1.09 mmol) in THF (5 mL) was added LAH (200 mg,0.42 mmol) under N2 atmosphere at 0 °C, and the mixture was stirred at 0 °C for 0.5 hour. The mixture was quenched with water (0.2 mL), 15% aq. NaOH solution (0.2 mL) and water (0.6 mL) successively at 0 °C and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filter cake was washed EtOAc twice. The filtrate was concentrated under reduced pressure to dryness, and the residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (250 mg, yield 82.2%) as a yellow solid. LC/MS (ESI) (m/z): 281 (M+H)⁺. Step 5: tert-Butyl (2-(azidomethyl)thieno[3,2-c]pyridin-7-yl)carbamate To a mixture of ethyl 7-((tert-butoxycarbonyl)amino)thieno[3,2-c]pyridine-2-carboxylate (250 mg, 0.90 mmol) and DBU (271 mg,1.78 mmol) in THF (80 mL) was added DPPA (735 mg, 2.68 mmol) under N₂ atmosphere at room temperature and the mixture was stirred at 0 °C for 10 mins and at 70 °C for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (200 mg, yield 73.4%) as a white solid. LC/MS (ESI) (m/z): 306 (M+H)⁺. Step 6: tert-Butyl (2-(aminomethyl)thieno[3,2-c]pyridin-7-yl)carbamate To a mixture of tert-butyl (2-(azidomethyl)thieno[3,2-c]pyridin-7-yl)carbamate (200 mg, 0.65 mmol) in THF (2 mL)/water (2 mL) was added PPh₃ (515 mg, 1.96 mmol) under N₂ atmosphere at room temperature, and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% MeOH in DCM) to give the title compound (160 mg, yield 87.4%) as a yellow solid. LC/MS (ESI) (m/z): 280 (M+H)⁺. Step 7: tert-Butyl (S)-(2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-7-yl)-carbamate To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (70 mg, 0.22 mmol) in DMF (3 mL) was added DIPEA (87 mg, 0.66 mmol) and T3P (107 mg, 0.33 mmol, 50% wt. in EtOAc) under N₂ atmosphere at 0 °C, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH=10: 1) to give the title compound (53 mg, yield 54.1%) as a white solid. LC/MS (ESI) (m/z): 575 (M+H)⁺. Step 8: ((S)-N-((7-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((3-phenylpropyl) amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 160) A solution of tert-butyl (S)-(2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-7-yl) carbamate (70 mg, 0.12 mmol) in HCl/1,4- dioxane (2 mL, 4M) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 160 (6.5 mg, yield 11.2%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 8.34 - 8.30 (m, 1H), 7.77 (s, 1H), 7.37 (s, 1H), 7.26 - 7.15 (m, 5H), 6.96 (s, 1H), 5.12 - 5.07 (m, 1H), 4.71 (d, J = 2.6 Hz, 2H), 3.13 - 3.07 (m, 3H), 3.01 - 2.94 (m, 1H), 2.74 - 2.69 (m, 2H), 2.62 - 2.54 (m, 1H), 2.32 - 2.24 (m, 1H), 1.97 - 1.91 (m, 2H). LC/MS (ESI) m/z: 475 (M+H)⁺. RT (Method A): 1.13 min. Scheme 55. Synthesis of (S)-N-((2-Aminothieno[2,3-d]pyrimidin-6-yl)methyl)-4-oxo-3-((3- phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 161) Step 1: 6-Bromo-2-chlorothieno[2,3-d]pyrimidine To a solution of 2-chlorothieno[2,3-d]pyrimidine (900 mg, 5.28 mmol) in THF (20 mL) was added aq. HBr (1.2 mL, 48% wt.) followed by dropwise addition of H₂O₂ (0.5 mL, 30% wt.) at -20 °C and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 35% EtOAc in PE) to give the title compound (920 mg, yield 70%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 7.87 (s, 1H). LC/MS (ESI) m/z: 249 (M+H)⁺. Step 2: 6-Bromo-N-(3,4-dimethylbenzyl)thieno[2,3-d]pyrimidin-2-amine To a mixture of 6-bromo-2-chlorothieno[2,3-d]pyrimidine (400 mg, 1.6 mmol) and (3,4- dimethylphenyl)methanamine (535 mg, 3.2 mmol) in DMF (8 mL) was added K2CO3 (442 mg, 3.2 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (400 mg, yield 65.6%) as a white solid. LC/MS (ESI) m/z: 380 (M+H)⁺. Step 3: tert-Butyl ((2-((3,4-dimethylbenzyl)amino)thieno[2,3-d]pyrimidin-6-yl)methyl)carbamate To a mixture of 6-bromo-N-(3,4-dimethylbenzyl)thieno[2,3-d]pyrimidin-2-amine (200 mg, 0.53 mmol) and potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (628 mg, 2.65 mmol) in 1,4- dioxane (8 mL) was added Cs₂CO₃ (518 mg, 1.59 mmol) and CataCXium A Pd G3 (36 mg, 0.05 mmol), the reaction mixture was degassed under N2 atmosphere three times and stirred at 100 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (130 mg, yield 57.4%) as a light-yellow solid. LC/MS (ESI) m/z: 431 (M+H)⁺. Step 4: 6-(Aminomethyl)-N-(3,4-dimethylbenzyl)thieno[2,3-d]pyrimidin-2-amine To a solution of tert-butyl ((2-((3,4-dimethylbenzyl)amino)thieno[2,3-d]pyrimidin-6- yl)methyl)carbamate (60 mg, 0.14 mmol) in DCM (3 mL) was added HCl/1,4-dioxane (1 mL, 4 M) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (40 mg, yield 87%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 331 (M+H)⁺. Step 5: (S)-N-((2-((3,4-Dimethylbenzyl)amino)thieno[2,3-d]pyrimidin-6-yl)methyl)-4-oxo-3-((3- phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide To a mixture of 6-(aminomethyl)-N-(3,4-dimethylbenzyl)thieno[2,3-d]pyrimidin-2-amine (40 mg, 0.12 mmol) and (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (38 mg, 0.12 mmol) in DMF (2 mL) was added DIPEA (47 mg, 0.36 mmol) and T3P (57 mg, 0.18 mmol, 50% wt. in DMF). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (40 mg, yield 53%) as a brown solid. LC/MS (ESI) m/z: 626 (M+H)⁺. Step 6: (S)-N-((2-Aminothieno[2,3-d]pyrimidin-6-yl)methyl)-4-oxo-3-((3-phenyl-propyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 161) A solution of (S)-N-((2-((3,4-dimethylbenzyl)amino)thieno[2,3-d]pyrimidin-6-yl)-methyl)-4-oxo-3- ((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxamide (40 mg, 0.06 mmol) in TFA (1 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (C₁₈, 0 - 50% MeCN in water with 0.1% NH3.H2O) to give Compound 161 (5.4 mg, yield 18%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (t, J = 5.8 Hz, 1H), 8.65 (s, 1H), 7.30 - 7.17 (m, 5H), 7.07 (s, 1H), 6.91 (s, 1H), 6.70 (d, J = 29.7 Hz, 2H), 5.17 - 5.10 (m, 1H), 5.00 - 4.94 (m, 1H), 4.46 (d, J = 4.2 Hz, 2H), 3.04 - 2.99 (m, 2H), 2.93 (m, J = 9.3 Hz, 1H), 2.87 – 2.82 (m, 1H), 2.66 - 2.62 (m, 2H), 2.07 - 1.96 (m, 2H), 1.88 - 1.82 (m, 2H). LC/MS (ESI) (m/z): 476 (M+H)⁺. RT (Method A): 1.47 min. Scheme 56. Synthesis of (S)-N-((8-Methylpyrrolo[1,2-a]pyrazin-7-yl)methyl)-4-oxo-3-((3- phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 162) To a solution of ethyl 1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate (1.8 g, 10.6 mmol) in MeCN (25 mL) was added NBS (1.6 g, 9.1 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (2.7 g, yield 79.6%) as a white solid. LC/MS (ESI) m/z: 317 (M+H)⁺. Step 2: Ethyl 6-bromo-8-iodo-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate To a solution of ethyl 6-bromo-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate (2.7 g, 9.1 mmol) in MeCN (27 mL) was added NIS (3.0 g, 13.65 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (2.8 g, yield 70.2%) as a white solid. LC/MS (ESI) m/z: 441 (M+H)⁺. Step 3: Ethyl 6-bromo-8-methyl-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate To a solution of ethyl 6-bromo-8-iodo-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate (2.8 mg, 6.3 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added K₂CO₃ (2.6 g, 18.9 mmol), 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (1.6 g, 5.2 mmol), and Pd(dtbpf)Cl2 (371 mg, 0.63 mmol) under N2 atmosphere. The reaction mixture was degassed under N₂ atmosphere three times and stirred at 80 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (1.4 g, yield 66.7%) as a yellow solid. LC/MS (ESI) m/z: 329 (M+H)⁺. Step 4: Ethyl 8-methylpyrrolo[1,2-a]pyrazine-7-carboxylate To a solution of ethyl 6-bromo-8-methyl-1-(methylthio)pyrrolo[1,2-a]pyrazine-7-carboxylate (1.4 g, 4.2 mmol) in 1,4-dioxane (14 mL) was added Pd/C (445 mg, 4.2 mmol) and Et3SiH (1.5 g, 12.6 mmol). The mixture was stirred under N₂ atmosphere at 80 °C overnight. The mixture was filtered. The filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (450 mg, yield 52.3%) as a yellow oil. LC/MS (ESI) (m/z): 205 (M+H)⁺. Step 5: (8-Methylpyrrolo[1,2-a]pyrazin-7-yl)methanol To a solution of ethyl 8-methylpyrrolo[1,2-a]pyrazine-7-carboxylate (450 mg, 2.2 mmol) in THF (5 mL) was added LiAlH₄ (167 mg, 4.4 mmol) under N₂ atmosphere at 0 °C, and the mixture was stirred at 0 °C for 0.5 hour. The mixture was quenched with water (0.2 mL), 15% aq. NaOH solution (0.2 mL), and water (0.6 mL) successively at 0 °C and dried over anhydrous Na2SO4. The mixture was filtered, and the filter cake was washed EtOAc twice. The filtrate was concentrated under reduced pressure to dryness, and the residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (270 mg, yield 75.3%) as a yellow solid. LC/MS (ESI) (m/z): 281 (M+H)⁺. Step 6: 7-(Azidomethyl)-8-methylpyrrolo[1,2-a]pyrazine To a mixture of (8-methylpyrrolo[1,2-a]pyrazin-7-yl)methanol (270 mg, 1.6 mmol) and DBU (250 mg, 3.2 mmol) in toluene (3 mL) was added DPPA (735 mg, 3.2 mmol) under N₂ atmosphere at room temperature, and the mixture was stirred at 0 °C for 10 mins and at 70 °C for 2 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (160 mg, yield 53.1%) as a white solid. LC/MS (ESI) (m/z): 188 (M+H)⁺. Step 7: (8-Methylpyrrolo[1,2-a]pyrazin-7-yl)methanamine To a solution of 7-(azidomethyl)-8-methylpyrrolo[1,2-a]pyrazine (160 mg, 0.85 mmol) in THF (2 mL) and water (2 mL) was added PPh₃ (480 mg, 1.7 mmol) under N₂ atmosphere at room temperature, and the reaction mixture was stirred at 50 °C overnight. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (80 mg, yield 57.4%) as a yellow solid. LC/MS (ESI) (m/z): 280 (M+H)⁺. Step 8: (S)-N-((8-Methylpyrrolo[1,2-a]pyrazin-7-yl)methyl)-4-oxo-3-((3-phenylpropyl) amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 162) To a mixture of (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (70 mg, 0.22 mmol) and (8-methylpyrrolo[1,2-a]pyrazin-7-yl)methanamine (80 mg, 0.49 mmol) in DMF (3 mL) was added DIPEA (87 mg, 0.66 mmol) and HATU (107 mg, 0.33 mmol) under N2 atmosphere, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20%-95% MeCN in water with 0.1% FA) to give Compound 162 (6 mg, yield 10.5%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.47 (d, J = 5.7 Hz, 1H), 8.26 (s, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.21 - 7.15 (m, 3H), 6.98 (s, 1H), 5.11 - 5.10 (m, 1H), 4.67 - 4.66 (m, 1H), 4.50 - 4.46 (m, 1H), 3.15 - 3.07 (m, 4H), 2.73 - 2.69 (m, 2H), 2.56 (s, 3H), 2.31 - 2.19 (m, 2H), 1.97 - 1.92 (m, 2H). LC/MS (ESI) (m/z): 457 (M+H)⁺. RT (Method A): 1.18 min. Scheme 57. Synthesis of (S)-N-(4-Oxo-6-((thieno[3,2-c]pyridin-2-ylmethyl)carbamoyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 163) To a solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (500 mg, 2.12 mmol) in toluene/water (6 mL, v/v=5/1) was added phenylboronic acid (388 mg, 3.18 mmol), NMM (471 mg, 4.66 mmol), XantPhos (121 mg, 0.21 mmol), and Pd(OAc)2 (47 mg, 0.21 mmol) under N2 atmosphere and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (350 mg, yield 70.5%) as a white solid. LC/MS (ESI) m/z: 235 (M+H)⁺. Step 2: 5-Phenyl-1,3,4-thiadiazole-2-carboxylic acid To a solution of ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (150 mg, 0.64 mmol) in MeOH/water (3 mL, v/v= 2/1) was added LiOH (46 mg, 1.92 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (180 mg) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 207 (M+H)⁺. Step 3: (S)-N-(4-Oxo-6-((thieno[3,2-c]pyridin-2-ylmethyl)carbamoyl)-4,6,7,8-tetra-hydropyrrolo[1,2- a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 163) To a mixture of (S)-3-amino-4-oxo-N-(thieno[3,2-c]pyridin-2-ylmethyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (62 mg, 0.18 mmol) and 5-phenyl-1,3,4-thiadiazole-2- carboxylic acid (74 mg, 0.36 mmol) in MeCN (3 mL) was added TCFH (151 mg, 0.54 mmol) and NMI (44 mg, 0.54 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 30% - 75% MeCN in water with 0.1% NH₃.H₂O) to give Compound 163 (1.5 mg, yield 1.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 1H), 9.27 (t, J = 5.8 Hz, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.13 - 8.10 (m, 2H), 8.01 (d, J = 5.6 Hz, 1H), 7.66 - 7.60 (m, 3H), 7.48 (s, 1H), 5.16 - 5.12 (m, 1H), 4.69 - 4.62 (m, 2H), 3.18 - 3.06 (m, 3H), 2.64 - 2.58 (m, 1H). LC/MS (ESI) (m/z): 530 (M+H)⁺. RT (Method A): 1.23 min. Scheme 58. Synthesis of (S)-N-((4-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((3-phenyl- propyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 164) To a mixture of 2,4-dichloroisonicotinaldehyde (5.0 g, 28.40 mmol) and K₂CO₃ (7.85 g, 56.81 mmol) in DMF (60 mL) was added ethyl 2-mercaptoacetate (3.41g, 28.40 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (4.50 g, yield 65.7%) as a yellow solid. LC/MS (ESI) m/z: 242 (M+H)⁺. Step 2: (4-Chlorothieno[3,2-c]pyridin-2-yl)methanol To a solution of ethyl 4-chlorothieno[3,2-c]pyridine-2-carboxylate (4.5 g, 18.6 mmol) in anhydrous tetrahydrofuran (50.0 mL) was added LiAlH4 (74.6 mL, 74.68 mmol, 1M in THF) dropwise at 0 °C and the reaction mixture was stirred for 1 hour under N2 atmosphere. The mixture was quenched with water (4 mL), 15% aq. NaOH solution (4 mL), and water (12 mL) successively at 0 °C and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filter cake was washed EtOAc twice. The filtrate was concentrated under reduced pressure to dryness and the residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (610.0 mg, yield 16.4%) as a white solid. LC/MS (ESI) m/z: 200 (M+H)⁺. Step 3: tert-Butyl (2-(hydroxymethyl)thieno[3,2-c]pyridin-4-yl)carbamate To a mixture of (4-chlorothieno[3,2-c]pyridin-2-yl)methanol (610.0 mg, 3.06 mmol) and tert-butyl carbamate (538.6 mg, 4.59 mmol) in 1,4-dioxane (8 mL) was added K3PO4 (3.25 g, 15.3 mmol), X-Phos (584.5 mg, 1.22 mmol) and Pd2(dba)3 (561.3 mg, 0.61 mmol). The mixture was degassed under N2 atmosphere three times and stirred at 110 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (260 mg, yield 30.3%) as a brown solid. LC/MS (ESI) m/z: 281 (M+H)⁺. Step 4: tert-Butyl (2-(azidomethyl)thieno[3,2-c]pyridin-4-yl)carbamate To a solution of tert-butyl (2-(hydroxymethyl)thieno[3,2-c]pyridin-4-yl)carbamate (260 mg, 0.92 mmol) in toluene (5 mL) was added DBU (212 mg, 1.39 mmol) and DPPA (383 mg, 1.39 mmol) at 25 °C under N2 atmosphere, and the reaction mixture was degassed under N2 atmosphere three times and then stirred at 120 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (200 mg, yield 71.2%) as a yellow solid. LC/MS (ESI) m/z: 306 (M+H)⁺. Step 5: tert-Butyl (2-(aminomethyl)thieno[3,2-c]pyridin-4-yl)carbamate To a solution of tert-butyl (2-(azidomethyl)thieno[3,2-c]pyridin-4-yl)carbamate (200 mg, 0.65 mmol) in THF (2 mL) and water (2 mL) was added PPh3 (343.9 mg, 1.30 mmol). The mixture was stirred under N2 atmosphere at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and washed with EtOAc twice. The aqueous phase was basified to pH 8 with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the title compound (60 mg, yield 33.1%) as a yellow solid. LC/MS (ESI) m/z: 280 (M+H)⁺. Step 6: tert-Butyl (S)-(2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-4-yl)-carbamate To a mixture of tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-4-yl)carbamate (26 mg, 0.09 mmol) and (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxylic acid (30 mg, 0.09 mmol) in DMF (2 mL) was added DIPEA (24.7 mg, 0.19 mmol) and HATU (54.6 mg, 0.14 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (11 mg, yield 21.2%) as a yellow solid. LC/MS (ESI) m/z: 575 (M+H)⁺. Step 7: (S)-N-((4-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((3-phenylpropyl) amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 164) To a solution of tert-butyl (S)-(2-((4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-4-yl)carbamate (11 mg, 0.02 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 15 - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 164 (1.8 mg, yield 18.9%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.28 - 7.23 (m, 2H), 7.21 - 7.15 (m, 3H), 7.09 (s, 1H), 6.96 (s, 1H), 6.87 - 6.84 (m, 1H), 5.11 - 5.07 (m, 1H), 4.67 - 4.61 (m, 2H), 3.18 - 3.13 (m, 1H), 3.10 - 3.07 (m, 2H), 3.01 - 2.95 (m, 1H), 2.74 - 2.69 (m, 2H), 2.61 - 2.56 (m, 1H), 2.21 - 2.16 (m, 1H), 1.97 - 1.92 (m, 2H). LC/MS (ESI) (m/z): 475 (M+H)⁺. RT (Method A): 1.23 min. Scheme 59. Synthesis of (S)-N-((6-Amino-7-fluorothieno[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2- fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 168) 4,6-Dichloro-5-fluoro-pyridine-3-carboxylic acid (5000 mg, 23.811 mmol), DMF (20 mL), and K2CO3 (7000 mg, 50.65 mmol) were combined and cooled to 0 °C in a brine/ice bath. Iodomethane (2.5 mL, 40 mmol) was added slowly, and the resulting mixture was warmed to room temperature then heated to 55 °C for 1 hour. Afterwards, the mixture was poured onto ice water and filtered. The filtered solid was then washed with water (5 x 25 mL) and dried to afford the title compound (5.3 g, 99% yield) as a white solid. LC/MS: (ESI+) m/z = 224 [M+H]⁺. Step 2: (4,6-Dichloro-5-fluoro-3-pyridyl)methanol Methyl 4,6-dichloro-5-fluoro-pyridine-3-carboxylate (5.3 g, 24 mmol) and MeOH (30 mL) were combined and cooled to 0 °C in a brine/ice bath. NaBH4 (1700 mg, 44.93 mmol) was added portionwise slowly. The resulting mixture was quenched with water and extracted with EtOAc (3 x 75 mL). The combined organics were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 10-75% EtOAc in hexanes) afforded the title compound (4.6 g, 99% yield) as a white solid. LC/MS: (ESI+) m/z = 196 [M+H]⁺. Step 3: 4,6-Dichloro-5-fluoro-pyridine-3-carbaldehyde Oxalyl chloride (7.0 mL, 82 mmol) in DCM (50 mL, 780.0 mmol) was cooled to -78 °C in a dry ice/acetone bath. DMSO (12.0 mL, 170 mmol) was added dropwise, and the resulting solution was stirred for 30 minutes at -78 °C. A solution of (4,6-dichloro-5-fluoro-3-pyridyl)methanol (4.5 g, 23 mmol) in DCM (20 mL) was then added dropwise and allowed to stir at -78 °C for 30 minutes. Afterwards, TEA (30 mL, 215 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and stir for 1 hour. Afterwards, the mixture was washed with 0.5M HCl (3 x 100 mL). The organic layer was then washed with saturated NaHCO3 solution (50 mL) and brine (100 mL). The organic layer was then dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica 40g, 10- 75% EtOAc in hexanes) afforded the title compound (3.2 g, 72% yield) as a white solid. LC/MS: (ESI+) m/z = 212 [Mhydrate+H]⁺. Step 4: Methyl 6-chloro-7-fluoro-thieno[3,2-c]pyridine-2-carboxylate 4,6-Dichloro-5-fluoro-pyridine-3-carbaldehyde (2500 mg, 12.887 mmol) and DCM (5 mL) were combined and cooled to 0 °C in a brine/ice bath. Methyl 2-sulfanylacetate (1.2 mL, 13 mmol) and TEA (3.7 mL, 27 mmol) were then added, and the resulting mixture was allowed to warm to room temperature and stir for an hour. Afterwards, the precipitate was filtered and washed with DCM. The filtrate was concentrated in vacuo and taken up in DMF (10 mL). K2CO3 (2800 mg, 20.26 mmol) was then added, and the mixture was stirred overnight at room temperature. Afterwards, the mixture was diluted with water (~100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (10-50% EtOAc in hexanes) afforded the title compound (1930 mg, 61% yield) as a light-yellow solid. LC/MS: (ESI+) m/z = 246 [M+H]⁺. Step 5: (6-Chloro-7-fluoro-thieno[3,2-c]pyridin-2-yl)methanol Methyl 6-chloro-7-fluoro-thieno[3,2-c]pyridine-2-carboxylate (1930 mg, 7.86 mmol) and 2- methyltetrahydrofuran (40 mL) were combined and cooled to 0 °C in a brine/ice bath. LiAlH4 (2.0M in THF, 8.0 mL, 16 mmol) was added dropwise, and the resulting solution was stirred at 0 °C for 20 minutes. Afterwards, the mixture was slowly quenched at 0 °C with water (~50 mL) followed by Rochelle's salt solution (~50 mL). The mixture was warmed to room temperature and stirred for 30 minutes. Next, the mixture was filtered over Celite and washed with EtOAc. The organic layer from the filtrate was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (1.4 g, 82% yield) as a white solid. No further purification was performed. LC/MS: (ESI+) m/z = 218 [M+H]⁺. Step 6: 2-(Azidomethyl)-6-chloro-7-fluoro-thieno[3,2-c]pyridine (6-Chloro-7-fluoro-thieno[3,2-c]pyridin-2-yl)methanol (2.2 g, 10 mmol) and THF (20 mL, 246 mmol) were combined and cooled to 0 °C in a brine/ice bath. DPPA (2.2 mL, 10 mmol) was added, followed by the slow addition of DBU (1.5 mL, 10 mmol). The mixture was then warmed to room temperature and stirred for 2 hours. Afterwards, the reaction mixture was quenched with saturated NaHCO₃ solution (25 mL). The organic layer was then washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 10-80% EtOAc in hexanes) afforded the title compound (1.05 g, 43% yield) as a white solid. LC/MS: (ESI+) m/z = 243 [M+H]⁺. Step 7: tert-Butyl N-[(6-chloro-7-fluoro-thieno[3,2-c]pyridin-2-yl)methyl]carbamate 2-(Azidomethyl)-6-chloro-7-fluoro-thieno[3,2-c]pyridine (1.05 g, 4.33 mmol) was combined with MeOH (20 mL) and Pd/C [10 wt% Pd] (~200 mg) in a flask affixed with a 3-way stopcock attached to a Schlenk line and a hydrogen balloon. The mixture, under nitrogen atmosphere, was then placed under hydrogen via 3 cycles of vacuum-hydrogen fill. The mixture was stirred until complete conversion was observed by LC/MS (~2 hours). The mixture was then filtered over Celite and concentrated in vacuo. The residue was then taken up in THF:water (1:1, 10 mL). NaHCO3 (800 mg, 9.523 mmol) was added followed by di-tert-butyl dicarbonate (1200 mg, 5.333 mmol). The mixture was stirred at room temperature for 30 minutes. Next, the mixture was diluted in EtOAc (50 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (1.4 g, 100% yield) as a light-yellow solid, which was used without further purification. LC/MS: (ESI+) m/z = 317 [M+H]⁺. Step 8. tert-Butyl N-[[6-[(2,4-dimethoxyphenyl)methylamino]-7-fluoro-thieno[3,2-c]pyridin-2- yl]methyl]carbamate A 20 mL microwave vial was charged with tert-butyl N-[(6-chloro-7-fluoro-thieno[3,2-c]pyridin-2- yl)methyl]carbamate (700 mg, 2.210 mmol), Cs2CO3 (1500 mg, 4.604 mmol), Pd(OAc)2 (25 mg, 0.111 mmol), and [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (150 mg, 0.241 mmol) and was subsequently crimp sealed and placed under nitrogen. (2,4-Dimethoxyphenyl)methanamine (1.0 mL, 6.7 mmol) and toluene (5 mL, 47.3 mmol) were added, and the resulting solution was sparged with nitrogen for 5 minutes. The vessel was then heated to 100 °C for 2 hours. Afterwards, the mixture was diluted with saturated NH₄Cl solution (10 mL) and EtOAc (25 mL). The organic layer was then washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 24g, 10-75% EtOAc in hexanes) afforded the title compound (258 mg, 26.1% yield) as a light- yellow solid. LC/MS: (ESI+) m/z = 448 [M+H]⁺. Step 9: 2-(Aminomethyl)-7-fluoro-thieno[3,2-c]pyridin-6-amine dihydrochloride Tert-Butyl N-[[6-[(2,4-dimethoxyphenyl)methylamino]-7-fluoro-thieno[3,2-c]pyridin-2- yl]methyl]carbamate (258 mg, 0.5765 mmol), MeOH (1.0 mL), and HCl (4.0M in dioxane, 3.0 mL, 12 mmol) were combined at room temperature. After 1 hour, the mixture was concentrated in vacuo. The crude material was then triturated with MTBE (3 x 2 mL) to afford the title compound (180 mg, >100% yield) as a yellow solid. LC/MS: (ESI+) m/z = 198 [M+H]⁺. Step 10: (S)-N-((6-Amino-7-fluorothieno[3,2-c]pyridin-2-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4- yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 168) A 20 mL vial was charged with 2-(aminomethyl)-7-fluoro-thieno[3,2-c]pyridin-6-amine dihydrochloride (55 mg, 0.204 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8- dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (50 mg, 0.135 mmol), DMF (2 mL, 25.9 mmol), and TEA (0.10 mL, 0.75 mmol) and cooled to 0 ˚C in a brine/ice bath. HATU (65 mg, 0.17095 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 30 minutes. Afterwards, the mixture was diluted in EtOAc (25 mL), washed with saturated NaHCO3 solution (20 mL), 0.5% LiOH solution (2 x 10 mL), and brine (25 mL). The organic layer was then dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 12g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 15-75% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 168 (30 mg, 40% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (t, J = 5.8 Hz, 1H), 8.29 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 10.6 Hz, 2H), 7.50 – 7.29 (m, 3H), 7.23 (d, J = 3.5 Hz, 1H), 7.10 (s, 1H), 6.10 (s, 2H), 5.57 (t, J = 6.3 Hz, 1H), 4.96 (d, J = 7.0 Hz, 1H), 4.48 (d, J = 5.7 Hz, 2H), 4.20 (d, J = 6.2 Hz, 2H), 3.01 – 2.88 (m, 1H), 2.88 – 2.78 (m, 1H), 2.47 – 2.38 (m, 1H), 2.10 – 1.97 (m, 1H). LC/MS: (ESI+) m/z = 549 [M+H]⁺. RT (Method A): 1.33 min. Scheme 60. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyloxazole-2-carboxamide (Compound 170) Step 1: 5-Phenyloxazole-2-carboxylic acid To a solution of ethyl 5-phenyloxazole-2-carboxylate (100 mg, 0.45 mmol) in MeCN (3.0 mL) and water (0.5 mL) was added TBD (192 mg, 1.3 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (70 mg, yield 82.3%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 190 (M+H)⁺. Step 2: tert-Butyl (S)-(2-((4-oxo-3-(5-phenyloxazole-2-carboxamido)-4,6,7,8-tetra-hydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate To a mixture of 5-phenyloxazole-2-carboxylic acid (20 mg, 0.1 mmol) and tert-butyl (S)-(2-((3- amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (30 mg, 0.06 mmol) in MeCN (10 mL) was added TCFH (87 mg, 0.31 mmol) and NMI (25 mg, 0.31 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (20 mg, yield 53.1%) as a white solid. LC/MS (ESI) m/z: 628 (M+H)⁺. Step 3: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyloxazole-2-carboxamide (Compound 170) To a solution of tert-butyl (S)-(2-((4-oxo-3-(5-phenyloxazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.03 mmol) in DCM (2 mL) was added HCl/1,4-dioxane (1 mL, 4.0 M). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH3.H2O to give Compound 170 (3 mg, yield 18.9%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 9.11 (t, J = 5.7 Hz, 1H), 8.73 (s, 1H), 8.42 (s, 1H), 8.02 (s, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.5 Hz, 2H), 7.49 (d, J = 7.3 Hz, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 5.85 (s, 2H), 5.10 (t, J = 7.5 Hz, 1H), 4.49 (m, 2H), 3.16 - 3.11 (m, 1H), 2.61 - 2.55 (m, 1H), 2.14 - 1.97 (m, 2H). LC/MS (ESI) (m/z): 528 (M+H)⁺. RT (Method A): 1.09 min. The following compounds were prepared based on the procedures set forth above.

^a Step 1 was performed with LiOH in THF/H₂O. ^b Step 3 was performed with TMSI in DCM. ^c Step 3 was performed with TFA in DCM. Scheme 61. Synthesis of (6S)-N-[(4-Hydroxythieno[3,2-c]pyridin-2-yl)methyl]-4-oxo-3-(3- phenylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 172) Benzyl alcohol (0.6 mL, 5.9 mmol) was added to a suspension of NaH (60 mass%) in oil (0.24 g, 5.9 mmol) in THF and allowed to stir at room temperature for 30 minutes.4-Chlorothieno[3,2-c]pyridine (0.5 g, 2.95 mmol) was added, and the mixture was stirred overnight at 60 °C. The solvent was evaporated, and the crude mass was extracted with EtOAc and water. The organic layer was isolated, dried over Na2SO4, and evaporated to dryness. The crude mass was purified using CombiFlash chromatography (20% EtOAc/Hexane) to give the title compound (450 mg, 63% yield). LC/MS: (ESI+) m/z = 242 [M+H]⁺. Step 2: 4-Benzyloxythieno[3,2-c]pyridine-2-carbaldehyde n-Butyllithium (2.5 M) in hexanes (1.1 mL, 2.8 mmol) was added dropwise into a solution of 4- benzyloxythieno[3,2-c]pyridine (0.45 g, 1.9 mmol) in THF at -78 °C, and the mixture was allowed to stir for 10 minutes. DMF (0.3 mL, 3.7 mmol) was added dropwise into the reaction mixture, which was stirred for 30 minutes then warmed to room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was isolated, dried over Na2SO4, and evaporated to dryness to give the title compound (327 mg, 65% yield), which was used in the next step without further purification. LC/MS: (ESI+) m/z = 270 [M+H]⁺. Step 3: 2-(Aminomethyl)thieno[3,2-c]pyridin-4-ol A reaction vial was charged with 4-benzyloxythieno[3,2-c]pyridine-2-carbaldehyde (0.33 g, 1.2 mmol), hydroxylamine hydrochloride (0.17 g, 2.4 mmol), pyridine (catalytic), and EtOH (10 mL). The reaction mixture was heated at 80 °C for 15 minutes. The solvent was evaporated to dryness, and the crude mass was dissolved into MeOH:AcOH (1:1). Zinc powder (0.16 g, 2.5 mmol) was added, and the suspension was stirred at room temperature for 30 minutes. The solvents were evaporated, and the crude mass was purified using CombiFlash chromatography (10% NH3 in MeOH/DCM) to give the title compound (150 mg, 69% yield). LC/MS: (ESI+) m/z = 181 [M+H]⁺. Step 4: (6S)-N-[(4-Hydroxythieno[3,2-c]pyridin-2-yl)methyl]-4-oxo-3-(3-phenylpropylamino)-7,8-dihydro- 6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 172) (6S)-4-Oxo-3-(3-phenylpropylamino)-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (0.02 g, 0.064 mmol), 2-(aminomethyl)thieno[3,2-c]pyridin-4-ol (0.013 g, 0.07 mmol) and DIPEA (0.06 mL, 0.32 mmol) were dissolved in DCM, and the mixture was allowed to cool at 0 °C. HATU (0.037 g, 0.096 mmol) was added, and the reaction was stirred at 0 °C for 30 minute. The reaction mixture was washed with saturated NaHCO_3. The organic layer was isolated, dried over Na₂SO₄, and concentrated. The crude mixture was purified using column chromatography (10-20 % MEOH in DCM) to give Compound 172 (8 mg, 26% yield).¹H NMR (400 MHz, MeOD) δ 7.48 (s, 1H), 7.32 – 7.23 (m, 2H), 7.23 – 7.13 (m, 4H), 6.95 (s, 1H), 6.81 (d, J = 7.0 Hz, 1H), 5.08 (dd, J = 9.3, 2.9 Hz, 1H), 4.71 (d, J = 15.4 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 3.20 (dt, J = 17.0, 9.4 Hz, 1H), 3.08 (t, J = 7.0 Hz, 2H), 2.97 (ddd, J = 17.0, 9.5, 3.3 Hz, 1H), 2.73 (t, J = 7.6 Hz, 2H), 2.55 (dq, J = 13.2, 9.5 Hz, 1H), 2.32 (ddt, J = 12.8, 9.3, 3.2 Hz, 1H), 2.07 – 1.91 (m, 2H). LC/MS: (ESI+) m/z = 476 [M+H]⁺. RT (Method A): 1.50 min. Scheme 62. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 175) To a solution of methyl (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate (300 mg, 0.98 mmol) in MeOH/water (4 mL, v/v=3/1) was added LiOH (47 mg, 1.94 mmol). The reaction mixture was stirred at room temperature for 30 mins. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (250 mg, yield 87.3%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 296 (M+H)⁺. Step 2: (S)-3-Amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxylic acid (250 mg, 0.85 mmol) in DCM (5 mL) was added HCl/1,4-dioxane (3 mL, 4 M), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound (240 mg, crude) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 196 (M+H)⁺. Step 3: tert-Butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (150 mg, 0.77 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (236 mg, 0.85 mmol) in DMF (3 mL) was added DIPEA (298 mg, 2.31 mmol) and HATU (351 mg, 0.92 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (130 mg, yield 37%) as a yellow solid. LC/MS (ESI) m/z: 457 (M+H)⁺. Step 4: tert-Butyl (S)-(2-((4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (40 mg, 0.09 mmol) and 5-phenyl-1,3,4- thiadiazole-2-carboxylic acid (29 mg, 0.14 mmol) in DMF (1 mL) was added DIPEA (23 mg, 0.18 mmol) and HATU (41 mg, 0.11 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (16 mg, yield 28.3%) as a yellow solid. LC/MS (ESI) m/z: 645 (M+H)⁺. Step 5: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 175) To a solution of tert-butyl (S)-(2-((4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2-c] pyridin-6-yl)carbamate (16 mg, 0.02 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M), and the reaction mixture was stirred room temperature for 1 hour. The mixture was concentrated to dryness then purified by prep-HPLC (YMC- Actus Triart C₁₈, 30 - 70% MeCN in water with 0.1% NH₃.H₂O) to give Compound 175 (4 mg, yield 29.6%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.13 - 8.10 (m, 2H), 7.65 - 7.60 (m, 3H), 7.13 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.13 - 5.10 (m, 1H), 4.54 - 4.45 (m, 2H), 3.17 - 3.05 (m, 2H), 2.66 - 2.57 (m, 1H), 2.17 - 2.10 (m, 1H). LC/MS (ESI) m/z: 545 (M+H)⁺. RT (Method A): 1.11 min. The following compounds were prepared according to the procedures above with the appropriate bicycles in Step 1 and the carboxylic acids in Step 4. a Step 4 was performed with TCFH and NMI in MeCN. Scheme 63. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-thiazole-2-carboxamide (Compound 176) To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (90 mg, 0.20 mmol) and 5-phenylthiazole-2- carboxylic acid (48 mg, 0.24 mmol) in MeCN (1 mL) was added NMI (49 mg, 0.6 mmol) and TCFH (168 mg, 0.6 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (60 mg, yield 47.3%) as a yellow solid. LC/MS (ESI) m/z: 644 (M+H)⁺. Step 2: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenylthiazole-2-carboxamide (Compound 176) To a solution of tert-butyl (S)-(2-((4-oxo-3-(5-phenylthiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (60 mg, 0.09 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (2 mL, 4 M), and the reaction mixture was stirred room temperature for 1 hour. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 30 - 60% MeCN in water with 0.1% FA) to give Compound 176 (21 mg, yield 41.4%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.79 (s, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 7.82 (d, J = 7.0 Hz, 2H), 7.53 - 7.46 (m, 3H), 7.13 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.13 - 5.09 (m, 1H), 4.48 (qd, J = 15.9, 5.6 Hz, 2H), 3.18 - 3.03 (m, 1H), 2.61 - 2.54 (m, 1H), 2.16 - 2.09 (m, 1H), 2.04 - 1.93 (m, 1H). LC/MS (ESI) m/z: 544 (M+H)⁺. RT (Method A): 1.39 min. The following compounds were prepared according to the procedures set forth above. ^a Step 2 was performed with TMSI in DCM. ^b Step 1 was performed in MeCN/DMF. ^c Step 2 was performed with TFA in DCM. Scheme 64. Synthesis of (6S,8S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methoxy-4-oxo-3- ((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 178) Step 1: (6S)-3-((tert-Butoxycarbonyl)amino)-8-hydroxy-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine- 6-carboxylic acid To a solution of methyl (6S)-8-acetoxy-3-((tert-butoxycarbonyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (1.0 g, 2.72 mmol) in MeOH (10 mL) was added saturated aq. NaHCO₃ (3.0 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (500 mg, yield 59.0%) as a yellow solid. LC/MS (ESI) (m/z): 312 (M+H)⁺. Step 2: Methyl (6S,8S)-3-((tert-butoxycarbonyl)amino)-8-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate and Methyl (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-hydroxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylate To a solution of (6S)-3-((tert-butoxycarbonyl)amino)-8-hydroxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (500 mg, 1.61 mmol) in THF/MeOH (10 mL) was added TMSCH₂N₂ (1.7 mL, 3.54 mmol) under N₂ atmosphere, and the reaction mixture was stirred under N2 atmosphere at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) and further purified by prep-SFC (ChiralCEL OX, 250×20mm I.D., 5µm, A for CO₂ and B for MeOH (0.1% DEA)) to give methyl (6S,8S)-3-((tert-butoxycarbonyl)amino)-8-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (peak 1, retention time: 1.316 min) (130 mg, yield 24.9%) as a colorless solid (¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.23 (s, 1H), 5.04 – 5.01 (m, 2H), 3.83 (s, 3H), 2.87 – 2.80 (m, 1H), 2.41 – 2.36 (m, 1H), 1.51 (s, 9H); LC/MS (ESI) m/z: 326 (M+H)⁺) and methyl (6S,8R)-3-((tert- butoxycarbonyl)amino)-8-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylate (peak 2, retention time: 1.912 min) (115 mg, yield 21.7%) as a colorless oil (¹H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.19 (s, 1H), 5.22 – 5.18 (m, 1H), 5.14 (dd, J = 9.7, 2.3 Hz, 1H), 3.82 (s, 3H), 2.75 – 2.69 (m, 1H), 2.56 – 2.48 (m, 1H), 1.51 (s, 9H); LC/MS (ESI) m/z: 326 (M+H)⁺). Step 3: Methyl (6S,8S)-3-((tert-butoxycarbonyl)amino)-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a solution of methyl (6S,8S)-3-((tert-butoxycarbonyl)amino)-8-hydroxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (120 mg, 0.37 mmol) in CHCl3 (3 mL) was added Ag2CO3 (152 mg, 0.55 mmol) and MeI (105 mg, 0.74 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (70 mg, yield 56%) as a yellow oil. LC/MS (ESI) m/z: 340 (M+H)⁺. Step 4: Methyl (6S,8S)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate A solution of methyl (6S,8S)-3-((tert-butoxycarbonyl)amino)-8-methoxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (60 mg, 0.18 mmol) in TFA (2 mL) was stirred under N₂ atmosphere at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (40 mg, yield 95.2%) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 240 (M+H)⁺. The methyl (6S,8S)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate was used to prepare Compound 178 based on the procedures set forth in, e.g., Scheme 27. ¹H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 7.28 - 7.24 (m, 2H), 7.22 - 7.19 (m, 2H), 7.18 - 7.14 (m, 2H), 7.04 (s, 1H), 6.96 (s, 1H), 5.08 - 5.06 (m, 1H), 4.77 - 4.76 (m, 1H), 4.60 - 4.58 (m, 2H), 3.50 (s, 3H), 3.14 - 3.10 (m, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.59 - 2.53 (m, 1H), 2.47 - 2.40 (m, 1H), 2.21 - 2.17 (m, 1H), 1.97 - 1.94 (m, 1H). LC/MS (ESI) (m/z): 505 (M+H)⁺. RT (Method A): 1.23 min. Compound 177 was prepared from the methyl (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-hydroxy- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylate obtained from Step 2 according to the procedures set forth above.¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.25 (d, J = 7.4 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 7.17 – 7.14 (m, 2H), 7.03 (s, 1H), 6.95 (s, 1H), 4.98 – 4.96 (m, 1H), 4.56 (s, 2H), 4.55 – 4.53 (m, 1H), 3.42 (s, 3H), 3.14 – 3.11 (m, 2H), 2.87 – 2.79 (m, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.32 – 2.26 (m, 1H), 2.20 – 2.17 (m, 1H), 1.97 – 1.95 (m, 1H). LC/MS (ESI) (m/z): 505 (M+H)⁺. RT (Method A): 1.29 min. Scheme 65. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-2-methyl-4-oxo-3-((3- phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 181) Step 1: Methyl (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate To a mixture of methyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (400 mg, 1.91 mmol) and 3-phenylpropanal (513 mg, 3.83 mmol) in MeOH (10 mL) was added MgSO4 (2.3 g, 19.13 mmol) and NaBH3CN (601 mg, 9.56 mmol), and the reaction mixture was stirred under N2 atmosphere at 50 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 50 - 80% PE in EtOAc) to give the title compound (400 mg, yield 64.0%) as a yellow solid. LC/MS (ESI) m/z: 328 (M+H)⁺. Step 2: Methyl (S)-2-bromo-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine- 6-carboxylate To a mixture of methyl (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate (400 mg, 1.22 mmol) in AcOH (4.0 mL) was added Br2 (2.3 g, 19.13 mmol) in AcOH (4.0 mL) dropwise at room temperature, and the reaction mixture was stirred under N₂ atmosphere at room temperature for 2 hours. The mixture was quenched with saturated aq. Na₂S₂O₃ solution and extracted with EtOAc twice. The combined organic layers were washed with saturated aq. NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 30 - 60% EtOAc in PE) to give the title compound (270 mg, yield 54.5%) as a yellow solid. LC/MS (ESI) m/z: 406 (M+H)⁺. Step 3: Methyl (S)-2-methyl-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine- 6-carboxylate To a mixture of methyl (S)-2-bromo-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (200 mg, 0.49 mmol), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (314 mg, 2.5 mmol), CsF (91 mg, 0.6 mmol), and K₂CO₃ (207 mg, 1.5 mmol) in 1,4- dioxane (4 mL) and water (1 mL) was added Pd(dtbpf)Cl₂ (37 mg, 0.05 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 20 - 60% EtOAc in PE) to give the title compound (30 mg, yield 18.9%) as a yellow oil. LC/MS (ESI) m/z: 342 (M+H)⁺. Step 4: (S)-2-Methyl-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxylic acid To a solution of methyl (S)-2-methyl-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (30 mg, 0.59 mmol) in MeOH (2 mL) and water (0.5 mL) was added LiOH (28 mg, 1.17 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (20 mg, yield 62.6%) as a yellow solid, which was used in next step without purification. LC/MS (ESI) (m/z): 328 (M+H)⁺. Step 5: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-2-methyl-4-oxo-3-((3-phenylpropyl)amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 181) To a mixture of 2-(aminomethyl)thieno[3,2-c]pyridin-6-amine (17 mg, 0.09 mmol) and (S)-2- methyl-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylic acid (20 mg, 0.06 mmol) in DMF (0.4 mL) was added HATU (38 mg, 0.1 mmol) and DIPEA (39 mg, 0.3 mmol), and the mixture was stirred at room temperature for 0.5 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) and further purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH_3.H₂O) to give Compound 181 (1.2 mg, yield 2.8%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.25 - 7.20 (m, 2H), 7.17 - 7.11 (m, 4H), 6.93 (s, 1H), 5.08 - 5.04 (m, 1H), 4.60 - 4.57 (m, 2H), 3.21 - 3.14 (m, 1H), 3.07 (t, J = 7.0 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.61 - 2.52 (m, 1H), 2.24 (s, 3H), 2.21 - 2.15 (m, 1H), 2.05 - 2.01 (m, 1H), 1.83 - 1.76 (m, 2H). LC/MS (ESI) (m/z): 489 (M+H)⁺. RT (Method A): 1.09 min. Scheme 66. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3-(1-(tert-butyl)-1H- pyrazol-4-yl)propyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 182) To a mixture of 4-bromo-1-(tert-butyl)-1H-pyrazole (5.0 g, 24.6 mmol) and tert-butyl prop-2-yn-1- ylcarbamate (4.9 mg, 31.9 mmol) in TEA (17 mL) and DMSO (50 mL) was added CuI (475 mg, 2.46 mmol) and Pd(PPh₃)₂Cl₂ (877 mg, 2.46 mmol) under N₂ atmosphere, and the mixture was degassed under N₂ atmosphere three times and stirred at 80 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (503 mg, yield 7.38%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.56 (s, 1H), 7.29 (s, 1H), 3.93 - 3.88 (m, 3H), 1.49 (s, 9H), 1.38 (s, 9H). LC/MS (ESI) m/z: 278 (M+H)⁺. Step 2: tert-Butyl (3-(1-(tert-butyl)-1H-pyrazol-4-yl)propyl)carbamate To a solution of tert-butyl (3-(1-(tert-butyl)-1H-pyrazol-4-yl)prop-2-yn-1-yl)carbamate (460 mg, 0.56 mmol) in EtOAc (5 mL) was added Pd/C (20 mg, 10% wt.) and Pd(OH)2/C (20 mg, 10% wt.), and the mixture was degassed under N2 atmosphere three times and stirred under a H2 balloon at 25 °C for 3 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (450 mg, yield 96.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 282 (M+H)⁺. Step 3: 3-(1-(tert-Butyl)-1H-pyrazol-4-yl)propan-1-amine hydrochloride To a solution of tert-butyl (3-(1-(tert-butyl)-1H-pyrazol-4-yl)propyl)carbamate (450 mg, 1.60 mmol) in DCM (1 mL) was added HCl/MeOH (5 mL, 4.0 M). The reaction mixture was stirred at 45 °C for 6 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (307 mg, yield 88.3%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 182 (M+H)⁺. The 3-(1-(tert-butyl)-1H-pyrazol-4-yl)propan-1-amine hydrochloride was used to prepare Compound 182 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (t, J = 5.7 Hz, 1H), 8.47 (s, 1H), 7.60 (s, 1H), 7.27 (s, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 6.94 (s, 1H), 6.46 (s, 2H), 5.09 (s, 1H), 5.00 - 4.95 (m, 1H), 4.52 - 4.43 (m, 2H), 3.04 - 2.99 (m, 2H), 2.97 - 2.81 (m, 2H), 2.48 - 2.42 (m, 3H), 2.09 - 2.02 (m, 1H), 1.83 - 1.75 (m, 2H), 1.47 (s, 9H). LC/MS (ESI) (m/z): 521 (M+H)⁺. RT (Method A): 1.01 min. Scheme 67. Synthesis of (S)-N-((3-Aminothieno[3,2-c]pyridazin-6-yl)methyl)-3-(((1-(2- fluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 183) Methyl 4,6-dichloropyridazine-3-carboxylate (2.51 g, 12.1 mmol) and THF (20 mL, 246 mmol) were combined and cooled to -78 °C in a dry ice/acetone bath. DIBAL-H (1.0M in toluene, 18 mL, 18 mmol) was added via syringe pump (1.5 mL/min), and the resulting mixture was stirred at -78 °C for 2 hours. Afterwards, the mixture was warmed to 0 °C in a brine/ice bath and quenched with 1M HCl solution (~10 mL). EtOAc (10 mL) and Rochelle's salt solution (~50 mL) were then added. The mixture was then warmed to room temperature and stirred for 20 minutes. The resulting slurry was filtered over Celite and washed with EtOAc. The organic layer was isolated, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (1.5 g, 70% yield) as a brown oil, which was used without further purification. LC/MS: (ESI+) m/z = 195 [Mhydrate+H]⁺. Step 2: Methyl 3-chlorothieno[3,2-c]pyridazine-6-carboxylate 4,6-Dichloropyridazine-3-carbaldehyde (2.4 g, 14 mmol) and MeCN (10 mL) were combined and cooled to 0 °C in a brine/ice bath. Methyl 2-sulfanylacetate (1.25 mL, 13.9 mmol) and TEA (4.0 mL, 29 mmol) were then added dropwise, and the resulting mixture was warmed to room termperature and stirred overnight. Afterwards, the mixture was diluted with water (~100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash chromatography (20-100% EtOAc in hexanes) afforded the title compound (608 mg, 20% yield) as a brown solid. LC/MS: (ESI+) m/z = 229 [M+H]⁺. Step 3: 3-[(2,5-Dimethoxyphenyl)methylamino]thieno[3,2-c]pyridazine-6-carboxamide Methyl 3-chlorothieno[3,2-c]pyridazine-6-carboxylate (330 mg, 1.44 mmol) was combined with NH3 in MeOH (7.0 N, 5 mL), and the mixture was heated to 60 °C for 1 hour. Afterwards, the mixture was concentrated in vacuo to afford the crude primary amide (LC/MS: (ESI+) m/z = 214). Next, the crude white solid was taken up in (2,4-dimethoxyphenyl)methanamine (2.2 mL, 15 mmol) in a 5 mL microwave vial and irradiated at 120 °C for 30 minutes. Afterwards, the mixture was subjected to flash chromatography (RediSep Rf Gold silica, 12g, 0-25% MeOH in DCM) to afford the title compound (40 mg, 8% yield) as an orange solid. LC/MS: (ESI+) m/z = 345 [M+H]⁺. Step 4: 6-(Aminomethyl)-N-[(2,5-dimethoxyphenyl)methyl]thieno[3,2-c]pyridazin-3-amine 3-[(2,5-Dimethoxyphenyl)methylamino]thieno[3,2-c]pyridazine-6-carboxamide (40 mg, 0.116 mmol) was dissolved in MeTHF (5.0 mL) and cooled to 0 °C in a brine/ice bath. LAH (1 mol/L) in THF (1.5 mL, 3.0 mmol) was added dropwise, and the resulting mixture was warmed to room temperature and stirred for 1 hour. Afterwards, the mixture was again cooled to 0 °C and quenched using an adapted Fieser method: 0.150 mL water was added slowly followed by 3.0 N NaOH solution (0.15 mL). Water (0.45 mL) was again added, and the mixture was warmed to room temperature. A spatula tip of MgSO4 was added, followed by 15 minutes of stirring at room temperature. The mixture was then filtered over Celite, and the filtrate was concentrated in vacuo to afford the title compound (38 mg, 99% yield) as an orange residue, which was carried forward without further purification. LC/MS: (ESI+) m/z = 331 [M+H]⁺. Step 5: 6-(Aminomethyl)thieno[3,2-c]pyridazin-3-amine dihydrochloride 6-(Aminomethyl)-N-[(2,5-dimethoxyphenyl)methyl]thieno[3,2-c]pyridazin-3-amine (38 mg, 0.115 mmol) was combined with 4N HCl in dioxane (3.0 mL) at room temperature, and the mixture was stirred for 2 hours. Afterwards, the mixture was concentrated in vacuo. The residue was then washed with MTBE (3 x 5 mL) and dried to afford the title compound (20 mg, 69% yield) as an orange solid, which was carried forward without further purification. LC/MS: (ESI+) m/z = 181 [M+H]⁺. Step 6: (S)-N-((3-Aminothieno[3,2-c]pyridazin-6-yl)methyl)-3-(((1-(2-fluorophenyl)-1H-pyrazol-4- yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 183) A 20 mL vial was charged with 6-(aminomethyl)thieno[3,2-c]pyridazin-3-amine dihydrochloride (19 mg, 0.075 mmol), (6S)-3-[[1-(2-fluorophenyl)pyrazol-4-yl]methylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (20 mg, 0.054 mmol), DMF (1 mL, 12.9 mmol), and TEA (0.050 mL, 0.38 mmol) and cooled to 0 ˚C in a brine/ice bath. HATU (26 mg, 0.068 mmol) was then added, and the resulting mixture was stirred at 0 ˚C for 10 minutes. Afterwards, the mixture was quenched with 1M HCl (~2 mL) and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 4g, 0-50% MeOH in DCM) followed by prep-HPLC (C18, 150 x 21 mm, 5 μM, 10-50% MeCN [0.1% FA] in water [0.1% FA]) and lyophilization afforded Compound 183 (1.7 mg, 6% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (t, J = 6.0 Hz, 1H), 8.20 (s, 1H), 7.84 – 7.73 (m, 2H), 7.53 – 7.31 (m, 4H), 7.22 (s, 1H), 7.10 (s, 1H), 6.33 (s, 2H), 5.58 (t, J = 5.9 Hz, 1H), 4.99 (d, J = 7.6 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 4.20 (d, J = 6.2 Hz, 2H), 3.05 – 2.70 (m, 2H), 2.14 – 1.97 (m, 1H), 0.93 – 0.76 (m, 1H). LC/MS: (ESI+) m/z = 532 [M+H]⁺. RT (Method A): 1.01 min. Scheme 68. Synthesis of (6S)-N-[(6-Aminothieno[3,2-c]pyridin-2-yl)methyl]-3-[3-(5-cyclopropyl- 1,3,4-thiadiazol-2-yl)propylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 184) To a suspension of 5-cyclopropyl-1,3,4-thiadiazol-2-amine (0.3 g, 2.1 mmol) in MeCN (15 mL) was added CuBr₂ (0.95 g, 4.3 mmol). The mixture turned dark green and was further stirred for 15 minutes at room temperature. Tert-butyl nitrite (0.5 mL, 4.3 mmol) was added dropwise over 15-20 minutes. The mixture became slightly warm, and gas evolved after 5 minutes and throughout the addition. After completion of the addition and gas evolution subsided, the mixture was heated at 60 °C for 30 minutes. The solvent was then evaporated in vacuo. Water and EtOAc were added, and the mixture was agitated in the flask until the dark-green color disappeared. The organic phase became light-brown, and the aqueous phase was green with insoluble material. The mixture was filtered through Celite and washed with EtOAc. The EtOAc layer was separated, washed with dilute brine solution, dried with Na₂SO₄, and concentrated to give the title compound (0.4 g, 90% yield), which was used in the next step without further purification. Step 2: 2-Cyclopropyl-5-[2-(1,3-dioxolan-2-yl)ethyl]-1,3,4-thiadiazole A vial was charged with 2-bromo-5-cyclopropyl-1,3,4-thiadiazole (0.2 g, 1 mmol), 2-[2-(1,3- dioxolan-2-yl)ethyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2 g, 1 mmol), K₂CO₃ (0.3 g, 2 mmol), and Pd(PPh3)4 (0.1 g, 0.1 mmol). Dioxane and water were added, and the mixture was purged with nitrogen for 3 minutes and heated at 100 °C overnight. The mixture was cooled to room temperature and extracted with EtOAc and NaHCO₃ solution. The organic layer was isolated, dried, and evaporated. The crude material was purified using CombiFlash chromatography to give the title compound (140 mg, 60% yield). LC/MS: (ESI+) m/z = 227 [M+H]⁺. Step 3: 3-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)propanal To a solution of 2-cyclopropyl-5-[2-(1,3-dioxolan-2-yl)ethyl]-1,3,4-thiadiazole (0.14 g, 0.62 mmol) in THF (5 mL) was added 1 N HCl(5 mL), and the mixture was stirred at room temperature for 6 hours. Saturated NaHCO3 solution was added, and the mixture was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to give the title compound (43 mg, 38% yield) as a clear, colorless gum, which was used in the next step without further purification. Step 4: tert-Butyl (6S)-3-[3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)propylamino]-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylate A vial was charged with tert-butyl (6S)-3-amino-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxylate (0.04 g, 0.16 mmol), 3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)propanal (0.043 g, 0.24 mmol), DCE, and AcOH (0.01 mL, 0.16 mmol) at room temperature under nitrogen. The mixture was stirred for 30 minutes, and sodium triacetoxyborohydride (0.051 g, 0.24 mmol) was added to the mixture. The reaction mixture was stirred overnight at room temperature. Afterwards, the mixture was diluted with DCM (25 mL), washed with saturated NaHCO₃ solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep Rf Gold silica, 40g, 0-10% MeOH in DCM) afforded tert-butyl (6S)-3-[3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)propylamino]-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylate (37 mg, 56% Yield). LC/MS: (ESI+) m/z = 371 [M+H]⁺. Step 5: (6S)-3-[3-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)propylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid Tert-Butyl (6S)-3-[3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)propylamino]-4-oxo-7,8-dihydro-6H- pyrrolo[1,2-a]pyrimidine-6-carboxylate (0.04 g, 0.09 mmol) was dissolved in DCM (2 mL). TFA (1 mL) was added, and the mixture was allowed to stir at room temperature for 3 hourrs. The solvent and the reagent were evaporated to complete dryness to give the title compound (32 mg, 100% yield), which was used in next step without further purification. LC/MS: (ESI+) m/z = 315 [M+H]⁺. Step 6: (6S)-N-[(6-Aminothieno[3,2-c]pyridin-2-yl)methyl]-3-[3-(5-cyclopropyl-1,3,4-thiadiazol-2- yl)propylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 184) (6S)-3-[3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)propylamino]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (0.032 g, 0.09 mmol), 2-(aminomethyl)thieno[3,2-c]pyridin-6-amine dihydrochloride (0.025 g, 0.1 mmol), and DIPEA (0.08 mL, 0.45 mmol) were dissolved in DCM, and the mixture was cooled to 0 °C. HATU (0.052 g, 0.13 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was washed with saturated NaHCO₃, and organic layer was isolated, dried over Na2SO4, and concentrated. The crude mixture was purified using column chromatography (10-20 % MeOH in DCM) to give Compound 184 (14 mg, 30% yield).¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (t, J = 5.9 Hz, 1H), 8.34 (s, 1H), 7.04 (s, 1H), 6.94 (d, J = 12.1 Hz, 1H), 6.76 (d, J = 3.0 Hz, 1H), 5.78 (s, 2H), 5.20 (t, J = 5.9 Hz, 1H), 4.90 (dd, J = 9.4, 2.6 Hz, 1H), 4.46 – 4.30 (m, 2H), 3.02 (dd, J = 12.6, 6.8 Hz, 4H), 2.92 – 2.84 (m, 1H), 2.80 – 2.74 (m, 1H), 2.40 – 2.36 (m, 2H), 2.04 – 1.83 (m, 3H), 1.16 – 1.05 (m, 2H), 0.94 – 0.87 (m, 2H). LC/MS: (ESI+) m/z = 523 [M+H]⁺. RT (Method A): 0.75 min. Compound 185 was synthesized according to the procedures set forth above using 2-bromo-5- methyl-thiazole in Step 2 (4 mg, 16% Yield).¹H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.38 (s, 1H), 7.30 (d, J = 1.4 Hz, 1H), 6.99 (s, 1H), 6.94 (s, 1H), 6.89 (s, 1H), 5.10 (dd, J = 8.9, 1.5 Hz, 1H), 4.73 – 4.62 (m, 3H), 4.54 (dd, J = 15.4, 5.6 Hz, 1H), 3.27 (dt, J = 16.8, 9.6 Hz, 1H), 3.12 – 2.85 (m, 5H), 2.80 – 2.70 (m, 1H), 2.44 (s, 3H), 2.40 – 2.25 (m, 1H), 2.07 (qt, J = 13.8, 6.9 Hz, 2H), 0.08 (s, 1H). LC/MS: (ESI+) m/z = 496 [M+H]⁺. RT (Method A): 0.80 min. Scheme 69. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3-(6-cyclopropyl- pyridin-3-yl)propyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 189) Step 1: 3-(6-Cyclopropylpyridin-3-yl)propan-1-ol To a solution of prop-2-en-1-ol (1.26 g, 21.7 mmol) in THF (11 mL) was added 9-BBN (100 mL, 50 mmol, 0.5 M in THF) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. Afterwards, 5-bromo-2-cyclopropylpyridine (3.6 g, 18.18 mmol), K2CO3 (25 mL, 75 mmol, 3M/L) and Pd(PPh3)4 (1.0 g, 0.86 mmol) was added successively to the above mixture at 25 °C under N2 atmosphere. The resulting mixture was degassed under N2 atmosphere three times and stirred at 70 °C for 3 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (2.0 g, yield 62.1%) as a yellow oil. LC/MS (ESI) (m/z): 178 (M+H)⁺. Step 2: 3-(6-Cyclopropylpyridin-3-yl)propyl methanesulfonate To a solution of 3-(6-cyclopropylpyridin-3-yl)propan-1-ol (2.0 g, 11.3 mmol) and TEA (3.43 g, 33.9 mmol) in DCM (20 mL) was added MsCl (1.93 g, 16.9 mmol) at 0 °C and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (1.8 g, yield 62.9%) as a yellow oil, which was used directly in the next reaction. LC/MS (ESI) (m/z): 256 (M+H)⁺. Step 3: 5-(3-Azidopropyl)-2-cyclopropylpyridine To a solution of 3-(6-cyclopropylpyridin-3-yl)propyl methanesulfonate (1.8 g, 7.05 mmol) and NaI (105.8 mg, 0.7 mmol) in DMSO (20 mL) was added NaN3 (1.37 g, 21.15 mmol) at 25 °C under N2 atmosphere, and the reaction mixture was degassed under N₂ atmosphere three times and stirred at 80 °C for 3 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to the title compound (1.2 g, yield 84.1%) as a yellow oil. LC/MS (ESI) m/z: 203 (M+H)⁺. Step 4: 3-(6-Cyclopropylpyridin-3-yl)propan-1-amine To a solution of 5-(3-azidopropyl)-2-cyclopropylpyridine (1.2 g, 5.94 mmol) and NH3.H2O (2.01 g, 59.4 mmol) in THF (15 mL) was added PPh₃ (3.12 g, 11.88 mmol), and the mixture was degassed under N₂ atmosphere three times and stirred at 50 °C overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 – 20% MeOH in DCM) to give the title compound (900 mg, yield 86.0%) as a yellow oil. LC/MS (ESI) m/z: 177 (M+H)⁺. The 3-(6-cyclopropylpyridin-3-yl)propan-1-amine was used to prepare Compound 189 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, CD₃OD) δ 8.44 (d, J = 11.4 Hz, 2H), 8.29 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 7.04 (s, 1H), 5.12 (d, J = 9.3 Hz, 1H), 4.62 (s, 2H), 3.20 - 3.17 (m, 2H), 3.15 - 3.01 (m, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.68 - 2.60 (m, 1H), 2.35 - 2.26 (m, 2H), 2.03 - 1.99 (m, 2H), 1.44 - 1.39 (m, 2H), 1.20 - 1.15 (m, 2H). LC/MS (ESI) (m/z): 516 (M+H)⁺. RT (Method A): 0.37 min. Scheme 70. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(5- phenylthiazol-2-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 191) Step 1: 2-(1-Ethoxyvinyl)-5-phenylthiazole To a mixture of 2-bromo-5-phenylthiazole (4.0 g, 16.74 mmol) and tributyl(1-ethoxyvinyl)stannane (12.1 g, 33.41 mmol) in 1,4-dioxane (50 mL) was added Pd(PPh3)2Cl2 (1.2 g, 1.71 mmol) and TEA (5.1 g, 50.4 mmol). The mixture was degassed under N₂ atmosphere three times, and the reaction mixture was stirred at 100 °C overnight. The mixture was diluted with EtOAc, washed with saturated aq. KF solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (2.9 g, yield 75.3%) as a yellow solid. LC/MS (ESI) m/z: 232 (M+H)⁺. Step 2: 1-(5-Phenylthiazol-2-yl)ethan-1-one To a solution of 2-(1-ethoxyvinyl)-5-phenylthiazole (2.9 g, 12.55 mmol) in THF (30 mL) was added 1N HCl (30 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (2.5 g, yield 98.1%) as a yellow solid. LC/MS (ESI) m/z: 204 (M+H)⁺. Step 3: (R,E)-2-Methyl-N-(1-(5-phenylthiazol-2-yl)ethylidene)propane-2-sulfinamide To a mixture of 1-(5-phenylthiazol-2-yl)ethan-1-one (2.5 g, 12 mmol) and (R)-2-methylpropane-2- sulfinamide (2.2 g, 18 mmol) in THF (30 mL) was added Ti(Oi-Pr)4 (8.8 g, 31 mmol) under N2 atmosphere, and the reaction mixture was stirred at 100 °C overnight. The mixture was poured into ice water and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (3 g, yield 79.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 307 (M+H)⁺. Step 4: (R)-2-Methyl-N-((R)-1-(5-phenylthiazol-2-yl)ethyl)propane-2-sulfinamide To a solution of (R,E)-2-methyl-N-(1-(5-phenylthiazol-2-yl)ethylidene)propane-2-sulfinamide (2.4 g, 7.84 mmol) in DCM (30 mL) was added DIBAL-H (2.2 g, 15.47 mmol) in portions at -40 °C. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with saturated aq. NH₄Cl solution and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (880 mg, yield 36.4%) as a yellow solid. The absolute configuration was confirmed by Mosher’s method after removing the protecting group. LC/MS (ESI) (m/z): 309 (M+H)⁺. Step 5: (R)-1-(5-Phenylthiazol-2-yl)ethan-1-amine To a solution of (R)-2-methyl-N-((R)-1-(5-phenylthiazol-2-yl)ethyl)propane-2-sulfinamide (880 mg, 2.86 mmol) in HCl/1,4-dioxane (3 mL, 4M) was stirred under N₂ atmosphere at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (490 mg, yield 84.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 6: Methyl (S)-4-oxo-3-(((R)-1-(5-phenylthiazol-2-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of (R)-1-(5-phenylthiazol-2-yl)ethan-1-amine (380 mg, 1.86 mmol) and methyl (S)-3- bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (557 mg, 2.05 mmol) in toluene (5 mL) was added Pd-175 (295 mg, 0.37 mmol) and Cs2CO3 (1.8 g, 5.52 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at 100 °C for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (133 mg, yield 18.0%) as a yellow solid. LC/MS (ESI) m/z: 397 (M+H)⁺. Step 7: (S)-4-Oxo-3-(((R)-1-(5-phenylthiazol-2-yl)ethyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine- 6-carboxylic acid To a solution of methyl (S)-4-oxo-3-(((R)-1-(5-phenylthiazol-2-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (90 mg, 0.23 mmol) in MeOH (1.5 mL) and water (0.5 mL) was added LiOH (16 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness and the residue was purified by prep-HPLC to give the title compound (51 mg, yield 58.6%) as a colorless solid. LC/MS (ESI) m/z: 383 (M+H)⁺. Step 8: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(5-phenylthiazol-2- yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 191) To a mixture of (S)-4-oxo-3-(((R)-1-(5-phenylthiazol-2-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (17 mg, 0.04 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (11 mg, 0.05 mmol) in DMF (2 mL) was added T3P (42 mg, 0.07 mmol, 50% wt. in EtOAc) and DIPEA (1.6 mg, 0.02 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 191 (3 mg, yield 12.4%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.97 (s, 1H), 7.58 (d, J = 7.3 Hz, 2H), 7.43 - 7.39 (m, 2H), 7.37 - 7.32 (m, 1H), 7.19 (s, 1H), 7.01 (d, J = 11.0 Hz, 2H), 5.14 - 5.08 (m, 1H), 4.83 - 4.77 (m, 2H), 4.60 - 4.57 (m, 1H), 3.18 - 3.11 (m, 1H), 2.99 - 2.92 (m, 1H), 2.62 - 2.55 (m, 1H), 2.31 - 2.26 (m, 1H), 1.73 (d, J = 6.7 Hz, 3H). LC/MS (ESI) (m/z): 544 (M+H)⁺. RT (Method A): 1.25 min. Compound 192 was prepared based on the procedures set forth above, using 5-bromo-2- phenylthiazole as the starting material in Step 1 and Pd₂(dba)₃ and RuPhos Pd G2 in place of Pd-175 in Step 6.¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.89 - 7.84 (m, 2H), 7.76 (s, 1H), 7.47 - 7.42 (m, 3H), 7.16 (s, 1H), 7.10 (s, 1H), 6.96 (s, 1H), 5.09 - 5.06 (m, 1H), 4.93 - 4.91 (m, 1H), 4.59 (d, J = 4.6 Hz, 2H), 3.16 - 3.08 (m, 1H), 2.98 - 2.91 (m, 1H), 2.61 - 2.49 (m, 1H), 2.26 - 2.19 (m, 1H), 1.70 (d, J = 6.7 Hz, 3H). LC/MS (ESI) m/z: 544 (M+H)⁺. RT (Method A): 1.19 min. The following compounds were also prepared following the procedures set forth above starting from Step 3, using the appropriate ketone. Scheme 71. Synthesis of (S)-N-((4-Aminothieno[2,3-d]pyridazin-2-yl)methyl)-4-oxo-3-(((R)-1-(2- phenylthiazol-5-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxamide (Compound 193) To a mixture of (S)-4-oxo-3-(((R)-1-(2-phenylthiazol-5-yl)ethyl)amino)-4,6,7,8-tetra- hydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (10 mg, 0.03 mmol) and 2-(amino-methyl)thieno[2,3- d]pyridazin-4-amine (6 mg, 0.03 mmol) in DMF (1 mL) was added DIPEA (17 mg, 0.13 mmol) and T3P (25 mg, 0.04 mmol, 50% wt. in DMF), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 193 (3.5 mg, yield 24.6%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.92 (s, 1H), 7.87 – 7.83 (m, 2H), 7.76 (s, 1H), 7.61 – 7.57 (m, 1H), 7.46 – 7.42 (m, 3H), 7.11 (s, 1H), 5.12 – 5.09 (m, 1H), 4.94 – 4.91 (m, 1H), 4.77 (d, J = 5.8 Hz, 2H), 3.15 – 3.09 (m, 1H), 2.99 – 2.91 (m, 1H), 2.63 – 2.53 (m, 1H), 2.30 – 2.22 (m, 1H), 1.70 (d, J = 6.7 Hz, 3H). LC/MS (ESI) m/z: 545 (M+H)⁺. RT (Method A): 1.16 min. The following compounds were prepared according to the procedures set forth above. Scheme 72. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(2- phenyloxazol-5-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 199) To a solution of 2-phenyloxazole-5-carbaldehyde (750 mg, 4.33 mmol) in THF (10 mL) was added MeMgBr (2.2 mL, 6.6 mmol, 3 M in THF) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with saturated aq. NH₄Cl solution and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (810 mg, yield 99.0%) as a yellow solid. LC/MS (ESI) (m/z): 190 (M+H)⁺. Step 2: 1-(2-Phenyloxazol-5-yl)ethan-1-one To a solution of 1-(2-phenyloxazol-5-yl)ethan-1-ol (810 mg, 4.3 mmol) in DCM (10 mL) was added DMP (2.72 g, 6.43 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated aq. Na₂S₂O₃ solution and filtered. The filtrate was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (700 mg, yield 87.3%) as a yellow solid. LC/MS (ESI) (m/z): 188 (M+H)⁺. Step 3: (R,E)-2-Methyl-N-(1-(2-phenyloxazol-5-yl)ethylidene)propane-2-sulfinamide To a mixture of 1-(2-phenyloxazol-5-yl)ethan-1-one (700 g, 3.74 mmol) and (R)-2-methylpropane- 2-sulfinamide (1.1 g, 9.8 mmol) in THF (10 mL) was added Ti(Oi-Pr)4 (4.4 g, 15.5 mmol) under N2 atmosphere, and the reaction mixture was stirred at 100 °C overnight. The mixture was poured into ice water and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (500 mg, yield 46.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 291 (M+H)⁺. Step 4: (R)-2-Methyl-N-((R)-1-(2-phenyloxazol-5-yl)ethyl)propane-2-sulfinamide To a solution of (R,E)-2-methyl-N-(1-(2-phenyloxazol-5-yl)ethylidene)propane-2-sulfinamide (490 mg, 1.69 mmol) in THF (10 mL) was added DIBAL-H (2.9 mL, 2.9 mmol, 1M in toluene) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated aq. NH₄Cl solution and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (376 mg, yield 76.2%) as a yellow solid. The absolute configuration was confirmed by Mosher’s method after removing the protecting group.¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (dd, J = 7.5, 2.0 Hz, 2H), 7.56 - 7.50 (m, 3H), 7.19 (s, 1H), 4.56 (p, J = 7.1 Hz, 1H), 1.53 (d, J = 6.9 Hz, 3H), 1.12 (s, 9H). LC/MS (ESI) (m/z): 293 (M+H)⁺. Step 5: (R)-1-(2-Phenyloxazol-5-yl)ethan-1-amine hydrochloride A solution of (R)-2-methyl-N-((R)-1-(2-phenyloxazol-5-yl)ethyl)propane-2-sulfinamide (150 mg, 0.51 mmol) in HCl/1,4-dioxane (3 mL, 4M) was stirred under N2 atmosphere at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (85 mg, yield 96.2%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 189 (M+H)⁺. Step 6: tert-Butyl (S)-4-oxo-3-(((R)-1-(2-phenyloxazol-5-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of (R)-1-(2-phenyloxazol-5-yl)ethan-1-amine hydrochloride (40 mg, 0.17 mmol) and tert-butyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (40 mg, 0.12 mmol) in toluene (2 mL) was added Pd-175 (29 mg, 0.037 mmol) and Cs₂CO₃ (167 mg, 0.5 mmol) under N₂ atmosphere and the reaction mixture was stirred under N2 atmosphere at 100 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (23 mg, yield 25.6%) as a yellow solid. LC/MS (ESI) m/z: 423 (M+H)⁺. Step 7: (S)-4-Oxo-3-(((R)-1-(2-phenyloxazol-5-yl)ethyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine- 6-carboxylic acid To a solution of tert-butyl (S)-4-oxo-3-(((R)-1-(2-phenyloxazol-5-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (10 mg, 0.02 mmol) in MeOH (1.5 mL) and water (0.5 mL) was added LiOH (16 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC to give the title compound (5 mg, yield 57.6%) as a yellow solid. LC/MS (ESI) m/z: 367 (M+H)⁺. Step 8: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(2-phenyloxazol-5- yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 199) To a mixture of (S)-4-oxo-3-(((R)-1-(2-phenyloxazol-5-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (5 mg, 0.01 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (11 mg, 0.05 mmol) in DMF (3 mL) was added HATU (42 mg, 0.07 mmol) and DIPEA (12.9 mg, 0.1 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 199 (5.0 mg, yield 69.4%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.98 - 7.94 (m, 2H), 7.51 - 7.47 (m, 3H), 7.22 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 6.96 (s, 1H), 5.10 - 5.06 (m, 1H), 4.83 - 4.80 (m, 1H), 4.63 - 4.55 (m, 2H), 3.15 - 3.12 (m, 1H), 3.00 - 2.92 (m, 1H), 2.59 - 2.48 (m, 1H), 2.28 - 2.21 (m, 1H), 1.68 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 528 (M+H)⁺. RT (Method A): 1.06 min. The following compounds were prepared according to the procedures set forth above. The following compounds were prepared based on the procedures above starting from Step 3. ^a Step 3 was performed with (S)-2-methylpropane-2-sulfinamide and Ti(OEt)4. Scheme 73. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3-(4-fluoro-phenoxy) propyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 200) To a mixture of 4-fluorophenol (5 g, 44.64 mmol) and 3-chloropropan-1-ol (6.3 g, 67.02 mmol) in i- PrOH (60 mL) was added KI (222 mg, 1.34 mmol) and K₂CO₃ (12.3 g, 89.0 mmol), and the reaction mixture was stirred under N₂ atmosphere at 100 °C overnight. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (7 g, yield 92.2%) as a colorless oil.¹H NMR (400 MHz, DMSO-d₆) δ 7.11 - 7.03 (m, 2H), 6.94 - 6.87 (m, 2H), 4.00 - 3.95 (m, 2H), 3.56 - 3.51 (m, 2H), 1.84 - 1.80 (m, 2H). Step 2: 3-(4-Fluorophenoxy)propanal To a solution of 3-(4-fluorophenoxy)propan-1-ol (500 mg, 2.94 mmol) in DCM (3 mL) was added PCC (950 mg, 4.41 mmol), and the reaction mixture was stirred under N2 atmosphere at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (400 mg, yield 81.0%) as a colorless oil, which was used directly in the next step without further purification.¹H NMR (400 MHz, DMSO-d₆) δ 9.73 (s, 1H), 7.13 - 7.10 (m, 2H), 6.97 - 6.94 (m, 2H), 4.27 - 4.24 (m, 2H), 2.89 - 2.86 (m, 2H). The 3-(4-fluorophenoxy)propanal was used to prepare Compound 200 based on the procedures set forth in, e.g., Scheme 23.¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.28 (d, J = 4.4 Hz, 2H), 7.07 (s, 1H), 6.97 - 6.93 (m, 2H), 6.91 - 6.87 (m, 2H), 5.10 - 5.06 (m, 1H), 4.66 (d, J = 16.1 Hz, 1H), 4.56 (d, J = 16.1 Hz, 1H), 4.07 - 4.02 (m, 2H), 3.29 (d, J = 6.5 Hz, 2H), 3.16 - 3.09 (m, 1H), 3.03 - 2.97 (m, 1H), 2.63 - 2.55 (m, 1H), 2.30 - 2.23 (m, 1H), 2.11 - 2.06 (m, 2H). LC/MS (ESI) (m/z): 509 (M+H)⁺. RT (Method A): 0.96 min. Scheme 74. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(3-(2- fluorophenyl)isoxazol-5-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 201) Step 1: (Z)-2-Fluoro-N-hydroxybenzimidoyl chloride To a solution of (E)-2-fluorobenzaldehyde oxime (1 g, 7.19 mmol) in DMF (10 mL) was added NCS (1.15 g, 8.63 mmol) in portions at room temperature and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (1 g, yield 79.9%) as a white solid. LC/MS (ESI) m/z: 174 (M+H)⁺. Step 2: tert-Butyl (R)-(1-(3-(2-fluorophenyl)isoxazol-5-yl)ethyl)carbamate To a solution of (Z)-2-fluoro-N-hydroxybenzimidoyl chloride (500 mg, 2.86 mmol) in TEA (5 mL) was added tert-butyl (R)-but-3-yn-2-ylcarbamate (531 mg, 3.14 mmol) at room temperature, and the mixture was stirred at 70 °C for 3 hours. The mixture was concentrated to dryness. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (330 mg, yield 37.7%) as a white solid. LC/MS (ESI) m/z: 307 (M+H)⁺. Step 3: (R)-1-(3-(2-Fluorophenyl)isoxazol-5-yl)ethan-1-amine To a solution of tert-butyl (R)-(1-(3-(2-fluorophenyl)isoxazol-5-yl)ethyl)carbamate (200 mg, 0.65 mmol) in DCM (2 mL) was added HCl/1,4-dioxane (1 mL, 4 M). The reaction mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure to dryness. The residue was diluted with DCM, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (120 mg, yield 89.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 207 (M+H)⁺. The (R)-1-(3-(2-fluorophenyl)isoxazol-5-yl)ethan-1-amine was used to prepare Compound 201 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (t, J = 5.9 Hz, 1H), 8.41 (s, 1H), 7.87 (t, J = 7.0 Hz, 1H), 7.60-7.53 (m, 1H), 7.42 - 7.32 (m, 2H), 7.12 (d, J = 5.3 Hz, 2H), 6.84 (s, 1H), 6.77 (d, J = 3.0 Hz, 1H), 5.84 (s, 2H), 5.55 (d, J = 8.6 Hz, 1H), 5.02 - 4.96 (m, 1H), 4.94 - 4.84 (m, 1H), 4.51 - 4.41 (m, 2H), 3.00 - 2.91 (m, 1H), 2.86 - 2.78 (m, 1H), 2.49 - 2.40 (m, 1H), 2.08 - 2.00 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 546 (M+H)⁺. RT (Method A): 1.18 min. The following compounds were prepared according to the procedures set forth above starting from Step 2 with the appropriate imidoyl chloride and bicycle in Step 3. Scheme 75. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(4-(5-methyl- 1,3,4-thiadiazol-2-yl)phenyl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine-6- carboxamide (Compound 204) To a mixture of (R)-1-(4-bromophenyl)ethan-1-amine (5 g, 25.1 mmol) in DCM (50 mL) was added Boc₂O (10.9 g, 50.2 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (5.8 g, yield 77.3%) as a white solid. LC/MS (ESI) m/z: 300 (M+H)⁺. Step 2: tert-Butyl (R)-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) ethyl)carbamate To a solution of tert-butyl (R)-(1-(4-bromophenyl)ethyl)carbamate (5.8 g, 19.4 mmol) in 1,4- dioxane (60 mL) was added KOAc (3.8 g, 19.4 mmol), B2pin2 (9.8 g, 38.8 mmol), and Pd(dppf)Cl2. The mixture was degassed under N₂ atmosphere three times. The mixture was stirred under N₂ atmosphere at 100 °C for 16 hours. The reaction mixture was used directly in the next step. LC/MS (ESI) m/z: 348 (M+H)⁺. Step 3: tert-Butyl (R)-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethyl)carbamate To a mixture of 2-bromo-5-methyl-1,3,4-thiadiazole (5.1 g, 28.5 mmol) and the solution from the previous step was added Pd(PPh3)4 (2.2 g, 1.9 mmol), K2CO3 (5.2 g, 38 mmol), and water (10 mL). The mixture was degassed under N2 atmosphere three times and stirred under N2 atmosphere at 100 °C for 4 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (2.3 g, yield 37.9% via two steps) as a yellow solid. LC/MS (ESI) m/z: 320 (M+H)⁺. Step 4: (R)-1-(4-(5-Methyl-1,3,4-thiadiazol-2-yl)phenyl)ethan-1-amine To a solution of tert-butyl (R)-(1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethyl)-carbamate (1 g, 3.1 mmol) in 1,4-dioxane (10 mL). The mixture was stirred under N2 atmosphere at room temperature for 1 hour. The reaction mixture was basified with saturated aq. NaHCO₃ solution. The filtrate was extracted with DCM twice. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (320 mg, yield 48.4%) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 220 (M+H)⁺. The (R)-1-(4-(5-Methyl-1,3,4-thiadiazol-2-yl)phenyl)ethan-1-amine was used to prepare Compound 204 based on the procedures set forth in, e.g., ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 7.17 (s, 1H), 6.97 (s, 1H), 6.73 (s, 1H), 5.07 (d, 1H), 4.60 (d, J = 5.0 Hz, 2H), 4.54 - 4.48 (m, 1H), 3.14 - 3.07 (m, 1H), 2.94 - 2.87 (m, 1H), 2.80 (s, 3H), 2.60 - 2.49 (m, 1H), 2.27 - 2.20 (m, 1H), 1.57 (d, J = 6.7 Hz, 3H). LC/MS (ESI) (m/z): 559 (M+H)⁺. RT (Method A): 0.93 min. Scheme 76. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(5- phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 207) and (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((S)-1-(5-phenyl- 1,3,4-oxadiazol-2-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 233) To a mixture of ((S)-6-(methoxycarbonyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidin-3-yl)-D- alanine (700 mg, 2.49 mmol) and benzohydrazide (407 mg, 2.99 mmol) in DMF (10 mL) was added DIPEA (1.6 g, 12.5 mmol) and T3P (2.4 g, 3.74 mmol, 50% wt. in DMF) at 0 °C under N2 atmosphere, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with CHCl₃/i-PrOH (v/v= 3/1) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) and further purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH3.H2O) to give the title compound (110 mg, yield 11.1%) as a white solid. LC/MS (ESI) m/z: 400 (M+H)⁺. Step 2: Methyl (6S)-4-oxo-3-((1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (S)-3-(((R)-1-(2-benzoylhydrazineyl)-1-oxopropan-2-yl)amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (100 mg, 0.05 mmol) in THF (1 mL) was added TEA (13 mg, 0.13 mmol) at 0 °C and the solution was stirred at room temperature for 1 hour. The above mixture was added dropwise to a solution of CBr₄ (36 mg, 0.1 mmol) and PPh₃ (26 mg, 0.1 mmol) in THF (1 mL) at 0 °C and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to give the title compound (60 mg, yield 63.2%) as a yellow oil. LC/MS (ESI) m/z: 382 (M+H)⁺. Step 3: (6S)-4-Oxo-3-((1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4,6,7,8-tetra-hydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (6S)-4-oxo-3-((1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (60 mg, 0.15 mmol) in THF (2 mL) and water (1 mL) was added LiOH (11 mg, 0.47 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (40 mg, yield 69.2%) as a colorless solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 368 (M+H)⁺. Step 4: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(5-phenyl-1,3,4-oxadiazol-2- yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 207) and (S)-N-((6- Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((S)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4,6,7,8- tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 233) To a mixture of (6S)-4-oxo-3-((1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (40 mg, 0.11 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (34 mg, 0.16 mmol) in DMF (2 mL) was added DIPEA (70 mg, 0.54 mmol) and HATU (62 mg, 0.16 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC- Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH₃.H₂O) and further purified by prep-SFC (ChiralCel OX, 250×30mm I.D., 5µm, A for CO2 and B for MeOH) to give Compound 207 (peak 2, retention time: 4.46 min) (7 mg, yield 12.2%) and Compound 233 (peak 3, retention time: 5.51) (2 mg, yield 3.5%) as a white solid. Compound 207: ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 - 8.99 (m, 1H), 8.41 (s, 1H), 7.98 - 7.94 (m, 2H), 7.63 - 7.58 (m, 3H), 7.23 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.64 (d, J = 8.5 Hz, 1H), 5.02 - 4.96 (m, 2H), 4.48 - 4.43 (m, 2H), 2.98 - 2.91 (m, 1H), 2.87 - 2.81 (m, 1H), 2.46 - 2.42 (m, 1H), 2.08 - 2.01 (m, 1H), 1.68 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 529 (M+H)⁺. Compound 233: ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 - 8.98 (m, 1H), 8.40 (s, 1H), 7.98 - 7.95 (m, 2H), 7.62 - 7.56 (m, 3H), 7.24 (s, 1H), 7.10 (s, 1H), 6.82 (s, 1H), 5.83 (s, 2H), 5.69 (d, J = 8.6 Hz, 1H), 5.03 - 4.96 (m, 2H), 4.48 - 4.42 (m, 2H), 3.00 - 2.92 (m, 1H), 2.91 - 2.85 (m, 1H), 2.46 - 2.44 (m, 1H), 2.08 - 2.01 (m, 1H), 1.66 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 529 (M+H)⁺. RT (Method A): 0.84 min. Compound 342 was prepared according to the procedures set forth above starting from Step 2, using methyl (S)-3-(((R)-1-(2-(3-fluorobenzoyl)hydrazineyl)-1-oxopropan-2-yl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate as the starting material.¹H NMR (400 MHz, DMSO-d6) δ 9.03 - 8.99 (m, 1H), 8.41 (s, 1H), 7.83 - 7.80 (m, 1H), 7.77 - 7.73 (m, 1H), 7.69 - 7.63 (m, 1H), 7.52 - 7.47 (m, 1H), 7.23 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.64 (d, J = 8.6 Hz, 1H), 5.03 - 4.96 (m, 2H), 4.49 - 4.42 (m, 2H), 3.01 - 2.92 (m, 1H), 2.87 - 2.80 (m, 1H), 2.48 - 2.43 (m, 1H), 2.08 - 2.01 (m, 1H), 1.68 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 547 (M+H)⁺. RT (Method A): 1.02 min. Scheme 77. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(1-(2- fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 211) Step 1: 1-(1-(2-Fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethan-1-one To a mixture of (2-fluorophenyl)hydrazine (1.0 g, 7.94 mmol) and 1-(2-amino-4-methylpyrimidin-5- yl)ethan-1-one (1.44 g, 9.53 mmol) in MeOH (10 mL) and water (4 mL) was added aq. HCl (2 mL, 12.0 M). The reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was neutralized with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) and to give the title compound (1.3 g, yield 75.1%) as a brown solid. LC/MS (ESI) m/z: 219 (M+H)⁺. Step 2: (R,E)-N-(1-(1-(2-Fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethylidene)-2-methylpropane-2- sulfinamide To a mixture of 1-(1-(2-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethan-1-one (1.3 g, 5.96 mmol) and (R)-2-methylpropane-2-sulfinamide (1.2 g, 17.88 mmol) in 1,4-dioxane (15 mL) was added Ti(OEt)₄ (4.1 g, 17.88 mmol) under N2 atmosphere, and the reaction mixture was stirred at 90 °C overnight. The mixture was poured into water and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.7 g, yield 89.0%) as a brown solid. LC/MS (ESI) m/z: 322 (M+H)⁺. Step 3: (R)-N-((R)-1-(1-(2-Fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethyl)-2-methyl-propane-2-sulfinamide To a solution of (R,E)-N-(1-(1-(2-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethylidene)-2- methylpropane-2-sulfinamide (600 mg, 1.87 mmol) in THF (6 mL) was added DIBAL-H (2.49 mL, 3.74 mmol, 1.5 M in THF) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. The mixture was quenched with saturated aq. NH4Cl solution and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (530 mg, yield 87.9%) as a yellow solid. LC/MS (ESI) (m/z): 324 (M+H)⁺. Step 4: (R)-1-(1-(2-Fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethan-1-amine To a solution of (R)-N-((R)-1-(1-(2-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethyl)-2-methylpropane- 2-sulfinamide (520 mg, 1.61 mmol) in DCM (5 mL) was added HCl/1,4-dioxane (1.0 mL, 4.0 M). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with saturated aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 16% MeOH in DCM) to give the title compound (350 mg, yield 99.3%) as a colorless oil. LC/MS (ESI) m/z: 220 (M+H)⁺. The (R)-1-(1-(2-Fluorophenyl)-3-methyl-1H-pyrazol-4-yl)ethan-1-amine was used to prepare Compound 211 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.90 (d, J = 2.7 Hz, 1H), 7.70 (s, 1H), 7.37 - 7.27 (m, 3H), 7.16 (s, 1H), 6.99 (s, 1H), 6.96 (s, 1H), 5.10 - 5.06 (m, 1H), 4.59 (d, J = 5.3 Hz, 2H), 4.55 (d, J = 6.6 Hz, 1H), 3.15 - 3.08 (m, 1H), 2.98 - 2.90 (m, 1H), 2.60 - 2.51 (m, 1H), 2.33 (s, 3H), 2.28 - 2.21 (m, 1H), 1.58 (d, J = 6.7 Hz, 3H). LC/MS (ESI) (m/z): 559 (M+H)⁺. RT (Method A): 1.12 min. Scheme 78. Synthesis of (S)-N-((6-Amino-1-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)- 4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydro-pyrrolo[1, 2-a]pyrimidine-6-carboxamide (Compound 212) To a mixture of 2-chloro-5-iodopyridin-4-amine (5.8 g, 23.0 mmol) and 2-(prop-2-yn-1- yloxy)tetrahydro-2H-pyran (3.55 g, 25.3 mmol) in TEA (12.5 mL) and MeCN (75 mL) was added CuI (650 mg, 3.42 mmol) and Pd(PPh₃)₂Cl₂ (806 mg, 1.15 mmol) under N₂ atmosphere, and the mixture was degassed under N₂ atmosphere three times and stirred at 50 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (6 g, yield 98.1%) as a yellow solid. LC/MS (ESI) m/z: 267 (M+H)⁺. Step 2: 6-Chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]pyridine To a solution of 2-chloro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-4-amine (6 g, 23 mmol) in MeCN (6 mL) was added KOH (2.57 g, 46 mmol) and the reaction mixture was stirred at 85 °C for 3 hours. The mixture was filtered, and the filter cake was washed with EtOAc twice. The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% MeOH in DCM) to give the title compound (4.9 g, yield 80.0%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (s, 1H), 8.56 (s, 1H), 7.36 (s, 1H), 6.55 (s, 1H), 4.77 (d, J = 12.8 Hz, 1H), 4.70 (t, J = 3.3 Hz, 1H), 4.60 (d, J = 12.8 Hz, 1H), 3.81 (m, 1H), 3.51 - 3.46 (m, 1H), 1.76 - 1.62 (m, 2H), 1.54 - 1.44 (m, 4H). LC/MS (ESI) m/z: 267 (M+H)⁺. Step 3: 6-Chloro-1-(difluoromethyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]pyridine To a solution of 6-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]pyridine (4 g, 15 mmol) in DMF (50 mL) was added K2CO3 (167 mg, 0.24 mmol) and ethyl 2-bromo-2,2-difluoroacetate (9 g, 45 mmol) under N₂ atmosphere, and the mixture was degassed under N₂ atmosphere three times and stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (1.5 g, yield 31.6%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (s, 1H), 8.56 (s, 1H), 7.36 (s, 1H), 6.55 (s, 1H), 4.77 (d, J = 12.8 Hz, 1H), 4.71 (t, J = 3.2 Hz, 1H), 4.60 (d, J = 12.8 Hz, 1H), 3.84 - 3.78 (m, 1H), 3.52 - 3.46 (m, 1H), 1.77 - 1.64 (m, 2H), 1.54 - 1.46 (m, 4H). LC/MS (ESI) m/z: 317 (M+H)⁺. Step 4: tert-Butyl (1-(difluoromethyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]pyridin-6- yl)carbamate To a mixture of 6-chloro-1-(difluoromethyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)-methyl)-1H- pyrrolo[3,2-c]pyridine (1.4 g, 4.43 mmol) and tert-butyl carbamate (1.55 g, 13.2 mmol) in toluene (5 mL) was added BrettPhos Pd G3 (362 mg, 0.22 mmol) and Cs2CO3 (2.96 g, 8.86 mmol) under N2 atmosphere, and the mixture was degassed under N₂ atmosphere three times and stirred at 110 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (597 mg, yield 33.9%) as a yellow solid. LC/MS (ESI) m/z: 398 (M+H)⁺. Step 5: (6-Amino-1-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol A solution of tert-butyl (1-(difluoromethyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)-methyl)-1H- pyrrolo[3,2-c]pyridin-6-yl)carbamate (200 mg, 0.94 mmol) in HCl/1,4-dioxane (3 mL, 4M) was stirred under N2 atmosphere at room temperature for 18 hours. The mixture was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 6% MeOH in DCM with 0.1% NH3.H2O) to give the title compound (52 mg, yield 52.0%) as a yellow solid. LC/MS (ESI) m/z: 214 (M+H)⁺. Step 6: 2-(Azidomethyl)-1-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-6-amine To a solution of (6-amino-1-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol (52 mg, 0.24 mmol) in toluene (3 mL) was added DBU (77 mg, 0.51 mmol) and DPPA (139 mg, 0.51 mmol) under N₂ atmosphere, and the mixture was degassed under N₂ atmosphere three times and stirred at 65 °C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 6% MeOH in DCM) to give the title compound (39 mg, yield 67.1%) as a yellow solid. LC/MS (ESI) m/z: 239 (M+H)⁺. Step 7: 2-(Aminomethyl)-1-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-6-amine hydrochloride To a solution of 2-(azidomethyl)-1-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-6-amine (39 mg, 0.16 mmol) in water (1 mL) and THF (2 mL) was added PPh₃ (42 mg, 0.16 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and washed with DCM. The aqueous phase was concentrated under reduced pressure to dryness to give the title compound (20 mg, yield 49.2%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 213(M+H)⁺. Step 8: (S)-N-((6-Amino-1-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((3- phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 212) To a mixture of 2-(aminomethyl)-1-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-6-amine hydrochloride (10 mg, 0.04 mmol) and (S)-4-oxo-3-((3-phenylpropyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (11 mg, 0.04 mmol) in DMF (1 mL) was added HATU (15 mg, 0.04 mmol) and DIPEA (50 mg, 0.38 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 10% - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 212 (2.0 mg, yield 9.86%) as a white solid.¹H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.70 - 7.40 (m, 1H), 7.27 - 7.15 (m, 5H), 6.98 - 6.93 (m, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 5.10 - 5.04 (m, 1H), 4.62 (s, 2H), 3.11 - 3.07 (m, 3H), 3.01 - 2.96 (m, 1H), 2.75 - 2.70 (m, 2H), 2.61 - 2.54 (m, 1H), 2.26 - 2.19 (m, 1H), 1.98 - 1.92 (m, 2H). LC/MS (ESI) (m/z): 508 (M+H)⁺. RT (Method A): 1.22 min. Scheme 79. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carboxamide (Compound 219) To a solution of methyl (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-methoxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (220 mg, 0.65 mmol) in THF/water (4 mL, v/v= 3/1) was added LiOH (31 mg, 1.3 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (190 mg, yield 90%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 326 (M+H)⁺. Step 2: (6S,8R)-3-Amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylic acid hydrochloride To a solution of (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-methoxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (190 mg, 0.58 mmol) in DCM (5 mL) was added HCl/1,4-dioxane (3 mL, 4 M), and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to dryness to give the title compound (240 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 226 (M+H)⁺. Step 3: tert-Butyl (2-(((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of (6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid hydrochloride (240 mg, 0.92 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6- yl)carbamate (257 mg, 0.92 mmol) in DMF (5 mL) was added DIPEA (356 mg, 2.76 mmol) and HATU (455 mg, 1.20 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (180 mg, yield 40%) as a yellow solid. LC/MS (ESI) m/z: 487 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,8R)-8-methoxy-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (40 mg, 0.08 mmol) and 5-phenyl- 1,3,4-thiadiazole-2-carboxylic acid (25 mg, 0.12 mmol) in MeCN (1 mL) was added TCFH (67 mg, 0.24 mmol) and NMI (33 mg, 0.40 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (20 mg, yield 37.1%) as a yellow solid. LC/MS (ESI) m/z: 675 (M+H)⁺. Step 5: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methoxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 219) To a solution of tert-butyl (2-(((6S,8R)-8-methoxy-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (20 mg, 0.03 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (2 mL, 4 M), and the reaction mixture was stirred room temperature for 3 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 30 - 70% MeCN in water with 0.1% NH3.H2O) to give Compound 219 (5 mg, yield 29.9%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 9.24 (t, J = 5.9 Hz, 1H), 8.80 (s, 1H), 8.42 (s, 1H), 8.14 - 8.10 (m, 2H), 7.66 - 7.60 (m, 3H), 7.14 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.15 (dd, J = 9.0, 2.7 Hz, 1H), 4.91 (t, J = 7.7 Hz, 1H), 4.53 - 4.44 (m, 2H), 3.56 (s, 3H), 2.59 - 2.54 (m, 1H), 2.45 - 2.38 (m, 1H). LC/MS (ESI) m/z: 575 (M+H)⁺. RT (Method A): 1.31 min. The following compounds were prepared according to the procedures set forth above using the appropriate bicycle in Step 1 or Step 2 and the appropriate carboxylic acid in Step 4. ^a Starting from Step 2. Compound 220 was prepared according to the procedures set forth above, using 5- phenylthiazole-2-carboxylic acid as the carboxylic acid in Step 4.¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.30 (t, J = 5.8 Hz, 1H), 8.97 (s, 1H), 8.88 (s, 1H), 8.55 (s, 1H), 7.85 - 7.82 (m, 2H), 7.67 - 7.60 (m, 2H), 7.53 - 7.46 (m, 3H), 7.20 (s, 1H), 7.16 (s, 1H), 5.15 (dd, J = 9.0, 2.8 Hz, 1H), 4.89 (t, J = 7.7 Hz, 1H), 4.53 - 4.49 (m, 2H), 3.55 (s, 3H), 2.45 - 2.39 (m, 1H), 2.12 - 1.89 (m, 1H). LC/MS (ESI) (m/z): 574 (M+H)⁺. RT (Method A): 1.51 min. Compound 356 was prepared according to the procedures set forth above starting from Step 3, using (6S,8R)-3-amino-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid and tert-butyl (2-(aminomethyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)carbamate as starting materials.¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.28 - 9.25 (m, 1H), 8.89 (s, 1H), 8.67 (d, J = 4.6 Hz, 1H), 8.40 (s, 1H), 8.13 - 8.08 (m, 1H), 7.82 - 7.78 (m, 1H), 6.83 (s, 2H), 6.69 (s, 1H), 6.57 (s, 1H), 6.21 - 6.04 (m, 1H), 5.30 - 5.27 (m, 1H), 4.64 - 4.58 (m, 1H), 4.49 - 4.44 (m, 1H), 3.60 (s, 3H), 2.79 - 2.70 (m, 2H). LC/MS (ESI) (m/z): 579 (M+H)⁺. RT (Method A): 1.50 min. Scheme 80. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluorophenyl) -1,3,4-thiadiazole-2-carboxamide (Compound Step 1: Ethyl To a solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (200 mg, 0.85 mmol) in toluene/water (3 mL, v/v= 5/1) was added (2-fluorophenyl)boronic acid (180 mg, 1.3 mmol), NMM (258 mg, 2.55 mmol), XantPhos (50 mg, 0.09 mmol), and Pd(OAc)2 (20 mg, 0.09 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (200 mg, yield 93%) as a white solid. LC/MS (ESI) m/z: 253 (M+H)⁺. Step 2: 5-(2-Fluorophenyl)-1,3,4-thiadiazole-2-carboxylic acid lithium salt To a solution of ethyl 5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxylate (60 mg, 0.24 mmol) in THF/water (3 mL, v/v= 2/1) was added LiOH (9 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give the title compound (60 mg) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 225 (M+H)⁺. Step 3: tert-Butyl (S)-(2-((3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (35 mg, 0.07 mmol) and 5-(2-fluorophenyl)-1,3,4- thiadiazole-2-carboxylic acid lithium salt (26 mg, 0.12 mmol) in MeCN (2 mL) was added TCFH (59 mg, 0.21 mmol) and NMI (23 mg, 0.28 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (25 mg, yield 50.2%) as a yellow solid. LC/MS (ESI) m/z: 663 (M+H)⁺. Step 4: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamide (Compound 221) To a solution of tert-butyl (S)-(2-((3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (25 mg, 0.038 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4M), and the reaction mixture was stirred room temperature for 3 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 30 - 95% MeCN in water with 0.1% HCl) to give Compound 221 (7 mg, yield 33.4%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 9.35 (t, J = 5.7 Hz, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 8.38 (t, J = 7.0 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.66 (s, 1H), 7.59 - 7.54 (m, 1H), 7.52 - 7.47 (m, 2H), 7.27 (s, 1H), 5.16 (dd, J = 9.4, 2.5 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 3.18 - 3.04 (m, 2H), 2.66 - 2.58 (m, 1H), 2.19 - 2.11 (m, 1H). LC/MS (ESI) m/z: 563 (M+H)⁺. RT (Method A): 1.24 min. The following compounds were prepared according to the procedures set forth above using the appropriate boronic acid in Step 1 and the appropriate carbamate in Step 3..

^a Step 4 was performed with TMSI in DCM. ^b Step 4 was performed with TFA in DCM. ^c Step 2 was performed with TBD in MeCN/H₂O. ^d Step 4 was formed in CHCl₃. ^e Methyl 5-bromothiazole-2-carboxylate used as the starting material in Step 1. Scheme 81. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl))-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-benzyl-1,3,4-thiadiazole-2-carboxamide (Compound 222) To a solution of 2-phenylacetohydrazide (5 g, 33.29 mmol) in DCM (50 mL) was added DIPEA (5.2 g, 39.95 mmol) followed by dropwise addition of ethyl 2-chloro-2-oxoacetate (5.5 g, 19.95 mmol) at 0 °C under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (6.5 g, yield 77.8%) as a white solid. LC/MS (ESI) m/z: 251 (M+H)⁺. Step 2: Ethyl 5-benzyl-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate (1 g, 4.0 mmol) in toluene (10 mL) was added Lawesson's Reagent (3.2 g, 8.0 mmol), and the mixture was stirred at 110 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (320 mg, yield 32.1%) as a yellow oil. LC/MS (ESI) m/z: 249 (M+H)⁺. Step 3: 5-benzyl-1,3,4-thiadiazole-2-carboxylic acid To a solution of ethyl 5-benzyl-1,3,4-thiadiazole-2-carboxylate (100 mg, 0.40 mmol) in THF/water (2 mL, v/v = 4/1) was added LiOH^.H₂O (34 mg, 0.81 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (100 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 221 (M+H)⁺. Step 4: tert-Butyl (S)-(2-((3-(5-benzyl-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (35 mg, 0.08 mmol) and 5-benzyl-1,3,4- thiadiazole-2-carboxylic acid (27 mg, 0.12 mmol) in MeCN (1 mL) was added NMI (20 mg, 0.24 mmol) and TCFH (67 mg, 0.24 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep- TLC (DCM: MeOH= 15: 1) to give the title compound (15 mg, yield 28.5%) as a white solid. LC/MS (ESI) m/z: 659 (M+H)⁺. Step 6: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-benzyl-1,3,4-thiadiazole-2-carboxamide (Compound 222) A solution of tert-butyl (S)-(2-((3-(5-benzyl-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c] pyridin-6-yl)carbamate (15 mg, 0.023 mmol) in HCl/1,4-dioxane (0.5 mL, 4M) was stirred under N2 atmosphere at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 30% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 222 (3.0 mg, yield 23.3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.66 (s, 1H), 8.42 (s, 1H), 7.40 - 7.38 (m, 3H), 7.34 - 7.30 (m, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.14 - 5.07 (m, 1H), 4.59 (s, 2H), 4.49 (d, J = 5.7 Hz, 1H), 4.42 (m, 1H), 3.14 - 3.04 (m, 2H), 2.59 - 2.54 (m, 1H), 2.16 - 2.10 (m, 1H). LC/MS (ESI) (m/z): 559 (M+H)⁺. RT (Method A): 1.17 min. The following compounds were prepared based on the procedures set forth above.

^a Step 3 was performed with TBD in MeCN/H2O. Scheme 82. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(5- chlorobenzo[d]oxazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamide (Compound 223) and (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((S)-1-(5- chlorobenzo[d]oxazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 224) To a mixture of methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (500 mg, 1.8 mmol) and benzyl D-alaninate (329 mg, 1.8 mmol) in toluene (7 mL) was added Cs₂CO₃ (1.2 g, 3.7 mmol) and Pd-175 (146 mg, 0.18 mmol) under N₂ atmosphere, and the reaction mixture was stirred at 100 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (385 mg, yield 56.4%) as a yellow oil. LC/MS (ESI) m/z: 372 (M+H)⁺. Step 2: ((S)-6-(Methoxycarbonyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-D-alanine To a solution of methyl (S)-3-(((R)-1-(benzyloxy)-1-oxopropan-2-yl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (380 mg, 1.02 mmol) in MeOH (5 mL) was added Pd/C (40 mg, 10% wt.), the mixture was degassed under N₂ atmosphere for three times and stirred under a H₂ balloon at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (210 mg, yield 72.9%) as a colorless oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 282 (M+H)⁺. Step 3: Methyl (S)-3-(((R)-1-((5-chloro-2-hydroxyphenyl)amino)-1-oxopropan-2-yl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of ((S)-6-(methoxycarbonyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidin-3-yl)-D- alanine (200 mg, 0.71 mol) and 2-amino-4-chlorophenol (102 mg, 0.71 mmol) in DCM (5 mL) was added HOBt (192 mg, 1.42 mmol) and EDCI (204 mg, 1.07 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) and further purified by prep-HPLC to give the title compound (110 mg, yield 38.0%) as a white solid. LC/MS (ESI) m/z: 407 (M+H)⁺. Step 4: Methyl (6S)-3-((1-(5-chlorobenzo[d]oxazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a solution of methyl (S)-3-(((R)-1-((5-chloro-2-hydroxyphenyl)amino)-1-oxo-propan-2- yl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.12 mmol) in THF (1 mL) was added PPh3 (71 mg, 0.27 mmol) and 4A molecular sieves (50 mg) at 0 °C. The mixture was stirred at room temperature for 1 hour. A solution of DIAD (55 mg, 0.27 mmol) in THF (1 mL) was added dropwise to the above mixture at 0 °C, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to give the title compound (40 mg, yield 83.7%) as a yellow oil. LC/MS (ESI) m/z: 389 (M+H)⁺. Step 5: (6S)-3-((1-(5-Chlorobenzo[d]oxazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetra-hydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (6S)-3-((1-(5-chlorobenzo[d]oxazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (40 mg, 0.10 mmol) in MeCN (2 mL) and water (1 mL) was added TBD (29 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (30 mg, yield 77.9%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 375 (M+H)⁺. Step 6: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(5-chlorobenzo[d]oxazol-2- yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 223) and (S)- N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((S)-1-(5-chlorobenzo[d]oxazol-2-yl)ethyl)amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 224) To a mixture of (6S)-3-((1-(5-chlorobenzo[d]oxazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (30 mg, 0.08 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (26 mg, 0.12 mmol) in MeCN (2 mL) was added NMI (20 mg, 0.24 mmol) and TCFH (67 mg, 0.24 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC and further purified by prep-SFC (ChiralCel OX, 250 × 30mm I.D., 5 µm, A for CO2 and B for MeOH) to give Compound 223 (peak 2, retention time: 10.37) (2.2 mg, yield 5.1%) and Compound 224 (peak 1, retention time: 6.82 min) (1.8 mg, yield 4.2%) as a white solid. Compound 223: ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 6.96 (s, 1H), 5.10 - 5.06 (m, 1H), 4.92 (d, J = 7.0 Hz, 1H), 4.57 (d, J = 9.1 Hz, 2H), 3.14 - 3.08 (m, 1H), 2.99 - 2.91 (m, 1H), 2.61 - 2.51 (m, 1H), 2.26 - 2.19 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 536 (M+H)⁺. RT (Method A): 1.12 min. Compound 224: ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.39 - 7.36 (m, 1H), 7.17 (d, J = 4.2 Hz, 2H), 6.96 (s, 1H), 5.09 - 5.05 (m, 1H), 4.92 (d, J = 6.9 Hz, 1H), 4.59 (d, J = 7.7 Hz, 2H), 3.14 - 3.09 (m, 1H), 2.97 - 2.89 (m, 1H), 2.58 - 2.51 (m, 1H), 2.26 - 2.20 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 536 (M+H)⁺. RT (Method A): 1.14 min. Scheme 83. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(cyclopentylmethyl)-1,3,4-thiadiazole-2- carboxamide (Compound 226) To a solution of 2-cyclopentylacetic acid (2 g, 15.6 mmol) in DCM (20 mL) was added DMF (0.5 mL) followed by dropwise addition of oxalyl chloride (8.6 mL, 17.2 mmol, 2 M in DCM) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour under N₂ atmosphere. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (2 g, yield 87.8%) as a yellow oil, which was used directly in the next step without further purification. Step 2: Ethyl 2-(2-(2-cyclopentylacetyl)hydrazinyl)-2-oxoacetate To a solution of ethyl 2-hydrazinyl-2-oxoacetate (1.5 g, 11.36 mmol) in DCM (15 mL) was added DIPEA (2.2 g, 17.04 mmol) followed by dropwise addition of 2-cyclopentylacetyl chloride (2 g, 13.6 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (1.2 g, yield 43.7%) as a yellow oil. LC/MS (ESI) m/z: 243 (M+H)⁺. Step 3: Ethyl 5-(cyclopentylmethyl)-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 2-(2-(2-cyclopentylacetyl)hydrazinyl)-2-oxoacetate (600 mg, 2.48 mmol) in toluene (10 mL) was added Lawesson reagent (2 g, 4.96 mmol). The mixture was stirred at 110 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10 - 30% EtOAc in PE) to give the title compound (400 mg, yield 67.2%) as a yellow oil. LC/MS (ESI) m/z: 241 (M+H)⁺. Step 4: 5-(Cyclopentylmethyl)-1,3,4-thiadiazole-2-carboxylic acid To a solution of ethyl 5-(cyclopentylmethyl)-1,3,4-thiadiazole-2-carboxylate (200 mg, 0.83 mmol) in THF/water (4 mL, v/v= 3/1) was added LiOH (30 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness to give the title compound (150 mg, yield 85.7%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 212 (M+H)⁺. Step 5: tert-Butyl (S)-(2-((3-(5-(cyclopentylmethyl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3, 2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (35 mg, 0.07 mmol) and 5-(cyclopentylmethyl)- 1,3,4-thiadiazole-2-carboxylic acid (23 mg, 0.11 mmol) in MeCN (2 mL) was added TCFH (59 mg, 0.21 mmol) and NMI (23 mg, 0.28 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (30 mg, yield 61.5%) as a yellow solid. LC/MS (ESI) m/z: 651 (M+H)⁺. Step 6: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(cyclopentylmethyl)-1,3,4-thiadiazole-2-carboxamide (Compound 225) To a solution of tert-butyl (S)-(2-((3-(5-(cyclopentylmethyl)-1,3,4-thiadiazole-2-carboxamido)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.046 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M), and the reaction mixture was stirred room temperature for 3 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 30 - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 225 (10 mg, yield 39.4%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.67 (s, 1H), 8.41 (s, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 5.89 (s, 2H), 5.10 (dd, J = 9.4, 2.7 Hz, 1H), 4.54 - 4.42 (m, 2H), 3.20 (d, J = 7.4 Hz, 2H),3.15 - 3.11 (m, 1H), 3.08 - 3.03 (m, 1H), 2.59 - 2.54 (m, 1H), 2.30 - 2.24 (m, 1H), 2.16 - 2.09 (m, 1H), 1.79 - 1.73 (m, 2H), 1.65 - 1.60 (m, 2H), 1.55 - 1.49 (m, 2H), 1.29 - 1.23 (m, 2H). LC/MS (ESI) m/z: 551 (M+H)⁺. RT (Method A): 1.36 min. Scheme 84. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,2,4-thiadiazole-3-carboxamide To a mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (400 mg, 2.02 mmol) and phenylboronic acid (275 mg, 2.42 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added CsF (614 g, 4.04 mmol) and PdCl2(Amphos)2 (143 mg, 0.202 mmol) under N2 atmosphere, and the reaction mixture was degassed under N2 atmosphere three times and stirred at 80 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (260 mg, yield 72.6%) as a white solid.¹H NMR (400 MHz, CDCl3) δ 8.00 - 7.90 (m, 2H), 7.60 - 7.55 (m, 1H), 7.54 - 7.49 (m, 2H). LC/MS (ESI) m/z: 240 (M+H)⁺. Step 2: Methyl 5-phenyl-1,2,4-thiadiazole-3-carboxylate To a mixture of 3-bromo-5-phenyl-1,2,4-thiadiazole (100 mg, 0.41 mmol) and TEA (124 mg, 1.23 mmol) in MeOH (2 mL) and DMSO (2 mL) was added Pd(dppf)Cl2 (67 mg, 0.082 mmol) under N2 atmosphere, and the reaction mixture was degassed under CO atmosphere three times and stirred at 80 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (20 mg, yield 22.1%) as a white solid. LC/MS (ESI) m/z: 221 (M+H)⁺. Step 3: 5-Phenyl-1,2,4-thiadiazole-3-carboxylic acid To a solution of methyl 5-phenyl-1,2,4-thiadiazole-3-carboxylate (20 mg, 0.09 mmol) in THF/water (1.25 mL, v/v= 4/1) was added LiOH^.H₂O (11 mg, 0.27 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (20 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 207 (M+H)⁺. Step 4: tert-Butyl (S)-(2-((4-oxo-3-(5-phenyl-1,2,4-thiadiazole-3-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (15 mg, 0.033 mmol) and 5-phenyl-1,2,4- thiadiazole-3-carboxylic acid (9 mg, 0.043 mmol) in MeCN (1 mL) was added NMI (8 mg, 0.099 mmol) and TCFH (28 mg, 0.099 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 15: 1) to give the title compound (10 mg, yield 47.0%) as a white solid. LC/MS (ESI) m/z: 645 (M+H)⁺. Step 5: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,2,4-thiadiazole-3-carboxamide (Compound 231) To a solution of tert-butyl (S)-(2-((4-oxo-3-(5-phenyl-1,2,4-thiadiazole-3-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2-c]pyridin-6-yl)carbamate (10 mg, 0.015 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M), and the reaction mixture was stirred room temperature for 2 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 30 - 70% MeCN in water with 0.1% NH3^.H2O) to give Compound 231 (1 mg, yield 11.8%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 9.12 (t, J = 5.8 Hz, 1H), 8.87 (s, 1H), 8.43 (s, 1H), 8.15 - 8.11 (m, 2H), 7.72 - 7.64 (m, 3H), 7.15 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.12 (dd, J = 9.5, 2.8 Hz, 1H), 4.55 - 4.44 (m, 2H), 3.15 - 3.07 (m, 2H), 2.62 - 2.56 (m, 1H), 2.17 - 2.11 (m, 1H). LC/MS (ESI) m/z: 545 (M+H)⁺. RT (Method A): 1.04 min. Scheme 85. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-2-(oxazol-2-yl)thiazole-5-carboxamide (Compound 241) Step 1: Ethyl 2-(oxazol-2-yl)thiazole-5-carboxylate To a mixture of ethyl 2-bromothiazole-5-carboxylate (300 mg, 1.21 mmol) and 2- (tributylstannyl)oxazole (458 mg, 1.21 mmol) in toluene (3 mL) was added Pd(PPh₃)₄ (147 mg, 0.12 mmol) under N₂ atmosphere, and the mixture was stirred at 100 °C for 2 hours. The mixture was quenched with saturated aq. KF solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (105 mg, yield 35.1%) as a white solid. LC/MS (ESI) (m/z): 225 (M+H)⁺. Step 2: 2-(Oxazol-2-yl)thiazole-5-carboxylic acid To a mixture of ethyl 2-(oxazol-2-yl)thiazole-5-carboxylate (105 mg, 0.41 mmol) in MeCN (1 mL) and H2O (1 mL) was added TBD (120 mg, 0.82 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (150 mg, yield 99.1%) as a white solid, which was directly used in the next reaction without purification. LC/MS (ESI) m/z: 197 (M+H)⁺. Step 3: tert-Butyl (S)-(2-((3-(2-(oxazol-2-yl)thiazole-5-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 2-(oxazol-2-yl)thiazole-5-carboxylic acid (30 mg, 0.11 mmol) and tert-butyl (S)-(2- ((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (25 mg, 0.07 mmol) in MeCN (1 mL) was added TCFH (40 mg, 0.14 mmol) and NMI (17.7 mg, 0.21 mmol) under N₂ atmosphere, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C18, 3% - 95% MeCN in water with 0.1% NH4HCO3) to give the title compound (11 mg, yield 24.8%) as a white solid. LC/MS (ESI) m/z: 635 (M+H)⁺. Step 4: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-2-(oxazol-2-yl)thiazole-5-carboxamide (Compound 241) A solution of tert-butyl (S)-(2-((3-(2-(oxazol-2-yl)thiazole-5-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin -6-yl)carbamate (10 mg, 0.01 mmol) in HCl/1,4-dioxane (1 mL, 2M) was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 241 (1.0 mg, yield 12.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.13 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.84 (s, 1H), 8.44 (d, J = 4.3 Hz, 2H), 8.41 (s, 1H), 7.57 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.08 (dd, J = 9.5, 2.9 Hz, 1H), 4.52 - 4.42 (m, 2H), 3.14 - 3.03 (m, 2H), 2.57 (d, J = 3.7 Hz, 1H), 2.15 - 2.08 (m, 1H). LC/MS (ESI) m/z: 535 (M+H)⁺. RT (Method A): 0.41 min. The following compounds were prepared using the appropriate heteroaryl bromide and tributylstannane in Step 1. ^a Step 4 was performed with TMSI in DCM. ^b Step 2 was performed with LiOH in THF/H₂O. ^c Step 5 was performed in TFA. Scheme 86. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluorophenyl)-1,2,4-oxadiazole-3-carboxamide (Compound 243) To a mixture of ethyl (Z)-2-amino-2-(hydroxyimino)acetate (5 g, 37.8 mmol) and DIPEA (7.3 g, 56.6 mmol) in DCM (100 mL) was added 2-fluorobenzoyl chloride (7.2 g, 45.5 mmol) dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to give the title compound (8 g, yield 84.9%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 255 (M+H)⁺. Step 2: Ethyl 5-(2-fluorophenyl)-1,2,4-oxadiazole-3-carboxylate A solution of ethyl (E)-2-(2-fluorobenzamido)-2-(hydroxyimino)acetate (2 g, 7.8 mmol) in NMP (10 mL) was stirred at 180 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) and to give the title compound (1 g, yield 54.6%) as a yellow solid. LC/MS (ESI) m/z: 237 (M+H)⁺. Step 3: 5-(2-Fluorophenyl)-1,2,4-oxadiazole-3-carboxylic acid lithium salt To a solution of ethyl 5-(2-fluorophenyl)-1,2,4-oxadiazole-3-carboxylate (60 mg, 0.25 mmol) in THF (2 mL) and water (1 mL) was added LiOH (12 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (55 mg, yield 100%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 209 (M+H)⁺. Step 4: Tert-butyl (S)-(2-((3-(5-(2-fluorophenyl)-1,2,4-oxadiazole-3-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 5-(2-fluorophenyl)-1,2,4-oxadiazole-3-carboxylic acid (55 mg, 0.25 mmol) and tert- butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate (30 mg, 0.06 mmol) in MeCN (1 mL) was added NMI (60 mg, 0.54 mmol) and TCFH (35 mg, 0.18 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (30 mg, yield 77.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 647 (M+H)⁺. Step 5: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6, 7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluorophenyl)-1,2,4-oxadiazole-3-carboxamide (Compound 243) To a solution of tert-butyl (S)-(2-((3-(5-(2-fluorophenyl)-1,2,4-oxadiazole-3-carboxamido)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.06 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 243 (10 mg, yield 45.6%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.26 - 8.19 (m, 1H), 7.87 - 7.80 (m, 1H), 7.61 - 7.51 (m, 2H), 7.13 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.10 (dd, J = 9.4, 2.8 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.19 -3.02 (m, 2H), 2.61 - 2.54 (m, 1H), 2.18 - 2.09 (m, 1H). LC/MS (ESI) (m/z): 547 (M+H)⁺. RT (Method A): 1.01 min. The following compounds were prepared according to the procedures set forth above with the appropriate acyl chloride in Step 1.

Scheme 87. Synthesis of (S)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((S)-1-(5- phenyl-1,3,4-thiadiazol-2-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 246) To a solution of methyl (S)-4-oxo-3-(((S)-1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)amino) -4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (15 mg, 0.04 mmol) in MeCN (1.5 mL) and water (0.5 mL) was added TBD (8 mg, 0.06 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness to give the title compound (18 mg, crude) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 384 (M+H)⁺. Step 2: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((S)-1-(5-phenyl-1,3,4-thiadiazol-2- yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 246) To a mixture of (S)-4-oxo-3-(((S)-1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (10 mg, 0.03 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (7 mg, 0.03 mmol) in MeCN (1 mL) were added TCFH (22 mg, 0.08 mmol) and NMI (6 mg, 0.08 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈250*21 mm, 30%-95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 246 (4 mg, yield 28.2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.47 - 8.42 (m, 1H), 7.95 - 7.89 (m, 2H), 7.56 - 7.49 (m, 3H), 7.12 - 7.07 (m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 5.98 - 5.93 (m, 1H), 5.84 (d, J = 1.6 Hz, 2H), 5.05 - 4.96 (m, 2H), 4.50 - 4.40 (m, 2H), 2.96 - 2.85 (m, 2H), 2.42 (d, J = 5.2 Hz, 1H), 2.09 - 2.02 (m, 1H), 1.69 (d, J = 3.5 Hz, 3H). LC/MS (ESI) m/z: 545 (M+H)⁺. RT (Method A): 1.01 min. Scheme 88. Synthesis of (S)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((2- phenylthiazole)-5-sulfonamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound Step 1: 5-(Be To a mixture of 5-bromo-2-phenylthiazole (750 mg, 3.1 mmol) and BnSH (750 mg, 6.0 mmol) in 1,4-dioxane (12 mL) was added DIPEA (1.9 g, 15 mmol), XantPhos (144 mg, 0.25mmol), and Pd2(dba)3 (228 mg, 0.24 mmol) under N2 atmosphere and the reaction mixture was stirred at 100 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (750 mg, yield 85%) as a yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ 7.92 - 7.89 (m, 2H), 7.77 (s, 1H), 7.56 - 7.54 (m, 3H), 7.36 - 7.30 (m, 5H), 4.20 (s, 2H).LC/MS (ESI) m/z: 284 (M+H)⁺. Step 2: 2-Phenylthiazole-5-sulfonyl chloride To a solution of 5-(benzylthio)-2-phenylthiazole (375 mg, 1.32 mmol) in AcOH (4 mL) and water (1 mL) was added NCS (500 mg, 3.70 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (300 mg, yield 87.3%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 260 (M+H)⁺. Step 3: Tert-butyl (S)-(2-((4-oxo-3-((2-phenylthiazole)-5-sulfonamido)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 2-phenylthiazole-5-sulfonyl chloride (20 mg, 0.077 mmol) and tert-butyl (S)-(2-((3- amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (15 mg, 0.033 mmol) in DCM (2 mL) and pyridine (0.5 mL) was added DMAP (3.0 mg, 0.02 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 5% - 95% MeCN in water with 0.1% NH3.H2O) to give the title compound (16 mg, yield 72%) as a white solid. LC/MS (ESI) (m/z): 680 (M+H)⁺. Step 4: (S)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-((2-phenylthiazole) -5-sulfonamido)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 249) To a solution of tert-butyl (S)-(2-((4-oxo-3-((2-phenylthiazole)-5-sulfonamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (16 mg, 0.025 mmol) in DCM (2 mL) was added TMSI (15 mg, 0.11 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness, and the residue was purified by prep-HPLC (YMC-Actus Triart C₁₈250*20mm, 10 - 95% MeCN in water with 0.1% NH₄OH) to give Compound 249 (5.4 mg, yield 40%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.44 - 10.35 (m, 1H), 8.97 - 8.90 (m, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.99 - 7.95 (m, 3H), 7.56 - 7.48 (m, 3H), 7.01 (s, 1H), 6.81 (s, 1H), 5.85 (s, 2H), 4.95 - 4.90 (m, 1H), 4.36 - 4.24 (m, 2H), 3.13 - 2.98 (m, 2H), 2.59 - 2.52 (m, 1H), 2.08 - 2.01 (m, 1H). LC/MS (ESI) m/z: 580 (M+H)⁺. RT (Method A): 1.04 min. Compound 273 was prepared according to the procedures set forth above, using 2-bromo-5- phenylthiazole as the starting material in Step 1.¹H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.61 - 7.57 (m, 2H), 7.41 - 7.35 (m, 3H), 7.04 (s, 1H), 6.89 (s, 1H), 5.03 - 4.98 (m, 1H), 4.42 (s, 2H), 3.26 - 3.19 (m, 1H), 3.11 - 3.01 (m, 1H), 2.63 - 2.51 (m, 2H), 2.27 - 2.20 (m, 2H). LC/MS (ESI) m/z: 580 (M+H)⁺. RT (Method A): 1.04 min. Scheme 89. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(2-fluorophenyl)-1,2,4-oxadiazole-5-carboxamide (Compound Step 1: (Z)-2 To a solution of 2-fluorobenzonitrile (1.5 g, 12.39 mmol) and NH₂OH.HCl (1.16 g, 16.69 mmol) in EtOH (15 mL) was added K₂CO₃ (1.71 g, 12.37 mmol). The reaction mixture was stirred at 80 °C for 3 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (1.3 g, yield 68.1%) as a green oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 155 (M+H)⁺. Step 2: Ethyl 3-(2-fluorophenyl)-1,2,4-oxadiazole-5-carboxylate To a solution of (Z)-2-fluoro-N'-hydroxybenzimidamide (1.15 g, 7.46 mmol) in THF (12 mL) was added ethyl 2-chloro-2-oxoacetate (1.53 g, 11.21 mmol) at 0 °C under N₂ atmosphere and the reaction mixture was stirred at 70 °C overnight. The mixture was quenched with saturated aq.NaHCO₃ solution at 0 °C and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 – 13% EtOAc in PE) to give the title compound (900 mg, yield 51.1%) as a white solid. LC/MS (ESI) m/z: 237 (M+H)⁺. The ethyl 3-(2-fluorophenyl)-1,2,4-oxadiazole-5-carboxylate was used to prepare Compound 255 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 9.11 (t, J = 5.7 Hz, 1H), 8.67 (s, 1H), 8.41 (s, 1H), 8.14 - 8.09 (m, 1H), 7.75 - 7.70 (m, 1H), 7.54 - 7.47 (m, 2H), 7.13 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.12 - 5.08 (m, 1H), 4.51 - 4.44 (m, 2H), 3.19 - 3.06 (m, 2H), 2.61 - 2.55 (m, 1H), 2.17 - 2.10 (m, 1H). LC/MS (ESI) m/z: 547 (M+H)⁺. RT (Method A): 1.09 min. Scheme 90. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8,8- dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carboxamide (Compound 257) Step 1: 1-(Tert-butyl) 2-methyl (S)-4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (20.0 g, 82.2 mmol) in THF (500 mL) was added LiHMDS (173 mL, 173 mmol, 1M in THF) dropwise at -78 °C, and the mixture was stirred at -78 °C under N2 atmosphere for 0.5 hour. MeI (35.0 g, 246.7 mmol) was added dropwisely to the above mixture at -78 °C and the resulting mixture was stirred at -78 °C under N2 atmosphere for 3 hours. The mixture was quenched with saturated aq. NH4Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (8.0 g, yield 35.9%) as a colorless oil. LC/MS (ESI) m/z: 272 (M+H)⁺. Step 2: Methyl (S)-4,4-dimethyl-5-oxopyrrolidine-2-carboxylate A solution of 1-(tert-butyl) 2-methyl (S)-4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (5.5 g, 20.3 mmol) in DCM (30 mL) and HCl/1,4-dioxane (20 mL, 4M) was stirred under N₂ atmosphere at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (3.4 g, yield 98.0%) as a colorless oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 172 (M+H)⁺. Step 3: Methyl (S)-5-methoxy-4,4-dimethyl-3,4-dihydro-2H-pyrrole-2-carboxylate A solution of methyl (S)-4,4-dimethyl-5-oxopyrrolidine-2-carboxylate (3.0 g, 17.5 mmol) in dimethyl sulfate (3.3 g, 26.3 mmol) was stirred at 60 °C overnight. The mixture was diluted with CHCl3/i- PrOH (3/1, v/v), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (2.1 g, yield 65.6%) as a colorless oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 186 (M+H)⁺. Step 4: Methyl (S)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (S)-5-methoxy-4,4-dimethyl-3,4-dihydro-2H-pyrrole-2-carboxylate (2.1 g, 11.4 mmol) in ethylbenzene (4 mL) was added 3-azatricyclo[4.2.1.02,5]non-7-en-4-one (2.0 g, 14.8 mmol), and the reaction mixture was stirred at 120 °C for 24 hours. The mixture was concentrated under reduced pressure to dryness, and the slurry was stirred at 170 °C for further 4 hours. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (900 mg, yield 36.0%) as a yellow oil. LC/MS (ESI) m/z: 223 (M+H)⁺. Step 5: Methyl (S)-3-bromo-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (S)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (900 mg, 4.1 mmol) in DMF (10 mL) was added NBS (865 mg, 4.9 mmol) and the mixture was stirred at 50 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (830 mg, yield 68.0%) as a colorless oil. LC/MS (ESI) m/z: 301 (M+H)⁺. Step 6: Methyl (S)-3-((tert-butoxycarbonyl)amino)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (S)-3-bromo-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine- 6-carboxylate (800 mg, 2.67 mmol) and tert-Butyl carbamate (624 mg, 5.3 mmol) in toluene (8 mL) was added K2CO3 (1.1 g, 8.0 mmol), BrettPhos (143 mg, 0.27 mmol), and Pd2(dba)3 (244 mg, 0.27 mmol), and the reaction mixture was stirred under N₂ atmosphere at 100 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (150 mg, yield 16.7%) as a white solid. LC/MS (ESI) m/z: 338 (M+H)⁺. Step 7: (S)-3-((tert-butoxycarbonyl)amino)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine- 6-carboxylic acid To a solution of methyl (S)-3-((tert-butoxycarbonyl)amino)-8,8-dimethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (150 mg, 0.45 mmol) in THF (2 mL) and water (1 mL) was added LiOH (16 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq.HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (120 mg, yield 83.3%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 324 (M+H)⁺. Step 8: (S)-3-amino-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid A solution of (S)-3-((tert-butoxycarbonyl)amino)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid (120 mg, 0.37 mmol) in DCM (1 mL) and HCl/1,4-dioxane (2 mL, 4M) was stirred under N₂ atmosphere at room temperature overnight. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (80 mg, yield 96.4%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 224 (M+H)⁺. Step 9: Tert-butyl (S)-(2-((3-amino-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of (S)-3-amino-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (169 mg, 0.61 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (90 mg, 0.40 mmol) in DMF (3 mL) was added DIPEA (260 mg, 2.0 mmol) and HATU (230 mg, 0.61 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (150 mg, yield 76.9%) as a white solid. LC/MS (ESI) (m/z): 485 (M+H)⁺. Step 10: tert-Butyl (S)-(2-((8,8-dimethyl-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl) carbamate (50 mg, 0.10 mmol) and 5- phenyl-1,3,4-thiadiazole-2-carboxylic acid (32 mg, 0.15 mmol) in MeCN (3 mL) was added NMI (42 mg, 0.52 mmol) and TCFH (87 mg, 0.31 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the title compound (50 mg, yield 72.5%) as a yellow oil. LC/MS (ESI) m/z: 673 (M+H)⁺. Step 11: (S)-N-(6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8,8-dimethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 257) To a solution of tert-butyl (S)-(2-((8,8-dimethyl-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl thieno[3,2-c]pyridin-6- yl)carbamate (50 mg, 0.07 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (2 mL, 4 M) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20mm*5um, 25 - 98% MeCN in water with 0.1% NH4HCO3) to give Compound 257 (5 mg, yield 11.8%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (s, 1H), 9.09 (t, J = 5.8 Hz, 1H), 8.76 (s, 1H), 8.41 (s, 1H), 8.11 (dd, J = 8.0, 1.4 Hz, 2H), 7.66 - 7.60 (m, 3H), 7.13 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.04 (dd, J = 9.9, 3.4 Hz, 1H), 4.58 - 4.52 (m, 1H), 4.48 - 4.42 (m, 1H), 2.53 (d, J = 1.5 Hz, 1H), 2.07 - 2.02 (m, 1H), 1.34 (s, 6H). LC/MS (ESI) m/z: 573 (M+H)⁺. RT (Method A): 1.42 min. Scheme 91. Synthesis of N-((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carboxamide (Compound 264) To a solution of methyl (6S)-3-bromo-8-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine- 6-carboxylate (1 g, 3.47 mmol) in DCM (10 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (1.2 g, 5.21 mmol) at 0 °C under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with aq.NaHCO3, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (400 mg, yield 39.6%) as a colorless oil. LC/MS (ESI) m/z: 291 (M+H)⁺. Step 2: Methyl (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-3-bromo-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine- 6-carboxylate (400 mg, 1.36 mmol) and tert-butyl carbamate (322 mg, 2.76 mmol) in toluene (4 mL) was added K₂CO₃ (563 mg, 4.08 mmol), BrettPhos (295 mg, 0.552 mmol), and Pd₂(dba)₃ (252 mg, 0.276 mmol) under N₂ atmosphere, and the reaction mixture was degassed under N₂ atmosphere for three times and stirred at 105 °C for 3 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC and further purified by prep-SFC (ChiralPak IB, 250 × 20mm I.D., 5 µm, A for CO₂ and B for MeOH (0.1% NH_3.H₂O)) to give the title compound (peak 1, retention time: 1.01 min) (92 mg, yield 20.6%) as a colorless oil. LC/MS (ESI) m/z: 328 (M+H)⁺. Step 3: (6S,8R)-3-((tert-Butoxycarbonyl)amino)-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine- 6-carboxylic acid To a solution of methyl (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-fluoro-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (85 mg, 0.26 mmol) in THF/MeOH/water (1.5 mL, 4/1/1) was added LiOH (16 mg, 0.39 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was acidified with 1 N aq.HCl to pH~3 and extracted with CHCl3/i-PrOH (v/v= 3/1). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (85 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 314 (M+H)⁺. Step 4: (6S,8R)-3-Amino-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid A solution of (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid (85 mg, 0.27 mmol) in HCl/1,4-dioxane (2 mL, 4M) was stirred under N₂ atmosphere at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (70 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 214 (M+H)⁺. Step 5: tert-Butyl (2-(((6S,8R)-3-amino-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of (6S,8R)-3-amino-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (70 mg, 0.282 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (118 mg, 0.423 mmol) in DMF (2 mL) was added DIPEA (182 mg, 1.41 mmol) and HATU (161 mg, 0.423 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (70 mg, yield 52.2%) as a white solid. LC/MS (ESI) m/z: 475 (M+H)⁺. The tert-butyl (2-(((6S,8R)-3-amino-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate was used to prepare Compound 264 based on the procedures set forth in, e.g., Scheme 63. ¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 9.30 (t, J = 5.7 Hz, 1H), 8.83 (s, 1H), 8.40 (s, 1H), 8.07 (d, J = 7.8 Hz, 2H), 7.62 – 7.55 (m, 3H), 7.12 (s, 1H), 6.88 (s, 1H), 6.38 – 5.73 (m, 3H), 5.25 – 5.20 (m, 1H), 4.48 (d, J = 13.9 Hz, 2H), 2.74 – 2.64 (m, 2H). LC/MS (ESI) (m/z): 563 (M+H)⁺. RT (Method A): 1.32 min. Scheme 92. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(2-(3- fluorophenyl)thiazol-5-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 265) To a solution of methyl 2-bromothiazole-5-carboxylate (26.0 g, 118 mmol) in THF (150 mL) and water (50 mL) was added LiOH (8.5 g, 353 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (23.6 g, yield 96.9%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 208 (M+H)⁺. Step 2: 2-Bromo-N-methoxy-N-methylthiazole-5-carboxamide To a mixture of 2-bromothiazole-5-carboxylic acid (20.4 g, 98.60 mmol) and N,O- dimethylhydroxylamine hydrochloride (11.5 g, 118 mmol) in DMF (100 mL) was added HATU (56.2 g, 147.90 mmol) and DIPEA (63.7 g, 493 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (12.8 g, yield 52.0%) as a yellow solid. LC/MS (ESI) m/z: 251 (M+H)⁺. Step 3: 1-(2-Bromothiazol-5-yl)ethan-1-one To a solution of 2-bromo-N-methoxy-N-methylthiazole-5-carboxamide (11.1 g, 44.42 mmol) in THF (100 mL) was added methylmagnesium bromide (66 mL, 66.6 mmol, 1M in THF) dropwise under N₂ atmosphere at -40 °C, and the mixture was stirred at -40 °C for 1 hour. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (7.1 g, yield 78.0%) as a yellow solid. LC/MS (ESI) m/z: 206 (M+H)⁺. Step 4: (R,E)-N-(1-(2-Bromothiazol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide To a mixture of 1-(2-bromothiazol-5-yl)ethan-1-one (6.0 g, 29.28 mmol) and (R)-2-methylpropane- 2-sulfinamide (7.1 g, 58.57 mmol) in THF (60 mL) was added Ti(Oi-Pr)4 (25.0 g, 87.85 mmol) under N2 atmosphere, and the reaction mixture was stirred at 70 °C overnight. The mixture was poured into ice water and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 15 - 30% EtOAc in PE) to give the title compound (8.3 g, yield 92.2%) as a yellow solid. LC/MS (ESI) m/z: 309 (M+H)⁺. Step 5: (R)-N-((R)-1-(2-Bromothiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide To a solution of (R,E)-N-(1-(2-bromothiazol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (8.1 g, 26.30 mmol) in DCM (80 mL) was added DIBAL-H (44.7 mL, 44.71 mmol, 1M in toluene) dropwise at - 10 °C, and the reaction mixture was stirred at -10 °C for 1 hour. The mixture was quenched with saturated aq. NH4Cl solution and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 40 - 60% EtOAc in PE) to give the title compound (4.3 g, yield 52.7%) as a yellow solid. The absolute configuration was confirmed by Mosher’s method after removing the protecting group. LC/MS (ESI) (m/z): 311 (M+H)⁺. Step 6: (R)-N-((R)-1-(2-(3-Fluorophenyl)thiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide To a mixture of (R)-N-((R)-1-(2-bromothiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 0.65 mmol) and (3-fluorophenyl)boronic acid (135 mg, 0.97 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Na₂CO₃ (205 mg, 1.94 mmol) and Pd(PPh₃)₄ (75 mg, 0.06 mmol) under N₂ atmosphere, and the reaction mixture was degassed under N₂ atmosphere for three times and stirred at 100 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (120 mg, yield 49.3%) as a yellow solid. LC/MS (ESI) m/z: 327 (M+H)⁺. Step 7: (R)-1-(2-(3-fluorophenyl)thiazol-5-yl)ethan-1-amine A solution of (R)-N-((R)-1-(2-(3-fluorophenyl)thiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.37 mmol) in HCl/1,4-dioxane (2 mL, 4M) was stirred under N₂ atmosphere at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (80 mg, yield 97.9%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 223 (M+H)⁺. Step 8: Methyl (S)-3-(((R)-1-(2-(3-fluorophenyl)thiazol-5-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of (R)-1-(2-(3-fluorophenyl)thiazol-5-yl)ethan-1-amine (80 mg, 0.36 mmol) and methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (118 mg, 0.43 mmol) in toluene (1 mL) was added Pd2(dba)3 (66 mg, 0.07 mmol), Ruphos Pd G2 (56 mg, 0.07 mmol), and Cs₂CO₃ (352 mg, 1.08 mmol) under N₂ atmosphere, and the reaction mixture was stirred under N₂ atmosphere at 100 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (54 mg, yield 36.2%) as a yellow solid. LC/MS (ESI) m/z: 415 (M+H)⁺. Step 9: (S)-3-(((R)-1-(2-(3-Fluorophenyl)thiazol-5-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (S)-3-(((R)-1-(2-(3-fluorophenyl)thiazol-5-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (54 mg, 0.13 mmol) in THF (1.5 mL) and water (0.5 mL) was added LiOH (9 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (35 mg, yield 67.1%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 401 (M+H)⁺. Step 10: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(2-(3-fluorophenyl)thiazol-5- yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 265) To a mixture of (S)-3-(((R)-1-(2-(3-fluorophenyl)thiazol-5-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (35 mg, 0.09 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (21 mg, 0.10 mmol) in DMF (1 mL) was added T3P (84 mg, 0.13 mmol, 50% wt. in EtOAc) and DIPEA (57 mg, 0.44 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 35% - 98% MeCN in water with 0.1% NH₄HCO₃) to give Compound 265 (2.5 mg, yield 5.1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (d, J = 3.5 Hz, 1H), 8.41 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.68 (t, J = 10.9 Hz, 2H), 7.52 (d, J = 6.9 Hz, 1H), 7.30 (t, J = 9.0 Hz, 1H), 7.13 – 7.10 (m, 1H), 7.08 - 7.05 (m, 1H), 6.85 - 6.82 (m, 1H), 5.86 - 5.79 (m, 2H), 5.57 (dd, J = 7.2, 2.8 Hz, 1H), 4.99 - 4.88 (m, 2H), 4.51 - 4.42 (m, 2H), 2.95 - 2.90 (m, 1H), 2.84 - 2.78 (m, 1H), 2.45 - 2.39 (m, 1H), 2.06 - 2.00 (m, 1H), 1.62 (d, J = 6.3 Hz 3H). LC/MS (ESI) (m/z): 562 (M+H)⁺. RT (Method A): 1.28 min. The following compounds were prepared according to the procedures set forth above starting from Step 6 with the appropriate sulfinamide and boronic acid.

^a Step 8 was performed without Pd2(dba)3. ^b Step 8 was performed with Pd 175 in place of Pd2(dba)3 and RuPhos Pd G2. Scheme 93. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-phenyl-1,2,4-oxadiazole-5- carboxamide (Compound 266) To a mixture of (Z)-3-fluoro-N'-hydroxybenzimidamide (300 mg, 1.94 mmol) and ethyl 2-chloro-2- oxoacetate (291 mg, 2.13 mmol) in THF (3 mL) was added TEA (590 mg, 4.95 mmol). The mixture was stirred at 70 °C for 48 hours. The mixture was quenched with ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (150 mg, yield 32.5%) as a yellow oil. LC/MS (ESI) m/z: 237 (M+H)⁺. Step 2: 3-(3-Fluorophenyl)-1,2,4-oxadiazole-5-carboxylic acid To a solution of ethyl 3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carboxylate (150 mg, 0.63 mmol) in MeCN (2 mL) and water (0.2 mL) was added TBD (132 mg, 0.94 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness to give the title compound (70 mg, yield 53.7%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 209 (M+H)⁺. Step 3: tert-Butyl (2-(((6S,8R)-3-(3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carboxamido) -8-methoxy-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)meth yl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carboxylic acid (30 mg, 0.14 mmol) and tert- butyl (2-(((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrol o[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30.0 mg, 0.06 mmol) in MeCN (2 mL) was added TCFH (101 mg, 0.34 mmol) and NMI (90.0 mg, 0.69 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (25.0 mg, yield 25.7%) as a white solid. LC/MS (ESI) m/z: 677 (M+H)⁺. Step 4: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-meth oxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carboxamide (Compound 266) To a solution of tert-butyl (2-(((6S,8R)-3-(3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carbo xamido)-8- methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (25.0 mg, 0.04 mmol) in DCM (1 mL) was added TMSI (4.9 mg, 0.03 mmol) and the mixture was stirred at room temperature for 5 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (C₁₈, 20% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 266 (8.00 mg, yield 38.7%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 9.01 (s, 1H), 8.38 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.68 - 7.56 (m, 1H), 7.41 - 7.30 (m, 1H), 7.18 (s, 1H), 6.97 (s, 1H), 5.24 - 5.18 (m, 1H), 4.97 - 4.92 (m, 1H), 4.61 (s, 2H), 3.62 (s, 3H), 2.72 - 2.64 (m, 1H), 2.57 - 2.46 (m, 2H). LC/MS (ESI) m/z: 577 (M+H)⁺. RT (Method A): 1.32 min. Scheme 94. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-cyclohexyl-1,3,4-thiadiazole-2-carboxamide (Compound 268) To a mixture of 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.81 mmol) and ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (1.1 g, 4.81 mmol) in toluene (10 mL) and water (2 mL) was added NMM (1.5 g, 14.85 mmol), XantPhos (556 mg, 0.96 mmol), and Pd(OAc)2 (108 mg, 0.48 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at 50 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (100 mg, yield 9.1%) as a yellow solid. LC/MS (ESI) m/z: 239 (M+H)⁺. Step 2: Ethyl 5-cyclohexyl-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 5-(cyclohex-1-en-1-yl)-1,3,4-thiadiazole-2-carboxylate (90 mg, 0.38 mmol) in MeOH (4 mL) was added Pd/C (20 mg, 10% w.t.), Pd(OH)2/C (20 mg, 10% w.t.), and the mixture was degassed under N2 atmosphere for three times and stirred under a H2 balloon at 40 °C for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (85 mg, yield 93.7%) as a yellow oil. LC/MS (ESI) m/z: 241 (M+H)⁺. Step 3: Lithium 5-cyclohexyl-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 5-cyclohexyl-1,3,4-thiadiazole-2-carboxylate (85 mg, 0.35 mmol) in MeOH (2 mL) and water (1 mL) was added LiOH (26 mg, 1.05 mmol), and the reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (75 mg, yield 98.2%) as a yellow solid. LC/MS (ESI) m/z: 213 (M+H)⁺. Step 4: tert-Butyl (S)-(2-((3-(5-cyclohexyl-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.07 mmol) and lithium 5-cyclohexyl- 1,3,4-thiadiazole-2-carboxylate (28 mg, 0.14 mmol) in MeCN (1 mL) was added NMI (32 mg, 0.42 mmol) and TCFH (92 mg, 0.35 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (30 mg, yield 70.2%) as a white solid. LC/MS (ESI) m/z: 651 (M+H)⁺. Step 5: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-cyclohexyl-1,3,4-thiadiazole-2-carboxamide (Compound 268) To a solution of tert-butyl (S)-(2-((3-(5-cyclohexyl-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.05 mmol) in DCM (2 mL) was added HCl/1,4-dioxane (1 mL, 4.0 M). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 268 (5.5 mg, yield 21.7%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.12 - 5.08 (m, 1H), 4.54 - 4.42 (m, 2H), 3.29 - 3.23 (m, 1H), 3.17 - 3.09 (m, 1H), 3.07 - 3.00 (m, 1H), 2.60 - 2.53 (m, 1H), 2.15 - 2.08 (m, 3H), 1.83 - 1.76 (m, 2H), 1.72 - 1.66 (m, 1H), 1.61 - 1.52 (m, 2H), 1.47 - 1.38 (m, 2H), 1.32 - 1.24 (m, 1H). LC/MS (ESI) (m/z): 551 (M+H)⁺. RT (Method A): 1.35 min. The following compounds were prepared according to the procedures set forth above using the appropriate dioxaborolane in Step 1. Scheme 95. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(5-(2- fluorophenyl)thiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 276) Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole To a solution of 1-(thiazol-2-yl)ethan-1-one (25 g, 196.6 mmol) and ethane-1,2-diol (24.4 g, 393.2 mmol) in toluene (250 mL) was added TsOH (3.39 g, 19.66 mmol). The reaction mixture was stirred with Dean-Stark trap at 120 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 11% EtOAc in PE) to give the title compound (23 g, yield 68.3%) as a yellow oil.¹HNMR (400 MHz, CDCl3) δ 7.79 (d, J = 3.2 Hz, 1H), 7.31 (d, J = 3.2 Hz, 1H), 4.15 - 4.12 (m, 2H), 4.11 - 4.05 (m, 2H), 1.85 (s, 3H). Step 2: 5-Bromo-2-(2-methyl-1,3-dioxolan-2-yl)thiazole To a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole (20 g, 116.8 mmol) in THF (150 mL) was added n-BuLi (51.40 mL, 128.5 mmol, 2.5 M) dropwise at -78 °C under N₂ atmosphere, and the reaction mixture was stirred at -78 °C for 0.5 hour. To the reaction mixture was added a solution of CBr₄ (42.61 g, 128.5 mmol) in THF (200 mL) dropwise at -78 °C under N₂ atmosphere, and the resulting mixture was stirred at -78 °C for 1 hour. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 – 9% EtOAc in PE) to give the title compound (23 g, yield 78.7%) as a brown oil.¹H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 4.11 - 4.07 (m, 2H), 4.03 - 3.98 (m, 2H), 1.78 (s, 3H). LC/MS (ESI) m/z: 250 (M+H)⁺. Step 3: 1-(5-Bromothiazol-2-yl)ethan-1-one A solution of 5-bromo-2-(2-methyl-1,3-dioxolan-2-yl)thiazole (23 g, 91.96 mmol) in Acetone (200 mL) and aq. HCl (200 mL, 6M) was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (15 g, yield 79.2%) as a brown solid, which was used in next step without further purification.¹H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 2.65 (s, 3H). Step 4: (R,E)-N-(1-(5-Bromothiazol-2-yl)ethylidene)-2-methylpropane-2-sulfinamide To a mixture of 1-(5-bromothiazol-2-yl)ethan-1-one (10.0 g, 48.53 mmol) and (R)-2- methylpropane-2-sulfinamide (17.65 g, 145.63 mmol) in THF (100 mL) was added Ti(OEt)4 (33.21 g, 145.6 mmol) under N2 atmosphere, and the reaction mixture was stirred at 70 °C overnight. The mixture was poured into ice water and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (11.4 g, yield 76.0%) as a yellow solid. LC/MS (ESI) m/z: 309 (M+H)⁺. Step 5: (R)-N-((R)-1-(5-Bromothiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide To a solution of (R,E)-N-(1-(5-bromothiazol-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (11.4 g, 36.86 mmol) in DCM (120 mL) was added DIBAL-H (55.3 mL, 55.30 mmol, 1M in toluene) dropwise at - 5 °C. The reaction mixture was stirred at -5 °C for 1 hour. The mixture was quenched with saturated aq. potassium sodium tartrate tetrahydrate solution and stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 49% EtOAc in PE) to give the title compound (5.1 g, yield 44.4%) as a yellow solid. The absolute configuration was confirmed by Mosher’s method after removing the protecting group.¹HNMR (400 MHz, CDCl₃) δ 7.60 (s, 1H), 4.81 - 4.77 (m, 1H), 4.17 - 4.14 (m, 1H), 1.65 (d, J = 6.7 Hz, 3H), 1.26 (s, 9H). LC/MS (ESI) m/z: 311 (M+H)⁺. Step 6: N-((R)-1-(5-(2-Fluorophenyl)thiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide To a mixture of (R)-N-((R)-1-(5-bromothiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (300 mg, 0.96 mmol) and (2-fluorophenyl)boronic acid (202 mg, 1.44 mmol) in toluene (4 mL) was added Pd(PPh3)4 (111 mg, 0.10 mmol) and Na2CO3 (255 mg, 2.41 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at 90 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (230 mg, yield 73.1%) as a brown solid. LC/MS (ESI) m/z: 327 (M+H)⁺. Step 7: (R)-1-(5-(2-Fluorophenyl)thiazol-2-yl)ethan-1-amine A solution of N-((R)-1-(5-(2-fluorophenyl)thiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (230 mg, 0.70 mmol) in HCl/1,4-dioxane (3 mL, 4M) was stirred under N2 atmosphere at room temperature for 2 hours. The mixture was neutralized with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (90 mg, yield 57.5%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 223 (M+H)⁺. The (R)-1-(5-(2-fluorophenyl)thiazol-2-yl)ethan-1-amine was used to prepare Compound 276 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.42 - 7.31 (m, 2H), 7.30 - 7.25 (m, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.85 - 6.82 (m, 1H), 5.84 (s, 2H), 5.81 - 5.76 (m, 1H), 5.04 - 4.97 (m, 1H), 4.88 - 4.78 (m, 1H), 4.52 - 4.41 (m, 2H), 2.97 - 2.91 (m, 1H), 2.84 - 2.78 (m, 1H), 2.47 - 2.43 (m, 1H), 2.08 - 2.02 (m, 1H), 1.65 - 1.60 (m, 3H). LC/MS (ESI) (m/z): 562 (M+H)⁺. RT (Method A): 1.26 min. Scheme 96. Synthesis of N-((6S,8R)-8-Methoxy-4-oxo-6-((thieno[3,2-c]pyridin-2- ylmethyl)carbamoyl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carboxamide (Compound 278) To a mixture of (6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (40 mg, 0.18 mmol) and thieno[3,2-c]pyridin-2-ylmethanamine hydrochloride (29 mg, 0.18 mmol) in MeCN (1 mL) was added NMI (87 mg, 1.08 mmol) and TCFH (249 mg, 0.90 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (30 mg, yield 45.5%) as a yellow solid. LC/MS (ESI) m/z: 372 (M+H)⁺. Step 2: N-((6S,8R)-8-Methoxy-4-oxo-6-((thieno[3,2-c]pyridin-2-ylmethyl)carbamoyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 278) To a solution of (6S,8R)-3-amino-8-methoxy-4-oxo-N-(thieno[3,2-c]pyridin-2-ylmethyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (30 mg, 0.08 mmol) and 5-phenyl-1,3,4-thiadiazole-2- carboxylic acid (33 mg, 0.16 mmol) in MeCN (1 mL) was added NMI (33 mg, 0.40 mmol) and TCFH (113 mg, 0.40 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 278 (4.2 mg, yield 9.3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 9.39 (t, J = 5.9 Hz, 1H), 9.05 (s, 1H), 8.80 (s, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.13 - 8.08 (m, 3H), 8.01 (d, J = 5.5 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.48 (s, 1H), 5.18 (dd, J = 9.0, 2.6 Hz, 1H), 4.91 (t, J = 7.7 Hz, 1H), 4.66 (d, J = 5.8 Hz, 2H), 3.56 (s, 3H), 2.58 - 2.55 (m, 1H), 2.46 - 2.41 (m, 1H). LC/MS (ESI) (m/z): 560 (M+H)⁺. RT (Method A): 1.29 min. Scheme 97. Synthesis of N-((6S,8R)-6-(((6-Amino-1-methyl-1H-pyrrolo[3,2-c]pyridin-2- yl)methyl)carbamoyl)-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidin-3-yl)-5-phenyl- 1,3,4-thiadiazole-2-carboxamide (Compound 282) To a solution of 6-chloro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]pyridine (2.0 g, 7.52 mmol) in THF (20 mL) was added NaH (451 mg, 11.28 mmol, 60% dispersion in mineral oil) in portions at 0 °C under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at room temperature for 20 minutes. To the above mixture was added a solution of MeI (1.6 g, 11.28 mmol) in THF (2 mL) dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 21% EtOAc in PE) to give the title compound (1.75 g, yield 83.3%) as a white solid. LC/MS (ESI) m/z: 281 (M+H)⁺. Step 2: tert-Butyl (1-methyl-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]pyridin-6- yl)carbamate To a mixture of 6-chloro-1-methyl-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2- c]pyridine (500 mg, 1.79 mmol) and tert-butyl carbamate (418 mg, 3.58 mmol) in 1,4-dioxane (5 mL) was added Cs2CO3 (1.74 g, 5.37 mmol), BrettPhos (96 mg, 0.18 mmol), and BrettPhos Pd G3 (162 mg, 0.18 mmol) under N₂ atmosphere, and the reaction mixture was stirred under N₂ atmosphere at 100 °C for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 25% EtOAc in PE) to give the title compound (230 mg, yield 35.7%) as a white solid. LC/MS (ESI) m/z: 362 (M+H)⁺. Step 3: tert-Butyl (2-(hydroxymethyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)carbamate To a solution of tert-butyl (1-methyl-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2- c]pyridin-6-yl)carbamate (230 mg, 0.64 mmol) in MeOH (5 mL) was added HCl/MeOH (1 mL, 2M) at 0 °C. The mixture was stirred at room temperature for 20 minutes. The mixture was quenched with saturated aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (170 mg, yield 96.6%) as a yellow solid. LC/MS (ESI) m/z: 278 (M+H)⁺. Step 4: tert-Butyl (2-(azidomethyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)carbamate To a solution of tert-butyl (2-(hydroxymethyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)carbamate (170 mg, 0.61 mmol) in toluene (3 mL) was added DBU (233 mg, 1.52 mmol) and DPPA (422 mg, 1.52 mmol) under N₂ atmosphere, and the reaction mixture was stirred under N₂ atmosphere at 70 °C for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (130 mg, yield 70.3%) as a white solid. LC/MS (ESI) m/z: 303 (M+H)⁺. Step 5: tert-Butyl (2-(aminomethyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)carbamate hydrochloride To a solution of tert-butyl (2-(azidomethyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)carbamate (130 mg, 0.43 mmol) in THF (1 mL) and water (1 mL) was added PPh₃ (282 mg, 1.07 mmol) and the reaction mixture was stirred at 50 °C for 3 hours. The mixture was acidified with 1N aq. HCl to pH~3 and washed with EtOAc twice. The aqueous layer was concentrated under reduced pressure to dryness to give the title compound (110 mg, yield 92.6%) as a white solid. LC/MS (ESI) m/z: 277 (M+H)⁺. Step 6: tert-Butyl (2-(((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxamido)methyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl) carbamate To a mixture of (6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid hydrochloride (50 mg, 0.22 mmol) and tert-butyl (2-(aminomethyl)-1-methyl-1H-pyrrolo[3,2- c]pyridin-6-yl)carbamate hydrochloride (61 mg, 0.22 mmol) in DMF (3 mL) was added DIPEA (172 mg, 1.32 mmol) and HATU (101 mg, 0.26 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 9% MeOH in DCM) to give the title compound (50 mg, yield 46.7%) as a yellow solid. LC/MS (ESI) m/z: 484 (M+H)⁺. Step 7: tert-Butyl (2-(((6S,8R)-8-methoxy-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6- yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)carbamate (50 mg, 0.10 mmol) and 5-phenyl-1,3,4-thiadiazole-2-carboxylic acid (43mg, 0.20 mmol) in DMF (1 mL) was added DIPEA (80 mg, 0.60 mmol) and COMU (89 mg, 0.20 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give the title compound (10 mg, yield 14.5%) as a yellow solid. LC/MS (ESI) m/z: 672 (M+H)⁺. Step 8: N-((6S,8R)-6-(((6-Amino-1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methoxy-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 282) To a solution of tert-butyl (2-(((6S,8R)-8-methoxy-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-1-methyl-1H-pyrrolo[3,2- c]pyridin-6-yl)carbamate (10 mg, 0.01 mmol) in DCM (1 mL) was added TMSI (9 mg, 0.03 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 10% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 282 (2.3 mg, yield 27.1%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 9.02 (t, J = 5.1 Hz, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 8.12 (d, J = 6.7 Hz, 2H), 7.67 – 7.59 (m, 3H), 6.32 (d, J = 3.2 Hz, 2H), 5.33 (s, 2H), 5.15 (dd, J = 9.0, 2.5 Hz, 1H), 4.91 (t, J = 7.6 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.43 - 4.36 (m, 1H), 3.55 (s, 3H), 3.50 (s, 3H), 2.58 - 2.55 (m, 1H), 2.42 - 2.38 (m, 1H). LC/MS (ESI) (m/z): 572 (M+H)⁺. RT (Method A): 1.28 min. Scheme 98. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(pyridin-4-yl)-1,2,4-oxadiazole-3-carboxamide (Compound Step 1: Ethyl To a mixture of isonicotinoyl chloride hydrochloride (3 g, 16.85 mmol) and DIPEA (4.34 g, 33.70 mmol) in DCM (50 mL) was added ethyl 2-chloro-2-oxoacetate (3.12 g, 22.98 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and filtered. The filter cake was dried under vacuum to give the title compound (2.2 g, yield 27.5%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 238 (M+H)⁺. Step 2: Ethyl 5-(pyridin-4-yl)-1,2,4-oxadiazole-3-carboxylate To a solution of ethyl (Z)-2-amino-2-((isonicotinoyloxy)imino)acetate (600 mg, 2.53 mmol) in NMP (6 mL), and the reaction mixture was stirred at 150 °C for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 37% EtOAc in PE) to give the title compound (490 mg, yield 88.4%) as a white solid. LC/MS (ESI) m/z: 220 (M+H)⁺. The ethyl 5-(pyridin-4-yl)-1,2,4-oxadiazole-3-carboxylate was used to prepare Compound 284 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.11 (t, J = 5.7 Hz, 1H), 8.94 (d, J = 5.8 Hz, 2H), 8.73 (s, 1H), 8.42 (s, 1H), 8.12 (d, J = 5.7 Hz, 2H), 7.14 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.10 (dd, J = 9.4, 2.7 Hz, 1H), 4.51 – 4.44 (m, 2H), 3.12 (t, J = 12.4 Hz, 2H), 2.60 – 2.58 (m, 1H), 2.17 – 2.10 (m, 1H). LC/MS (ESI) (m/z): 530 (M+H)⁺. RT (Method A): 0.47 min. Compound 296 was prepared according to the procedures above, using nicotinoyl chloride as a starting material in Step 1 and TMSI in DCM for deprotection in Step 5.¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 9.35 (d, J = 1.8 Hz, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.94 - 8.91 (m, 1H), 8.73 (s, 1H), 8.59 - 8.56 (m, 1H), 8.42 (s, 1H), 7.75 - 7.72 (m, 1H), 7.13 (s, 1H), 6.85 (s, 1H), 5.87 (s, 2H), 5.12 - 5.08 (m, 1H), 4.53 - 4.43 (m, 2H), 3.20 - 3.12 (m, 1H), 3.10 - 3.03 (m, 1H), 2.62 - 2.55 (m, 1H), 2.17 - 2.10 (m, 1H). LC/MS (ESI) (m/z): 530 (M+H)⁺. RT (Method A): 0.51 min. Compound 327 was prepared according to the procedures above starting from Step 3, using ethyl 3-(3-fluoropyridin-2-yl)-1,2,4-oxadiazole-5-carboxylate as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.75 - 8.69 (m, 1H), 8.67 (s, 1H), 8.41 (s, 1H), 8.10 - 8.04 (m, 1H), 7.83 - 7.78 (m, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.11 (dd, J = 9.4, 2.6 Hz, 1H), 4.54 – 4.42 (m, 2H), 3.15 - 3.04 (m, 2H), 2.62 - 2.54 (m, 1H), 2.18 - 2.09 (m, 1H). LC/MS (ESI) (m/z): 548 (M+H)⁺. RT (Method A): 0.71 min. Scheme 99. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-fluorobenzo[d]thi azole-2- To a solution of 5-fluoro-2-methylbenzo[d]thiazole (1.00 g, 5.98 mmol) in water (10 mL) was added KMnO₄ (1.89 g, 11.9 mmol), and the reaction mixture was stirred at 105 °C for 16 hours. The mixture was filtered, and the filtrate was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (150 mg, yield 10.5%) as a yellow Solid. LC/MS (ESI) m/z: 198 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-3-(5-fluorobenzo[d]thiazole-2-carboxamido)-8-metho xy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 5-fluorobenzo[d]thiazole-2-carboxylic acid (50.0 mg, 0.25 mmol) and tert-butyl(2- (((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (50.0 mg, 0.10 mmol) in MeCN (2 mL) was added TCFH (210 mg, 0.75 mmol) and NMI (96.7 mg, 0.75 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (20.0 mg, yield 11.9%) as a white solid. LC/MS (ESI) m/z: 666 (M+H)⁺. Step 3: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methoxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-fluorobenzo[d]thiazole-2-carboxamide (Compound 288) To a solution of tert-butyl (2-(((6S,8R)-3-(5-fluorobenzo[d]thiazole-2-carboxamido)-8-methoxy-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20.0 mg, 0.03 mmol) in DCM (1 mL) was added TMSI (5.30 mg, 0.04 mmol), and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (C₁₈, 20%- 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 288 (4.20 mg, yield 24.7%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.23 (t, J = 5.7 Hz, 1H), 8.90 (s, 1H), 8.42 (s, 1H), 8.38 - 8.31 (m, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.14 (d, J = 6.2 Hz, 1H), 4.89 (t, J = 7.6 Hz, 1H), 4.49 (d, J = 5.4 Hz, 2H), 3.55 (s, 3H), 2.58 - 2.54 (m, 1H), 2.43 - 2.38 (m, 1H). LC/MS (ESI) m/z: 566 (M+H)⁺. RT (Method A): 1.30 min. Scheme 100. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carboxamide (Compound 293) Step 1: 1-(tert-Butyl) 2-methyl (S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (20.0 g, 82.3 mmol) in toluene (200 mL) was added 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (28.6 g, 164.6 mmol), and the mixture was stirred at 100 °C for 16 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (10.0 g, yield 40.8%) as a yellow solid. LC/MS (ESI) m/z: 299 (M+H)⁺. Step 2: 1-(tert-Butyl) 2-methyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2- dicarboxylate (5.0 g, 16.8 mmol) in i-PrOH (60 mL) was added Pd(OH)2/C (250 mg, 10% wt.) and Pd/C (250 mg, 10% wt.), and the mixture was degassed under N2 atmosphere for three times and stirred under a H₂ balloon at 45 °C overnight. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (3.0 g, yield 70.0%) as a colorless oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 258 (M+H)⁺. Step 3: Methyl (2S)-4-methyl-5-oxopyrrolidine-2-carboxylate A solution of 1-(tert-butyl) 2-methyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (3.0 g, 11.7 mmol) in DCM (20 mL) and HCl/1,4-dioxane (10 mL, 4M) was stirred under N2 atmosphere at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (1.8 g, yield 98.4%) as a colorless oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 158 (M+H)⁺. Step 4: Methyl (2S)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate A solution of methyl (2S)-4-methyl-5-oxopyrrolidine-2-carboxylate (1.8 g, 11.5 mmol) in dimethyl sulfate (2.2 g, 17.2 mmol) was stirred at 60 °C overnight. The mixture was diluted with CHCl3/i-PrOH (3/1, v/v), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1.7 g, yield 86.7%) as a colorless oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 172 (M+H)⁺. Step 5: Methyl (6S)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (2S)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate (1.7 g, 9.9 mmol) in ethylbenzene (4 mL) was added 3-azatricyclo[4.2.1.02,5]non-7-en-4-one (2.0 g, 14.9 mmol), and the reaction mixture was stirred at 120 °C for 24 hours. The mixture was concentrated under reduced pressure to dryness and the slurry was stirred at 170 °C for further 4 hours. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (850 mg, yield 41.1%) as a yellow solid. LC/MS (ESI) m/z: 209 (M+H)⁺. Step 6: Methyl (6S)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylate To a solution of methyl (6S)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxylate (800 mg, 3.9 mmol) in DMF (10 mL) was added NBS (822 mg, 4.6 mmol), and the mixture was stirred at 50 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (400 mg, yield 36.4%) as a white solid. LC/MS (ESI) m/z: 287 (M+H)⁺. Step 7: Methyl (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (6S)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (370 mg, 1.29 mmol) and tert-butyl carbamate (303 mg, 2.59 mmol) in toluene (4 mL) was added K2CO3 (536 mg, 3.88 mmol), BrettPhos (69 mg, 0.13 mmol), and Pd2(dba)3 (118 mg, 0.13 mmol), and the reaction mixture was stirred under N₂ atmosphere at 100 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (130 mg, yield 31.2%) as a yellow solid. LC/MS (ESI) m/z: 324 (M+H)⁺. Step 8: (6S,8R)-3-((tert-Butoxycarbonyl)amino)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine- 6-carboxylic acid To a solution of methyl (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (125 mg, 0.39 mmol) in THF (3 mL) and water (1 mL) was added LiOH (28 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (110 mg, yield 92.0%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 310 (M+H)⁺. Step 9: (6S,8R)-3-Amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine -6-carboxylic acid A solution of (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid (100 mg, 0.32 mmol) in DCM (1 mL) and HCl/1,4-dioxane (2 mL, 4M) was stirred under N2 atmosphere at room temperature overnight. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (60 mg, yield 88.7%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 210 (M+H)⁺. Step 10: tert-Butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of (6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (60 mg, 0.29 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (96 mg, 0.34 mmol) in DMF (2 mL) was added DIPEA (185 mg, 1.43 mmol) and HATU (142 mg, 0.37 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (65 mg, yield 48.2%) as a yellow solid. LC/MS (ESI) (m/z): 471 (M+H)⁺. Step 11: tert-Butyl (2-(((6S,8R)-8-methyl-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.06 mmol) and 5-phenyl- 1,3,4-thiadiazole-2-carboxylic acid (16 mg, 0.08 mmol) in MeCN (1 mL) was added NMI (16 mg, 0.19 mmol) and TCFH (54 mg, 0.19 mmol) under N2 atmosphere and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the title compound (30 mg, yield 71.4%) as a yellow oil. LC/MS (ESI) m/z: 659 (M+H)⁺. Step 12: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 293) To a solution of tert-butyl (2-(((6S,8R)-8-methyl-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (25 mg, 0.04 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (2 mL, 4 M) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈250*20 mm*5 um, 25 - 98% MeCN in water with 0.1% NH₄HCO₃) to give Compound 293 (5 mg, yield 23.6%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (s, 1H), 9.14 - 9.10 (m, 1H), 8.73 (s, 1H), 8.41 (s, 1H), 8.12 - 8.09 (m, 2H), 7.65 - 7.59 (m, 3H), 7.12 (s, 1H), 6.85 - 6.84 (m, 1H), 5.84 (s, 2H), 5.10 - 5.06 (m, 1H), 4.53 - 4.43 (m, 2H), 2.68 - 2.65 (m, 1H), 2.37 (d, J = 11.8 Hz, 1H), 2.25 - 2.16 (m, 1H), 1.32 - 1.29 (m, 3H). LC/MS (ESI) m/z: 559 (M+H)⁺. RT (Method A): 1.32 min. Scheme 101. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(3-(5-cyclopropyl- 1,3,4-thiadiazol-2-yl)propanamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2 -a]pyrimidine-6- carboxamide (Compound 294) Step 1: Ethyl (E)-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)acrylate To a mixture of ethyl (E)-3-(5-bromo-1,3,4-thiadiazol-2-yl)acrylate (300 mg, 1.14 mmol) and cyclopropylboronic acid (381 mg, 3.42 mmol) in toluene (3 mL) and water (1 mL) were added Pd(OAc)₂ (26.4 mg, 0.12 mmol), SPhos (47.1 mg, 0.12 mmol), and Na2CO3 (242 mg, 2.28 mmol) under N2 atmosphere and the mixture was stirred at 80 °C for 3 hours. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (160 mg, yield 62.0%) as a white solid. LC/MS (ESI) (m/z): 225 (M+H)⁺. Step 2: Ethyl 3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)propanoate To a mixture of ethyl (E)-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)acrylate (70.0 mg, 0.31 mmol) in EtOH (1 mL) was added Pd/C (10.0 mg, 5% wt.) and Pd(OH)2/C (10.0 mg, 10% wt.), and the mixture was degassed under N₂ atmosphere for three times and stirred under a H₂ balloon at 25 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (56.0 mg, yield 99.1%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 227 (M+H)⁺. The ethyl 3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)propanoate was used to prepare Compound 294 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.69 - 9.38 (m, 1H), 9.06 (s, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 9.3 Hz, 1H), 4.46 (s, 2H), 3.26 (s, 2H), 3.17 (s, 2H), 3.04-2.96 (m, 2H), 2.92 (s, 2H), 2.08 (s, 1H), 1.16 (s, 2H), 0.96 (s, 2H). LC/MS (ESI) m/z: 537 (M+H)⁺. RT (Method A): 0.50 min. Compound 316 was prepared according to the procedures above, using tert-butyl (2-(((6S,8R)-3- amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate in place of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate in Step 4.¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.16 (t, J = 5.8 Hz, 1H), 8.80 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.07 (m, 1H), 4.81 (t, J = 7.5 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.51 (s, 3H), 2.94 (t, J = 7.1 Hz, 2H), 2.47 - 2.42 (m, 2H), 2.42 - 2.27 (m, 2H), 2.07 - 1.93 (m, 1H), 1.20 - 1.12 (m, 2H), 0.99 - 0.93 (m, 2H). LC/MS (ESI) m/z: 567 (M+H)⁺. RT (Method A): 0.73 min. Scheme 102. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(2-(2- fluorophenyl)thiazol-5-yl)ethyl)amino)-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxamide (Compound 301) To a mixture of methyl (6S,8R)-3-bromo-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxylate (98 mg, 0.32 mmol) and (R)-1-(2-(2-fluorophenyl) thiazol-5-yl)ethan-1-amine (60 mg, 0.27 mmol) in toluene (2 mL) was added Pd2(dba)3 (49 mg, 0.05 mmol), RuPhos Pd G2 (42 mg, 0.05 mmol), and Cs₂CO₃ (264 mg, 0.81 mmol) under N₂ atmosphere, and the reaction mixture was stirred under N₂ atmosphere at 100 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (52 mg, yield 43.3%) as a yellow solid. LC/MS (ESI) m/z: 445 (M+H)⁺. Step 2: (6S,8R)-3-(((R)-1-(2-(2-fluorophenyl)thiazol-5-yl)ethyl)amino)-8-methoxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-3-(((R)-1-(2-(2-fluorophenyl)thiazol-5-yl)ethyl)amino)-8-methoxy- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (52 mg, 0.12 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (6 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq.HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (30 mg, yield 59.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 431 (M+H)⁺. Step 3: (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(2-(2-fluorophenyl)thiazol-5- yl)ethyl)amino)-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamide (Compound 301) To a mixture of (6S,8R)-3-(((R)-1-(2-(2-fluorophenyl)thiazol-5-yl)ethyl)amino)-8-methoxy-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (30 mg, 0.07 mmol) and 2- (aminomethyl)thieno[3,2-c]pyridin-6-amine hydrochloride (18 mg, 0.08 mmol) in DMF (1 mL) was added T3P (66 mg, 0.10 mmol, 50% wt. in DMF) and DIPEA (36 mg, 0.28 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 301 (4.4 mg, yield 10.7%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (t, J = 5.8 Hz, 1H), 8.42 (s, 1H), 8.21 - 8.16 (m, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.42 - 7.33 (m, 2H), 7.16 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.89 - 5.83 (m, 3H), 5.03 - 4.96 (m, 2H), 4.68 (t, J = 7.1 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.43 (s, 3H), 2.43 - 2.37 (m, 1H), 2.33 - 2.27 (m, 1H), 1.64 (d, J = 6.7 Hz, 3H). LC/MS (ESI) (m/z): 592 (M+H)⁺. RT (Method A): 1.32 min. Compound 302 was prepared based on the procedures set forth above, using (R)-1-(5-(2- fluorophenyl)thiazol-2-yl)ethan-1-amine as the starting material and Pd-175 in place of Pd2(dba)3 and RuPhos Pd G2 in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.16 - 9.10 (m, 1H), 8.42 (d, J = 3.3 Hz, 1H), 8.18 (d, J = 3.9 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.42 - 7.26 (m, 3H), 7.13 (d, J = 2.8 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 3.8 Hz, 1H), 6.08 - 6.02 (m, 1H), 5.84 (s, 2H), 5.06 - 4.99 (m, 1H), 4.91 - 4.84 (m, 1H), 4.72 - 4.65 (m, 1H), 4.46 (s, 2H), 3.43 (d, J = 2.9 Hz, 3H), 2.42 - 2.39 (m, 1H), 2.02 - 1.95 (m, 1H), 1.66 - 1.62 (m, 3H). LC/MS (ESI) (m/z): 592 (M+H)⁺. RT (Method A): 1.35 min. Scheme 103. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-morpholino-1,3,4-thiadiazole-2-carboxamide (Compound Step 1: Ethyl To a solution of ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate (300 mg, 1.56 mmol) in DMF (5 mL) was added morpholine (204 mg, 2.34 mmol) and DIPEA (604 mg, 4.67 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature for an hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (140 mg, yield 36.9%) as a white solid. LC/MS (ESI) m/z: 244 (M+H)⁺. Step 2: 5-Morpholino-1,3,4-thiadiazole-2-carboxylic acid, lithium salt To a solution of ethyl 5-morpholino-1,3,4-thiadiazole-2-carboxylate (140 mg, 0.58 mmol) in THF/water (5 mL, v/v= 4/1) was added LiOH (28 mg, 1.15 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give the title compound (120 mg) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 216 (M+H)⁺. Step 3: tert-Butyl (S)-(2-((3-(5-morpholino-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.066 mmol) and 5-morpholino-1,3,4- thiadiazole-2-carboxylic acid lithium salt (21 mg, 0.099 mmol) in MeCN (2 mL) was added TCFH (92 mg, 0.33 mmol) and NMI (27 mg, 0.33 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (40 mg, yield 93.1%) as a yellow solid. LC/MS (ESI) m/z: 654 (M+H)⁺. Step 4: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-morpholino-1,3,4-thiadiazole-2-carboxamide (Compound 303) To a solution of tert-butyl (S)-(2-((3-(5-morpholino-1,3,4-thiadiazole-2-carboxamido)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (40 mg, 0.061 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4M), and the reaction mixture was stirred room temperature for 2 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C8, 40 - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 303 (6 mg, yield 17.7%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (d, J = 51.3 Hz, 1H), 9.09 (t, J = 5.8 Hz, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.11 – 5.07 (m, 1H), 4.54 – 4.43 (m, 2H), 3.76 – 3.72 (m, 4H), 3.60 – 3.56 (m, 4H), 3.14 – 3.02 (m, 2H), 2.61 – 2.53 (m, 1H), 2.15 – 2.08 (m, 1H). LC/MS (ESI) m/z: 554 (M+H)⁺. RT (Method A): 0.62 min. Compound 297 was prepared according to the procedures set forth above, using piperidine as a starting material in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 9.09 (t, J = 5.8 Hz, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.11 - 5.07 (m, 1H), 4.53 - 4.42 (m, 2H), 3.61 - 3.57 (m, 4H), 3.16 - 3.07 (m, 1H), 3.05 - 2.99 (m, 1H), 2.59 - 2.52 (m, 1H), 2.15 - 2.08 (m, 1H), 1.65 - 1.62 (m, 6H). LC/MS (ESI) (m/z): 552 (M+H)⁺. RT (Method A): 1.04 min. Scheme 104. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-(methylsulfonyl)phenyl)-1,3,4-thiadiazole-2- carboxamide (Compound 304) To a mixture of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (500 mg, 2.1 mmol) and (2- (methylthio)phenyl)boronic acid (532 mg, 3.2 mmol) in toluene (6 mL) and water (2 mL) was added Pd(OAc)2 (45 mg, 0.2 mmol), XantPhos (122 mg, 0.2 mmol), and NMM (640 mg, 6.2 mmol) under N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) and to give the title compound (500 mg, yield 85.6%) as a colorless solid. LC/MS (ESI) m/z: 281 (M+H)⁺. Step 2: Ethyl 5-(2-(methylsulfonyl)phenyl)-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 5-(2-(methylthio)phenyl)-1,3,4-thiadiazole-2-carboxylate (250 mg, 0.89 mmol) in DCM (5 mL) was added m-CPBA (462 mg, 2.67 mmol) at 0 °C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (200 mg, yield 37.6%) as a yellow solid. LC/MS (ESI) m/z: 313 (M+H)⁺. The ethyl 5-(2-(methylsulfonyl)phenyl)-1,3,4-thiadiazole-2-carboxylate was used to prepare Compound 304 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.64 (s, 1H), 8.41 (s, 1H), 8.22 - 8.18 (m, 1H), 7.96 - 7.92 (m, 2H), 7.90 - 7.86 (m, 1H), 7.13 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.12 (dd, J = 9.4, 2.7 Hz, 1H), 4.50 (dt, J = 16.0, 8.0 Hz, 2H), 3.46 (s, 3H), 3.17 - 3.03 (m, 2H), 2.62 - 2.56 (m, 1H), 2.17 - 2.10 (m, 1H). LC/MS (ESI) (m/z): 623 (M+H)⁺. RT (Method A): 0.87 min. Scheme 105. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-6-fluorobenzo[d]oxazole-2- carboxamide (Compound 306) To a solution of 2-amino-5-fluorophenol (1 g, 7.87 mmol) and DIPEA (2.03 g, 15.70 mmol) in DCM (20 mL) was added ethyl 2-chloro-2-oxoacetate (1.29 g, 9.44 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and filtered. The filter cake was concentrated under reduced pressure to give the title compound (1 g, yield 55.9%) as a black solid, which was used in next step without further purification. LC/MS (ESI) m/z: 228 (M+H)⁺. Step 2: Ethyl 6-fluorobenzo[d]oxazole-2-carboxylate To a solution of ethyl 2-((4-fluoro-2-hydroxyphenyl)amino)-2-oxoacetate (200 mg, 0.88 mmol) and PPh₃ (577 mg, 2.20 mmol) in THF (3 mL) was added DIAD (445 mg, 2.20 mmol) dropwise at 0 °C under N2 atmosphere, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 12% EtOAc in PE) to give the title compound (130 mg, yield 70.6%) as a yellow solid. LC/MS (ESI) m/z: 210 (M+H)⁺. The ethyl 6-fluorobenzo[d]oxazole-2-carboxylate was used to prepare Compound 306 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.23 (t, J = 5.7 Hz, 1H), 8.83 (s, 1H), 8.42 (s, 1H), 8.06 - 8.01 (m, 1H), 7.98 - 7.95 (m, 1H), 7.47 - 7.42 (m, 1H), 7.13 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.17 - 5.12 (m, 1H), 4.90 (t, J = 7.6 Hz, 1H), 4.48 (d, J = 4.9 Hz, 2H), 3.55 (s, 3H), 2.57 - 2.54 (m, 1H), 2.46 - 2.41 (m, 1H). LC/MS (ESI) m/z: 550 (M+H)⁺. RT (Method A): 1.07 min. Compound 287 was prepared according to the procedures set forth above, using 2-amino-4- fluorophenol as the starting material in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 9.23 (t, J = 5.7 Hz, 1H), 8.84 (s, 1H), 8.42 (s, 1H), 8.00 (dd, J = 9.1, 4.3 Hz, 1H), 7.90 (dd, J = 8.5, 2.5 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.13 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.15 (dd, J = 9.1, 2.6 Hz, 1H), 4.90 (t, J = 7.7 Hz, 1H), 4.51 - 4.46 (m, 2H), 3.55 (s, 3H), 2.57 - 2.54 (m, 1H), 2.45 - 2.39 (m, 1H). LC/MS (ESI) (m/z): 550 (M+H)⁺. RT (Method A): 1.06 min. Scheme 106. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(5-(3- fluorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1, 2-a]pyrimidine-6- carboxamide (Compound 307) To a mixture of ethyl (Z)-2-amino-2-(hydroxyimino)acetate (10 g, 75.7 mmol) and DIPEA (14.6 g, 113.5 mmol) in DCM (300 mL) was added 3-fluorobenzoyl chloride (14.4 g, 90.8 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) and to give the title compound (12 g, yield 67.2%) as a colorless solid. LC/MS (ESI) m/z: 237 (M+H)⁺. Step 2: Ethyl 5-(3-fluorophenyl)-1,2,4-oxadiazole-3-carboxylate A solution of ethyl (Z)-2-amino-2-(((3-fluorobenzoyl)oxy)imino)acetate (12 g, 47.2 mmol) in NMP (100 mL) was stirred at 180 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (10 g, yield 89.7%) as a yellow solid. LC/MS (ESI) m/z: 237 (M+H)⁺. Step 3: 5-(3-Fluorophenyl)-1,2,4-oxadiazole-3-carboxylic acid To a solution of ethyl 5-(3-fluorophenyl)-1,2,4-oxadiazole-3-carboxylate (10 g, 42.3 mmol) in THF (100 mL) and water (20 mL) was added LiOH (3 g, 126 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (8 g, yield 90.9%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 209 (M+H)⁺. Step 4: 5-(3-Fluorophenyl)-N-methoxy-N-methyl-1,2,4-oxadiazole-3-carboxamide To a mixture of 5-(3-fluorophenyl)-1,2,4-oxadiazole-3-carboxylic acid (8 g, 38.5 mmol) and N,O- dimethylhydroxylamine hydrochloride (4.48 g, 46.2 mmol) in DMF (100 mL) was added HATU (17.4 g, 46.2 mmol) and DIPEA (14.9 g, 115.5 mmol), and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (8 g, yield 82.8%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 252 (M+H)⁺. Step 5: 1-(5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethan-1-one To a solution of 5-(3-fluorophenyl)-N-methoxy-N-methyl-1,2,4-oxadiazole-3-carboxamide (8 g, 31.9 mmol) in THF (100 mL) was methylmagnesium bromide (38.2 mL, 38.2 mmol, 1.0M) dropwise at -40 °C under N2 atmosphere, and the reaction mixture was stirred at -40 °C for 1 hour. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 9% EtOAc in PE) to give the title compound (5 g, yield 76.1%) as a yellow solid. LC/MS (ESI) m/z: 207 (M+H)⁺. Step 6: (R,E)-N-(1-(5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethylidene)-2-methyl-propane-2-sulfinamide To a mixture of 1-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethan-1-one (5.0 g, 24.2 mmol) and (R)- 2-methylpropane-2-sulfinamide (3.5 g, 29.16 mmol) in 1,4-dioxane (100 mL) was added Ti(Oi-Pr)₄ (20.7 g, 72.9 mmol) under N2 atmosphere, and the reaction mixture was stirred at 70 °C overnight. The mixture was poured into ice water and filtered. The filtrate was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (4.5 g, yield 60.2%) as a yellow solid. LC/MS (ESI) m/z: 310 (M+H)⁺. Step 7: (R)-N-((R)-1-(5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)-2-methyl-propane-2-sulfinamide To a solution of (R,E)-N-(1-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethylidene)-2-methylpropane- 2-sulfinamide (2 g, 6.47 mmol) in DCM (50 mL) was added DIBAL-H (9.7 mL, 9.7 mmol, 1M in toluene) dropwise at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour. The mixture was quenched with saturated aq. potassium sodium tartrate tetrahydrate solution and stirred at room temperature for 1 hour. The mixture was extracted with EtOAc twice. The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 49% EtOAc in PE) to give the title compound (1.5 g, yield 74.3%) as a yellow solid. The absolute configuration was confirmed by Mosher’s method after removing the protecting group. LC/MS (ESI) m/z: 312 (M+H)⁺. Step 8: (R)-1-(5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethan-1-amine A solution of (R)-N-((R)-1-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)-2-methyl-propane-2- sulfinamide (500 mg, 1.6 mmol) in HCl/1,4-dioxane (3 mL, 4M) was stirred under N₂ atmosphere at room temperature for 2 hours. The mixture was neutralized with saturated aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (200 mg, yield 60.3%) as a yellow liquid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 208 (M+H)⁺. Step 9: Methyl (S)-3-(((R)-1-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of (R)-1-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethan-1-amine (100 mg, 0.48 mmol) and methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxylate (200 mg, 0.73 mmol) in toluene (3 mL) was added Pd-175 (36 mg, 0.05 mmol) and Cs₂CO₃ (468 mg, 1.44 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at 100 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (20 mg, yield 10.4%) as a yellow solid. LC/MS (ESI) m/z: 400 (M+H)⁺. Step 10: (S)-3-(((R)-1-(5-(3-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (S)-3-(((R)-1-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethyl) amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (20 mg, 0.05 mmol) in THF (1.5 mL) and water (0.5 mL) was added LiOH (3 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (16 mg, yield 83.1%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 386 (M+H)⁺. Step 11: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(5-(3-fluoro-phenyl)-1,2,4-oxadiazol-3- yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6-carboxamide (Compound 307) To a mixture of (S)-3-(((R)-1-(5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (16 mg, 0.04 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine dihydrochloride (10 mg, 0.04 mmol) in DMF (1 mL) was added T3P (36 mg, 0.06 mmol, 50% wt. in EtOAc) and DIPEA (24 mg, 0.19 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 98% MeCN in water with 0.1% NH₄HCO₃) to give Compound 307 (1.6 mg, yield 7.3%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.40 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 5.1 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.12 (d, J = 7.5 Hz, 2H), 6.83 (s, 1H), 5.83 (s, 2H), 5.36 (d, J = 8.2 Hz, 1H), 4.97 (d, J = 9.2 Hz, 1H), 4.90 - 4.82 (m, 1H), 4.50 - 4.39 (m, 2H), 2.98 - 2.91 (m, 1H), 2.85 - 2.79 (m, 1H), 2.47 - 2.40 (m, 1H), 2.07 - 2.00 (m, 1H), 1.61 (d, J = 6.5 Hz, 3H). LC/MS (ESI) (m/z): 547 (M+H)⁺. RT (Method A): 1.19 min. Compound 374 was prepared according to the procedures set forth above starting from Step 4, using 5-phenyl-1,2,4-oxadiazole-3-carboxylic acid as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (t, J = 5.5 Hz, 1H), 8.41 (s, 1H), 8.09 (d, J = 7.8 Hz, 2H), 7.73 - 7.69 (m, 1H), 7.65 - 7.61 (m, 2H), 7.13 (d, J = 9.8 Hz, 2H), 6.84 (s, 1H), 5.84 (s, 2H), 5.35 (d, J = 8.5 Hz, 1H), 4.98 - 4.96 (m, 1H), 4.87 - 4.84 (m, 1H), 4.47 - 4.42 (m, 2H), 2.97 - 2.96 (m, 2H), 2.83 - 2.82 (m, 1H), 2.04 - 2.03 (m, 1H), 1.62 (d, J = 6.6 Hz, 3H). LC/MS (ESI) (m/z): 529 (M+H)⁺. RT (Method A): 2.21 min. Scheme 107. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-thiazolo[4,5-c]pyridine-2- carboxamide (Compound Step 1: Thiazolo[4,5-c]pyridine-2-carboxylic acid To a solution of thiazolo[4,5-c]pyridine (300 mg, 2.2 mmol) in THF (5 mL) was added n-BuLi (1 mL, 2.4 mmol) dropwise at -78 °C and the mixture was stirred at -78 °C under N2 atmosphere for 1 hour. CO2 atmosphere was pumped into the reaction mixture for 10 minutes. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (100 mg, yield 55.6%) as a white solid. LC/MS (ESI) m/z: 181 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-8-methoxy-4-oxo-3-(thiazolo[4,5-c]pyridine-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of thiazolo[4,5-c]pyridine-2-carboxylic acid (11 mg, 0.062 mmol) and tert-butyl(2- (((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.062 mmol) in DMF (1 mL) was added NMI (10 mg, 0.12 mmol) and TCFH (34 mg, 0.12 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 8% MeOH in DCM) to give the title compound (10 mg, yield 24.9%) as a yellow solid. LC/MS (ESI) m/z: 649 (M+H)⁺. Step 3: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methoxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)thiazolo[4,5-c] pyridine-2-carboxamide (Compound 309) To a solution of tert-butyl (2-(((6S,8R)-8-methoxy-4-oxo-3-(thiazolo[4,5-c]pyridine-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (10 mg, 0.015 mmol) in DCM (2 mL) was added TMSI (1 drop). The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈250*20mm, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 309 (5 mg, yield 60.8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s, 1H), 9.54 (s, 1H), 9.23 (t, J = 5.6 Hz, 1H), 8.88 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 8.43 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H), 7.14 (s, 1H), 6.86 (s, 1H), 5.86 (s, 2H), 5.17 – 5.14 (m, 1H), 4.90 (t, J = 7.7 Hz, 1H), 4.49 (d, J = 5.3 Hz, 2H), 3.55 (s, 3H), 2.45 – 2.41 (m, 1H), 2.01 – 1.98 (m, 1H). LC/MS (ESI) (m/z): 549 (M+H)⁺. RT (Method A): 0.77 min. Scheme 108. Synthesis of (S)-3-(3-(1,3,4-Thiadiazol-2-yl) propanamido)-N-((6-aminothieno[3,2- c]pyridin-2-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 310) Step 1: Ethyl (E)-3-(1,3,4-thiadiazol-2-yl)acrylate To a mixture of 2-bromo-1,3,4-thiadiazole (1.42 g, 8.51 mmol) and ethyl (E)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (3.82 g, 17.1 mmol) in 1,4-dioxane (14 mL) and water (4 mL) were added Pd(PPh3)4 (490 mg, 0.85 mmol) and K2CO3 (2.34 g, 17.1 mmol) under N2 atmosphere, and the mixture was stirred at 80 °C for 5 hours. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (300 mg, yield 18.9%) as a white solid. LC/MS (ESI) (m/z): 185 (M+H)⁺. Step 2: Ethyl 3-(1,3,4-thiadiazol-2-yl)propanoate To a solution of ethyl (E)-3-(1,3,4-thiadiazol-2-yl)acrylate (90.0 mg, 0.48 mmol) in EtOH (1 mL) was added Pd/C (10.0 mg, 5% wt.) and Pd(OH)2/C (10.0 mg, 10% wt.), and the mixture was degassed under N2 atmosphere three times and stirred under a H2 balloon at 25 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (85.0 mg, yield 95.8%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 187 (M+H)⁺. Step 3: Lithium 3-(1,3,4-thiadiazol-2-yl)propanoate To a solution of ethyl 3-(1,3,4-thiadiazol-2-yl)propanoate (40.0 mg, 0.21 mmol) in THF (1 mL) and water (0.5 mL) was added LiOH (14.0 mg, 0.63 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, and concentrated under reduced pressure to give the title compound (50.0 mg, yield 99.1%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 159 (M+H)⁺. Step 4: tert-Butyl (S)-(2-((3-(3-(1,3,4-thiadiazol-2-yl)propanamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of lithium 3-(1,3,4-thiadiazol-2-yl)propanoate (30.0 mg, 0.15 mmol) and tert-butyl (S)- (2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin- 6-yl)carbamate (35.0 mg, 0.10 mmol) in MeCN (1 mL) were added TCFH (40.1 mg, 0.14 mmol) and NMI (17.7 mg, 0.21 mmol) under N₂ atmosphere, and the mixture was stirred at room temperature for 30 minutes. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to give the title compound (10.0 mg, yield 22.7%) as a white solid. LC/MS (ESI) m/z: 597 (M+H)⁺. Step 5: (S)-3-(3-(1,3,4-Thiadiazol-2-yl)propanamido)-N-((6-aminothieno[3,2-c]pyridi n-2-yl)methyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 310) To a mixture of tert-butyl (S)-(2-((3-(3-(1,3,4-thiadiazol-2-yl)propanamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyri din-6-yl)carbamate (10.0 mg, 0.01 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4M) under N₂ atmosphere, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 310 (1.50 mg, yield 18.7%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.43 (s, 1H), 9.02 (t, J = 5.7 Hz, 1H), 8.66 (s, 1H), 8.38 (s, 1H), 7.08 (s, 1H), 6.80 (s, 1H), 5.82 (s, 2H), 5.01 (dd, J = 9.3, 2.2 Hz, 1H), 4.43 (d, J = 5.5 Hz, 2H), 3.37 (d, J = 8.6 Hz, 2H), 3.08 – 2.98 (m, 2H), 2.97 – 2.93 (m, 2H), 2.55 – 2.51 (m, 1H), 2.09 – 2.03 (m, 1H). LC/MS (ESI) m/z: 497 (M+H)⁺. RT (Method A): 0.24 min. Compound 358 was prepared according to the procedures set forth above, using 2-bromo-5- (trifluoromethyl)-1,3,4-thiadiazole as the starting material in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.16 (t, J = 5.8 Hz, 1H), 8.79 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.10 – 5.05 (m, 1H), 4.82 (t, J = 7.5 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.51 (s, 3H), 3.50 – 3.47 (m, 2H), 3.09 – 3.05 (m, 2H), 2.39 – 2.33 (m, 2H). LC/MS (ESI) m/z: 595 (M+H)⁺. RT (Method A): 0.99 min. Scheme 109. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(5-(3- fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1, 2-a]pyrimidine- 6-carboxamide (Compound 311) To a mixture of ((S)-6-(methoxycarbonyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-D- alanine (500 mg, 1.78 mmol) and 3-fluorobenzohydrazide (274 mg, 1.78 mmol) in DMF (2 mL) was added DIPEA (1.1 g, 8.89 mmol) and T3P (1.7 g, 2.67 mmol, 50% wt. in EtOAc), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (210 mg, yield 28.3%) as a yellow solid. LC/MS (ESI) (m/z): 418 (M+H)⁺. Step 2: Methyl (S)-3-(((R)-1-(5-(3-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (S)-3-(((R)-1-(2-(3-fluorobenzoyl)hydrazineyl)-1-oxopropan-2-yl)amino)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (70 mg, 0.17 mmol) in THF (3 mL) was added Lawesson's reagent (170 mg, 0.42 mmol). The reaction mixture was degassed under N2 atmosphere three times, and the reaction mixture was stirred under N₂ atmosphere at 60 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to give the title compound (32 mg, yield 45.9%) as a yellow solid. LC/MS (ESI) m/z: 416 (M+H)⁺. Step 3: (S)-3-(((R)-1-(5-(3-Fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (S)-3-(((R)-1-(5-(3-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)-amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (20 mg, 0.05 mmol) in THF (3 mL) and water (1 mL) was added LiOH (3 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (15 mg, yield 77.6%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 402 (M+H)⁺. Step 4: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(5-(3-fluoro-phenyl)-1,3,4-thiadiazol-2- yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1, 2-a]pyrimidine-6-carboxamide (Compound 311) To a mixture of (S)-3-(((R)-1-(5-(3-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (11 mg, 0.03 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (6 mg, 0.03 mmol) in MeCN (1 mL) was added TCFH (23 mg, 0.08 mmol) and NMI (7 mg, 0.08 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 311 (5 mg, yield 32.4%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.05 - 8.99 (m, 1H), 8.42 (s, 1H), 7.80 - 7.75 (m, 2H), 7.59 - 7.55 (m, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 7.09 (s, 1H), 6.83 (s, 1H), 5.98 (d, J = 7.7 Hz, 1H), 5.84 (s, 2H), 5.04 - 4.99 (m, 2H), 4.46 - 4.44 (m, 2H), 2.94 - 2.94 (m, 1H), 2.92 - 2.92 (m, 1H), 2.35 - 2.34 (m, 1H), 2.08 - 2.07 (m, 1H), 1.69 (d, J = 6.7 Hz, 3H). LC/MS (ESI) (m/z): 563 (M+H)⁺. RT (Method A): 1.11 min. The following compounds were prepared according to the procedures set forth above with the appropriate hydrazide in Step 1. ^a Step 3 was performed with TBD in MeCN/H2O. Scheme 110. Synthesis of (S)-N-(4-Oxo-6-((pyrrolo[1,2-a]pyrazin-7-ylmethyl)carbamoyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 272) To a mixture of pyrrolo[1,2-a]pyrazin-7-ylmethanamine (30 mg, 0.20 mmol) and (S)-3-amino-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (39 mg, 0.20 mmol) in DMF (1 mL) was added HATU (100 mg, 0.26 mmol) and DIPEA (77 mg, 0.60 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to give the title compound (20 mg, yield 30.8%) as a yellow oil. LC/MS (ESI) m/z: 325 (M+H)⁺. Step 2: (S)-N-(4-Oxo-6-((pyrrolo[1,2-a]pyrazin-7-ylmethyl)carbamoyl)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 272) To a solution of (S)-3-amino-4-oxo-N-(pyrrolo[1,2-a]pyrazin-7-ylmethyl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (20 mg, 0.06 mmol) and 5-phenyl-1,3,4-thiadiazole-2- carboxylic acid (24 mg, 0.12 mmol) in MeCN (1 mL) was added NMI (15 mg, 0.18 mmol) and TCFH (50 mg, 0.18 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% FA) to give Compound 272 (4.5 mg, yield 14.7%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.89 - 9.86 (m, 1H), 9.19 (s, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.70 (s, 1H), 8.59 (d, J = 5.3 Hz, 1H), 8.15 - 8.09 (m, 3H), 7.67 - 7.60 (m, 4H), 7.33 (s, 1H), 5.14 (dd, J = 9.5, 2.8 Hz, 1H), 4.57 - 4.47 (m, 2H), 3.17 - 3.06 (m, 2H), 2.68 - 2.57 (m, 1H), 2.20 - 2.13 (m, 1H). LC/MS (ESI) (m/z): 513 (M+H)⁺. RT (Method A): 1.08 min. Scheme 111. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(2- (pyridin-4-yl)thiazol-5-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxamide (Compound 313) To a mixture of (R)-N-((R)-1-(2-bromothiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (210 mg, 0.67 mmol) and 4-(tributylstannyl)pyridine (373 mg, 1.01 mmol) in toluene (4 mL) was added Pd(PPh₃)₄ (78 mg, 0.07 mmol) and CuI (128 mg, 0.67 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at 100 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (170 mg, yield 81.4%) as a yellow solid. LC/MS (ESI) m/z: 310 (M+H)⁺. Step 2: (R)-1-(2-(Pyridin-4-yl)thiazol-5-yl)ethan-1-amine A solution of (R)-2-methyl-N-((R)-1-(2-(pyridin-4-yl)thiazol-5-yl)ethyl)propane-2-sulfinamide (150 mg, 0.48 mmol) in HCl/1,4-dioxane (2 mL, 4M) was stirred under N2 atmosphere at room temperature for 2 hours. The reaction was filtered, and the filter cake was diluted with EtOAc, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (65 mg, yield 65.3%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 206 (M+H)⁺ Step 3: Methyl (S)-4-oxo-3-(((R)-1-(2-(pyridin-4-yl)thiazol-5-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of (R)-1-(2-(pyridin-4-yl)thiazol-5-yl)ethan-1-amine (65 mg, 0.32 mmol) and methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (104 mg, 0.38 mmol) in toluene (2 mL) was added Pd-175 (50 mg, 0.06 mmol) and Cs₂CO₃ (309 mg, 0.95 mmol) under N₂ atmosphere, and the reaction mixture was stirred under N2 atmosphere at 100 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (35 mg, yield 27.8%) as a yellow solid. LC/MS (ESI) m/z: 398 (M+H)⁺. Step 4: (S)-4-Oxo-3-(((R)-1-(2-(pyridin-4-yl)thiazol-5-yl)ethyl)amino)-4,6,7,8-tetra-hydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (S)-4-oxo-3-(((R)-1-(2-(pyridin-4-yl)thiazol-5-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (35 mg, 0.09 mmol) in THF (1 mL) and water (0.3 mL) was added LiOH (4 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (20 mg, yield 59.2%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 384 (M+H)⁺. Step 5: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(2-(pyridin-4-yl)thiazol-5- yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 313) To a mixture of (S)-4-oxo-3-(((R)-1-(2-(pyridin-4-yl)thiazol-5-yl)ethyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (20 mg, 0.05 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (14 mg, 0.06 mmol) in DMF (1 mL) was added T3P (50 mg, 0.08 mmol, 50% wt. in DMF) and DIPEA (27 mg, 0.21 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 85% MeCN in water with 0.1% NH₄HCO₃) to give Compound 313 (4.4 mg, yield 15.5%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.00 (t, J = 5.8 Hz, 1H), 8.68 - 8.65 (m, 2H), 8.41 (s, 1H), 7.99 (s, 1H), 7.82 - 7.79 (m, 2H), 7.11 (s, 1H), 7.07 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.63 (d, J = 7.5 Hz, 1H), 4.99 - 4.92 (m, 2H), 4.50 - 4.41 (m, 2H), 2.99 - 2.90 (m, 1H), 2.84 - 2.76 (m, 1H), 2.45 - 2.39 (m, 1H), 2.06 - 2.02 (m, 1H), 1.63 (d, J = 6.7 Hz, 3H). LC/MS (ESI) m/z: 545 (M+H)⁺. RT (Method A): 0.35 min. RT (Method A): 0.35 min. The following compounds were prepared based on the procedures set forth above using the appropriate sulfinamide or carbamate and tributylstannane in Step 1. ^a Step 4 was performed with TBD in MeCN/H₂O. ^b Step 5 was performed with HATU in place of T3P. ^c In Step 1, the reaction was quenched with aqueous KF prior to extraction with EtOAc. Scheme 112. Synthesis of (S)-N-(6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(6-fluoropyridin-2-yl)-1,3,4-thiadiazole-2- carboxamide (Compound 317) To a mixture of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (600 mg, 2.53 mmol) and 2-fluoro- 6-(tributylstannyl)pyridine (1.46 g, 3.78 mmol) in toluene (10 mL) were added Pd(PPh₃)₄ (293 mg, 0.25 mmol) and CuI (482 mg, 2.53 mmol) under N₂ atmosphere, and the reaction mixture was degassed under N2 atmosphere for three times and stirred at 100 °C overnight. The mixture was quenched with saturated aq. KF solution and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 23% EtOAc in PE) to give the title compound (180 mg, yield 28.1%) as a white solid. LC/MS (ESI) m/z: 254 (M+H)⁺. Step 2: Lithium 5-(6-fluoropyridin-2-yl)-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 5-(6-fluoropyridin-2-yl)-1,3,4-thiadiazole-2-carboxylate (90 mg, 0.36 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (17 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (90 mg, crude) as a white solid, which was used directly in the next step without further purification LC/MS (ESI) m/z: 226 (M+H)⁺ Step 3: Tert-butyl (S)-(2-((3-(5-(6-fluoropyridin-2-yl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.06 mmol) and lithium 5-(6- fluoropyridin-2-yl)-1,3,4-thiadiazole-2-carboxylate (30 mg, 0.13 mmol) in MeCN (1 mL) were added NMI (22 mg, 0.27 mmol) and TCFH (37 mg, 0.13 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) to give the title compound (20 mg, yield 45.8%) as a yellow solid. LC/MS (ESI) m/z: 664 (M+H)⁺. Step 4: (S)-N-(6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(6-fluoropyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide (Compound 317) A solution of tert-butyl (S)-(2-((3-(5-(6-fluoropyridin-2-yl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.03 mmol) in HCl/1,4-dioxane (1 mL, 4M) was stirred at room temperature for 3 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 25 - 90% MeCN in water with 0.1% NaHCO3) to give Compound 317 (1.5 mg, yield 8.8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (t, J = 6.1 Hz, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.33 - 8.29 (m, 2H), 7.52 - 7.50 (m, 1H), 7.13 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.32 (t, J = 4.7 Hz, 1H), 5.13 - 5.09 (m, 1H), 4.52 - 4.44 (m, 2H), 3.13 - 3.09 (m, 1H), 2.61 - 2.59 (m, 1H), 2.16 - 2.11 (m, 1H), 2.03 - 2.00 (m, 1H). LC/MS (ESI) m/z: 564 (M+H)⁺. RT (Method A): 1.12 min. The following compounds were prepared according to the procedures above using the appropriate heteroaryl or aryl bromide and tributylstannane in Step 1 and tert-butyl (2-(((6S,8R)-3-amino- 8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate in Step 3. ^a Step 1 was performed in the presence of Pd(PPh3)2Cl2 in 1,4-dioxane. ^b Step 3 was performed with TFA in DCM. Scheme 113. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(5-fluoropyridin-2-yl)-1,3,4-thiadiazole-2- carboxam Step 1: Ethyl 2-(2-(5-fluoropicolinoyl)hydrazineyl)-2-oxoacetate To a mixture of 5-fluoropicolinic acid (480 mg, 3.4 mmol) and CDI (468 mg, 3.5 mmol) in DMF (10 mL) was added ethyl 2-hydrazineyl-2-oxoacetate at 25 °C and the reaction mixture was stirred at 25 °C for 12 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (500 mg, yield 57.6%) as a yellow solid. LC/MS (ESI) m/z: 256 (M+H)⁺. Step 2: Ethyl 5-(5-fluoropyridin-2-yl)-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 2-(2-(5-fluoropicolinoyl)hydrazineyl)-2-oxoacetate (400 mg, 1.56 mmol) in toluene (10 mL) was added Lawesson's Reagent (1.27 g, 3.13 mmol), and the reaction mixture was stirred at 60 °C for 6 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (396 mg, yield 99.8%) as a yellow solid. LC/MS (ESI) m/z: 254 (M+H)⁺. The ethyl 5-(5-fluoropyridin-2-yl)-1,3,4-thiadiazole-2-carboxylate was used to prepare Compound 318 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.92 - 9.82 (m, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.82 (d, J = 2.8 Hz, 1H), 8.71 (s, 1H), 8.49 - 8.44 (m, 1H), 8.41 (s, 1H), 8.07 - 8.01 (m, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.14 - 5.09 (m, 1H), 4.55 - 4.43 (m, 2H), 3.16 - 3.06 (m, 2H), 2.64 - 2.53 (m, 1H), 2.17 - 2.10 (m, 1H). LC/MS (ESI) (m/z): 564 (M+H)⁺. RT (Method A): 1.05 min. Scheme 114. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-fluoropyridin-2-yl)-1,2,4- oxadiazole-5-carboxamide (Compound 324) To a mixture of 3-fluoropicolinonitrile (1 g, 8.2 mmol) and hydroxylamine hydrochloride (643 mg, 9.2 mmol) in EtOH (15 mL) was added NaOH (360 mg, 9.2 mmol) under N2 atmosphere, and the reaction mixture was stirred at 90 °C for 2 hours. The mixture was quenched with saturated aq.NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (900 mg, yield 70.8%) as a yellow solid. LC/MS (ESI) m/z: 156 (M+H)⁺. Step 2: Ethyl 2-((3-fluoropicolinimidamido)oxy)-2-oxoacetate To a mixture of 3-fluoro-N-hydroxypicolinimidamide (900 mg, 5.8 mmol) and DIPEA (1.12 g, 8.7 mmol) in DCM (100 mL) was added 2-fluorobenzoyl chloride (1.18 g, 8.7 mmol) under N₂ atmosphere, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into ice- water and filtered. The filter cake was dried under vacuum to give the title compound (800 mg, yield 53.8%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 256 (M+H)⁺. Step 3: Ethyl 3-(3-fluoropyridin-2-yl)-1,2,4-oxadiazole-5-carboxylate A solution of ethyl 2-((3-fluoropicolinimidamido)oxy)-2-oxoacetate (800 mg, 3.1 mmol) in NMP (10 mL) was stirred at 180 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (600 mg, yield 80.8%) as a yellow solid. LC/MS (ESI) m/z: 238 (M+H)⁺. The ethyl 3-(3-fluoropyridin-2-yl)-1,2,4-oxadiazole-5-carboxylate was used to prepare Compound 324 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (t, J = 5.8 Hz, 1H), 8.83 (s, 1H), 8.73 – 8.70 (m, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 8.11 – 8.05 (m, 1H), 7.83 – 7.79 (m, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 6.23 – 6.02 (m, 1H), 5.85 (s, 2H), 5.27 – 5.22 (m, 1H), 4.49 (d, J = 5.6 Hz, 2H), 2.75 – 2.66 (m, 2H). LC/MS (ESI) (m/z): 566 (M+H)⁺. RT (Method A): 0.85 min. The following compounds were prepared according to the procedures set forth above starting from Step 2. Scheme 115. Synthesis of N-((S)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2- To a mixture of ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate (200 mg, 1.04 mmol) and (3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-ol (266 mg, 1.15 mmol) in THF (5 mL) was added t-BuOK (128 mg, 1.15 mmol) under N₂ atmosphere, and the reaction mixture was stirred at 0 °C for 20 minutes. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (170 mg, yield 51.5%) as a yellow solid. LC/MS (ESI) m/z: 317 (M+H)⁺. The ethyl 5-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1,3,4-thiadiazole-2- carboxylate was used to prepare Compound 338 based on the procedures set forth in, e.g., Scheme 60. ¹H NMR (400 MHz, DMSO-d₆): δ 9.63 (s, 1H), 9.11 (d, J = 5.4 Hz, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.47 (d, J = 3.0 Hz, 1H), 5.09 (dd, J = 9.4, 2.8 Hz, 1H), 4.78 (t, J = 4.7 Hz, 1H), 4.74 (d, J = 4.6 Hz, 1H), 4.52 – 4.43 (m, 2H), 4.18 (d, J = 11.6 Hz, 1H), 4.02 (dd, J = 11.4, 3.4 Hz, 1H), 3.95 (d, J = 4.9 Hz, 1H), 3.87 (d, J = 2.3 Hz, 1H), 3.52 (d, J = 7.0 Hz, 1H), 3.35 (s, 3H), 3.14 – 3.00 (m, 3H), 2.60 – 2.55 (m, 1H). LC/MS (ESI) (m/z): 627 (M+H)⁺. RT (Method A): 0.81 min. Scheme 116. Synthesis of N-((S)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(((3R, 3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2- b]furan-3-yl)oxy)-1,3,4-thiadiazole-2-carboxamide (Compound 339) To a solution of (3R,3aR,6R,6aS)-6-((tert-butyldiphenylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (300 mg, 0.78 mmol) in THF (3 mL) was added NaH (90 mg, 2.34 mmol, 60% dispersion in mineral oil) in portions at 0 °C, and the reaction mixture was stirred at 0 °C for 15 minutes. Afterwards, ethyl 5-chloro- 1,3,4-thiadiazole-2-carboxylate (225 mg, 1.17 mmol) was added at 0 °C, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was quenched with saturated aq.NH₄Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (80 mg, yield 20.0%) as a yellow solid. LC/MS (ESI) m/z: 513 (M+H)⁺. Step 2: Tert-butyl (2-(((S)-3-(5-(((3R,3aR,6R,6aS)-6-((tert-butyldiphenylsilyl)oxy) hexahydrofuro[3,2- b]furan-3-yl)oxy)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.06 mmol) and 5-(((3R,3aR,6R,6aS)-6- ((tert-butyldiphenylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-1,3,4-thiadiazole-2-carboxylic acid (51 mg, 0.09 mmol) in MeCN (1 mL) was added NMI (32 mg, 0.36 mmol) and TCFH (55 mg, 0.18 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (50 mg, yield 80.0%) as a white solid. LC/MS (ESI) m/z: 951 (M+H)⁺. Step 3: N-((S)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3- yl)oxy)-1,3,4-thiadiazole-2-carboxamide (Compound 339) To a solution of tert-butyl (2-(((S)-3-(5-(((3R,3aR,6R,6aS)-6-((tert-butyldiphenylsilyl) oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c] pyridin -6-yl)carbamate (30 mg, 0.03 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 339 (4.2 mg, yield 23.6%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 7.12 (s, 1H), 6.86 (s, 1H), 5.89 (s, 2H), 5.54 - 5.49 (m, 1H), 5.11 - 5.07 (m, 1H), 5.00 (d, J = 6.8 Hz, 1H), 4.86 (t, J = 5.1 Hz, 1H), 4.53 - 4.42 (m, 2H), 4.34 (t, J = 4.9 Hz, 1H), 4.12 (dt, J = 9.0, 4.7 Hz, 1H), 4.08 - 4.03 (m, 1H), 4.01 - 3.97 (m, 1H), 3.78 (t, J = 7.4 Hz, 1H), 3.39 (d, J = 8.6 Hz, 2H), 3.18 - 3.07 (m, 2H), 3.06 - 3.00 (m, 1H). LC/MS (ESI) (m/z): 613 (M+H)⁺. RT (Method A): 0.40 min. Scheme 117. Synthesis of (S)-2-(5-((6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamoyl) -1,3,4-thiadiazol-2-yl)benzoic acid (Compound Step 1: Ethyl To a mixture of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (250 mg, 1.05 mmol) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (640 mg, 2.10 mmol) in toluene (6 mL) and water (2 mL) were added Pd(OAc)₂ (23 mg, 0.11 mmol), XantPhos (64 mg, 0.11 mmol), and NMM (320 mg, 3.15 mmol) under N₂ atmosphere, and the mixture was stirred at 80 °C for 3 hours. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (140 mg, yield 40.1%) as a white solid. LC/MS (ESI) (m/z): 335 (M+H)⁺. Step 2: 5-(2-(tert-Butoxycarbonyl)phenyl)-1,3,4-thiadiazole-2-carboxylic acid To a solution of ethyl 5-(2-(tert-butoxycarbonyl)phenyl)-1,3,4-thiadiazole-2-carboxylate (70 mg, 0.21 mmol) in MeCN (1 mL) and water (1 mL) was added TBD (115 mg, 0.61 mmol) under N₂ atmosphere, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness to give the title compound (80.0 mg, yield 99.0%) as a white solid. LC/MS (ESI) m/z: 307 (M+H)⁺. Step 3: tert-Butyl (S)-2-(5-((6-(((6-((tert-butoxycarbonyl)amino)thieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamoyl)-1,3,4-thiadiazol-2-yl)benzoate To a mixture of 5-(2-(tert-butoxycarbonyl)phenyl)-1,3,4-thiadiazole-2-carboxylic acid (40.0 mg, 0.11 mmol) and tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (25.0 mg, 0.10 mmol) in MeCN (1 mL) were added TCFH (63.2 mg, 0.22 mmol) and NMI (26.4 mg, 0.33 mmol) under N2 atmosphere, and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to give the title compound (10.3 mg, yield 25.5%) as a white solid. LC/MS (ESI) (m/z): 745 (M+H)⁺. Step 4: (S)-2-(5-((6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4, 6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamoyl)-1,3,4-thiadiazol-2-yl) benzoic acid (Compound 353) To a solution of tert-butyl (S)-2-(5-((6-(((6-((tert-butoxycarbonyl)amino)thieno[3,2-c] pyridin-2- yl)methyl)carbamoyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamoyl)-1,3,4-thiadiazol-2- yl)benzoate (10.0 mg, 0.01 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL) under N2 atmosphere, and the mixture was stirred at room temperature for 30 minutes. The mixture was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 353 (3.1 mg, yield 34.8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (s, 1H), 9.13 (t, J = 6.0 Hz, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 7.90 (s, 1H), 7.80 (d, J = 3.7 Hz, 1H), 7.70 (s, 2H), 7.15 (s, 1H), 6.87 (s, 1H), 5.96 (s, 1H), 5.14 - 5.09 (m, 1H), 4.49 (t, J = 4.9 Hz, 2H), 3.21-3.20 (m, 2H), 2.56-2.54 (m, 1H), 2.16-2.12 (m, 1H). LC/MS (ESI) m/z: 589 (M+H)⁺. RT (Method A): 0.92 min. Scheme 118. Synthesis of (S)-N-(6-(((4-Aminothieno[2,3-d]pyridazin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 361) To a solution of 2-(aminomethyl)thieno[2,3-d]pyridazin-4-amine (450 mg, 2.50 mmol) in DCM (5 mL) was added (Boc)2O (1.4 g, 6.25 mmol), DMAP (31 mg, 0.25 mmol) and TEA (759 mg, 7.50 mmol) at 25 °C, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (150 mg, yield 15.8%) as a white solid. LC/MS (ESI) m/z: 381 (M+H)⁺. Step 2: Tert-butyl (2-(aminomethyl)thieno[2,3-d]pyridazin-4-yl)carbamate To a solution of tert-butyl (2-(((tert-butoxycarbonyl)amino)methyl)thieno[2,3-d]pyridazin-4- yl)carbamate (140 mg, 0.37 mmol) in DMF (1 mL) was added HCl/MeOH (2 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aq.NaHCO3 solution and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (70 mg, yield 70.0%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 281 (M+H)⁺. Step 3: Tert-butyl (S)-(2-((4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[2,3-d] pyridazin-4-yl)carbamate To a mixture of tert-butyl (2-(aminomethyl)thieno[2,3-d]pyridazin-4-yl)carbamate (20 mg, 0.07 mmol) and (S)-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid (27 mg, 0.07 mmol) in DMF (1 mL) were added T3P (68 mg, 0.11 mmol, 50% wt. in EtOAc) and DIPEA (46 mg, 0.36 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% MeOH in DCM) to give the title compound (20 mg, yield 43.4%) as a white solid. LC/MS (ESI) m/z: 646 (M+H)⁺. Step 4: (S)-N-(6-(((4-aminothieno[2,3-d]pyridazin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 361) A solution of tert-butyl (S)-(2-((4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[2,3-d]pyridazin-4-yl)carbamate (20 mg, 0.03 mmol) in DCM (1 mL) and HCl/1,4-dioxane (1 mL, 4M) was stirred at room temperature overnight. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 25 - 85% MeCN in water with 0.1% NH₄HCO₃) to give Compound 361 (1.6 mg, yield 9.5%) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.29 (s, 1H), 9.01 (s, 1H), 8.70 (s, 1H), 8.11 (d, J = 6.8 Hz, 2H), 7.65 - 7.60 (m, 3H), 7.57 (s, 1H), 6.79 (s, 2H), 5.12 (d, J = 9.0 Hz, 1H), 4.71 - 4.60 (m, 2H), 3.18 - 3.13 (m, 2H), 2.19 - 2.15 (m, 1H), 2.02 - 1.97 (m, 1H). LC/MS (ESI) m/z: 546 (M+H)⁺. RT (Method A): 1.21 min. Scheme 119. Synthesis of N-((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)thiazolo[5,4-c]pyridine-2- carbox Step 1: To a solution of N-(pyridin-4-yl)pivalamide (12.0 g, 67.4 mmol) in THF (120 mL) was added n-BuLi (67.3 mL, 134.8 mmol, 2M in hexane) dropwise at −10 °C, and the mixture was stirred at −10 °C under N₂ atmosphere for 2 hours. Disulfiram (59.0 g, 67.4 mmol) was added to the above mixture at −10 °C, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (120 mL) and extracted with EtOAc three times. The combined organic layers were concentrated under reduced pressure to dryness, and the residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (3.0 g, yield 14.2%) as a yellow oil. LC/MS (ESI) (m/z): 326 (M+H)⁺. Step 2: 4-Aminopyridin-3-yl diethylcarbamodithioate To a solution of 4-pivalamidopyridin-3-yl diethylcarbamodithioate (3.0 g, 9.2 mmol) in MeOH (30.0 mL) was added NaOH (30.0 mL, 9.2 mmol, 4M in water) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (1.40 g, yield 66.6%) as a yellow oil. LC/MS (ESI) m/z: 242 (M+H)⁺. Step 3: 4-Acetamidopyridin-3-yl diethylcarbamodithioate To a solution of 4-aminopyridin-3-yl diethylcarbamodithioate (1.4 g, 5.8 mmol) in acetic anhydride (14.0 mL) was added HClO₄ (7.0 mL, 5.8 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1.0 g, yield 62.5%) as a yellow solid. LC/MS (ESI) m/z: 284 (M+H)⁺. Step 4: 2-Methylthiazolo[5,4-c]pyridine A solution of 4-acetamidopyridin-3-yl diethylcarbamodithioate (1.0 g, 3.5 mmol) in HCOOH (10 mL) was stirred at 105 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (360 mg, yield 64.4%) as a yellow solid. LC/MS (ESI) m/z: 151 (M+H)⁺. Step 5: Thiazolo[5,4-c]pyridine-2-carboxylic acid To a solution of 2-methylthiazolo[5,4-c]pyridine (300 mg, 1.9 mmol) in water (6 mL) was added KMnO4 (800 mg, 5.7 mmol), and the reaction mixture was stirred at 105 °C for 5 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (196 mg, yield 57.1%) as a yellow solid. LC/MS (ESI) m/z: 181 (M+H)⁺. Step 6: (6-((tert-Butoxycarbonyl)amino)thieno[3,2-c]pyridin-2-yl)methyl (6S,8R)-8-methoxy-4-oxo-3- (thiazolo[5,4-c]pyridine-2-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of thiazolo[5,4-c]pyridine-2-carboxylic acid (40.0 mg, 0.22 mmol) and tert-butyl (2- (((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (40.0 mg, 0.08 mmol) in MeCN (3 mL) were added TCFH (184 mg, 0.66 mmol) and NMI (90.0 mg, 0.85 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (25.0 mg, yield 47.1%) as a white solid. LC/MS (ESI) m/z: 649 (M+H)⁺. Step 7: N-((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methoxy-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)thiazolo[5,4-c]pyridine-2-carboxamide (Compound 370) To a solution of (6-((tert-butoxycarbonyl)amino)thieno[3,2-c]pyridin-2-yl)methyl (6S,8R)-8- methoxy-4-oxo-3-(thiazolo[5,4-c]pyridine-2-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylate (25.0 mg, 0.03 mmol) in DCM (1 mL) was added TMSI (5.30 mg, 0.04 mmol), and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 370 (5.0 mg, yield 16.0%) as a white solid.¹H NMR (400 MHz, DMSO-_d6) δ 9.95 (s, 1H), 9.58 (s, 1H), 9.24 - 9.22 (m, 1H), 8.89 (s, 1H), 8.78 (d, J = 5.7 Hz, 1H), 8.43 (s, 1H), 8.25 (d, J = 5.8 Hz, 1H), 7.14 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.17 - 5.14 (m, 1H), 4.92 - 4.88 (m, 1H), 4.49 (d, J = 5.5 Hz, 2H), 3.55 (s, 3H), 2.45 - 2.39 (m, 2H). LC/MS (ESI) m/z: 549 (M+H)⁺. RT (Method A): 0.78 min. Scheme 120. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(4-fluoro-5- phenylthiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxamide (Compound 372) Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)-5-phenylthiazole To a mixture of 5-bromo-2-(2-methyl-1,3-dioxolan-2-yl)thiazole (4 g, 15.99 mmol) and phenylboronic acid (2.93 g, 24.03 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added Pd(PPh₃)₄ (1.85 g, 1.60 mmol) and Na2CO3 (3.39 g, 31.98 mmol) under N2 atmosphere, and the reaction mixture was degassed under N2 atmosphere for three times and stirred at 90 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 12% EtOAc in PE) to give the title compound (2.5 g, yield 63.2%) as a brown solid. LC/MS (ESI) m/z: 248 (M+H)⁺ Step 2: 4-Fluoro-2-(2-methyl-1,3-dioxolan-2-yl)-5-phenylthiazole To a solution of 2-(2-methyl-1,3-dioxolan-2-yl)-5-phenylthiazole (2.5 g, 10.11 mmol) in PhBr (25 mL) was added NFSI (4.78 g, 15.16 mmol), and the reaction mixture was stirred under N2 atmosphere at 150 °C for 3 hours. The mixture was washed with water, dried over Na2SO4 and filtered. The filtrate was purified by flash chromatography (silica gel, 0 - 17% EtOAc in PE) to give the title compound (1.5 g, yield 55.9%) as a yellow solid. LC/MS (ESI) m/z: 266 (M+H)⁺. Step 3: 1-(4-Fluoro-5-phenylthiazol-2-yl)ethan-1-one A solution of 4-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)-5-phenylthiazole (1.5 g, 5.65 mmol) in acetone (15 mL) and aq.HCl (15 mL, 6N) was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 11% EtOAc in PE) to give the title compound (600 mg, yield 48.0%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 7.70 - 7.65 (m, 2H), 7.49 - 7.39 (m, 3H), 2.68 (s, 3H). Step 4: (R,E)-N-(1-(4-fluoro-5-phenylthiazol-2-yl)ethylidene)-2-methylpropane-2-sulfinamide To a mixture of 1-(4-fluoro-5-phenylthiazol-2-yl)ethan-1-one (600 mg, 2.71 mmol) and (R)-2- methylpropane-2-sulfinamide (986 mg, 8.13 mmol) in THF (10 mL) was added Ti(OEt)₄ (1.86 g, 8.15 mmol), and the reaction mixture was stirred under N₂ atmosphere at 70 °C for 5 hours. The mixture was poured into water and filtered. The filtrate was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (580 mg, yield 65.9%) as a yellow solid. LC/MS (ESI) m/z: 325 (M+H)⁺. Step 5: (R)-N-((R)-1-(4-Fluoro-5-phenylthiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide To a solution of (R,E)-N-(1-(4-fluoro-5-phenylthiazol-2-yl)ethylidene)-2-methylpropane-2- sulfinamide (580 mg, 1.79 mmol) in DCM (6 mL) was added DIBAL-H (3 mL, 3.04 mmol, 1M in toluene) dropwisely at -5 °C. The reaction mixture was stirred at -5 °C for 1 hour. The mixture was quenched with saturated aq. potassium sodium tartrate solution and stirred at room temperature for 1 hour. The layers were separated, and the organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 49% EtOAc in PE) to give the title compound (360 mg, yield 61.7%) as a yellow solid. The absolute configuration was confirmed by Mosher’s method after removing the protecting group. LC/MS (ESI) m/z: 327 (M+H)⁺. Step 6: (R)-1-(4-fluoro-5-phenylthiazol-2-yl)ethan-1-amine A solution of (R)-N-((R)-1-(4-fluoro-5-phenylthiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (360 mg, 1.10 mmol) in HCl/1,4-dioxane (4 mL, 4M) was stirred under N2 atmosphere at room temperature for 2 hours. The mixture was filtered, and the filter cake was neutralized with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (190 mg, yield 77.5%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 223 (M+H)⁺. The (R)-1-(4-fluoro-5-phenylthiazol-2-yl)ethan-1-amine was used to prepare Compound 372 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (t, J = 5.9 Hz, 1H), 8.41 (s, 1H), 7.55 - 7.53 (m, 2H), 7.47 - 7.43 (m, 2H), 7.38 - 7.34 (m, 1H), 7.12 (d, J = 0.5 Hz, 1H), 7.02 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.82 (s, 1H), 5.03 - 5.00 (m, 1H), 4.81 - 4.75 (m, 1H), 4.48 - 4.45 (m, 2H), 2.98 - 2.92 (m, 1H), 2.87 - 2.79 (m, 1H), 2.47 - 2.44 (m, 1H), 2.08 - 2.03 (m, 1H), 1.60 (d, J = 6.7 Hz, 3H). LC/MS (ESI) m/z: 562 (M+H)⁺. RT (Method A): 1.54 min. Scheme 121. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8,8- difluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carb Step To a solution of (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (20 g, 79.61 mmol) in t-BuOH (200 mL) was added Boc2O (26.06 g, 119.40 mmol) and DMAP (1.95 g, 15.96 mmol), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 7% EtOAc in PE) to give the title compound (22 g, yield 89.9%) as a colorless oil.¹HNMR (400 MHz, CDCl3) δ 4.45 - 4.30 (m, 1H), 3.86 - 3.72 (m, 2H), 2.76 - 2.57 (m, 1H), 2.47 - 2.35 (m, 1H), 1.46 (s, 9H), 1.43 (s, 9H). Step 2: Di-tert-Butyl (S)-4,4-difluoro-5-oxopyrrolidine-1,2-dicarboxylate To a solution of di-tert-butyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (20 g, 65.07 mmol) in MeCN (200 mL) and water (100 mL) was added RuCl3 (2.70 g, 13.02 mmol) and NaIO4 (41.76 g, 195.24 mmol). The mixture was stirred at room temperature for 48 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 11% EtOAc in PE) to give the title compound (7 g, yield 33.5%) as a white solid.¹HNMR (400 MHz, CDCl3) δ 4.58 - 4.50 (m, 1H), 2.80 - 2.65 (m, 1H), 2.59 - 2.48 (m, 1H), 1.54 (d, J = 0.8 Hz, 9H), 1.48 (s, 9H). Step 3: tert-Butyl (S)-4,4-difluoro-5-oxopyrrolidine-2-carboxylate To a solution of di-tert-butyl (S)-4,4-difluoro-5-oxopyrrolidine-1,2-dicarboxylate (3.6 g, 11.2 mmol) in THF (36 mL) was added Yb(OTf)3 (3.48 g, 5.6 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.89 g, yield 76.2%) as a white solid. LC/MS (ESI) m/z: 222 (M+H)⁺. Step 4: tert-Butyl (S)-4,4-difluoro-5-thioxopyrrolidine-2-carboxylate To a solution of tert-butyl (S)-4,4-difluoro-5-oxopyrrolidine-2-carboxylate (1.89 g, 8.55 mmol) in toluene (19 mL) was added Lawesson’s reagent (3.46 g, 8.55 mmol), and the mixture was stirred at 70 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.4 g, yield 68.9%) as a white solid. LC/MS (ESI) m/z: 238 (M+H)⁺. Step 5: tert-Butyl (S)-4,4-difluoro-5-(methylthio)-3,4-dihydro-2H-pyrrole-2-carboxylate To a solution of tert-butyl (S)-4,4-difluoro-5-thioxopyrrolidine-2-carboxylate (1.4 g, 5.1 mmol) in 2- Methyltetrahydrofuran (14 mL) was added MeI (3.55 g, 23.63 mmol) and DIPEA (1.53 g, 11.81 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (1.43 g, yield 96.0%) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 252 (M+H)⁺. Step 6: tert-Butyl (S)-5-amino-4,4-difluoro-3,4-dihydro-2H-pyrrole-2-carboxylate To a solution of tert-butyl (S)-4,4-difluoro-5-(methylthio)-3,4-dihydro-2H-pyrrole-2-carboxylate (1.4 g, 5.56 mmol) in MeOH (14 mL) was added NH4Cl (2.97 g, 55.6 mmol), and the mixture was stirred at 70 °C for 6 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (1.2 g, yield 97.7%) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 221 (M+H)⁺. Step 7: 6-(tert-Butyl) 3-methyl (S)-8,8-difluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-3,6- dicarboxylate To a solution of tert-butyl (S)-5-amino-4,4-difluoro-3,4-dihydro-2H-pyrrole-2-carboxylate (1.2 g, 5.43 mmol) in MeOH (14 mL) was added dimethyl 2-(methoxymethylene)malonate (661 mg, 3.8 mmol), and the mixture was stirred at 70 °C for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (230 mg, yield 12.8%) as a yellow solid. LC/MS (ESI) m/z: 331 (M+H)⁺. Step 8: (S)-6-(tert-Butoxycarbonyl)-8,8-difluoro-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine-3- carboxylic acid To a solution of 6-(tert-butyl) 3-methyl (S)-8,8-difluoro-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-3,6-dicarboxylate (230 mg, 0.69 mmol) in DCE (3 mL) was added trimethyltin hydroxide (251 mg, 1.39 mmol), and the mixture was stirred at 70 °C for 2 hours. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (215 mg, yield 98.3%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 317 (M+H)⁺. Step 9: tert-Butyl (S)-3-amino-8,8-difluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of (S)-6-(tert-butoxycarbonyl)-8,8-difluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-3-carboxylic acid (230 mg, 0.73 mmol) in toluene (1 mL) was added DPPA (299 mg, 1.09 mmol) and DBU (166 mg, 1.09 mmol) and the mixture was stirred at 70 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (4 mL) and water (1 mL), and the resulting mixture was stirred at 80 °C overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (60 mg, yield 28.6%) as a yellow solid. LC/MS (ESI) m/z: 288 (M+H)⁺. Step 10: tert-Butyl (S)-8,8-difluoro-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of tert-butyl (S)-3-amino-8,8-difluoro-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxylate (60 mg, 0.21 mmol) and lithium 5-phenyl-1,3,4-thiadiazole-2-carboxylate (89 mg, 0.42 mmol) in MeCN (1 mL) was added NMI (83 mg, 1.04 mmol) and TCFH (291 mg, 1.04 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (34 mg, yield 34.0%) as a yellow solid. LC/MS (ESI) m/z: 476 (M+H)⁺. Step 11: (S)-8,8-Difluoro-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid A solution of tert-butyl (S)-8,8-difluoro-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (34 mg, 0.071 mmol) in HCl/1,4-dioxane (1 mL, 4M) was stirred under N₂ atmosphere at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (23 mg, yield 77.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 420 (M+H)⁺. Step 12: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8,8-difluoro-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 375) To a mixture of (S)-8,8-difluoro-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (17 mg, 0.04 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (17 mg, 0.08 mmol) in DMF (1 mL) was added DIPEA (26 mg, 0.2 mmol) and HATU (23 mg, 0.06 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 10% - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 375 (4 mg, yield 17.2%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.28 (t, J = 5.7 Hz, 1H), 8.94 (s, 1H), 8.42 (s, 1H), 8.14 - 8.10 (m, 2H), 7.67 - 7.59 (m, 3H), 7.14 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.24 (d, J = 9.6 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.25 - 3.20 (m, 1H), 2.86 - 2.76 (m, 1H). LC/MS (ESI) (m/z): 581 (M+H)⁺. RT (Method A): 1.42 min. Scheme 122. Synthesis of N-((6S,8S)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carboxamide (Compound 376) To a solution of methyl (6S,8S)-3-((tert-butoxycarbonyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.15 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (5 mg, 0.22 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (32 mg, yield 67.1%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 310 (M+H)⁺. Step 2: (6S,8S)-3-Amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxylic acid A solution of (6S,8S)-3-((tert-butoxycarbonyl)amino)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid (30 mg, 0.1 mmol) in HCl/1,4-dioxane (2 mL, 4M) was stirred under N₂ atmosphere at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (20 mg, yield 92.9%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 210 (M+H)⁺. Step 3: tert-Butyl (2-(((6S,8S)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of (6S,8S)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylic acid (20 mg, 0.09 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.11 mmol) in DMF (60 mL) was added HATU (42 mg, 0.11 mmol) and DIPEA (35 mg, 0.27 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (20 mg, yield 47.2%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 471 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,8S)-8-methyl-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8S)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.04 mmol) and 5-phenyl- 1,3,4-thiadiazole-2-carboxylic acid (50 mg, 0.24 mmol) in MeCN (2 mL) was added NMI (49 mg, 0.60 mmol) and TCFH (168 mg, 0.60 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (20 mg, yield 75.9%) as a yellow solid. LC/MS (ESI) m/z: 659 (M+H)⁺. Step 5: N-((6S,8S)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 376) To a mixture of tert-butyl (2-(((6S,8S)-8-methyl-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (20 mg, 0.03 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 376 (3 mg, yield 17.9%) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ 9.13 (t, J = 5.8 Hz, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 8.12 - 8.09 (m, 2H), 7.65 - 7.59 (m, 3H), 7.12 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.08 (d, J = 8.9 Hz, 1H), 4.53 - 4.44 (m, 2H), 2.94 - 2.87 (m, 1H), 2.41 - 2.36 (m, 1H), 2.26 - 2.20 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 559 (M+H)⁺. RT (Method A): 1.31 min. Compound 359 was prepared according to the procedures set forth above using methyl (6S,8S)- 3-((tert-butoxycarbonyl)amino)-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate as the starting material in Step 1 and 5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxylic acid in place of 5-phenyl- 1,3,4-thiadiazole-2-carboxylic acid in Step 4.¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 9.10 (t, J = 5.7 Hz, 1H), 8.90 (s, 1H), 8.78 (d, J = 4.4 Hz, 1H), 8.42 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.11 (t, J = 7.2 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.14 (s, 1H), 6.85 (s, 1H), 5.93 - 5.79 (m, 3H), 5.09 (d, J = 9.2 Hz, 1H), 4.50 (s, 2H), 3.12 - 3.00 (m, 1H), 2.30 - 2.22 (m, 1H). LC/MS (ESI) m/z: 564 (M+H)⁺. RT (Method A): 1.09 min. Compound 382 was prepared according to the procedures set forth above using methyl (6S,8R)- 3-((tert-butoxycarbonyl)amino)-8-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate as the starting material in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 8.81 (s, 1H), 8.41 (s, 1H), 8.12 (d, J = 6.9 Hz, 2H), 7.72 - 7.54 (m, 3H), 7.13 (s, 1H), 6.85 (s, 1H), 6.29 (d, J = 6.5 Hz, 1H), 5.84 (s, 2H), 5.21 - 4.98 (m, 2H), 4.62 - 4.36 (m, 2H), 2.62 - 2.54 (m, 1H), 2.39 - 2.24 (m, 1H). LC/MS (ESI) m/z: 561 (M+H)⁺. RT (Method A): 1.37 min. Scheme 123. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methoxy-3-(4-(5- methyl-1,3,4-thiadiazol-2-yl)benzamido)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a] pyrimidine-6- carboxamide (Compound 377) To a mixture of 4-cyanobenzoic acid (1.0 g, 6.80 mmol) and acetohydrazide (503 mg, 6.80 mmol) in EtOAc (10 mL) was added Lawesson's Reagent (5.5 g, 13.61 mmol), T3P (6.5 g, 10.20 mmol, 50% in DMF wt.) and DIPEA (4.4 g, 34.06 mmol), and the mixture was stirred at 70 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (450 mg, yield 32.9%) as a yellow solid. LC/MS (ESI) m/z: 202 (M+H)⁺. Step 2: 4-(5-Methyl-1,3,4-thiadiazol-2-yl)benzoic acid A solution of 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzonitrile (150 mg, 0.75 mmol) in 10% aq. NaOH (3 mL) was stirred at 90 °C for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (130 mg, yield 79.2%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 221 (M+H)⁺. Step 3: tert-Butyl (2-(((6S,8R)-8-methoxy-3-(4-(5-methyl-1,3,4-thiadiazol-2-yl)-benzamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methoxy-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.06 mmol) and 4-(5- methyl-1,3,4-thiadiazol-2-yl)benzoic acid (50 mg, 0.22 mmol) in MeCN (2 mL) was added NMI (49 mg, 0.60 mmol) and TCFH (168 mg, 0.60 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated and purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (23 mg, yield 54.2%) as a yellow solid. LC/MS (ESI) m/z: 689 (M+H)⁺. Step 4: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methoxy-3-(4-(5-methyl-1,3,4-thiadiazol-2- yl)benzamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 377) To a mixture of tert-butyl (2-(((6S,8R)-8-methoxy-3-(4-(5-methyl-1,3,4-thiadiazol-2-yl)benzamido)- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (23 mg, 0.03 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 377 (5 mg, yield 25.7%) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ 9.75 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 8.12 - 8.06 (m, 4H), 7.13 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.11 (dd, J = 9.0, 2.8 Hz, 1H), 4.88 (t, J = 7.6 Hz, 1H), 4.53 - 4.42 (m, 2H), 3.55 (s, 3H), 2.81 (s, 3H), 2.56 - 2.52 (m, 1H), 2.46 - 2.40 (m, 1H). LC/MS (ESI) (m/z): 589 (M+H)⁺. RT (Method A): 1.29 min. Scheme 124. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methoxy-4-oxo- 3-(4-(thiazol-2-yl)benzamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 378) To a mixture of 2-bromothiazole (1 g, 6.17 mmol) and 4-boronobenzoic acid (1.5 g, 9.14 mmol) in MeCN (15 mL) and water (5 mL) was added Cs₂CO₃ (6 g, 18.46 mmol) and Pd(PPh₃)₄ (705 mg, 0.61 mmol) under N2 atmosphere, the reaction mixture was degassed under N2 atmosphere three times and stirred at 90 °C for 48 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (200 mg, yield 16.0%) as a white solid. LC/MS (ESI) m/z: 206 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-8-methoxy-4-oxo-3-(4-(thiazol-2-yl)benzamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 4-(thiazol-2-yl)benzoic acid (30 mg, 0.14 mmol) and tert-butyl (2-(((6S,8R)-3- amino-8-methoxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate (20 mg, 0.04 mmol) in MeCN (3 mL) was added NMI (16.4 mg, 0.2 mmol) and TCFH (22.4 mg, 0.08 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Welch xbidge xb 5 um 21.2*250 mm, 15 - 90% MeCN in water with 0.1% FA) to give the title compound (30 mg, yield 72.3%) as a white solid. LC/MS (ESI) m/z: 674 (M+H)⁺. Step 3: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methoxy-4-oxo-3-(4-(thiazol-2- yl)benzamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 378) To a solution of tert-butyl (2-(((6S,8R)-8-methoxy-4-oxo-3-(4-(thiazol-2-yl)-benzamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.045 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4M), and the mixture was stirred under N₂ atmosphere at room temperature for 4 hours. The mixture was concentrated. The residue was purified by prep-HPLC (Welch xbidge xb 5 um 21.2*250 mm, 15 - 90% MeCN in water with 0.1% NH₄HCO₃) to give Compound 378 (10 mg, yield 39.1%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆): δ 9.68 (s, 1H), 9.21 (t, J = 5.8 Hz, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 8.11 - 8.06 (m, 4H), 8.01 (d, J = 3.1 Hz, 1H), 7.90 (d, J = 3.1 Hz, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 5.86 (s, 2H), 5.12 (d, J = 8.8 Hz, 1H), 4.88 (t, J = 7.5 Hz, 1H), 4.52 - 4.44 (m, 2H), 3.55 (s, 3H), 2.45 - 2.38 (m, 2H). LC/MS (ESI) (m/z): 574 (M+H)⁺. RT (Method A): 1.58 min. Scheme 125. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-5-phenylthiazole-2-carboxamide (Compound Step 1: Ethyl To a solution of ethyl 5-phenylthiazole-2-carboxylate (500 mg, 2.14 mmol) in MeCN (5 mL) was added Selectfluor (2.28 g, 6.43 mmol), and the mixture was stirred at 80 °C under N₂ atmosphere overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (256 mg, yield 47.5%) as a white solid. LC/MS (ESI) m/z: 252 (M+H)⁺. Step 2: Lithium 4-fluoro-5-phenylthiazole-2-carboxylate To a solution of ethyl 4-fluoro-5-phenylthiazole-2-carboxylate (200 mg, 0.79 mmol) in THF/H₂O (2.5 mL, 4/1) was added LiOH (23 mg, 0.95 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give the title compound (230 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 224 (M+H)⁺. Step 3: tert-Butyl (S)-(2-((3-(4-fluoro-5-phenylthiazole-2-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (S)-(2-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.044 mmol) and lithium 4-fluoro-5- phenylthiazole-2-carboxylate (20 mg, 0.088 mmol) in MeCN (1 mL) was added NMI (35 mg, 0.44 mmol) and TCFH (123 mg, 0.44 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (20 mg, yield 69.0%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 662 (M+H)⁺. Step 4: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-5-phenylthiazole-2-carboxamide (Compound 383) To a solution of tert-butyl (S)-(2-((3-(4-fluoro-5-phenylthiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.03 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M). The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 383 (3.9 mg, yield 23.1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 7.74 (d, J = 7.4 Hz, 2H), 7.55 (t, J = 7.4 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 5.88 (s, 2H), 5.12 - 5.08 (m, 1H), 4.54 - 4.42 (m, 2H), 3.15 - 3.00 (m, 2H), 2.60 - 2.54 (m, 1H), 2.16 - 2.09 (m, 1H). LC/MS (ESI) (m/z): 562 (M+H)⁺. RT (Method A): 1.47 min. Scheme 126. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-2-hydroxy-1-(5- phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 384) Step 1: tert-Butyl (R)-(1-(2-benzoylhydrazinyl)-3-(benzyloxy)-1-oxopropan-2-yl)-carbamate To a mixture of O-benzyl-N-(tert-butoxycarbonyl)-D-serine (10.0 g, 33.9 mmol) and benzohydrazide (4.61 g, 33.9 mmol) in MeCN (100 mL) was added NMI (8.35 g, 102 mmol) and TCFH (11.4 g, 40.7 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (8.00 g, yield 57.1%) as a yellow oil. LC/MS (ESI) m/z: 414 (M+H)⁺. Step 2: tert-Butyl (R)-(2-(benzyloxy)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)-carbamate To a mixture of tert-butyl (R)-(1-(2-benzoylhydrazinyl)-3-(benzyloxy)-1-oxopropan-2-yl)carbamate (2.0 g, 4.84 mmol) and TEA (978 mg, 9.68 mmol) in DCM (20 mL) was added 4-toluenesulfonyl chloride (923 mg, 4.84 mmol) under N2 atmosphere, and the reaction mixture was stirred 25 °C for 2 hours. The mixture was diluted with DCM, washed with saturated aq. NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.30 g, yield 68.0%) as a yellow solid. LC/MS (ESI) m/z: 396 (M+H)⁺. Step 3: (R)-2-(Benzyloxy)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethan-1-amine To a solution of tert-butyl (R)-(2-(benzyloxy)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)carbamate (500 mg, 1.26 mmol) in DCM (5 mL) was added HCl/1,4-dioxane (2 mL, 4 M). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was diluted with DCM, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (300 mg, yield 80.3%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 296 (M+H)⁺. Step 4: Methyl (S)-3-(((R)-2-(benzyloxy)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)-amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of (R)-2-(benzyloxy)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethan-1-amine (300 mg, 1.02 mmol) and methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxylate (333 mg, 1.22 mmol) in toluene (6 mL) were added Pd-175 (81 mg, 0.10 mmol) and Cs2CO3 (665 mg, 2.04 mmol) under N2 atmosphere, and the reaction mixture was stirred under N2 atmosphere at 100 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (200 mg, yield 40.4%) as a yellow oil. LC/MS (ESI) m/z: 488 (M+H)⁺. Step 5: Methyl (S)-3-(((R)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (S)-3-(((R)-2-(benzyloxy)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (60 mg, 0.12 mmol) in DCM (2 mL) was added BCl3 (0.6 mL, 0.60 mmol, 1M in hexanes) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was quenched with saturated aq. NaHCO3 solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (30 mg, yield 61.3%) as a yellow solid. LC/MS (ESI) m/z: 398 (M+H)⁺. Step 6: (S)-3-(((R)-2-Hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of (S)-3-(((R)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (30 mg, 0.08 mmol) in THF (1.5 mL) and water (0.5 mL) was added LiOH (6 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH 3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (20 mg, yield 69.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 384 (M+H)⁺. Step 7: (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2- yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 384) To a mixture of (S)-3-(((R)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (20 mg, 0.05 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine (11 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (10 mg, 0.08 mmol) and HATU (24 mg, 0.06 mmol), and the mixture was stirred at 25 °C for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 384 (2.5 mg, yield 8.8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (t, J = 5.7 Hz, 1H), 8.41 (s, 1H), 7.99 - 7.95 (m, 2H), 7.64 - 7.58 (m, 3H), 7.19 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.54 (d, J = 8.7 Hz, 1H), 5.38 (t, J = 6.0 Hz, 1H), 5.02 - 4.97 (m, 1H), 4.97 - 4.91 (m, 1H), 4.51 - 4.42 (m, 2H), 3.99 (t, J = 5.8 Hz, 2H), 3.01 - 2.92 (m, 1H), 2.87 - 2.79 (m, 1H), 2.46 - 2.41 (m, 1H), 2.08 - 2.02 (m, 1H). LC/MS (ESI) (m/z): 545 (M+H)⁺. RT (Method A): 1.26 min. Scheme 127. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-4-oxo-3-(((R)-1-(3- phenyl-1,2,4-oxadiazol-5-yl)ethyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 386) To a mixture of benzonitrile (10.0 g, 97.0 mmol) and hydroxylamine hydrochloride (26.8 g, 388 mmol) in EtOH (120 mL) was added K₂CO₃ (31.4 g, 97.0 mmol) under N₂ atmosphere and the reaction mixture was stirred at 80 °C for 4 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (10.0 g, yield 75.7%) as a yellow solid. LC/MS (ESI) m/z: 137 (M+H)⁺. Step 2: tert-Butyl (R)-(1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)carbamate To a mixture of (Z)-N'-hydroxybenzimidamide (3.0 g, 22.0 mmol) and (tert-butoxy-carbonyl)-D- alanine (4.17 g, 22.0 mmol) in DMF (40 mL) was added HOBt (5.95 g, 44.0 mmol), HATU (8.36 g, 22.0 mmol) and DIPEA (4.26 g, 33.0 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (700 mg, yield 11.0 %) as a yellow solid. LC/MS (ESI) m/z: 290 (M+H)⁺. Step 3: (R)-1-(3-Phenyl-1,2,4-oxadiazol-5-yl)ethan-1-amine To a solution of tert-butyl (R)-(1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)carbamate (600 mg, 2.07 mmol) in DCM (6 mL) was added HCl/1,4-dioxane (3 mL, 4 M). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was neutralized with saturated aq. NaHCO₃ solution and extracted with DCM twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (320 mg, yield 81.6%) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 190 (M+H)⁺. The (R)-1-(3-Phenyl-1,2,4-oxadiazol-5-yl)ethan-1-amine was used to prepare Compound 386 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (t, J = 5.7 Hz, 1H), 8.41 (s, 1H), 8.03 - 7.95 (m, 2H), 7.61 - 7.53 (m, 3H), 7.17 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.78 (t, J = 9.1 Hz, 1H), 5.13 - 5.05 (m, 1H), 5.02 - 4.95 (m, 1H), 4.47 (s, 2H), 2.98 - 2.81 (m, 2H), 2.46 - 2.41 (m, 1H), 2.09 - 2.02 (m, 1H), 1.68 (t, J = 6.4 Hz, 3H). LC/MS (ESI) (m/z): 529 (M+H)⁺. RT (Method A): 1.10 min. Scheme 128. Synthesis (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(3-(3- fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1, 2-a]pyramidine- 6-carboxamide (Compound 387) To a mixture of 3-fluorobenzonitrile (10.0 g, 97.0 mmol) and NH2OH (26.0 g, 376 mmol) in EtOH (100 mL) was added K2CO3 (31.4 g, 97.0 mmol) under N2 atmosphere and the mixture was stirred at 80 °C for 16 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (10.5 g, yield 93.7%) as a yellow oil, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 155 (M+H)⁺. Step 2: tert-Butyl (R)-(1-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate To a mixture of (Z)-3-fluoro-N'-hydroxybenzimidamide (10.0 g, 64.9 mmol) and tert- butoxycarbonyl)-D-alanine (24.5 g, 129 mmol) in 1,4-dioxane (100 mL) was added DCC (26.7 g, 129 mmol), and the reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 5% EtOAc in PE) to give the title compound (3.50 g, yield 18.4%) as a yellow solid. LC/MS (ESI) m/z: 308 (M+H)⁺. Step 3: Methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate hydrochloride To a solution of tert-butyl (R)-(1-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (1.10 g, 3.58 mmol) in DCM (10 mL) was added HCl/1,4-dioxane (10 mL, 4M), and the mixture was stirred under N2 atmosphere at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (820 mg, yield 94.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 208 (M+H)⁺. The methyl (S)-3-bromo-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate hydrochloride was used to prepare Compound 387 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.05 - 8.98 (m, 1H), 8.41 (s, 1H), 7.90 - 7.83 (m, 1H), 7.79 - 7.70 (m, 1H), 7.66 - 7.60 (m, 1H), 7.49 - 7.42 (m, 1H), 7.19 - 7.16 (m, 1H), 7.11 (s, 1H), 6.84 - 6.82 (m, 1H), 5.84 (s, 2H), 5.81 - 5.73 (m, 1H), 5.16 - 5.07 (m, 1H), 5.02 - 4.97 (m, 1H), 4.50 - 4.38 (m, 2H), 2.99 - 2.80 (m, 2H), 2.48 - 2.43 (m, 1H), 2.09 - 2.01 (m, 1H), 1.71 - 1.65 (m, 3H). LC/MS (ESI) m/z: 547 (M+H)⁺. RT (Method A): 1.18 min. Scheme 129. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-fluoro-3-(((R)-1- (5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 412) Step 1: tert-Butyl (R)-(1-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate To a mixture of tert-butyl (R)-(1-(5-bromo-1,3,4-thiadiazol-2-yl)ethyl)carbamate (500 mg, 1.63 mmol) and (2-fluorophenyl)boronic acid (456 mg, 3.26 mmol) in toluene (6 mL) and water (1 mL) was added NMM (493 mg, 4.89 mmol), XantPhos, (94 mg, 0.16 mmol), and Pd(OAc)₂ (36 mg, 0.16 mmol) under a dry nitrogen atmosphere, and the reaction was stirred at 50 °C overnight. The mixture was cooled and diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 27% EtOAc in PE) to give the title compound (500 mg, yield 95.1%) as a white solid. LC/MS (ESI) m/z: 324 (M+H)⁺. Step 2: (R)-1-(5-(2-Fluorophenyl)-1,3,4-thiadiazol-2-yl)ethan-1-amine To a solution of tert-butyl (R)-(1-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl) carbamate (500 mg, 1.55 mmol) in DCM (4 mL) was added HCl in 1,4-dioxane (4M, 4 mL, 16 mmol), and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to dryness. The residue was neutralized with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (340 mg, yield 98.5%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 224 (M+H)⁺. Step 3: Methyl (8R)-8-fluoro-3-(((R)-1-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl) amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-3-bromo-8-fluoro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]- pyrimidine-6-carboxylate (150 mg, 0.52 mmol) and (R)-1-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethan-1- amine (115 mg, 0.52 mmol) in toluene (2 mL) was added Cs2CO3 (507 mg, 1.56 mmol) and Pd-175 (81 mg, 0.10 mmol), and the reaction was stirred under a dry nitrogen atmosphere at 100 °C for 20 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C18, 20 - 95% MeCN in water with 0.1% FA) and further purified by chiral-SFC (ChiralCel OJ, 250×30mm I.D., 5µm, A for CO2 and B for MeOH (0.1% 7mol/L NH3 in MeOH)) to give the title compound (25 mg, yield 11.2%) as a white solid. LC/MS (ESI) m/z: 434 (M+H)⁺. Step 4: (6S,8R)-8-Fluoro-3-(((R)-1-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl) amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (8R)-8-fluoro-3-(((R)-1-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)- ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (25 mg, 0.06 mmol) in DCE (3 mL) was added trimethyltin hydroxide (21 mg, 0.12 mmol). The reaction mixture was stirred at 70 °C for 4 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (20 mg, yield 83.3%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 420 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-fluoro-3-(((R)-1-(5-(2-fluorophenyl)-1,3,4- thiadiazol-2-yl)ethyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 412) To a mixture of (6S,8R)-8-fluoro-3-(((R)-1-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)-amino)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (20 mg, 0.05 mmol) and 2- (aminomethyl)thieno[3,2-c]pyridin-6-amine hydrochloride (15 mg, 0.08 mmol) in DMF (2 mL) was added DIPEA (37 mg, 0.30 mmol) and HATU (22 mg, 0.06 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 412 (9.0 mg, yield 32.6%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (t, J = 5.8 Hz, 1H), 8.42 (s, 1H), 8.27 - 8.21 (m, 1H), 7.67 - 7.61 (m, 1H), 7.50 - 7.40 (m, 2H), 7.24 (s, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 6.45 (d, J = 7.8 Hz, 1H), 6.00 - 5.82 (m, 3H), 5.18 (t, J = 7.2 Hz, 1H), 5.15 - 5.11 (m, 1H), 4.47 (d, J = 5.6 Hz, 2H), 2.68 - 2.54 (m, 2H), 1.73 (d, J = 6.8 Hz, 3H). LC/MS (ESI) m/z: 581 (M+H)⁺. RT (Method A): 1.18 min. The following compounds were prepared according to the methods set forth above starting from Step 3 with the appropriate aldehyde and bicycle. Scheme 130. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-2-(2-fluorophenyl) oxazole-5- carboxamide (Compound 415) Step 1: Ethyl 2-(2-fluorophenyl)oxazole-5-carboxylate To a mixture of ethyl 2-bromooxazole-5-carboxylate (300 mg, 1.36 mmol) and (2- fluorophenyl)boronic acid (286 mg, 2.05 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added MeCgPPh (79 mg, 0.27 mmol), Pd2(dba)3 (125 mg, 0.13 mmol) and K2CO3 (378 mg, 2.74 mmol), and the reaction was stirred under a dry nitrogen atmosphere at 100 °C for 2 hours. The mixture was cooled and diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (301 mg, yield 46.2%) as a yellow oil. LC/MS (ESI) m/z: 236 (M+H)⁺. Step 2: 2-(2-Fluorophenyl)oxazole-5-carboxylic acid To a solution of ethyl 2-(2-fluorophenyl)oxazole-5-carboxylate (120 mg, 0.51 mmol) in THF (2 mL) and water (1 mL) was added LiOH (25 mg, 1.02 mmol) and the reaction was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (50 mg, yield 47.3%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 208 (M+H)⁺. Step 3: tert-Butyl (2-(((6S,8R)-3-(2-(2-fluorophenyl)oxazole-5-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (10 mg, 0.02 mmol) and 2-(2- fluorophenyl)oxazole-5-carboxylic acid (6 mg, 0.03 mmol) in MeCN (1 mL) was added TCFH (17 mg, 0.06 mmol) and NMI (5 mg, 0.06 mmol), and the reaction was stirred under a dry nitrogen atmosphere at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (7 mg, yield 49.9%) as a yellow solid. LC/MS (ESI) m/z: 660 (M+H)⁺. Step 4: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-2-(2-fluorophenyl)oxazole-5-carboxamide (Compound 415) To a solution of tert-butyl (2-(((6S,8R)-3-(2-(2-fluorophenyl)oxazole-5-carboxamido)-8-methyl-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (7 mg, 0.01 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol), and the reaction was stirred under a dry nitrogen atmosphere at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 415 (3.0 mg, yield 50.5%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) ¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.20 - 8.16 (m, 1H), 7.71 - 7.66 (m, 1H), 7.50 - 7.43 (m, 2H), 7.13 (s, 1H), 6.87 (s, 1H), 5.92 (s, 2H), 5.06 (d, J = 8.6 Hz, 1H), 4.49 (dd, J = 14.5, 8.1 Hz, 2H), 3.38 - 3.35 (m, 1H), 2.40 - 2.35 (m, 1H), 2.27 - 2.19 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 560 (M+H)⁺. RT (Method A): 1.08 min. The following compounds were prepared according to the methods set forth above.

^a Step 1 was performed with Pd(dppf)Cl2 and Na2CO3 in 1,4-dioxane/water. ^b Step 1 was performed with Pd(OAc)₂, XantPhos, and NMM in toluene and water. ^c Step 1 was performed with Pd2(dba)3, XantPhos, Cs2CO3 in 1,4-dioxan. Scheme 131. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 416) Step 1: 1-(tert-Butyl)-2-methyl (2S)-5-cyanopyrrolidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-methyl (S)-pyrrolidine-1,2-dicarboxylate (6 g, 26.2 mmol) in DCM (240 mL) was added K₂CO₃ (5.6 g, 52.4 mmol), (S)-(+)-BNPA (460 mg), and (Ir[dF(CF₃)ppy]₂(5,5'- CF₃bpy))PF₆ (298 mg, 0.26 mmol). The mixture was degassed under a dry nitrogen atmosphere three times. The mixture was stirred at room temperature under Blue LED illuminating (430 nm) for 16 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (2 g, yield 30.2%) as a yellow oil. LC/MS (ESI) m/z: 255 (M+H)⁺. Step 2: Methyl (2S)-5-cyanopyrrolidine-2-carboxylate A mixture of 1-(tert-butyl) 2-methyl (2S)-5-cyanopyrrolidine-1,2-dicarboxylate (2 g, 7.9 mmol) in TFA (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (900 mg, yield 73.4%) as a yellow oil. LC/MS (ESI) m/z: 155 (M+H)⁺. Step 3: Methyl (S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a mixture of methyl (2S)-5-cyanopyrrolidine-2-carboxylate (900 mg, 5.8 mmol) in toluene (15 mL) was added oxalyl chloride (2.2 g, 17.4 mmol). The mixture was stirred at 100°C under a dry nitrogen atmosphere for 2 hours. The mixture was cooled and diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (400 mg, yield 26.3%) as a yellow solid. LC/MS (ESI) m/z: 263 (M+H)⁺. Step 4: Methyl (S)-1-chloro-3-((2,4-dimethoxybenzyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrazine-6-carboxylate To a mixture of methyl (S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine -6- carboxylate (480 mg, 1.83 mmol) and (2,4-dimethoxyphenyl)methanamine (612 mg, 3.66 mmol) in DMF (5 mL) was added K₂CO₃ (505 mg, 3.66 mmol) and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 25% EtOAc in PE) to give the title compound (300 mg, yield 41.7%) as a yellow oil. LC/MS (ESI) m/z: 394 (M+H)⁺. Step 5: Methyl (S)-3-((2,4-dimethoxybenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrazine-6- carboxylate To a solution of methyl (S)-1-chloro-3-((2,4-dimethoxybenzyl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (300 mg, 0.76 mmol) in MeOH (5 mL) was added Pd/C (200 mg, 5% wt.) and Pd(OH)₂/C (200 mg, 10% wt.). The mixture was degassed under a dry nitrogen atmosphere three times and stirred under a hydrogen balloon at 25°C for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (260 mg, yield 96.3%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 360 (M+H)⁺. Step 6: Methyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate A solution of methyl (S)-3-((2,4-dimethoxybenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrazine-6-carboxylate (260 mg, 0.72 mmol) in TFA (3 mL) was stirred at 50°C for 1 hour. The mixture was cooled and then concentrated under reduced pressure to dryness. The residue was basified with saturated aq. NaHCO3 solution to pH~8 and extracted with CHCl3/i-PrOH (20 mL, v/v=3/1) twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (75 mg, yield 49.6%) as a yellow solid. LC/MS (ESI) m/z: 210 (M+H)⁺. Step 7: Methyl (S)-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrazine-6-carboxylate To a cold (0°C ) mixture of methyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxylate (75 mg, 0.36 mmol) and 5-phenyl-1,3,4-thiadiazole-2-carboxylic acid (149 mg, 0.72 mmol) in pyridine (2 mL) was added POCl₃ (0.10 mL, 1.08 mmol) and the reaction was stirred at 0°C for 30 minutes. The reaction was concentrated under reduced pressure to dryness. The residue was diluted with EtOAc, washed with 1N aq. HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (30 mg, yield 21.1%) as a yellow solid. LC/MS (ESI) m/z: 398 (M+H)⁺. Step 8: (S)-4-Oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrazine- 6-carboxylic acid To a solution of methyl (S)-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (30 mg, 0.07 mmol) in THF (2 mL) and water (1 mL) was added LiOH (5 mg, 0.21 mmol) and the reaction was stirred at room temperature for 30 minutes. The mixture was acidified with 1N aq. HCl to pH~3, and the suspension was filtered, and concentrated under reduced pressure to dryness to give the title compound (23 mg, yield 79.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 384 (M+H)⁺. Step 9: (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 416) To a mixture of (S)-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrazine-6-carboxylic acid (20.0 mg, 0.05 mmol) and 2-(aminomethyl)thieno-[3,2-c]pyridin-6- amine hydrochloride (13 mg, 0.06 mmol) in DMF (1 mL) was added DIPEA (19 mg, 0.15 mmol) and T3P (68 mg, 0.11 mmol, 50% wt. in DMF) and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C18, 25 - 98% MeCN in water with 0.1% NH4HCO3) to give Compound 416 (10 mg, yield 35.2%) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.08 (t, J = 5.8 Hz, 1H), 8.41 (s, 1H), 8.11 (d, J = 6.7 Hz, 2H), 7.67 - 7.60 (m, 3H), 7.26 (s, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.12 (d, J = 6.8 Hz, 1H), 4.53 - 4.43 (m, 2H), 3.16 - 3.10 (m, 2H), 2.58 - 2.55 (m, 1H), 2.22 - 2.14 (m, 1H). LC/MS (ESI) m/z: 545 (M+H)⁺. RT (Method A): 1.08 min. Scheme 132. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-(2- fluorophenyl)-1H-1,2,3-triazole-4-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 417) Step 1: 1-Azido-2-fluorobenzene To a solution of 2-fluoroaniline (12 g, 108 mmol) in MeCN (200 mL) was added t-BuONO (13.4 g, 130 mmol) followed by dropwise addition of TMSN₃ (14.9 g, 130 mmol) at 0 °C and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% EtOAc in PE) to give the title compound (5 g, yield 28.1%) as a yellow oil. LC/MS (ESI) m/z: 138 (M+H)⁺. Step 2: Ethyl 1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate To a solution of 1-azido-2-fluorobenzene (5 g, 36.5 mmol) in toluene (100 mL) was added ethyl propiolate (11 g, 112 mmol) and the mixture was heated and stirred at 100 ^°C for 2 hours. The mixture was cooled and then concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (2 g, yield 23.3%) as a yellow oil.¹H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.6 Hz, 1H), 8.00 – 7.93 (m, 1H), 7.52 – 7.43 (m, 1H), 7.36 – 7.27 (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). LC/MS (ESI) m/z: 236 (M+H)⁺. The ethyl 1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate was used to prepare Compound 417 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 9.32 (d, J = 1.6 Hz, 1H), 9.12 (t, J = 5.8 Hz, 1H), 8.86 (s, 1H), 8.41 (d, J = 0.6 Hz, 1H), 7.93-7.89 (m, 1H), 7.72 - 7.66 (m, 1H), 7.65 - 7.60 (m, 1H), 7.51 - 7.47 (m, 1H), 7.12 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.08 (dd, J = 9.2, 0.8 Hz, 1H), 4.54 - 4.43 (m, 2H), 3.39 - 3.33 (m, 1H), 2.41 - 2.35 (m, 1H), 2.26 - 2.17 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 560 (M+H)⁺. RT (Method A): = 1.10 min. Scheme 133. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-(2- fluorophenyl)-1H-pyrazole-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 418) Step 1: Methyl 1-(2-fluorophenyl)-1H-pyrazole-3-carboxylate To a mixture of methyl 1H-pyrazole-3-carboxylate (5 g, 39.64 mmol), 1-fluoro-2-iodobenzene (10.56 g, 47.57 mmol) and K₃PO₄ (33.66 g, 158.58 mmol) in DMSO (60 mL) was added (1R,2R)-N₁,N₂- dimethylcyclohexane-1,2-diamine (4.51 g, 31.72 mmol) and CuI (3.02 g, 15.86 mmol) under a dry nitrogen atmosphere, the reaction mixture was degassed under a dry nitrogen atmosphere three times and stirred at 100 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 21% EtOAc in PE) to give the title compound (3.7 g, yield 42.4%) as a brown solid. LC/MS (ESI) m/z: 221 (M+H)⁺. The methyl 1-(2-fluorophenyl)-1H-pyrazole-3-carboxylate was used to prepare Compound 418 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (s, 1H), 9.09 (t, J = 5.9 Hz, 1H), 8.88 (s, 1H), 8.41 - 8.38 (m, 2H), 7.90 - 7.85 (m, 1H), 7.58 - 7.53 (m, 2H), 7.47 - 7.43 (m, 1H), 7.12 - 7.11 (m, 1H), 7.08 (d, J = 2.5 Hz, 1H), 6.85 - 6.83 (m, 1H), 5.84 (s, 2H), 5.07 - 5.03 (m, 1H), 4.51 - 4.40 (m, 2H), 3.36 - 3.33 (m, 1H), 2.40 - 2.34 (m, 1H), 2.24 - 2.16 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 559 (M+H)⁺. RT (Method A): = 1.24 min. Scheme 134. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluoro-phenyl)oxazole-2- carboxamide (Compound 419) Step 1: Ethyl 2-((2-(2-fluorophenyl)-2-oxoethyl) amino)-2-oxoacetate To a mixture of 2-amino-1-(2-fluorophenyl) ethan-1-one (3.20 g, 20.9 mmol) and TEA (4.22 g, 41.8 mmol) in DCM (30.0 mL) was added ethyl 2-chloro-2-oxoacetate (4.28 g, 31.4 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (2.30 g, yield 43.4%) as a yellow oil. LC/MS (ESI) m/z: 254 (M+H)⁺. Step 2: Ethyl 5-(2-fluorophenyl) oxazole-2-carboxylate To a solution of ethyl 2-((2-(2-fluorophenyl)-2-oxoethyl) amino)-2-oxoacetate (500 mg, 1.97 mmol) in toluene (10.0 mL) was added POCl3 (906 mg, 5.91 mmol) dropwise at 0 °C. The mixture was heated and stirred under a dry nitrogen atmosphere at 110 °C for 16 hours. The reaction mixture was cooled, and then concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (370 mg, yield 79.8%) as a yellow oil. LC/MS (ESI) m/z: 236 (M+H)⁺. The ethyl 5-(2-fluorophenyl) oxazole-2-carboxylate was used to prepare Compound 419 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.16 - 9.07 (m, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 7.97 - 7.88 (m, 1H), 7.85 (d, J = 3.5 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.49 - 7.41 (m, 2H), 7.12 (s, 1H), 6.86 (s, 1H), 5.89 (s, 2H), 5.07 (d, J = 8.8 Hz, 1H), 4.54 - 4.43 (m, 2H), 3.39 - 3.34 (m, 1H), 2.41 - 2.35 (m, 1H), 2.26 - 2.17 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 560 (M+H)⁺. RT (Method A): = 1.32 min. Scheme 135. Synthesis of (S)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(((R)-1-(5-(2- fluorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)amino)-4-oxo-4,6-dihydropyrrolo [1,2-a]-pyrimidine-6- carboxamide (Compound 422) To a solution of Compound 412 (4 mg, 0.007 mmol) in THF (1 mL) and water (0.5 mL) was added LiOH (0.3 mg, 0.01 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 422 (0.3 mg, yield 7.8%) as a brown solid. ¹H NMR (400 MHz, CD3OD) δ 8.40 – 8.36 (m, 2H), 7.75 (s, 1H), 7.68 – 7.62 (m, 1H), 7.44 – 7.38 (m, 2H), 7.16 (s, 1H), 6.95 (s, 1H), 5.19 (dd, J = 9.2, 3.1 Hz, 1H), 4.61 (s, 2H), 4.58 (s, 3H), 1.29 (d, J = 0.6 Hz, 3H). LC/MS (ESI) m/z: 561 (M+H)⁺. RT (Method A): 1.16 min. Scheme 136: Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(2-fluorophenyl)isothiazole-5- carboxamide (Compound 423) Step 1: 5-(2-Fluorophenyl)-1,3,4-oxathiazol-2-one To a solution of 2-fluorobenzamide (2.80 g, 20.1 mmol) in toluene (30.0 mL) was added carbonochloridic hypochlorous thioanhydride (3.95 g, 30.2 mmol) dropwise at 0 °C and the mixture was then heated and stirred at 110 °C for 16 hours. The mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (2.80 g, yield 70.6%) as a yellow oil. LC/MS (ESI) m/z: 198 (M+H)⁺. Step 2: Ethyl 3-(2-fluorophenyl) isothiazole-5-carboxylate To solution of ethyl 3-(2-fluorophenyl) isothiazole-5-carboxylate (800 mg, 4.1 mmol) in ethylbenzene (10.0 mL) was added ethyl propiolate (597 mg, 6.1 mmol) dropwise at room temperature. The mixture was heated and stirred under a dry nitrogen atmosphere at 120 °C for 16 hours. The reaction mixture was then cooled and concentrated under reduced pressure to dryness and the residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (160 mg, yield 15.7%) as a yellow oil. LC/MS (ESI) m/z: 252 (M+H)⁺. The ethyl 3-(2-fluorophenyl) isothiazole-5-carboxylate was used to prepare Compound 423 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.16 – 9.06 (m, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.12 - 8.04 (m, 1H), 7.60 - 7.53 (m, 1H), 7.46 - 7.36 (m, 2H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.05 (d, J = 9.0 Hz, 1H), 4.54 - 4.41 (m, 2H), 3.39 - 3.35 (m, 1H), 2.40 - 2.33 (m, 1H), 2.28 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 576 (M+H)⁺. RT(Method A): 1.47 min. Scheme 137. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(3-(2- fluorophenyl)-1H-pyrazole-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 424) Step 1: Ethyl 3-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate To a solution of ethyl 3-(2-fluorophenyl)-1H-pyrazole-5-carboxylate (70 mg, 0.30 mmol) in THF (5 mL) was added NaH (60% in oil, 24 mg, 0.60 mmol) in portions at 0°C and the reaction mixture was stirred at 0°C for 15 minutes. Afterwards, to the reaction mixture was added SEM-Cl (75 mg, 0.45 mmol) at 0°C and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was quenched with saturated aq. NH4Cl solution at 0°C and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (90 mg, yield 82.7%) as a yellow oil. LC/MS (ESI) m/z: 365 (M+H)⁺. The ethyl 3-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate was used to prepare Compound 424 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 14.01 (s, 1H), 9.34 (s, 1H), 9.10 (t, J = 5.9 Hz, 1H), 8.91 (s, 1H), 8.41 (s, 1H), 7.92 - 7.86 (m, 1H), 7.53 - 7.46 (m, 1H), 7.43 - 7.35 (m, 2H), 7.15 (s, 1H), 7.12 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.07 (d, J = 9.1 Hz, 1H), 4.52 - 4.43 (m, 2H), 3.29 - 3.27 (m, 1H), 2.40 - 2.35 (m, 1H), 2.24 - 2.17 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 559 (M+H)⁺. RT (Method A): 1.31 min. Scheme 138. Synthesis of (R*)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-6- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carboxamide (Compound 425) and (S*)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)- 6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2- carboxamide (Compound 426) Step1: tert-Butyl 6-(hydroxymethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of tert-butyl (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (8.0 g, 33.8 mmol) in THF (120 mL) was added LDA (33.0 mL, 66.0 mmol, 2M in hexane) dropwise at −50 °C under a dry nitrogen atmosphere over 1 hour.2-(hydroxy-methyl)-isoindoline-1,3-dione (12.0 g, 67.7 mmol) was added to the above mixture and the resulting mixture was stirred at −50 °C for 2 hours. The reaction mixture was quenched with saturated aq. NH4Cl solution at 0°C and extracted with EtOAc three times. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (450 mg, yield 5%) as a white solid. LC/MS (ESI) (m/z): 267 (M+H)⁺. Step 2: tert-Butyl 6-(((((5-fluoroborinin-2-yl)oxy)carbonothioyl)oxy)methyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of tert-butyl 6-(hydroxymethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylate (450 mg, 1.69 mmol) and O-(4-fluorophenyl) carbonochlorido-thioate (500 mg, 2.63 mmol) in DCM (5 mL) was added DMAP (450 mg, 3.68 mmol) and the reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (450 mg, yield 63.8%) as a white solid. LC/MS (ESI) m/z: 421 (M+H)⁺. Step 3: tert-Butyl 6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of tert-butyl 6-(((((5-fluoroborinin-2-yl)oxy)carbonothioyl)oxy)methyl) -4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (450 mg, 1.06 mmol) in 1,4-dioxane (5 mL) was added TMS3SiH (384 mg, 1.54 mmol) and AIBN (80.0 mg, 0.48 mmol) and the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (250 mg, yield 96.8%) as a white solid. LC/MS (ESI) m/z: 251 (M+H)⁺. Step 4: tert-Butyl 3-bromo-5-methyl-4-oxo-4a,5,6,7-tetrahydro-4H-cyclopenta [b]pyridine-5-carboxylate To a solution of tert-butyl 6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (250 mg, 0.99 mmol) in DMF (3 mL) was added NBS (239 mg, 1.32 mmol) and the mixture was stirred at 50 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (250 mg, yield 76.2%) as a white solid. LC/MS (ESI) m/z: 329 (M+H)⁺. Step 5: tert-Butyl 3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of tert-butyl 3-bromo-5-methyl-4-oxo-4a,5,6,7-tetrahydro-4H-cyclopenta[b]-pyridine- 5-carboxylate (250 mg, 0.75 mmol) and tert-butyl carbamate (327 mg, 2.79 mmol) in toluene (3 mL) was added K2CO3 (463 mg, 3.35 mmol), BrettPhos (60 mg, 0.12 mmol) and Pd2(dba)3 (118 mg, 0.13 mmol) under a dry nitrogen atmosphere and the reaction mixture was stirred under a dry nitrogen atmosphere at 110 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (240 mg, yield 86.6%) as a yellow oil. LC/MS (ESI) m/z: 366 (M+H)⁺. Step 6: 3-Amino-6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid A solution of tert-butyl 3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylate (240 mg, 0.65 mmol) in DCM (1 mL) and HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) was stirred under a dry nitrogen atmosphere at room temperature overnight. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (130 mg, yield 94.8%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 210 (M+H)⁺. Step 7: tert-Butyl (2-((3-amino-6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 3-amino-6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (120 mg, 0.57 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (96 mg, 0.64 mmol) in DMF (2 mL) was added DIPEA (222 mg, 1.43 mmol) and HATU (261 mg, 0.68 mmol), the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (220 mg, yield 81.4%) as a yellow solid. LC/MS (ESI) (m/z): 471 (M+H)⁺. Step 8: tert-Butyl (2-((6-methyl-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-((3-amino-6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine- 6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (77.0 mg, 0.16 mmol) and 5-phenyl-1,3,4- thiadiazole-2-carboxylic acid (34.0 mg, 0.08 mmol) in MeCN (1 mL) was added NMI (16 mg, 0.19 mmol) and TCFH (54 mg, 0.19 mmol) under a dry nitrogen atmosphere and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the title compound (35 mg, yield 73.4%) as a yellow oil. LC/MS (ESI) m/z: 659 (M+H)⁺. Step 9: (R*)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-6-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 425) and (S*)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-6-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 426) To a solution of tert-butyl (2-((6-methyl-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate (35.0 mg, 0.05 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC and further purified by chiral SFC (ChiralPak IH, 250×20 mm I.D., 5µm, A for CO₂ and B for MEOH+CAN (0.1% 7 mol/L NH₃ in MeOH)) to give Compound 425 (peak 1, retention time: 2.66 min) (2.5 mg, yield 8.30%) and Compound 426 (peak 2, retention time: 3.31 min) (2.0 mg, yield 6.80%) as a white solid. The absolute configuration was tentatively assigned. Compound 425: ¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.73 (s, 2H), 8.39 (s, 1H), 8.12 (d, J = 7.2 Hz, 2H), 7.62 (dd, J = 15.9, 8.2 Hz, 3H), 7.08 (s, 1H), 6.82 (s, 1H), 5.81 (s, 2H), 4.51 - 4.37 (m, 2H), 3.17 (d, J = 8.5 Hz, 1H), 3.04 - 2.98 (m, 1H), 2.40 - 2.33 (m, 1H), 2.25 - 2.18 (m, 1H), 1.79 (s, 3H). LC/MS (ESI) (m/z): 559 (M+H)⁺. RT (Method A): 1.56 min. Compound 426: ¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 8.12 (d, J = 7.2 Hz, 2H), 7.67 - 7.59 (m, 3H), 7.08 (s, 1H), 6.82 (s, 1H), 5.81 (s, 2H), 4.51 – 4.37 (m, 2H), 2.46 – 2.29 (m, 2H), 2.24 (d, J = 8.8 Hz, 1H), 1.79 (s, 3H). LC/MS (ESI) (m/z): 559 (M+H)⁺. RT (Method A): 1.56 min. Scheme 139. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(3-(2- fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 429) Step 1: Ethyl 3-(2-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate To a solution of ethyl 3-(2-fluorophenyl)-1H-pyrazole-5-carboxylate (500 mg, 2.14 mmol) in DMF (5 mL) was added K2CO3 (590 mg, 4.28 mmol) and MeI (607 mg, 4.28 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 27% EtOAc in PE) to give the title compound (440 mg, yield 83.0%) as a white solid.LC/MS (ESI) m/z: 249 (M+H)⁺. The ethyl 3-(2-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxylate was used to prepare Compound 429 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 3.3 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.36 - 7.27 (m, 2H), 7.11 (s, 1H), 6.84 (s, 1H), 5.86 (s, 2H), 5.04 (d, J = 9.0 Hz, 1H), 4.54 - 4.40 (m, 2H), 4.16 (s, 3H), 3.39 - 3.34 (m, 1H), 2.40 - 2.33 (m, 1H), 2.27 - 2.18 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 573 (M+H)⁺. RT (Method A): 1.35 min. Scheme 140. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(2-fluorophenyl)-4-methylisoxazole- 5-carboxamide (Compound 430) To a mixture of (E)-2-fluorobenzaldehyde oxime (1.0 g, 7.19 mmol) and ethyl but-2-ynoate (967 mg, 8.63 mmol) in MeCN (10 mL) was added CrO2 (6.04 g, 71.9 mmol) and the reaction mixture was stirred at 80 °C overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) and further purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% FA) to give the title compound (40 mg, yield 2.23%) as a white solid.LC/MS (ESI) m/z: 250 (M+H)⁺. The ethyl 3-(2-fluorophenyl)-4-methylisoxazole-5-carboxylate was used to prepare Compound 430 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.69 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 7.68 - 7.61 (m, 2H), 7.48 - 7.40 (m, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 9.0 Hz, 1H), 4.54 - 4.41 (m, 2H), 3.41 - 3.35 (m, 1H), 3.06 (d, J = 15.6 Hz, 1H), 2.40 - 2.33 (m, 1H), 2.23 (s, 3H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 574 (M+H)⁺. RT (Method A): 1.50 min. The following compounds were prepared following the procedures above using the appropriate oxime in Step 1: Scheme 141. Synthesis of (S)-N-(6'-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4'-oxo- 6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidin]-3'-yl)-5-(pyridin-2-yl)-1,3,4- thiadiazole-2 Step 1: Benzyl (S)-4-thioxo-5-azaspiro[2.4]heptane-6-carboxylate To a solution of benzyl (S)-4-oxo-5-azaspiro[2.4]heptane-6-carboxylate (6.6 g, 26.94 mmol) in toluene (19 mL) was added Lawesson’s reagent (10.88 g, 26.94 mmol) and the mixture was stirred at 70 °C for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (6 g, yield 85.1%) as a white solid. LC/MS (ESI) m/z: 262 (M+H)⁺. Step 2: Benzyl (S)-4-(methylthio)-5-azaspiro[2.4]hept-4-ene-6-carboxylate To a solution of benzyl (S)-4-thioxo-5-azaspiro[2.4]heptane-6-carboxylate (6 g, 22.9 mmol) in THF (60 mL) was added MeI (13 g, 90.6 mmol) and DIPEA (5.92 g, 45.8 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (5.8 g, yield 91.8%) as a yellow oil. LC/MS (ESI) m/z: 276 (M+H)⁺. Step 3: Benzyl (S)-4-amino-5-azaspiro[2.4]hept-4-ene-6-carboxylate To a solution of benzyl (S)-4-(methylthio)-5-azaspiro[2.4]hept-4-ene-6-carboxylate (5.8 g, 20.01 mmol) in MeOH (58 mL) was added NH₄Cl (3.37 g, 60.04 mmol) and the mixture was stirred at 80 °C for 2 hours. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (2.5 g, yield 51.0%) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 245 (M+H)⁺. Step 4: 6'-Benzyl 3'-methyl (S)-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]- 3',6'-dicarboxylate To a solution of benzyl (S)-4-amino-5-azaspiro[2.4]hept-4-ene-6-carboxylate (2.5 g, 10.2 mmol) in i-PrOH (25 mL) was added dimethyl 2-(methoxymethylene)malonate (1.78 g, 10.2 mmol) and the mixture was stirred at 90 °C for 4 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.02 g, yield 28.2%) as a yellow oil. LC/MS (ESI) m/z: 355 (M+H)⁺. Step 5: (S)-3'-(Methoxycarbonyl)-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo-[1,2- a]pyrimidine]-6'-carboxylic acid To a solution of 6'-benzyl 3'-methyl (S)-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'- pyrrolo[1,2-a]pyrimidine]-3',6'-dicarboxylate (850 mg, 2.39 mmol) in EtOAc (9 mL) was added Pd/C (50 mg, 10% wt.), the mixture was degassed under a dry nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 0.5 hour. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (600 mg, yield 94.8%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 265 (M+H)⁺. Step 6: Methyl (S)-6'-(((6-((tert-butoxycarbonyl)amino)thieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4'-oxo- 6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]-3'-carboxylate To a mixture of (S)-3'-(methoxycarbonyl)-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'- pyrrolo[1,2-a]pyrimidine]-6'-carboxylic acid (600 mg, 2.26 mmol) and tert-butyl (2-(amino- methyl)thieno[3,2-c]pyridin-6-yl)carbamate hydrochloride (819 mg, 2.94 mmol) in DMF (12 mL) was added DIPEA (1.46 g, 11.3 mmol) and HATU (1.12 g, 2.94 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (690 mg, yield 50.1%) as a yellow solid. LC/MS (ESI) m/z: 526 (M+H)⁺. Step 7: (S)-6'-(((6-((tert-Butoxycarbonyl)amino)thieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4'-oxo-6',7'- dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]-3'-carboxylic acid To a solution of methyl (S)-6'-(((6-((tert-butoxycarbonyl)amino)thieno[3,2-c]pyridin-2-yl)- methyl)carbamoyl)-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]-pyrimidine]-3'- carboxylate (690 mg, 1.31 mmol) in THF (5 mL) and water (1 mL) was added LiOH (42 mg, 1.97 mmol) and the mixture was stirred at 50 °C for 2 hours. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (500 mg, yield 76.4%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 512 (M+H)⁺. Step 8: tert-Butyl (S)-(2-((3'-amino-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2- a]pyrimidine]-6'-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a solution of (S)-6'-(((6-((tert-butoxycarbonyl)amino)thieno[3,2-c]pyridin-2- yl)methyl)carbamoyl)-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]-3'- carboxylic acid (500 mg, 0.98 mmol) in DCM (5 mL) was added DPPA (403 mg, 1.46 mmol) and DBU (222 mg, 1.46 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in 1,4-dioxane (1 mL) and water (0.25 mL). The reaction mixture was stirred at 90 °C overnight. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (71 mg, yield 15.0%) as a yellow solid. LC/MS (ESI) m/z: 483 (M+H)⁺. Step 9: tert-Butyl (S)-(2-((4'-oxo-3'-(5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamido)-6',7'-dihydro-4'H- spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]-6'-carboxamido)-methyl)-thieno[3,2-c]pyridin-6- yl)carbamate To a mixture of tert-butyl (S)-(2-((3'-amino-4'-oxo-6',7'-dihydro-4'H-spiro[cyclopropane-1,8'- pyrrolo[1,2-a]pyrimidine]-6'-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (10 mg, 0.02 mmol) and lithium 5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxylate (9 mg, 0.04 mmol) in MeCN (1 mL) was added NMI (16 mg, 0.2 mmol) and TCFH (56 mg, 0.2 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 15: 1) to give the title compound (10 mg, yield 74.4%) as a yellow solid. LC/MS (ESI) m/z: 672 (M+H)⁺. Step 10: (S)-N-(6'-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4'-oxo-6',7'-dihydro-4'H- spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidin]-3'-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide (Compound 434) A solution of tert-butyl (S)-(2-((4'-oxo-3'-(5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamido)-6',7'- dihydro-4'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]pyrimidine]-6'-carboxamido)-methyl)thieno[3,2-c]pyridin- 6-yl)carbamate (10 mg, 0.015 mmol) in HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) was stirred under a dry nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 10% - 95% MeCN in water with 0.1% NH₃.H₂O) to give Compound 434 (2 mg, yield 23.3%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 9.10 (s, 1H), 8.77 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.37 (d, J = 7.0 Hz, 1H), 8.10 (s, 1H), 7.67 (d, J = 4.2 Hz, 1H), 7.14 (s, 1H), 6.91 (s, 1H), 6.02 (s, 2H), 5.17 (d, J = 9.9 Hz, 1H), 4.58 - 4.39 (m, 2H), 2.81 (t, J = 10.6 Hz, 1H), 2.10 (d, J = 12.9 Hz, 1H), 1.32 - 1.25 (m, 1H), 1.22 - 1.11 (m, 3H). LC/MS (ESI) (m/z): 572 (M+H)⁺. RT (Method A): 1.18 min. Scheme 142. Synthesis of N-((6R,6aS,7aR)-6-(((6-Aminothieno[3,2-c]pyridin-2- yl)methyl)carbamoyl)-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidin-3-yl)-5- (2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamide (Compound 435) Step 1: 3-(4-Methoxybenzyl)-3-azabicyclo [3.1.0] hexane-2,4-dione To a solution of 3-oxabicyclo [3.1.0] hexane-2,4-dione (50 g, 446 mmol) in AcOH (300 mL) was added DMAP (5.45 g, 44.6 mmol) and (4-methoxyphenyl) methanamine (64.2 g, 468 mmol) at 0 °C and the mixture was then heated and stirred at 100°C for 16 hours. The cooled mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (59 g, yield 57.2%) as a white solid. LC/MS (ESI) m/z: 232 (M+H)⁺. Step 2: 4-(Furan-2-yl)-4-hydroxy-3-(4-methoxybenzyl)-3-azabicyclo [3.1.0] hexan-2-one To a solution of furan (31 g, 455.9 mmol) in THF (450 mL) was added n-BuLi (91 mL, 227.5 mmol, 2.5 M in THF) dropwise at -78 °C and the mixture was stirred at 0°C for 2 hours. The mixture was cooled to -78°C, followed by added a solution of 3-(4-methoxybenzyl)-3-azabicyclo[3.1.0] hexane-2,4- dione (35 g, 151.3 mmol) in THF (400 mL) dropwise, and the mixture was stirred at -78 °C for 30 minutes. The reaction mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (42 g, yield 92.7%) as a yellow oil. LC/MS (ESI) m/z: 300 (M+H)⁺. Step 3: 4-(Furan-2-yl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of 4-(furan-2-yl)-4-hydroxy-3-(4-methoxybenzyl)-3-azabicyclo [3.1.0] hexan-2-one (42 g, 140.3 mmol) in DCE (400 mL) was added TFA (40 mL) at 0 °C and followed by added triethylsilane (80 mL) dropwise, and the mixture was stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 3% MeOH in DCM) to give the title compound (35 g, yield 88%) as a brown oil. LC/MS (ESI) m/z: 284 (M+H)⁺. Step 4: 3-(4-Methoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of NaIO4 (160 g, 741 mmol) in CCl4 (400 mL)/MeCN (600 mL)/water (600 mL) was added RuCl₃ (1.28 g, 6.18 mmol) at 0°C and the mixture was stirred at 0°C for 50 minutes. A solution of 4- (Furan-2-yl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.0] hexan-2-one in MeCN (200 mL) was added to the above mixture at 0°C. the mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated aq. Na2SO3 solution and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (26 g, yield 80.5%) as a yellow oil. LC/MS (ESI) m/z: 262 (M+H)⁺. Step 5: Benzyl 3-(4-methoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of 3-(4-Methoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (26 g, 99.5 mmol) and K2CO3 (21 g, 152.2 mmol) in DMF (200 mL) was added BnBr (26 g, 152 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (30 g, yield 85.8%) as a white solid. LC/MS (ESI) (m/z): 352 (M+H)⁺. Step 6: Benzyl 4-oxo-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of Benzyl 3-(4-methoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2-carboxylate (30 g, 85.37 mmol) in MeCN (1.2 L) and water (240 mL) was added CAN (234 g, 426.83 mmol) at -15 °C and the reaction mixture was stirred at 0 °C for 4 hours. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 35% EtOAc in PE) to give the title compound (14 g, yield 76.9%) as a yellow oil. LC/MS (ESI) m/z: 232 (M+H)⁺. Step 7: Benzyl 4-methoxy-3-azabicyclo[3.1.0]hex-3-ene-2-carboxylate To a solution of Benzyl 4-oxo-3-azabicyclo[3.1.0]hexane-2-carboxylate (8 g, 34.6 mmol) in anhydrous DCM (150 mL) was added Me3OBF4 (10 g, 67.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 7 hours. The mixture was poured into saturated aq. NH4Cl solution and extracted with DCM twice. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (7.5 g, yield 88.4%) as a yellow oil. LC/MS (ESI) m/z: 246 (M+H)⁺. Step 8: Benzyl 4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of benzyl 4-methoxy-3-azabicyclo[3.1.0]hex-3-ene-2-carboxylate (7 g, 28.5 mmol) in anhydrous ethylbenzene (20 mL) was added 3-azatricyclo [4.2.1.02,5] non-7-en-4-one (9.6 g, 71 mmol) at room temperature, and the reaction mixture was stirred at 120 °C for 16 hours. The mixture was cooled and then concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (6.2 g, yield 76.9%) as a yellow oil. LC/MS (ESI) m/z: 283 (M+H)⁺. Step 9: Benzyl 3-bromo-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6- carboxylate To a solution of benzyl 4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a] pyrimidine-6- carboxylate (6 g, 21.3 mmol) in DMF (80 mL) was added NBS (7.5 g, 42.1 mmol) at 0 °C, and the reaction mixture was then stirred at 50 °C for 4 hours. The mixture was quenched with saturated aq. Na2SO3 solution and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 35% EtOAc in PE) to give the title compound (2.1 g, yield 27.4%) as a brown oil. LC/MS (ESI) m/z: 361/363 (M+H)⁺. Step 10: Benzyl (6R,6aS,7aR)-3-((tert-butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro-4H- cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylate and benzyl (6S,6aR,7aS)-3-((tert- butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]-pyrimidine-6- carboxylate To a solution of benzyl 3-bromo-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2- a]pyrimidine-6-carboxylate (2 g, 5.5 mmol) and NH2Boc (1.3 g, 11.1 mmol) in toluene (30 mL) was added K₂CO₃ (2.3 g, 16.7 mmol), BrettPhos (590 mg, 1.1 mmol) and Pd₂(dba)₃ (504 mg, 0.55 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at 100 °C for 1 hour. The mixture was diluted with EtOAc, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give benzyl 3-((tert- butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6- carboxylate (750 mg, yield 34.1%) as a white solid which was purified by chiral SFC (ChiralPak IC, 250×30mm I.D., 5µm, Mobile phase: A for CO2 and B for MEOH (0.1% 7mol/L NH3 in MeOH) Gradient: B 30%) to give benzyl (6R,6aS,7aR)-3-((tert-butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro-4H- cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylate (350 mg, retention time:1.669 minutes, yield 16.7%). LC/MS (ESI) m/z: 398 (M+H)⁺ and benzyl (6S,6aR,7aS)-3-((tert-butoxycarbonyl)amino)-4-oxo- 6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylate (336 mg, retention time:1.871 minutes, yield 15.4%) Step 11: Benzyl (6R,6aS,7aR)-3-amino-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa [3,4]pyrrolo[1,2- a]pyrimidine-6-carboxylate hydrochloride To a solution of benzyl (6R,6aS,7aR)-3-((tert-butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro- 4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.12 mmol) in HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) was stirred under a nitrogen atmosphere at room temperature overnight. The mixture was concentrated under reduced pressure to dryness to give the title compound (32 mg, yield 80.1%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 298 (M+H)⁺. The benzyl (6R,6aS,7aR)-3-amino-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa [3,4]pyrrolo[1,2- a]pyrimidine-6-carboxylate hydrochloride was used to prepare Compound 435 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 9.38 (t, J = 5.8 Hz, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.39 – 8.35 (m, 1H), 7.76 – 7.72 (m, 1H), 7.59 – 7.54 (m, 1H), 7.52 – 7.48 (m, 1H), 7.39 (s, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 5.04 (s, 1H), 4.59 – 4.53 (m, 2H), 2.72 – 2.68 (m, 1H), 2.25 – 2.20 (m, 1H), 1.41 – 1.35 (m, 1H), 1.00 – 0.95 (m, 1H). LC/MS (ESI) (m/z): 575 (M+H)⁺. RT (Method A): 1.34 min. Scheme 143. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluorophenyl)isothiazole-3- carboxamide (Compound 437) Step 1: 5-Iodo-3-methylisothiazole To a solution of 3-methylisothiazol-5-amine (4.0 g, 35.0 mmol) in water (14 mL) and H₂SO₄ (100 mL) was added NaNO₂ (2.52 g, 36.5 mmol) and KI (6.06 mg, 36.5 mmol) at 0 °C, the reaction mixture was stirred at 80 °C for 2 hours. The mixture was diluted with water and extracted with DCM twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (3.4 g, yield 43.1%) as a yellow solid.¹H NMR (400 MHz, DMSO- d₆) δ 7.43 (s, 1H), 2.43 (s, 3H), LC/MS (ESI) m/z: 226 (M+H)⁺. Step 2: 5-(2-Fluorophenyl)-3-methylisothiazole To a mixture of 5-iodo-3-methylisothiazole (2.0 g, 8.85 mmol) and (2-fluorophenyl)boronic acid (2.5 g, 17.7 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added K2CO3 (2.44 g, 17.7 mmol) and Pd(dppf)Cl2 (650 mg, 0.88 mmol) at 25 °C under a dry nitrogen atmosphere and the reaction mixture was degassed under a dry nitrogen atmosphere three times and stirred at 80 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (400 mg, yield 23.4%) as a yellow solid. LC/MS (ESI) m/z: 194 (M+H)⁺. Step 3: 5-(2-Fluorophenyl)isothiazole-3-carboxylic acid To a solution of 5-(2-fluorophenyl)-3-methylisothiazole (200 mg, 1.03 mmol) in water/pyridine (6 mL, 5/1) was added KMnO4 (490 mg, 3.10 mmol) at 0 °C and the reaction mixture was then heated and stirred at 50 °C for 3 hours. The mixture was cooled, acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC to give the title compound (80 mg, yield 35%) as a yellow solid. LC/MS (ESI) m/z: 224 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,8R)-3-(5-(2-fluorophenyl)isothiazole-3-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (80 mg, 0.17 mmol) and 5-(2- fluorophenyl)isothiazole-3-carboxylic acid (76 mg, 0.34 mmol) in MeCN (2 mL) was added NMI (56 mg, 0.68 mmol) and TCFH (95 mg, 0.34 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (80 mg, yield 69.6%) as a yellow solid. LC/MS (ESI) m/z: 676 (M+H)⁺. Step 5: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluorophenyl) isothiazole-3-carboxamide (Compound 437) A solution of tert-butyl (2-(((6S,8R)-3-(5-(2-fluorophenyl)isothiazole-3-carboxamido)-8-methyl-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (80 mg, 0.12 mmol) in HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 437 (22 mg, yield 32.3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.89 (s, 1H), 8.49 (s, 1H), 8.43 – 8.40 (m, 1H), 8.22 – 8.16 (m, 1H), 7.62 - 7.56 (m, 1H), 7.53 - 7.47 (m, 1H), 7.43 - 7.39 (m, 1H), 7.14 - 7.11 (m, 1H), 6.85 (t, J = 0.9 Hz, 1H), 5.85 (s, 2H), 5.10 - 5.06 (m, 1H), 4.53 - 4.43 (m, 2H), 3.38 - 3.37 (m, 1H), 2.42 - 2.36 (m, 1H), 2.26 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 576 (M+H)⁺. RT (Method A): 1.56 min. Scheme 144. Synthesis of N-((6S*,8R*)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- fluoro-8-(methoxymethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4- thiadiazole-2-carboxamide (Compound 440) Step 1: tert-Butyl (6S*,8R*)-3-((tert-butoxycarbonyl)amino)-8-fluoro-8-(methoxymethyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of tert-butyl (6S*,8R*)-3-((tert-butoxycarbonyl)amino)-8-fluoro-8-(hydroxy-methyl)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (300 mg, 0.75 mmol) in CHCl₃ (4 mL) was added Ag₂CO₃ (1.03 g, 3.74 mmol) and CH₃I (640 mg, 4.51 mmol), and the reaction mixture was stirred at 50 °C overnight. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 47% EtOAc in PE) to give the title compound (150 mg, yield 48.3%) as a yellow solid. LC/MS (ESI) m/z: 414 (M+H)⁺ Step 2: (6S*,8R*)-3-amino-8-fluoro-8-(methoxymethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine- 6-carboxylic acid hydrochloride A solution of tert-butyl (6S*,8R*)-3-((tert-butoxycarbonyl)amino)-8-fluoro-8-(methoxy-methyl)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (130 mg, 0.31 mmol) in HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to dryness to give the title compound (86 mg, yield 100%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 258 (M+H)⁺. Step 3: tert-Butyl (2-(((6S*,8R*)-3-amino-8-fluoro-8-(methoxymethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate To a mixture of (6S*,8R*)-3-amino-8-fluoro-8-(methoxymethyl)-4-oxo-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylic acid hydrochloride (86 mg, 0.29 mmol) and tert-butyl (2- (aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (97 mg, 0.35 mmol) in DMF (3 mL) was added HATU (140 mg, 0.37 mmol) and DIPEA (77 mg, 0.60 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 9% MeOH in DCM) to give the title compound (100 mg, yield 55.2%) as a yellow solid. LC/MS (ESI) m/z: 519 (M+H)⁺. Step 4: tert-Butyl (2-(((6S*,8R*)-8-fluoro-8-(methoxymethyl)-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3,2-c]pyridin-6- yl)carbamate To a mixture of tert-butyl (2-(((6S*,8R*)-3-amino-8-fluoro-8-(methoxymethyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (50 mg, 0.09 mmol) and 5-phenyl-1,3,4-thiadiazole-2-carboxylic acid (36 mg, 0.18 mmol) in MeCN (2 mL) was added NMI (21 mg, 0.26 mmol) and TCFH (73 mg, 0.26 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (30 mg, yield 47.2%) as a yellow solid. LC/MS (ESI) m/z: 707 (M+H)⁺. Step 5: N-((6S*,8R*)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-fluoro-8-(methoxymethyl)- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 440) To a solution of tert-butyl (2-(((6S*,8R*)-8-fluoro-8-(methoxymethyl)-4-oxo-3-(5-phenyl-1,3,4- thiadiazole-2-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate (30 mg, 0.04 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 440 (7 mg, yield 18.1%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 9.28 (t, J = 5.8 Hz, 1H), 8.87 (s, 1H), 8.43 (s, 1H), 8.12 (dd, J = 8.1, 1.4 Hz, 2H), 7.66 - 7.60 (m, 3H), 7.16 (s, 1H), 6.90 (s, 1H), 6.00 (s, 2H), 5.24 (dd, J = 9.3, 3.7 Hz, 1H), 4.57 - 4.44 (m, 2H), 3.90 - 3.72 (m, 2H), 3.34 (s, 3H), 2.89 - 2.78 (m, 1H), 2.70 - 2.64 (m, 1H). LC/MS (ESI) (m/z): 607 (M+H)⁺. RT (Method A): 1.49 min. Compound 481 was prepared following the procedures set forth above using lithium 5-(2- fluorophenyl)-1,3,4-thiadiazole-2-carboxylate in Step 4.¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (s, 1H), 9.38 (t, J = 5.9 Hz, 1H), 8.87 (s, 1H), 8.56 (s, 1H), 8.41 - 8.35 (m, 1H), 7.77 - 7.72 (m, 1H), 7.60 - 7.54 (m, 1H), 7.52 - 7.48 (m, 1H), 7.46 - 7.42 (m, 1H), 7.33 - 7.29 (m, 2H), 7.25 (s, 1H), 5.28 - 5.22 (m, 1H), 4.58 - 4.49 (m, 2H), 3.92 - 3.85 (m, 1H), 3.80 - 3.70 (m, 1H), 3.33 (s, 3H), 2.90 - 2.83 (m, 1H), 2.01 - 1.97 (m, 1H). LC/MS (ESI) m/z: 625 (M+H)⁺. RT (Method A): 1.66 min. Scheme 145. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-methyl-3-(pyridin-2-yl)isoxazole-5- carboxamide (Compound 444) Step 1: Methyl 4-methyl-3-(pyridin-2-yl)isoxazole-5-carboxylate To solution of (Z)-N-hydroxypicolinimidoyl chloride (1 g, 6.39 mmol) and methyl but-2-ynoate (752 mg, 7.66 mmol) in DCM (10.0 mL) was added TEA (1.29 g, 12.75 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% FA) to give the title compound (50 mg, yield 3.6%) as a yellow oil.¹H NMR (400 MHz, CDCl3) δ 8.73 - 8.70 (m, 1H), 7.83 - 7.78 (m, 1H), 7.69 - 7.65 (m, 1H), 7.40 - 7.36 (m, 1H), 3.75 (s, 3H), 2.73 (s, 3H). LC/MS (ESI) m/z: 219 (M+H)⁺. The methyl 4-methyl-3-(pyridin-2-yl)isoxazole-5-carboxylate was used to prepare Compound 444 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 13.71 (s, 1H), 9.14 - 9.09 (m, 2H), 8.97 - 8.94 (m, 1H), 8.37 (s, 1H), 8.19 - 8.15 (m, 1H), 8.13 - 8.08 (m, 1H), 7.60 - 7.56 (m, 1H), 7.14 (s, 1H), 6.84 (s, 1H), 5.88 (s, 2H), 5.09 (d, J = 9.3 Hz, 1H), 4.49 (d, J = 5.7 Hz, 2H), 3.39 - 3.35 (m, 1H), 2.82 (s, 3H), 2.41 - 2.35 (m, 1H), 2.24 - 2.15 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 557 (M+H)⁺. RT (Method A): 1.30 min. The following compounds were prepared according to the procedures above using the appropriate imidoyl chloride and alkyne starting materials. ^a Step 4 was performed with HCl/1,4-dioxane in DCM. Scheme 146. Synthesis of ethyl hydrogen ((((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2- yl)methyl)carbamoyl)-4-oxo-3-(5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidin-8-yl)oxy)methyl)phosphonate (Compound 447) Step 1: tert-Butyl (2-(((6S,8R)-8-hydroxy-4-oxo-3-(5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamido)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (600 mg, 1.27 mmol) in MeCN (5 mL) was added NMI (521 mg, 6.36 mmol) and TCFH (1.07 g, 3.81 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (301 mg, yield 35.8%) as a yellow solid. LC/MS (ESI) m/z: 662 (M+H)⁺. Step 2: Ethyl hydrogen ((((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-3-(5- (pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8- yl)oxy)methyl)phosphonate (Compound 447) To a solution of tert-butyl (2-(((6S,8R)-8-hydroxy-4-oxo-3-(5-(pyridin-2-yl)-1,3,4-thiadiazole-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6- yl)carbamate (100 mg, 0.15 mmol) in DMF (2 mL) was added NaH (60%, 30.0 mg, 0.75 mmol) in portions at 0 °C and the reaction mixture was stirred at room temperature for 30 minutes. Diethyl (tosylmethyl)phosphonate (68.9 mg, 0.23 mmol) was then added to the reaction at 0°C and the resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aq. NH₄Cl solution at 0°C and purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 447 (10.1 mg, yield 9.8%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 10.09 - 9.70 (m, 1H), 9.41 - 9.10 (m, 1H), 8.86 - 8.65 (m, 2H), 8.45 - 8.27 (m, 2H), 8.09 (t, J = 8.5 Hz, 1H), 7.73 - 7.57 (m, 1H), 7.55 - 6.92 (m, 3H), 6.87 (s, 1H), 6.18 - 5.68 (m, 1H), 5.45 - 4.76 (m, 2H), 4.57 - 4.36 (m, 2H), 4.03 - 3.79 (m, 4H), 3.06 - 2.68 (m, 2H), 1.14 (t, J = 12.1, 5.0 Hz, 3H). LC/MS (ESI) m/z: 684 (M+H)⁺. RT (Method A): 0.90 min. Scheme 147. Synthesis of N-((6R*,8S*)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- fluoro-8-(fluoromethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl-1,3,4- thiad Step 1: tert-Butyl (6R*,8S*)-3-((tert-butoxycarbonyl)amino)-8-fluoro-8-(fluoromethyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of tert-butyl (6R*,8S*)-3-((tert-butoxycarbonyl)amino)-8-fluoro-8-(hydroxy-methyl)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (500 mg, 1.25 mmol) in chloroform (6 mL) was added DAST (1.01 g, 6.26 mmol) and the reaction mixture was stirred at 60 °C for 3 hours. The mixture was quenched with saturated aq. NaHCO3 solution at 0 °C and extracted with DCM twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 43% EtOAc in PE) to give the title compound (250 mg, yield 49.8%) as a yellow solid. LC/MS (ESI) m/z: 402 (M+H)⁺ Step 2: (6R*,8S*)-3-Amino-8-fluoro-8-(fluoromethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid hydrochloride A solution of tert-butyl (6R*,8S*)-3-((tert-butoxycarbonyl)amino)-8-fluoro-8-(fluoromethyl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (250 mg, 0.62 mmol) in HCl in 1,4-dioxane (4M, 3 mL, 12 mmol) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (170 mg, yield 97.7%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 246 (M+H)⁺. Step 3: tert-Butyl (2-(((6R*,8S*)-3-amino-8-fluoro-8-(fluoromethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate To a mixture of (6R*,8S*)-3-amino-8-fluoro-8-(fluoromethyl)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid hydrochloride (175 mg, 0.62 mmol) and tert-butyl (2- (aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate hydrochloride (196 mg, 0.62 mmol) in DMF (3 mL) was added HATU (354 mg, 0.93 mmol) and DIPEA (321 mg, 2.48 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 9% MeOH in DCM) to give the title compound (150 mg, yield 47.6%) as a yellow solid. LC/MS (ESI) m/z: 507 (M+H)⁺. Step 4: tert-Butyl (2-(((6R*,8S*)-8-fluoro-8-(fluoromethyl)-4-oxo-3-(5-phenyl-1,3,4-thiadiazole-2- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3,2-c]pyridin-6- yl)carbamate To a mixture of tert-butyl (2-(((6R*,8S*)-3-amino-8-fluoro-8-(fluoromethyl)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate (45 mg, 0.088 mmol) and 5-phenyl-1,3,4-thiadiazole-2-carboxylic acid (36 mg, 0.18 mmol) in MeCN (2 mL) was added NMI (21 mg, 0.26 mmol) and TCFH (73 mg, 0.26 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (20 mg, yield 32.7%) as a yellow solid. LC/MS (ESI) m/z: 695 (M+H)⁺. To a solution of tert-butyl (2-(((6R*,8S*)-8-fluoro-8-(fluoromethyl)-4-oxo-3-(5-phenyl-1,3,4- thiadiazole-2-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3,2- c]pyridin-6-yl)carbamate (20 mg, 0.028 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 448 (3.1 mg, yield 18.1%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.55 (t, J = 5.7 Hz, 1H), 8.87 (s, 1H), 8.61 (s, 1H), 8.12 (d, J = 6.8 Hz, 2H), 7.70 - 7.57 (m, 4H), 7.56 - 7.48 (m, 1H), 7.46 (s, 1H), 7.29 (s, 1H), 5.32 (dd, J = 9.3, 3.0 Hz, 1H), 5.00 - 4.82 (m, 2H), 4.57 (d, J = 5.6 Hz, 2H), 3.03 - 2.92 (m, 2H). LC/MS (ESI) (m/z): 595 (M+H)⁺. RT (Method A): 1.69 min. Compound 482 was prepared according to the procedures set forth above using lithium 5-(2- fluorophenyl)-1,3,4-thiadiazole-2-carboxylate in Step 4.¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 9.37 (t, J = 5.8 Hz, 1H), 8.88 (s, 1H), 8.42 (s, 1H), 8.41 - 8.36 (m, 1H), 7.78 - 7.72 (m, 1H), 7.60 - 7.54 (m, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.15 (s, 1H), 6.85 (s, 1H), 5.87 (s, 2H), 5.29 (dd, J = 9.4, 2.8 Hz, 1H), 5.05 - 4.90 (m, 1H), 4.88 - 4.76 (m, 1H), 4.57 - 4.47 (m, 2H), 3.01 - 2.91 (m, 1H), 2.70 - 2.64 (m, 1H). LC/MS (ESI) (m/z): 613 (M+H)⁺. RT (Method A): 1.71 min. Scheme 148. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2,6-difluoro-phenyl)isoxazole-3- carboxamide (Compound 453) Step 1: Ethyl 5-(2,6-difluorophenyl)isoxazole-3-carboxylate To a mixture of 2-ethynyl-1,3-difluorobenzene (500 mg, 3.6 mmol) in NMP (8 mL) was added ethyl 2-nitroacetate (2.9 g, 21.7 mmol) and DABCO (282 mg, 2.52 mmol). The mixture was stirred at 70 °C for 16 hours. The reaction was cooled and diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (330 mg, yield 36.2%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 7.49 - 7.42 (m, 1H), 7.11 (t, J = 1.8 Hz, 1H), 7.10 - 7.04 (m, 2H), 4.52 - 4.46 (m, 2H), 1.45 (t, J = 7.1 Hz, 3H). LC/MS (ESI) m/z: 254 (M+H)⁺. The ethyl 5-(2,6-difluorophenyl)isoxazole-3-carboxylate was used to prepare Compound 453 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.69 (s, 1H), 8.41 (d, J = 0.8 Hz, 1H), 7.76 - 7.68 (m, 1H), 7.43 - 7.36 (m, 3H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.07 (d, J = 8.4 Hz, 1H), 4.54 - 4.42 (m, 2H), 3.40 - 3.35 (m, 1H), 2.41 - 2.34 (m, 1H), 2.27 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 578 (M+H)⁺. RT (Method A): 1.52 min. Scheme 149. Synthesis of N-((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-phenyl-1,2,5-oxadiazole-3- carboxamide (Compound 454) Step 1: 4-Phenyl-1,2,5-oxadiazole-3-carboxylic acid To a solution of 3-phenylisoxazol-5(4H)-one (1.61 g, 9.9 mmol) in MeOH (10 mL) was added NaOMe (2.7 g, 15 mmol, 30% wt. in MeOH) under a dry nitrogen atmosphere and the reaction was stirred at room temperature for 2 hours. tert-Butyl nitrite (1.37 g, 13.3 mmol) was added dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was acidified with 4N aq. HCl to pH~1 and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% FA) to give the title compound (103 mg, yield 5.6%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 7.94 - 7.87 (m, 2H), 7.64 - 7.55 (m, 3H). LC/MS (ESI) m/z: 191 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-8-methyl-4-oxo-3-(4-phenyl-1,2,5-oxadiazole-3-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 4-phenyl-1,2,5-oxadiazole-3-carboxylic acid (25 mg, 0.13 mmol) and tert-butyl(2- (((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (61.1 mg, 0.13 mmol) in MeCN (1.0 mL) was added NMI (40 mg, 0.49 mmol) and TCFH (56 mg, 0.2 mmol) and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (10 mg, yield 36.6%) as a yellow solid. LC/MS (ESI) m/z: 643 (M+H)⁺. Step 3: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-phenyl-1,2,5-oxadiazole-3-carboxamide (Compound 454) To a solution of tert-butyl (2-(((6S,8R)-8-methyl-4-oxo-3-(4-phenyl-1,2,5-oxadiazole-3- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (10 mg, 0.015 mmol) in DCM (1.0 mL) was added HCl in 1,4-dioxane (4M, 0.2 mL, 0.8 mmol) and the reaction was stirred room temperature for 3 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 454 (2.0 mg, yield 23.7%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.09 (t, J = 5.8 Hz, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.85 - 7.78 (m, 2H), 7.61 - 7.54 (m, 3H), 7.10 (s, 1H), 6.82 (s, 1H), 5.83 (s, 2H), 5.04 (d, J = 8.9 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 2.56 - 2.51 (m, 1H), 2.40 - 2.32 (m, 1H), 2.25 - 2.15 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 543 (M+H)⁺. RT (Method A): 1.58 min. Scheme 150. Synthesis of Diethyl ((((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2- yl)methyl)carbamoyl)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)oxy)methyl)phosphonate (Compound 458) Step 1: tert-Butyl (2-(((6S,8R)-8-((diethoxyphosphoryl)methoxy)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2- carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate To a cold (0°C) solution of NaH (12 mg, 0.30 mmol, 60% dispersion in mineral oil) in DMF (2 mL) was added tert-butyl (2-(((6S,8R)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-8-hydroxy-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (100 mg, 0.14 mmol) under a dry nitrogen atmosphere and the reaction was stirred at 0 °C for 20 minutes. Diethyl (tosylmethyl)phosphonate (54 mg, 0.18 mmol) was added under a dry nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% DCM in MeOH) to give the title compound (90 mg, yield 73.7%) as a white solid. LC/MS (ESI) (m/z): 829 (M+H)⁺. Step 2: Diethyl ((((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-3-(5-(2-fluorophenyl)- 1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidin-8- yl)oxy)methyl)phosphonate (Compound 458) To a solution of tert-butyl (2-(((6S,8R)-8-((diethoxyphosphoryl)methoxy)-3-(5-(2-fluoro-phenyl)- 1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30 mg, 0.03 mmol) in DCM (1 mL) was added TFA (1 mL) under a dry nitrogen atmosphere and the reaction was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and then purified by prep-HPLC (YMC- Actus TriartC₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 458 (4.0 mg, yield 15.4%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 9.26 (t, J = 6.0 Hz, 1H), 8.82 (s, 1H), 8.42 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.75 (dd, J = 12.2, 5.7 Hz, 1H), 7.67 – 7.39 (m, 2H), 7.14 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.18 (t, J = 8.0 Hz, 2H), 4.57 – 4.46 (m, 2H), 4.43 – 4.32 (m, 1H), 4.22 – 4.16 (m, 1H), 4.13 – 3.97 (m, 4H), 3.44 – 3.33 (m, 2H), 1.34 – 1.10 (m, 6H). LC/MS (ESI) m/z: 729 (M+H)⁺. RT (Method A): 1.67 min. Scheme 151. Synthesis of Ethyl hydrogen ((((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2- yl)methyl)carbamoyl)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)oxy)methyl)phosphonate (Compound 459) and ((((6S,8R)-6- (((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2- carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidin-8-yl)oxy)methyl)phosphonic acid (Compound 464) To a solution of tert-butyl (2-(((6S,8R)-8-((diethoxyphosphoryl)methoxy)-3-(5-(2-fluoro-phenyl)- 1,3,4-thiadiazole-2-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (30.0 mg, 0.03 mmol) in DCM (2 mL) was added TMSBr (45.9 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 459 (2.6 mg, yield 10.4%) and Compound 464 (1.9 mg, yield 7.9%) as yellow solids. Compound 459: ¹H NMR (400 MHz, DMSO- d₆) δ 9.94 (s, 1H), 9.36 - 9.15 (m, 1H), 8.81 (s, 1H), 8.45 - 8.36 (m, 2H), 7.76 - 7.69 (m, 1H), 7.60 - 7.47 (m, 2H), 7.13 (s, 1H), 6.86 (s, 1H), 5.92 - 5.82 (m, 1H), 5.20 - 5.14 (m, 2H), 4.54 - 4.44 (m, 2H), 4.20 - 4.02 (m, 1H), 3.96 - 3.88 (m, 3H), 2.67 (s, 2H), 2.33 (s, 2H), 1.20 - 1.15 (m, 3H). LC/MS (ESI) (m/z): 701 (M+H)⁺. RT (Method A): 1.19 min. Compound 464: ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 8.80 (s, 1H), 8.40 (s, 1H), 8.34 - 8.25 (m, 1H), 7.68 (d, J = 6.5 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.12 (s, 1H), 6.86 (s, 1H), 5.82 (s, 1H), 5.24 - 5.08 (m, 2H), 4.47 (s, 2H), 3.94 - 3.87 (m, 1H), 3.84 - 3.72 (m, 2H), 2.69 - 2.61 (m, 1H), 2.54 - 2.53 (m, 2H). LC/MS (ESI) (m/z): 673 (M+H)⁺. RT (Method A): 1.06 min. Scheme 152. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(pyridazin-3-yl)isoxazole-5- carboxamide (Compound 461) Step 1: Pyridazine-3-carbaldehyde To a solution of pyridazin-3-ylmethanol (4.50 g, 40.9 mmol) in DCE (50 mL) was added MnO₂ (18.0 g, 206 mmol) under a dry nitrogen atmosphere and the reaction was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (2.10 g, yield 46.6%) as a white solid. LC/MS (ESI) m/z: 109 (M+H)⁺. Step 2: (E)-Pyridazine-3-carbaldehyde oxime To a solution of pyridazine-3-carbaldehyde (2.10 g, 19.4 mmol) in EtOH (20 mL) was added NH₂OH-HCl (2.18 g, 38.8 mmol) and K₂CO₃ (4.30 g, 38.8 mmol) under a dry nitrogen atmosphere and the reaction was stirred under a dry nitrogen atmosphere at 80 °C for 2 hours. The mixture was cooled and diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 25% EtOAc in PE) to give the title compound (1.50 g, yield 65.2%) as a white solid. LC/MS (ESI) m/z: 124 (M+H)⁺. Step 3: Ethyl 3-(pyridazin-3-yl)isoxazole-5-carboxylate To a mixture of (E)-pyridazine-3-carbaldehyde oxime (800 mg, 6.45 mmol) and ethyl propiolate (1.90 g, 19.3 mmol) in THF (10 mL) was added NCS (960 mg, 7.16 mmol) and TEA (656 mg, 6.49 mmol). The reaction was stirred at 55 °C for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (500 mg, yield 35.7%) as a white solid. LC/MS (ESI) m/z: 220 (M+H)⁺. The ethyl 3-(pyridazin-3-yl)isoxazole-5-carboxylate was used to prepare Compound 461 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J = 4.1 Hz, 1H), 9.11 (s, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 8.36 (d, J = 9.1 Hz, 1H), 8.05 (s, 1H), 7.93 (dd, J = 8.7, 5.0 Hz, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.5 Hz, 1H), 4.54 – 4.43 (m, 2H), 2.67 (s, 1H), 2.38 – 2.32 (m, 2H), 1.31 (d, J = 7.0 Hz, 3H). LC/MS (ESI) (m/z): 544 (M+H)⁺. RT (Method A): 0.70 min. Compound 479 was prepared based the procedures set forth above starting from Step 3, using (E)-2-fluorobenzaldehyde oxime and ethyl 4,4,4-trifluorobut-2-ynoate as the starting materials.¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 9.10 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.71 (d, J = 6.0 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.9 Hz, 1H), 4.48 (s, 2H), 2.54 - 2.53 (m, 1H), 2.40 - 2.34 (m, 1H), 2.26 - 2.18 (m, 1H), 1.30 (d, J = 5.6 Hz, 3H). LC/MS (ESI) (m/z): 628 (M+H)⁺. RT (Method A): 1.73 min. Scheme 153. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-cyclopropyl-3-phenylisoxazole-5- carboxamide (Compound 471) Step 1: Methyl 4-iodo-3-phenylisoxazole-5-carboxylate To a solution of methyl 3-phenylisoxazole-5-carboxylate (1 g, 4.9 mmol) in TFA (20 mL) was added NIS (1.3 g, 5.9 mmol) under a dry nitrogen atmosphere and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) and to give the title compound (1.1 g, yield 68.2%) as a colorless solid. LC/MS (ESI) m/z: 330 (M+H)⁺. Step 2: Methyl 4-cyclopropyl-3-phenylisoxazole-5-carboxylate To a mixture of methyl 4-iodo-3-phenylisoxazole-5-carboxylate (330 mg, 1.0 mmol) and potassium propyl fluoroborate (265 mg, 1.8 mmol) in toluene (6 mL) and water (2 mL) was added Pd(OAc)2 (22 mg, 0.1 mmol), cataCXiumA (36 mg, 0.1 mmol), Cs2CO3 (975 mg, 3.0 mmol) under a dry nitrogen atmosphere, and the reaction was stirred at 100 °C for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) and further purified by Chiral SFC (ChiralPak IB, 250×30 mm I.D., 5µm, A for CO2 and Gradient 20% B for MeOH (0.1% 7mol/L NH3)) to give the title compound (50 mg, yield 20.5%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 8.1 Hz, 2H), 7.23 (s, 1H), 7.16 (d, J = 8.1 Hz, 2H), 4.00 (s, 3H), 2.00 - 1.91 (m, 1H), 1.07 - 1.00 (m, 2H), 0.80 - 0.71 (m, 2H). LC/MS (ESI) (m/z): 244 (M+H)⁺. The methyl 4-cyclopropyl-3-phenylisoxazole-5-carboxylate was used to prepare Compound 471 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 9.17 (t, J = 5.9 Hz, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.89 - 7.78 (m, 3H), 7.25 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 7.04 (s, 1H), 6.45 (s, 2H), 5.07 (d, J = 9.1 Hz, 1H), 4.53 - 4.46 (m, 2H), 2.69 - 2.56 (m, 1H), 2.39 - 2.35 (m, 1H), 2.27 - 2.20 (m, 1H), 2.04 - 1.97 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H), 1.08 - 0.97 (m, 2H), 0.82 - 0.72 (m, 2H). LC/MS (ESI) (m/z): 582 (M+H)⁺. RT (Method A): 1.76 min. Scheme 154. Synthesis of N-((3S,6S,8aR)-3-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)- 5-oxooctahydroindolizin-6-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 472) Step 1: Methyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxohept-6-enoate To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (20 g, 82.3 mmol) in THF (400 mL) was added vinylmagnesium bromide (99 mL, 98.7 mmol, 1 M in THF) at -40 °C under a dry nitrogen atmosphere, and the reaction was stirred at -40 °C for 3 hours. The mixture was quenched with AcOH/MeOH (100 mL, v/v). The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (7.55 g, yield 33.8%) as a colorless oil. LC/MS (ESI) m/z: 272 (M+H)⁺. Step 2: 9-(tert-Butyl) 1-methyl (2S)-2-((tert-butoxycarbonyl)amino)-8-((diphenyl-methylene)amino)-5- oxononanedioate To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxohept-6-enoate (7.50 g, 27.7 mmol) and tert-butyl 2-((diphenylmethylene)amino)acetate (8.98 g, 30.44 mmol) in THF (3 mL) was added Cs2CO3 (9.02 g, 27.7 mmol) at room temperature and the reaction was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (11.5 g, yield 73.6%) as a yellow solid. LC/MS (ESI) m/z: 567 (M+H)⁺. Step 3: tert-Butyl (3R,6S,8aR)-6-((tert-butoxycarbonyl)amino)-5-oxooctahydroindolizine-3-carboxylate To a mixture of 9-(tert-butyl) 1-methyl (2S)-2-((tert-butoxycarbonyl)amino)-8-((diphenyl- methylene)amino)-5-oxononanedioate (10 g, 17.7 mmol) in EtOH (180 mL) and AcOH (20 mL) was added Pd/C (1.00 g, 10% wt.) at room temperature under a dry nitrogen atmosphere and the reaction was stirred under a hydrogen balloon at room temperature overnight. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (2.63 g, yield 42.1%) as a colorless oil. LC/MS (ESI) m/z: 355 (M+H)⁺. Step 4: tert-Butyl (3S,6S,8aR)-6-((tert-butoxycarbonyl)amino)-5-oxooctahydroindolizine-3-carboxylate To a solution of tert-butyl (3R,6S,8aR)-6-((tert-butoxycarbonyl)amino)-5-oxooctahydro-indolizine- 3-carboxylate (500 mg, 1.41 mmol) in THF (10 mL) was added LDA (3.5 mL, 7.06 mmol, 2 M in THF/hexane) dropwise at -78°C under a dry nitrogen atmosphere and the reaction was stirred at -78°C for 1 hour. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈250*20 mm, 10 - 70% MeCN in water with 0.1% NH₄HCO₃) to give the title compound (110 mg, yield 22.1%) as a colorless oil. LC/MS (ESI) m/z: 355 (M+H)⁺. Step 5: tert-Butyl (3S,6S,8aR)-6-amino-5-oxooctahydroindolizine-3-carboxylate To a solution of tert-butyl (3S,6S,8aR)-6-amino-5-oxooctahydroindolizine-3-carboxylate (110 mg, 0.31 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) at 0°C and the reaction was stirred at room temperature for 1 hour. The mixture was quenched with saturated aq. NaHCO₃ solution, filtered, and purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10 - 70% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (32 mg, yield 40.7%) as a colorless oil. LC/MS (ESI) m/z: 255 (M+H)⁺. Step 6: tert-Butyl (3S,6S,8aR)-5-oxo-6-(5-phenyl-1,3,4-thiadiazole-2-carboxamido) octahydroindolizine-3- carboxylate To a mixture of tert-butyl (3S,6S,8aR)-6-amino-5-oxooctahydroindolizine-3-carboxylate (32 mg, 0.13 mmol) and lithium 5-phenyl-1,3,4-thiadiazole-2-carboxylate (53 mg, 0.25 mmol) in DMF (2 mL) was added DIPEA (81 mg, 0.63 mmol) and HATU (239 mg, 0.63 mmol) at room temperature and the reaction was stirred for 1 hour. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (50 mg, yield 90.5%) as a yellow solid. LC/MS (ESI) m/z: 443 (M+H)⁺. Step 7: (3S,6S,8aR)-5-Oxo-6-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)octahydro-indolizine-3-carboxylic acid To a solution of tert-butyl (3S,6S,8aR)-5-oxo-6-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)- octahydroindolizine-3-carboxylate (50 mg, 0.11 mmol) in DCM (1 mL) was added TFA (0.5 mL) at room temperature and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (41 mg, yield 94.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 387 (M+H)⁺. Step 8: N-((3S,6S,8aR)-3-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-5-oxooctahydroindolizin- 6-yl)-5-phenyl-1,3,4-thiadiazole-2-carboxamide (Compound 472) To a mixture of (3S,6S,8aR)-5-oxo-6-(5-phenyl-1,3,4-thiadiazole-2-carboxamido)octahydro- indolizine-3-carboxylic acid (41 mg, 0.11 mmol) and 2-(aminomethyl)thieno[3,2-c]pyridin-6-amine hydrochloride (46 mg, 0.21 mmol) in DMF (1 mL) was added DIPEA (69 mg, 0.53 mmol) and HATU (203 mg, 0.53 mmol) at room temperature and the reaction was stirred for 1 hour. The mixture was filtered and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 472 (8 mg, yield 14.2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.25 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.7 Hz, 2H), 7.65 - 7.57 (m, 3H), 7.10 (s, 1H), 6.84 (s, 1H), 5.91 (s, 2H), 4.47 - 4.32 (m, 4H), 3.74 - 3.63 (m, 1H), 2.36 - 2.28 (m, 1H), 2.15 - 2.03 (m, 4H), 1.79 - 1.68 (m, 1H), 1.60 - 1.41 (m, 2H). LC/MS (ESI) m/z: 548 (M+H)⁺. RT (Method A): 1.19 min. Scheme 155. Synthesis of N-((6S,6aR,7aS)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)- methyl)carbamoyl)-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidin-3-yl)-5-(2- fluorophenyl)-1,3,4-thiadiazole-2-carboxamide (Compound 473) Step 1: Benzyl (6S,6aR,7aS)-3-3-amino-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]-pyrrolo[1,2- a]pyrimidine-6-carboxylate hydrochloride To a solution of benzyl (6S,6aR,7aS)-3-((tert-butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro- 4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.12 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to dryness to give the title compound (35 mg, yield 95.5%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 298 (M+H)⁺. Step 2: Benzyl (6S,6aR,7aS)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-6,6a,7,7a- tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of lithium 5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxylate (36 mg, 0.15 mmol) and benzyl (6S,6aR,7aS)-3-amino-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]-pyrrolo[1,2-a]pyrimidine-6- carboxylate hydrochloride (35 mg, 0.10 mmol) in MeCN (3 mL) was added TCFH (140 mg, 0.5 mmol) and NMI (123 mg, 1.5 mmol) and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness, The residue was purified by flash chromatography (silica gel, 0 - 6% MeOH in DCM) to give the title compound (36 mg, yield 68.8%) as a yellow solid. LC/MS (ESI) m/z: 504 (M+H)⁺. Step 3: (6S,6aR,7aS)-3-(5-(2-Fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo-6,6a,7,7a-tetrahydro- 4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of benzyl (6S,6aR,7aS)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-4- oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a] pyrimidine-6-carboxylate (36 mg, 0.1 mmol) in THF (2 mL) and water (0.5 mL) was added NaOH (1 mL, 1 N) and the reaction was stirred at room temperature for 20 minutes. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (13 mg, yield 31.4%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 414 (M+H)⁺. Step 4: N-((6S,6aR,7aS)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-6,6a,7,7a- tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluorophenyl)-1,3,4-thiadiazole-2- carboxamide (Compound 473) To a mixture of (6S,6aR,7aS)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-4-oxo- 6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (13 mg, 0.03 mmol) in DMF (1 mL) was added T3P (75 mg, 0.12 mmol, 50% wt. in EtOAc) and DIPEA (97 mg, 0.75 mmol) and the reaction was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH3.H2O) to give Compound 473 (5 mg, yield 67.1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 9.15 (dt, J = 10.9, 5.8 Hz, 1H), 8.67 (d, J = 9.9 Hz, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.38 (t, J = 7.6 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.60 - 7.54 (m, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 6.1 Hz, 1H), 6.85 (d, J = 6.1 Hz, 1H), 5.84 (s, 2H), 5.18 - 5.01 (m, 1H), 4.58 - 4.44 (m, 2H), 2.71 - 2.67 (m, 1H), 2.37 - 2.14 (m, 1H), 1.40 - 1.24 (m, 1H), 1.23 - 1.17 (m, 1H). LC/MS (ESI) (m/z): 575 (M+H)⁺. RT (Method A): 1.36 min. Scheme 156. Synthesis of N-((6S,6aR,7aS)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)- methyl)carbamoyl)-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidin-3-yl)-5- (pyridin-2-yl)-isoxazole-3-carboxamide (Compound 478) Step 1: (6S,6aR,7aS)-3-((tert-Butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro-4H- cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of benzyl (6S,6aR,7aS)-3-((tert-butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro- 4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylate (230 mg, 0.58 mmol) in EtOAc (5 mL) was added Pd/C (25 mg, 10% wt.), the mixture was degassed under a dry nitrogen atmosphere three times and stirred under a hydrogen balloon at 25°C for 2.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (165 mg, yield 92.8%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 308 (M+H)⁺. Step 2: (6S,6aR,7aS)-3-Amino-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]-pyrimidine-6- carboxylic acid hydrochloride To a solution of (6S,6aR,7aS)-3-((tert-butoxycarbonyl)amino)-4-oxo-6,6a,7,7a-tetrahydro-4H- cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (160 mg, 0.52 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) at room temperature and the reaction was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (130 mg, yield 100%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 208 (M+H)⁺ Step 3: tert-Butyl (2-(((6S,6aR,7aS)-3-amino-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa-[3,4]pyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of (6S,6aR,7aS)-3-amino-4-oxo-6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo-[1,2- a]pyrimidine-6-carboxylic acid hydrochloride (130 mg, 0.53 mmol) and tert-butyl (2- (aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (160 mg, 0.58 mmol) in DMF (3 mL) was added DIPEA (193 mg, 1.50 mmol) and HATU (242 mg, 0.64 mmol) and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 8% MeOH in DCM) to give the title compound (157 mg, yield 63.3%) as a yellow solid. LC/MS (ESI) m/z: 469 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,6aR,7aS)-4-oxo-3-(5-(pyridin-2-yl)isoxazole-3-carboxamido)-6,6a,7,7a- tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3,2-c]pyridin-6- yl)carbamate To a mixture of tert-butyl (2-(((6S,6aR,7aS)-3-amino-4-oxo-6,6a,7,7a-tetrahydro-4H- cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.047 mmol) and 5-(pyridin-2-yl)isoxazole-3-carboxylic acid (10.0 mg, 0.052 mmol) in MeCN (2 mL) was added NMI (11 mg, 0.14 mmol) and TCFH (39 mg, 0.14 mmol) and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (15 mg, yield 69.4%) as a yellow solid. LC/MS (ESI) m/z: 641 (M+H)⁺. Step 5: N-((6S,6aR,7aS)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-oxo-6,6a,7,7a- tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidin-3-yl)-5-(pyridin-2-yl)-isoxazole-3-carboxamide (Compound 478) To a solution of tert-butyl (2-(((6S,6aR,7aS)-4-oxo-3-(5-(pyridin-2-yl)isoxazole-3-carboxamido)- 6,6a,7,7a-tetrahydro-4H-cyclopropa[3,4]pyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate (15 mg, 0.02 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 478 (7.0 mg, yield 55.3%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 9.05 (t, J = 5.8 Hz, 1H), 8.77 (d, J = 4.7 Hz, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.07 - 8.02 (m, 1H), 7.60 - 7.56 (m, 1H), 7.54 (s, 1H), 7.15 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.14 (d, J = 6.6 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 2.68 - 2.65 (m, 1H), 2.54 - 2.52 (m, 1H), 1.24 - 1.18 (m, 2H). LC/MS (ESI) (m/z): 541 (M+H)⁺. RT (Method A): 0.89 min. Scheme 157. Synthesis of N-((6S,8S)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazin-3-yl)-5-(2-fluoro-phenyl)-1,3,4-thiadiazole-2- carboxamide (Compound 480) Step 1: 1-(tert-Butyl) 2-methyl (2S,4S)-5-acetoxy-4-methylpyrrolidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (5.0 g, 19.4 mmol) in DCM (50 mL) was added LiHBEt₃ (22 mL, 22 mmol, 1M in THF) dropwise at -70 °C and the reaction solution was stirred at -70°C for 3 hours. Then a solution of Ac2O (2.2 g, 22 mmol) in THF (4 mL) was added at -70 °C and the resulting mixture was warmed and stirred at room temperature for 18 hours. The mixture was quenched with saturated aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (5.0 g, yield 85.6%) as a yellow solid. LC/MS (ESI) (m/z): 158 (M-OAc-Boc)⁺. Step 2: Methyl (2S,4S)-5-cyano-4-methylpyrrolidine-2-carboxylate To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-5-acetoxy-4-methylpyrrolidine-1,2-dicarboxylate (5.0 g, 16.6 mmol) in DCM (50 mL) was added TMSCN (5.2 g, 52.5 mmol) followed by dropwise addition BF₃.Et₂O (7.5 g, 52.5 mmol) at -70 °C and the reaction solution was then warmed and stirred at 25°C overnight. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (1.0 g, yield 35.8%) as a yellow solid. LC/MS (ESI) (m/z): 169 (M+H)⁺. Step 3: Methyl 1,3-dichloro-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrazine-6-carboxylate To a solution of methyl (2S,4S)-5-cyano-4-methylpyrrolidine-2-carboxylate (500 mg, 2.97 mmol) in toluene (5.0 mL) was added oxalyl chloride (2.0 mL) dropwise under a dry nitrogen atmosphere and the reaction was stirred at 110 °C for 3 hours. The reaction mixture was cooled and then concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 4% MeOH in DCM) to give the title compound (350 mg, yield 42.7%) as a yellow solid. LC/MS (ESI) m/z: 277 (M+H)⁺. Step 4: Methyl 1-chloro-3-((2,4-dimethoxybenzyl)amino)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrazine-6-carboxylate To a solution of methyl 1,3-dichloro-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrazine-6- carboxylate (290 mg, 1.05 mmol) in DMF (5.0 mL) was added K₂CO₃ (290 mg, 2.09 mmol) and 2,4- dimethoxybenzylamine (350 mg, 2.09 mmol) under a dry nitrogen atmosphere and the reaction was stirred at room temperature for 18 hours. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (240 mg, yield 56.0%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 408 (M+H)⁺. Step 5: Methyl (6S,8S)-3-((2,4-dimethoxybenzyl)amino)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrazine-6-carboxylate To a solution of methyl 1-chloro-3-((2,4-dimethoxybenzyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (200 mg, 0.49 mmol) in MeOH (5 mL) was added Pd/C (50 mg, 10% wt.) and Pd(OH)₂/C (50 mg, 10% wt.), and the mixture was degassed under a dry nitrogen atmosphere three times and stirred under a hydrogen balloon at 25 °C overnight. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by SFC (Chiral Cel OJ, 250×20 mm I.D., 5µm, A for CO₂ and B for MeOH (0.1% 7N NH₃/MeOH), Gradient: 20%) to give the title compound (retention time: 3.42 minute) (150 mg, yield 81.8%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, J = 8.1 Hz, 1H), 6.82 (s, 1H), 6.45 (s, 1H), 6.42 (d, 1H), 4.88 - 4.71 (m, 1H), 4.51 (d, J = 5.6 Hz, 2H), 3.82 - 3.79 (m, 9H), 3.35 - 3.26 (m, 1H), 2.73 - 2.64 (m, 1H), 1.94 - 1.85 (m, 1H), 1.34 - 1.30 (m, 3H). LC/MS (ESI) m/z: 374 (M+H)⁺. Step 6: Methyl (6S,8S)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate A solution of methyl (6S,8S)-3-((2,4-dimethoxybenzyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (150 mg, 0.40 mmol) in TFA (2.0 mL) was stirred under a dry nitrogen atmosphere at 0 °C for 6 hours. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (75 mg, yield 84.0%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 224 (M+H)⁺. The methyl (6S,8S)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxylate was used to prepare Compound 480 based on the procedures set forth in, e.g., Scheme 22. ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.07 (t, J = 5.8 Hz, 1H), 8.41 (s, 1H), 8.40 - 8.34 (m, 1H), 7.77 - 7.71 (m, 1H), 7.59 - 7.54 (m, 1H), 7.52 - 7.47 (m, 1H), 7.27 (s, 1H), 7.14 (s, 1H), 6.84 (s, 1H), 5.83 (s, 2H), 5.03 - 4.94 (m, 1H), 4.54 - 4.44 (m, 2H), 2.80 - 2.69 (m, 2H), 1.79 - 1.72 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H). LC/MS (ESI) (m/z): 577 (M+H)⁺. RT (Method A): 1.31 min. Scheme 158. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(3-(isoxazol-3- yl)benzamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 494) Step 1: Methyl-3-((hydroxyimino)methyl)benzoate To a solution of methyl 3-formylbenzoate (6 g, 36.6 mmol) in MeOH (60 mL) was added hydroxylamine hydrochloride (3.05 g, 43.9 mmol) and NaHCO3 (3.99 g, 47.6 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (4.2 g, yield 64.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 180 (M+H)⁺. Step 2: Methyl-3-(chloro(hydroxyimino)methyl)benzoate To a solution of methyl-3-((hydroxyimino)methyl)benzoate (1 g, 5.58 mmol) in DMF (10 mL) was added NCS (783 mg, 1.05 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1 g, yield 84.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 214 (M+H)⁺. The methyl-3-(chloro(hydroxyimino)methyl)benzoate was used to prepare Compound 494 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 9.07 (d, J = 1.2 Hz, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.05 (d, J = 9.3 Hz, 1H), 4.53 - 4.42 (m, 2H), 3.39 - 3.36 (m, 1H), 2.40 - 2.34 (m, 1H), 2.27 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 542 (M+H)⁺. RT (Method A: 1.02 min. Scheme 159. Synthesis of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (6-phenoxypyridazine-3-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Comp Step1: 6-Phenoxypyridazine-3-carboxylic acid To a mixture of methyl 6-chloropyridazine-3-carboxylate (200 mg, 1.15 mmol) and phenol (164 mg, 1.72 mmol) in NMP (2 mL) was added Cs2CO3 (565 mg, 1.73 mmol) and the reaction was stirred at 100°C for 2 hours. The reaction was cooled and then diluted with water and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the title compound (250 mg, yield 93.6%) as a yellow oil. LC/MS (ESI) (m/z): 217 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-8-methyl-4-oxo-3-(6-phenoxypyridazine-3-carboxamido)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 6-phenoxypyridazine-3-carboxylic acid (14.0 mg, 0.06 mmol) and tert-butyl (2- (((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (25.0 mg, 0.05 mmol) in MeCN (2 mL) was added NMI (41.1 mg, 0.50 mmol) and TCFH (72.2 mg, 0.25 mmol) and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (31.0 mg, yield 84.5%) as a white solid. LC/MS (ESI) m/z: 669 (M+H)⁺. Step 3: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3-(6-phenoxypyridazine-3- carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 500) To a solution of tert-butyl (2-(((6S,8R)-8-methyl-4-oxo-3-(6-phenoxypyridazine-3-carboxamido)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (31.0 mg, 0.04 mmol) in DCM (0.5 mL) was added HCl in 1,4-dioxane (4M, 0.5 mL, 2 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 500 (9.0 mg, yield 34.2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 9.11 (d, J = 5.8 Hz, 1H), 8.95 (s, 1H), 8.40 – 8.36 (m, 2H), 7.69 (d, J = 9.1 Hz, 1H), 7.51 (t, J = 7.9 Hz, 2H), 7.32 (d, J = 7.9 Hz, 3H), 7.10 (s, 1H), 6.84 (s, 1H), 5.83 (s, 2H), 5.07 (d, J = 9.0 Hz, 1H), 4.54 – 4.41 (m, 2H), 3.36 – 3.33 (m, 1H), 2.41 – 2.35 (m, 1H), 2.25 – 2.16 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 569 (M+H)⁺. RT (Method A): 1.31 min. Scheme 160. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(6- (cyclohexyloxy)nicotinamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carb Step 1: 6-(Cyclohexyloxy)nicotinic acid To a mixture of 6-(cyclohexyloxy)nicotinic acid (500 mg, 3.18 mmol) and cyclohexanol (637 mg, 6.36 mmol) in DMA (10 mL) was added NaH (636 mg, 15.9 mmol, 60% dispersion in mineral oil) under a dry nitrogen atmosphere and the reaction was stirred at 130 °C for 1 hour. The mixture was cooled to 0 °C and quenched with 1 N aq. HCl and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (201 mg, yield 28.5%) as a yellow solid. LC/MS (ESI) (m/z): 222 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-3-(6-(cyclohexyloxy)nicotinamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate To a mixture of 6-(cyclohexyloxy)nicotinic acid (10 mg, 0.04 mmol) and tert-butyl (2-(((6S,8R)-3- amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate (20 mg, 0.04 mmol) in MeCN (1 mL) was added TCFH (18.7 mg, 0.06 mmol) and NMI (18.3 mg, 0.20 mmol) under a dry nitrogen atmosphere and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to give the title compound (15 mg, yield 51.4%) as a white solid. LC/MS (ESI) (m/z): 674 (M+H)⁺. Step 3: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(6-(cyclohexyloxy) nicotinamido)-8-methyl- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 502) To a mixture of tert-butyl (2-(((6S,8R)-3-(6-(cyclohexyloxy)nicotinamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (15 mg, 0.02 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) under a dry nitrogen atmosphere and the reaction was stirred at room temperature for 30 minutes. The mixture was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 502 (6 mg, yield 52.7%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 9.10 (m, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.24 – 8.13 (m, 1H), 7.11 (s, 1H), 6.96 – 6.68 (m, 2H), 5.85 (s, 2H), 5.24 – 5.09 (m, 1H), 5.08 – 5.03 (m, 1H),4.63 – 4.29 (m, 2H), 2.40 – 2.17 (m, 2H), 1.99 – 1.96 (m, 2H), 1.75 – 1.72 (m, 2H), 1.52 – 1.34 (m, 6H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 574 (M+H)⁺. RT (Method A): 1.62 min. Scheme 161. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(4-(2- fluorophenyl)piperazin-1-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Co Step 1: Methyl (6S,8R)-3-(4-(2-fluorophenyl)piperazin-1-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxylate (50 mg, 0.17 mmol), 1-(2-fluorophenyl)piperazine (38 mg, 0.21 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol) in toluene (1 mL) was added Pd₂(dba)₃ (16 mg, 0.02 mmol) and RuPhos (16 mg, 0.03 mmol) under a dry nitrogen atmosphere and the reaction was stirred at 100°C for 2 hours. The mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% FA) to give the title compound (45 mg, yield 66.9%) as a yellow solid. LC/MS (ESI) m/z: 387 (M+H)⁺. Step 2: (6S,8R)-3-(4-(2-Fluorophenyl)piperazin-1-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-3-(4-(2-fluorophenyl)piperazin-1-yl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (45 mg, 0.12 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (5 mg, 0.21 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (34 mg, yield 78.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 373 (M+H)⁺. Step 3: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(4-(2-fluorophenyl)piperazin-1-yl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 503) To a mixture of (6S,8R)-3-(4-(2-fluorophenyl)piperazin-1-yl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (34 mg, 0.09 mmol) and 2-(amino-methyl)thieno[3,2- c]pyridin-6-amine hydrochloride (24 mg, 0.11 mmol) in DMF (1 mL) was added HATU (52 mg, 0.14 mmol) and DIPEA (47 mg, 0.36 mmol) and the reaction was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 85% MeCN in water with 0.1% NH₄HCO₃) to give Compound 503 (5.8 mg, yield 11.9%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (t, J = 5.3 Hz, 1H), 8.40 (s, 1H), 7.45 (s, 1H), 7.16 - 7.08 (m, 4H), 7.01 - 6.97 (m, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 4.96 (d, J = 9.0 Hz, 1H), 4.52 - 4.40 (m, 2H), 3.37 - 3.36 (m, 1H), 3.25 - 3.22 (m, 2H), 3.18 - 3.14 (m, 2H), 3.14 - 3.11 (m, 4H), 2.33 - 2.29 (m, 1H), 2.18 - 2.10 (m, 1H), 1.25 (d, J = 6.7 Hz, 3H). LC/MS (ESI) m/z: 534 (M+H)⁺. RT (Method A): 1.25 min. Compound 526 was prepared according to the procedures above, using 2-(piperidin-4-yl)pyridine as the starting material in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (t, J = 5.7 Hz, 1H), 8.53 - 8.50 (m, 1H), 8.48 (s, 1H), 7.77 - 7.72 (m, 1H), 7.43 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 7.04 - 5.89 (m, 2H), 4.95 (d, J = 9.1 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.78 - 3.65 (m, 2H), 2.85 - 2.79 (m, 1H), 2.67 - 2.56 (m, 2H), 2.34 - 2.28 (m, 1H), 2.18 - 2.10 (m, 1H), 2.03 - 1.91 (m, 1H), 1.90 - 1.79 (m, 4H), 1.25 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 516 (M+H)⁺. RT (Method A): 0.31 min. Scheme 162. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-methylpyridin-2-yl)isoxazole-5- carboxamide (Compound 506) Ste p1: (E)-3-Methylpicolinaldehyde oxime To a solution of 3-methylpicolinaldehyde (4.50 g, 37.1 mmol) in EtOH (50 mL) was added hydroxylamine hydrochloride (7.70 g, 112 mmol) and K2CO3 (5.10 g, 36.9 mmol) under a dry nitrogen atmosphere and the reaction was stirred at 80°C for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 35% EtOAc in PE) to give the title compound (3.22 g, yield 64.4%) as a white solid. LC/MS (ESI) m/z: 137 (M+H)⁺. Step 2: (Z)-N-Hydroxy-3-methylpicolinimidoyl chloride To a solution of (E)-3-methylpicolinaldehyde oxime (1.66 g, 12.2 mmol) in DMF (18 mL) was added NCS (1.96 g, 14.6 mmol) and the reaction was stirred under a dry nitrogen atmosphere at room temperature for 3 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (653 mg, yield 31.8%) as a white solid. LC/MS (ESI) m/z: 171 (M+H)⁺. Step 3: Ethyl 3-(3-methylpyridin-2-yl)isoxazole-5-carboxylate To a mixture of (Z)-N-hydroxy-3-methylpicolinimidoyl chloride (300 mg, 1.76 mmol) and ethyl propiolate (250 mg, 2.55 mmol) in DCM (5 mL) was added TEA (260 mg, 2.57 mmol) under a dry nitrogen atmosphere and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (160 mg, yield 38.9%) as a white solid. LC/MS (ESI) m/z: 233 (M+H)⁺. Step 4: Lithium 3-(3-methylpyridin-2-yl)isoxazole-5-carboxylate To a solution of ethyl 3-(3-methylpyridin-2-yl)isoxazole-5-carboxylate (140 mg, 0.60 mmol) in THF (2.0 mL) and water (0.5 mL) was added LiOH (42.3 mg, 1.76 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness to give the title compound (112 mg, yield 91.0%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 5: tert-Butyl (2-(((6S,8R)-8-methyl-3-(3-(3-methylpyridin-2-yl)isoxazole-5-carboxamido)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of Lithium 3-(3-methylpyridin-2-yl)isoxazole-5-carboxylate (112 mg, 0.54 mmol) and tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (90.0 mg, 0.19 mmol; see Scheme 100) in MeCN (2 mL) was added NMI (234 mg, 2.85 mmol) and TCFH (346 mg, 1.23 mmol) under a dry nitrogen atmosphere and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 2% MeOH in DCM) to give the title compound (122 mg, yield 34.7%) as a yellow oil. LC/MS (ESI) m/z: 657 (M+H)⁺. Step 6: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-methylpyridin-2-yl)isoxazole-5-carboxamide (Compound 506) To a solution of tert-butyl (2-(((6S,8R)-8-methyl-3-(3-(3-methylpyridin-2-yl)isoxazole-5- carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2- c]pyridin-6-yl)carbamate (112 mg, 0.17 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 506 (23.0 mg, yield 24.2%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 9.13 - 9.08 (m, 1H), 8.63 - 8.59 (m, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 7.90 - 7.86 (m, 1H), 7.81 (s, 1H), 7.50 - 7.46 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.10 - 4.98 (m, 1H), 4.53 - 4.41 (m, 2H), 2.60 (s, 3H), 2.46 - 2.31 (m, 2H), 2.27 - 2.19 (m, 1H), 1.34 - 1.29 (m, 3H). LC/MS (ESI) m/z: 557 (M+H)⁺. RT (Method A): 1.07 min. The following compounds were prepared according to the procedures above with the appropriate aldehyde in Step 1.

Scheme 163. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(4-(isoxazol-3- yl)-benzamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 508) Step 1: Methyl 4-(isoxazol-3-yl)benzoate To a solution of methyl 4-(5-(trimethylsilyl)isoxazol-3-yl)benzoate (300 mg, 1.09 mmol) in MeOH (5 mL) was added K₂CO₃ (451 mg, 3.27 mmol) at room temperature and the reaction was stirred for 3 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) give the title compound (61 mg, yield 27.5%) as a white solid. LC/MS (ESI) m/z: 204 (M+H)⁺. The methyl 4-(isoxazol-3-yl)benzoate was used to prepare Compound 508 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.13 (t, J = 5.9 Hz, 1H), 9.08 (d, J = 1.7 Hz, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 8.08 (q, J = 8.5 Hz, 4H), 7.27 (d, J = 1.7 Hz, 1H), 7.15 (s, 1H), 6.97 (s, 1H), 6.20 (s, 2H), 5.08 - 5.03 (m, 1H), 4.52 – 4.44 (m, 2H), 3.39 - 3.36 (m, 1H), 2.41 - 2.35 (m, 1H), 2.27 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 542 (M+H)⁺. RT (Method A): 1.02 min. Scheme 164. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(5- (cyclohexyloxy)picolinamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 511) Step 1: 5-(Cyclohexyloxy)picolinic acid To a mixture of 5-fluoropicolinic acid (705 mg, 5.00 mmol) and cyclohexanol (500 mg, 5.00 mmol) in DMA (8 mL) was added NaH (360 mg, 15.0 mmol, 60% dispersion in mineral oil) and the reaction was then heated and stirred at 130°C for 2 hours. The mixture was cooled, quenched with ice-water and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (658 mg, yield 56.8%) as a white solid. LC/MS (ESI) (m/z): 222 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-3-(5-(cyclohexyloxy)picolinamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate To a mixture of 5-(cyclohexyloxy)picolinic acid (20 mg, 0.09 mmol) and tert-butyl (2-(((6S,8R)-3- amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2- c]pyridin-6-yl)carbamate (25.0 mg, 0.05 mmol) in MeCN (2 mL) was added NMI (41.0 mg, 0.50 mmol) and TCFH (72.0 mg, 0.25 mmol) and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (15.0 mg, yield 24.9%) as a white solid. LC/MS (ESI) m/z: 674 (M+H)⁺. Step 3: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(5-(cyclohexyloxy)picolinamido)-8-methyl- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 511) To a solution of tert-butyl (2-(((6S,8R)-3-(5-(cyclohexyloxy)picolinamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate (15.0 mg, 0.02 mmol) in DCM (0.50 mL) was added HCl in 1,4-dioxane (4M, 0.50 mL, 2 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 511 (7.5 mg, yield 59.2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H), 9.16 (t, J = 6.3 Hz, 1H), 8.99 (s, 1H), 8.50 (s, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 8.8, 2.9 Hz, 1H), 7.19 (t, J = 15.2 Hz, 2H), 7.04 (d, J = 51.1 Hz, 1H), 6.69 (s, 1H), 5.07 (d, J = 8.4 Hz, 1H), 4.62 – 4.55 (m, 1H), 4.50 (d, J = 6.1 Hz, 2H), 2.47 – 2.28 (m, 2H), 2.26 – 2.18 (m, 1H), 2.01 – 1.95 (m, 2H), 1.76 – 1.69 (m, 2H), 1.58 – 1.32 (m, 6H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 574 (M+H)⁺. RT (Method A): 1.77 min. The following compounds were prepared according to the procedures set forth above using the appropriate carboxylic acid/carboxylate and alcohol.

^a Step 1 was performed in the presence of K₂CO₃ in DMF at 100 °C over 2 hours. ^b Step 1 was performed in the presence of t-BuOK in THF under a dry nitrogen atmosphere at room temperature over 1 hour. ^c Step 1 was performed in the presence of Cs₂CO₃ in NMP at 90 °C over 2 hours. ^d Step 1 was performed in the presence of KOH in DMSO at 100 °C over 2 hours. ^e Step 3 was performed with TFA in DCM. ^f The intermediate from Step 1 was deprotected with LiOH in THF/H2O prior to Step 2. Scheme 165. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(4- (oxazol-2-yl)benzamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 517) Step 1: Methyl 4-((2,2-dimethoxyethyl)carbamoyl)benzoate To a mixture of 4-(methoxycarbonyl)benzoic acid (5.0 g, 27.75 mmol) and 2,2-dimethoxy-ethan-1- amine (2.92 g, 27.75 mmol) in DCM (50 mL) was added EDCI (10.64 g, 55.51 mmol) and NMM (7.02 g, 69.38 mmol) under a dry nitrogen atmosphere and the reaction was stirred at room temperature overnight. The mixture was acidified with 1 N aq. HCl solution to pH~2 and extracted with DCM twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. to give the title compound (6.4 g, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 268 (M+H)⁺. Step 2: Methyl 4-(oxazol-2-yl)benzoate To a solution of methyl 4-((2,2-dimethoxyethyl)carbamoyl)benzoate (3.0 g, 11.22 mmol) in MeSO₃H (22 mL) was added P₄O₁₀ (15.14 g, 47.70 mmol) under a dry nitrogen atmosphere and the reaction was stirred at 140 °C for 9 hours. The mixture was cooled, quenched with ice water, and extracted with DCM twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 66% EtOAc in PE) to give the title compound (120 mg, yield 5.3%) as a yellow solid. LC/MS (ESI) m/z: 204 (M+H)⁺. The methyl 4-(oxazol-2-yl)benzoate was used to prepare Compound 517 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.65 (s, 1H), 9.10 (t, J = 5.9 Hz, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 8.11 (d, J = 1.3 Hz, 4H), 7.46 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.05 (d, J = 9.0 Hz, 1H), 4.52 – 4.41 (m, 2H), 3.30 – 3.29 (m, 1H), 2.40 – 2.34 (m, 1H), 2.26 – 2.17 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 542 (M+H)⁺. Scheme 166. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(4-((2,2-difluoro- cyclohexyl)oxy)benzamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carbo Step 1: Ethyl 4-((2-oxocyclohexyl)oxy) benzoate To a solution of ethyl 4-hydroxybenzoate (1.70 g, 10.2 mmol) in DMF (20 mL) was added 2- bromocyclohexan-1-one (3.62 g, 20.5 mmol) and K₂CO₃ (2.82 g, 20.5 mmol), the mixture was stirred at 100 °C for 2 hours. The mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (1.50 g, yield 55.9%) as a white solid. LC/MS (ESI) m/z: 263 (M+H)⁺. Step 2: Ethyl 4-((2,2-difluorocyclohexyl)oxy)benzoate To a solution of ethyl 4-((2-oxocyclohexyl)oxy) benzoate (200 mg, 0.76 mmol) in DCM (10 mL) was added DAST (612 mg, 3.8 mmol) dropwise at 0 °C and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (110 mg, yield 50.7%) as a white solid. LC/MS (ESI) m/z: 285 (M+H)⁺. The ethyl 4-((2,2-difluorocyclohexyl)oxy)benzoate was used to prepare Compound 519 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.13 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.9 Hz, 3H), 7.01 (s, 1H), 6.57 – 6.03 (m, 2H), 5.04 (d, J = 8.4 Hz, 1H), 4.93 – 4.82 (m, 1H), 4.54 – 4.42 (m, 2H), 3.40 – 3.35 (m, 1H), 2.41 – 2.35 (m, 1H), 2.25 – 2.19 (m, 1H), 2.00 – 1.90 (m, 2H), 1.81 – 1.46 (m, 6H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 609 (M+H)⁺. RT (Method A): 1.60 min. Compound 714 was prepared based on the procedures set forth above, where methyl 6- hydroxynicotinate and 2-chlorocyclohexan-1-one were used as the starting material in Step 1, where the reaction was performed in acetone, and the final deprotection step was performed with TFA in DCM.¹H NMR (400 MHz, DMSO-d₆) δ 9.65 (s, 1H), 9.15 – 9.05 (m, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.85 (s, 1H), 5.88 (s, 2H), 5.61 – 5.43 (m, 1H), 5.04 (d, J = 9.3 Hz, 1H), 4.57 – 4.37 (m, 2H), 3.40 – 3.31 (m, 1H), 2.29 – 2.10 (m, 2H), 2.04 – 1.95 (m, 2H), 1.79 – 1.69 (m, 2H), 1.68 – 1.61 (m, 2H), 1.60 – 1.46 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H). LC/MS (ESI) m/z: 610 (M+H)⁺. RT (Method A): 1.49 min. Scheme 167. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-methylcyclopropyl)-1,3,4- thiadiazole-2-carboxamide (Compound 523) Step1: Ethyl 5-(2-methylcyclopropyl)-1,3,4-thiadiazole-2-carboxylate To a mixture of ethyl 1,3,4-thiadiazole-2-carboxylate (500 mg, 3.16 mmol) and 2- methylcyclopropane-1-carboxylic acid (1.10 g, 11.0 mmol) in DCE (10 mL) and water (2 mL) was added AgNO3 (320 mg, 1.88 mmol), TFA (900 mg, 7.89 mmol) and ammonium persulfate (2.16 g, 9.47 mmol) and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 35% EtOAc in PE) to give the title compound (105 mg, yield 15.5%) as a white solid. LC/MS (ESI) m/z: 213 (M+H)⁺. Step 2: Lithium 5-(2-methylcyclopropyl)-1,3,4-thiadiazole-2-carboxylate To a solution of ethyl 5-(2-methylcyclopropyl)-1,3,4-thiadiazole-2-carboxylate (80.0 mg, 0.37 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (32 mg, 1.33 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1N aq. HCl to pH~5 and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (65.8 mg, yield 94.2%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 185 (M+H)⁺. Step 3: tert-Butyl (2-(((6S,8R)-8-methyl-3-(5-(2-methylcyclopropyl)-1,3,4-thiadiazole-2-carboxamido)-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 5-(2-methylcyclopropyl)-1,3,4-thiadiazole-2-carboxylic acid (40.0 mg, 0.20 mmol) and tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (25.1 mg, 0.05 mmol) in MeCN (2 mL) was added NMI (41.1 mg, 0.50 mmol) and TCFH (72.2 mg, 0.25 mmol) and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (15.8 mg, yield 47.8%) as a white solid. LC/MS (ESI) m/z: 637 (M+H)⁺. Step 4: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-methylcyclopropyl)-1,3,4-thiadiazole-2-carboxamide (Compound 523) To a solution of tert-butyl (2-(((6S,8R)-8-methyl-3-(5-(2-methylcyclopropyl)-1,3,4-thiadiazole-2- carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2- c]pyridin-6-yl)carbamate (15.8 mg, 0.02 mmol) in DCM (0.5 mL) was added HCl in 1,4-dioxane (4M, 0.50 mL, 2 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 523 (7.50 mg, yield 59.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.13 – 9.08 (m, 1H), 8.71 (s, 1H), 8.44 – 8.36 (m, 1H), 7.13 – 7.06 (m, 1H), 6.85 – 6.83 (m, 1H), 5.85 (s, 2H), 5.06 (d, J = 8.4 Hz, 1H), 4.54 – 4.42 (m, 2H), 3.36 – 3.35 (m, 1H), 2.44 – 2.42 (m, 1H), 2.23 – 2.18 (m, 1H), 2.01 – 1.97 (m, 1H), 1.58 – 1.52 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H), 1.25 – 1.22 (m, 2H), 1.21 (d, J = 5.9 Hz, 3H). LC/MS (ESI) (m/z): 537 (M+H)⁺. RT (Method A): 1.23 min. The following compounds were prepared according to the procedures above using the appropriate carboxylic acid in Step 1. Scheme 168. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-methylcyclopropyl)-1,3,4- thiadiazole-2-carboxamide (Compound 524) Step 1: Ethyl 5-(tributylstannyl)isoxazole-3-carboxylate To a solution of ethyl (Z)-2-chloro-2-(hydroxyimino)acetate (12.0 g, 78.9 mmol) in DCM (150 mL) was added tributyl(ethynyl)stannane (20.0 g, 63.4 mmol) and K2CO3 (14.0 g, 101 mmol) at 0°C and the reaction was then stirred at room temperature for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (13.5 g, yield 39.7%) as a white solid. LC/MS (ESI) m/z: 432 (M+H)⁺. Step 2: Ethyl 5-(pyridazin-4-yl)isoxazole-3-carboxylate To a mixture of ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (1.35 g, 3.12 mmol) and 4- bromopyridazine (500 mg, 2.08 mmol) in toluene (6 mL) was added Pd(t-Bu3P)2 (105 mg, 0.21 mmol) under a dry nitrogen atmosphere and the reaction was stirred under a dry nitrogen atmosphere at 110°C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness and purified by flash chromatography (silica gel, 0 - 35% EtOAc in PE) to give the title compound (123 mg, yield 26.8%) as a yellow solid. LC/MS (ESI) m/z: 220 (M+H)⁺. The ethyl 5-(pyridazin-4-yl)isoxazole-3-carboxylate was used to prepare Compound 524 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 9.65 (s, 1H), 9.54 - 9.46 (m, 1H), 9.20 - 9.08 (m, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 8.24 - 8.19 (m, 1H), 8.00 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.09 - 5.01 (m, 1H), 4.53 - 4.38 (m, 2H), 2.47 - 2.30 (m, 2H), 2.26 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 544 (M+H)⁺. RT (Method A): 0.66 min. Scheme 169. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-((2-fluoro- phenoxy)methyl)cyclopropane-1-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 528) Step 1: Ethyl 1-[(2-fluorophenoxy)methyl]cyclopropanecarboxylate 2-Fluorophenol (100 mg, 0.89 mmol), triphenylphosphine (350 mg, 1.33 mmol) and ethyl 1- (hydroxymethyl)cyclopropanecarboxylate (192 mg, 1.33 mmol) were dissolved in THF (5 mL) at room temperature. Diisopropyl azodicarboxylate (0.27 mL, 1.34 mmol) was added dropwise, and the resulting solution was allowed to stir at room temperature for 2 hours. Afterwards, the mixture was concentrated in vacuo and purified by flash column chromatography (RediSep Rf Gold silica, 24g, 0-75% EtOAc in hexanes) to afford ethyl 1-[(2-fluorophenoxy)methyl]cyclopropanecarboxylate (182 mg, 0.76 mmol, 86% Yield) as a yellow oil. LC/MS: (ESI⁺) m/z = 239 [M+H]⁺. Step 2: 1-[(2-Fluorophenoxy)methyl]cyclopropanecarboxylic acid Ethyl 1-[(2-fluorophenoxy)methyl]cyclopropanecarboxylate (182 mg, 0.76 mmol) was dissolved in THF/MeOH (3:1, 2 mL), and sodium hydroxide (2M, 0.7 mL, 1.4 mmol) was added at room temperature and allowed to stir for 2 hours. The mixture was acidified to pH ~3 with 1N HCl and extracted with EtOAc (3x 5 mL). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the 1-[(2-fluorophenoxy)methyl]cyclopropanecarboxylic acid (100 mg, 0.47574 mmol, 62.26% Yield) as a yellow residue. LC/MS: (ESI⁺) m/z = 211 [M+H]⁺. Step 3: tert-Butyl (6S,8R)-3-[[1-[(2-fluorophenoxy)methyl]cyclopropanecarbonyl]amino]-8-methyl-4-oxo- 7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate 1-[(2-Fluorophenoxy)methyl]cyclopropanecarboxylic acid (100 mg, 0.48 mmol), tert-butyl (6S,8R)- 3-amino-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxylate (60 mg, 0.2262 mmol), and NMI (0.045 mL, 0.57 mmol) were combined in MeCN (5 mL) and cooled to 0 °C in an ice bath. HATU (165 mg, 0.58 mmol) in MeCN (1 mL) was added dropwise, and the resulting solution was stirred for 1.5 hours. Afterwards, the mixture was diluted with saturated NH₄Cl (25 mL) and EtOAc (25 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash column chromatography (RediSep Rf Gold silica, 12g, 0-75% EtOAc in hexanes) afforded tert-butyl (6S,8R)-3-[[1- [(2-fluorophenoxy)methyl]cyclopropanecarbonyl]-amino]-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylate (68 mg, 0.15 mmol, 66% Yield) as a colorless film. LC/MS: (ESI⁺) m/z = 458 [M+H]⁺. Step 4: (6S,8R)-3-(1-((2-Fluorophenoxy)methyl)cyclopropane-1-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid TFA (1.5 mL) was added to a solution of tert-Butyl (6S,8R)-3-(1-((2- fluorophenoxy)methyl)cyclopropane-1-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate (68 mg, 0.15 mmol) in DCM (2 mL), and the reaction was stirred at room temperature for 2 hours. Afterwards, the mixture was concentrated in vacuo, maintaining the temperature below 20°C. The mixture was then diluted in DCM and concentrated again to afford (6S,8R)-3-(1-((2- fluorophenoxy)methyl)cyclopropane-1-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid (68 mg) as a colorless solid. LC/MS: (ESI⁺) m/z = 402 [M+H]⁺. Step 5: (6S,8R)-N-[(6-Aminothieno[3,2-c]pyridin-2-yl)methyl]-3-[[1-[(2-fluorophenoxy)-methyl]- cyclopropanecarbonyl]amino]-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 528) 2-(Aminomethyl)thieno[3,2-c]pyridin-6-amine dihydrochloride (66 mg, 0.26 mmol), (6S,8R)-3-[[1- [(2-fluorophenoxy)methyl]cyclopropanecarbonyl]amino]-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]- pyrimidine-6-carboxylic acid (60 mg, 0.15 mmol) and TEA (0.065 mL, 0.47 mmol) were combined in DMF (1 mL) and cooled to 0°C in a brine/ice bath. HATU (85 mg, 0.22 mmol) was added, and the resulting mixture was stirred for 20 minutes. Afterwards, the mixture was quenched with a few drops of water and directly purified by prep-HPLC purification (RediPrep Rf C18Aq, 20x150mm, 5µm, 100Å, 15-65% MeCN in water). Lyophilization afforded Compound 528 (19.8 mg, 24% Yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.09 – 8.98 (m, 2H), 8.74 (t, J = 1.8 Hz, 1H), 8.37 (s, 1H), 7.24 (q, J = 10.2 Hz, 2H), 7.14 (t, J = 8.0 Hz, 1H), 7.07 (s, 1H), 7.05 – 6.96 (m, 1H), 6.82 (s, 1H), 5.84 (s, 2H), 4.99 (d, J = 9.3 Hz, 1H), 4.49 (dd, J = 15.6, 6.1 Hz, 1H), 4.42 – 4.32 (m, 2H), 4.18 (d, J = 11.0 Hz, 1H), 3.29 – 3.20 (m, 1H), 2.40 – 2.27 (m, 1H), 2.15 (q, J = 10.8 Hz, 1H), 1.31 – 1.20 (m, 5H), 1.02 – 0.93 (m, 2H). LC/MS: (ESI⁺) m/z = 563 [M+H]⁺. RT (Method A): 1.28 min. The following compounds were prepared according to the procedures above using the appropriate alcohols as the starting materials in Step 1. ^a Step 1 was performed with NaH in DMF. Scheme 170. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(2- methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 548) Step 1: Ethyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylate To a solution of ethyl 3-bromo-1H-pyrazole-5-carboxylate (3 g, 13.76 mmol) in MeCN (60 mL) was added tert-butyl (2-bromoethyl)carbamate (3.68 g, 16.5 mmol) and Cs₂CO₃ (8.06 g, 24.75 mmol), the reaction mixture was stirred at 40 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (2.5 g, yield 50.3%) as a white solid. LC/MS (ESI) m/z: 362 (M+H)⁺ Step 2: Ethyl 1-(2-aminoethyl)-3-bromo-1H-pyrazole-5-carboxylate hydrochloride A solution of ethyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylate (2 g, 5.54 mmol) in HCl in 1,4-dioxane (10 mL, 4M) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (1.61 g, yield 98.2%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 262 (M+H)⁺. Step 3: 2-Bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one To a solution of ethyl 1-(2-aminoethyl)-3-bromo-1H-pyrazole-5-carboxylate hydrochloride (1.6 g, 5.38 mmol) in MeOH (5 mL) was added TEA (544 mg, 5.38 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (800 mg, yield 69.2%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 216 (M+H)⁺. Step 4: 2-Methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one To a mixture of 2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (800 mg, 3.72 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.1 mL, 7.44 mmol, 3.5 M in THF) in 1,4-dioxane (10 mL) was added K₂CO₃ (1.28 g, 9.30 mmol) and Pd(PPh₃)₄ (427 mg, 0.37 mmol) under a nitrogen atmosphere and the reaction mixture was stirred under a nitrogen atmosphere at 90 °C for 4 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 9% MeOH in DCM) to give the title compound (400 mg, yield 71.3%) as a yellow solid. LC/MS (ESI) m/z: 152 (M+H)⁺. Step 5: Methyl (6S,8R)-8-methyl-3-(2-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of 2-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (200 mg, 1.32 mmol) and methyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (500 mg, 1.32 mmol) in toluene (5 mL) was added K₂CO₃ (546 mg, 3.96 mmol), XantPhos (75 mg, 0.13 mmol) and Pd2(dba)3 (118 mg, 0.13 mmol) under a nitrogen atmosphere. The reaction mixture was stirred under a nitrogen atmosphere at 100°C for 4 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (45 mg, yield 9.5%) as a yellow oil. LC/MS (ESI) m/z: 358 (M+H)⁺. Step 6: Lithium (6S,8R)-8-methyl-3-(2-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (6S,8R)-8-methyl-3-(2-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin- 5(4H)-yl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (40 mg, 0.11 mmol) in THF/water (3 mL, v/v=1/1) was added LiOH (5 mg, 0.22 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (35 mg, yield 93.8%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 344 (M+H)⁺. Step 7: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(2-methyl-4-oxo-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6-carboxamide (Compound 548) To a mixture of (6S,8R)-8-methyl-3-(2-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (30 mg, 0.08 mmol) and 2- (aminomethyl)thieno[3,2-c]pyridin-6-amine hydrochloride (24 mg, 0.11 mmol) in DMF (2 mL) was added DIPEA (31 mg, 0.24 mmol) and T3P (70 mg, 0.16 mmol, 50% wt. in EtOAc), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 548 (6 mg, yield 13.7%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (t, J = 5.8 Hz, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 6.62 (s, 1H), 5.84 (s, 2H), 5.02 (d, J = 8.5 Hz, 1H), 4.57 - 4.49 (m, 1H), 4.43 - 4.36 (m, 3H), 3.96 - 3.88 (m, 2H), 3.43 - 3.36 (m, 1H), 2.40 - 2.34 (m, 1H), 2.29 - 2.23 (m, 1H), 2.23 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 505 (M+H)⁺. RT (Method A): 0.44 min. Scheme 171. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(5-(2- fluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 549) Step 1: Ethyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate To a solution of ethyl 5-bromo-1H-imidazole-2-carboxylate (600 mg,2.75 mmol) in DMF (6 mL) was added K₂CO₃ (570 mg, 4.12 mmol) and MeI (586 mg, 4.12 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (520 mg, yield 81.4%) as a colorless oil. LC/MS (ESI) m/z: 233 (M+H)⁺. Step 2: Ethyl 5-(2-fluorophenyl)-1-methyl-1H-imidazole-2-carboxylate To a mixture of ethyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate (520 mg, 2.24 mmol) and (2- fluorophenyl)boronic acid (628 mg, 4.48 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was added Na2CO3 (713 mg, 6.72 mmol) and Pd(dppf)Cl2 (164 mg, 0.22 mmol), and the reaction mixture was stirred at 80 °C overnight. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (90 mg, yield 16.2%) as a brown oil. The structure of ethyl 5-(2-fluorophenyl)-1-methyl-1H-imidazole-2-carboxylate was confirmed by 2D NMR (HOESY).¹H NMR (400 MHz, CDCl3) δ 7.47 - 7.39 (m, 1H), 7.33 - 7.28 (m, 1H), 7.22 (s, 1H), 7.20 - 7.14 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 3.83 (d, J = 1.8 Hz, 3H), 1.42 (t, J = 7.1 Hz, 3H). LC/MS (ESI) m/z: 249 (M+H)⁺. The ethyl 5-(2-fluorophenyl)-1-methyl-1H-imidazole-2-carboxylate was used to prepare Compound 549 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.12 (t, J = 5.7 Hz, 1H), 8.90 (s, 1H), 8.42 (s, 1H), 7.62 - 7.53 (m, 2H), 7.46 - 7.36 (m, 2H), 7.30 (s, 1H), 7.13 (s, 1H), 6.88 (s, 1H), 5.93 (s, 2H), 5.08 (d, J = 9.3 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.88 (s, 3H), 3.39 - 3.35 (m, 1H), 2.40 - 2.34 (m, 1H), 2.25 - 2.17 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 573 (M+H)⁺. RT (Method A): 1.46 min. The following compounds were prepared according to the procedures above using the appropriate staring materials. Scheme 172. Synthesis of (6S,8R)-3-(4-(1,3,4-Oxadiazol-2-yl)benzamido)-N-((6-Aminothieno-[3,2- c]pyridin-2-yl)methyl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamide (Compound 552) Step 1: Methyl 4-(hydrazinecarbonyl)benzoate To a solution of dimethyl terephthalate (2 g, 10.31 mmol) in EtOH (20 mL) was added NH₂NH₂.H₂O (2 mL, 80% wt.) and the mixture was stirred 50°C for 2 hours. The mixture was cooled and then diluted with water and extracted with CHCl3/i-PrOH= 3/1 twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.8 g, yield 89.6%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 195 (M+H)⁺. Step 2: Methyl 4-(1,3,4-oxadiazol-2-yl)benzoate To a solution of methyl 4-(hydrazinecarbonyl)benzoate (500 mg, 2.56 mmol) in trimethoxymethane (5 mL) was added TsOH (44 mg, 0.26 mmol) and the mixture was stirred at 70 °C for 1 hour. The mixture was cooled and then diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) give the title compound (140 mg, yield 26.7%) as a white solid. LC/MS (ESI) m/z: 205 (M+H)⁺. The methyl 4-(1,3,4-oxadiazol-2-yl)benzoate was used to prepare Compound 552 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.43 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 8.18 - 8.15 (m, 4H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.05 (d, J = 9.0 Hz, 1H), 4.52 - 4.41 (m, 2H), 3.39 - 3.34 (m, 1H), 2.40 - 2.34 (m, 1H), 2.27 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 543 (M+H)⁺. RT (Method A): 0.76 min. Scheme 173. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(4-fluoro-pyridin-3-yl)isoxazole-3- carboxamide (Compound 554) Step 1: Ethyl 5-(4-fluoropyridin-3-yl)isoxazole-3-carboxylate To a mixture of ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (978 g, 2.27 mmol) and 3-bromo- 4-fluoropyridine (200 mg, 1.13 mmol) in toluene (6 mL) was added Pd(t-Bu3P)2 (56 mg, 0.11 mmol) under a nitrogen atmosphere and the reaction mixture was stirred under a nitrogen atmosphere at 110°C for 3 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 35% EtOAc in PE) to give the title compound (122 mg, yield 45.7%) as a yellow solid. LC/MS (ESI) m/z: 237 (M+H)⁺. Step 2: Lithium 5-(4-fluoropyridin-3-yl)isoxazole-3-carboxylate To a solution of ethyl 5-(4-fluoropyridin-3-yl)isoxazole-3-carboxylate (50 mg, 0.21 mmol) in THF (5 mL) and water (1 mL) was added LiOH (8 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (47 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 209 (M+H)⁺. Step 3: tert-Butyl (2-(((6S,8R)-3-(5-(4-fluoropyridin-3-yl)isoxazole-3-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno-[3,2-c]pyridin-6-yl)carbamate To a mixture of lithium 5-(4-fluoropyridin-3-yl)isoxazole-3-carboxylate (20.0 mg, 0.09 mmol) and tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (25 mg, 0.05 mmol) in MeCN (2 mL) was added NMI (41 mg, 0.50 mmol) and TCFH (72 mg, 0.25 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (18 mg, yield 54.5%) as a white solid. LC/MS (ESI) m/z: 661 (M+H)⁺. Step 4: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(4-fluoropyridin-3-yl)isoxazole-3-carboxamide (Compound 554) To a solution of tert-butyl (2-(((6S,8R)-3-(5-(4-fluoropyridin-3-yl)isoxazole-3-carboxamido)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (18 mg, 0.02 mmol) in DCM (0.50 mL) was added TFA (0.50 mL). The reaction mixture was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 554 (3.0 mg, yield 21.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, 1H), 9.22 (d, J = 10.1 Hz, 1H), 9.12 (t, J = 5.8 Hz, 1H), 8.80 (dd, J = 7.9, 5.7 Hz, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 7.65 (dd, J = 10.8, 5.7 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.12 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.07 (d, J = 8.9 Hz, 1H), 4.55 – 4.41 (m, 2H), 2.56 – 2.51 (m, 1H), 2.41 – 2.34 (m, 1H), 2.27 – 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 561 (M+H)⁺. RT (Method A): 1.01 min. The following compounds were prepared based on the procedures above using the appropriate tributylstannanes and heteroaryl bromides in Step 1.

^a The Stille reaction was performed in the presence of Pd(PPh3)2Cl2 in 1,4-dioxane. ^b The Stille reaction was performed in the presence of Pd(PPh₃)₂Cl₂ in toluene. ^c Step 4 was performed with HCl/1,4-dioxane in DCM. ^d The Stille reaction was performed in the presence of Pd(PPh3)4 and CuI in DMF. Scheme 174. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((3-phenylbenzo[d]isoxazol-7-yl)amino)-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamide (Compou Step 1: (3-Bromo-2-fluorophenyl)(phenyl)methanone To a solution of (3-bromo-2-fluorophenyl)(phenyl)methanol (4.0 g, 17.3 mmol) in DCM (40 mL) was added DMP (1.10 g, 101 mmol) at 0 °C and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 25% EtOAc in PE) to give the title compound (3.70 g, yield 95.5%) as a white solid. LC/MS (ESI) m/z: 279 (M+H)⁺. Step 2: (E)-(3-bromo-2-fluorophenyl)(phenyl)methanone oxime To a solution of (3-bromo-2-fluorophenyl)(phenyl)methanone (3.50 g, 12.5 mmol) in EtOH (40 mL) was added K₂CO₃ (6.30 g, 61.3 mmol) and NH₂OH.HCl (4.23 g, 124 mmol) at 0 °C and the mixture was then stirred at 80 °C for 3 hours. The mixture was cooled and then diluted with water and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (3.58 g, yield 81.3%) as a white solid. LC/MS (ESI) m/z: 294 (M+H)⁺. Step 3: 7-Bromo-3-phenylbenzo[d]isoxazole To a solution of (E)-(3-bromo-2-fluorophenyl)(phenyl)methanone oxime (2.70 g, 9.25 mmol) in DMF (15 mL) and THF (30 mL) was added NaH (552 mg, 23.0 mmol, 60% dispersion in mineral oil) under a nitrogen atmosphere and the mixture was stirred at 35 °C for 3 hours. The mixture was quenched with 1 N aq. HCl and extract with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 25% EtOAc in PE) to give the title compound (1.10 g, yield 44.0%) as a white solid. LC/MS (ESI) (m/z): 274 (M+H)⁺. Step 4: tert-Butyl (3-phenylbenzo[d]isoxazol-7-yl)carbamate To a mixture of 7-bromo-3-phenylbenzo[d]isoxazole (500 mg, 1.83 mmol) and N-Boc- Ethylenediamine (420 mg, 3.59 mmol) in toluene (5 mL) was added Pd2(dba)3 (170 mg, 0.18 mmol), BrettPhos (100 mg, 0.17 mmol) and Cs₂CO₃ (1.81 g, 5.55 mmol). The mixture was degassed under a nitrogen atmosphere three times and stirred at 100°C for 8 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (150 mg, yield 26.4%) as a yellow solid. LC/MS (ESI) m/z: 311 (M+H)⁺. Step 5: 3-Phenylbenzo[d]isoxazol-7-amine To a solution of tert-butyl (3-phenylbenzo[d]isoxazol-7-yl)carbamate (150 mg, 0.48 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (2 mL, 4M) under a nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and extracted with CHCl3/i- PrOH (3/1, v/v) twice. The combined organic layers were washed with saturated aq. NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (63.2 mg, yield 62.3%) as a white solid. LC/MS (ESI) m/z: 211 (M+H)⁺. The 3-phenylbenzo[d]isoxazol-7-amine was used to prepare Compound 557 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.11 - 9.05 (m, 1H), 8.40 (s, 1H), 8.07 - 8.04 (m, 1H), 8.02 - 7.99 (m, 2H), 7.66 - 7.61 (m, 4H), 7.57 (s, 1H), 7.38 - 7.29 (m, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.9 Hz, 1H), 4.54 - 4.45 (m, 2H), 3.37 - 3.34 (m, 1H), 2.39 - 2.35 (m, 1H), 2.26 - 2.19 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 564 (M+H)⁺. RT (Method A): 1.64 min. Scheme 175. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1H- benzo[d]imidazol-2-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound Step 1: Methyl (6S,8R)-8-methyl-4-oxo-3-(tributylstannyl)-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6- carboxylate To a solution of methyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]- pyrimidine-6-carboxylate (500 mg, 1.75 mmol) in 1,4-dioxane (3 mL) was added (n-Bu)₃SnH (1.02 g, 3.50 mmol) and Pd(PPh3)2Cl2 (123 mg, 0.17 mmol) at room temperature and the mixture was stirred under a nitrogen atmosphere at 100 °C overnight. The mixture was cooled and then diluted with EtOAc, washed with brine, and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (358 mg, yield 41.1%) as a brown oil. LC/MS (ESI) m/z: 499 (M+H)⁺. Step 2: Methyl (6S,8R)-3-(1H-benzo[d]imidazol-2-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-8-methyl-4-oxo-3-(tributylstannyl)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate (180 mg, 0.36 mmol) and 2-bromo-1H-benzo[d]-imidazole (107 mg, 0.54 mmol) in toluene (3 mL) was added Pd-PEPPSI-IPent (28 mg, 0.04 mmol) and CuI (14 mg, 0.07 mmol) at room temperature and the mixture was stirred under a nitrogen atmosphere at 110 °C overnight. The mixture was cooled and then diluted with saturated aq. KF solution, stirred for 5 mins, and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (38 mg, yield 32.5%) as a brown solid. LC/MS (ESI) m/z: 325 (M+H)⁺. Step 3: Lithium (6S,8R)-3-(1H-benzo[d]imidazol-2-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-3-(1H-benzo[d]imidazol-2-yl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (38 mg, 0.12 mmol) in THF (2 mL) and water (1 mL) was added LiOH (6 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (28 mg, yield 74.7%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 311 (M+H)⁺. Step 4: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1H-benzo[d]imidazol-2-yl)-8-methyl-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 558) To a mixture of lithium (6S,8R)-3-(1H-benzo[d]imidazol-2-yl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (28 mg, 0.09 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine hydrochloride (56 mg, 0.26 mmol) in DMF (2 mL) was added DIPEA (34 mg, 0.26 mmol) and HATU (50 mg, 0.13 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 70% MeCN in water with 0.1% NH4HCO3) to give Compound 558 (5 mg, yield 13.2%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 9.17 (t, J = 5.8 Hz, 1H), 9.04 (s, 1H), 8.43 (s, 1H), 7.66 – 7.61 (m, 2H), 7.20 – 7.16 (m, 2H), 7.13 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.18 (d, J = 9.3 Hz, 1H), 4.53 - 4.45 (m, 2H), 3.52 – 3.41 (m, 1H), 2.45 – 2.39 (m, 1H), 2.31 – 2.23 (m, 1H), 1.36 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 472 (M+H)⁺. RT (Method A): 0.48 min. Scheme 176. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-(2-fluoro-3- methylphenyl)-1H-1,2,3-triazole-4-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a] Step 1: 1-Azido-2-fluoro-3-methylbenzene To a solution of 2-fluoro-3-methylaniline (1.0 g, 8.0 mmol) in water (10 mL) and 15% aq. HCl (2 mL) was added a solution of NaNO₂ (662.4 mg, 9.6 mmol) in water (5 mL) dropwise at 0°C and the mixture was stirred at 0°C for 0.5 hour. Afterwards, a solution of NaN3 (624 mg, 9.6 mmol) in water (7 mL) was added to the mixture dropwise at 0 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (1.0 g, crude) as a yellow oil, which was used directly in the next step without further purification. Step 2: Methyl 1-(2-fluoro-3-methylphenyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of 1-azido-2-fluoro-3-methylbenzene (500 mg, 3.31 mmol) and methyl (E)-3- methoxyacrylate (384 mg, 3.31 mmol) in CHCl3 (8 mL) was added DBU (236 mg, 1.55 mmol) and the reaction mixture was stirred at 85°C overnight. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (50 mg, yield 6.4%) as a yellow oil. LC/MS (ESI) m/z: 236 (M+H)⁺. The Methyl 1-(2-fluoro-3-methylphenyl)-1H-1,2,3-triazole-4-carboxylate was used to prepare Compound 561 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 9.28 (d, J = 1.6 Hz, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.86 (s, 1H), 8.41 (s, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.12 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.08 (d, J = 9.0 Hz, 1H), 4.55 - 4.43 (m, 2H), 3.38 - 3.33 (m, 1H), 2.39 - 2.35 (m, 4H), 2.26 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 574 (M+H)⁺. RT (Method A): 1.37 min. Scheme 176. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-cyclopropyl-3- (2-fluorophenyl)-1H-pyrazole-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 563) To a mixture of ethyl 3-(2-fluorophenyl)-1H-pyrazole-5-carboxylate (300 mg, 1.28 mmol) and cyclopropylboronic acid (220 mg, 2.56 mmol) in DCE (5 mL) was added Na2CO3 (271 mg, 2.56 mmol), 2,2-bipyridine (240 mg, 1.53 mmol) and Cu(OAc)2 (232 mg, 1.28 mmol) and the reaction mixture was stirred at 70°C for 4 hours. The mixture was cooled and then diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give ethyl 1-cyclopropyl-3-(2- fluorophenyl)-1H-pyrazole-5-carboxylate (65 mg, yield 18.5%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 7.97 – 7.91 (m, 1H), 7.44 – 7.37 (m, 1H), 7.34 – 7.25 (m, 2H), 7.16 (d, J = 3.8 Hz, 1H), 4.43 – 4.32 (m, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.27 – 1.22 (m, 2H), 1.12 – 1.05 (m, 2H). LC/MS (ESI) m/z: 275 (M+H)⁺. The ethyl 1-cyclopropyl-3-(2-fluorophenyl)-1H-pyrazole-5-carboxylate was then used to produce Compound 563 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 7.97 – 7.92 (m, 1H), 7.44 – 7.37 (m, 2H), 7.34 – 7.26 (m, 2H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.05 (d, J = 9.0 Hz, 1H), 4.53 – 4.41 (m, 3H), 3.39 – 3.33 (m, 1H), 2.40 – 2.34 (m, 1H), 2.27 – 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H), 1.24 – 1.21 (m, 2H), 1.07 – 1.00 (m, 2H). LC/MS (ESI) m/z: 599 (M+H)⁺. RT (Method A): 1.64 min. Scheme 177. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((R)-1-(pyridin-2-yl)piperidine-3-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 564) To a solution of ethyl (R)-piperidine-3-carboxylate (356 mg, 2.27 mmol) in NMP (5 mL) was added 2-fluoropyridine (200 mg, 2.06 mmol) and K₂CO₃ (854 mg, 6.18 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at 120 °C overnight. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give ethyl (R)-1-(pyridin-2-yl)piperidine-3-carboxylate (50 mg, yield 10.4%) as a white solid. LC/MS (ESI) m/z: 235 (M+H)⁺. The ethyl (R)-1-(pyridin-2-yl)piperidine-3-carboxylate was then used to produce Compound 564 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.43 (s, 1H), 9.06 (t, J = 5.8 Hz, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.09 (dd, J = 4.8, 1.5 Hz, 1H), 7.50 (dd, J = 7.7, 6.0 Hz, 1H), 7.10 (s, 1H), 6.84 (d, J = 6.3 Hz, 2H), 6.59 (dd, J = 6.9, 5.0 Hz, 1H), 5.84 (s, 2H), 5.01 (d, J = 9.1 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 4.30 (d, J = 42.0 Hz, 1H), 3.26 – 3.25 (m, 1H), 2.97 – 2.91 (m, 1H), 2.87 – 2.77 (m, 3H), 2.36 – 2.32 (m, 1H), 2.19 – 2.13 (m, 1H), 1.95 – 1.90 (m, 1H), 1.70 – 1.62 (m, 2H), 1.48 – 1.42 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 559 (M+H)⁺. RT (Method A): 0.40 min. Compound 581 was prepared according to the procedures above using methyl (R)-pyrrolidine-3- carboxylate as the starting material in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 9.06 (t, J = 5.7 Hz, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 8.07 - 8.04 (m, 1H), 7.50 - 7.45 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 6.56 - 6.52 (m, 1H), 6.44 (d, J = 8.5 Hz, 1H), 5.86 (s, 2H), 5.04 - 5.00 (m, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.68 - 3.63 (m, 1H), 3.55 - 3.47 (m, 3H), 3.40 - 3.38 (m, 1H), 2.36 - 2.31 (m, 1H), 2.25 - 2.16 (m, 2H), 2.15 - 2.09 (m, 1H), 2.07 -1.89 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 545 (M+H)⁺. RT (Method A): 0.35 min. Scheme 178. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-((R)-1- (5-methyl-1,3,4-thiadiazol-2-yl)pyrrolidine-3-carboxamido)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 565) To a mixture of methyl (R)-pyrrolidine-3-carboxylate (50 mg, 0.30 mmol) and 2-chloro-5-methyl- 1,3,4-thiadiazole (41 mg, 0.30 mmol) in DMF (8 mL) was added DIPEA (195 mg, 1.55 mmol) and the reaction was stirred at 100°C for 3 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give methyl (R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)pyrrolidine-3-carboxylate (25 mg, yield 36.2%) as a white solid. LC/MS (ESI) m/z: 228 (M+H)⁺. The methyl (R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)pyrrolidine-3-carboxylate was then used to produce Compound 565 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1H), 9.06 (t, J = 5.6 Hz, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 7.10 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.02 (d, J = 9.1 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.65 - 3.57 (m, 2H), 3.53 - 3.47 (m, 2H), 3.44 - 3.36 (m, 2H), 3.30 (s, 3H), 2.35 - 2.32 (m, 1H), 2.29 - 2.22 (m, 1H), 2.20 - 2.11 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 566 (M+H)⁺. RT (Method A): 0.68 min. Scheme 179. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((R)-1-(2- fluorophenyl)pyrrolidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 566) To a mixture of methyl (R)-pyrrolidine-3-carboxylate (250 mg, 1.9 mmol) and 1-fluoro-2- iodobenzene (642 mg, 2.93 mmol) in toluene (5 mL) was added XantPhos (110 mg, 0.19 mmol), K₂CO₃ (805 mg, 5.8 mmol) and Pd₂(dba)₃ (177 mg, 0.20 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 80°C for 2 hours. The reaction mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give methyl (R)-1-(2-fluorophenyl)pyrrolidine-3- carboxylate (80 mg, yield 18.9%) as orange solid. LC/MS (ESI) m/z: 224 (M+H)⁺. RT (Method A): 1.38 min. The methyl (R)-1-(2-fluorophenyl)pyrrolidine-3-carboxylate carboxylate was then used to produce Compound 566 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.55 (s, 1H), 9.06 (t, J = 5.9 Hz, 1H), 8.73 (s, 1H), 8.41 (s, 1H), 7.10 (s, 1H), 7.09 - 6.98 (m, 2H), 6.83 (s, 1H), 6.78 - 6.67 (m, 2H), 5.85 (s, 2H), 5.02 (d, J = 9.0 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.59 - 3.53 (m, 1H), 3.52 - 3.43 (m, 2H), 3.40 - 3.35 (m, 2H), 3.29 - 3.26 (m, 1H), 2.38 - 2.32 (m, 1H), 2.23 - 2.14 (m, 2H), 2.08 (d, J = 5.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 562 (M+H)⁺. The following compounds were prepared according to the procedures above using the appropriate amine and aryl halide in Step 1.

^a Step 4 was performed with TFA in DCM. ^b Step 1 was performed with Pd₂(dba)₃, BINAP, and Cs₂CO₃ in toluene. ^c Step 1 was performed with BrettPhos Pd G3, BrettPhos, and Cs2CO3 in toluene. Scheme 180. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-3-phenylisoxazole-5- carboxamide (Compound 575) Step 1: Lithium 3-phenylisoxazole-5-carboxylate To a solution of methyl 3-phenylisoxazole-5-carboxylate (800 mg, 3.94 mmol) in THF/water (12 mL, v/v= 3/1) was added LiOH (189 mg, 7.88 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (750 mg, yield 97.6%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 190 (M+H)⁺. Step 2: N-(4-(tert-Butyl)phenyl)-3-phenylisoxazole-5-carboxamide To a mixture of lithium 3-phenylisoxazole-5-carboxylate (600 mg, 3.07 mmol) and 4-(tert- butyl)aniline (504 mg, 3.38 mmol) in DMF (10 mL) was added DIPEA (1.18 g, 9.21 mmol) and HATU (1.39 g, 3.68 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (800 mg, yield 81.4%) as a white solid. LC/MS (ESI) m/z: 321 (M+H)⁺. Step 3: N-(4-(tert-Butyl)phenyl)-4-fluoro-3-phenylisoxazole-5-carboxamide To a solution of N-(4-(tert-butyl)phenyl)-3-phenylisoxazole-5-carboxamide (600 mg, 1.87 mmol) in THF (12 mL) was added n-BuLi (3 mL, 7.5 mmol, 2.5 M in hexane) dropwise at -60 °C under a nitrogen atmosphere. After stirred at -60°C for 1 hour, a solution of NFSI (1.18 g, 3.74 mmol) in THF (5 mL) was added to the mixture dropwise at -60°C and the resulting mixture was stirred at -60°C for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (230 mg, yield 73.9%) as a yellow solid. LC/MS (ESI) m/z: 339 (M+H)⁺. Step 4: tert-Butyl (4-(tert-butyl)phenyl)(4-fluoro-3-phenylisoxazole-5-carbonyl)carbamate To a solution of N-(4-(tert-butyl)phenyl)-4-fluoro-3-phenylisoxazole-5-carboxamide (200 mg, 0.59 mmol) in THF (10 mL) was added NaH (50 mg, 1.18 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred at room temperature for 30 minutes. (Boc)₂O (257 mg, 1.18 mmol) was added to the above mixture at room temperature and the resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aq. NH4Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give title compound (230 mg, yield 89.1%) as a colorless oil. LC/MS (ESI) m/z:383 (M+H-t-Bu)⁺. Step 5: 4-Fluoro-3-phenylisoxazole-5-carboxylic acid To a solution of H2O2 (258 mg, 2.28 mmol, 30% wt. in water) in THF/water (2 mL, v/v=1:1) was added LiOH (54 mg, 2.28 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of tert-butyl(4-(tert-butyl)phenyl)(4-fluoro-3-phenylisoxazole- 5-carbonyl)carbamate (200 mg, 0.46 mmol) in THF (1 mL) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (70 mg, yield 74.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 206 (M-H)-. Step 6: tert-Butyl (2-(((6S,8R)-3-(4-fluoro-3-phenylisoxazole-5-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (50 mg, 0.10 mmol) and 4-fluoro- 3-phenylisoxazole-5-carboxylic acid (30 mg, 0.14 mmol) in MeCN (3 mL) was added NMI (25 mg, 0.31 mmol) and TCFH (84 mg, 0.31 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (45 mg, yield 68.3%) as a yellow solid. LC/MS (ESI) m/z: 660 (M+H)⁺. Step 7: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-3-phenylisoxazole-5-carboxamide (Compound 575) To a solution of tert-butyl (2-(((6S,8R)-3-(4-fluoro-3-phenylisoxazole-5-carboxamido)-8-methyl-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (45 mg, 0.06 mmol) in CHCl3 (2 mL) was added HCl in 1,4-dioxane (1 mL, 4M) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 575 (17.2 mg, yield 45.2%) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.12 (s, 1H), 8.62 (s, 1H), 8.42 (s, 1H), 7.89 (s, 2H), 7.66 – 7.62 (m, 3H), 7.12 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.07 (d, J = 8.7 Hz, 1H), 4.53 – 4.44 (m, 2H), 3.50 – 3.47 (m, 1H), 2.41 – 2.35 (m, 1H), 2.27 – 2.20 (m, 1H), 1.31 (d, J = 4.8 Hz, 3H). LC/MS (ESI) (m/z): 560 (M+H)⁺. RT (Method A): 1.51 min. Compound 603 was prepared according to the procedures above using methyl 3-(pyridin-2- yl)isoxazole-5-carboxylate in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.67 - 8.64 (m, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 8.04 - 7.98 (m, 1H), 7.86 (s, 1H), 7.73 - 7.69 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.5 Hz, 1H), 4.53 - 4.42 (m, 2H), 3.40 - 3.33 (m, 1H), 2.39 - 2.33 (m, 1H), 2.28 - 2.19 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 561 (M+H)⁺. RT (Method A): 1.11 min. Compound 636 was prepared according to the procedures above starting from Step 2, using lithium 3-(3-methylpyridin-2-yl)isoxazole-5-carboxylate as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.63 (d, J = 4.7 Hz, 2H), 8.41 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.54 (dd, J = 7.8, 4.7 Hz, 1H), 7.12 (s, 1H), 6.85 (s, 1H), 5.86 (s, 2H), 5.06 (d, J = 8.6 Hz, 1H), 4.54 - 4.41 (m, 2H), 3.42 - 3.34 (m, 1H), 2.48 (s, 3H), 2.42 - 2.34 (m, 1H), 2.28 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 575 (M+H)⁺. RT (Method A): 1.48 min. Compound 688 was prepared according to the procedures above starting from Step 2, using lithium 3-(2-fluorophenyl)isoxazole-5-carboxylate as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 7.81 - 7.76 (m, 1H), 7.75 - 7.69 (m, 1H), 7.55 - 7.49 (m, 1H), 7.49 - 7.44 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.8 Hz, 1H), 4.54 - 4.42 (m, 2H), 3.41 - 3.34 (m, 1H), 2.41 - 2.35 (m, 1H), 2.27 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 578 (M+H)⁺. RT (Method A): 1.64 min. Scheme 181. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (4-(pyridin-2-yl)cyclohexane-1-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 577) Step 1: Ethyl 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylate To a mixture of 2-bromopyridine (565 mg, 3.57 mmol) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1.00 g, 3.57 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl₂ (260 mg, 0.36 mmol) and K₂CO₃ (1.48 g, 10.7 mmol) under a nitrogen atmosphere and the mixture was stirred at 100 °C for 3 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (400 mg, yield 48.6%) as a white solid. LC/MS (ESI) m/z: 232 (M+H)⁺. Step 2: Ethyl 4-(pyridin-2-yl)cyclohexane-1-carboxylate To a mixture of ethyl 4-(pyridin-2-yl)cyclohex-3-ene-1-carboxylate (200 mg, 0.86 mmol) in EtOAc (10 mL) was added PtO₂ (20 mg), the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at 25°C for 20 minutes. The mixture was then filtered and the filtrate was concentrated to dryness to give the title compound (180 mg, yield 89.5%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 234 (M+H)⁺. The ethyl 4-(pyridin-2-yl)cyclohexane-1-carboxylate was used to prepare Compound 577 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.07 (t, J = 5.9 Hz, 1H), 8.73 (s, 1H), 8.48 (d, J = 4.1 Hz, 1H), 8.41 (s, 1H), 7.74 – 7.65 (m, 1H), 7.29 – 7.24 (m, 1H), 7.23 – 7.16 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.07 – 4.94 (m, 1H), 4.52 – 4.32 (m, 2H), 3.23 – 3.12 (m, 1H), 2.56 – 2.53 (m, 2H), 2.39 – 2.27 (m, 1H), 2.25 – 2.11 (m, 1H), 1.98 – 1.82 (m, 4H), 1.65 – 1.47 (m, 4H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 558 (M+H)⁺. RT (Method A): 0.49 min. Scheme 182. Synthesis of (6S,8R)-3-(4-(1,2,4-Oxadiazol-3-yl)benzamido)-N-((6-aminothieno-[3,2- c]pyridin-2-yl)methyl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 802) Step 1: Methyl 4-(1,2,4-oxadiazol-3-yl)benzoate To a solution of methyl (E)-4-(N'-hydroxycarbamimidoyl)benzoate (500 mg, 2.58 mmol) in trimethoxymethane (5 mL) was added TsOH (89 mg, 0.52 mmol) and the mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (500 mg, yield 95.1%) as a white solid. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 2: 4-(1,2,4-Oxadiazol-3-yl)benzoic acid To a solution of methyl 4-(1,2,4-oxadiazol-3-yl)benzoate (250 mg, 1.23 mmol) in DCM (2 mL) was added BBr3 (10 mL, 1 M in DCM) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with saturated aq. NaHCO₃ solution at 0 °C and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (70 mg, yield 30%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 189 (M-H)-. Step 3: tert-Butyl (2-(((6S,8R)-3-(4-(1,2,4-oxadiazol-3-yl)benzamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (25 mg, 0.05 mmol) and 4-(1,2,4- oxadiazol-3-yl)benzoic acid (15 mg, 0.08 mmol) in MeCN (2 mL) was added TCFH (54 mg, 0.18 mmol) and NMI (16 mg, 0.18 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (20 mg, yield 58.6%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 643 (M+H)⁺. Step 4: (6S,8R)-3-(4-(1,2,4-Oxadiazol-3-yl)benzamido)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 579) To a mixture of tert-butyl (2-(((6S,8R)-3-(4-(1,2,4-oxadiazol-3-yl)benzamido)-8-methyl-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.03 mmol) in DCM (2 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC- Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 579 (8 mg, yield 47.4%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 9.71 (s, 1H), 9.10 (t, J = 5.9 Hz, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 8.20 - 8.13 (m, 4H), 7.11 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.05 (d, J = 9.1 Hz, 1H), 4.52 – 4.43 (m, 2H), 3.39 - 3.34 (m, 1H), 2.40 - 2.35 (m, 1H), 2.26 - 2.19 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 543 (M+H)⁺. RT (Method A): 1.06 Scheme 183. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (4-phenyl-1H-imidazol-2-yl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 585) Step 1: Methyl (6S,8R)-3-formyl-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate A solution of methyl (6S,8R)-8-methyl-4-oxo-3-vinyl-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxylate (170 mg, 0.72 mmol) in DCM (3 mL) was bubbled with O3 at -78°C for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (130 mg, yield 76.5%) as a yellow oil, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 237 (M+H)⁺. Step 2: Methyl (6S,8R)-8-methyl-4-oxo-3-(4-phenyl-1H-imidazol-2-yl)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylate To a solution of methyl (6S,8R)-3-formyl-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxylate (130 mg, 0.55 mmol) in EtOH (3 mL) was added 2-oxo-2-phenyl-acetaldehyde (74 mg, 0.55 mmol) and NH₄OAc (127 mg, 1.65 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (30 mg, yield 15.5%) as a yellow solid. LC/MS (ESI) m/z: 351 (M+H)⁺. Step 3: Lithium (6S,8R)-8-methyl-4-oxo-3-(4-phenyl-1H-imidazol-2-yl)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a solution of methyl (6S,8R)-8-methyl-4-oxo-3-(4-phenyl-1H-imidazol-2-yl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (30 mg, 0.08 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (4 mg, 0.16 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness to give the title compound (28 mg, yield 96.3%) as a white solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 337 (M+H)⁺. Step 4: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3-(4-phenyl-1H-imidazol-2- yl)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 585) To a mixture of lithium (6S,8R)-8-methyl-4-oxo-3-(4-phenyl-1H-imidazol-2-yl)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (28 mg, 0.08 mmol) and 2-(aminomethyl)-thieno[3,2- c]pyridin-6-Amine hydrochloride (12 mg, 0.07 mmol) in DMF (1 mL) was added DIPEA (36 mg, 0.30 mmol) and HATU (21 mg, 0.06 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 25 - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 585 (3.5 mg, yield 8.6%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.14 (t, J = 5.8 Hz, 1H), 8.82 (s, 1H), 8.43 (s, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.14 (d, J = 9.0 Hz, 1H), 4.60 – 4.42 (m, 2H), 3.46 – 3.38 (m, 1H), 2.42 – 2.35 (m, 1H), 2.29 – 2.20 (m, 1H), 1.34 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 498 (M+H)⁺. Scheme 184. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-cyclopropyl-2- (2-fluorophenyl)-1H-imidazole-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 586) Step 1: Ethyl 2-bromo-1-cyclopropyl-1H-imidazole-5-carboxylate To a mixture of ethyl 2-bromo-1H-imidazole-5-carboxylate (200 mg, 0.91 mmol) and cyclopropylboronic acid (118 mg, 1.37 mmol) in DCE (3 mL) was added 2,2'-Bipyridine (171 mg, 1.09 mmol), Cu(OAc)₂ (166 mg, 0.91 mmol) and Na₂CO₃ (194 mg, 1.83 mmol) and the reaction mixture was stirred under an oxygen atmosphere at 70°C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 27% EtOAc in PE) to give the title compound (60 mg, yield 25.4%) as a yellow solid.¹HNMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 4.32 (q, J = 7.1, 3.9 Hz, 2H), 3.25 - 3.19 (m, 1H), 1.35 (t, J = 3.6 Hz, 3H), 1.28 - 1.26 (m, 2H), 1.03 - 0.99 (m, 2H). LC/MS (ESI) m/z: 259 (M+H)⁺. Step 2: Ethyl 1-cyclopropyl-2-(2-fluorophenyl)-1H-imidazole-5-carboxylate To a mixture of ethyl 2-bromo-1-cyclopropyl-1H-imidazole-5-carboxylate (60 mg, 0.23 mmol) and (2-fluorophenyl)boronic acid (49 mg, 0.35 mmol) in 1,4-dioxane (2 mL) and water (0.3 mL) was added Na₂CO₃ (74 mg, 0.69 mmol) and Pd(dppf)Cl₂ (17 mg, 0.02 mmol) under a nitrogen atmosphere and the reaction mixture was stirred under a nitrogen atmosphere at 80°C overnight. The mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 31% EtOAc in PE) to give the title compound (41 mg, yield 64.5%) as a yellow solid. LC/MS (ESI) m/z: 275 (M+H)⁺. The ethyl 1-cyclopropyl-2-(2-fluorophenyl)-1H-imidazole-5-carboxylate was used to prepare Compound 586 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.66 - 8.62 (m, 1H), 8.41 (s, 1H), 7.76 (s, 1H), 7.65 - 7.58 (m, 2H), 7.42 - 7.35 (m, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.08 - 5.01 (m, 1H), 4.53 - 4.41 (m, 2H), 3.62 - 3.57 (m, 1H), 3.36 - 3.34 (m, 1H), 2.40 - 2.34 (m, 1H), 2.26 - 2.16 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H), 0.84 - 0.80 (m, 2H), 0.44 - 0.38 (m, 2H). LC/MS (ESI) m/z: 599 (M+H)⁺. RT (Method A): 1.25 min. Compound 587 was prepared according to the procedures above using ethyl 5-bromo-1H- imidazole-2-carboxylate as the starting material in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.11 (t, J = 5.7 Hz, 1H), 8.90 (s, 1H), 8.42 (s, 1H), 8.09 - 8.03 (m, 1H), 7.70 (d, J = 3.4 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.32 - 7.26 (m, 1H), 7.14 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.07 (d, J = 9.3 Hz, 1H), 4.55 - 4.42 (m, 2H), 4.16 - 4.10 (m, 1H), 3.31 - 3.27 (m, 1H), 2.41 - 2.35 (m, 1H), 2.26 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H), 1.15 - 1.09 (m, 4H). LC/MS (ESI) m/z: 599 (M+H)⁺. RT (Method A): 1.88 min. Scheme 185. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2- cyclopentylpyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine- 6-carboxamide (Compound 588) Step1: Ethyl 2-(cyclopent-1-en-1-yl)pyrimidine-5-carboxylate To a mixture of ethyl 2-chloropyrimidine-5-carboxylate (310 mg, 1.7 mmol) and cyclopent-1-en-1- ylboronic acid (281 mg, 2.5 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl2 (124 mg, 0.17 mmol) and Na₂CO₃ (540 mg, 5.1 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 80°C for 3 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (80 mg, yield 18.9%) as an orange solid. LC/MS (ESI) m/z: 219 (M+H)⁺. Step 2: Ethyl 2-cyclopentylpyrimidine-5-carboxylate To a solution of ethyl 2-(cyclopent-1-en-1-yl)pyrimidine-5-carboxylate (211 mg, 0.98 mmol) in EtOAc (5 mL) was added PtO₂ (13 mg, 0.05 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 10% - 95% MeCN in water with 0.1% NH₃.H2O) to give the title compound (55.0 mg, yield 25.5%) as a white solid. LC/MS (ESI) m/z: 221 (M+H)⁺. The ethyl 2-cyclopentylpyrimidine-5-carboxylate was used to produce Compound 588 as a yellow solid based on the procedures set forth in, e.g., Scheme 60. ¹H NMR (400 MHz, DMSO-d₆) ) δ 10.02 (s, 1H), 9.16 - 9.05 (m, 3H), 8.61 (s, 1H), 8.40 (s, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 9.2 Hz, 1H), 4.53 - 4.40 (m, 2H), 3.51 - 3.45 (m, 1H), 2.54 - 2.51 (m, 1H), 2.39 - 2.32 (m, 1H), 2.26 - 2.17 (m, 1H), 2.09 - 2.00 (m, 2H), 1.92 - 1.82 (m, 2H), 1.82 - 1.73 (m, 2H), 1.71 - 1.61 (m, 2H), 1.30 (d, J = 5.8 Hz, 3H). LC/MS (ESI) m/z: 545 (M+H)⁺. RT (Method A): 1.29 min. Scheme 186. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2- cyclohexylpyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 589) Step1: Ethyl 2-(cyclohex-1-en-1-yl)pyrimidine-5-carboxylate To a mixture of ethyl 2-chloropyrimidine-5-carboxylate (300 mg, 1.61 mmol) and cyclohex-1-en-1- ylboronic acid (405 mg, 3.22 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added Pd(dppf)Cl2 (118 mg, 0.16 mmol) and Na₂CO₃ (512 mg, 4.83 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 80 °C for 5 hours. The reaction mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (170 mg, yield 45.5%) as an orange solid. LC/MS (ESI) m/z: 233 (M+H)⁺. Step 2: Ethyl 2-cyclohexylpyrimidine-5-carboxylate To a solution of ethyl 2-(cyclohex-1-en-1-yl)pyrimidine-5-carboxylate (170 mg, 0.73 mmol) in EtOAc (5 mL) was added Pd/C (17 mg) under a nitrogen atmosphere. The mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 12 hours. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (100 mg, yield 58.5%) as a white solid. LC/MS (ESI) m/z: 235 (M+H)⁺. The ethyl 2-cyclohexylpyrimidine-5-carboxylate was used to produce Compound 589 as a white solid based on the procedures set forth in, e.g., Scheme 60. ¹H NMR (400 MHz, DMSO-d₆) ) δ 10.02 (s, 1H), 9.16 - 9.05 (m, 3H), 8.61 (s, 1H), 8.40 (s, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 9.2 Hz, 1H), 4.53 - 4.40 (m, 2H), 3.51 - 3.45 (m, 1H), 2.54 - 2.51 (m, 1H), 2.39 - 2.32 (m, 1H), 2.26 - 2.17 (m, 1H), 2.09 - 2.00 (m, 2H), 1.92 - 1.82 (m, 2H), 1.82 - 1.73 (m, 2H), 1.71 - 1.61 (m, 2H), 1.30 (d, J = 5.8 Hz, 3H). LC/MS (ESI) m/z: 545 (M+H)⁺..¹H NMR (400 MHz, DMSO-d₆) ) δ 10.04 (s, 1H), 9.14 (s, 2H), 9.12 - 9.07 (m, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 8.3 Hz, 1H), 4.53 - 4.41 (m, 2H), 3.38 - 3.35 (m, 1H), 2.93 - 2.86 (m, 1H), 2.39 - 2.33 (m, 1H), 2.26 - 2.18 (m, 1H), 1.97 - 1.93 (m, 2H), 1.82 - 1.77 (m, 2H), 1.73 - 1.69 (m, 1H), 1.62 - 1.55 (m, 2H), 1.46 - 1.33 (m, 3H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 559 (M+H)⁺. Scheme 187. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (2-(pyridin-2-yl)thiomorpholino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 591) Step 1: 2-Nitro-1-(pyridin-2-yl)ethan-1-ol To a solution of picolinaldehyde (10 g, 93.45 mmol) in DCM (100 mL) was added nitromethane (6.84 g, 112.2 mmol) and TMG (21.49 g, 186.9 mmol), the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (15 g, yield 86.52%) as a brown oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 169 (M+H)⁺. Step 2: (E)-2-(2-Nitrovinyl)pyridine To a solution of 2-nitro-1-(pyridin-2-yl)ethan-1-ol (15 g, 89.3 mmol) in DCM (100 mL) was added TEA (18.1 g, 178.6 mmol) and acetyl chloride (10.51 g, 133.9 mmol) dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 hours. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (4.1 g, yield 29.8%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J = 4.2 Hz, 1H), 7.95 (d, J = 13.2 Hz, 1H), 7.85 (d, J = 13.2 Hz, 1H), 7.72 (td, J = 7.7, 1.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.31 (m, 1H). Step 3: Ethyl 2-((2-nitro-1-(pyridin-2-yl)ethyl)thio)acetate To a mixture of (E)-2-(2-nitrovinyl)pyridine (2 g, 13.33 mmol) and R,R-TUC (550 mg, 1.33 mmol) in DCM (40 mL) was added ethyl 2-mercaptoacetate (1.91 g, 15.99 mmol) dropwise at -60 °C under a nitrogen atmosphere and the mixture was stirred at -60°C for 2 hours. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (4 g, crude) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 271 (M+H)⁺. Step 4: 6-(Pyridin-2-yl)thiomorpholin-3-one To a solution of ethyl 2-((2-nitro-1-(pyridin-2-yl)ethyl)thio)acetate (4 g, 14.8 mmol) in EtOH/water (45 mL, v/v= 2/1) was added NH4Cl (3.14 g, 59.3 mmol) and Fe (6.64 g, 118.5 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 45 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (1.1 g, yield 38.3%) as a yellow oil. LC/MS (ESI) m/z: 195 (M+H)⁺. Step 5: 2-(Pyridin-2-yl)thiomorpholine To a solution of 6-(pyridin-2-yl)thiomorpholin-3-one (1 g, 5.15 mmol) in THF (15 mL) was added LiAlH₄ (6.2 mL, 15.45 mmol, 2.5 M in THF) under a nitrogen atmosphere at 0 °C and the mixture was stirred at 0°C for 1 hour. The mixture was quenched with water (0.62 mL), 15% aq. NaOH solution (0.62 mL) and water (1.8 mL) successively at 0 °C and dried over anhydrous Na2SO4. The mixture was filtered, and the filter cake was washed EtOAc twice. The filtrate was concentrated under reduced pressure to dryness and the residue was purified by flash column chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (750 mg, yield 71.4 %) as a yellow oil. LC/MS (ESI) (m/z): 181 (M+H)⁺. The 2-(pyridin-2-yl)thiomorpholine was used to prepare Compound 591 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.52 (s, 1H), 8.38 (d, J = 7.9 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.49 (s, 2H), 7.34 – 7.28 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 6.8 Hz, 1H), 5.84 (s, 2H), 4.96 – 4.79 (m, 1H), 4.53 – 4.35 (m, 2H), 4.30 – 4.24 (m, 1H), 4.06 – 3.95 (m, 1H), 3.84 – 3.73 (m, 1H), 3.25 – 3.12 (m, 2H), 3.04 – 2.91 (m, 2H), 2.74 (d, J = 12.8 Hz, 1H), 2.38 – 2.24 (m, 1H), 2.20 – 1.98 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 534 (M+H)⁺. RT (Method A): 0.89 min. Scheme 188. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(2- methyl-6-phenoxynicotinamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 593) Step 1: Methyl 2-methyl-6-phenoxynicotinate To a mixture of methyl 6-chloro-2-methylnicotinate (200 mg, 1.00 mmol) and phenol (150 mg, 1.59 mmol) in DMF (6 mL) was added K2CO3 (207 mg, 1.5 mmol) under a nitrogen atmosphere and the reaction mixture was stirred under a nitrogen atmosphere at 60°C for 3 hours. The mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (75 mg, yield 30.8%) as a yellow solid. LC/MS (ESI) m/z: 244 (M+H)⁺. The methyl 2-methyl-6-phenoxynicotinate was used to prepare Compound 593 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.65 (s, 1H), 9.09 (t, J = 5.8 Hz, 1H), 8.64 (s, 1H), 8.40 (d, J = 0.7 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.27 - 7.21 (m, 1H), 7.18 - 7.13 (m, 2H), 7.11 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.07 - 4.99 (m, 1H), 4.52 - 4.38 (m, 2H), 3.31 - 3.28 (m, 1H), 2.43 (s, 3H), 2.39 - 2.33 (m, 1H), 2.24 - 2.14 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 582 (M+H)⁺. RT (Method A): 1.48 min. Scheme 189. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((1S,3R)-3-(2- fluorophenoxy)cyclopentane-1-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 594) Step 1: Methyl (S)-3-oxocyclopentane-1-carboxylate To a solution of (S)-3-oxocyclopentane-1-carboxylic acid (1.0 g, 7.81 mmol) in DCM (20 mL) and MeOH (2 mL) was added TMSCHN2 (5.1 mL, 10.2 mmol, 2M in Hexanes) under a nitrogen atmosphere at 0 °C and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.0 g, yield 90.1%) as a white solid. LC/MS (ESI) m/z: 143 (M+H)⁺. Step 2: Methyl (1S)-3-hydroxycyclopentane-1-carboxylate To a solution of methyl (S)-3-oxocyclopentane-1-carboxylate (900 mg, 6.33 mmol) in THF (10 mL) was added NaBH₄ (264 mg, 6.96 mmol) under a nitrogen atmosphere at 0 °C and the reaction mixture was then stirred at room temperature for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give title compound (660 mg, yield 72.3%) as a white solid. LC/MS (ESI) (m/z): 145 (M+H)⁺. Step 3: Methyl (1S,3R)-3-(2-fluorophenoxy)cyclopentane-1-carboxylate To a mixture of methyl (1S)-3-hydroxycyclopentane-1-carboxylate (400 mg, 2.78 mmol), 2- fluorophenol (467 mg, 4.16 mmol) and PPh₃ (1.09 g, 4.16 mmol) in THF (5 mL) was added DIAD (842 mg, 4.16 mmol) under a nitrogen atmosphere at 0 °C and the reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (60 mg, yield 9.1%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 7.08 – 7.00 (m, 2H), 6.95 – 6.85 (m, 2H), 4.82 – 4.78 (m, 1H), 3.69 (s, 3H), 2.90 – 2.79 (m, 1H), 2.36 – 2.23 (m, 2H), 2.21 – 2.14 (m, 1H), 2.10 – 2.03 (m, 1H), 2.01 – 1.85 (m, 2H). LC/MS (ESI) m/z: 239 (M+H)⁺. The methyl (1S,3R)-3-(2-fluorophenoxy)cyclopentane-1-carboxylate was used to prepare Compound 594 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.06 (t, J = 5.8 Hz, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 7.21 – 7.16 (m, 1H), 7.14 – 7.08 (m, 3H), 6.95 – 6.89 (m, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.00 (d, J = 8.8 Hz, 1H), 5.01 - 4.86 (s, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.28 – 3.24 (m, 1H), 3.17 – 3.11 (m, 1H), 2.43 – 2.31 (m, 2H), 2.20 – 2.12 (m, 1H), 1.94 – 1.85 (m, 5H), 1.26 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 577 (M+H)⁺. RT (Method A): 1.62 min. The following compounds were prepared according to the procedures above starting from Step 3. ^a Step 4 was performed with TFA in DCM. Scheme 190. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-((R)-3- hydroxypyrrolidin-1-yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a Step 1: Methyl (R)-2-(3-hydroxypyrrolidin-1-yl)pyrimidine-5-carboxylate TEA (0.73 mL, 5.2 mmol) was added to a stirred suspension of methyl 2-chloro-pyrimidine-5- carboxylate (300mg, 1.74 mmol) and (3R)-pyrrolidin-3-ol hydrochloride (270mg, 2.18 mmol) in dry THF (8 mL). The reaction was flushed with nitrogen and then capped and stirred overnight at room temperature. The reaction was poured into water and extracted 3x with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a white solid (380 mg, 98%), which was used in the next step without further purification. LC/MS (ESI) m/z: 223.63 (M+H)⁺. Step 2: (R)-2-(3-Hydroxypyrrolidin-1-yl)pyrimidine-5-carboxylic acid LiOH monohydrate (214 mg, 5.1 mmol) was added as a solid to a solution of methyl 2-[(3R)-3- hydroxypyrrolidin-1-yl]pyrimidine-5-carboxylate (380 mg, 1.70 mmol) in a mixture of THF (6 mL), MeOH (2 mL) and water (2 mL) at room temperature. The reaction was stirred at room temperature overnight at which time complete consumption of the ester was observed. The reaction was acidified to pH 3 with 2N HCl, diluted with brine and extracted 5x with EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated to give the desired product as a white solid (316 mg, 89%), which was used without further purification. LC/MS (ESI) m/z: 209.56 (M+H)⁺. Step 3: tert-Butyl (6S,8R)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate A suspension of tert-butyl (6S,8R)-3-amino-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo-[1,2-a]- pyrimidine-6-carboxylate (160mg, 0.60mmol) and 2-[(3R)-3-hydroxypyrrolidin-1-yl]-pyrimidine-5-carboxylic acid (130 mg, 0.62 mmol) in dry ACN (6mL) was flushed with nitrogen and then stirred at 0 °C. TCFH (391 mg, 1.37 mmol, 2.2eq) was added and the mixture was stirred for 2 mins at 0 °C. A solution of N- methylimidazole (0.13 mL, 2.6 eq) in dry ACN (1 mL) was added dropwise to the reaction, and then the reaction was stirred at 0 °C for 15 mins and then allowed to warm to room temperature and stirred overnight. The reaction was poured into water and extracted with DCM (3x). The combined organic phase was washed with saturated NaHCO₃ solution, then saturated NH₄Cl solution, then brine, dried over MgSO₄, filtered, and concentrated in vacuo. The reaction was purified on silica cartridge chromatography, eluting with 0-20% MeOH in DCM, to afford the desired product as a white foam (186 mg, 66%). LC/MS (ESI) m/z: 456.9 (M+H)⁺. Step 4: (6S,8R)-3-(2-((R)-3-Hydroxypyrrolidin-1-yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid TFA (5mL) was added to a stirred solution of tert-butyl (6S,8R)-3-[[2-[(3R)-3-hydroxy-pyrrolidin-1- yl]pyrimidine-5-carbonyl]amino]-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]-pyrimidine-6-carboxylate (115mg, 0.244 mmol) in dry DCM (10mL) at room temperature. The reaction was stirred for 4 hours, and monitored by LC/MS, until all the t-Bu ester starting material had been consumed. The reaction was concentrated in vacuo to dryness, and then azeotroped 5x with MeOH and then 2x with DCM, to give the desired product as a colorless glass (168 mg), which was used without further purification. LC/MS (ESI) m/z: 401 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-((R)-3-hydroxy-pyrrolidin-1- yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 596) HATU (233 mg, 0.60 mmol) was added as a solid to a 0 °C suspension of (6S,8R)-3-[[2-[(3R)-3- hydroxypyrrolidin-1-yl]pyrimidine-5-carbonyl]amino]-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid (120 mg, 0.30 mmol), and 2-(aminomethyl)thieno[3,2-c]pyridin-6-amine dihydrochloride (152 mg, 0.6 mmol) in DMF (3 mL). TEA (0.13 mL, 0.93 mmol) was added, and the reaction was stirred at 0 °C for 25 mins, at which time LC/MS showed the complete consumption of the carboxylic acid starting material. The reaction was quenched at 0 °C with 3-4 drops of water, and then filtered through a syringe filter into a small test tube (with a 1mL DMF rinse). The reaction mixture was purified by prep-HPLC, eluting with 5-50% ACN in water. Clean fractions were combined, concentrated, and then lyophilized overnight to give Compound 596 as a white solid (8 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H, NH), 9.21 (t, J = 6.0 Hz, 1H, NH), 8.85 (s, 2H), 8.56 (s, 2H), 7.37 (s, 1H), 7.31 - 7.17 (m, 2H), 5.05 (d, J = 8.5 Hz, 1H), 4.62 – 4.47 (m, 2H), 4.41 (s, 1H), 3.68 (t, J = 9.3 Hz , 1H), 3.63 – 3.48 (m, 3H), 3.00 – 2.86 (m, 3H), 2.37 (t, J = 10.5 Hz, 1H), 2.25 (q, J = 10.5 Hz, 1H), 2.04 (m, 1H), 1.93 (m, 1H) and 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 562.14 (M+H)⁺. RT (Method A): 0.68 min. The following compounds were prepared according to the procedures above using the appropriate amines and coupling partners in Step 1.

^a Step 1 was carried out overnight at 90 °C in DMF. ^b Step 1 was carried out overnight at 65 °C in DMF. ^c Step 1 was carried out overnight at 120 °C in DMF. Scheme 191. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(2-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 602) Step 1: tert-Butyl 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate To a mixture of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (3.0 g, 14.1 mmol) and oxetan-3-one (1.53 g, 21.2 mmol) in DCE (30 mL) was added NaBH(OAc)3 (4.48 g, 21.2 mmol) at room temperature and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (2.2 g, yield 58.0%) as a yellow solid. LC/MS (ESI) m/z: 269 (M+H)⁺. Step 2: 8-(Oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane To a solution of tert-butyl 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2.2 g, 8.2 mmol) in DCM (20 mL) was added TFA (10 mL) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was diluted with CHCl₃/i-PrOH (3/1, v/v), washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.1 g, yield 79.7%) as a yellow oil, which was used directly in the next reaction. LC/MS (ESI) (m/z): 169 (M+H)⁺. Step 3: 2-(8-(Oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carboxylic acid To a mixture of 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (300 mg, 1.78 mmol) and 2- chloropyrimidine-5-carboxylic acid (283 mg, 1.78 mmol) in 1,4-dioxane (5 mL) was added DIPEA (574 mg, 4.45 mmol) at room temperature and the mixture was stirred at 70°C for 12 hours. The mixture was cooled, acidified with 1N aq. HCl to pH~4 and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 – 95% MeCN in water with 0.1% NH₄HCO₃) to give the title compound (90 mg, yield 17.4%) as a white solid. LC/MS (ESI) m/z: 291 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,8R)-8-methyl-3-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo [3.2.1]octan-3-yl)pyrimidine- 5-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate To a mixture of 2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carboxylic acid (90 mg, 0.31 mmol) and tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)-carbamate (146 mg, 0.31 mmol) in MeCN (2 mL) was added NMI (76 mg, 0.93 mmol) and TCFH (261 mg, 0.93 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to give the title compound (80 mg, yield 34.7%) as a white solid. LC/MS (ESI) (m/z): 743 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(2-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrimidine-5-carboxamido)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 602) To a solution tert-butyl (2-(((6S,8R)-8-methyl-3-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo [3.2.1]-octan- 3-yl)pyrimidine-5-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (80 mg, 0.11 mmol) in DCM (1 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 602 (27.2 mg, yield 39.3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 9.08 (t, J = 5.8 Hz, 1H), 8.83 (s, 2H), 8.58 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.83 (s, 2H), 5.03 (d, J = 9.1 Hz, 1H), 4.62 – 4.56 (m, 2H), 4.53 – 4.41 (m, 2H), 4.41 – 4.34 (m, 4H), 3.67 – 3.58 (m, 1H), 3.39 – 3.32 (m, 1H), 3.23 – 3.19 (m, 2H), 3.13 (d, J = 12.0 Hz, 2H), 2.39 – 2.33 (m, 1H), 2.25 – 2.15 (m, 1H), 1.84 – 1.72 (m, 2H), 1.47 – 1.38 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 643 (M+H)⁺. RT (Method A): 0.57 min. Scheme 192. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(4-((3,3- difluorocyclohexyl)oxy)benzamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carboxamide (Compound 604) Step 1: 4-((3-Hydroxycyclohexyl)oxy)benzoic acid To a mixture of methyl 4-fluorobenzoate (2.0 g, 12.9 mmol) and cyclohexane-1,3-diol (3.0 g, 25.9 mmol) in DMA (20 mL) was added NaH (2.6 g, 64.5 mmol, 60% dispersion in mineral oil) in portions at 0 °C. After addition, the mixture was heated and stirred at 130 °C for 2 hours. The mixture was cooled, quenched with 1 N aq. HCl at 0 °C and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (2.5 g, yield 81.5%) as a yellow oil. LC/MS (ESI) m/z: 237 (M+H)⁺. Step 2: Methyl 4-((3-hydroxycyclohexyl)oxy)benzoate To a solution of 4-((3-hydroxycyclohexyl)oxy)benzoic acid (2.5 g, 10.6 mmol) in DMF (25 mL) was added K₂CO₃ (2.2 g, 15.9 mmol) and MeI (2.3 g, 15.9 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (1.2 g, yield 45.3%) as a yellow oil. LC/MS (ESI) m/z: 251 (M+H)⁺. Step 3: Methyl 4-((3-oxocyclohexyl)oxy)benzoate To a solution of methyl 4-((3-hydroxycyclohexyl)oxy)benzoate (500 mg, 2.00 mmol) in DCM (5 mL) was added DMP (1.70 g, 4.00 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (180 mg, yield 36.3%) as a yellow oil. LC/MS (ESI) m/z: 249 (M+H)⁺. Step 4: Methyl 4-((3,3-difluorocyclohexyl)oxy)benzoate To a solution of methyl 4-((3-oxocyclohexyl)oxy)benzoate (180 mg, 0.72 mmol) in DCM (3 mL) was added DAST (351 mg, 2.18 mmol) dropwise at 0°C and the reaction mixture was stirred at 40°C for 2 hours. The mixture was diluted with DCM, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (110 mg, yield 56.1%) as a yellow solid. LC/MS (ESI) m/z: 271 (M+H)⁺. The methyl 4-((3,3-difluorocyclohexyl)oxy)benzoate was used to prepare Compound 604 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.09 (t, J = 5.7 Hz, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.12 – 7.06 (m, 3H), 6.84 (s, 1H), 5.85 (s, 2H), 5.04 (d, J = 9.3 Hz, 1H), 4.74 – 4.59 (m, 1H), 4.53 – 4.41 (m, 2H), 3.39 – 3.34 (m, 1H), 2.43 – 2.33 (m, 2H), 2.26 – 2.00 (m, 4H), 1.91 – 1.75 (m, 2H), 1.63 – 1.48 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 609 (M+H)⁺. RT (Method A): 1.45 min. Scheme 193. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(6- cyclopropylpyridazine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine- 6-carboxamide (Compound 605) To a mixture of methyl 6-chloropyridazine-3-carboxylate (203 mg, 1.16 mmol) and cyclopropylboronic acid (200.4 mg, 2.33 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added K₂CO₃ (488 mg, 3.5 mmol) and Pd(dppf)Cl₂ (95 mg, 0.13 mmol) under a nitrogen atmosphere, and the mixture was degassed under a nitrogen atmosphere three times and stirred at 80°C for 2 hours. The reaction mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (150 mg, yield 72.8%) as a white solid. LC/MS (ESI) m/z: 179 (M+H)⁺. The methyl 6-cyclopropylpyridazine-3-carboxylate was then used to produce Compound 605 as a white solid based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.12 (s, 1H), 8.98 (s, 1H), 8.41 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.09 (d, J = 8.3 Hz, 1H), 4.51 - 4.46 (m, 2H), 2.55 - 2.53 (m, 1H), 2.42 - 2.38 (m, 2H), 2.24 - 2.19 (m, 1H), 1.31 (d, J = 2.7 Hz, 3H), 1.25 - 1.23 (m, 2H), 1.22 - 1.20 (m, 2H). LC/MS (ESI) m/z: 517 (M+H)⁺. RT (Method A): 1.16 min. Scheme 194. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-2,8- dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidin-3-yl)-3-(2-fluorophenyl)isoxazole-5- carboxamide (Compound 607) Step 1: Methyl (6S,8R)-3-((tert-Butoxycarbonyl)amino)-2,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-2-bromo-3-((tert-butoxycarbonyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (329 mg, 0.82 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (0.24 mL, 3.5 M in THF) in 1,4-dioxane (3 mL) and water (0.3 mL) was added K₂CO₃ (395 mg, 2.86 mmol) and Pd(dppf₂)Cl₂ (68 mg, 0.08 mmol) at 25 °C under a nitrogen atmosphere, the reaction mixture was degassed under a nitrogen atmosphere three times and stirred at 60 °C for 3 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (150 mg, yield 54.2%) as a yellow solid. LC/MS (ESI) m/z: 338 (M+H)⁺. Step 2: (6S,8R)-3-((tert-Butoxycarbonyl)amino)-2,8-dimethyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-3-((tert-butoxycarbonyl)amino)-2,8-dimethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (140 mg, 0.41 mmol) in THF/water (3 mL, v/v= 2/1) was added LiOH (19 mg, 0.82 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (100 mg, yield 74.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 324 (M+H)⁺. Step 3: (6S,8R)-3-Amino-2,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid hydrochloride To a solution of (6S,8R)-3-((tert-butoxycarbonyl)amino)-2,8-dimethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (90 mg, 0.28 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (70 mg, yield 96.6%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 224 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,8R)-3-amino-2,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (103 mg, 0.37 mmol) and (6S,8R)-3-amino-2,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6-carboxylic acid hydrochloride (70 mg, 0.27 mmol) in DMF (3 mL) was added DIPEA (52 mg, 0.4 mmol) and HATU (154 mg, 0.4 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) to give the title compound (122 mg, yield 99.4%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.35 (s, 1H), 8.17 (t, J = 5.7 Hz, 1H), 7.67 (s, 1H), 7.10 (s, 1H), 5.09 (d, J = 8.5 Hz, 1H), 4.71 - 4.53 (m, 2H), 3.51 - 3.39 (m, 1H), 3.09 - 3.03 (m, 1H), 2.26 (s, 3H), 1.94 - 1.82 (m, 1H), 1.36 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 485 (M+H)⁺. Step 5: tert-Butyl (2-(((6S,8R)-3-(3-(2-fluorophenyl)isoxazole-5-carboxamido)-2,8-dimethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-2,8-dimethyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (15 mg, 0.03 mmol) and 3-(2- fluorophenyl)isoxazole-5-carboxylic acid (13 mg, 0.06 mmol) in MeCN (1 mL) was added NMI (10 mg, 0.12 mmol) and TCFH (34 mg, 0.12 mmol) at 0 °C under a nitrogen atmosphere and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aq. NaHCO3 solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) to give the title compound (15 mg, yield 53.9%) as a yellow solid. LC/MS (ESI) (m/z): 674 (M+H)⁺. Step 6: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-2,8-dimethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(2-fluorophenyl)isoxazole-5-carboxamide (Compound 607) To a solution of tert-butyl (2-(((6S,8R)-3-(3-(2-fluorophenyl)isoxazole-5-carboxamido)-2,8- dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno-[3,2-c]pyridin-6- yl)carbamate (10 mg, 0.01 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 607 (5.0 mg, yield 50.7%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.07 (t, J = 5.5 Hz, 1H), 8.40 (s, 1H), 8.02 - 7.96 (m, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.66 - 7.61 (m, 1H), 7.50 - 7.44 (m, 1H), 7.43 - 7.38 (m, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 4.98 (d, J = 8.7 Hz, 1H), 4.53 - 4.39 (m, 2H), 3.38 - 3.32 (m, 1H), 2.37 - 2.32 (m, 1H), 2.26 - 2.18 (m, 4H), 1.31 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 574 (M+H)⁺. RT (Method A): 1.34 min. Scheme 195. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(3,3- difluorocyclohexyl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamide (Compound 608) Step 1: Ethyl 2-(3-oxocyclohexyl)pyrimidine-5-carboxylate To a solution of ethyl 2-(5-oxocyclohex-1-en-1-yl)pyrimidine-5-carboxylate (300 mg, 1.2 mmol) in EtOAc (5 mL) was added Pd/C (30 mg, 10% wt.), the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (290 mg, yield 95.9%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 249 (M+H)⁺. Step 2: Ethyl 2-(3,3-difluorocyclohexyl)pyrimidine-5-carboxylate To a solution of ethyl 2-(3-oxocyclohexyl)pyrimidine-5-carboxylate (290 mg, 1.16 mmol) in DCM (10 mL) was added DAST (941 mg, 5.84 mmol) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (120 mg, yield 38.2%) as a white solid. LC/MS (ESI) m/z: 271 (M+H)⁺. The ethyl 2-(3,3-difluorocyclohexyl)pyrimidine-5-carboxylate was used to prepare Compound 608 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 9.18 (s, 2H), 9.10 (t, J = 5.8 Hz, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.05 (d, J = 9.0 Hz, 1H), 4.55 - 4.39 (m, 2H), 3.39 - 3.33 (m, 1H), 3.25 - 3.09 (m, 1H), 2.42 - 2.32 (m, 2H), 2.29 - 2.13 (m, 2H), 2.11 - 2.00 (m, 2H), 1.97 - 1.75 (m, 2H), 1.72 - 1.46 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 595 (M+H)⁺. RT (Method A): 1.37 min. Scheme 196. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((1S,2S)-2- (benzo[d]oxazol-2-yl)cyclopropane-1-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 611) Step 1: Ethyl (1S,2S)-2-((benzyloxy)methyl)cyclopropane-1-carboxylate To a solution of NaH (5.9 g, 0.146 mol, 60% dispersion in mineral oil) in toluene (300 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (32.8 g, 0.146 mol) under a nitrogen atmosphere at 0 °C and the mixture was stirred at room temperature for 1 hour. Afterwards, to the reaction mixture was added (S)- 2-((benzyloxy)methyl)oxirane (20.0 g, 0.12 mol) and the resulting mixture was heated and stirred at 110 °C for 16 hours. The mixture was cooled, quenched with saturated aq. NH4Cl solution, and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (12 g, yield 42.6%) as a colorless oil. LC/MS (ESI) m/z: 235 (M+H)⁺. Step 2: Ethyl (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate To a solution of ethyl (1S,2S)-2-((benzyloxy)methyl)cyclopropane-1-carboxylate (12 g, 0.051 mol) in EtOH (120 mL) was added Pd/C (1.0 g, 10% wt.), the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (6 g, yield 81.2%) as a colorless oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 145 (M+H)⁺. Step 3: (1S,2S)-2-(Ethoxycarbonyl)cyclopropane-1-carboxylic acid To a mixture of ethyl (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (5 g, 34.48 mmol), TEMPO (536 mg, 3.44 mmol), NaH2PO4 (6.6 g, 55.17 mmol) and Na2HPO4 (7.8 g, 55.17 mmol) in MeCN (50 mL) was added a mixture of aq. NaClO solution (0.5 mL, 5% w.t.) and NaClO₂ (6.2 g, 68.96 mmol) in water (25 mL) at 0 °C and the reaction mixture was then stirred at room temperature for 18 hours. The mixture was quenched with saturated aq. Na2CO3 solution and washed with EtOAc twice. The aqueous phase was acidified with 6N aq. HCl solution to pH~3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (3.1 g, yield 56.6%) as a colorless oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 159 (M+H)⁺. Step 4: Ethyl (1S,2S)-2-((2-bromophenyl)carbamoyl)cyclopropane-1-carboxylate To a mixture of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (200 mg, 1.3 mmol) and 2-bromoaniline (215 mg, 1.3 mmol) in DMF (2 mL) was added DIPEA (504 mg, 3.9 mmol) and HATU (642 mg, 1.69 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (60 mg, yield 14.8%) as a white solid. LC/MS (ESI) m/z: 312 (M+H)⁺. Step 5: Ethyl (1S,2S)-2-(benzo[d]oxazol-2-yl)cyclopropane-1-carboxylate To a mixture of ethyl (1S,2S)-2-((2-bromophenyl)carbamoyl)cyclopropane-1-carboxylate (60 mg, 0.19 mmol) and Cs2CO3 (186 mg, 0.57 mmol) in DME (3 mL) was added o-phenanthroline (7 mg, 0.038 mmol) and CuI (7 mg, 0.038 mmol) under a nitrogen atmosphere, the reaction mixture was degassed under a nitrogen atmosphere three times and stirred at 80 °C overnight. The mixture was cooled, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (13 mg, yield 29.5%) as a white solid. LC/MS (ESI) m/z: 232 (M+H)⁺. The ethyl (1S,2S)-2-(benzo[d]oxazol-2-yl)cyclopropane-1-carboxylate was used to prepare Compound 611 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.06 (t, J = 5.9 Hz, 1H), 8.72 (s, 1H), 8.40 (s, 1H), 7.68 - 7.65 (m, 2H), 7.37 - 7.33 (m, 2H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 8.4 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.29 - 3.26 (m, 1H), 3.09 - 3.03 (m, 1H), 2.63 - 2.58 (m, 1H), 2.35 - 2.31 (m, 1H), 2.22 - 2.14 (m, 1H), 1.65 (t, J = 7.4 Hz, 2H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 556 (M+H)⁺. RT (Method A): 1.33 min. The following compounds were prepared based on the procedures above starting from Step 4, using the appropriate amines as the starting materials. ^a The first amide coupling reaction was performed in the presence of TCFH, NMI, and MeCN. ^b The deprotection step was performed with HCl/1,4-dioxane in DCM. ^c The cyclization step was carried out in the presence of Lawesson’s Reagent in toluene under a nitrogen atmosphere at 100 °C for 16 hours. Scheme 197. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((1S,2S)-2- (benzo[d]thiazol-2-yl)cyclopropane-1-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 613) Step 1: Ethyl (1S,2S)-2-((2-fluorophenyl)carbamoyl)cyclopropane-1-carboxylate To a mixture of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (150 mg, 0.95 mmol) and 2-fluoroaniline (115 mg, 1.04 mmol) in MeCN (3 mL) was added NMI (233 mg, 2.85 mmol) and TCFH (798 mg, 2.85 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (110 mg, yield 46.2%) as a white solid. LC/MS (ESI) m/z: 252 (M+H)⁺. Step 2: Ethyl (1S,2S)-2-((2-fluorophenyl)carbamothioyl)cyclopropane-1-carboxylate To a solution of ethyl (1S,2S)-2-((2-fluorophenyl)carbamoyl)cyclopropane-1-carboxylate (100 mg, 0.40 mmol) in toluene (3 mL) was added Lawesson's Reagent (323 mg, 0.80 mmol) and the resulting mixture was stirred at 100 °C for 3 hours. The mixture was cooled, quenched with saturated aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (100 mg, yield 93.6%) as a yellow solid. LC/MS (ESI) m/z: 268 (M+H)⁺. Step 3: Ethyl (1S,2S)-2-(benzo[d]thiazol-2-yl)cyclopropane-1-carboxylate To a solution of ethyl (1S,2S)-2-((2-fluorophenyl)carbamothioyl)cyclopropane-1-carboxylate (100 mg, 0.37 mmol) in DMF (2 mL) was added Cs2CO3 (244 mg, 0.75 mmol). The mixture was stirred at 100 °C for 16 hours. The mixture was cooled, quenched with saturated aq. NH4Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 20% EtOAc in PE) to give title compound (50 mg, yield 54.7%) as a yellow oil. LC/MS (ESI) m/z: 248 (M+H)⁺. The ethyl (1S,2S)-2-(benzo[d]thiazol-2-yl)cyclopropane-1-carboxylate was used to prepare Compound 613 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.06 (t, J = 5.9 Hz, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 8.9 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.29 - 3.26 (m, 1H), 3.11 - 3.06 (m, 1H), 2.91 - 2.87 (m, 1H), 2.36 - 2.32 (m, 1H), 2.20 - 2.12 (m, 1H), 1.70 - 1.64 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 572 (M+H)⁺. RT (Method A): 1.43 min. Scheme 198. Synthesis of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((5-(2- fluorophenyl)-1,2,4-oxadiazol-3-yl)amino)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 614) Step 1: 2-Fluoro-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide To a mixture of 5-methyl-1,2,4-oxadiazol-3-amine (800 mg, 8.1 mmol) and 2-fluorobenzoyl chloride (1.95 g, 12.3 mmol) in toluene (12 mL) was added pyridine (1.92 g, 24.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1.2 g, yield 66.8%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 222 (M+H)⁺. Step 2: 5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-amine To a solution of 2-fluoro-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (1.2 g, 5.43 mmol) in EtOH (3 mL) was added HCl/EtOH (9 mL, 6M). The reaction mixture was stirred at 80 °C for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (903 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 180 (M+H)⁺. The 5-(2-fluorophenyl)-1,2,4-oxadiazol-3-amine was used to prepare Compound 614 based on the procedures set forth in, e.g., Scheme 14.¹HNMR (400 MHz, DMSO-d₆) δ 9.09 (t, J = 5.8 Hz, 1H), 9.05 (s, 1H), 8.42 (s, 1H), 8.39 (s, 1H), 8.14 - 8.08 (m, 1H), 7.81 - 7.74 (m, 1H), 7.57 - 7.50 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 8.3 Hz, 1H), 4.53 - 4.42 (m, 2H), 2.54 - 2.52 (m, 1H), 2.39 - 2.33 (m, 1H), 2.24 - 2.15 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 533 (M+H)⁺. RT (Method A): 1.46 min. Scheme 199. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((5-(pyridin-2-yl)isoxazol-3-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 616) Step 1: 5-(Pyridin-2-yl)isoxazol-3-amine To a solution of 3-oxo-3-(pyridin-2-yl)propanenitrile (200 mg, 1.4 mmol) in 1,4-dioxane (2 mL) and water (2 mL) was added hydroxylamine hydrochloride (94 mg, 1.4 mmol) and NaOH (71 mg, 1.8 mmol) and the mixture was stirred at 100°C for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (170 mg, yield 77.1%) as a yellow solid. LC/MS (ESI) m/z: 162 (M+H)⁺. The 5-(pyridin-2-yl)isoxazol-3-amine was used to prepare Compound 616 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.65 (s, 1H), 9.08 (t, J = 5.8 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.97 – 7.93 (m, 2H), 7.52 – 7.48 (m, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 6.14 (s, 1H), 5.84 (s, 2H), 5.05 (d, J = 8.5 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H), 3.29 – 3.25 (m, 1H), 2.39 – 2.33 (m, 1H), 2.24 – 2.16 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 515 (M+H)⁺. Scheme 200. Synthesis of N-((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(5-methyl-pyridin-3-yl)isoxazole-5- carboxamide (Compound 618) Step 1: 5-Methylnicotinaldehyde oxime To a solution of 5-methylnicotinaldehyde (1.00 g, 8.26 mmol) in MeOH (5 mL) was added hydroxylamine hydrochloride (855 mg, 12.40 mmol) at room temperature and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (1.09 g, yield 97.1%) as a white solid. LC/MS (ESI) m/z: 137 (M+H)⁺. Step 2: Ethyl 3-(5-methylpyridin-3-yl)isoxazole-5-carboxylate To a mixture of 5-methylnicotinaldehyde oxime (1.09 g, 8.02 mmol) and ethyl propiolate (1.18 g, 12.0 mmol) in MeCN (5 mL) and water (5 mL) was added (diacetoxyiodo)benzene (3.10 g, 9.63 mmol) at room temperature and the mixture was at room temperature for 1 hour. The mixture was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (95 mg, yield 5.1%) as a white solid. LC/MS (ESI) m/z: 233 (M+H)⁺. The ethyl 3-(5-methylpyridin-3-yl)isoxazole-5-carboxylate was then used to prepare Compound 618 as a white solid following, e.g., Steps 4-6 in Scheme 162..¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 9.12 (t, J = 5.8 Hz, 1H), 8.95 (d, J = 1.4 Hz, 1H), 8.70 - 8.47 (m, 2H), 8.42 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.12 (s, 1H), 6.85 (s, 1H), 5.86 (s, 2H), 5.07 (d, J = 8.9 Hz, 1H), 4.54 - 4.43 (m, 2H), 3.40 - 3.37 (m, 1H), 2.41 (s, 3H), 2.39 - 2.35 (m, 1H), 2.28 - 2.20 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 557 (M+H)⁺. RT (Method A): 1.16 min. The following compounds were prepared according to the procedures above, using the appropriate aldehydes and alkynes as the starting materials.

^a Step 4 was performed with TFA in DCM. Scheme 201. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(3-chloropyridin-2-yl)-1,2,4- oxadiazole-3-carboxamide (Compound 625) Step 1: 3-Chloropicolinoyl chloride To a mixture of 3-chloropicolinic acid (10 g, 63.47 mmol) and DMF (10 drops) in DCM (110 mL) was added SOCl2 (18.88 g, 158.69 mmol) dropwise at 0 °C and the mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (11 g, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 176 (M+H)⁺. Step 2: Ethyl (Z)-2-(3-chloropicolinamido)-2-(hydroxyimino)acetate To a mixture of 3-chloropicolinoyl chloride (10.66 g, 60.55 mmol) and DIPEA (19.56 g, 151.35 mmol) in DCM (110 mL) was added a solution of ethyl (Z)-2-amino-2-(hydroxyimino)acetate (4 g, 30.28 mmol) in DCM (40 mL) dropwise at 0 °C and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (8 g, crude) as a brown oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 272 (M+H)⁺. Step 3: Ethyl 5-(3-chloropyridin-2-yl)-1,2,4-oxadiazole-3-carboxylate A solution of ethyl (Z)-2-(3-chloropicolinamido)-2-(hydroxyimino)acetate (8 g, 29.45 mmol) in NMP (50 mL) was stirred at 100°C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 5 - 63% EtOAc in PE) to give the title compound (800 mg, yield 10.7%) as a colorless oil. LC/MS (ESI) (m/z): 254 (M+H)⁺. The ethyl 5-(3-chloropyridin-2-yl)-1,2,4-oxadiazole-3-carboxylate was used to prepare Compound 625 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 1H), 9.11 (t, J = 5.7 Hz, 1H), 8.85 - 8.83 (m, 1H), 8.79 (s, 1H), 8.41 (s, 1H), 8.33 - 8.30 (m, 1H), 7.83 - 7.80 (m, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.09 - 5.05 (m, 1H), 4.53 - 4.45 (m, 2H), 3.39 - 3.37 (m, 1H), 2.41 - 2.36 (m, 1H), 2.26 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 578 (M+H)⁺. RT (Method A): 1.31 min. Scheme 202. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3S,5R)-5- hydroxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 627) Step 1: Methyl (3S,5R)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperidine-3- carboxylate To a solution of methyl (3S,5R)-5-((tert-butyldiphenylsilyl)oxy)piperidine-3-carboxylate (100 mg, 0.25 mmol) and 2-chloro-5-methyl-1,3,4-thiadiazole (68 mg, 0.51 mmol) in DMF (2 mL) was added DIPEA (98 mg, 0.76 mmol) and the mixture was stirred at 100 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 10 - 69% EtOAc in PE) to give the title compound (13 mg, yield 10.4 %) as a white solid. LC/MS (ESI) m/z: 496 (M+H)⁺. Step 2: Lithium (3S,5R)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3- carboxylate To a solution of methyl (3S,5R)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2- yl)piperidine-3-carboxylate (13 mg, 0.03 mmol) in THF/water (2 mL, v/v= 2/1) was added LiOH (2 mg, 0.08 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (13 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 482 (M+H)⁺. Step 3: tert-Butyl (2-(((6S,8R)-3-((3S,5R)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2- yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (10 mg, 0.02 mmol) and lithium (3S,5R)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-piperidine-3-carboxylate (13 mg, 0.03 mmol) in MeCN (1 mL) was added NMI (7 mg, 0.08 mmol) and TCFH (12 mg, 0.04 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CHCl₃/i-PrOH (3/1, v/v), washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (12 mg, yield 60.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 934 (M+H)⁺. Step 4: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3S,5R)-5-((tert-butyl-diphenylsilyl)oxy)-1- (5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide A solution of tert-butyl (2-(((6S,8R)-3-((3S,5R)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4- thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (12 mg, 0.01 mmol) in DCM (0.5 mL) and TFA (0.5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (12 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 834 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3S,5R)-5-hydroxy-1-(5-methyl-1,3,4- thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 627) To a solution of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3S,5R)-5-((tert- butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (8 mg, 0.01 mmol) in DMF (0.5 mL) was added CsF (15 mg, 0.10 mmol) and the mixture was stirred at 30 °C overnight. The mixture was filtered, and filtrate was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 627 (1.4 mg, yield 24.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 9.07 (t, J = 5.7 Hz, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.22 (d, J = 4.8 Hz, 1H), 5.05 – 4.99 (m, 1H), 4.46 (d, J = 5.9 Hz, 2H), 3.86 - 3.78 (m, 2H), 3.61 - 3.54 (m, 1H), 3.36 - 3.35 (m, 1H), 3.30 (s, 3H), 3.14 - 3.03 (m, 2H), 2.83 - 2.76 (m, 1H), 2.35 - 2.32 (m, 1H), 2.21 - 2.12 (m, 2H), 1.51 - 1.44 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 596 (M+H)⁺. Scheme 203. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-chloro-pyridin-2-yl)-1,2,4- oxadiazole-5-carboxamide (Compound 644) Step 1: (Z)-3-Chloro-N'-hydroxypicolinimidamide To a solution of 3-chloropicolinonitrile (5 g, 36.2 mmol) in EtOH (50 mL) was added hydroxylamine hydrochloride (3.0 g, 43.5 mmol) and TEA (7.3 g, 72.4 mmol), and the reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (3.1 g, yield 50.1%) as a white solid. LC/MS (ESI) m/z: 172 (M+H)⁺. Step 2: Methyl 3-(3-chloropyridin-2-yl)-1,2,4-oxadiazole-5-carboxylate To a solution of (Z)-3-chloro-N'-hydroxypicolinimidamide (1.5 g, 8.77 mmol) in MeCN (50 mL) was added methyl 2-chloro-2-oxoacetate (1.6 g, 13.2 mmol) and TEA (1.77 g, 17.54 mmol) and the reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (1.1 g, yield 52.4%) as a white solid. LC/MS (ESI) m/z: 240 (M+H)⁺. The methyl 3-(3-chloropyridin-2-yl)-1,2,4-oxadiazole-5-carboxylate was used to prepare Compound 644 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (t, J = 5.8 Hz, 1H), 8.79 (d, J = 4.6, 1.3 Hz, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 8.26 (d, J = 8.3, 1.3 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.60 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 9.0 Hz, 1H), 4.54 - 4.41 (m, 2H), 3.41 - 3.35 (m, 1H), 2.41 - 2.34 (m, 1H), 2.26 - 2.17 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 578 (M+H)⁺. RT (Method A): 1.49 min. Compound 684 was prepared according to the procedures above, using 3-methylpicolinonitrile as the tarting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (t, J = 5.7 Hz, 1H), 8.69 (s, 1H), 8.63 (d, J = 3.6 Hz, 1H), 8.41 (s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.56 (dd, J = 7.8, 4.6 Hz, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 6.05 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.9 Hz, 1H), 4.52 – 4.44 (m, 2H), 3.22 – 3.11 (m, 1H), 2.55 (s, 3H), 2.40 – 2.34 (m, 1H), 2.25 – 2.17 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 558 (M+H)⁺. RT (Method A): 1.33 min. Scheme 204. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3S,5S)-5- hydroxy-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 645) Step1: Lithium (3R,5S)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3- carboxylate To a solution of methyl (3R,5S)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2- yl)piperidine-3-carboxylate (15 mg, 0.03 mmol) in THF (1 mL) and water (0.5 mL) was added LiOH (2 mg, 0.08 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to dryness to give the title compound (15 mg, crude) as a white solid, which was used directly in the next reaction without purification. LC/MS (ESI) m/z: 482 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-3-((3S,5S)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2- yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.04 mmol) and lithium (3R,5S)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3-carboxylate (15 mg, 0.06 mmol) in MeCN (1 mL) was added NMI (14 mg, 0.17 mmol) and TCFH (24 mg, 0.08 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to give the title compound (25 mg, yield 48.4%) as a yellow solid. LC/MS (ESI) (m/z): 934 (M+H)⁺. Step 3: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3R,5S)-5-((tert-butyl-diphenylsilyl)oxy)-1- (5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide A solution of tert-butyl (2-(((6S,8R)-3-((3S,5S)-5-((tert-butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4- thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (25 mg, 0.03 mmol) in DCM (0.5 mL) and TFA (0.5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (22 mg, crude) as a white solid, which was used directly in the next reaction without purification. LC/MS (ESI) m/z: 834 (M+H)⁺. Step 4: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3S,5S)-5-hydroxy-1-(5-methyl-1,3,4- thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 645) To a solution of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3R,5S)-5-((tert- butyldiphenylsilyl)oxy)-1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (22 mg, 0.03 mmol) in DMF (1 mL) was added CsF (9 mg, 0.06 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 645 (3.6 mg, yield 23.0%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.55 (s, 1H), 9.13 (t, J = 7.6 Hz, 1H), 8.70 (s, 1H), 8.49 (s, 1H), 7.21 – 7.11 (m, 2H), 6.96 – 6.33 (m, 2H), 5.21 (s, 1H), 5.02 (d, J = 9.0 Hz, 1H), 4.49 (d, J = 6.1 Hz, 2H), 3.87 – 3.84 (m, 1H), 3.83 – 3.82 (m, 1H), 3.61 – 3.54 (m, 2H), 3.46 – 3.42 (m, 1H), 3.27 – 3.25 (m, 1H), 3.13 – 3.04 (m, 2H), 2.82 – 2.75 (m, 1H), 2.67 (s, 3H), 2.19 – 2.12 (m, 2H), 1.27 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 596 (M+H)⁺. RT (Method A): 1.13 min. Scheme 205. Synthesis of N-((6S,8R)-6-(((6-aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(4-hydroxypiperidin-1-yl)-1,3,4- thiadiazole-2-carboxamide (Compound 647) Step 1: Ethyl 5-(4-hydroxypiperidin-1-yl)-1,3,4-thiadiazole-2-carboxylate TEA (1.2 mL, 8.6 mmol) was added to a stirred suspension of ethyl 5-bromo-1,3,4-thiadiazole-2- carboxylate (1.0 g, 4.21 mmol) and 4-hydroxypiperidine (640 mg, 6.42 mmol) in dry ACN (12 mL). The reaction was flushed with nitrogen and then capped and stirred at 50 °C for 2 hours. The reaction was cooled to room temperature and then poured into saturated NH₄Cl solution and extracted 3x with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification on silica gel column, eluting with 20-100% EtOAc in hexanes gave the desired product as a white solid (1.0 g, 92%). LC/MS (ESI) m/z: 258.08 (M+H)⁺. Step 2: Lithium 5-(4-hydroxypiperidin-1-yl)-1,3,4-thiadiazole-2-carboxylate LiOH monohydrate (240 mg, 5.72 mmol) was added as a solid to a solution ethyl 5-(4- hydroxypiperidin-1-yl)-1,3,4-thiadiazole-2-carboxylate (1.0 g, 3.92 mmol) in a mixture of THF (20 mL), MeOH (3 mL) and water (3 mL) at room temperature. The reaction was stirred at room temperature for 3 hours at which time complete consumption of the ester was observed by LC/MS. The reaction mixture was dried until almost complete dryness, and then diluted with water (5 mL), frozen and lyophilized overnight to give the desired product as a white solid (905 mg, 99%) which was used without further purification. LC/MS (ESI) m/z: 236 (M+H)⁺. The lithium 5-(4-hydroxypiperidin-1-yl)-1,3,4-thiadiazole-2-carboxylate was then used to prepare Compound 647 following the procedures set forth in, e.g., Scheme 22.¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (br s, 1H), 9.10 (t, J = 5.0 Hz, 1H), 8.73 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.85 (s, 1H), 5.83 (s, 2H), 5.06 (d, J = 9.3 Hz, 1H), 4.86 (s, 1H), 4.47 (m, 2H), 3.81 (m, 3H), 3.42 (m, 2H), 3.34 (m, 1H), 2.37 (m, 1H), 2.20 (m, 1H), 1.86 (m, 2H), 1.52 (m, 2H) and 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 582.30 (M+H)⁺. Scheme 206. Synthesis of (6S,8R)-N-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (5-pyrrolidine-1-carbonyl)nicotinamido)-4,6,7,8-tetrahydropyrrolo-[1,2-a]-pyrimidine-6-carboxamide (Compound 648) Step 1: Methyl 5-(pyrrolidine-1-carbonyl)nicotinate A solution of 5-methoxycarbonylpyridine-3-carboxylic acid (300mg, 1.66 mmol) and pyrrolidine (130mg, 1.83 mmol) in dry DMF (4 mL) was cooled to 0 °C and stirred under a dry a nitrogen atmosphere. HATU (693 mg, 1.83 mmol) and Hunig’s base (0.9 mL, 3.0 eq) were added, and the reaction was stirred at 0 °C for 30 mins and then allowed to warm to room temperature overnight. The reaction was diluted with DCM, and then washed with saturated NH4Cl solution (2x), brine (3x), dried over MgSO4, filtered, and concentrated in vacuo to give a dark brown oil, which was passed through a pad of silica gel, eluting with 10% MeOH in DCM to give the desired product as a pale brown oil (312 mg, 80%). LC/MS (ESI) m/z: 234.56 (M+H)⁺. Step 2: 5-(Pyrrolidine-1-carbonyl)nicotinic acid LiOH monohydrate (112mg, 2.7 mmol) was added to a solution of Methyl 5-(pyrrolidine-1- carbonyl)nicotinate (312 mg, 1.33 mmol) in a mixture of THF (4 mL), MeOH, (1 mL) and water (1mL). The reaction was capped and stirred overnight at room temperature, at which time LC/MS showed complete consumption of the methyl ester starting material. The reaction was adjusted to pH 5 with 2N HCl, and then concentrated and then lyophilized overnight to give a pale brown powder (330 mg). LC/MS (ESI) m/z: 220.8 (M+H)⁺. The 5-(pyrrolidine-1-carbonyl)nicotinic acid was then used to prepare Compound 648 following the procedures set forth in, e.g., Scheme 3.¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (br s, 1H), 9.09 (m, 2H), 8.89 (s, 1H), 8.57 (s, 1H), 8.40 (s, 2H), 7.10 (s, 1H), 6.83 (s, 1H), 5.83 (s, 2H), 5.05 (d, J = 9.3 Hz, 1H), 4.47 (m, 2H), 3.51 (t, d = 6.9 Hz, 2H), 3.43 (t, J = 6.9 Hz, 2H), 3.34 (m, 1H), 2.36 (m, 1H), 2.22 (m, 1H), 1.92-1.79 (m, 4H) and 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 573.13 (M+H)⁺. RT (Method A): 1.15 min. Compound 649 was prepared according to the procedures set forth above, using (R)-3- (hydroxymethyl)pyrrolidine as the amine in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (br s, 1H), 9.10 (m, 2H), 8.88 (s, 1H), 8.57 (s, 1H), 8.41 (s, 2H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.05 (d, J = 9.3 Hz, 1H), 4.75-4.64 (m, 1H), 4.47 (m, 2H), 3.61 (m, 1H), 3.47 (m, 3H), 3.35 (m, 1H), 3.24 (m, 1H), 2.36 (m, 2H), 2.22 (m, 1H), 1.93 (m, 1H), 1.68 (m, 1H) and 1.31 (d, J = 6.8 Hz, 3H). LC/MS (ESI) m/z: 603.59 (M+H)⁺. RT (Method A): 0.90 min. Scheme 207. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(6-(3,3- difluorocyclo-butoxy)nicotinamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 650) Step 1: tert-Butyl 6-(3,3-difluorocyclobutoxy)pyridine-3-carboxylate In a pre-dried two-necked flask, 3,3-difluorocyclobutanol (2 g, 18.50 mmol) was dissolved in 1,4- dioxane (20 mL, 234.3 mmol) under a nitrogen atmosphere, and cooled to 0 °C. Potassium tert-butoxide (0.6 g, 5 mmol) was added into the flask at 0 °C. After 0.5 hours, tert-butyl 6-fluoro-pyridine-3-carboxylate (0.4 g, 2 mmol) was added, and the reaction was stirred at 0 °C for 2 hours. The reaction was quenched with the addition of 30 mL saturated NH4Cl solution and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and the solvents were removed on vacuo. The crude residue was purified by flash column chromatography eluting with 10% EtOAc in hexanes, to afford the desired product, tert-butyl 6-(3,3-difluorocyclobutoxy)pyridine-3-carboxylate (270 mg, 50% Yield). LC/MS (ESI) m/z: 286.3 (M+H)⁺. Step 2: 6-(3,3-Difluorocyclobutoxy)pyridine-3-carboxylic acid Trifluoroacetic acid (3 mL, 39.7 mmol) was added to a stirred solution of tert-butyl 6-(3,3- difluorocyclobutoxy)pyridine-3-carboxylate (270 mg, 0.95 mmol) in dry dichloromethane (6 mL) at room temperature. The reaction was stirred for 4 hours until all the t-Bu ester starting material had been consumed. The reaction was concentrated in vacuo to dryness, and then azeotroped 5x with MeOH and then 2x with DCM to give an orange oil. The mixture was purified on silica gel eluting with 0-50% EtOAc in hexane (1% AcOH modifier) to provide 6-(3,3-difluorocyclo-butoxy)pyridine-3-carboxylic acid (193 mg, 89% Yield). LC/MS (ESI) m/z: 230 (M+H)⁺. The 6-(3,3-difluorocyclobutoxy)pyridine-3-carboxylic acid was used to prepare Compound 650 based on the procedures set forth in, e.g., Scheme 3.¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (t, J = 5.9 Hz, 1H), 8.81 (s, 1H), 8.71 (s, 1H), 8.34 (s, 1H), 7.04 (s, 1H), 6.78 (s, 1H), 5.77 (s, 2H), 4.95 (d, J = 9.3 Hz, 1H), 4.39 (t, J = 5.9 Hz, 2H), 4.06 (t, J = 11.1 Hz, 2H), 3.29 (d, J = 10.4 Hz, 1H), 3.21 (s, 1H), 2.95 (d, J = 8.5 Hz, 1H), 2.35 – 2.25 (m, 1H), 2.05 (td, J = 27.9, 13.7 Hz, 4H), 1.73 – 1.57 (m, 3H), 1.20 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 582.12 (M+H)⁺. RT (Method A): 1.68 min. Scheme 208. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((S)-1-(3,3- difluorocyclo-butyl)pyrrolidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]- pyrimidine-6-carboxamide (Compound 659) Step 1: Methyl (3S)-1-(3,3-difluorocyclobutyl)pyrrolidine-3-carboxylate A mixture of methyl (3S)-pyrrolidine-3-carboxylate (0.150 g, 1.16 mmol) and 3,3-difluoro- cyclobutanone (106 mg, 1.0 mmol) in 4 mL MeOH were added to a 20 mL vial. A solution of sodium cyanoborohydride (0.125 g, 1.99 mmol) in MeOH (1 mL) was added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with TFA, neutralized with saturated NaHCO₃ solution, and extracted with EtOAc (3x 15 mL). The organic layers were combined, concentrated, and purified using silica gel column, eluting with 0-20 MeOH in DCM to afford the desired product (101 mg, 49% Yield). LC/MS (ESI) m/z: 220.2 (M+H)⁺. Step 2: (3S)-1-(3,3-Difluorocyclobutyl)pyrrolidine-3-carboxylic acid A 25.0 mL round bottom was used to combine the (3S)-1-(3,3-difluorocyclobutyl)pyrrolidine-3- carboxylic acid (101 mg, 0.49 mmol) and hydrochloric acid (3M, 3.5 mL, 10.5 mmol) The reaction was heated to reflux for 2 hours. The reaction was then cooled and evaporated off in vacuo to afford (3S)-1- (3,3-difluorocyclobutyl)pyrrolidine-3-carboxylic acid (101 mg, 100% Yield). LC/MS (ESI) m/z: 206.2 (M+H)⁺. The (3S)-1-(3,3-difluorocyclobutyl)pyrrolidine-3-carboxylic acid was used to prepare Compound 659 based on the procedures set forth in, e.g., Scheme 3.¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 9.05 (t, J = 6.1 Hz, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.10 (d, J = 8.9 Hz, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 9.4 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.26 (t, J = 10.0 Hz, 2H), 2.84 (s, 1H), 2.71 (dd, J = 18.5, 9.7 Hz, 3H), 2.59 – 2.52 (m, 2H), 2.34 (t, J = 10.7 Hz, 1H), 2.15 (q, J = 11.1 Hz, 1H), 2.05 (d, J = 17.2 Hz, 1H), 1.97 – 1.86 (m, 1H), 1.43 (d, J = 7.6 Hz, 1H), 1.26 (d, J = 7.1 Hz, 3H). LC/MS (ESI) m/z: 557.34 (M+H)⁺. RT (Method A): 0.58 min. Compound 660 was prepared according to the procedures above, using 4,4-difluorocyclohexan- 1-one as the starting material in Step 1.¹H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.98 (t, J = 6.1 Hz, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.76 (s, 1H), 5.77 (s, 2H), 4.94 (d, J = 9.3 Hz, 1H), 4.39 (s, 2H), 3.15 (d, J = 38.7 Hz, 2H), 2.76 – 2.46 (m, 5H), 2.35 – 2.18 (m, 2H), 2.09 (t, J = 11.0 Hz, 1H), 1.95 (s, 3H), 1.78 (d, J = 36.4 Hz, 4H), 1.52 (s, 2H), 1.19 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 586.77 (M+H)⁺. RT (Method A): 0.87 min. Scheme 209. Synthesis of (6S,8R)-N-[(6-Aminothieno[3,2-c]pyridin-2-yl)methyl]-3-[[4-(4,4-difluoro- cyclohexen-1-yl)benzoyl]amino]-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 665) Step 1. Ethyl 4-(4,4-difluorocyclohexen-1-yl)benzoate A mixture of (4-ethoxycarbonylphenyl)boronic acid (0.80 g, 4.12 mmol), 1-bromo-4,4- difluorocyclohexene (1.0 g, 5.076 mmol), Pd(PPh₃)₂dppf.DCM (0.30 g, 0.36 mmol), Cs₂CO₃ (3.0 g, 9.2 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was stirred at 100 °C for 16 hours. The reaction was filtered through a Celite pad. The filter-cake was washed with water and EtOAc, diluted with water and EtOAc. The two layers were separated, and the aqueous layer was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. Purification by Combi Flash: 24g column, solvent A=DCM, solvent B=MeOH, 100% A to 5% B gave ethyl 4-(4,4-difluorocyclohexen-1-yl)benzoate (0.79 g, 72% Yield). LC/MS (ESI) m/z: 267 (M+H)⁺. Step 2.4-(4,4-Difluorocyclohexen-1-yl)benzoic acid To a solution of ethyl 4-(4,4-difluoro-cyclohexen-1-yl)benzoate (0.20 g, 0.75 mmol) in MeOH (3.0 mL) was added NaOH (1 M, 0.75 mL, 0.75 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was then concentrated to remove MeOH and then diluted with EtOAc. The pH was adjusted to pH 1 using 1 N HCl. The two layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to give 4-(4,4-difluorocyclohexen-1-yl)benzoic acid (155 mg, 86.6% Yield) as a brown solid, which was used in the next step without further purification. LC/MS (ESI) m/z: 239 (M+H)⁺. The 4-(4,4-difluorocyclohexen-1-yl)benzoic acid was used to prepare Compound 665 based on the procedures set forth in, e.g., Scheme 3. LC/MS (ESI) m/z: 591 (M+H)⁺. RT (Method A)): 1.72 min. Scheme 210. Synthesis of (6S,8R)-N-[(6-Aminothieno[3,2-c]pyridin-2-yl)methyl]-3-[[4-(4,4-difluoro- cyclohexyl)-benzoyl]amino]-8-methyl-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 666) To a solution of Compound 665 (5.0 mg, 0.0085 mmol) in MeOH (2 mL) was added 5% Pd/C (0.0018 g, 5 mass%, 0.1 equiv.). The flask was evacuated and then backfilled with hydrogen in a balloon. The reaction was stirred at room temperature overnight and then filtered through a Celite pad. The filtrate was concentrated in vacuo to give Compound 666 (4.9 mg, 98% Yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.02 (t, J = 5.9 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.04 (s, 1H), 6.77 (s, 1H), 5.76 (d, J = 6.6 Hz, 2H), 4.98 (d, J = 9.3 Hz, 1H), 4.40 (qd, J = 15.8, 5.3 Hz, 2H), 2.85 (s, 1H), 2.73 (t, J = 12.4 Hz, 1H), 2.43 (s, 3H), 2.30 (dd, J = 13.0, 8.4 Hz, 1H), 2.14 (q, J = 11.3 Hz, 1H), 2.05 (s, 1H), 2.04 – 1.93 (m, 1H), 1.83 (d, J = 14.6 Hz, 2H), 1.63 (q, J = 12.6 Hz, 2H), 1.23 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 593 (M+H)⁺. RT (Method A): 1.78 min. Scheme 211. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(4,4- difluorocyclohexyl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamide (Compound 671) Step 1: Methyl 2-(4,4-difluorocyclohex-1-en-1-yl)pyrimidine-5-carboxylate To a mixture of methyl 2-chloropyrimidine-5-carboxylate (1.0 g, 5.8 mmol) and 2-(4,4- difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.8 g, 11.6 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl2 (420 mg, 0.58 mmol) and K2CO3 (2.01 g, 14.5 mmol) under a nitrogen atmosphere and the mixture was stirred at 100 °C for 3 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (640 mg, yield 43.5%) as a white solid. LC/MS (ESI) m/z: 255 (M+H)⁺. Step 2: Methyl 2-(4,4-difluorocyclohexyl)pyrimidine-5-carboxylate To a mixture of methyl 2-(4,4-difluorocyclohex-1-en-1-yl)pyrimidine-5-carboxylate (500 mg, 1.96 mmol) in EtOAc (10 mL) was added Pd/C (50 mg, 10% wt.), the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at 25°C for 2 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (400 mg, yield 81.5%) as a white solid. which was used directly in the next step without further purification. LC/MS (ESI) m/z: 257 (M+H)⁺. The methyl 2-(4,4-difluorocyclohexyl)pyrimidine-5-carboxylate was used to prepare Compound 671 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.17 (s, 2H), 9.10 (t, J = 5.8 Hz, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.05 (d, J = 9.2 Hz, 1H), 4.58 – 4.28 (m, 2H), 3.31 – 3.24 (m, 1H), 3.17 – 3.05 (m, 1H), 2.42 – 2.31 (m, 1H), 2.28 – 2.18 (m, 1H), 2.13 – 2.05 (m, 4H), 2.02 – 1.77 (m, 4H), 1.31 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 595 (M+H)⁺. RT (Method A): 1.32 min. Scheme 212. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(2,2- difluorocyclopropyl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamide (Compound 672) Step 1: Methyl 2-vinylpyrimidine-5-carboxylate To a mixture of methyl 2-chloropyrimidine-5-carboxylate (1.0 g, 5.79 mmol) and potassium trifluoro(vinyl)borate (1.55 g, 11.6 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl₂ (424 mg, 0.58 mmol) and K2CO3 (2.4 g, 17.4 mmol) under a nitrogen atmosphere and the mixture was stirred at 100 °C for 16 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (600 mg, yield 63.2%) as a white solid. LC/MS (ESI) m/z: 165 (M+H)⁺. Step 2: Methyl 2-(2,2-difluorocyclopropyl)pyrimidine-5-carboxylate To a solution of methyl 2-vinylpyrimidine-5-carboxylate (500 mg, 3.05 mmol) in THF (10 mL) was added NaI (457 mg, 3.05 mmol) and TMSCF3 (5 mL) under a nitrogen atmosphere at room temperature and the mixture was stirred at 100 °C for 16 hours. The mixture was concentrated under reduced pressure to dryness, the residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (300 mg, yield 46.1%) as a brown solid. LC/MS (ESI) m/z: 215 (M+H)⁺. The methyl 2-(2,2-difluorocyclopropyl)pyrimidine-5-carboxylate was used to prepare Compound 672 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.17 (s, 2H), 9.10 (t, J = 5.8 Hz, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.05 (d, J = 8.8 Hz, 1H), 4.53 – 4.42 (m, 2H), 3.40 – 3.33 (m, 2H), 2.42 – 2.33 (m, 2H), 2.26 – 2.17 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 553 (M+H)⁺. RT (Method A): 1.08 min. Scheme 213. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(4- hydroxycyclohexyl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo--[1,2- a]pyrimidine-6 Step 1: Ethyl 2-(4-hydroxycyclohexyl)pyrimidine-5-carboxylate To a solution of ethyl 2-(4-oxocyclohexyl)pyrimidine-5-carboxylate (40 mg, 0.16 mmol) in THF (1 mL) was added NaBH4 (7 mg, 0.19 mmol) under a nitrogen atmosphere at 0 °C and the mixture was stirred at 0 °C for 1 hour. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (PE: EtOAc= 2: 1) to give the title compound (37 mg, yield 92.3%) as a white solid. LC/MS (ESI) (m/z): 251 (M+H)⁺. The ethyl 2-(4-hydroxycyclohexyl)pyrimidine-5-carboxylate was then used to prepare Compound 674 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.13 (s, 2H), 9.12 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 7.13 (s, 1H), 6.94 (s, 1H), 6.13 (s, 2H), 5.05 (d, J = 8.7 Hz, 1H), 4.60 (s, 1H), 4.53 - 4.42 (m, 2H), 3.46 (s, 2H), 2.82 (t, J = 7.6 Hz, 1H), 2.39 - 2.34 (m, 1H), 2.26 - 2.18 (m, 1H), 1.98 - 1.92 (m, 4H), 1.68 - 1.58 (m, 2H), 1.34 - 1.28 (m, 5H). LC/MS (ESI) (m/z): 575 _(M+H) ⁺ _{. RT (Method A): 0.87 min.} Scheme 214. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(4,4- difluoropiperidin-1-yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 674) Step 1: Methyl 2-(4,4-difluoropiperidin-1-yl)pyrimidine-5-carboxylate To a mixture of methyl 2-chloropyrimidine-5-carboxylate (1 g, 5.81 mmol) and 4,4- difluoropiperidine (1.5 g, 8.7 mmol) in 1,4-dioxane (20 mL) was added DIPEA (3.72 g, 29.05 mmol) under a nitrogen atmosphere and the mixture was stirred at 70 °C for 1 hour. The mixture was cooled and then diluted with EtOAc, washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (640 mg, yield 40.2%) as a white solid. LC/MS (ESI) m/z: 258 (M+H)⁺. The methyl 2-(4,4-difluoropiperidin-1-yl)pyrimidine-5-carboxylate was used to prepare Compound 674 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.09 (t, J = 5.7 Hz, 1H), 8.90 (s, 2H), 8.57 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.04 (d, J = 9.0 Hz, 1H), 4.59 – 4.30 (m, 2H), 4.10 – 3.91 (m, 4H), 3.29 – 3.24 (m, 1H), 2.41 – 2.31 (m, 1H), 2.26 – 2.14 (m, 1H), 2.11 – 1.95 (m, 4H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 596 (M+H)⁺. RT (Method A: 1.37 min. Scheme 215. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(5-(2- fluorophenyl)-1,3,4-thiadiazol-2-yl)acetamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamide (Compound 675) Step 1: tert-Butyl 2-(2-fluorobenzoyl)hydrazine-1-carboxylate To a mixture of 2-fluorobenzoic acid (20.0 g, 142.8 mmol) and tert-butyl hydrazine-carboxylate (28.3 g, 214.2 mmol) in DMF (200 mL) was added DIPEA (55.3 g, 428.4 mmol) and HATU (65.1 g, 171.4 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (27 g, yield 74.4%) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 255 (M+H)⁺. Step 2: tert-Butyl 2-(2-fluorophenylcarbonothioyl)hydrazine-1-carboxylate To a mixture of tert-butyl 2-(2-fluorobenzoyl)hydrazine-1-carboxylate (5.0 g, 19.7 mmol) in THF (50 mL) was added Lawesson's reagent (11.9 g, 41.2 mmol) and the reaction mixture was stirred at 45°C for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 23% EtOAc in PE) to give the title compound (880 mg, yield 16.6%) as a yellow solid. LC/MS (ESI) m/z: 271 (M+H)⁺. Step 3: 2-Fluorobenzothiohydrazide hydrochloride To a solution of tert-butyl 2-(2-fluorophenylcarbonothioyl)hydrazine-1-carboxylate (880 mg, 3.26 mmol) in DCM (8 mL) was added HCl in 1,4-dioxane (2 mL, 4 M) and the reaction mixture was stirred at room temperature overnight. The mixture was filtered to give the title compound (550 mg, yield 99.3%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 171 (M+H)⁺. Step 4: Ethyl 2-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)acetate To a mixture of 2-fluorobenzothiohydrazide hydrochloride (500 mg, 2.94 mmol) and ethyl 3,3,3- trifluoropropanoate (505 mg, 3.23 mmol) in EtOH (6 mL) was added Na₂CO₃ (623 mg, 5.88 mmol), and the reaction mixture was stirred at 80 °C overnight. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (360 mg, yield 46.0%) as a yellow solid. LC/MS (ESI) m/z: 267 (M+H)⁺. The ethyl 2-(5-(2-fluorophenyl)-1,3,4-thiadiazol-2-yl)acetate was used to prepare Compound 675 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.08 (t, J = 5.9 Hz, 1H), 8.73 (s, 1H), 8.41 (s, 1H), 8.29 - 8.24 (m, 1H), 7.67 - 7.62 (m, 1H), 7.52 - 7.47 (m, 1H), 7.45 - 7.41 (m, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.06 - 5.01 (m, 1H), 4.57 (s, 2H), 4.47 (d, J = 5.7 Hz, 2H), 3.34 - 3.33 (m, 1H), 2.38 - 2.34 (m, 1H), 2.22 - 2.16 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 591 (M+H)⁺. RT (Method A): 1.39 min. Scheme 216. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((3-phenyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-yl)amino)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 677) Step 1: (Z)-N-hydroxybenzimidoyl chloride To a solution of (E)-benzaldehyde oxime (10.0 g, 82.5 mmol) in DMF (100 mL) was added NCS (11.6 g, 86.7 mmol) at room temperature and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (10.8 g, yield 84.3%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 – 7.52 (m, 1H), 2.62 – 2.54 (m, 2H), 2.46 – 2.41 (m, 2H), 2.02 – 1.90 (m, 2H). LC/MS (ESI) m/z: 156 (M+H)⁺. Step 2: 3-Phenyl-5,6-dihydrobenzo[d]isoxazol-7(4H)-one To a solution of (Z)-N-hydroxybenzimidoyl chloride (9.65 g, 62.0 mmol) in THF (100 mL) was added 2-bromocyclohex-2-en-1-one (10.7 g, 62.0 mmol) and TEA (7.44 g, 74.4 mmol) at room temperature and the mixture was stirred at 70°C for 3 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (3.8 g, yield 28.7%) as a white solid.¹H NMR (400 MHz, CDCl3) δ 7.79 – 7.71 (m, 2H), 7.53 – 7.48 (m, 3H), 3.01 – 2.92 (m, 2H), 2.77 – 2.66 (m, 2H), 2.33 – 2.23 (m, 2H). LC/MS (ESI) m/z: 214 (M+H)⁺. Step 3: N-(2,4-Dimethoxybenzyl)-3-phenyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-amine To a mixture of 3-phenyl-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (500 mg, 2.35 mmol) and (2,4- dimethoxyphenyl) methanamine (471 mg, 2.82 mmol) in THF (20 mL) was added Ti(i-PrO)₄ (2.68 g, 11.8 mmol) at room temperature and the mixture was stirred at 60°C for 16 hours. The mixture was cooled down to room temperature and diluted with EtOH (10 mL). NaBH4 (179 mg, 4.7 mmol) was added to the above mixture in small portions, and the resulting mixture was stirred at 0 °C for 1 hour. The mixture was quenched with ice-water and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (720 mg, yield 84.1%) as a yellow oil. LC/MS (ESI) m/z: 365 (M+H)⁺. Step 4: 3-Phenyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-amine A solution of methyl N-(2,4-dimethoxybenzyl)-3-phenyl-4,5,6,7-tetrahydrobenzo [d]isoxazol-7- amine (720 mg, 2.0 mmol) in TFA (3 mL) was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure to dryness. The residue was neutralized with ammonia pH to 7~8 and purified by reversed phase chromatography (C₁₈, 0 – 100% MeCN in Water) to give the title compound (380 mg, yield 88.7%) as a white solid. LC/MS (ESI) m/z: 215 (M+H)⁺. The 3-phenyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-amine was used to prepare Compound 677 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.07 – 8.98 (m, 1H), 8.40 (d, J = 3.0 Hz, 1H), 7.76 – 7.71 (m, 2H), 7.55 – 7.50 (m, 3H), 7.38 (d, J = 15.2 Hz, 1H), 7.10 (s, 1H), 6.83 (d, J = 2.4 Hz, 1H), 5.83 (d, J = 3.0 Hz, 2H), 5.44 – 5.36 (m, 1H), 5.02 – 4.88 (m, 1H), 4.81 (s, 1H), 4.51 – 4.40 (m, 2H), 3.24 – 3.19 (m, 1H), 2.69 – 2.60 (m, 2H), 2.35 – 2.30 (m, 1H), 2.18 – 2.03 (m, 2H), 1.99 – 1.91 (m, 2H), 1.83 – 1.74 (m, 1H), 1.27 – 1.23 (m, 3H). LC/MS (ESI) m/z: 568 (M+H)⁺. RT (Method A): 1.68 min. Scheme 217. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-(2- fluorophenyl)piperidin-4-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 678) Step 1: 8-(2-Fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane To a mixture of 1,4-dioxa-8-azaspiro[4.5]decane (12 g, 84 mmol), 1-bromo-2-fluorobenzene (22 g, 126 mmol), BINAP (3.1 g, 5 mmol) and t-BuONa (16 g, 168 mmol) in toluene (100 mL) was added Pd2(dba)3 (2.3 g, 2.5 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 90°C for 1 hour. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (10 g, yield 50.2%) as a yellow solid. LC/MS (ESI) m/z: 238 (M+H)⁺. Step 2: 1-(2-Fluorophenyl)piperidin-4-one To a solution of 8-(2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (10 g, 42 mmol), in acetone (100 mL) and water (100 mL) was added TsOH (10 g, 58 mmol) under a nitrogen atmosphere and the reaction mixture was stirred under a nitrogen atmosphere at 90 °C for 16 hours. The mixture was basified with 0.5 M aq. NaOH solution to pH~8 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (8 g, yield 98.6%) as a white solid. LC/MS (ESI) m/z: 194 (M+H)⁺. Step 3: 1-(2-Fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate To a solution of 1-(2-fluorophenyl)piperidin-4-one (5.0 g, 25.9 mmol) in THF (70 mL) was added a solution of LiHMDS (31 mL, 31 mmol, 1 M in THF) dropwise at -78°C and the mixture was stirred at -78°C for 1 hour. Afterwards, a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methane- sulfonamide (11.1 g, 31.1 mmol) in THF (70 mL) was added to the mixture dropwise at -78°C for 1 hour. The reaction mixture was stirred at -78 °C for 2 hours under a nitrogen atmosphere. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (2.5 g, yield 29.8%) as a white solid. LC/MS (ESI) m/z: 326 (M+H)⁺. Step 4: 1-(2-Fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine To a mixture of 1-(2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (2.5 g, 7.7 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.9 g, 19.2 mmol) in 1,4-dioxane (40 mL) was added KOAc (2.3 g, 23.1 mmol) and Pd(dppf)Cl2 (562 mg, 0.8 mmol) under a nitrogen atmosphere, the reaction mixture was degassed under a nitrogen atmosphere three times and stirred at 90 °C for 1 hour. The mixture was cooled and then diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (1.0 g, yield 42.9%) as a white solid. LC/MS (ESI) m/z: 304 (M+H)⁺. Step 5: Methyl (6S,8R)-3-(1-(2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of 1-(2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine (316 mg, 1.0 mmol) and methyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (300 mg, 1.0 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was added K₂CO₃ (433 mg, 3.1 mmol) and Pd(dppf)Cl₂ (76 mg, 0.1 mmol) under a nitrogen atmosphere, the reaction mixture was degassed under a nitrogen atmosphere three times and stirred at 40 °C for 5 hours. The mixture was cooled and then diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (100 mg, yield 25%) as a white solid. LC/MS (ESI) m/z: 384 (M+H)⁺. Step 6: Methyl (6S,8R)-3-(1-(2-fluorophenyl)piperidin-4-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate To a solution of methyl (6S,8R)-3-(1-(2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-methyl-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (30 mg, 0.08 mmol) in EtOAc (5 mL) was added Pd/C (5 mg, 10% w.t.), the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 4 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (28 mg, yield 92.7%) as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 386 (M+H)⁺. Step 7: (6S,8R)-3-(1-(2-fluorophenyl)piperidin-4-yl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-3-(1-(2-fluorophenyl)piperidin-4-yl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (25 mg, 0.06 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (3 mg, 0.13 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (20 mg, yield 83.3%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 372 (M+H)⁺. Step 8: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-(2-fluorophenyl) piperidin-4-yl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 678) To a mixture of (6S,8R)-3-(1-(2-fluorophenyl)piperidin-4-yl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (20 mg, 0.05 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-Amine hydrochloride (17 mg, 0.08 mmol) in DMF (3 mL) was added DIPEA (35 mg, 0.27 mmol) and T3P (51 mg, 0.08 mmol, 50% w.t. in EtOAc) and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aq. NaHCO3 solution and extracted with CHCl3/i- PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 678 (2.2 mg, yield 7.7%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (t, J = 5.9 Hz, 1H), 8.40 (s, 1H), 7.87 (s, 1H), 7.14 - 7.07 (m, 4H), 6.99 - 6.94 (m, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 4.97 (d, J = 9.2 Hz, 1H), 4.54 - 4.39 (m, 2H), 3.45 - 3.39 (m, 2H), 3.29 - 3.26 (m, 1H), 2.76 - 2.68 (m, 3H), 2.34 - 2.29 (m, 1H), 2.18 - 2.11 (m, 1H), 1.87 - 1.80 (m, 3H), 1.79 - 1.70 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 533 (M+H)⁺. RT (Method A): 1.45 min. Scheme 218. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(4-(8- (oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzamido)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 679) Step 1: Methyl 4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzoate To a solution of 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (1.5 g, 11.6 mmol) in toluene (20 mL) was added methyl 4-bromobenzoate (5 g, 23.3 mmol), Pd₂(dba)₃ (1 g, 1.16 mmol), RuPhos (518 mg, 1.16 mmol), and Cs₂CO₃ (11.3 g, 34.8 mmol), the mixture was degassed under a nitrogen atmosphere three times and stirred at 100 °C for 16 hours. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (650 mg, yield 18.5%) as a yellow oil. LC/MS (ESI) m/z: 303 (M+H)⁺. The methyl 4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzoate was used to prepare Compound 679 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (t, J = 5.8 Hz, 1H), 9.01 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.11 (s, 1H), 6.91 - 6.83 (m, 3H), 5.85 (s, 2H), 5.04 (d, J = 8.8 Hz, 1H), 4.60 (t, J = 6.2 Hz, 2H), 4.55 - 4.41 (m, 2H), 4.38 (t, J = 5.7 Hz, 2H), 3.70 - 3.62 (m, 1H), 3.53 (d, J = 10.4 Hz, 2H), 3.32 - 3.28 (m, 1H), 3.26 - 3.22 (m, 2H), 2.98 - 2.92 (m, 2H), 2.40 - 2.33 (m, 1H), 2.25 - 2.15 (m, 1H), 1.89 - 1.77 (m, 2H), 1.66 - 1.56 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 641 (M+H)⁺. RT (Method A): 0.88 min. Scheme 219. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(3-methyl-pyridin-2-yl)-1,2,4- oxadiazole-3-carboxamide (Compound 685) Step 1: 3-Methylpicolinoyl chloride To a mixture of 3-methylpicolinic acid (5.0 g, 36.5 mmol) in DCM (70 mL) was added a solution of (COCl)2 (22 mL, 43.8 mmol) dropwise, followed by DMF (5 drops) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (5.6 g, crude) as a yellow oil, which was used directly in the next step without further purification. The 3-methylpicolinoyl chloride was then used to produce Compound 685 following the procedures set forth in, e.g., Scheme 201.¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.79 (s, 1H), 8.70 (d, J = 4.4 Hz, 1H), 8.41 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.07 (d, J = 9.3 Hz, 1H), 4.53 - 4.43 (m, 2H), 3.40 - 3.36 (m, 1H), 2.73 (s, 3H), 2.42 - 2.36 (m, 1H), 2.27 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 558 (M+H)⁺. RT (Method A): 1.27 min. Scheme 220. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(2- hydroxycyclohexyl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamide (Compound 686) Step 1: Ethyl 2-(cyclohex-1-en-1-yl)pyrimidine-5-carboxylate To a mixture of ethyl 2-chloropyrimidine-5-carboxylate (5 g, 26.88 mmol) and cyclohex-1-en-1- ylboronic acid (5.08 g, 40.32 mmol) in 1,4-dioxane/water (50 mL, v/v= 4/1) was added K₂CO₃ (11.13 g, 80.64 mmol) and Pd(dppf)Cl2 (1.1 g, 1.5 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 80 °C overnight. The reaction mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (4.2 g, yield 67.4%) as a white solid. LC/MS (ESI) m/z: 233 (M+H)⁺. Step 2: Ethyl 2-(7-oxabicyclo[4.1.0]heptan-1-yl)pyrimidine-5-carboxylate To a solution of ethyl 2-(cyclohex-1-en-1-yl)pyrimidine-5-carboxylate (4 g, 17.24 mmol) in DCM (40 mL) was added 3-chloroperoxybenzoic acid (5.93 g, 34.48 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (3.1 g, yield 72.5%) as a yellow oil. LC/MS (ESI) m/z: 249 (M+H)⁺. Step 3: Ethyl 2-(2-hydroxycyclohexyl)pyrimidine-5-carboxylate To a solution of ethyl 2-(7-oxabicyclo[4.1.0]heptan-1-yl)pyrimidine-5-carboxylate (1 g, 4.03 mmol) in THF (40 mL) was added TEA (1.02 g, 10.1 mmol) and Pd/C (200 mg, 10% wt.), the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at 25 °C for 6 hours. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (240 mg, yield 23.8%) as a yellow oil. LC/MS (ESI) m/z: 251 (M+H)⁺. The ethyl 2-(2-hydroxycyclohexyl)pyrimidine-5-carboxylate was used to prepare Compound 686 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.16 (s, 2H), 9.10 (t, J = 5.7 Hz, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.04 (d, J = 9.3 Hz, 1H), 4.52 – 4.43 (m, 2H), 4.40 – 4.36 (m, 1H), 4.36 – 4.34 (m, 1H), 3.01 – 2.95 (m, 1H), 2.40 – 2.31 (m, 2H), 2.26 – 2.18 (m, 1H), 2.10 – 2.00 (m, 1H), 1.83 – 1.76 (m, 2H), 1.67 – 1.56 (m, 2H), 1.45 – 1.34 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 575 (M+H)⁺. RT (Method A): 1.22 min. Scheme 221. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(2-(2- methylcyclopropyl)pyrimidine-5-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 687) Step 1: Ethyl 2-(prop-1-yn-1-yl)pyrimidine-5-carboxylate To a mixture of ethyl 2-chloropyrimidine-5-carboxylate (900 mg, 4.84 mmol) and tributyl-(prop-1- yn-1-yl)stannane (2.07 g, 6.29 mmol) in DMF (10 mL) was added CuI (92 mg, 0.48 mmol) and Pd(PPh₃)₄ (559 mg, 0.48 mmol), the mixture was degassed under a nitrogen atmosphere three times and stirred at 80 °C overnight. The reaction mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 6% EtOAc in PE) to give the title compound (600 mg, yield 65.3%) as a brown solid. LC/MS (ESI) m/z: 191 (M+H)⁺. Step 2: Ethyl (E)-2-(prop-1-en-1-yl)pyrimidine-5-carboxylate To a mixture of ethyl 2-(prop-1-yn-1-yl)pyrimidine-5-carboxylate (550 mg, 2.89 mmol) in EtOAc (15 mL) was added PtO₂ (66 mg, 0.29 mmol), the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 70 minutes. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% EtOAc in PE) to give the title compound (200 mg, yield 36.1%) as a colorless oil. LC/MS (ESI) m/z: 193 (M+H)⁺. Step 3: 2-(2-Methylcyclopropyl)pyrimidine-5-carboxylic acid To a solution of NaH (91 mg, 2.28 mmol, 60% dispersion in mineral oil) in DMSO (3 mL) was added Me₃SOI (498 mg, 2.28 mmol) under a nitrogen atmosphere at 0 °C and the mixture was then stirred at 55 °C for 30 minutes. Afterwards, to the reaction mixture was ethyl (E)-2-(prop-1-en-1- yl)pyrimidine-5-carboxylate (145 mg, 0.76 mol) in DMSO (2 mL) and the resulting mixture was stirred at 55 °C overnight. The mixture was quenched with saturated aq. NH₄Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% FA) to give the title compound (60 mg, yield 44.8%) as a white solid. LC/MS (ESI) m/z: 179 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,8R)-8-methyl-3-(2-(2-methylcyclopropyl)pyrimidine-5-carboxamido)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.04 mmol) and 2-(2- methylcyclopropyl)pyrimidine-5-carboxylic acid (9 mg, 0.05 mmol) in MeCN (2 mL) was added TCFH (36 mg, 0.12 mmol) and NMI (10 mg, 0.12 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (23 mg, yield 85.8%) as a white solid. LC/MS (ESI) m/z: 631 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-(2-(2-methyl- cyclopropyl)pyrimidine-5-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 687) To a mixture of tert-butyl (2-(((6S,8R)-8-methyl-3-(2-(2-methylcyclopropyl)pyrimidine-5- carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin- 6-yl)carbamate (23 mg, 0.04 mmol) in DCM (2 mL) was added TFA (0.5 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 687 (6.0 mg, yield 31.0%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.96 (s, 1H), 9.09 (t, J = 5.7 Hz, 1H), 9.03 (s, 2H), 8.60 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 8.2 Hz, 1H), 4.52 - 4.40 (m, 2H), 3.37 - 3.33 (m, 1H), 2.38 - 2.32 (m, 1H), 2.26 - 2.16 (m, 1H), 2.06 - 2.01 (m, 1H), 1.52 - 1.45 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H), 1.28 - 1.26 (m, 1H), 1.20 (d, J = 6.0 Hz, 3H), 1.01 - 0.96 (m, 1H). LC/MS (ESI) m/z: 531 (M+H)⁺. RT (Method A): 1.29 min. Scheme 222. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(5-(2- fluorophenyl)isoxazol-3-yl)acetamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine- 6-carboxamide (Compound 689) Step 1: (5-(2-Fluorophenyl)isoxazol-3-yl)methanol To a solution of methyl 5-(2-fluorophenyl)isoxazole-3-carboxylate (12 g, 54.25 mmol) in THF (120 mL) was added NaBH₄ (8.2 g, 217 mmol) in portions under a nitrogen atmosphere at 0°C and the mixture was then stirred at 50°C for 3 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 5 - 47% EtOAc in PE) to give the title compound (8 g, yield 76.3%) as a white solid. LC/MS (ESI) m/z: 194 (M+H)⁺. Step 2: (5-(2-Fluorophenyl)isoxazol-3-yl)methyl methanesulfonate To a solution of (5-(2-fluorophenyl)isoxazol-3-yl)methanol (830 mg, 4.30 mmol) and DIPEA (1.66 g, 12.84 mmol) in THF (10 mL) was added MsCl (738 mg, 6.44 mmol) dropwise at 0°C and the mixture was stirred at 0°C under a nitrogen atmosphere for 1 hour. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (600 mg, yield 51.5%) as a yellow solid. LC/MS (ESI) m/z: 272 (M+H)⁺. Step 3: 2-(5-(2-Fluorophenyl)isoxazol-3-yl)acetonitrile To a solution of (5-(2-fluorophenyl)isoxazol-3-yl)methyl methanesulfonate (300 mg, 1.11 mmol) and 18-Crown-6 (438. mg, 1.66 mmol) in MeCN (5 mL) was added KCN (86 mg, 1.32 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 17% EtOAc in PE) to give the title compound (210 mg, yield 93.9%) as a white solid. LC/MS (ESI) m/z: 203 (M+H)⁺. Step 4: 2-(5-(2-Fluorophenyl)isoxazol-3-yl)acetic acid A solution of 2-(5-(2-fluorophenyl)isoxazol-3-yl)acetonitrile (20 mg, 0.10 mmol) in HCl (1 mL, 10M) was stirred at 80°C for 2 hours. The mixture was cooled and then neutralized with saturated aq. NaHCO3 solution to pH 6~7 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (25 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 222 (M+H)⁺. Step 5: tert-Butyl (2-(((6S,8R)-3-(2-(5-(2-fluorophenyl)isoxazol-3-yl)acetamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.04 mmol) and 2-(5-(2- fluorophenyl)isoxazol-3-yl)acetic acid (14 mg, 0.06 mmol) in MeCN (1 mL) was added NMI (14 mg, 0.17 mmol) and TCFH (24 mg, 0.08 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CHCl₃/i-PrOH (3/1, v/v), washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to give the title compound (15 mg, yield 52.4%) as a yellow solid. LC/MS (ESI) (m/z): 674 (M+H)⁺. Step 6: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(5-(2-fluorophenyl)-isoxazol-3- yl)acetamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamide (Compound 689) A solution of tert-butyl (2-(((6S,8R)-3-(2-(5-(2-fluorophenyl)isoxazol-3-yl)acetamido)-8-methyl-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (15 mg, 0.02 mmol) in DCM (0.5 mL) and TFA (0.5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 689 (4.5 mg, yield 35.2%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 9.07 (t, J = 5.8 Hz, 1H), 8.73 (s, 1H), 8.41 (s, 1H), 7.97 - 7.91 (m, 1H), 7.61 - 7.56 (m, 1H), 7.48 - 7.43 (m, 1H), 7.42 - 7.38 (m, 1H), 7.11 (s, 1H), 6.88 (d, J = 3.5 Hz, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.06 - 5.00 (m, 1H), 4.47 (d, J = 5.6 Hz, 2H), 4.02 (s, 2H), 3.37 - 3.34 (m, 1H), 2.38 - 2.34 (m, 1H), 2.22 - 2.16 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 574 (M+H)⁺. RT (Method A): 1.51 min. Scheme 223. Synthesis of (6S,8R)-3-(4-(1,2,4-oxadiazol-5-yl)benzamido)-N-((6-aminothieno-[3,2- c]pyridin-2-yl)methyl)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamide (Compound 691) Step 1: Methyl (E)-4-(((dimethylamino)methylene)carbamoyl)benzoate A solution of 4-carbamoylbenzoic acid (1 g, 6 mmol) in DMF-DMA (10 mL) was stirred at 80 °C for 2 hours. The mixture was cooled and then concentrated under reduced pressure to give the title compound (1.34 g, yield 95.1%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 235 (M+H)⁺. Step 2: Methyl 4-(1,2,4-oxadiazol-5-yl)benzoate To a solution of methyl (E)-4-(((dimethylamino)methylene)carbamoyl)benzoate (1 g, 4.2 mmol) in AcOH (10 mL) and 1,4-dioxane (10 mL) was added NH₂OH.HCl (353 mg, 5.1 mmol) and aq. NaOH solution (1 mL, 5 M) and the mixture was stirred at 80 °C for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (50 mg, yield 6.4%) as a yellow oil. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 3: 4-(1,2,4-Oxadiazol-5-yl)benzoic acid To a solution of methyl 4-(1,2,4-oxadiazol-5-yl)benzoate (100 mg, 0.49 mmol) in DCM (2 mL) was added BBr3 (5 mL, 1 M in DCM) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with saturated aq. NaHCO3 solution at 0 °C and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (42 mg, yield 45.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 191 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,8R)-3-(4-(1,2,4-oxadiazol-5-yl)benzamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of 4-(1,2,4-oxadiazol-5-yl)benzoic acid (20 mg, 0.1 mmol) and tert-butyl(2-(((6S,8R)- 3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate (20 mg, 0.04 mmol) in MeCN (2 mL) was added NMI (24 mg, 0.3 mmol) and TCFH (84 mg, 0.3 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to give the title compound (22 mg, yield 80.5%) as a white solid. LC/MS (ESI) m/z: 643 (M+H)⁺. Step 5: (6S,8R)-3-(4-(1,2,4-oxadiazol-5-yl)benzamido)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 691) To a solution of tert-butyl (2-(((6S,8R)-3-(4-(1,2,4-oxadiazol-5-yl)benzamido)-8-methyl-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (22 mg, 0.03 mmol) in DCM (0.50 mL) was added TFA (0.50 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 691 (25 mg, yield 27.9%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.81 (s, 1H), 9.19 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 8.59 (s, 1H), 8.41 (d, J = 0.7 Hz, 1H), 8.29 – 8.25 (m, 2H), 8.20 – 8.16 (m, 2H), 7.11 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.05 (d, J = 8.3 Hz, 1H), 4.54 – 4.42 (m, 2H), 3.41 – 3.34 (m, 1H), 2.40 – 2.34 (m, 1H), 2.27 – 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 543 (M+H)⁺. RT (Method A): 1.25 min. Scheme 224. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(3-methyl-pyridin-2-yl)-1,3,4- oxadiazole-2-carboxamide (Compound 700) To a mixture of 3-methylpicolinic acid (5 g, 36.4 mmol) and ethyl 2-hydrazineyl-2-oxoacetate (4.81 g, 36.4 mmol) in DMF (50 mL) was added EDCI (10.51 g, 54.6 mmol) and HOBt (7.39 g, 54.6 mmol) under a nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (3 g, yield 32.7%) as a white solid. LC/MS (ESI) m/z: 252 (M+H)⁺. Step 2: Ethyl 5-(3-methylpyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate To a mixture of ethyl 2-(2-(3-methylpicolinoyl)hydrazinyl)-2-oxoacetate (3 g, 11.9 mmol) and TosCl (2.27 g, 11.9 mmol) in DCM (50 mL) was added TEA (1.81 g, 17.85 mmol) under a nitrogen atmosphere and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.4 g, yield 50.3%) as a white solid. LC/MS (ESI) m/z: 234 (M+H)⁺. The ethyl 5-(3-methylpyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate was used to prepare Compound 700 following the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 9.23 – 8.98 (m, 1H), 8.69 (s, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.7, 4.8 Hz, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.14 – 4.97 (m, 1H), 4.56 – 4.35 (m, 2H), 3.29 – 3.24 (m, 1H), 2.72 (s, 3H), 2.42 – 2.33 (m, 1H), 2.28 – 2.17 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 558 (M+H)⁺. RT (Method A): 1.26 min. Scheme 225. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(3,3- difluorocyclo-pentyl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]- pyrimidine-6-carboxamide (Compound 702) Step 1: Methyl 2-(3-oxocyclopent-1-en-1-yl)pyrimidine-5-carboxylate To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (1.00 g, 4.81 mmol) and methyl 2-chloropyrimidine-5-carboxylate (829 mg, 4.81 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added Pd(dppf)Cl2 (352 mg, 0.48 mmol) and K2CO3 (1.66 g, 12.0 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 100 °C for 3 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (430 mg, yield 41.0%) as a brown solid. LC/MS (ESI) m/z: 219 (M+H)⁺. Step 2: Methyl 2-(3-oxocyclopentyl)pyrimidine-5-carboxylate To a solution of methyl 2-(3-oxocyclopent-1-en-1-yl)pyrimidine-5-carboxylate (100 mg, 0.46 mmol) in EtOAc (5 mL) was added PtO₂ (13 mg, 0.05 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 10% - 95% MeCN in water with 0.1% NH₃.H₂O) to give the title compound (60 mg, yield 59.4%) as a white solid. LC/MS (ESI) m/z: 221 (M+H)⁺. Step 3: Methyl 2-(3,3-difluorocyclopentyl)pyrimidine-5-carboxylate To a solution of Methyl 2-(3-oxocyclopentyl)pyrimidine-5-carboxylate (60 mg, 0.27 mmol) in DCE (3 mL) was added DAST (435 mg, 2.7 mmol) dropwise at 0 °C and then the reaction mixture was warmed to 80 °C for 2 hours. The mixture was diluted with DCM, washed with saturated aq. NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (40 mg, yield 60.6%) as a yellow solid. LC/MS (ESI) m/z: 243 (M+H)⁺. The methyl 2-(3,3-difluorocyclopentyl)pyrimidine-5-carboxylate was used to prepare Compound 702 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.18 (s, 2H), 9.10 (t, J = 5.8 Hz, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.86 (s, 2H), 5.05 (d, J = 8.6 Hz, 1H), 4.53 – 4.40 (m, 2H), 3.77 – 3.66 (m, 1H), 3.39 – 3.33 (m, 1H), 2.63 – 2.54 (m, 2H), 2.40 – 2.23 (m, 4H), 2.21 – 2.12 (m, 1H), 2.09 – 2.01 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 581 (M+H)⁺. RT (Method A): 1.40 min. Scheme 226. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-(3- hydroxycyclo-hexyl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]- pyrimidine-6-carboxamide (Compound 703) Step 1: Ethyl 2-(3-oxocyclohex-1-en-1-yl)pyrimidine-5-carboxylate To a mixture of ethyl 2-chloropyrimidine-5-carboxylate (5 g, 22.5 mmol) and 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-one (4.1 g, 22.5 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was added K2CO3 (6.2 g, 45 mmol) and Pd(PPh3)4 (2.6 g, 2.25 mmol) at 25 °C under a nitrogen atmosphere, the reaction mixture was degassed under a nitrogen atmosphere three times and then stirred at 80 °C for 18 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (4.5 g, yield 81.3%) as a yellow solid.¹H NMR (400 MHz, CDCl3) δ 9.31 (s, 2H), 7.35 (t, J = 1.5 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.98 (td, J = 6.1, 1.6 Hz, 2H), 2.58 - 2.53 (m, 2H), 2.21 - 2.15 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H). LC/MS (ESI) m/z: 247 (M+H)⁺. Step 2: Ethyl 2-(3-oxocyclohexyl)pyrimidine-5-carboxylate To a solution of ethyl 2-(3-oxocyclohex-1-en-1-yl)pyrimidine-5-carboxylate (4.5 g, 18.3 mmol) in MeOH (50 mL) was added Pd/C (200 mg, 10% wt.), the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at 25 °C for 3 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (4.5 g, yield 99.2%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 249 (M+H)⁺. Step 3: Ethyl 2-(3-hydroxycyclohexyl)pyrimidine-5-carboxylate To a solution of ethyl 2-(3-oxocyclohexyl)pyrimidine-5-carboxylate (4 g, 16.1 mmol) in THF (3 mL) was added NaBH4 (695 mg, 18.3 mmol) at 0 °C under a nitrogen atmosphere and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 90% EtOAc in PE) to give the title compound (1.1 g, yield 27.3%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.19 - 9.13 (m, 2H), 4.38 - 4.34 (m, 2H), 3.64 - 3.44 (m, 1H), 2.99 - 2.89 (m, 1H), 2.14 - 2.08 (m, 1H), 1.90 - 1.76 (m, 4H), 1.71 - 1.54 (m, 1H), 1.44 - 1.39 (m, 2H), 1.35 - 1.31 (m, 3H). LC/MS (ESI) (m/z): 251 (M+H)⁺. The ethyl 2-(3-hydroxycyclohexyl)pyrimidine-5-carboxylate was used to prepare Compound 703 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, 1H), 9.15 – 9.13 (m, 2H), 9.10 (t, J = 6.0 Hz, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.85 (s, 2H), 5.04 (d, J = 9.1 Hz, 1H), 4.65 (d, J = 4.7 Hz, 1H), 4.50 – 4.44 (m, 2H), 3.54 – 3.35 (m, 1H), 3.30 – 3.28 (m, 1H), 3.04 – 2.87 (m, 1H), 2.68 – 2.66 (m, 1H), 2.33 – 2.32 (m, 1H), 2.25 – 2.11 (m, 2H), 1.91 – 1.85 (m, 2H), 1.83 – 1.61 (m, 2H), 1.48 – 1.41 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 575 (M+H)⁺. RT (Method A): 1.12 min. Scheme 227. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(3-(5-(2-fluoro- phenyl)isoxazol-3-yl)propanamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 705) Step 1: Methyl 4-(2-fluorophenyl)-2,4-dioxobutanoate To a mixture of 1-(2-fluorophenyl)ethan-1-one (20 g, 144.9 mmol) and dimethyl oxalate (34 g, 288.1 mmol) in MeOH (300 mL) was added sodium methoxide (36 g, 211.8 mmol, 30% wt. in EtOAc) and the mixture was stirred at 50 C for 12 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% EtOAc in PE) to give the title compound (25 g, yield 78.2%) as a white solid. LC/MS (ESI) m/z: 225 (M+H)⁺. Step 2: Methyl 5-(2-fluorophenyl)isoxazole-3-carboxylate To a solution of methyl 4-(2-fluorophenyl)-2,4-dioxobutanoate (5 g, 22.3 mmol) in EtOH (50 mL) was added NH2OH^.HCl (1.7 g, 24.3 mmol) and the reaction mixture was stirred at 60 °C for 4 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% EtOAc in PE) to give the title compound (2.4 g, yield 49.2%) as a white solid. LC/MS (ESI) m/z: 222 (M+H)⁺. Step 3: (5-(2-Fluorophenyl)isoxazol-3-yl)methanol To a solution of methyl 5-(2-fluorophenyl)isoxazole-3-carboxylate (6 g, 26.14 mmol) in THF (60 mL) was added NaBH4 (4.2 g, 110.01 mmol) in portions under a nitrogen atmosphere at 0 °C and the mixture was then stirred at 50 °C for 3 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (4 g, yield 76.3%) as a white solid. LC/MS (ESI) m/z: 194 (M+H)⁺. Step 4: 5-(2-Fluorophenyl)isoxazole-3-carbaldehyde To a solution of (5-(2-fluorophenyl)isoxazol-3-yl)methanol (3.1 g, 16.1 mmol) in CHCl3 (30 mL) was added MnO2 (14.0 g, 161 mmol) and the reaction mixture was stirred at 50 °C for 6 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (1.5 g, yield 49.2%) as a white solid. LC/MS (ESI) m/z: 192 (M+H)⁺. Step 5: Ethyl (E)-3-(5-(2-fluorophenyl)isoxazol-3-yl)acrylate To a solution of 5-(2-fluorophenyl)isoxazole-3-carbaldehyde (1.5 g, 7.8 mmol) in DCM (20 mL) was added ethyl (triphenylphosphoranylidene)acetate (2.7 g, 7.8 mmol) and the reaction mixture was stirred at 30 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% EtOAc in PE) to give the title compound (1.5 g, yield 74.4%) as a white solid. LC/MS (ESI) m/z: 262 (M+H)⁺. Step 6: Ethyl 3-(5-(2-fluorophenyl)isoxazol-3-yl)propanoate To a solution of ethyl (E)-3-(5-(2-fluorophenyl)isoxazol-3-yl)acrylate (208 mg, 0.77 mmol) in EtOH (5 mL) was added Pd/C (30 mg, 10% wt.). The mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (143 mg, yield 70.3%) as a white solid. LC/MS (ESI) m/z: 264 (M+H)⁺. The ethyl 3-(5-(2-fluorophenyl)isoxazol-3-yl)propanoate was used to prepare Compound 705 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 9.05 (t, J = 5.7 Hz, 1H), 8.73 (s, 1H), 8.41 (s, 1H), 7.93 - 7.89 (m, 1H), 7.59 - 7.54 (m, 1H), 7.46 - 7.41 (m, 1H), 7.41 - 7.36 (m, 1H), 7.10 (s, 1H), 6.83 (d, J = 3.3 Hz, 2H), 5.84 (s, 2H), 5.01 (d, J = 8.6 Hz, 1H), 4.46 (d, J = 5.5 Hz, 2H), 3.28 - 3.24 (m, 1H), 3.00 - 2.95 (m, 2H), 2.92 - 2.87 (m, 2H), 2.70 - 2.65 (m, 1H), 2.35 - 2.32 (m, 1H), 2.20 - 2.13 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 588 (M+H)⁺. RT (Method A): 1.59 min. Scheme 228. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-5-(5-methylpyridin-3- yl)isoxazole-3-carboxamide (Compound 706) Step 1: Ethyl 5-(5-methylpyridin-3-yl)isoxazole-3-carboxylate To a mixture of ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (3.75 g, 8.7 mmol) and 3-bromo-5- methylpyridine (1.0 g, 5.8 mmol) in toluene (15 mL) was added Pd(t-Bu3P)2 (297 mg, 0.58 mmol) under a dry nitrogen atmosphere, the mixture was degassed under a dry nitrogen atmosphere three times and stirred at 110 °C overnight. The mixture was cooled, diluted with saturated aq. KF solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (1.0 g, yield 74.1%) as a yellow solid. LC/MS (ESI) m/z: 233 (M+H)⁺. Step 2: Lithium 5-(5-methylpyridin-3-yl)isoxazole-3-carboxylate To a solution of ethyl 5-(5-methylpyridin-3-yl)isoxazole-3-carboxylate (1.0 g, 4.3 mmol) in THF/water (15 mL, v/v= 3/1) was added LiOH (207 mg, 8.6 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (850 mg, yield 96.2%) as a white solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 3: N-(4-(tert-Butyl)phenyl)-5-(5-methylpyridin-3-yl)isoxazole-3-carboxamide To a mixture of lithium 5-(5-methylpyridin-3-yl)isoxazole-3-carboxylate (850 mg, 4.05 mmol) and 4-(tert-butyl)aniline (724 mg, 4.85 mmol) in DMF (10 mL) was added DIPEA (2.6 g, 20.2 mmol) and HATU (2.3 g, 6.07 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (1.1 g, yield 80.9%) as a yellow solid. LC/MS (ESI) m/z: 336 (M+H)⁺. Step 4: N-(4-(tert-Butyl)phenyl)-4-fluoro-5-(5-methylpyridin-3-yl)isoxazole-3-carboxamide To a solution of N-(4-(tert-butyl)phenyl)-5-(5-methylpyridin-3-yl)isoxazole-3-carboxamide (1 g, 2.99 mmol) in THF (15 mL) was added n-BuLi (3.6 mL, 9.0 mmol, 2.5 M in hexane) dropwise at -70 °C under a dry nitrogen atmosphere and the mixture was stirred at -70 °C for 1 hour. Afterwards, to the reaction mixture was added a solution of NFSI (1.9 g, 5.97 mmol) in THF (10 mL) dropwise at -70°C and the resulting mixture was stirred at -70 °C for 2 hours. The mixture was warmed to 0°C and quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (200 mg, yield 19.0%) as a white solid. LC/MS (ESI) m/z: 354 (M+H)⁺. Step 5: tert-Butyl (4-(tert-butyl)phenyl)(4-fluoro-5-(5-methylpyridin-3-yl)isoxazole-3-carbonyl)carbamate To a solution of N-(4-(tert-butyl)phenyl)-4-fluoro-5-(5-methylpyridin-3-yl)isoxazole-3-carboxamide (200 mg, 0.57 mmol) in MeCN (5 mL) was added DMAP (7 mg, 0.06 mmol) and (Boc)₂O (247 mg, 1.13 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give title compound (150 mg, yield 58.4%) as a white solid. LC/MS (ESI) m/z: 454 (M+H)⁺. Step 6: 4-Fluoro-5-(5-methylpyridin-3-yl)isoxazole-3-carboxylic acid To a solution of H₂O₂ (0.17 mL, 1.66 mmol, 30% wt. in water) in water (2 mL) was added LiOH (32 mg, 1.32 mmol) at room temperature and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of tert-butyl (4-(tert-butyl)phenyl)(4-fluoro-5-(5-methylpyridin-3- yl)isoxazole-3-carbonyl)carbamate (150 mg, 0.33 mmol) in THF (3 mL) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (55 mg, yield 74.8%) as a white solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 223 (M+H)⁺. Step 7: tert-Butyl (2-(((6S,8R)-3-(4-fluoro-5-(5-methylpyridin-3-yl)isoxazole-3-carboxamido)-8-methyl-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (90 mg, 0.19 mmol) and 4-fluoro- 5-(5-methylpyridin-3-yl)isoxazole-3-carboxylic acid (55 mg, 0.25 mmol) in MeCN (7 mL) was added NMI (47 mg, 0.57 mmol) and TCFH (161 mg, 0.57 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with CHCl₃/i-PrOH (3/1, v/v), washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 8% MeOH in DCM) to give the title compound (100 mg, yield 77.5%) as a white solid. LC/MS (ESI) m/z: 675 (M+H)⁺. Step 8: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-5-(5-methylpyridin-3-yl)isoxazole-3-carboxamide (Compound 706) To a solution of tert-butyl (2-(((6S,8R)-3-(4-fluoro-5-(5-methylpyridin-3-yl)isoxazole-3- carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)- methyl)thieno[3,2-c]pyridin-6-yl)carbamate (100 mg, 0.15 mmol) in DCM (6 mL) was added HCl in 1,4- dioxane (4M, 2 mL, 8 mmol) at 0 °C and the reaction mixture was then stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 706 (20 mg, yield 23.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.85 (s, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.7 Hz, 1H), 4.47 (p, J = 9.8 Hz, 2H), 3.41 - 3.33 (m, 1H), 2.43 (s, 3H), 2.39 - 2.34 (m, 1H), 2.26 - 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 575 (M+H)⁺. RT (Method A): 1.00 min. The following compounds were prepared based on the procedures above using the appropriate heteroaryl bromides in Step 1. Scheme 229. Synthesis of N-(6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-3-(4-methylpyridin-2-yl)- isoxazole-5-carboxamide (Compound 707) Step 1: N-(4-(tert-Butyl)phenyl)-3-(4-methylpyridin-2-yl)isoxazole-5-carboxamide To a mixture of lithium 3-(4-methylpyridin-2-yl)isoxazole-5-carboxylate (2 g, 9.5 mmol) and 4-(tert- butyl)aniline (1.4 g, 9.5 mmol) in DMF (20 mL) was added DIPEA (3.6 g, 28.5 mmol) and HATU (4.3 g, 11.4 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (2.8 g, yield 87.9%) as a white solid. LC/MS (ESI) m/z: 336 (M+H)⁺. Step 2: N-(4-(tert-Butyl)phenyl)-4-fluoro-3-(4-methylpyridin-2-yl)isoxazole-5-carboxamide To a solution of N-(4-(tert-butyl)phenyl)-3-(4-methylpyridin-2-yl)isoxazole-5-carboxamide (2.8 g, 8.3 mmol) in THF (150 mL) was added n-BuLi (10 mL, 25 mmol, 2.5 M in hexane) dropwise at -60°C under a dry nitrogen atmosphere and the mixture was stirred at -60 °C for 1 hour. Afterwards, to the reaction mixture was added a solution of NFSI (10.4 g, 33.2 mmol) in THF (50 mL) dropwise at -60 °C and the resulting mixture was stirred at -60 °C for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution at 0°C and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (420 mg, yield 14.3%) as a yellow solid. LC/MS (ESI) m/z: 354 (M+H)⁺. Step 3: tert-Butyl (4-(tert-butyl)phenyl)(4-fluoro-3-(4-methylpyridin-2-yl)isoxazole-5-carbonyl)carbamate To a solution of N-(4-(tert-butyl)phenyl)-4-fluoro-3-(4-methylpyridin-2-yl)isoxazole-5-carboxamide (420 mg, 1.18 mmol) in MeCN (10 mL) was added DMAP (15 mg, 0.12 mmol) and (Boc)₂O (386 mg, 1.77 mmol) at 0 °C and the mixture was then stirred at room temperature for 1 hour. The mixture was quenched with saturated aq. NH4Cl solution at 0°C and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give title compound (380 mg, yield 71.1%) as a yellow oil. LC/MS (ESI) m/z: 454 (M+H)⁺. Step 4: 4-Fluoro-3-(4-methylpyridin-2-yl)isoxazole-5-carboxylic acid To a solution of H₂O₂ (0.42 mL, 4.1 mmol, 30% wt. in water) in THF/water (4 mL, v/v= 1/1) was added LiOH (98 mg, 4.1 mmol) at room temperature and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of tert-butyl(4-(tert-butyl)phenyl)(4-fluoro-3-(4- methylpyridin-2-yl)isoxazole-5-carbonyl)carbamate (380 mg, 0.83 mmol) in THF (3 mL) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (166 mg, yield 90.1%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 223 (M+H)⁺. Step 5: tert-Butyl (2-(((6S,8R)-3-(4-fluoro-3-(4-methylpyridin-2-yl)isoxazole-5-carboxamido)-8-methyl-4- oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (100 mg, 0.21 mmol) and 4-fluoro- 3-(4-methylpyridin-2-yl)isoxazole-5-carboxylic acid (70 mg, 0.31 mmol) in MeCN (5 mL) was added NMI (50 mg, 0.62 mmol) and TCFH (168 mg, 0.62 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (86 mg, yield 60.7%) as a yellow solid. LC/MS (ESI) m/z: 675 (M+H)⁺. Step 6: N-(6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-3-(4-methylpyridin-2-yl)-isoxazole-5-carboxamide (Compound 707) To a solution of tert-butyl (2-(((6S,8R)-3-(4-fluoro-3-(4-methylpyridin-2-yl)isoxazole-5- carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)- methyl)thieno[3,2-c]pyridin-6-yl)carbamate (86 mg, 0.12 mmol) in DCM (1 mL) was added TFA (1 mL) at 0°C and the reaction mixture was then stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 707 (19.7 mg, yield 22.8%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 9.11 (t, J = 5.6 Hz, 1H), 8.74 - 8.54 (m, 2H), 8.41 (s, 1H), 7.86 (s, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.06 (d, J = 9.3 Hz, 1H), 4.56 - 4.40 (m, 2H), 3.45 - 3.34 (m, 1H), 2.45 (s, 3H), 2.38 - 2.32 (m, 1H), 2.27 - 2.19 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 575 (M+H)⁺. RT (Method A): 1.12 min. The following compounds were prepared based on the procedures above, using the appropriate carboxylates in Step 1. ^a Step 2 was performed with NFSI in the presence of LDA in THF. ^b Step 6 was performed with HCl/1,4- dioxane in DCM. Scheme 230. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (Compound 708) Step 1: Ethyl 5-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxylate To a solution of ethyl 5-chloroisoxazole-3-carboxylate (1.0 g, 5.71 mmol) in DMF (10 mL) was added 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (2.88 g, 17.14 mmol) and K₂CO₃ (1.46 g, 21.27 mmol) under a dry nitrogen atmosphere and then reaction mixture was heated and stirred at 100 °C for 16 hours. The reaction mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (900 mg, yield 51.4%) as a yellow solid. LC/MS (ESI) m/z: 308 (M+H)⁺. The ethyl 5-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxylate was subsequently used to prepare Compound 708 based on the procedure set forth in, e.g., Scheme 188 starting from Step 2.¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 2H), 8.74 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.65 (s, 1H), 5.05 (d, J = 9.4 Hz, 1H), 4.58 (t, J = 6.1 Hz, 2H), 4.51 - 4.42 (m, 2H), 4.37 (t, J = 5.5 Hz, 2H), 3.64 - 3.61 (m, 1H), 3.45 - 3.40 (m, 3H), 3.23 - 3.19 (m, 4H), 2.39 - 2.34 (m, 1H), 2.23 - 2.16 (m, 1H), 1.88 - 1.81 (m, 2H), 1.62 - 1.57 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 632 (M+H)⁺. RT (Method A): 0.37 min. Scheme 231. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((1S,2S)-2-(thiazolo[4,5-b]pyridin-2-yl)cyclopropane-1-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 709) Step 1: Ethyl (1S,2S)-2-((3-fluoropyridin-2-yl)carbamoyl)cyclopropane-1-carboxylate To a mixture of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (500 mg, 3.16 mmol) and 3-fluoropyridin-2-amine (390 mg, 3.48 mmol) in MeCN (5 mL) was added NMI (778 mg, 9.48 mmol) and TCFH (2.66 g, 9.48 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with 0.5 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (400 mg, yield 50.1%) as a yellow oil. LC/MS (ESI) (m/z): 253 (M+H)⁺. Step 2: Ethyl (1S,2S)-2-(thiazolo[4,5-b]pyridin-2-yl)cyclopropane-1-carboxylate To a solution of ethyl (1S,2S)-2-((3-fluoropyridin-2-yl)carbamoyl)cyclopropane-1-carboxylate (300 mg, 1.19 mmol) in toluene (5 mL) was added Lawesson's Reagent (963 mg, 2.38 mmol) and the resulting mixture was heated and stirred at 100 °C for 12 hours. The mixture was cooled and then concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give the title compound (70 mg, yield 23.7%) as a yellow solid. LC/MS (ESI) (m/z): 249 (M+H)⁺. The ethyl (1S,2S)-2-(thiazolo[4,5-b]pyridin-2-yl)cyclopropane-1-carboxylate was used to prepare Compound 709 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.06 (t, J = 5.8 Hz, 1H), 8.73 (s, 1H), 8.66 – 8.62 (m, 1H), 8.57 – 8.53 (m, 1H), 8.41 (s, 1H), 7.44 – 7.40 (m, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 8.5 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 3.17 – 3.13 (m, 1H), 2.99 – 2.95 (m, 1H), 2.34 – 2.31 (m, 1H), 2.22 – 2.12 (m, 2H), 1.74 – 1.70 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 573 (M+H)⁺. RT (Method A): 0.88 min. Compound 731 was prepared according to the procedures above, using 4-bromopyridin-3-amine as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (s, 1H), 9.16 (s, 1H), 9.10 – 8.98 (m, 1H), 8.73 (s, 1H), 8.48 (d, J = 5.4 Hz, 1H), 8.41 (s, 1H), 8.15 (d, J = 5.5 Hz, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 8.9 Hz, 1H), 4.46 (d, J = 5.5 Hz, 2H), 3.28 – 3.21 (m, 1H), 3.18 – 3.09 (m, 1H), 3.07 – 2.93 (m, 1H), 2.35 – 2.29 (m, 1H), 2.23 – 2.12 (m, 1H), 1.77 – 1.65 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 573 (M+H)⁺. RT (Method A): 0.54 min. Scheme 232. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3- ((1S,2S)-2-(5-methylbenzo[d]oxazol-2-yl)cyclopropane-1-carboxamido)-4-oxo-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 710) Step 1: Ethyl (1S,2S)-2-((2-bromo-5-methylphenyl)carbamoyl)cyclopropane-1-carboxylate To a mixture of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (350 mg, 2.21 mmol) and 2-bromo-5-methylaniline (410 mg, 2.21 mmol) in MeCN (5 mL) were added TCFH (1.27 g, 3.31 mmol) and NMI (532 mg, 6.63 mmol) under a dry nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with 1 N aq. HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (500 mg, yield 69.2%) as a white solid. LC/MS (ESI) m/z: 326 (M+H)⁺. Step 2: Ethyl (1S,2S)-2-(5-methylbenzo[d]oxazol-2-yl)cyclopropane-1-carboxylate To a mixture of ethyl (1S,2S)-2-((2-bromo-5-methylphenyl)carbamoyl)cyclopropane-1-carboxylate (400 mg, 1.22 mmol) in DME (10 mL) was added o-phenanthroline (44 mg, 0.24 mmol), CuI (44 mg, 0.24 mmol) and Cs₂CO₃ (1.18 g, 3.66 mmol) under a dry nitrogen atmosphere and the mixture was heated and stirred at 90 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (150 mg, yield 49.8%) as a white solid. LC/MS (ESI) m/z: 246 (M+H)⁺. The ethyl (1S,2S)-2-(5-methylbenzo[d]oxazol-2-yl)cyclopropane-1-carboxylate was used to prepare Compound 710 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.06 (t, J = 5.9 Hz, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 8.9 Hz, 1H), 4.56 – 4.37 (m, 2H), 3.27 – 3.24 (m, 1H), 3.08 – 2.99 (m, 1H), 2.62 – 2.55 (m, 1H), 2.41 (s, 3H), 2.37 – 2.29 (m, 1H), 2.24 – 2.10 (m, 1H), 1.69 – 1.55 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H).LC/MS (ESI) (m/z): 570 (M+H)⁺. RT (Method A): 1.32 min. The following compounds were prepared according to the procedures above using the appropriate amines in Step 1. ^a Step 2 was performed with N,N-bis(2-phenylphenyl)-oxamide in place of o-phenanthroline ^b Step 5 was performed with HCl/1,4-dioxane in DCM. Scheme 233. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((1S,2S)-2-(thiazolo[5,4-c]pyridin-2-yl)cyclopropane-1-carboxamido)-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 712) Step 1: Ethyl (1S,2S)-2-((3-bromopyridin-4-yl)carbamoyl)cyclopropane-1-carboxylate To a mixture of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (400 mg, 2.53 mmol) and 3-bromopyridin-4-amine (438 mg, 2.53 mmol) in MeCN (8 mL) were added TCFH (1.4 g, 5 mmol) and NMI (1 g, 12.6 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with 1 N aq. HCl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (600 mg, yield 75.9%) as a white solid. LC/MS (ESI) (m/z): 313 (M+H)⁺. Step 2: Ethyl (1S,2S)-2-((3-bromopyridin-4-yl)carbamothioyl)cyclopropane-1-carboxylate To a mixture of ethyl (1S,2S)-2-((3-bromopyridin-4-yl)carbamoyl)cyclopropane-1-carboxylate (600 mg, 1.92 mmol) in toluene (8 mL) were added Lawesson's Reagent (1.56 g, 3.84 mmol) and the mixture was heated and stirred at 100 °C for 6 minutes. The mixture was cooled, diluted with EtOAc, washed with aq. NaHCO₃ and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (270 mg, yield %) as a yellow solid. LC/MS (ESI) (m/z): 329 (M+H)⁺. Step 3: Ethyl (1S,2S)-2-(thiazolo[5,4-c]pyridin-2-yl)cyclopropane-1-carboxylate To a mixture of ethyl (1S,2S)-2-((3-bromopyridin-4-yl)carbamothioyl)cyclopropane-1-carboxylate (270 mg, 0.83 mmol) and o-Phenanthroline (12 mg, 0.067 mmol) in DME (4 mL) was added CuI (12.7 mg, 0.067 mmol) and Cs₂CO₃ (657 mg, 2.02 mmol) under a dry nitrogen atmosphere and the mixture was heated and stirred at 100 °C for 4 hours. The mixture was cooled, diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (177 mg, yield 86.8%) as a white solid. LC/MS (ESI) m/z: 249 (M+H)⁺. The ethyl (1S,2S)-2-(thiazolo[5,4-c]pyridin-2-yl)cyclopropane-1-carboxylate was used to prepare Compound 712 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.30 (s, 1H), 9.08 – 9.03 (m, 1H), 8.73 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H), 7.89 (d, J = 5.6 Hz, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 8.8 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.29 – 3.25 (m, 1H), 3.19 – 3.13 (m, 1H), 3.06 – 3.00 (m, 1H), 2.34 – 2.31 (m, 1H), 2.21 – 2.13 (m, 1H), 1.76 – 1.70 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 573 (M+H)⁺. RT (Method A): 0.41 min. Compound 787 was prepared according to the procedures above, using 5-bromo-2- methylpyridin-4-amine in place of 3-bromopyridin-4-amine in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.25 – 8.99 (m, 2H), 8.78 (d, J = 4.9 Hz, 1H), 8.47 (s, 1H), 7.80 (s, 1H), 7.16 (s, 1H), 6.89 (s, 1H), 5.91 (s, 2H), 5.08 (d, J = 8.7 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 3.35 – 3.30 (m, 1H), 3.22 – 3.17 (m, 1H), 3.06 – 3.01 (m, 1H), 2.65 (s, 3H), 2.41 – 2.38 (m, 1H), 2.27 – 2.19 (m, 1H), 1.81 – 1.73 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 587 (M+H)⁺. RT (Method A): 0.36 min. Scheme 234. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (((1R,3R)-3-(pyrimidin-2-ylamino)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 715) Step 1: Methyl (6S,8R)-3-(((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl) amino)-8-methyl-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxylate (200 mg, 0.70 mmol) and tert-butyl ((1R,3R)-3-aminocyclo-pentyl)carbamate (167 mg, 0.84 mmol) in toluene (10 mL) was added BrettPhos Pd G3 (63 mg, 0.07 mmol) and K₂CO₃ (289 mg, 2.09 mmol). The reaction mixture was degassed under a dry nitrogen atmosphere three times and then heated and stirred at 100 °C overnight. The mixture was cooled, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (85 mg, yield 30.0%) as a yellow solid. LC/MS (ESI) m/z: 407 (M+H)⁺. Step 2: Methyl (6S,8R)-3-(((1R,3R)-3-aminocyclopentyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (6S,8R)-3-(((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)-amino)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (85 mg, 0.21 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (60 mg, yield 93.8%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 307 (M+H)⁺. Step 3: Methyl (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(pyrimidin-2-ylamino) cyclopentyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-3-(((1R,3R)-3-aminocyclopentyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.21 mmol) and 2-chloropyrimidine (28 mg, 0.25 mmol) in NMP (3 mL) was added K₂CO₃ (68 mg, 0.49 mmol) and the reaction mixture was heated and stirred at 140 °C for 1 hour. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 80% EtOAc in PE) to give the title compound (15 mg, yield 23.9%) as a yellow oil. LC/MS (ESI) m/z: 385 (M+H)⁺. Step 4: (6S,8R)-8-Methyl-4-oxo-3-(((1R,3R)-3-(pyrimidin-2-ylamino)cyclopentyl) amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(pyrimidin-2-ylamino)cyclo- pentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (15 mg, 0.04 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (2 mg, 0.08 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1N aq. HCl to pH~5 and concentrated under reduced pressure to dryness to give the title compound (10 mg, yield 69.0%) as a yellow solid, which was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 371 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3-(((1R,3R)-3-(pyrimidin-2- ylamino)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 715) To a mixture of (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(pyrimidin-2-ylamino)cyclopentyl)-amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (10 mg, 0.03 mmol) and 2- (aminomethyl)thieno[3,2-c]pyridin-6-amine hydrochloride (9 mg, 0.04 mmol) in DMF (2 mL) was added DIPEA (26 mg, 0.20 mmol) and HATU (23 mg, 0.06 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 715 (2.0 mg, yield 9.3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) ¹δ 8.41 – 8.38 (m, 1H), 8.26 – 8.23 (m, 1H), 8.07 (s, 2H), 7.77 (d, J = 4.8 Hz, 1H), 7.24 (s, 1H), 7.22 – 7.20 (m, 3H), 6.87 (s, 1H), 6.66 – 6.62 (m, 1H), 6.53 (s, 1H), 5.87 – 5.82 (m, 1H), 5.33 – 5.31 (m, 2H), 4.94 – 4.91 (m, 1H), 4.46 – 4.43 (m, 1H), 3.01 (d, J = 1.0 Hz, 1H), 2.05 – 2.04 (m, 2H), 2.03 – 2.02 (m, 2H), 1.99 – 1.98 (m, 2H), 1.97 – 1.97 (m, 2H), 1.26 (d, J = 0.5 Hz, 3H). LC/MS (ESI) m/z: 532 (M+H)⁺. RT (Method A): 0.64 min. Scheme 235. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((5-(o-tolyl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrimidine-6-carboxamide (Compound 716) Step 1: 2-Methyl-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide To a mixture of 5-methyl-1,2,4-oxadiazol-3-amine (800 mg, 8.1 mmol) and 2-methylbenzoyl chloride (1.95 g, 12.3 mmol) in toluene (12 mL) was added pyridine (1.92 g, 24.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1.1 g, yield 62.4%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 218 (M+H)⁺. Step 2: 5-(O-tolyl)-1,2,4-oxadiazol-3-amine To a solution of 2-methyl-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (1.1 g, 5.06 mmol) in EtOH (3 mL) was added aq. HCl in EtOH (6M, 9 mL, 54 mmol). The reaction mixture was stirred at 80°C for 2 hours. The mixture was cooled, and then concentrated under reduced pressure to dryness to give the title compound (880 mg, crude) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 176 (M+H)⁺. The 5-(o-tolyl)-1,2,4-oxadiazol-3-amine was used to prepare Compound 716 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (t, J = 5.9 Hz, 1H), 8.92 - 8.87 (m, 1H), 8.42 (s, 1H), 8.40 (s, 1H), 8.03 - 8.00 (m, 1H), 7.60 - 7.55 (m, 1H), 7.48 - 7.41 (m, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 - 5.02 (m, 1H), 4.52 - 4.43 (m, 2H), 2.66 (s, 3H), 2.33 - 2.32 (m, 1H), 2.22 - 2.17 (m, 1H), 2.01 - 1.98 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 529 (M+H)⁺. RT (Method A): 1.53 min. Scheme 236. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (((1R,3R)-3-(pyridin-2-yloxy)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 721) Step 1: tert-Butyl ((1R,3R)-3-(pyridin-2-yloxy) cyclopentyl) carbamate To a mixture of tert-butyl ((1R,3S)-3-hydroxycyclopentyl) carbamate (500 mg, 2.48 mmol), pyridin- 2-ol (236 mg, 2.48 mmol) and PPh3 (1.31 g, 4.96 mmol) in THF (15 mL) was added DIAD (1.00 g, 4.96 mmol) and the reaction mixture was stirred under a nitrogen atmosphere at 25 °C for 16 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (510 mg, yield 72.3%) as a white solid. LC/MS (ESI) m/z: 279 (M+H)⁺. Step 2: (1R,3R)-3-(pyridin-2-yloxy)cyclopentan-1-amine To a solution of tert-butyl ((1R,3R)-3-(pyridin-2-yloxy)cyclopentyl)carbamate (400 mg, 1.44 mmol) in DCM (2 mL) was added TFA (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give the title compound (200 mg, yield 78.1%) as a white solid. LC/MS (ESI) m/z: 179 (M+H)⁺. The (1R,3R)-3-(pyridin-2-yloxy)cyclopentan-1-amine was used to prepare Compound 721 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (t, J = 5.9 Hz, 1H), 8.41 (s, 1H), 8.16 – 8.13 (m, 1H), 7.70 – 7.65 (m, 1H), 7.10 (s, 1H), 7.03 (s, 1H), 6.96 – 6.92 (m, 1H), 6.83 (s, 1H), 6.77 (d, J = 8.3 Hz, 1H), 5.84 (s, 2H), 5.46 – 5.39 (m, 1H), 5.05 (d, J = 7.0 Hz, 1H), 4.94 (d, J = 8.5 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 3.90 – 3.81 (m, 1H), 3.21 – 3.14 (m, 1H), 2.32 – 2.27 (m, 1H), 2.22 – 2.16 (m, 1H), 2.15 – 1.96 (m, 4H), 1.77 – 1.58 (m, 2H), 1.22 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 532 (M+H)⁺. RT (Method A): 1.11 min. Compound 740 was prepared according to the procedures above, using phenol as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (t, J = 5.8 Hz, 1H), 8.42 (s, 1H), 7.30 – 7.25 (m, 2H), 7.11 (s, 1H), 7.03 (s, 1H), 6.92 – 6.88 (m, 4H), 5.98 (s, 2H), 5.08 (d, J = 7.0 Hz, 1H), 4.94 (d, J = 9.0 Hz, 1H), 4.92 – 4.88 (m, 1H), 4.45 (d, J = 5.7 Hz, 2H), 3.89 – 3.82 (m, 1H), 3.20 – 3.15 (m, 1H), 2.30 (dd, J = 12.7, 8.4 Hz, 1H), 2.19 – 2.07 (m, 4H), 2.03 – 1.98 (m, 1H), 1.78 – 1.70 (m, 1H), 1.64 – 1.56 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 531 (M+H)⁺. RT (Method A): 1.56 min. Scheme 237. Synthesis of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3- ((1S,3S)-3-((4-methylpyridin-2-yl)oxy)cyclopentane-1-carboxamido)-4-oxo-4,6,7,8-tetrahydro- pyrrolo[1,2-a]-pyrimidine-6-carboxamide (Compound 723) Step 1: 4-Methylpyridin-2-ol To a solution of 2-methoxy-4-methylpyridine (1 g, 8.1 mmol) in DMF (10 mL) was added TsOH (6.9 g, 40.6 mmol) and LiCl (1.7 g, 40.6 mmol) under a nitrogen atmosphere at 0 °C and the reaction mixture was stirred at 80 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (360 mg, yield 40.7%) as a white solid, which was used directly in the next reaction without purification. LC/MS (ESI) m/z: 110 (M+H)⁺. Step 2: Methyl (1S,3S)-3-((4-methylpyridin-2-yl)oxy)cyclopentane-1-carboxylate To a mixture of 4-methylpyridin-2-ol (360 mg, 3.3 mmol), methyl (1S,3R)-3-hydroxycyclopentane- 1-carboxylate (480 mg, 3.3 mmol) and PPh₃ (1.2 g, 4.9 mmol) in THF (5 mL) was added DIAD (1 g, 4.9 mmol) under a nitrogen atmosphere at 0 °C and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (220 mg, yield 28.3%) as a yellow solid. LC/MS (ESI) m/z: 236 (M+H)⁺. The methyl (1S,3S)-3-((4-methylpyridin-2-yl)oxy)cyclopentane-1-carboxylate was used to prepare Compound 723 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 9.06 (t, J = 5.8 Hz, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.00 (d, J = 5.2 Hz, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 6.78 (d, J = 4.8 Hz, 1H), 6.58 (s, 1H), 5.85 (s, 2H), 5.49 – 5.34 (m, 1H), 5.00 (d, J = 8.5 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.36 (d, J = 4.3 Hz, 1H), 3.27 (dd, J = 8.9, 6.5 Hz, 1H), 2.36 – 2.31 (m, 1H), 2.25 (s, 3H), 2.21 – 2.14 (m, 1H), 2.14 – 2.06 (m, 2H), 2.04 – 1.95 (m, 2H), 1.80 – 1.70 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 574 (M+H)⁺. Scheme 238. Synthesis of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((3-(2- fluorophenyl)-1,2,4-oxadiazol-5-yl)amino)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 724) Step 1: 3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-amine A solution of 5-chloro-3-(2-fluorophenyl)-1,2,4-oxadiazole (260 mg, 1.31 mmol) in NH₃/1,4- dioxane (5 mL, 0.4 M) was stirred under a nitrogen atmosphere at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (235 mg, yield 99.9%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 180 (M+H)⁺. The 3-(2-fluorophenyl)-1,2,4-oxadiazol-5-amine was used to prepare Compound 724 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (t, J = 5.7 Hz, 1H), 8.64 (s, 1H), 8.41 (s, 1H), 8.06 - 8.00 (m, 1H), 7.64 - 7.57 (m, 1H), 7.42 - 7.35 (m, 2H), 7.11 (s, 1H), 6.84 (s, 1H), 6.11 - 6.03 (m, 1H), 5.84 (s, 2H), 5.03 (d, J = 8.7 Hz, 1H), 4.53 - 4.43 (m, 2H), 2.54 - 2.52 (m, 1H), 2.39 - 2.33 (m, 1H), 2.23 - 2.15 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 533 (M+H)⁺. RT (Method A): 1.21 min. Scheme 239. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((5-(pyridin-2-yl)isoxazol-3-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compoun Step 1: Ethyl 5-(pyridin-2-yl)isoxazole-3-carboxylate To a mixture of 2-bromopyridine (1.00 g, 6.37 mmol) and ethyl 5-(tributylstannyl)isoxazole-3- carboxylate (4.10 g, 9.56 mmol) in toluene (15 mL) was added Pd(t-Bu3P)2 (323 mg, 0.64 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at 110 °C overnight. The mixture was cooled and diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 16% EtOAc in PE) to give the title compound (900 mg, yield 64.8%) as a yellow solid. LC/MS (ESI) m/z: 219 (M+H)⁺. Step 2: 5-(Pyridin-2-yl)isoxazole-3-carboxylic acid To a solution of ethyl 5-(pyridin-2-yl)isoxazole-3-carboxylate (900 mg, 4.13 mmol) in THF/water (12 mL, v/v= 9/3) was added LiOH (149 mg, 6.19 mmol) at room temperature and the mixture was stirred at room temperature for 5 hours. The mixture was acidified with 1N aq. HCl to pH~3 and filtered to give the title compound (490 mg, yield 62.5%) as a white solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 3: tert-Butyl (5-(pyridin-2-yl)isoxazol-3-yl)carbamate To a solution of 5-(pyridin-2-yl)isoxazole-3-carboxylic acid (490 mg, 2.58 mmol) in t-BuOH (10 mL) was added TEA (521 mg, 5.16 mmol) and DPPA (3.55 g, 12.90 mmol), and the mixture was stirred at 90 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 33% EtOAc in PE) to give the title compound (400 mg, yield 59.4%) as a white solid. LC/MS (ESI) (m/z): 262 (M+H)⁺. Step 4: 5-(Pyridin-2-yl)isoxazol-3-amine To a solution of tert-butyl (5-(pyridin-2-yl)isoxazol-3-yl)carbamate (400 mg, 1.53 mmol) in DCM (5 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) and the mixture was stirred at room temperature for 5 hours. The mixture was quenched with aq. NaHCO3 solution and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (180 mg, yield 72.9%) as a white solid. LC/MS (ESI) m/z: 162 (M+H)⁺. The 5-(pyridin-2-yl)isoxazol-3-amine was used to prepare Compound 725 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.14 - 9.03 (m, 2H), 8.71 (d, J = 4.6 Hz, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.02 - 7.97 (m, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.11 (s, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.8 Hz, 1H), 4.54 - 4.42 (m, 2H), 3.27 - 3.24 (m, 1H), 2.38 - 2.33 (m, 1H), 2.23 - 2.15 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 515 (M+H)⁺. RT (Method A): 1.04 min. Scheme 240. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- (difluoromethoxy)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluoro-phenyl)-1,3,4- thiadiazole-2-carboxamide (Compound 726) Step 1: tert-Butyl (2-(((6S,8R)-8-(difluoromethoxy)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)- 4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2-c]-pyridin-6- yl)carbamate To a solution of tert-butyl (2-(((6S,8R)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-8- hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)thieno[3,2-c]pyridin-6- yl)carbamate (150 mg, 0.22 mmol) in DCM (3 mL) was added KOAc (87 mg, 0.88 mmol) in water (2 mL) dropwise at 0 °C. Afterwards, to the reaction mixture was added a solution of TMSCF₂Br (90 mg, 0.44 mmol) in DCM (3 mL) dropwise at 0°C and the reaction was stirred for 4 hours. The mixture was quenched with MeOH and diluted with DCM. The organic layer washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 15% MeOH in DCM) to give the title compound (80 mg, yield 49.7%) as a yellow oil. LC/MS (ESI) m/z: 729 (M+H)⁺. Step 2: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-(difluoromethoxy)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamide (Compound 726) To a solution of tert-butyl (2-(((6S,8R)-8-(difluoromethoxy)-3-(5-(2-fluorophenyl)-1,3,4-thiadiazole- 2-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2- c]pyridin-6-yl)carbamate (80 mg, 0.11 mmol) in DCM (5 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) at 0°C and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% FA) to give Compound 726 (8 mg, yield 11.6%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 9.36 - 9.24 (m, 1H), 8.80 (s, 1H), 8.43 - 8.31 (m, 3H), 8.21 (s, 1H), 7.76 - 7.72 (m, 1H), 7.59 - 7.55 (m, 1H), 7.51 - 7.48 (m, 1H), 7.22 - 6.86 (m, 2H), 5.17 - 5.05 (m, 2H), 4.62 - 4.51 (m, 1H), 4.42 - 4.38 (m, 1H), 2.38 - 2.33 (m, 2H). LC/MS (ESI) (m/z): 629 (M+H)⁺ _. RT (Method A): 1.19 min. Compound 769 was prepared according to the procedures above, using tert-butyl (2-(((6S,8S)-3- (5-(2-fluorophenyl)-1,3,4-thiadiazole-2-carboxamido)-8-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)-methyl)thieno[3,2-c]pyridin-6-yl)carbamate as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 9.15 (t, J = 5.3 Hz, 1H), 8.82 (s, 1H), 8.42 – 8.36 (m, 2H), 8.17 (s, 1H), 7.94 (t, J = 59.5 Hz, 1H), 7.73 (t, J = 5.8 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.24 – 6.92 (m, 2H), 6.20 (d, J = 5.8 Hz, 1H), 5.04 – 4.94 (m, 1H), 4.92 – 4.85 (m, 1H), 4.48 – 4.35 (m, 2H), 1.98 – 1.88 (m, 2H). LC/MS (ESI) (m/z): 629 (M+H)⁺. RT (Method A): 1.22 min. Scheme 241. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-cyclobutyl- pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carboxamide (Compound 727) Step 1: Ethyl 2-cyclobutylpyrimidine-5-carboxylate To a solution of ethyl 2-chloropyrimidine-5-carboxylate (300 mg, 1.61 mmol) in THF (6 mL) was added cyclobutylzinc(II) bromide (646 mg, 3.22 mmol, 1mol/L) and Pd(dppf)Cl2 (117 mg, 0.16 mmol) at room temperature and the mixture was stirred under a nitrogen atmosphere at 70 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 10 - 30% EtOAc in PE) to give the title compound (166 mg, yield 50%) as a yellow solid, which was directly used in the next reaction without purification. LC/MS (ESI) m/z: 207 (M+H)⁺. The ethyl 2-cyclobutylpyrimidine-5-carboxylate was used to prepare Compound 727 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (d, J = 5.7 Hz, 2H), 9.12 - 9.08 (m, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.05 (d, J = 8.5 Hz, 1H), 4.50 - 4.42 (m, 2H), 3.90 - 3.79 (m, 1H), 3.38 - 3.36 (m, 1H), 2.39 - 2.36 (m, 2H), 2.34 - 2.32 (m, 2H), 2.24 - 2.19 (m, 1H), 2.08 - 1.98 (m, 2H), 1.92 - 1.86 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 531 (M+H)⁺. Scheme 242. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(3-(2- fluorophenyl)-bicyclo[1.1.1]pentane-1-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]-pyrimidine-6-carboxamide (Compound 732) Step 1: 1-(1,3-Dioxoisoindolin-2-yl)3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate To a stirred mixture of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (600 mg, 3.53 mmol) in DCM (6 mL) were added DIC (534 mg, 4.24 mmol), DMAP (43 mg, 0.35 mmol) and 2-hydroxy- isoindoline-1,3-dione (691 mg, 4.24 mmol) and the mixture was stirred at room temperature for 2 hours. Then the reaction mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed by brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The reside was purified by column chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (600 mg, yield 53.9%) as a white solid. LC/MS (ESI) m/z: 316 (M+H)⁺. Step 2: Methyl 3-(2-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxylate To a solution of 1-(1,3-dioxoisoindolin-2-yl)3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate (300 mg, 0.95 mmol), Ni₂(Cl)₂(bipy)₂(H₂O)₂ (578 mg, 0.95 mmol), Zn (63 mg, 0.95 mmol) and 1-fluoro-2-iodo- benzene (211 mg, 0.95 mmol) in DMA (3 mL) was added TMSCl (105 mg, 0.95mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The reside was purified by column chromatography (silica gel, 0 - 15% EtOAc in PE) to give the title compound (60 mg, yield 28.6%) as a yellow oil. LC/MS (ESI) m/z: 221 (M+H)⁺. The methyl 3-(2-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxylate was used to prepare Compound 732 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 5.8 Hz, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 7.34 – 7.28 (m, 1H), 7.24 (t, J = 6.7 Hz, 1H), 7.17 (d, J = 6.6 Hz, 1H), 7.14 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.86 (s, 2H), 5.01 (d, J = 8.3 Hz, 1H), 4.46 (d, J = 14.0 Hz, 2H), 3.30 – 3.25 (m, 1H), 2.40 (s, 6H), 2.35 – 2.32 (m, 1H), 2.23 – 2.15 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 559 (M+H)⁺. RT (Method A): 1.38 min. Compound 736 was prepared according to the procedures above, using (1R,3S)-3- (methoxycarbonyl)cyclopentane-1-carboxylic acid as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (d, J = 11.5 Hz, 1H), 9.14 – 8.97 (m, 1H), 8.74 (d, J = 2.7 Hz, 1H), 8.41 (s, 1H), 7.46 – 7.34 (m, 1H), 7.29 – 7.20 (m, 1H), 7.18 – 7.09 (m, 3H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 9.2 Hz, 1H), 4.46 (d, J = 5.1 Hz, 2H), 3.45 – 3.36 (m, 1H), 3.29 – 3.23 (m, 2H), 2.39 – 2.21 (m, 2H), 2.20 – 2.08 (m, 2H), 2.06 – 1.92 (m, 2H), 1.85 – 1.64 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 561 (M+H)⁺. Compound 756 was prepared according to the procedures above, using (1R,3S)-3- (methoxycarbonyl)cyclopentane-1-carboxylic acid as the starting material in Step 1 and 2-iodopyridine in place of 1-fluoro-2-iodo-benzene in Step 2.¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 9.07 (t, J = 5.7 Hz, 1H), 8.74 (s, 1H), 8.51 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 7.73 – 7.63 (m, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.22 – 7.15 (m, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 9.3 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.26 – 3.16 (m, 2H), 2.48 – 2.25 (m, 2H), 2.25 – 2.07 (m, 2H), 2.07 – 1.98 (m, 2H), 1.97 – 1.87 (m, 2H), 1.87 – 1.75 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 544 (M+H)⁺. Scheme 243. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-((5-(3- methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 734) Step 1: 3-Methyl-N-(5-methyl-1,2,4-oxadiazol-3-yl)picolinamide To a mixture of 5-methyl-1,2,4-oxadiazol-3-amine (500 mg, 5.05 mmol) and 3-methylpicolinic acid (830 mg, 6.06 mmol) in MeCN (3 mL) was added NMI (1.24 g, 15.2 mmol) and TCFH (4.24 g, 15.2 mmol) at room temperature and the mixture was stirred at 40 °C for 2 hours. The mixture was cooled and diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (540 mg, yield 49.1%) as a white solid. LC/MS (ESI) m/z: 219 (M+H)⁺. Step 2: 5-(3-Methylpyridin-2-yl)-1,2,4-oxadiazol-3-amine To a solution of 3-methyl-N-(5-methyl-1,2,4-oxadiazol-3-yl)picolinamide (540 mg, 2.48 mmol) in EtOH (5 mL) was added aq. HCl (2 mL, 6 M) at room temperature and the mixture was stirred at 80 °C for 2 hours. The mixture was neutralized with saturated aq. NaHCO₃ solution and extracted with CHCl₃/i- PrOH (v/v= 3/1) twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (181 mg, yield 41.5%) as a white solid. LC/MS (ESI) m/z: 177 (M+H)⁺. The 5-(3-methylpyridin-2-yl)-1,2,4-oxadiazol-3-amine was used to prepare Compound 734 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (t, J = 5.8 Hz, 1H), 9.01 (s, 1H), 8.65 (d, J = 4.3 Hz, 1H), 8.45 - 8.39 (m, 2H), 7.94 (d, J = 7.8 Hz, 1H), 7.61 (dd, J = 7.9, 4.6 Hz, 1H), 7.13 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.06 (d, J = 9.3 Hz, 1H), 4.54 - 4.43 (m, 2H), 2.68 (s, 3H), 2.41 - 2.35 (m, 1H), 2.25 - 2.17 (m, 1H), 2.04 - 1.96 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 530 (M+H)⁺. RT (Method A): 1.03 min. Scheme 244. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((5-(m-tolyl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6-carboxamide (Compound 735) Step 1: 3-Methyl-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide To a mixture of 5-methyl-1,2,4-oxadiazol-3-amine (800 mg, 8.1 mmol) and 3-methylbenzoyl chloride (1.24 g, 8.1 mmol) in toluene (12 mL) was added pyridine (1.92 g, 24.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1 g, yield 56.8%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 218 (M+H)⁺. Step 2: 5-(m-tolyl)-1,2,4-oxadiazol-3-amine To a solution of 3-methyl-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide (1 g, 4.59 mmol) in EtOH (10 mL) was added aq. HCl (2 mL, 6M). The reaction mixture was stirred at 80 °C for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (600 mg, yield 74.3%) as a white solid. LC/MS (ESI) m/z: 176 (M+H)⁺. The 5-(m-tolyl)-1,2,4-oxadiazol-3-amine was used to prepare Compound 735 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (t, J = 5.9 Hz, 1H), 8.94 (s, 1H), 8.42 (s, 1H), 8.39 (s, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 4.7 Hz, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 8.9 Hz, 1H), 4.53 - 4.42 (m, 2H), 2.43 (s, 3H), 2.40 - 2.36 (m, 1H), 2.35 - 2.31 (m, 1H), 2.24 - 2.18 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 529 (M+H)⁺. RT (Method A): 1.56 min. The following compounds were prepared according to the procedures above, using the appropriate acyl chlorides as the starting material. Scheme 245. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-4-fluoro-5-(2-methylpyridin-3- yl)isoxazole-3-carboxamide (Compound 737) Step 1: Ethyl 5-(2-chloropyridin-3-yl)isoxazole-3-carboxylate To a mixture of ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (1.9 g, 4.4 mmol) and 3-bromo-2- chloropyridine (1.0 g, 5.28 mmol) in 1,4-dioxane (20 mL) was added Pd(t-Bu3P)2 (226 mg, 0.44 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred in a sealed tube at 115 °C for 16 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (1.05 g, yield 94.3%) as a yellow oil. LC/MS (ESI) m/z: 253 (M+H)⁺. Step 2 Lithium 5-(2-chloropyridin-3-yl)isoxazole-3-carboxylate To a mixture of ethyl 5-(2-chloropyridin-3-yl)isoxazole-3-carboxylate (1.05 g, 4.14 mmol) in THF (10 mL) and water (2 mL) was added LiOH (149 mg, 6.23 mmol) under a nitrogen atmosphere and the mixture was stirred at 25 °C for 2 hours. The mixture concentrated under reduced pressure to dryness to give the title compound (900 mg, yield 94.1%) as a yellow solid. LC/MS (ESI) m/z: 225 (M+H)⁺. Step 3: N-(4-(tert-Butyl)phenyl)-5-(2-chloropyridin-3-yl)isoxazole-3-carboxamide To a mixture of lithium 5-(2-chloropyridin-3-yl)isoxazole-3-carboxylate (900 mg, 4.1 mmol) and 4- (tert-butyl)aniline (630 mg, 4.28 mmol) in DMF (10 mL) was added DIPEA (1.65 g, 12.84 mmol) and HATU (1.95 g, 5.14 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 10 - 40% EtOAc in PE) to give the title compound (800 mg, yield 54.8%) as a white solid. LC/MS (ESI) m/z: 336 (M+H)⁺. Step 4: N-(4-(tert-Butyl)phenyl)-5-(2-chloropyridin-3-yl)-4-fluoroisoxazole-3-carboxamide To a solution of N-(4-(tert-butyl)phenyl)-5-(2-chloropyridin-3-yl)isoxazole-3-carboxamide (500 mg, 1.49 mmol) in THF (10 mL) was dropwise added n-BuLi (1.5 mL, 3.75 mmol, 2.5 M in hexane) at -65°C and the mixture was stirred at -65 °C for 1 hour. A solution of NFSI (1.18 g, 3.75 mmol) in THF (10 mL) was added to the reaction solution and the resulting mixture was stirred at -65 °C for 1 hour. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (260 mg, yield 46.3%) as a white solid. LC/MS (ESI) (m/z): 354 (M+H)⁺. Step 5: N-(4-(tert-Butyl)phenyl)-4-fluoro-5-(2-methylpyridin-3-yl)isoxazole-3-carboxamide To a mixture of N-(4-(tert-butyl)phenyl)-5-(2-chloropyridin-3-yl)-4-fluoroisoxazole-3-carboxamide (100 mg, 0.27 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.76 mL, 2.7 mmol, 3.5 M in THF) in 1,4-dioxane (3 mL) and water (1 mL) was added K₃PO₄ (170 mg, 0.8 mmol) and Pd(dtbpf)Cl₂ (17 mg, 0.03 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 100°C for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (85 mg, yield 90.0%) as a colorless oil. LC/MS (ESI) m/z: 354 (M+H)⁺. Step 6: tert-Butyl (4-(tert-butyl)phenyl)(4-fluoro-5-(2-methylpyridin-3-yl)isoxazole-3-carbonyl)-carbamate To a solution of N-(4-(tert-butyl)phenyl)-4-fluoro-5-(2-methylpyridin-3-yl)isoxazole-3-carboxamide (85 mg, 0.24 mmol) in MeCN (5 mL) was added DMAP (3 mg, 0.02 mmol) and (Boc)2O (105 mg, 0.48 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give title compound (50 mg, yield 45.9%) as a white solid. LC/MS (ESI) m/z:454 (M+H)⁺. Step 7: 4-Fluoro-5-(2-methylpyridin-3-yl)isoxazole-3-carboxylic acid To a solution of H2O2 (63 mg, 0.55 mmol, 30% wt. in water) in water (1 mL) was added LiOH (13 mg, 0.55 mmol) at room temperature and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of tert-butyl (4-(tert-butyl)phenyl)(4-fluoro-5-(2-methylpyridin-3-yl)- isoxazole-3-carbonyl)carbamate (50 mg, 0.11 mmol) in THF (2 mL) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (20 mg, yield 81.6%) as a white solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 223 (M+H)⁺. The 4-fluoro-5-(2-methylpyridin-3-yl)isoxazole-3-carboxylic acid was used to prepare Compound 737 based on the procedures set forth in, e.g., Scheme 63.¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.71 (s, 1H), 8.70 - 8.68 (m, 1H), 8.41 (s, 1H), 8.04 (d, J = 6.5 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.06 (d, J = 8.9 Hz, 1H), 4.54 - 4.43 (m, 2H), 3.38 (d, J = 1.6 Hz, 1H), 2.62 (s, 3H), 2.41 - 2.36 (m, 1H), 2.26 - 2.20 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 575 (M+H)⁺. RT (Method A): 1.01 min. Compound 772 was prepared based on the procedures above using 3-bromo-4-chloropyridine in place of 3-bromo-2-chloropyridine in Step 1.¹H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.12 (t, J = 5.7 Hz, 1H), 8.76 (s, 1H), 8.71 (s, 1H), 8.65 (d, J = 5.1 Hz, 1H), 8.42 (s, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.12 (s, 1H), 6.86 (s, 1H), 5.92 (s, 2H), 5.06 (d, J = 8.9 Hz, 1H), 4.53 – 4.42 (m, 2H), 3.39 – 3.34 (m, 1H), 2.46 (s, 3H), 2.40 – 2.35 (m, 1H), 2.26 – 2.18 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 575 (M+H)⁺ _. RT (Method A): 1.00 min. Compound 757 was prepared based on the procedures above starting from Step 3, using 3-(4- chloropyridin-3-yl)isoxazole-5-carboxylic acid as the starting material.¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.69 (s, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.09 - 5.04 (m, 1H), 4.54 - 4.42 (m, 2H), 3.40 - 3.35 (m, 1H), 2.44 (s, 3H), 2.40 - 2.33 (m, 1H), 2.28 - 2.20 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 575 (M+H)⁺. RT (Method A): 0.89 min. Scheme 246. Synthesis of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 739) Step 1: N-(5-methyl-1,2,4-oxadiazol-3-yl)picolinamide To a mixture of 5-methyl-1,2,4-oxadiazol-3-amine (1.0 g, 8.1 mmol) and picolinic acid (805 mg, 8.1 mmol) in MeCN (20 mL) was added NMI (2.0 g, 24.4 mmol) and TCFH (6.8 g, 24.4 mmol). The mixture was stirred at 40°C overnight. The mixture was diluted with CHCl3/i-PrOH (3/1, v/v), washed with 1 N aq. HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 8% MeOH in DCM) to give the title compound (1.2 g, yield 72.3%) as a white solid. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 2: 5-(Pyridin-2-yl)-1,2,4-oxadiazol-3-amine To a solution of N-(5-methyl-1,2,4-oxadiazol-3-yl)picolinamide (1.2 g, 5.9 mmol) in EtOH (15 mL) was added 6N aq. HCl (5.0 mL, 30 mmol) and the mixture was stirred at 80 °C for 4 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 8% MeOH in DCM) and further purified by prep-HPLC (YMC-Actus Triart C18250*20 mm*5 um, 15 - 95% MeCN in water with 0.1% FA) to give the title compound (150 mg, yield 15.7%) as a white solid. LC/MS (ESI) m/z: 163 (M+H)⁺. Step 3: Methyl (6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of methyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxylate (100 mg, 0.35 mmol) and 5-(pyridin-2-yl)-1,2,4-oxadiazol-3-amine (56 mg, 0.35 mmol) in toluene (3 mL) was added XantPhos (40 mg, 0.07 mmol), Pd2(dba)3 (64 mg, 0.07 mmol) and Cs₂CO₃ (340 mg, 1.0 mmol) under a nitrogen atmosphere. The mixture was degassed under a nitrogen atmosphere three times and stirred at 105 °C for 2 hours. The mixture was cooled and diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 20: 1) to give the title compound (30 mg, yield 23.4%) as a yellow oil. LC/MS (ESI) m/z: 369 (M+H)⁺. Step 4: (6S,8R)-8-Methyl-4-oxo-3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (30 mg, 0.08 mmol) in THF/water (3 mL, v/v= 2/1) was added LiOH (4.0 mg, 0.16 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (25 mg, yield 86.5%) as a white solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 355 (M+H)⁺. Step 5: tert-Butyl (2-(((6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of (6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetra-hydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (25 mg, 0.07 mmol) and tert-butyl (2-(aminomethyl)- thieno[3,2-c]pyridin-6-yl)carbamate (20 mg, 0.07 mmol) in DMF (3 mL) was added DIPEA (45 mg, 0.35 mmol) and HATU (40 mg, 0.11 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-TLC (DCM: MeOH= 10: 1) to give the title compound (20 mg, yield 46.5%) as a white solid. LC/MS (ESI) m/z: 616 (M+H)⁺. Step 6: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3-((5-(pyridin-2-yl)-1,2,4- oxadiazol-3-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 739) To a solution of tert-butyl (2-(((6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-2-yl)-1,2,4-oxadiazol-3- yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (20 mg, 0.03 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% NH4CO3) to give Compound 739 (2 mg, yield 12.0%) as a white solid.¹H NMR (400 MHz, DMSO- d₆) δ 9.09 (s, 2H), 8.83 (s, 1H), 8.44 - 8.40 (m, 2H), 8.23 - 8.19 (m, 1H), 8.14 - 8.09 (m, 1H), 7.74 - 7.70 (m, 1H), 7.15 - 7.11 (m, 1H), 6.86 - 6.83 (m, 1H), 5.85 (s, 2H), 5.09 - 5.01 (m, 1H), 4.54 - 4.43 (m, 2H), 3.19 - 3.18 (m, 1H), 2.24 - 2.20 (m, 1H), 2.01 - 1.98 (m, 1H), 1.30 (d, J = 1.2 Hz, 3H). LC/MS (ESI) m/z: 516 (M+H)⁺. RT (Method A): 0.98 min. Scheme 247. Synthesis of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (((1R,3R)-3-(pyrimidin-2-yloxy)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 722) Step 1: tert-Butyl ((1R,3R)-3-(pyrimidin-2-yloxy)cyclopentyl)carbamate To a mixture of tert-butyl ((1R,3R)-3-hydroxycyclopentyl)carbamate (1.0 g, 4.97 mmol) in THF (20 mL) was added NaH (1.19 g, 14.91 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was degassed under a nitrogen atmosphere three times and stirred at 25 °C for 1 hour. Afterwards, to the reaction mixture was added a solution of 2-chloropyrimidine (1.13 g, 9.94 mmol) and the resulting mixture was stirred at 70 °C for 5 hours. The mixture was quenched with saturated aq. NH₄Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (900 mg, yield 64.8%) as a white solid. LC/MS (ESI) m/z: 280 (M+H)⁺. The tert-butyl ((1R,3R)-3-(pyrimidin-2-yloxy)cyclopentyl)carbamate was then used to prepare Compound 722 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (t, J = 6.0 Hz, 1H), 8.59 (d, J = 4.8 Hz, 2H), 8.41 (s, 1H), 7.12 - 7.09 (m, 2H), 7.04 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.44 - 5.39 (m, 1H), 5.08 (d, J = 6.9 Hz, 1H), 4.94 (d, J = 8.5 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 3.90 - 3.83 (m, 1H), 3.21 - 3.14 (m, 1H), 2.33 - 2.28 (m, 1H), 2.21 - 2.13 (m, 3H), 2.10 - 1.99 (m, 2H), 1.81 - 1.73 (m, 1H), 1.66 - 1.58 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 533 (M+H)⁺. RT (Method A): 0.80 min. Scheme 248. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((1S,2S)-2-(thiazol-2-yl)cyclopropane-1-carboxamido)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 742) Step 1: Ethyl (1S,2S)-2-carbamoylcyclopropane-1-carboxylate To a mixture of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (500 mg, 3.16 mmol) and NH4Cl (338 mg, 6.32 mmol) in DMF (8 mL) was added DIPEA (2.04 g, 15.8 mmol) and HATU (1.44 g, 3.79 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was and diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (480 mg, yield 96.6%) as a yellow oil, which was used directly in the next step without purification. LC/MS (ESI) m/z: 158 (M+H)⁺. Step 2: Ethyl (1S,2S)-2-carbamothioylcyclopropane-1-carboxylate To a solution of ethyl (1S,2S)-2-carbamoylcyclopropane-1-carboxylate (480 mg, 3.06 mmol) in THF (30 mL) was added Lawesson's reagent (1.48 g, 3.67 mmol) and the mixture was stirred at 80 °C overnight. The mixture was cooled and diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (500 mg, yield 94.5%) as a yellow oil, which was used directly in the next step without purification. LC/MS (ESI) m/z: 174 (M+H)⁺. Step 3: Ethyl (1S,2S)-2-(thiazol-2-yl)cyclopropane-1-carboxylate To a mixture of ethyl (1S,2S)-2-carbamothioylcyclopropane-1-carboxylate (100 mg, 0.58 mmol) and 2-bromo-1,1-diethoxyethane (171 mg, 0.87 mmol) in EtOH (3 mL) was added TsOH (119 mg, 0.70 mmol) and the mixture was stirred at 80°C for 5 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 17% EtOAc in PE) to give the title compound (60 mg, yield 52.7%) as a brown oil. LC/MS (ESI) m/z: 198 (M+H)⁺. The ethyl (1S,2S)-2-(thiazol-2-yl)cyclopropane-1-carboxylate was used to prepare Compound 742 based on the procedure set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 1H), 9.06 (t, J = 5.8 Hz, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 7.68 (d, J = 3.3 Hz, 1H), 7.54 (d, J = 3.3 Hz, 1H), 7.10 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.01 (d, J = 8.6 Hz, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.29 - 3.26 (m, 1H), 2.90 - 2.85 (m, 1H), 2.81 - 2.76 (m, 1H), 2.34 - 2.31 (m, 1H), 2.20 - 2.13 (m, 1H), 1.60 - 1.54 (m, 1H), 1.52 - 1.47 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 522 (M+H)⁺. RT (Method A): 0.83 min. Scheme 249. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(4-fluoro-3-(5- methyl-1,3,4-thiadiazol-2-yl)benzamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]- pyrimidine Step 1: 4-Fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzoic acid To a mixture of 2-bromo-5-methyl-1,3,4-thiadiazole (500 mg, 2.80 mmol) and (2-fluoro-5- (methoxycarbonyl)phenyl)boronic acid (834 mg, 4.21 mmol) in 1,4-dioxane (6 mL) and water (3 mL) was added Pd(dppf)Cl₂ (204 mg, 0.28 mmol) and K₂CO₃ (1.15 g, 8.4 mmol), the mixture was degassed under a nitrogen atmosphere three times and stirred at 80 °C overnight. The mixture was cooled and diluted with water, washed with DCM twice. The aqueous layer was acidified with 1 N aq. HCl to pH~4 and extracted with DCM twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (230 mg, yield 34.5%) as a yellow solid, which was used in next step without purification. LC/MS (ESI) (m/z): 239 (M+H)⁺. The 4-fluoro-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzoic acid was used to prepare Compound 743 based on the procedures set forth in, e.g., Scheme 19.¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 9.25 (t, J = 4.9 Hz, 1H), 8.83 (dd, J = 6.8, 2.3 Hz, 1H), 8.59 (s, 1H), 8.54 (s, 1H), 8.22 - 8.16 (m, 1H), 7.68 - 7.62 (m, 1H), 7.58 - 7.45 (m, 2H), 7.44 (s, 1H), 7.26 (s, 1H), 5.07 (d, J = 9.3 Hz, 1H), 4.56 - 4.46 (m, 2H), 3.36 - 3.32 (m, 1H), 2.84 (s, 3H), 2.40 - 2.34 (m, 1H), 2.30 - 2.21 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 591 (M+H)⁺. RT (Method A): 1.09 min. Scheme 250. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((S)-1-phenylpyrrolidine-2-carboxamido)-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6- carboxamide (Compound 744) Step 1: Phenyl-L-proline To a mixture of L-proline (1.00 g, 8.69 mmol) and bromobenzene (1.63 g, 10.4 mmol) in DMF (5 mL) were added K2CO3 (1.80 g, 13.0 mmol) and CuI (83 mg, 0.43 mmol) at room temperature and the mixture was stirred under a nitrogen atmosphere at 100 °C overnight. The mixture was cooled, filtered and the filtrate was concentrated under reduced pressure to dryness to give the title compound (1.62 g, yield 97.5%) as a brown oil, which was used directly in the next step without purification. LC/MS (ESI) m/z: 192 (M+H)⁺. The phenyl-L-proline was used to prepare Compound 744 based on the procedures set forth in, e.g., Scheme 19.¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (s, 1H), 9.05 (t, J = 5.8 Hz, 1H), 8.78 (s, 1H), 8.41 (s, 1H), 7.21 - 7.16 (m, 2H), 7.10 (s, 1H), 6.84 (s, 1H), 6.68 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 5.86 (s, 2H), 4.99 - 4.94 (m, 1H), 4.51 - 4.39 (m, 2H), 4.34 - 4.30 (m, 1H), 3.67 - 3.60 (m, 1H), 3.30 - 3.24 (m, 2H), 2.36 - 2.27 (m, 2H), 2.19 - 2.10 (m, 1H), 2.10 - 1.97 (m, 3H), 1.25 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 544 (M+H)⁺. RT (Method A): 1.31 min. Scheme 251. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 745) Step 1: 3-Bromo-1-phenylpyridin-2(1H)-one To a mixture of 3-bromopyridin-2(1H)-one (2.00 g, 11.5 mmol) and phenylboronic acid (2.10 g, 17.2 mmol) in DCM (15 mL) was added pyridine (1.82 g, 23.0 mmol), Cu(OAc)2 (418 mg, 2.30 mmol) and 4A molecular sieves (500 mg) at room temperature and the mixture was stirred under an oxygen atmosphere at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (2.72 g, yield 95.2%) as a yellow solid. LC/MS (ESI) m/z: 250 (M+H)⁺. Step 2: tert-Butyl (2-(((6S,8R)-8-methyl-4-oxo-3-((2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)-amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6-yl)carbamate To a mixture of 3-bromo-1-phenylpyridin-2(1H)-one (64 mg, 0.26 mmol) and tert-butyl (2- (((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (80 mg, 0.17 mmol) in toluene (3 mL) was added Cs2CO3 (111 mg, 0.34 mmol), Pd2(dba)3 (16 mg, 0.02 mmol) and XantPhos (10 mg, 0.02 mmol) at room temperature and the mixture was stirred under a nitrogen atmosphere at 100°C for 3 hours. The mixture was filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (65 mg, yield 59.8%) as a brown solid. LC/MS (ESI) m/z: 640 (M+H)⁺. Step 3: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3-((2-oxo-1-phenyl-1,2- dihydropyridin-3-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 745) To a solution of tert-butyl (2-(((6S,8R)-8-methyl-4-oxo-3-((2-oxo-1-phenyl-1,2-dihydropyridin-3- yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6- yl)carbamate (65 mg, 0.10 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 70% MeCN in water with 0.1% NH₄HCO₃) to give Compound 745 (12 mg, yield 22.4%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.08 (t, J = 5.8 Hz, 1H), 8.40 (d, J = 0.6 Hz, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.57 - 7.51 (m, 2H), 7.50 - 7.45 (m, 3H), 7.27 (dd, J = 7.4, 1.4 Hz, 1H), 7.17 (dd, J = 6.9, 1.5 Hz, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 6.36 (t, J = 7.2 Hz, 1H), 5.83 (s, 2H), 5.04 (dd, J = 9.3, 0.9 Hz, 1H), 4.53 - 4.40 (m, 2H), 3.30 - 3.24 (m, 1H), 2.39 - 2.32 (m, 1H), 2.23 - 2.14 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 540 (M+H)⁺. RT (Method A): 1.13 min. Compound 746 was prepared according to the procedures above, using 5-bromopyrimidin- 4(3H)-one in place of 3-bromopyridin-2(1H)-one in Step 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (t, J = 5.9 Hz, 1H), 8.41 (s, 1H), 8.06 (d, J = 2.9 Hz, 2H), 7.89 (s, 1H), 7.62 (s, 1H), 7.59 – 7.52 (m, 5H), 7.12 (s, 1H), 6.85 (s, 1H), 5.84 (s, 2H), 5.05 (d, J = 9.5 Hz, 1H), 4.53 – 4.42 (m, 2H), 3.31 – 3.29 (m, 1H), 2.41 – 2.35 (m, 1H), 2.24 – 2.16 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 541 (M+H)⁺. RT (Method A): 0.87 min. Scheme 252. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-((S)-2- (hydroxymethyl)pyrrolidin-1-yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 749) To a solution of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-chloropyrimidine-5- carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (30 mg, 0.05 mmol) in DMF (3 mL) was added (S)-pyrrolidin-2-ylmethanol (11 mg, 0.1 mmol) and K₂CO₃ (13.8 mg, 0.1 mmol) and the reaction mixture was stirred at 80 °C for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC- Actus Triart C₁₈, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 749 (4.6 mg, yield 15.9%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 9.09 (t, J = 5.9 Hz, 1H), 8.84 (s, 2H), 8.58 (s, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.04 (d, J = 8.8 Hz, 1H), 4.82 (t, J = 5.7 Hz, 1H), 4.53 - 4.41 (m, 2H), 4.18 (s, 1H), 3.66 - 3.61 (m, 1H), 3.61 - 3.55 (m, 1H), 3.54 - 3.46 (m, 1H), 3.42 - 3.33 (m, 2H), 2.40 - 2.33 (m, 1H), 2.24 - 2.16 (m, 1H), 2.11 - 2.00 (m, 2H), 1.98 - 1.87 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 576 (M+H)⁺. RT (Method A): 0.74 min. The following compounds were prepared using the procedure above, using the appropriate amines in place of (S)-pyrrolidin-2-ylmethanol. Scheme 253. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-((R)-3- (methoxymethyl)pyrrolidin-1-yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 750) Step 1: Methyl (R)-2-(3-(methoxymethyl)pyrrolidin-1-yl)pyrimidine-5-carboxylate To a solution of methyl 2-chloropyrimidine-5-carboxylate (500 mg, 2.91 mmol) in DMF (5 mL) was added (R)-3-(methoxymethyl)pyrrolidine (402 mg, 3.49 mmol) and K2CO3 (1.2 g, 8.73 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (300 mg, yield 41.0%) as a white solid. LC/MS (ESI) m/z: 252 (M+H)⁺. The methyl (R)-2-(3-(methoxymethyl)pyrrolidin-1-yl)pyrimidine-5-carboxylate was then used to prepare Compound 750 following the procedures set forth in, e.g., Scheme 214.¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 9.12 – 9.08 (m, 1H), 8.84 (s, 2H), 8.57 (s, 1H), 8.42 (s, 1H), 7.12 (s, 1H), 6.88 (s, 1H), 5.98 (s, 2H), 5.05 – 5.02 (m, 1H), 4.51 – 4.42 (m, 2H), 3.72 – 3.65 (m, 2H), 3.54 – 3.48 (m, 1H), 3.41 – 3.36 (m, 2H), 3.35 – 3.33 (m, 2H), 3.27 (s, 3H), 2.60 – 2.55 (m, 1H), 2.40 – 2.34 (m, 1H), 2.23 – 2.05 (m, 2H), 1.78 – 1.72 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 590 (M+H)⁺. RT (Method A): 0.92 min. The following compounds were prepared based on the procedures above, using the appropriate amines as the starting material. Scheme 254. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-((3R)-3-(1- hydroxyethyl)pyrrolidin-1-yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 759) Step 1: tert-Butyl (3R)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-3-formylpyrrolidine-1-carboxylate (2 g, 10.04 mmol) in THF (20 mL) was dropwise added MeMgBr (6.0 mL, 12.04 mmol, 2.0 M in THF) at 0°C and the mixture was stirred at 25 °C for 2 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 10 - 57% EtOAc in PE) to give the title compound (810 mg, yield 37.5%) as a colorless oil.¹H NMR (400 MHz, CDCl3) δ 3.72 - 3.64 (m, 1H), 3.60 - 3.39 (m, 2H), 3.29 - 2.93 (m, 2H), 2.17 - 1.84 (m, 3H), 1.76 - 1.56 (m, 1H), 1.44 (s, 9H), 1.23 - 1.18 (m, 3H). Step 2: 1-((R)-Pyrrolidin-3-yl)ethan-1-ol hydrochloride A solution of tert-butyl (3R)-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (200 mg, 0.93 mmol) in HCl/MeOH (4M, 3 mL, 12 mmol) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (200 mg, crude) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) (m/z): 116 (M+H)⁺. Step 3: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-((3R)-3-(1-hydroxy-ethyl)pyrrolidin-1- yl)pyrimidine-5-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine-6-carboxamide (Compound 759) To a mixture of (6S,8R)-N-((6-aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(2-chloropyrimidine-5- carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (30 mg, 0.06 mmol) and 1-((R)-pyrrolidin-3-yl)ethan-1-ol hydrochloride (11 mg, 0.07 mmol) in DMF (1 mL) was added K₂CO₃ (16 mg, 0.12 mmol) at room temperature and the mixture was stirred at 80 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 95% MeCN in water with 0.1% NH₄CO₃) to give Compound 759 (5.8 mg, yield 16.7%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.84 (s, 2H), 8.57 (s, 1H), 8.44 (s, 1H), 7.13 (s, 1H), 6.93 (s, 1H), 6.10 (s, 2H), 5.06 - 5.01 (m, 1H), 4.73 - 4.64 (m, 1H), 4.53 - 4.42 (m, 2H), 3.77 - 3.63 (m, 2H), 3.62 - 3.53 (m, 1H), 3.49 - 3.41 (m, 1H), 3.41 - 3.35 (m, 1H), 3.25 - 3.17 (m, 1H), 2.39 - 2.33 (m, 1H), 2.25 - 2.17 (m, 2H), 2.10 - 1.94 (m, 1H), 1.84 - 1.69 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H), 1.12 (t, J = 6.7 Hz, 3H). LC/MS (ESI) (m/z): 590 (M+H)⁺. RT (Method A): 0.73 min. Scheme 255. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3- ((1S,2S)-2-(oxazol-2-yl)cyclopropane-1-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 763) Step 1: Ethyl (1S,2S)-2-((2,2-dimethoxyethyl)carbamoyl)cyclopropane-1-carboxylate To a mixture of (1S,2S)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (1 g, 6.33 mmol) and 2,2-dimethoxyethan-1-amine (790 mg, 7.60 mmol) in MeCN (10 mL) was added NMI (779 mg, 9.50 mmol) and TCFH (2.66 g, 9.50 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 10 - 30% EtOAc in PE) to give the title compound (1.2 g, yield 77.4%) as a white solid. LC/MS (ESI) m/z: 246 (M+H)⁺. Step 2: Ethyl (1S,2S)-2-(oxazol-2-yl)cyclopropane-1-carboxylate A solution of ethyl (1S,2S)-2-((2,2-dimethoxyethyl)carbamoyl)cyclopropane-1-carboxylate (1.2 g, 4.76 mmol) in polyphosphoric acid (50 g) was stirred at 120°C overnight. The mixture was cooled, quenched with saturated aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (100 mg, crude) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) (m/z): 182 (M+H)⁺. The ethyl (1S,2S)-2-(oxazol-2-yl)cyclopropane-1-carboxylate was used to prepare Compound 763 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 9.08 (t, J = 5.8 Hz, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.01 (s, 1H), 7.12 (d, J = 4.5 Hz, 2H), 6.87 (s, 1H), 5.93 (s, 2H), 5.02 (d, J = 8.3 Hz, 1H), 4.47 (d, J = 5.6 Hz, 2H), 3.30 - 3.25 (m, 1H), 2.87 - 2.80 (m, 1H), 2.47 - 2.44 (m, 1H), 2.37 - 2.32 (m, 1H), 2.22 - 2.14 (m, 1H), 1.52 - 1.43 (m, 2H), 1.28 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 506 (M+H)⁺. RT (Method A): 0.66 min. Scheme 256. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((3-oxo-4-phenyl-3,4-dihydropyrazin-2-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 766) Step 1: N1-(2,2-Dimethoxyethyl)-N2-phenyloxalamide To a mixture of 2-oxo-2-(phenylamino)acetic acid (2 g, 12.12 mmol) and 2,2-dimethoxyethan-1- amine (1.28 g, 12.12 mmol) in DMF (20 mL) was added DIPEA (4.69 g, 36.36 mmol) and HATU (5.53 g, 14.55 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (1.5 g, yield 42.8%) as a white solid. LC/MS (ESI) m/z: 253 (M+H)⁺. Step 2: 3-Hydroxy-1-phenylpyrazin-2(1H)-one To a solution of N1-(2,2-dimethoxyethyl)-N2-phenyloxalamide (1.2 g, 4.76 mmol) in AcOH (10 mL) was added TFA (2 mL) and the mixture was stirred at 100 °C overnight. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (700 mg, yield 36.7%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) (m/z): 189 (M+H)⁺. Step 3: 3-Bromo-1-phenylpyrazin-2(1H)-one To a solution of 3-hydroxy-1-phenylpyrazin-2(1H)-one (500 mg, 2.65 mmol) in DCE (10 mL) was added POBr3 (7.56 g, 26.5 mmol) and the mixture was stirred at 80 °C for 5 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 10 - 50% EtOAc in PE) to give the title compound (320 mg, yield 48.3%) as a brown oil. LC/MS (ESI) m/z: 251 (M+H)⁺. Step 4: tert-Butyl (2-(((6S,8R)-8-methyl-4-oxo-3-((3-oxo-4-phenyl-3,4-dihydropyrazin-2-yl)-amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]-pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (62 mg, 0.13 mmol) and 3-bromo- 1-phenylpyrazin-2(1H)-one (50 mg, 0.20 mmol) in 1,4-dioxane (3 mL) was added XantPhos (55 mg, 0.01 mmol), Pd2(dba)3 (90 mg, 0.01 mmol) and Cs2CO3 (127 mg, 0.39 mmol) under a nitrogen atmosphere and the mixture was degassed under a nitrogen atmosphere three times and stirred at 100°C for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (50 mg, yield 59.2%) as a white solid. LC/MS (ESI) m/z: 641 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3-((3-oxo-4-phenyl-3,4- dihydropyrazin-2-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 766) To a solution of tert-butyl (2-(((6S,8R)-8-methyl-4-oxo-3-((3-oxo-4-phenyl-3,4-dihydropyrazin-2- yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6- yl)carbamate (50 mg, 0.08 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 95% MeCN in water with 0.1% NH₄CO₃) to give Compound 766 (11 mg, yield 23.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 7.59 - 7.50 (m, 5H), 7.16 (d, J = 4.7 Hz, 1H), 7.13 - 7.10 (m, 2H), 6.86 (s, 1H), 5.87 (s, 2H), 5.07 (d, J = 8.5 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.32 - 3.28 (m, 1H), 2.41 - 2.35 (m, 1H), 2.26 - 2.15 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 541 (M+H)⁺. RT (Method A): 1.22 min. Scheme 257. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (((1R,3R)-3-(phenylamino)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 767) Step 1: tert-Butyl ((1R,3R)-3-(phenylamino)cyclopentyl)carbamate To a mixture of tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (300 mg, 1.50 mmol) and bromobenzene (353 mg, 2.25 mmol) in toluene (10 mL) was added Pd-175 (30 mg) and Cs2CO3 (978 mg, 3.00 mmol) at room temperature and the mixture was stirred under a nitrogen atmosphere at 100°C for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (306 mg, yield 74.0%) as a brown solid. LC/MS (ESI) m/z: 277 (M+H)⁺. Step 2: (1R,3R)-N¹-Phenylcyclopentane-1,3-diamine hydrochloride To a solution of tert-butyl ((1R,3R)-3-(phenylamino)cyclopentyl)carbamate (307 mg, 1.11 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (4M, 2 ml, 8 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness to give the title compound (231 mg, yield 98.3%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 177 (M+H)⁺. Step 3: Methyl (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(phenylamino)cyclopentyl) amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of (1R,3R)-N¹-phenylcyclopentane-1,3-diamine (89 mg, 0.42 mmol) and methyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (100 mg, 0.35 mmol) in toluene (3 mL) was added Cs₂CO₃ (228 mg, 0.70 mmol) and (t-Bu)PhCPhos Pd G3 (27 mg, 0.04 mmol) at room temperature and the mixture was stirred under a nitrogen atmosphere at 100°C overnight. The mixture was cooled, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 10% MeOH in DCM) to give the title compound (10 mg, yield 7.5%) as a brown solid. LC/MS (ESI) m/z: 383 (M+H)⁺. Step 4: Lithium (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(phenylamino)cyclopentyl) amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a solution of methyl (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(phenylamino)cyclopentyl)-amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (10 mg, 0.03 mmol) in THF/water (1 mL, v/v= 2/1) was added LiOH (2 mg, 0.05 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (9 mg, yield 92.6%) as a brown solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 369 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3-(((1R,3R)-3- (phenylamino)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 767) To a mixture of lithium (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(phenylamino)cyclopentyl)-amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (9 mg, 0.02 mmol) and 2- (aminomethyl)thieno[3,2-c]pyridin-6-amine hydrochloride (11 mg, 0.05 mmol) in DMF (1 mL) was added DIPEA (10 mg, 0.07 mmol) and HATU (14 mg, 0.04 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 70% MeCN in water with 0.1% NH4HCO3) to give Compound 767 (8 mg, yield 64.1%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (t, J = 5.8 Hz, 1H), 8.41 (s, 1H), 7.11 (s, 1H), 7.08 - 7.03 (m, 3H), 6.84 (s, 1H), 6.56 (d, J = 7.8 Hz, 2H), 6.50 (t, J = 7.3 Hz, 1H), 5.85 (s, 2H), 5.61 (d, J = 6.5 Hz, 1H), 5.01 (d, J = 6.9 Hz, 1H), 4.95 (d, J = 8.9 Hz, 1H), 4.52 - 4.40 (m, 2H), 3.87 - 3.77 (m, 2H), 3.22 - 3.15 (m, 1H), 2.34 - 2.28 (m, 1H), 2.17 - 2.05 (m, 3H), 1.94 - 1.84 (m, 2H), 1.61 - 1.45 (m, 2H), 1.23 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 530 (M+H)⁺. RT (Method A): 0.85 min. Scheme 258. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (((1R,3R)-3-(pyridin-2-ylamino)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 768) Step 1: tert-butyl ((1R,3R)-3-((6-bromopyridin-2-yl)amino)cyclopentyl)carbamate To a mixture of tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (600 mg, 3.00 mmol) and 2- bromo-6-fluoropyridine (525 mg, 3.00 mmol) in DMSO (8 mL) was added K₂CO₃ (1.24 g, 9.00 mmol) and the mixture was stirred at 120°C overnight. The mixture was cooled, diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 13% EtOAc in PE) to give the title compound (840 mg, yield 78.9%) as a white solid. LC/MS (ESI) m/z: 356 (M+H)⁺. Step 2: tert-Butyl ((1R,3R)-3-(pyridin-2-ylamino)cyclopentyl)carbamate To a mixture of tert-butyl ((1R,3R)-3-((6-bromopyridin-2-yl)amino)cyclopentyl) carbamate (800 mg, 2.25 mmol) in MeOH (13 mL) was added Pd/C (50 mg, 10% wt.), and the mixture was degassed under a nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 3% MeOH in DCM) to give the title compound (550 mg, yield 88.1%) as a white solid. LC/MS (ESI) m/z: 278 (M+H)⁺. Step 3: (1R,3R)-N¹-(Pyridin-2-yl)cyclopentane-1,3-diamine To a solution of tert-butyl ((1R,3R)-3-(pyridin-2-ylamino)cyclopentyl)carbamate (550 mg, 1.98 mmol) in DCM (5 mL) was added HCl in 1,4-dioxane (4M, 2 mL, 8 mmol) and the mixture was stirred at room temperature for 5 hours. The mixture was quenched with aq. NaHCO3 solution and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (180 mg, yield 51.3%) as a brown solid. LC/MS (ESI) m/z: 178 (M+H)⁺. The (1R,3R)-N1-(pyridin-2-yl)cyclopentane-1,3-diamine was used to prepare Compound 768 based on the procedures set forth in, e.g., Scheme 14.¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (t, J = 5.8 Hz, 1H), 8.41 (s, 1H), 7.95 (d, J = 3.3 Hz, 1H), 7.33 (t, J = 8.7 Hz, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 6.83 (s, 1H), 6.50 (d, J = 7.0 Hz, 1H), 6.44 - 6.41 (m, 2H), 5.83 (s, 2H), 4.95 (d, J = 7.1 Hz, 1H), 4.86 - 4.81 (m, 1H), 4.52 - 4.40 (m, 2H), 4.27 - 4.20 (m, 1H), 3.82 - 3.75 (m, 1H), 3.30 - 3.27 (m, 1H), 3.17 - 3.11 (m, 1H), 2.15 - 2.05 (m, 2H), 1.93 - 1.83 (m, 2H), 1.68 - 1.62 (m, 1H), 1.55 - 1.45 (m, 2H), 1.25 (d, J = 7.1 Hz, 3H). LC/MS (ESI) m/z: 531 (M+H)⁺. RT (Method A): 0.35 min. Scheme 259. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-methyl-pyridin-2-yl)isoxazole-5- carboxamide (Compound 770) Step 1: tert-Butyl 4-((6S,8R)-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)benzoate To a solution of tert-butyl (S)-4-(4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)benzoate (5.0 g, 14.07 mmol) in THF (100 mL) was added LiHMDS (56.3 mL, 56.3 mmol, 1M in THF) dropwise at -65 °C for 10 minutes and the mixture was stirred at -65 °C for one hour. Ethyl iodide (2.41 g, 15.47 mol) was added to the above mixture dropwise at -65 °C in 15 minutes while keeping the temperature below -65 °C. The resulting mixture was stirred at -65 °C for another 30 minutes and then quenched with saturated aq. NH4Cl solution at 0°C and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 40 - 60% DCM in EtOAc) to give the title compound (1.7 g, yield 31.5%) as a white solid. LC/MS (ESI) (m/z): 384 (M+H)⁺. Step 2: tert-Butyl 4-((6S,8R)-3-bromo-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamido)benzoate To a solution of tert-butyl 4-((6S,8R)-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamido)benzoate (1.7 g, 4.43 mmol) in MeCN (15 mL) and DMF (3 mL) was added PTSA (76 mg, 0.44 mmol) and NBS (1.18 g, 6.65 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aq. NaHCO3 solution at 0 °C and extracted with MTBE twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1.35 g, yield 65.9%) as a yellow solid, which was used in next step without purification. LC/MS (ESI) (m/z): 462 (M+H)⁺. Step 3: tert-Butyl 4-((6S,8R)-3-((tert-butoxycarbonyl)amino)-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)benzoate To a solution of tert-butyl 4-((6S,8R)-3-bromo-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2- a]pyrimidine-6-carboxamido)benzoate (1.35 g, 2.92 mmol) in toluene (20 mL) was added NH2Boc (855 mg, 7.32 mmol), K₂CO₃ (1.21 g, 8.76 mmol), BrettPhos (235 mg, 0.44 mmol), and Pd₂(dba)₃ (267 mg, 0.29 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 120 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1.2 g, yield 83.0%) as a brown solid, which was used in next step without purification. LC/MS (ESI) (m/z): 499 (M+H)⁺. Step 4: tert-Butyl 4-((6S,8R)-3-(bis(tert-butoxycarbonyl)amino)-N-(tert-butoxycarbonyl)-8-ethyl-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)benzoate To a solution of tert-butyl 4-((6S,8R)-3-((tert-butoxycarbonyl)amino)-8-ethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)benzoate (1.2 g, 2.41 mmol) in MeCN (20 mL) was added DMAP (59 mg, 0.48 mmol) and Boc2O (2.10 g, 9.63 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was poured into 0.5 N aq. HCl at 0 °C and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% EtOAc in PE/DCM (v/v= 1/1)) to give the title compound (1.08 g, yield 64.2%) as a yellow solid. LC/MS (ESI) (m/z): 699 (M+H)⁺. Step 5: (6S,8R)-3-((tert-Butoxycarbonyl)amino)-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine- 6-carboxylic acid To a solution of tert-butyl 4-((6S,8R)-3-(bis(tert-butoxycarbonyl)amino)-N-(tert-butoxy-carbonyl)-8- ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)benzoate (1.08 g, 1.55 mmol) in THF (9 mL) and water (3 mL) was added a solution of H2O2 (15.8 mL, 15.5 mmol, 30% wt.) and LiOH.H2O (195 mg, 4.64 mmol) in water (3 mL) dropwise and the mixture was stirred at 0 °C for 30 minutes. The reaction mixture was washed with MTBE twice. The aqueous layer was acidified with 1 N aq. HCl solution to pH~3 and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (490 mg, yield 98.1%) as a brown solid, which was used in next step without purification. LC/MS (ESI) (m/z): 324 (M+H)⁺. Step 6: (6S,8R)-3-Amino-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of (6S,8R)-3-((tert-butoxycarbonyl)amino)-8-ethyl-4-oxo-4,6,7,8-tetrahydro- pyrrolo[1,2-a]pyrimidine-6-carboxylic acid (460 mg, 1.42 mmol) in DCM (5 mL) was added HCl in 1,4- dioxane (4M, 5 mL, 20 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The suspension was filtered, and the filter cake was dried under vacuum to give the title compound (310 mg, crude) as a white solid, which was used in next step without purification. LC/MS (ESI) (m/z): 224 (M+H)⁺. Step 7: tert-Butyl (2-(((6S,8R)-3-amino-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a solution of (6S,8R)-3-amino-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxylic acid (100 mg, 0.45 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]pyridin-6-yl)carbamate (138 mg, 0.49 mmol) in DMF (3 mL) was added HATU (255 mg, 0.67 mmol) and DIPEA (347 mg, 2.69 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (200 mg, yield 92.1%) as a yellow solid. LC/MS (ESI) (m/z): 485 (M+H)⁺. Step 8: tert-Butyl (2-(((6S,8R)-8-ethyl-3-(3-(3-methylpyridin-2-yl)isoxazole-5-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of tert-butyl (2-(((6S,8R)-3-amino-8-ethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrimidine-6-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (50 mg, 0.10 mmol), lithium 3-(3- methylpyridin-2-yl)isoxazole-5-carboxylate (33 mg, 0.15 mmol) and NMI (42 mg, 0.52 mmol) in MeCN (2 mL) was added TCFH (87 mg, 0.31 mmol). The mixture was stirred at room temperature for 3 hours. Then the mixture was poured into saturated aq. NH4Cl solution at 0 °C and extracted with CHCl3/i-PrOH (v/v= 3/1) twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (50 mg, yield 66.0%) as a white solid. LC/MS (ESI) (m/z): 671 (M+H)⁺. Step 9: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8-ethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-methylpyridin-2-yl)isoxazole-5-carboxamide (Compound 770) To a solution of tert-butyl (2-(((6S,8R)-8-ethyl-3-(3-(3-methylpyridin-2-yl)isoxazole-5- carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-thieno[3,2- c]pyridin-6-yl)carbamate (40 mg, 0.060 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) at 0 °C and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aq. NaHCO₃ solution at 0 °C and extracted with CHCl₃/i-PrOH (v/v = 3/1) twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 95% MeCN in water with 0.1% NH4CO3) to give Compound 770 (10 mg, yield 29.4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 9.12 (t, J = 5.8 Hz, 1H), 8.61 (d, J = 4.5 Hz, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.81 (s, 1H), 7.47 (dd, J = 7.7, 4.7 Hz, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.08 (d, J = 8.8 Hz, 1H), 4.54 – 4.43 (m, 2H), 3.28 – 3.21 (m, 1H), 2.60 (s, 3H), 2.35 – 2.21 (m, 2H), 2.03 – 1.94 (m, 1H), 1.58 – 1.47 (m, 1H), 0.97 (t, J = 7.4 Hz, 3H). LC/MS (ESI) (m/z): 571 (M+H)⁺. RT (Method A): 1.25 min. Scheme 260. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8,8- diethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-methylpyridin-2-yl)-isoxazole-5- carboxamide (Compound 771) Step 1: tert-Butyl (S)-4-(8,8-diethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamido)benzoate To a solution of tert-butyl (S)-4-(4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)benzoate (2.0 g, 5.63 mmol) in THF (40 mL) was added LiHMDS (22.5 mL, 22.5 mmol, 1M in THF) dropwise at -40 °C for 10 minutes and the mixture was stirred at -40 °C for an hour. Ethyl iodide (2.63 g, 16.88 mol) was added to the above mixture dropwise at -40 °C in 5 minutes while keeping the temperature below -40 °C. The resulting mixture was stirred at -40 °C for another 30 minutes and then quenched with saturated aq. NH4Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 40 - 60% DCM in EtOAc) to give the title compound (350 mg, yield 15.1%) as a white solid. LC/MS (ESI) (m/z): 412 (M+H)⁺. The tert-Butyl (S)-4-(8,8-diethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6- carboxamido)benzoate was then used to prepare Compound 771 according to the procedures set forth in Scheme 259, starting from Step 2.¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 9.03 (t, J = 5.7 Hz, 1H), 8.65 – 8.49 (m, 2H), 8.41 (s, 1H), 7.89 – 7.74 (m, 2H), 7.51 – 7.39 (m, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.03 – 4.88 (m, 1H), 4.59 – 4.38 (m, 2H), 2.61 (s, 3H), 2.45 – 2.40 (m, 1H), 2.04 – 1.92 (m, 1H), 1.77 – 1.70 (m, 2H), 1.70 – 1.58 (m, 2H), 0.90 – 0.73 (m, 6H). LC/MS (ESI) (m/z): 599 (M+H)⁺. RT (Method A): 1.45 min. Scheme 261. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-((S)-3-fluoro-1- (2-fluorophenyl)pyrrolidine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 774) Step 1: Methyl (S)-3-fluoropyrrolidine-3-carboxylate To a solution of 1-(tert-butyl) 3-methyl (S)-3-fluoropyrrolidine-1,3-dicarboxylate (250 mg, 1.01 mmol) in DCM (3 mL) was added TFA (1 mL) and the mixture was stirred at 25°C overnight. The mixture concentrated under reduced pressure to dryness to give the title compound (200 mg, crude) as a colorless oil, which was used directly in the next step without purification. LC/MS (ESI) m/z: 148 (M+H)⁺. Step 2: Methyl (S)-3-fluoro-1-(2-fluorophenyl)pyrrolidine-3-carboxylate To a mixture of methyl (S)-3-fluoropyrrolidine-3-carboxylate (200 mg, 1.01 mmol) and 1-fluoro-2- iodobenzene (302 mg, 1.36 mmol) in DME (6 mL) was added Cs2CO3 (1.33 g, 4.08 mmol), CuI (129 mg, 0.68 mmol) and 2-Isobutyrylcyclohexanone (114 mg, 0.68 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 90°C for 2 days. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 95% MeCN in water with 0.1% FA) to give the title compound (5 mg, yield 0.02%) as a colorless oil. LC/MS (ESI) m/z: 242 (M+H)⁺. The methyl (S)-3-fluoro-1-(2-fluorophenyl)pyrrolidine-3-carboxylate was used to prepare Compound 774 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (d, J = 4.8 Hz, 1H), 9.09 (t, J = 5.7 Hz, 1H), 8.65 (s, 1H), 8.41 (s, 1H), 7.13 - 7.07 (m, 2H), 7.04 (d, J = 7.2 Hz, 1H), 6.84 (s, 1H), 6.83 - 6.73 (m, 2H), 5.86 (s, 2H), 5.04 (d, J = 8.6 Hz, 1H), 4.53 - 4.40 (m, 2H), 4.01 - 3.84 (m, 1H), 3.82 - 3.71 (m, 1H), 3.65 - 3.50 (m, 2H), 3.30 - 3.28 (m, 1H), 2.47 - 2.45 (m, 1H), 2.39 - 2.36 (m, 1H), 2.34 - 2.32 (m, 1H), 2.24 - 2.19 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 580 (M+H)⁺. RT (Method A): 1.55 min. Scheme 262. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- (((1R,3R)-3-(pyridin-2-yl)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrimidine-6- carboxamide (Compound 775) O Step 1: 3-(Pyridin-2-yl)cyclopentan-1-one To a mixture of 2-iodopyridine (9.00 g, 43.9 mmol) and cyclopent-2-en-1-one (10.8 g, 132 mmol) in DMSO (90 mL) and water (27 mL) was added Hantzsch ester (14.4 g, 57.1 mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (493 mg, 0.44 mmol) at room temperature and the mixture was stirred under irradiation with 450 nm blue LEDs at room temperature overnight. The mixture was quenched with saturated aq. NaHCO₃ solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (6.10 g, yield 86.2%) as a yellow oil. LC/MS (ESI) m/z: 162 (M+H)⁺. Step 2: 3-(Pyridin-2-yl)cyclopentan-1-ol To a solution of 3-(pyridin-2-yl)cyclopentan-1-one (6.10 g, 37.8 mmol) in MeOH (10 mL) was added NaBH₄ (1.72 g, 45.4 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (2.52 g, yield 40.8%) as a yellow oil. LC/MS (ESI) m/z: 164 (M+H)⁺. Step 3: 2-((1R,3R)-3-(Pyridin-2-yl)cyclopentyl)isoindoline-1,3-dione To a mixture of ethyl 3-(1-methyl-1H-imidazol-2-yl)isoxazole-5-carboxylate (2.52 g, 15.4 mmol), isoindoline-1,3-dione (2.50 g, 17.0 mmol) and PPh3 (4.45 g, 17.0 mmol) in THF (15 mL) was added DIAD (3.43 g, 17.0 mmol) at room temperature under a nitrogen atmosphere and the mixture was stirred at room temperature under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) and further purified by chiral-SFC (ChiralPak IA, 250×20 mm I.D., 5µm, 20% EtOH with 0.1% NH3H2O in CO2) to give the title compound (retention time: 3.114 minute) (1.74 g, yield 38.6%) as a white solid. LC/MS (ESI) m/z: 293 (M+H)⁺. Step 4: (1R,3R)-3-(Pyridin-2-yl)cyclopentan-1-amine To a solution of 2-((1R,3R)-3-(pyridin-2-yl)cyclopentyl)isoindoline-1,3-dione (1.74 g, 5.95 mmol) in EtOH (20 mL) was added hydrazine hydrate (1 mL, 80% wt.) at room temperature and the mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was suspended in EtOAc (20 mL) and stirred at 80°C under a nitrogen atmosphere for 2 hours. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (710 mg, yield 73.8%) as a yellow oil, which was used directly in the next step without purification. LC/MS (ESI) m/z: 163 (M+H)⁺. Step 5: Methyl (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(pyridin-2-yl)cyclopentyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of (1R,3R)-3-(pyridin-2-yl)cyclopentan-1-amine (171 mg, 1.05 mmol) and methyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylate (201 mg, 0.70 mmol) in toluene (3 mL) was added Pd-175 (60 mg, 0.07 mmol) and Cs2CO3 (683 mg,2.1 mmol) under a nitrogen atmosphere at room temperature and the mixture was stirred under a nitrogen atmosphere at 100 °C for 3 hours. The mixture was diluted with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 100% EtOAc in PE) to give the title compound (61 mg, yield 23.7%) as a brown solid. LC/MS (ESI) m/z: 369 (M+H)⁺. Step 6: (6S,8R)-8-Methyl-4-oxo-3-(((1R,3R)-3-(pyridin-2-yl)cyclopentyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(pyridin-2-yl)cyclopentyl)-amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (61 mg, 0.16 mmol) in THF/water (3 mL, v/v = 2/1) was added LiOH (11.8 mg, 0.49 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (45 mg, yield 79.7%) as a brown solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 355 (M+H)⁺. Step 7: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3-(((1R,3R)-3-(pyridin-2- yl)cyclopentyl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 775) To a mixture of (6S,8R)-8-methyl-4-oxo-3-(((1R,3R)-3-(pyridin-2-yl)cyclopentyl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (45 mg, 0.13 mmol) and 2-(aminomethyl)thieno[3,2- c]pyridin-6-amine (35 mg, 0.2 mmol) in DMF (2 mL) was added DIPEA (51 mg, 0.4 mmol) and HATU (56 mg, 0.2 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈, 20 - 70% MeCN in water with 0.1% NH₄HCO₃) to give Compound 775 (12 mg, yield 18.1%) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J = 5.9 Hz, 1H), 8.50 (d, J = 4.2 Hz, 1H), 8.42 (s, 1H), 7.71 – 7.67 (m, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.11 (s, 1H), 7.04 (s, 1H), 6.85 (s, 1H), 5.85 (s, 2H), 5.02 - 4.94 (m, 2H), 4.46 (d, J = 4.4 Hz, 2H), 3.94 - 3.77 (m, 1H), 3.44 - 3.35 (m, 1H), 3.23 - 3.16 (m, 1H), 2.34 - 2.29 (m, 1H), 2.26 - 2.21 (m, 1H), 2.16 - 2.08 (m, 3H), 2.01 - 1.94 (m, 1H), 1.83 - 1.74 (m, 1H), 1.72 - 1.65 (m, 1H), 1.23 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 516 (M+H)⁺. RT (Method A): 0.35 min. Scheme 263. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 776) Step 1: N-(5-Methyl-1,2,4-oxadiazol-3-yl)isonicotinamide To a mixture of 5-methyl-1,2,4-oxadiazol-3-amine (500 mg, 5.05 mmol) and isonicotinoyl chloride (1.07 g, 7.65 mmol) in toluene (3 mL) was added pyridine (1.19 g, 15.2 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 15% MeOH in DCM) to give the title compound (750 mg, yield 72.8%) as a white solid. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 2: 5-(Pyridin-4-yl)-1,2,4-oxadiazol-3-amine To a solution of N-(5-methyl-1,2,4-oxadiazol-3-yl)isonicotinamide (750 mg, 3.68 mmol) in EtOH (5 mL) was added aq. HCl (6M, 3 mL, 18 mmol) at room temperature and the mixture was stirred at 80°C for 2 hours. The mixture was cooled, and then neutralized with saturated aq. NaHCO3 solution and extracted with CHCl₃/i-PrOH (v/v= 3/1) twice. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (210 mg, yield 35.1%) as a white solid. LC/MS (ESI) m/z: 163 (M+H)⁺. Step 3: Methyl (6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of 5-(pyridin-4-yl)-1,2,4-oxadiazol-3-amine (210 mg, 1.28 mmol) and methyl (6S,8R)- 3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrimidine-6-carboxylate (307 mg, 1.07 mmol) in toluene (3 mL) was added Pd-175 (85 mg, 0.1 mmol) and Cs2CO3 (1043 mg,3.21 mmol) under a nitrogen atmosphere at room temperature and the mixture was stirred under a nitrogen atmosphere at 100°C for 12 hours. The mixture was cooled, diluted with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 100% EtOAc in PE) to give the title compound (21 mg, yield 5.1%) as a brown solid. LC/MS (ESI) m/z: 369 (M+H)⁺. Step 4: (6S,8R)-8-Methyl-4-oxo-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)-amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (21 mg, 0.06 mmol) in THF/water (3 mL, v/v= 2/1) was added LiOH (2.9 mg, 0.12 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (17 mg, yield 79.7%) as a brown solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 355 (M+H)⁺. The (6S,8R)-8-Methyl-4-oxo-3-((5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid was used to prepare Compound 776 based on the procedures set forth in, e.g., Scheme 19.¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (s, 1H), 9.13 (t, J = 5.9 Hz, 1H), 8.90 (d, J = 6.0 Hz, 2H), 8.46 (s, 1H), 8.40 (s, 1H), 8.00 (d, J = 6.0 Hz, 2H), 7.16 (s, 1H), 6.97 (s, 1H), 6.18 (s, 2H), 5.05 (d, J = 8.7 Hz, 1H), 4.55 - 4.44 (m, 2H), 2.42 - 2.32 (m, 2H), 2.26 - 2.19 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 516 (M+H)⁺. RT (Method A): 0.87 min. Scheme 264. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-((5-(4- methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 777) Step 1: 4-Methyl-N-(5-methyl-1,2,4-oxadiazol-3-yl)picolinamide To a mixture of 4-methylpicolinic acid (500 mg, 3.65 mmol) and 5-methyl-1,2,4-oxadiazol-3-amine (361 mg, 3.65 mmol) in MeCN (5 mL) was added NMI (899 mg, 10.9 mmol) and TCFH (3.07 g, 10.9 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 7% MeOH in DCM) to give the title compound (700 mg, yield 87.9%) as a white solid. LC/MS (ESI) m/z: 219 (M+H)⁺. Step 2: 5-(4-Methylpyridin-2-yl)-1,2,4-oxadiazol-3-amine To a solution of 4-methyl-N-(5-methyl-1,2,4-oxadiazol-3-yl)picolinamide (700 mg, 3.21 mmol) in EtOH (7 mL) was added aq. HCl (6M, 2.6 mL, 15.6 mmol) at room temperature and the mixture was then stirred at 80°C for 2 hours. The mixture was cooled, and then neutralized with saturated aq. NaHCO3 solution and extracted with CHCl3/i-PrOH (v/v= 3/1) twice. The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (240 mg, yield 42.5%) as a white solid. LC/MS (ESI) m/z: 177 (M+H)⁺. Step 3: tert-Butyl (6S,8R)-8-methyl-3-((5-(4-methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl)-amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of 5-(4-methylpyridin-2-yl)-1,2,4-oxadiazol-3-amine (200 mg, 1.14 mmol) and tert- butyl (6S,8R)-3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (448 mg, 1.36 mmol) in toluene (5 mL) was added Pd₂(dba)₃ (209 mg, 0.22 mmol), XantPhos (131 mg, 0.22 mmol) and Cs2CO3 (1.11 g, 3.41 mmol) under a nitrogen atmosphere at room temperature and the mixture was stirred under a nitrogen atmosphere at 105 °C for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (20 mg, yield 4.1%) as a brown solid. LC/MS (ESI) m/z: 425 (M+H)⁺. Step 4: (6S,8R)-8-Methyl-3-((5-(4-methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of tert-butyl (6S,8R)-8-methyl-3-((5-(4-methylpyridin-2-yl)-1,2,4-oxadiazol-3- yl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (20 mg, 0.05 mmol) in DCM (1 mL) was added TFA (0.5 mL) at room temperature and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 10 - 70% MeCN in water with 0.1% NH4HCO3) to give the title compound (8.0 mg, yield 46.1%) as a white solid. LC/MS (ESI) m/z: 369 (M+H)⁺. Step 5: (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3-((5-(4-methyl-pyridin-2-yl)-1,2,4- oxadiazol-3-yl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]-pyrimidine-6-carboxamide (Compound 777) To a mixture of (6S,8R)-8-methyl-3-((5-(4-methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl)amino)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (8 mg, 0.02 mmol) and 2- (aminomethyl)thieno[3,2-c]pyridin-6-amine (6 mg, 0.03 mmol) in DMF (1 mL) was added DIPEA (4 mg, 0.03 mmol) and HATU (9 mg, 0.02 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 70% MeCN in water with 0.1% NH4HCO3) to give Compound 777 (0.5 mg, yield 4.3%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.42 -7.40 (m, 1H), 7.31 (s, 1H), 7.15 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 4.96 – 4.94 (m, 1H), 4.56 – 4.43 (m, 2H), 2.93 (s, 3H), 2.81 – 2.79 (m, 1H), 2.68 – 2.66 (m, 1H), 1.75 – 1.70 (m, 1H), 1.32 (d, J = 4.9 Hz, 3H). LC/MS (ESI) m/z: 530 (M+H)⁺. RT (Method A): 1.04 min. Scheme 265. Synthesis of (S)-N-(6'-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4'-oxo- 6',7'-dihydro-4'H-spiro[cyclopentane-1,8'-pyrrolo[1,2-a] pyrimidin]-3'-yl)-3-(3-methylpyridin-2- yl)isoxazole-5-carboxamide (Compound 778) Step 1: tert-butyl (S)-4-(4'-oxo-6',7'-dihydro-4'H-spiro[cyclopentane-1,8'-pyrrolo[1,2-a]-pyrimidine]-6'- carboxamido)benzoate To a solution of tert-butyl (S)-4-(4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)benzoate (5.0 g, 14.07 mmol) in THF (100 mL) was added LiHMDS (56.3 mL, 56.3 mmol, 1M in THF) dropwise at -40 °C for 10 minutes and the mixture was stirred at -40 °C for 1 hour.1,4- Dibromobutane (9.11 g, 42.21 mol) was added to the above mixture dropwise at -40 °C for 5 minutes while keeping the temperature below -40 °C. The resulting mixture was stirred at -40 °C for another 30 minutes. The mixture was quenched with saturated aq. NH₄Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 40 - 60% DCM in PE) to give the title compound (1.28 g, yield 22.2%) as a white solid. LC/MS (ESI) (m/z): 410 (M+H)⁺. The tert-butyl (S)-4-(4'-oxo-6',7'-dihydro-4'H-spiro[cyclopentane-1,8'-pyrrolo[1,2-a]-pyrimidine]-6'- carboxamido)benzoate was then used to prepare Compound 778 following the procedures set forth in Scheme 260.¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 9.08 (t, J = 5.7 Hz, 1H), 8.61 (d, J = 4.6 Hz, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.82 (s, 1H), 7.48 (dd, J = 7.7, 4.7 Hz, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 6.00 (s, 2H), 5.03 (dd, J = 9.6, 2.8 Hz, 1H), 4.58 – 4.50 (m, 1H), 4.47 – 4.40 (m, 1H), 2.60 (s, 3H), 2.12 – 2.05 (m, 2H), 1.97 – 1.59 (m, 8H). LC/MS (ESI) (m/z): 597 (M+H)⁺. RT (Method A): 1.35 min. Scheme 266. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(6-cyclopropyl- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 779) Step 1: Methyl 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate To a solution of 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (200 mg, 1.00 mmol) and TEA (303 mg, 3.0 mmol) in MeOH (4 mL) was added Pd(dppf)Cl2 (36.5 mg, 0.05 mmol) and the reaction mixture was stirred under CO atmosphere at 80 °C overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (170 mg, yield 95.0%) as a yellow oil. LC/MS (ESI) m/z: 179 (M+H)⁺. Step 2: Methyl 6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate To a solution of methyl 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate (170 mg, 0.95 mmol) in MeOH (3mL) was added (1-ethoxycyclopropoxy)trimethylsilane (198 mg, 1.14 mmol), AcOH (0.03 ml) and NaBH3CN (179 mg, 2.85 mmol) and the reaction mixture was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (100 mg, yield 48.2%) as a white solid. LC/MS (ESI) m/z: 219 (M+H)⁺. Step 3: Lithium 6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate To a solution of methyl 6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate (100 mg, 0.46 mmol) in THF (2 mL) and water (1 mL) was added LiOH (33 mg, 1.38 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (80 mg, yield 82.8%) as a white solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 205 (M+H)⁺. The lithium 6-cyclopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate was used to prepare Compound 779 based on the procedures set forth in, e.g., Scheme 63.¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.12 – 9.05 (m, 1H), 8.88 (s, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 9.5 Hz, 1H), 4.52 – 4.41 (m, 2H), 4.09 – 4.03 (m, 4H), 3.35 – 3.35 (m, 1H), 3.30 – 3.29 (m, 1H), 2.37 – 2.33 (m, 1H), 2.15 – 2.10 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H), 0.53 – 0.47 (m, 2H), 0.47 – 0.43 (m, 2H). LC/MS (ESI) m/z: 557 (M+H)⁺. RT (Method A): 0.23 min. Scheme 267. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(5-methyl-pyrimidin-4-yl)isoxazole-5- carboxamide (Compound 780) Step 1: 5-Methyl-4-vinylpyrimidine To a mixture of 4-chloro-5-methylpyrimidine (1.0 g, 7.81 mmol) and potassium vinyltrifluoroborate (1.05 mg, 7.81 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was added K₃PO₄ (3.31 g, 15.6 mmol) and Pd(dppf)Cl2 (241 mg, 0.21 mmol) at 25 °C under a nitrogen atmosphere and the reaction mixture was degassed under a nitrogen atmosphere three times and stirred at 100 °C overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (300 mg, yield 32%) as a colorless oil. LC/MS (ESI) m/z: 121 (M+H)⁺. Step 2: 5-Methylpyrimidine-4-carbaldehyde To a solution of 5-methyl-4-vinylpyrimidine (300 mg, 2.5 mmol) in acetone (3.0 mL)/ water (3.0 mL) was added NMO (144 mg, 0.61 mmol), K2OsO4 (22.5 mg, 0.06 mmol), NaIO4 (500 mg, 2.31 mmol) at 25 °C and the reaction mixture was stirred at 25 °C for 18 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with saturated aq. Na₂S₂O₃ and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (150 mg, yield 49.2%) as a yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 9.31 (s, 1H), 8.95 (s, 1H), 2.53 (s, 3H). LC/MS (ESI) m/z: 123 (M+H)⁺. The 5-methylpyrimidine-4-carbaldehyde was used to prepare Compound 780 following the procedures set forth in Scheme 200.¹H NMR (400 MHz, CD₃OD) δ 9.16 (s, 1H), 8.88 (s, 1H), 8.85 (s, 1H), 8.38 (s, 1H), 7.77 (s, 1H), 7.16 (s, 1H), 6.97 (s, 1H), 5.17 - 5.14 (m, 1H), 4.62 - 4.59 (m, 2H), 3.51 - 3.48 (m, 1H), 2.69 (s, 3H), 2.59 - 2.52 (m, 1H), 2.32 - 2.23 (m, 1H), 1.41 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 558 (M+H)⁺. RT (Method A): 0.87 min. Scheme 268. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(piperidin-1-yl)isoxazole-5- carboxamide (Compound Step 1: 3-(Piperidin-1-yl)isoxazole-5-carboxylic acid To a mixture of 3-bromoisoxazole-5-carboxylic acid (300 mg, 1.57 mmol) in piperidine (2 mL) was added CsF (716 mg, 4.71 mmol) and the mixture was stirred in a CEM microwave reactor at 100 °C for 2 hours. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with CHCl3/i-PrOH (3/1, v/v) twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20 - 95% MeCN in water with 0.1% FA) to give the title compound (50 mg, yield 16.2%) as a yellow solid. LC/MS (ESI) m/z: 197 (M+H)⁺. The 3-(piperidin-1-yl)isoxazole-5-carboxylic acid was used to prepare Compound 781 based on the procedures set forth in, e.g., Scheme 63.¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 7.17 (s, 1H), 7.11 (s, 1H), 6.83 (s, 1H), 5.86 (s, 2H), 5.08 - 5.00 (m, 1H), 4.53 - 4.40 (m, 2H), 3.27 - 3.23 (m, 4H), 2.43 - 2.14 (m, 4H), 1.60 - 1.53 (m, 6H), 1.29 (d, J = 5.1 Hz, 3H). LC/MS (ESI) m/z: 549 (M+H)⁺. RT (Method A) 1.22 min. Scheme 269. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(5-methyl-oxazol-4-yl)isoxazole-5- car Step 1: N-Methoxy-N,5-dimethyloxazole-4-carboxamide To a mixture of 5-methyloxazole-4-carboxylic acid (10 g, 78.7 mmol) and N,O- dimethylhydroxylamine (5.77 g, 94.4 mmol) in DMF (50 mL) was added DIPEA (20.3 g, 157 mmol) and HATU (44.8 g,118 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (5 g, yield 37.3%) as a colorless oil. LC/MS (ESI) m/z: 171 (M+H)⁺. Step 2: 5-Methyloxazole-4-carbaldehyde To a solution of N-methoxy-N,5-dimethyloxazole-4-carboxamide (1.0 g, 5.88 mmol) in DCM (10 mL) was added DIBAL-H (9.8 mL, 14.7 mmol, 1.5 M in toluene) dropwise at -70 °C under a nitrogen atmosphere and the mixture was stirred at -70 °C for 2 hours. The mixture was quenched with saturated aq. NH₄Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (300 mg, yield 45.9%) as a yellow oil. LC/MS (ESI) m/z: 112 (M+H)⁺. The 5-methyloxazole-4-carbaldehyde was used to prepare Compound 782 following the procedures set forth in Scheme 200. ¹H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.11 (t, J = 5.8 Hz, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 7.64 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.85 (s, 2H), 5.05 (d, J = 9.1 Hz, 1H), 4.52 – 4.42 (m, 2H), 3.40 – 3.34 (m, 1H), 2.63 (s, 3H), 2.37 – 2.32 (m, 1H), 2.26 – 2.19 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 547 (M+H)⁺. RT (Method A): 0.92 min. Scheme 270. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-4-oxo-3- ((5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamide (Compound 783) Step 1: N-(5-Methyl-1,2,4-oxadiazol-3-yl)nicotinamide To a mixture of 5-methyl-1,2,4-oxadiazol-3-amine (1 g, 10.09 mmol) and nicotinoyl chloride hydrochloride (2.16 g, 12.13 mmol) in toluene (10 mL) was added pyridine (2.39 g, 30.21 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 15% MeOH in DCM) to give the title compound (1.5 g, yield 72.8%) as a white solid. LC/MS (ESI) m/z: 205 (M+H)⁺. Step 2: 5-(Pyridin-3-yl)-1,2,4-oxadiazol-3-amine To a solution of N-(5-methyl-1,2,4-oxadiazol-3-yl)nicotinamide (1.5 g, 7.25 mmol) in EtOH (10 mL) was added aq. HCl (5 mL, 6 M) at room temperature and the mixture was stirred at 80 °C for 2 hours. The mixture was neutralized with saturated aq. NaHCO3 solution and extracted with CHCl3/i-PrOH (v/v= 3/1) twice. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (200 mg, yield 16.8%) as a yellow solid. LC/MS (ESI) m/z: 163 (M+H)⁺. Step 3: Methyl (6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate To a mixture of 5-(pyridin-3-yl)-1,2,4-oxadiazol-3-amine (200 mg, 1.23 mmol) and methyl (6S,8R)- 3-bromo-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (390 mg, 1.36 mmol) in toluene (4 mL) was added Cs₂CO₃ (1.21 g, 3.71 mmol) and ALPhos Pd G6 BR (141 mg, 0.12 mmol) under a nitrogen atmosphere and the reaction mixture was then heated and stirred under a nitrogen atmosphere at 110 °C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 20 - 84% EtOAc in PE) to give the title compound (10 mg, yield 2.2%) as a yellow solid. LC/MS (ESI) m/z: 369 (M+H)⁺. Step 4: (6S,8R)-8-Methyl-4-oxo-3-((5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid To a solution of methyl (6S,8R)-8-methyl-4-oxo-3-((5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)-amino)- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (10 mg, 0.03 mmol) in THF (1 mL) and water (0.3 mL) was added LiOH (2 mg, 0.08 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (7 mg, yield 72.8%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) (m/z): 355 (M+H)⁺. The (6S,8R)-8-Methyl-4-oxo-3-((5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)amino)-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid was used to prepare Compound 783 based on the procedures set forth in, e.g., Scheme 19.¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (d, J = 1.4 Hz, 1H), 9.12 (s, 1H), 9.10 (t, J = 4.9 Hz, 1H), 8.88 - 8.86 (m, 1H), 8.46 - 8.43 (m, 1H), 8.43 (s, 1H), 8.40 (s, 1H), 7.70 - 7.67 (m, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 5.91 (s, 2H), 5.06 - 5.02 (m, 1H), 4.52 – 4.43 (m, 2H), 3.38 - 3.36 (m, 1H), 2.24 - 2.18 (m, 1H), 2.03 - 1.96 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H). LC/MS (ESI) (m/z): 516 (M+H)⁺. RT (Method A): 1.14 min. Scheme 271. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-1- chloro-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazin-3-yl)-3-(3-methylpyridin-2- yl)isoxazole-5-carboxamide (Compound 784) Step 1: Methyl (6S,8R)-3-amino-1-chloro-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a]pyrazine-6- carboxylate A solution of methyl (6S,8R)-1-chloro-3-((3,4-dimethylbenzyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (100 mg, 0.25 mmol) in TFA (1 mL) was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO₃ solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (54 mg, yield 85.4%) as a yellow oil, which was used directly in the next step without purification. LC/MS (ESI) m/z: 258 (M+H)⁺. Step 2: Methyl (6S,8R)-1-chloro-8-methyl-3-(3-(3-methylpyridin-2-yl)isoxazole-5-carboxamido)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a mixture of methyl (6S,8R)-3-amino-1-chloro-8-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrazine-6-carboxylate (54 mg, 0.21 mmol) and lithium 3-(3-methylpyridin-2-yl)-isoxazole-5-carboxylate (67 mg, 0.32 mmol) in pyridine (2 mL) was added POCl3 (36 mg, 0.23 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with saturated 0.3 N aq. HCl solution and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (15 mg, yield 10.5%) as a white solid. LC/MS (ESI) (m/z): 444 (M+H)⁺. Step 3: Lithium (6S,8R)-1-chloro-8-methyl-3-(3-(3-methylpyridin-2-yl)isoxazole-5-carboxamido)-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a solution of methyl (6S,8R)-1-chloro-8-methyl-3-(3-(3-methylpyridin-2-yl)isoxazole-5- carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (30 mg, 0.068 mmol) in THF (1 mL) and water (0.4 mL) was added LiOH.H₂O (10 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (26 mg, yield 88.6%) as a white solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 430 (M+H)⁺. Step 4: N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-1-chloro-8-methyl-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazin-3-yl)-3-(3-methylpyridin-2-yl)isoxazole-5-carboxamide (Compound 784) To a mixture of lithium (6S,8R)-1-chloro-8-methyl-3-(3-(3-methylpyridin-2-yl)isoxazole-5- carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (26 mg, 0.060 mmol) and 2- (aminomethyl)thieno[3,2-c]pyridin-6-amine (16 mg, 0.089 mmol) in DMF (1 mL) was added DIPEA (23 mg, 0.18 mmol) and HATU (35 mg, 0.09 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C₁₈250*20 mm, 20% - 95% MeCN in water with 0.1% NH₄HCO₃) to give Compound 784 (5.1 mg, yield 14.5%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (t, J = 5.6 Hz, 1H), 8.61 (d, J = 4.6 Hz, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.12 (s, 1H), 6.83 (s, 1H), 5.83 (s, 2H), 5.12 – 5.04 (m, 1H), 4.51 – 4.39 (m, 2H), 3.64 – 3.47 (m, 1H), 2.60 (s, 3H), 2.41 – 2.34 (m, 1H), 2.24 – 2.16 (m, 1H), 1.39 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 591 (M+H)⁺. RT (Method A): 1.14 min. Scheme 272. Synthesis of (S)-N-(6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8,8- dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(3-methylpyridin-2-yl)-isoxazole-5- carboxamide (Compound 785) Step 1: tert-Butyl (S)-4-(8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)benzoate To a solution of tert-butyl (S)-4-(4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)benzoate (5.0 g, 14.07 mmol) in THF (100 mL) was added LiHMDS (56.3 mL, 56.3 mmol, 1M in THF) dropwise at -40 °C for 10 minutes and the mixture was stirred at -40 °C for 1 hour. Methyl Iodide (6.0 g, 42.21 mol) was added to the above mixture dropwise at -40 °C in 5 minutes while keeping the temperature below -40 °C, and the resulting mixture was stirred at -40 °C for another 30 minutes. The mixture was quenched with saturated aq. NH₄Cl solution at 0 °C and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 60% DCM in EtOAc) to give the title compound (1.65 g, yield 30.6%) as a white solid. LC/MS (ESI) (m/z): 384 (M+H)⁺. The tert-butyl (S)-4-(8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6- carboxamido)benzoate was then used to prepare Compound 785 following the procedures set forth in Scheme 260.¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 9.08 (t, J = 5.7 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.82 (s, 1H), 7.50 – 7.46 (m, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.01 (dd, J = 9.8, 3.3 Hz, 1H), 4.57 – 4.51 (m, 1H), 4.48 – 4.41 (m, 1H), 3.34 – 3.33 (m, 1H), 2.60 (s, 3H), 2.03 (dd, J = 13.2, 3.4 Hz, 1H), 1.34 (s, 6H). LC/MS (ESI) (m/z): 571 (M+H)⁺. RT (Method A): 1.06 min. Scheme 273. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3- ((1S,2S)-2-(6-methyloxazolo[5,4-c]pyridin-2-yl)cyclopropane-1-carboxamido)-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 786) Step 1: Ethyl (1S,2S)-2-((5-bromo-2-methylpyridin-4-yl)carbamoyl)cyclopropane-1-carboxylate To a mixture of 5-bromo-2-methylpyridin-4-amine (1.0 g, 5.38 mmol) and (1S,2S)-2- (ethoxycarbonyl)cyclopropane-1-carboxylic acid (1.27 g, 8.07 mmol) in DMF (10 mL) was added DIPEA (4.16 g, 32.28 mmol) and HATU (2.45 g, 6.46 mmol) and the mixture was stirred at room temperature overnight. The mixture was and diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (480 mg, yield 96.6%) as a yellow solid. LC/MS (ESI) m/z: 327 (M+H)⁺. Step 2: Ethyl (1S,2S)-2-(6-methyloxazolo[5,4-c]pyridin-2-yl)cyclopropane-1-carboxylate To a solution of ethyl (1S,2S)-2-((5-bromo-2-methylpyridin-4-yl)carbamoyl) cyclopropane-1- carboxylate (150 mg, 0.46 mmol) in 1,4-dioxane (5 mL) was added Cs2CO3 (450 mg, 1.38 mmol), CuI (44 mg, 0.23 mmol) and BPPO (90 mg, 0.23 mmol) under a nitrogen atmosphere and the reaction mixture was heated and stirred at 100°C overnight. The mixture was and diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (50 mg, yield 44.2%) as a yellow oil. LC/MS (ESI) m/z: 247 (M+H)⁺. Step 3: (1S,2S)-2-(6-Methyloxazolo[5,4-c]pyridin-2-yl)cyclopropane-1-carboxylic acid To a mixture of ethyl (1S,2S)-2-(6-methyloxazolo[5,4-c]pyridin-2-yl)cyclopropane-1-carboxylate (40 mg, 0.16 mmol) in DCE (3 mL) was added Me₃SnOH (110 mg, 0.48 mmol). The mixture was stirred at 70°C overnight. The mixture was concentrated under reduced pressure to dryness to give the title compound (40 mg, yield 90.3%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 219 (M+H)⁺. The (1S,2S)-2-(6-Methyloxazolo[5,4-c]pyridin-2-yl)cyclopropane-1-carboxylic acid was used to prepare Compound 786 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (t, J = 6.3 Hz, 1H), 8.87 & 8.72 (s, 1H), 8.55 (s, 1H), 8.41 & 8.05 (s, 1H), 7.63 (m, 1H), 7.33 (s, 1H), 7.23 (s, 2H), 7.10 (s, 1H), 6.97 (s, 1H), 5.03 (d, J = 9.5 Hz, 1H), 4.50 (d, J = 5.7 Hz, 2H), 3.28 - 3.26 (m, 1H), 3.15 - 3.11 (m, 1H), 2.70 - 2.65 (m, 1H), 2.38 - 2.33 (m, 1H), 2.23 - 2.15 (m, 1H), 2.04 - 1.93 (m, 1H), 1.72 - 1.68 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H), 1.23 (s, 3H). LC/MS (ESI) m/z: 571 (M+H)⁺.RT (Method A): 0.30 min. Scheme 274. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-8-methyl-3- ((2S,3R)-1-methyl-3-phenylpyrrolidine-2-carboxamido)-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2- a]pyrimidine-6-carboxamide (Compound 788) Step 1: tert-butyl (S)-2-(quinolin-8-ylcarbamoyl)pyrrolidine-1-carboxylate To a mixture of quinolin-8-amine (2 g, 13.9 mmol), HOBt (2.81 g, 20.9 mmol) and (tert- butoxycarbonyl)-L-proline (2.99 g, 13.9 mmol) in DCM (20 mL) was added EDCI (4.4 g, 22.9 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 25% EtOAc in PE) to give the title compound (2.3 g, yield 50.1%) as a white solid. LC/MS (ESI) (m/z): 342 (M+H)⁺. Step 2: tert-Butyl (2S,3R)-3-phenyl-2-(quinolin-8-ylcarbamoyl)pyrrolidine-1-carboxylate To a solution of tert-butyl (S)-2-(quinolin-8-ylcarbamoyl)pyrrolidine-1-carboxylate (2 g, 5.8 mmol), iodobenzene (2.38 g, 11.7 mmol), pivalic acid (56.2 mg, 0.58 mmol) and Ag₂CO₃ (160 mg, 0.58 mmol) in toluene (20 mL) was added Pd(OAc)2 (65 mg, 0.29 mmol) under a nitrogen atmosphere, the mixture was degassed under a nitrogen atmosphere three times and stirred at 100 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (890 mg, yield 36.7%) as a white solid. LC/MS (ESI) m/z: 418 (M+H)⁺. Step 3: (2S,3R)-1-(tert-Butoxycarbonyl)-3-phenylpyrrolidine-2-carboxylic acid To a solution of tert-butyl (2S,3R)-3-phenyl-2-(quinolin-8-ylcarbamoyl)pyrrolidine-1-carboxylate (245 mg, 0.59 mmol) in EtOH (5 mL) was added NaOH (235 mg, 5.87 mmol) and the mixture was stirred at 100°C overnight. The mixture was diluted with water and washed with EtOAc twice. The aqueous layer was acidified with 1N aq. HCl to pH~3 and extracted with CHCl₃/i-PrOH (3/1, v/v) twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (60 mg, yield 35.1%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) m/z: 292 (M+H)⁺. Step 4: (2S,3R)-3-Phenylpyrrolidine-2-carboxylic acid A solution of (2S,3R)-1-(tert-butoxycarbonyl)-3-phenylpyrrolidine-2-carboxylic acid (60 mg, 0.01 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (60 mg, yield 72.8%) as a yellow solid, which was used directly in the next step without purification. LC/MS (ESI) (m/z): 192 (M+H)⁺. Step 5: (2S,3R)-1-Methyl-3-phenylpyrrolidine-2-carboxylic acid To a mixture of (2S,3R)-3-phenylpyrrolidine-2-carboxylic acid (60 mg, 0.31 mmol) and paraformaldehyde (85 mg, 0.94 mmol) in MeOH (2 mL) was added NaBH3CN (99 mg, 1.57 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (YMC- Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give the title compound (5 mg, yield 7.8%) as a white solid. LC/MS (ESI) m/z: 206 (M+H)⁺. The (2S,3R)-1-Methyl-3-phenylpyrrolidine-2-carboxylic acid was used to prepare Compound 788 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 9.08 (t, J = 5.8 Hz, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 7.32 - 7.30 (m, 2H), 7.29 - 7.28 (m, 1H), 7.27 - 7.25 (m, 1H), 7.24 - 7.22 (m, 1H), 7.12 (s, 1H), 6.84 (s, 1H), 5.86 (s, 2H), 5.02 (d, J = 9.3 Hz, 1H), 4.53 - 4.40 (m, 2H), 3.27 - 3.24 (m, 1H), 3.13 - 3.10 (m, 1H), 2.54 - 2.52 (m, 1H), 2.43 (s, 3H), 2.35 - 2.30 (m, 4H), 2.19 - 2.14 (m, 1H), 1.91 - 1.86 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). LC/MS (ESI) (m/z): 558 (M+H)⁺. RT (Method A): 0.31 min. Scheme 275. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(4-methyl-pyridazin-3-yl)isoxazole-5- carboxamide (Compound 789) Step 1: 4-Methyl-3-vinylpyridazine To a mixture of 3-chloro-4-methylpyridazine (4 g, 31 mmol) and potassium trifluoro(vinyl)-borate (8.4 g, 62.5 mmol) in 1,4-dioxane (40 mL)/water (5 mL) was added Pd(dppf)Cl₂ (2.3 g, 3.1 mmol) and K₂CO₃ (12.8 g, 93 mmol) under a nitrogen atmosphere and the mixture was stirred at 100 °C for 3 hours. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 5% MeOH in DCM) to give the title compound (3 g, yield 81%) as a white solid. LC/MS (ESI) m/z: 121 (M+H)⁺. Step 2: 4-Methylpyridazine-3-carbaldehyde Ozone was bubbled into a solution of 4-methyl-3-vinylpyridazine (2.5 g, 21 mmol) in DCM (30 mL) at -65°C for 15 minutes. After excess ozone was purged by nitrogen bubbling, dimethyl sulfide (2 mL) was added at 0 °C and the mixture was stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (2 g, yield 77.5%) as a brown oil, which was used directly for the next step without purification. LC/MS (ESI) m/z: 123 (M+H)⁺. The 4-methylpyridazine-3-carbaldehyde was then used to prepare Compound 789 following the procedures set forth in Scheme 267.¹H NMR (400 MHz, CD3OD) δ 9.12 (d, J = 5.3 Hz, 1H), 8.86 (s, 1H), 8.41 (s, 1H), 7.81 (s, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 14.9 Hz, 2H), 5.16 (d, J = 7.9 Hz, 1H), 4.62 – 4.60 (m, 2H), 3.50 – 3.47 (m, 1H), 2.73 (s, 3H), 2.59 – 2.53 (m, 1H), 2.33 – 2.25 (m, 1H), 1.42 (d, J = 7.0 Hz, 3H). LC/MS (ESI) (m/z): 558 (M+H)⁺. RT (Method A): 0.65 min. Scheme 276. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-1,8- dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazin-3-yl)-3-(3-methyl-pyridin-2-yl)isoxazole-5- carboxamide (Compound 790) Step 1: Methyl (6S,8R)-3-((3,4-dimethylbenzyl)amino)-1,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2- a]pyrazine-6-carboxylate To a solution of methyl (6S,8R)-1-chloro-3-((3,4-dimethylbenzyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (60 mg, 0.15 mmol) in 1,4-dioxane (1 mL) and water (0.4 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.21 mL, 0.74 mmol, 3.5 M in THF), Pd(dtbpf)Cl2 (10 mg, 0.015 mmol) and K3PO4 (95 mg, 0.45 mmol), the reaction mixture was degassed under a nitrogen atmosphere three times and stirred at 100 °C for 4 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (17 mg, yield 29.3%) as a white solid. LC/MS (ESI) (m/z): 388 (M+H)⁺. Step 2: Methyl (6S,8R)-3-amino-1,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrazine-6- carboxylate To a solution of methyl (6S,8R)-3-((3,4-dimethylbenzyl)amino)-1,8-dimethyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (17 mg, 0.044 mmol) in DCM (0.5 mL) was added TfOH (0.5 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (8 mg, yield 76.7%) as a yellow oil, which was used directly in the next step without purification. LC/MS (ESI) m/z: 238 (M+H)⁺. The methyl (6S,8R)-3-amino-1,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]-pyrazine-6- carboxylate was used to prepared Compound 790 based on the procedures set forth in, e.g., Scheme 22..¹H NMR (400 MHz, DMSO-d₆) δ 10.67 (s, 1H), 9.04 (t, J = 5.9 Hz, 1H), 8.62 (d, J = 4.5 Hz, 1H), 8.41 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.50 – 7.48 (m, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.11 – 5.02 (m, 1H), 4.54 – 4.39 (m, 2H), 2.90 – 2.80 (m, 1H), 2.61 (s, 3H), 2.36 – 2.32 (m, 1H), 2.26 (s, 3H), 2.20 – 2.13 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H). LC/MS (ESI) (m/z): 571 (M+H)⁺. Scheme 277. Synthesis of N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-6-(3-(3-methyl-pyridin-2- yl)isoxazole-5-carboxamido)oxazolo[4,5-b]pyridine-2-carboxamide (Compound 791) Step 1: Ethyl 6-bromooxazolo[4,5-b]pyridine-2-carboxylate To a mixture of 2-amino-5-bromopyridin-3-ol (600 mg, 3.17 mmol) and ethyl 2,2,2-triethoxyacetate (1.5 mL) in 1,4-dioxane (9 mL) was added TsOH (28.76 g, 101.19 mmol) and the reaction mixture was stirred under a nitrogen atmosphere at 110 °C for 5 hours. The mixture was cooled, diluted with EtOAc, washed with saturated aq. NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 0 - 27% EtOAc in PE) to give the title compound (510 mg, yield 59.3%) as a white solid. LC/MS (ESI) m/z: 271 (M+H)⁺. Step 2: Ethyl 6-(3-(3-methylpyridin-2-yl)isoxazole-5-carboxamido)oxazolo[4,5-b]pyridine-2-carboxylate To a mixture of ethyl 6-bromooxazolo[4,5-b]pyridine-2-carboxylate (400 mg, 1.48 mmol), 3-(3- methylpyridin-2-yl)isoxazole-5-carboxamide (450 mg, 2.21 mmol) and Cs2CO3 (1.46 g, 4.48 mmol) in toluene (4 mL) was added XantPhos (171 mg, 0.30 mmol) and Pd2(dba)3 (135 mg, 0.15 mmol) under a nitrogen atmosphere and the reaction mixture was stirred under a nitrogen atmosphere at 100°C for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash column chromatography (silica gel, 35 - 95% EtOAc in PE) to give the title compound (160 mg, yield 27.6%) as a yellow solid. LC/MS (ESI) (m/z): 394 (M+H)⁺. Step 3: tert-Butyl (2-((6-(3-(3-methylpyridin-2-yl)isoxazole-5-carboxamido)oxazolo[4,5-b]-pyridine-2- carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate To a mixture of ethyl 6-(3-(3-methylpyridin-2-yl)isoxazole-5-carboxamido)oxazolo[4,5-b]-pyridine- 2-carboxylate (160 mg, 0.41 mmol) and tert-butyl (2-(aminomethyl)thieno[3,2-c]-pyridin-6-yl)carbamate (136 mg, 0.49 mmol) in THF (2 mL) was added DABAL-Me3 (156 mg, 0.61 mmol) at 0 °C and the mixture was warmed and stirred at 40 °C for 1 hour. The mixture was diluted with MeOH and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC- Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give the title compound (35 mg, yield 13.7%) as a white solid. LC/MS (ESI) m/z: 627 (M+H)⁺. Step 4: N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-6-(3-(3-methylpyridin-2-yl)isoxazole-5- carboxamido)oxazolo[4,5-b]pyridine-2-carboxamide (Compound 791) A solution of tert-butyl (2-((6-(3-(3-methylpyridin-2-yl)isoxazole-5-carboxamido)oxazolo[4,5-b]- pyridine-2-carboxamido)methyl)thieno[3,2-c]pyridin-6-yl)carbamate (35 mg, 0.06 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20% - 95% MeCN in water with 0.1% NH4HCO3) to give Compound 791 (1.0 mg, yield 3.4%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 10.12 (t, J = 5.7 Hz, 1H), 8.99 (d, J = 2.2 Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.65 - 8.62 (m, 1H), 8.46 (s, 1H), 7.91 - 7.88 (m, 1H), 7.87 (s, 1H), 7.52 - 7.48 (m, 1H), 7.21 (s, 1H), 6.97 (s, 1H), 6.20 (s, 2H), 4.68 - 4.64 (m, 2H), 2.64 (s, 3H). LC/MS (ESI) (m/z): 527 (M+H)⁺. Scheme 278. Synthesis of N-((6S,8R)-6-(((7-Aminothieno[2,3-d]pyridazin-2-yl)methyl)carbamoyl)-8- methyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(2,6-difluorophenyl)-isoxazole-5- carboxam Step 1: Ethyl-7-((2,4-dimethoxybenzyl)amino)thieno[2,3-d]pyridazine-2-carboxylate To a solution of ethyl 4-chloro-7-((2,4-dimethoxybenzyl)amino)thieno[2,3-d]pyridazine-2- carboxylate (500 mg, 1.22 mmol) in MeOH (5 mL) was added Pd/C (100 mg, 10% wt.), and the mixture was degassed under a dry nitrogen atmosphere three times and stirred under a hydrogen balloon at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (340 mg, yield 74.2%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 374 (M+H)⁺. Step 2: (7-((2,4-Dimethoxybenzyl)amino)thieno[2,3-d]pyridazin-2-yl)methanol To a solution of ethyl 7-((2,4-dimethoxybenzyl)amino)thieno[2,3-d]pyridazine-2-carboxylate (340 mg, 0.91 mmol) in MeOH (10 mL) was added NaBH₄ (345 mg, 9.10 mmol) at 0 °C. The mixture was then warmed and stirred at room temperature for 5 hours. The mixture was quenched with saturated aq. NH₄Cl solution and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (280 mg, yield 93.0%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 332 (M+H)⁺. Step 3: 2-(Azidomethyl)-N-(2,4-dimethoxybenzyl)thieno[2,3-d]pyridazin-7-amine To a solution of (7-((2,4-dimethoxybenzyl)amino)thieno[2,3-d]pyridazin-2-yl)methanol (280 mg, 0.84 mmol) in THF (3 mL) was added DBU (192 mg, 1.26 mmol) and DPPA (346 mg, 1.26 mmol). The mixture was degassed under a dry nitrogen atmosphere three times and stirred at 50°C for 1 hour. The mixture was cooled and diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 10 - 50% EtOAc in PE) to give the title compound (100 mg, yield 33.3%) as a yellow solid. LC/MS (ESI) m/z: 357 (M+H)⁺. Step 4: 2-(Aminomethyl)thieno[2,3-d]pyridazin-7-amine To a solution of 2-(azidomethyl)-N-(2,4-dimethoxybenzyl)thieno[2,3-d]pyridazin-7-amine (100 mg, 0.28 mmol) in THF/water (4 mL, v/v= 1/1) was added PPh3 (220 mg, 0.84 mmol) and the reaction was stirred at 50 °C for 1 hour. The mixture was acidified with 1N aq. HCl to pH~3 and washed with EtOAc twice. The aqueous phase was concentrated under reduced pressure to dryness and purified by prep- HPLC (YMC-Actus Triart C18, 25 - 98% MeCN in water with 0.1% NH4HCO3) to give the title compound (22 mg, yield 35.2%) as a white solid. LC/MS (ESI) m/z: 181 (M+H)⁺. Step 5: N-((6S,8R)-6-(((7-Aminothieno[2,3-d]pyridazin-2-yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(2,6-difluorophenyl) isoxazole-5-carboxamide (Compound 804) To a mixture of (6S,8R)-3-(3-(2,6-difluorophenyl)isoxazole-5-carboxamido)-8-methyl-4-oxo- 4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (40 mg, 0.09 mmol) and 2- (aminomethyl)thieno[2,3-d]pyridazin-7-amine (18 mg, 0.10 mmol) in DMF (1.5 mL) was added DIPEA (35 mg, 0.27 mmol) and T3P (75 mg, 0.27 mmol, 50% wt. in DMF) and the reaction was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to dryness and purified by prep-HPLC (YMC-Actus Triart C18, 25 - 98% MeCN in water with 0.1% NH4HCO3) to give Compound 804 (3 mg, yield 5.3%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H), 9.31 (t, J = 5.8 Hz, 1H), 8.87 (s, 1H), 8.53 (s, 1H), 7.72 - 7.65 (m, 2H), 7.41 - 7.34 (m, 3H), 6.77 (s, 2H), 5.09 (d, J = 8.7 Hz, 1H), 4.72 - 4.62 (m, 2H), 3.19 - 3.16 (m, 1H), 2.42 - 2.39 (m, 1H), 2.30 - 2.24 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H). LC/MS (ESI) m/z: 579 (M+H)⁺. RT (Method A): 1.22 min. Scheme 279. Synthesis of (6S,8R)-N-((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)-3-(1-(2-fluoro-3- methylphenyl)-1H-pyrazole-4-carboxamido)-8-methyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2- a]pyrimidine-6-carboxamide (Compound 805) Step 1: Methyl 1-(2-fluoro-3-methylphenyl)-1H-pyrazole-4-carboxylate To a mixture of methyl 1H-pyrazole-4-carboxylate (100 mg, 0.79 mmol) and 1-bromo-2-fluoro-3- methylbenzene (165 mg, 0.88 mmol) in MeCN (3 mL) was added Cs2CO3 (776 mg, 2.37 mmol), Cu2O (164 mg, 0.79 mmol) and salicylaldoxime (109 mg, 0.79 mmol) and the reaction mixture was stirred at 80°C overnight. The mixture was cooled and then diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (17 mg, yield 9.15%) as a colorless oil. LC/MS (ESI) m/z: 235 (M+H)⁺. The methyl 1-(2-fluoro-3-methylphenyl)-1H-pyrazole-4-carboxylate was used to prepare Compound 805 based on the procedures set forth in, e.g., Scheme 60.¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 9.09 (t, J = 5.6 Hz, 1H), 8.95 (s, 1H), 8.59 - 8.55 (m, 1H), 8.41 (s, 1H), 8.33 - 8.29 (m, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.30 - 7.25 (m, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.04 (d, J = 9.4 Hz, 1H), 4.52 - 4.42 (m, 2H), 3.48 - 3.41 (m, 1H), 2.35 (s, 3H), 2.35 - 2.31 (m, 1H), 2.26 - 2.17 (m, 1H), 1.30 (d, J = 7.0 Hz, 3H). LC/MS (ESI) m/z: 573 (M+H)⁺. RT (Method A): 1.28 min. Scheme 280. Synthesis of N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2-yl)methyl)carbamoyl)-1,8- dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazin-3-yl)-3-(3-methylpyridin-2-yl)-isoxazole-5- carboxa Step 1: Methyl (6S,8R)-1-cyclopropyl-3-((3,4-dimethylbenzyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate To a solution of methyl (6S,8R)-1-chloro-3-((3,4-dimethylbenzyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (50 mg, 0.12 mmol) in 1,4-dioxane (1 mL) and water (0.4 mL) was added potassium cyclopropyltrifluoroborate (91 mg, 0.62 mmol), Pd(dtbpf)Cl₂ (10 mg, 0.015 mmol) and K3PO4 (95 mg, 0.45 mmol), and the reaction mixture was degassed under a N2 atmosphere three times and then stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 - 40% EtOAc in Petroleum ether) to give the title compound (20 mg, yield 39.4%) as a white solid. LC/MS (ESI) (m/z): 414 (M+H)⁺. The methyl (6S,8R)-1-cyclopropyl-3-((3,4-dimethylbenzyl)amino)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate was used to prepare Compound 807 based on the procedures set forth in, e.g., Scheme 276.¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (t, J = 5.8 Hz, 1H), 8.62 (d, J = 3.8 Hz, 1H), 8.41 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.58 – 7.35 (m, 2H), 7.13 (s, 1H), 6.84 (s, 1H), 5.84 (s, 2H), 5.11 – 5.04 (m, 1H), 4.53 – 4.38 (m, 2H), 3.78 – 3.70 (m, 1H), 2.61 (s, 3H), 2.39 – 2.34 (m, 1H), 2.23 – 2.17 (m, 1H), 1.98 – 1.92 (m, 1H), 1.40 (d, J = 6.9 Hz, 3H), 0.98 – 0.92 (m, 1H), 0.88 – 0.81 (m, 2H), 0.70 – 0.64 (m, 1H). LC/MS (ESI) (m/z): 597 (M+H)⁺. Example 2. Non-Limiting Examples of Compounds of the Present Disclosure Table 1 shows illustrative complement pathway inhibitors. Table 1. Non-limiting Examples of Compounds of the Present Disclosure 3 3 3 3 3 3

O ^N O _O ^N O H N HN N _O O _H N F HN N O N F H₂N S N N O 93 394 H₂N S 3 N N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2- yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(2- yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- fluorophenyl)isoxazole-5-carboxamide tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-3-(2,6- difluorophenyl)isoxazole-5-carboxamide F F O ^N O O H _O O ^S _N N HN H N HN N _N N _N N N 395 O H₂N S 396 _H2N S ^O N N N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2- N-((6S,8R)-6-(((6-Aminothieno[3,2-c]pyridin-2- yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- yl)methyl)carbamoyl)-8-methyl-4-oxo-4,6,7,8- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-phenyl- tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)-5-(2,6- 1,2,4-oxadiazole-3-carboxamide difluorophenyl)-1,3,4-thiadiazole-2-carboxamide

EXAMPLE 3. Human C1s Enzyme Assay The IC50 values of the compounds of Table 1 were determined with the human C1s enzyme assay described below. Other standard complement assays are also available. Human complement C1s enzyme (purified from human serum, Complement Technology, Inc.) at 1.16 nM final concentration was incubated with test compound at various concentrations for 5 min at RT in 50 mM Tris, 1M NaCl, pH 7.5. A synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman’s reagent) were added to final concentrations of 100 µM each. Absorbance at 405 nm (A405) was recorded at 30 second intervals for 30 min using a microplate spectrophotometer. IC50 values were calculated by nonlinear regression of complement C1s reaction rates as a function of test compound concentration. Table 2 shows the IC50 values of the compounds obtained from the above-described human C1s enzyme assay. Three stars (***) are used to denote compounds with an IC₅₀ less than 100 nanomolar; two stars (**) indicates a compound with an IC50 greater than or equal to 100 nanomolar and less than 1 micromolar, one star (*) denotes compounds with an IC50 greater or equal to than 1 micromolar. ND indicates a compound for which the IC50 value is not determined. Table 2. C1s Inhibiting Activity of Compounds of the Present Disclosure

EXAMPLE 4. Hemolysis Assays The hemolysis assay was previously described by Dodds, A.W. and Sim, R.B. (1997); Morgan, B.P. (2000). Prior to the assay, the optimum concentration of Normal Human Serum (NHS) needed to achieve 100% lysis of antibody sensitized sheep erythrocytes (EA) was determined by titration. EA were sheep erythrocytes with rabbit IgM anti-sheep erythrocyte antibodies bound to their surface. In the assay, NHS (Complement Technology) was diluted in GVB++ Buffer (0.1 % gelatin, 5 mM Veronal, 145 mM NaCl, 0.025 % NaN3, pH 7.3, 0.15 mM calcium chloride and 0.5 mM magnesium chloride, Complement Technology) and incubated with test compound at various concentrations for 2 min at room temperature. EA (Complement Technology) freshly suspended in GVB++ were added to a final concentration of 1 x 10⁸ cells/mL and reactions were incubated for 60 min at 37 °C. Positive control reactions (100% lysis) consisted of GVB++ with NHS and EA but without test compound; negative control reactions (0% lysis) consisted of GVB++ with EA only. Samples were centrifuged at 2000g for 3 min and supernatants collected. Absorbance at 405 nm (A405) was recorded using a microplate spectrophotometer. IC₅₀ values were calculated by nonlinear regression from the percentage of hemolysis as a function of test compound concentration. 0.5% EsH CP hemolysis procedure: A functional hemolytic assay was employed to evaluate complement pathway activity and inhibitor effect in ~0.5% human serum. Sheep erythrocytes (Es, 1 x 10⁸ cells/mL, Complement Technology) were sensitized in-house using hemolysin (0.1^µL/mL, Complement Technology) than washed, and resuspended in cold GVB++ (0.1 % gelatin, 5 mM Veronal, 145 mM NaCl, 0.025 % NaN3, pH 7.3, 0.15 mM calcium chloride and 0.5 mM magnesium chloride, Complement Technology). Assays were conducted in 96-well plates at a final reaction volume of 130^µL per well and a final serum concentration of ~0.5%. Test and reference compounds were added in an 8-point concentration series prepared in DMSO. A master mix of GVB++ buffer and normal human serum (NHS, Complement Technology) was prepared and dispensed into wells, followed by addition of sensitized Es (EsH). Plates were sealed, briefly mixed, and incubated at 37^°C for 30–60 minutes with periodic shaking. Neutral (DMSO) and lysis controls were included on each plate. After incubation, plates were centrifuged at 800×g for 3 minutes at 4^°C, and hemolysis was assessed by transferring supernatant to a new plate and measuring absorbance at 405^nm (A₄₀₅). Released hemoglobin served as a direct readout for CP-mediated lysis and inhibitor efficacy. IC₅₀ values for test compounds were calculated by nonlinear regression analysis from the percentage of hemolysis as a function of test compound concentration. 10% Es CP hemolysis procedure: A functional hemolytic assay was employed to evaluate complement pathway activity and inhibitor effect in ~10% human serum using Es. Assays were conducted in 96-well plates at a final reaction volume of 130^μL and serum concentration of ~10%. Es cells were washed and resuspended in cold GVB++ before use. Test and reference compounds were added in an 8-point concentration series prepared in DMSO, followed by of a master mix of GVB++ and NHS. Washed Es cells were added last. Neutral (DMSO) and lysis controls were included on each plate. Plates were sealed, briefly mixed, and incubated at 37^°C for 6- 13 minutes, then centrifuged at 800×g for 3 minutes at 4^°C and hemolysis was assessed by transferring supernatant to a new plate and measuring absorbance at 405^nm (A405). Released hemoglobin served as a direct readout for CP-mediated lysis and inhibitor efficacy. IC₅₀ values for test compounds were calculated by nonlinear regression analysis from the percentage of hemolysis as a function of test compound concentration. 33% EA CP hemolysis procedure: A functional hemolytic assay was employed to evaluate complement pathway activity and inhibitor effect in ~33% human serum using Ab-sensitized sheep erythrocytes (EA, Complement Technology). Assays were conducted in 96-well plates at a final reaction volume of 101^μL and serum concentration of ~33%. EA cells were washed and resuspended in cold GVB++ and diluted 3-fold before use. Test and reference compounds were added in an 8-point concentration series prepared in DMSO, followed by of a master mix of GVB++ and NHS. Diluted EA cells were added last. Neutral (DMSO) and lysis controls were included on each plate. Plates were sealed, briefly mixed, and incubated at 37^°C for 5–6 minutes, then centrifuged at 800×g for 3 minutes at 4^°C and hemolysis was assessed by transferring supernatant to a new plate and measuring absorbance at 405^nm (A405). Released hemoglobin served as a direct readout for CP-mediated lysis and inhibitor efficacy. IC₅₀ values for test compounds were calculated by nonlinear regression analysis from the percentage of hemolysis as a function of test compound concentration. EXAMPLE 5. Microsomal Stability Assay The microsomal stability of compounds of the disclosure were analyzed as described below. Materials Methodology The phosphate buffer solution was prepared by mixing 15.2 mL of deionized water with 1.9 mL of 0.5 M phosphate buffer and 1.9 mL of 33 mM MgCl2. The microsomal working solution was prepared by mixing 14.655 mL of deionized water with 1.9 mL of 0.5 mM phosphate buffer, 1.9 mL of 33 mM MgCl₂, and 545 µL of 20 mg/mL of liver microsomes (species specific). The cofactor solution was prepared by mixing 8.12 mL of deionized water with 1.45 mL of 0.5 mM phosphate buffer, 1.45 mL of 33 mM MgCl2, 1.16 mL of 100 mM NADP+ solution, 1.16 mL of 100 mM glucose-6-phosphate solution, and 1.16 mL of 100 U/mL glucose-6-phosphate dehydrogenase solution. Final assay reagent concentrations were 0.1 µM test article, 0.5 mg/mL liver microsomes, 1 mM NADP+, 5 mM glucose-6-phosphate, 1 U/mL glucose- 6-phosphate dehydrogenase, 50 mM phosphate buffer (pH 7.4), 3.3 mM MgCl2, and 0.2% DMSO. The assay reaction mixture was prepared by taking 436 µL of microsomal working solution and mixing it with 63 µL of cofactor solution in a 1.5 mL 96-well plate and preincubated at 37 °C for 5 minutes. The assay was initiated by the addition of 1 µL of 50 µM solution of a test compound in DMSO. At 0 minutes, 30 minutes, and 120 minutes, 100 µL aliquots of the incubation mixture were removed and mixed with 200 µL of cold MeCN containing 0.2µM tolbutamide (internal standard) in a separate 96-well plate. At the conclusion of the assay, the sample collection plate were vortexed for thirty seconds, and centrifuged at 3000 xg and 4 °C for 10 minutes. The supernatants were transferred to clean 96-well bioanalysis plates for analysis and stored at 4 °C. Sample Bioanalysis The test compound concentrations in liver microsome samples were analyzed by a LC-MS/MS method on a Sciex API 5500 Q-Trap mass spectrometer using turbo ion spray with MRM monitoring in the positive mode. Analyst^® software (Version 1.6.2) was used to capture the LC-MS/MS data and integrate the peak areas. EXAMPLE 6. Hepatic Clearance Assay The hepatic clearance of compounds of the present disclosure were analyzed following the procedures described below. Thawing Media and Test Article Preparation The thawing media was warmed in a water bath 37 °C. The test compounds were diluted 200 x from 20 mM to 100 µM in DMSO, then to 0.2 µM by adding 3 µL of test compound solution into 1.5 mL of Williams E medium. Midazolam (1 mM) and 7-ethoxycoumarin (100 mM) controls were thawed, and 3 µL of each control was added to 1.5 mL Williams E medium. Cold MeCN (150 µL) with internal standards were then added to a 96-well plate. Cell Viability Determination Cryopreserved hepatocytes (human, rat, dog, or monkey) were thawed in water bath for ~ 90 s, transferred into warm thawing media, and centrifuged at 100 g for 5 min. The supernatant fluid was then aspirated, and the pellets were resuspended in 5 mL Williams E medium. The cell suspension (50 µL) was mixed with Trypan blue, then an aliquot was placed on a hemacytometer for cell viability determination. If the cell viability was determined to be over 70%, the cell concentration in the hepatocyte medium was then adjusted to 10⁶/mL by adding the appropriate amount of Williams E medium. Incubation The hepatocyte suspension (500 µL) was added to each well of 24-well plate. The test compound solution (500 µL) was then added. At 0 min, 75 µL of the sample was taken and quenched with 150 µL cold MeCN in the 96-well plate. Samples were taken and quenched at 30 min, 50 min, and 120 min (15 min and 120 min for 7-ethoxycoumarin). After incubation and quenching, the samples were stored at -20 °C overnight. LC-MS/MS Analysis After the mass spectrometer was tuned for each compound using a 2 mL solution of 0.05 MS tuning for each compound 0.05 µM of the test compound in 1:1 Water/Acetonitrile, the 96-well plate containing the incubation samples and quench solutions was centrifuged at 25°C, 3000 rpm for 15 min. The samples (160 µL) were transferred to deep well plates and queued in LC-MS/MS for analysis. To determine the intrinsic clearance and hepatic clearance (%Qh) of the test compounds, the in peak area ratio (compound peak area/internal standard peak area) was plotted against time and the gradient of the line determined. EXAMPLE 7. Caco-2 Permeability Assay The bidirectional permeability and efflux probability of compounds of the present disclosure in Caco-2 cell monolayers with and without efflux inhibitors were determined following the procedure described below. Materials and Reagents Caco-2 cells were obtained from the American type culture collection (ATCC), and the ATCC® Number is HTB-37. Hepes, Penicillin, Streptomycin, Trypsin/EDTA and DMSO are purchased from Solarbio. Bovine Serum Albumin (BSA) was purchased from Solarbio Biotechnology Co., Ltd. Fetal bovine serum, Hank’s balanced salt solution (HBSS) and non-essential amino acids (NEAA) were all purchased from Gibco by Thermo Fisher Scientific. Dulbecco’s Modified Eagle’s Medium (DMEM) is purchased from Corning Corporation or Hyclone. HTS Transwell-96 Well (Cat. No.3391) Permeable Supports and other sterile plastic ware were purchased from Corning Corporation. Millicell Epithelial Volt- Ohm measuring system was purchased from Millipore. Cellometer® Vision is purchased from Nexcelom Bioscience LLC. Infinite 200 PRO microplate reader was purchased from Tecan. MTS2/4 orbital shaker was purchased from IKA Labortechnik. Transport buffer: HBSS containing 25 mM HEPES, pH 7.4, and 3% BSA To prepare the HBSS containing 25 mM HEPES at pH 7.4, 5.958 g of HEPES and 0.35 g of sodium hydrogen carbonate were added to 900 mL of pure water, and the mixture was sonicated until the contents were dissolved. Then, 100 mL of 10× HBSS was transferred into the solution, which was placed on a stirrer and the pH was slowly adjusted to 7.4 with sodium hydroxide. The solution was then filtered, and 3% BSA was added. Transport buffer with efflux inhibitors: HBSS containing 25 mM HEPES, pH 7.4 and 3% BSA To prepare the HBSS containing 25 mM HEPES at pH 7.4, 5.958 g of HEPES and 0.35 g of sodium hydrogen carbonate were accurately weighed and added to 900 mL of pure water. The mixture was sonicated until the contents were dissolved. Then, 100 mL of 10× HBSS was transferred into the solution, which was placed on a stirrer, and the pH was slowly adjusted to 7.4 with sodium hydroxide. The solution was then filtered. Before the experiment, stock solutions of zosuquidar (10 mM), benzbromarone (30 mM), and KO-143 (2 mM) were added to the HBSS (25 mM HEPES, pH 7.4) at 1:1000 dilution and 3% BSA at final concentrations of 1 μM zosuquidar, 30 μM benzbromarone, and 2 μM KO-143. Preparation for Cell Seeding 1. Prepare transport buffer (HBSS containing 25 mM HEPES, pH 7.4): accurately weigh 5.958 g of HEPES and 0.35 g sodium hydrogen carbonate and add into 900 mL of pure water, then sonicate to dissolve the content. Transfer 100 mL of 10× HBSS into the solution, and place the solution on a stirrer, slowly adjust pH with sodium hydroxide to 7.4, following with filtering. 2. Prepare Caco-2 cell culture medium consisting of Dulbecco’s Modified Eagle’s Medium (DMEM) with high glucose and L-glutamine supplemented with 10% FBS, 0.1 mg/mL of streptomycin, 100 units of penicillin, 0.6 μg/mL of Kanamycin sulfate and 1x non-essential amino acids (NEAA). 3. Add 50 μL of culture medium to each well of the Transwell insert. Remove Transwell insert from reservoir and add 25 mL of culture medium. 4. Incubate at 37 °C, 5% CO₂ for 1 hour. Plates are ready for cell seeding. 5. Cultivate cells in T-75 flasks in a cell culture incubator set at 37°C, 5% CO2, 95% relative humidity. Allow cells to reach 80-90% confluence before detaching and splitting. 6. Rinse cultivated cells in T-75 flasks with 5 mL PBS. Aspirate off, add 1.5 mL trypsin/EDTA, and incubate at 37 °C for approximately 5 to 10 minutes or until the cells detach and float. Inactivate trypsin/EDTA by adding excess medium containing serum. 7. Transfer cell suspension to a conical tube and pellet cells by centrifugation at 120x g for 10 minutes. 8. Resuspend cells in seeding medium at a density of 6.86 х 10⁵ cells/mL. This cell concentration can be used to seed 2.4х 10⁵ cells/cm². Seeding and Feeding of Caco-2 Cells into Transwell Plates 1. Add 50 μL of above cell suspension to each well of a previously prepared Transwell plate. 2. Incubate the plate for 14-18 days. Replace the medium every other day, beginning no sooner than 48 hours after initial plating. Medium must be replaced on the day before conducting the experiment. 3. The procedure for medium changes is as follows. Remove the plate from incubator and place in hood. Aspirate the medium from reservoir and each Transwell insert. Add 100 μL of culture medium to each well of Transwell inserts and 25 mL of culture medium to reservoir tray. Return plate to incubator. Assessment of Cell Monolayer Integrity 1. When the 14-day cultured Caco-2 cells have reached confluence and are differentiated, they are ready to be used for transport studies. 2. Measure the electrical resistance across the monolayer using Millicell Epithelial Volt-Ohm measuring system (Millipore). 3. Record the electrical resistance for each well. 4. Once all wells have been measured, return plate to incubator. 5. Calculation of TEER values: TEER measurement (ohms) x Area of membrane (cm²) = TEER value (ohm·cm²). Any monolayer with a TEER value < 230 ohms·cm², indicating poor monolayer formation, will be discarded. Performing the Drug Transport Assay 1. Remove the Caco-2 plate from the incubator. Next, wash the monolayer, exchange the volume two times using pre-warmed transport buffer. Then, incubate the plate at 37 °C for 30 minutes. 2. For test compounds and control compound digoxin, prepare stock solutions in DMSO at 2 mM and dilute by transport buffer with or without efflux Inhibitors to get 10 μM working solution. For control compound metoprolol, prepare stock solutions in DMSO at 2 mM and dilute by HBSS without 3% BSA to get 10 μM working solution. The final DMSO concentration is 0.8%. 3. Prepare bulk donor solutions with 597 μL transport buffer (with or without efflux inhibitors) and 3 μL 2 mM test compound or control compound. 4. Prepare bulk receiver solutions with 597 μL transport buffer (with or without efflux inhibitors) and 3 μL DMSO. 5. To determine the rate of drug transport in the apical to basolateral direction. Add 108 μL of the donor solution to the Transwell insert (apical compartment), and transfer 8 μL sample immediately from the apical compartment to 72 μL transport buffer and 240 μL quenching solvents in a new 96-well plate as the initial donor sample (A-B). Shake the plate at 1000 rpm for 5 minutes. Fill the wells in the receiver plate (basolateral compartment) with 300 μL of receiver solution. 6. To determine the rate of drug transport in the basolateral to apical direction. Add 308 μL of the donor solution to the receiver plate wells (basolateral compartment), and transfer 8 μL sample immediately from the basolateral compartment to 72 μL transport buffer and 240 μL quenching solvents in a new 96-well plate as the initial donor sample (B-A). Fill the Transwell insert (apical compartment) with 100 μL of receiver solution. Shake the plate at 1000 rpm 5 minutes. 7. Incubate at 37 °C for 2 hours. At the end of the transport period, transfer 8 μL of samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap flux) to 72 μL transport buffer and 240 μL quenching solvents in a new 96-well plate. Remove 80 μL directly from receiver sides (basolateral compartment for Ap→Bl flux, and apical compartment for Bl→Ap flux) and transfer to new 96-well plates with 240 μL quenching solvents. Vortex at 1000 rpm for 10 minutes. Centrifuge the quenching plates of each time point for 30 minutes at 4,000 rpm and 4°C. Transfer 100 µL of supernatant of each compound into a 96-well analysis plate containing 100 µL of pure water in the corresponding wells. Shake the analysis plate at 1,000 rpm for 2 minutes and the sample is analyzed by LC-MS/MS. All incubations are performed in duplicate. 8. To determine the Lucifer yellow leakage after 2-hour transport period, prepare stock solutions of Lucifer yellow in water and dilute with transport buffer to reach the final concentration of 100 μM. Add 100 μL of the Lucifer yellow solution to the Transwell insert (apical compartment). Fill the wells in the receiver plate (basolateral compartment) with 300 μL of transport buffer. Incubate at 37 °C for 30 minutes. Remove 80 μL directly from the apical and basolateral wells (using the basolateral access holes) and transfer to new 96 wells plates. Measure Lucifer Yellow fluorescence (to monitor monolayer integrity) in a fluorescence plate reader at 485 nm excitation and 530 nm emission. EXAMPLE 8. Pharmacokinetic Profile following IV and PO Administration The pharmacokinetic profile of compounds of the present disclosure following intravenous (IV) or oral (PO) administration in male Wistar Han rats and non-naïve Male Beagle dogs at various dosages was assessed based on the general procedure described below. Pharmacokinetic Study in Male Wistar Han Rats Exemplary Dosing Information IV dosing: For Male Wistar Han rats previously fitted with a jugular vein catheter (JVC) for blood collection, the animals will receive a single IV dose of a test compound (e.g., at a dose level of 0.5 mg/kg or more). Sampling will be done from the cannulated carotid artery. PO dosing: For Male Wistar Han rats previously fitted with a jugular vein catheter for blood collection animals will receive a single oral dose of compound, e.g., at a dose level of 5 mg/kg or more. Animal feeding control: All animals for IV and PO administration will be fasted overnight and fed after 4 hours collection post dosing. Dose formulation processing during dosing: The dose formulations will be kept at room temperature and administered within 2 hours after preparation. Exemplary Pharmacokinetic (PK) Schedule: IV dosing: Plasma: Pre-dose, 0.33, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours pose dose. PO dosing: Plasma: Pre-dose, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post dose. PK Samples Analyses Concentrations of test compounds in the plasma samples were analyzed using a LC-MS/MS method. WinNonlin (Phoenix^TM, version 8.3) or other a similar software will be used for pharmacokinetic calculations. The following pharmacokinetic parameters will be calculated, whenever possible, from the plasma concentrations versus time data: IV administration: T_1/2, C₀, AUC_last, AUC_inf, MRT, Cl, Vss PO administration: T1/2, Cmax, Tmax, AUCinf, AUClast, F% Pharmacokinetic Study in Male Beagle Dogs Non-naïve Male Beagle dogs aged 8 months – 3 years that weigh between 8.0 – 12.0 kg are used. Single IV and PO dosing at 1 mg/kg for IV and 5 mg/kg for PO. Oral gavage is used for PO dosing, peripheral veins are used for IV dosing. Study time is 24-hours with blood sampling times at Pre-dose, 0.033, 0.083, 0.25, 0.5, 1, 2-, 4-, 8-, and 24-hours post-dose. K2EDTA is used as anticoagulant. Dogs are fasted overnight and fed 2-hours post dose. IV and PO vehicles are 10%DMSO/60%PEG400/30%Saline. Plasma concentrations are determined by LC-MS/MS. Pharmacokinetic analysis is conducted using WinNonlin (Phoenix v8.3) or equivalent. EXAMPLE 9. MASP-2 Protease Assay Compounds of the present disclosure were assessed with a MASP-2 protease assay. Materials Method The test compounds and/or DMSO are preincubated with enzyme in buffer for 5 minutes at Room temperature (RT), and also without enzyme as a control. The reaction was initiated by addition of substrate and DTNB mix. In this assay, the concentrations of the enzyme, substrate, and DTNB concentration were 16 nM, 200 µM and 200 µM, respectively. The absorbance was measured on a microplate reader with 405 nm (A₄₀₅) in a kinetic mode every 30 second for at least 30 minutes at room temperature. The test compounds were screened at a concentration of 0.1 μM or in an 8 point half log dilution series with a starting concentration of 10 μM. The compound, (2R,4S)-N-((S)-1-(((1H-pyrrolo[3,2- c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide was included in each assay in an 8 point half log dilution series with a starting concentration of 1 μM. EXAMPLE 10. hERG Assay The in vitro inhibitory effects of compounds of the present disclosure on the hERG (human ether- à-go-go-related gene) potassium channel current using the manual patch-clamp technique. HEK293 cells stably expressing the hERG channel were cultured under standard conditions and induced with doxycycline prior to electrophysiological evaluation. Test compounds were solubilized in DMSO and serially diluted to create five working concentrations (30, 10, 3.33, 1.11, and 0.37 μM). The final DMSO concentration was controlled between 0.1%–0.3% (v/v). Patch-clamp recordings were obtained at a holding potential of –90 mV, and hERG tail currents were elicited by depolarizing to +30 mV followed by repolarization to –50 mV. Data quality criteria included a seal resistance >1 GΩ, a membrane resistance >500 MΩ, and access resistance <15 MΩ, among others. The inhibitory effect of each compound was assessed by perfusing each concentration sequentially, and the percentage inhibition of hERG current was determined relative to control. Dose– response curves were constructed using GraphPad Prism and fit to a variable-slope sigmoidal function to determine IC₅₀ values. Each experiment was performed in triplicate. Test compound potency was categorized as low (IC₅₀ >10 μM), moderate (1–10 μM), or high (<1 μM) inhibition. A positive control (dofetilide) was included to validate assay performance. EEXAMPLE 11. Protease Selectivity Assays Compounds of the present disclosure were assessed with trypsin, thrombin, and tryptase protease assays. Trypsin Assay A fluorescence-based assay was utilized to assess the activity of native human trypsin (Abcam) using Z-Gly-Pro-Arg-AMC.HCl (Sigma-Aldrich) as substrate. Test compounds, or DMSO as control, were preincubated with trypsin (0.8^nM final concentration) in buffer (50^mM Tris HCl pH 7.5, 100^mM NaCl) for 10 to 15 minutes at room temperature, including a no enzyme control. The reaction was initiated by the addition of substrate (10^μM final concentration). Fluorescence was monitored kinetically (Ex/Em 350/450^nm) every minute for either 15 or 30 minutes at 37^°C. Data from the 10- or- 15-minute timepoint were used for analysis. IC50 values were calculated by nonlinear regression from percentage of enzyme activity as a function of test compound concentration. Thrombin Assay A fluorescence-based assay was performed using Thrombin enzyme from human plasma (Sigma- Aldrich) and the substrate Z-Gly-Pro-Arg-AMC.HCL (Sigma Aldrich) in buffer (50^mM Tris HCl, pH 7.5, 100^mM NaCl). Test compounds or DMSO were preincubated with the enzyme (100^mU/mL final concentration) for 10 minutes at room temperature, with a no enzyme control included. The reaction was initiated by addition of substrate (10^μM final concentration), and fluorescence was measured kinetically (Ex/Em 350/450^nm) every minute for either 20 or 30 minutes at room temperature. Data from the 15- minute timepoint were used for analysis. IC50 values were calculated by nonlinear regression from percentage of enzyme activity as a function of test compound concentration. Tryptase Assay A fluorescence-based assay was performed using recombinant human lung β tryptase (Promega) and the substrate Z-Gly-Pro-Arg-AMC.HCL (Sigma Aldrich) in buffer (50^mM Tris HCl, pH 7.5, 100^mM NaCl, 0.1^mg/mL heparin). Test compounds or DMSO were preincubated with the enzyme (1^nM final concentration) for 5 minutes at room temperature, with a no enzyme control included. The reaction was initiated by addition of substrate (10^μM final concentration), and fluorescence was measured kinetically (Ex/Em 350/450^nm) every minute for at least 60 minutes at room temperature. Data from the 60-minute timepoint were used for analysis.. IC₅₀ values were calculated by nonlinear regression from percentage of enzyme activity as a function of test compound concentration. EXAMPLE 12. Toxicity Assays The cytotoxicity of compounds of the present disclosure were assessed as described below. HepG2, THP-1 and PBMC Cytotoxicity Assay Cell Lines and Primary Cells: The human hepatoma cell line HepG2 and the human monocyte cell line THP-1 were purchased from ATCC (Manassas, VA). Cryopreserved peripheral blood mononuclear cells (PBMCs) pooled from multiple human donors were purchased from Lonza (Walkersville, MD). HepG2 cells, THP-1 cells, and PBMCs were maintained at 37ºC in an atmosphere of 5% CO2. in RPMI 1640 medium (HyClone, Logan, UT) supplemented with 10% fetal bovine serum (FBS), penicillin (100 IU/mL), and streptomycin (100 μg/mL), and for PBMCs with DNAse I (20 U/mL). Evaluation of Cellular Toxicity: Cells of the adherent HepG2 cell line were plated at a seeding density of 8,000 cells per well and incubated for one day prior to addition of compounds. Cells of the non- adherent THP-1 cell line and non-adherent PBMCs were plated at 40,000 and 200,000 cells per well, respectively. Compounds were dissolved in half-log dilution series in dimethyl sulfoxide (DMSO) and added to cells in culture media at a final DMSO concentration of 0.5% (vol/vol) (HepG2 cells and THP-1) or 0.25% (vol/vol) (PBMCs). the same DMSO concentrations were also present in all vehicle control wells (no compound treatment) to rule out any potential effect of DMSO on cell growth. Plates were incubated for 72 hours (HepG2 cells and THP-1) or 120 hours (PBMCs). Cell viability was measured using the Cell Counting Kit-8 (Dojindo Molecular Technologies, Rockville, MD). The kit utilized a metabolic indicator. Percent reduction in cell viability at each concentration of compound, in comparison to untreated cells, was calculated and the concentration that reduced cell viability by 50% (50% cytotoxic concentration, or CC₅₀) was obtained with a Microsoft Excel-based program. HepG2, Mitochondrial Toxicity Assay Cell Lines and media preparation: The human hepatoma cell line HepG2 were purchased from ATCC (Manassas, VA). HepG2 cells were maintained in RPMI-1640 medium (Life Technologies, Carlsbad, CA) supplemented with 10% fetal bovine serum (FBS), 100 IU/mL penicillin, and 100 μg/mL streptomycin. Glucose-containing medium was prepared from glucose-free RPMI-1640 medium (Life Technologies) with supplements of 25 mM glucose, 2 mM glutamine, 10% dialyzed FBS (Life Technologies), and penicillin-streptomycin. Galactose-containing medium was prepared from glucose-free RPMI-1640 medium with supplements of 10 mM galactose, 2 mM glutamine, 10% dialyzed FBS, and penicillin-streptomycin. Evaluation of mitochondrial Toxicity: Cell monolayers of HepG2 cells were detached with trypsin- EDTA solution and resuspended in RPMI growth medium in two equal portions. After a brief spin, cell pellets were washed twice with glucose- or galactose-containing medium. Cells were resuspended in medium containing glucose or galactose and 10% dialyzed FBS. Cell suspensions in glucose- or galactose-containing medium were seeded into 96-well plates in at a density of 10,000 cells per well. Compound stock solutions were prepared and diluted into half-log concentration series in dimethyl sulfoxide (DMSO). Compounds were added to cells in the appropriate culture media at a final DMSO concentration of 0.5% (vol/vol) one day after plating HepG2 cells. The same DMSO concentrations were also present in all vehicle control wells (no compound treatment) to rule out any potential effect of DMSO on cell growth. Plates were incubated for 72 hours. Cell viability was measured using the Cell Counting Kit-8 (Dojindo Molecular Technologies, Rockville, MD). The kit utilizes a metabolic indicator. Percent reduction in cell viability at each concentration of compound, in comparison to untreated cells, was calculated and the concentration that reduced cell viability by 50% (50% cytotoxic concentration, or CC50) was obtained with a Microsoft Excel-based program. Other Embodiments This specification has been described with reference to various specific embodiments. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of the claims. We claim:

Claims

Claims 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein wherein X¹ is O, S, C(R^a)₂, or NR^a, wherein each R^a is independently selected from absent, H, C₁- C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl; X² is N or CR^b, wherein R^b is absent or H; each of X³, X⁴, and X⁵ is independently selected from NR^c and C(R^c)2, wherein each R^c is independently selected from absent, H, halo, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂, and C₁-C₆ alkyl, and only one of X³ and X⁵ can be NR^c when X⁴ is NR^c; R³ is H or halo; and R⁴ is H, halo, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, or C3-C6 cycloalkyl; and each is independently selected from a single bond and a double bond; each of R¹ and R^1’ is independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, or (C1-C6 alkoxy)(C1-C6 alkyl); each of R², R^2’, R⁵, and R^5’ is independently selected from H; halo; OH, C1-C6 alkyl; C1-C6 haloalkyl; C₁-C₆ hydroxyalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; (C₁-C₆ alkoxy)(C₁-C₆ alkyl); OCH₂P(O)(OR^f)₂, wherein each R^f is independently selected from H and C₁-C₆ alkyl; and (4- to 10- membered heterocyclyl)oxy containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with oxo; or R² and R^2’, together with the carbon atom to which they are attached, form spirocyclic C₃-C₈ cycloalkyl or 4- to 6-membered spirocyclic heterocycloalkyl containing 1 or 2 oxygen ring atoms; or R² and R⁵ or R^2’ and R^5’, together with the carbon atoms to which each is attached, form cyclopropyl; R⁶ is H or C₁-C₆ alkyl; each of X and X’ is independently selected from N and CR^d, wherein R^d is H, halo, C₁-C₆ alkyl, C₁- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or cyclopropyl; L¹ is a bond, NH, NHC(O), NHC(O)O, NHC(O)NH, or NHS(O)2; L² is a bond or C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, (C₁-C₆ alkoxy)(C₁-C₆ alkyl), and oxo; L³ is a bond, NH, NHC(O), C(O), O, or S(O)2CH2; and B is C6-C14 aryl; C3-C14 carbocyclyl; 5- to 14-membered heterocyclyl containing 1, 2, or 3 ring atoms independently selected from N, O, and S; or 5- to 10-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S; wherein B is optionally substituted with one or more substituents independently selected from halo; cyano; COOR^e, wherein R^e is H or C₁-C₆ alkyl; S(O)₂(C₁- C₆ alkyl); C₁-C₆ alkyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₆-C₁₄ aryl optionally substituted with one or more substituents independently selected from halo, COOH, SF5, S(O)2NH2, S(O)2(C1-C6 alkyl), S(O)(NH)CH3, P(O)(OH)2, P(O)(OH)CH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C₃-C₆ carbocyclyl; C₆-C₁₄ aryloxy optionally substituted with one or more halo; C₃-C₆ cycloalkyl optionally substituted with one or more halo; C₃-C₆ cycloalkyloxy optionally substituted with one or more halo; (C3-C8 cycloalkyl)(C1-C6 alkyl); (C6-C14 aryl)(C1-C6 alkyl); 5- to 8-membered heterocyclyl containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents independently selected from C₁-C₆ alkyl, OH, C₁-C₆ hydroxyalkyl, and oxetanyl; 6-membered heteroaryloxy containing 1 or 2 nitrogen ring atoms and optionally substituted with C₁-C₆ alkyl; and 5- or 6-membered heteroaryl containing 1,

2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, and C1-C6 haloalkyl; provided that when A is or at least one of the following is true: (i) L¹ is a bond, NHC(O), NHC(O)O, NHC(O)NH, or NHS(O)₂; (ii) L² is a bond or C2-C6 alkylene optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, (C1-C6 alkoxy)(C1-C6 alkyl), and oxo; (iii) L³ is NH, NHC(O), C(O), O, or S(O)₂CH₂; (iii) at least one of R², R^2’, R⁵, and R^5’ is not H; (iv) at least one of R¹ and R^1’ is not H; (v) X’ is N; and (vi) B is not 2. The compound of claim 1, where the compound is of Formula (I’): or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein A is R ^X .

4. The compound of claim 3, wherein X³ is CH or CNH2.

5. The compound of claim 3 or 4, wherein X⁵ is CH.

6. The compound of any one of claims 3-5, wherein X⁴ is N.

7. The compound of any one of claims 3-6, wherein X¹ is S or NH.

8. The compound of any one of claims 3-7, wherein R³ is H and R⁴ is H.

9. The compound of claim 1 or 2, wherein A is selected from:

10. The compound of any one of claims 1-9, wherein R¹ and R^1’ are both H.

11. The compound of any one of claims 1-10, wherein R² is H or C1-C6 alkyl.

12. The compound of any one of claims 1-11, wherein R^2’ is H, C₁-C₆ alkyl, or C₁-C₆ alkoxy.

13. The compound of claim 12, wherein R^2’ is H, methyl, or methoxy.

14. The compound of any one of claims 1-10, wherein R² and R^2’, together with the carbon atom to which they are attached, form spirocyclic C3-C8 cycloalkyl.

15. The compound of any one of claims 1-10, wherein R² and R⁵ or R^2’ and R^5’, together with the carbon atom to which they are attached form cyclopropyl.

16. The compound of any one of claims 1-15, wherein X is N or CH and X’ is N or CH.

17. The compound of any one of claims 1-16, wherein L¹ is NH or NHC(O).

18. The compound of any one of claims 1-17, wherein L² is a bond or C1-C6 alkylene optionally substituted with C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl.

19. The compound of any one of claims 1-18, wherein L³ is a bond.

20. The compound of any one of claims 1-19, wherein B is phenyl optionally substituted with one or more substituents independently selected from halo; cyano; COOR^e, wherein R^e is C1-C6 alkyl; S(O)2(C1-C6 alkyl); C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; phenyl optionally substituted with one or more halo; phenoxy; C₃-C₆ cycloalkyl; C₃-C₆ cycloalkyloxy optionally substituted with 1 or 2 halo; 5- to 8-membered heterocyclyl containing 1 or 2 ring atoms independently selected from N and O and optionally substituted with hydroxymethyl or oxetanyl; 5- or 6-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl and cyclopropyl; and -O(pyridyl).

21. The compound of any one of claims 1-19, wherein B is C3-C6 cycloalkyl optionally substituted with phenyl optionally substituted with one or more halo; benzoxazolyl optionally substituted with one or more halo or C₁-C₆ alkyl, -O(pyridyl) optionally substituted with C₁-C₆ alkyl, thiazolopyridinyl, oxazolopyridinyl optionally substituted with C₁-C₆ alkyl, or benzothiazolyl, or phenoxy optionally substituted with one or more halo.

22. The compound of any one of claims 1-19, wherein B is 5- to 14-membered heterocyclyl containing 1 or 2 ring atoms independently selected from O and N and optionally substituted with C₁-C₆ alkyl and further optionally substituted with pyridyl or phenyl optionally substituted with one or more halo.

23. The compound of any one of claims 1-19, wherein B is 5- to 10-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S; wherein B is optionally substituted with one or more substituents independently selected from halo; C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; phenoxy; phenyl optionally substituted with one or more substituents selected from halo, COOH, S(O)₂NH₂, S(O)₂(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₃-C₆ cycloalkyl; C₃-C₆ carbocyclyl optionally substituted with C₁-C₆ alkyl or halo; (C₃-C₆ cycloalkyl)(C₁-C₆ alkyl); phenyl(C1-C6 alkyl); 5- to 8-membered heterocyclyl containing 1 or 2 ring atoms independently selected from N and O and optionally substituted with halo, OH, C1-C6 alkyl, C1-C6 hydroxyalkyl, and oxetanyl; and 5- or 6-membered heteroaryl containing 1 or 2 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents independently selected from C₁-C₆ alkyl and halo.

24. The compound of claim 23, wherein B is 6-membered heteroaryl containing 1 or 2 nitrogen ring atoms and optionally substituted with C₁-C₆ alkyl; C₁-C₆ alkoxy; phenoxy; C₃-C₆ cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halo; 5- to 8-membered heterocyclyl containing one or two nitrogen ring atoms and optionally substituted with one or more substituents independently selected from halo, OH, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, and oxetanyl; and 5-membered heteroaryl containing 1 or 2 ring atoms independently selected from N and S.

25. The compound of claim 23, wherein B is 5-membered heteroaryl containing 1, 2, or 3 ring atoms independently selected from N, O, and S and optionally substituted with one or more substituents independently selected from halo; C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; phenyl optionally substituted with one or more substituents selected from halo, COOH, S(O)₂NH₂, S(O)₂(C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, and C₃-C₆ cycloalkyl; C₃-C₆ carbocyclyl; (C₃-C₆ cycloalkyl)(C₁-C₆ alkyl); phenyl(C₁- C6 alkyl); 5- or 6-membered heterocyclyl containing 1 or 2 ring atoms independently selected from N and O and optionally substituted with OH; and 5- or 6-membered heteroaryl containing 1 or 2 ring atoms independently selected from N and O and optionally substituted with one or more substituents independently selected from halo and C₁-C₆ alkyl.

26. The compound of claim 23, wherein B is pyridyl optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkoxy, and C₃-C₆ cycloalkyl.

27. The compound of claim 23, wherein B is 9-membered bicyclic heteroaryl including 1, 2, or 3 heteroatoms independently selected from N, O, and S and optionally substituted with one or more halo.

28. The compound of any one of claims 1-127, wherein R⁵ is H and/or R^5’ is H, and R⁶ is H.

29. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

30. The compound of any one of claims 1-29, having C1 esterase (C1s) inhibiting activity.

31. A pharmaceutical comprising a compound of any one of claims 1-30 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

32. A method of treating a C1s mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-30 or a pharmaceutically acceptable salt thereof.

33. A method of inhibiting C1s activity in a subject having a C1s mediated disorder, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-30 or a pharmaceutically acceptable salt thereof.

34. The method of claim 32 or 33, where in the subject is a human.

35. The method of any one of claims 32-34, wherein is the disorder is acute antibody- mediated rejection, amyotrophic lateral sclerosis, autoimmune blistering disease, bullous pemphigoid, chronic inflammatory demyelinating polyneuropathy, geographic atrophy, Guillain-Barré Syndrome, Huntington’s Disease, immune thrombocytopenia purpura, lupus nephritis, multifocal motor neuropathy, rheumatoid arthritis, traumatic brain injury, or warm autoimmune hemolytic anemia.