HK40103076A - Gpr84 antagonists and uses thereof - Google Patents

Description

GPR84 antagonist and its uses

Cross-references to related applications

This application claims the benefit and priority of U.S. Provisional Patent Application Serial No. 63/144,720, filed February 2, 2021, the contents of which are hereby incorporated by reference.

Technical Field

This invention relates to compounds and methods suitable for antagonizing G protein-coupled receptor 84 (GPR84). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods for treating various conditions using said compositions.

Background of the Invention

G protein-coupled receptor 84 (GPR84), also known as EX33, GPCR4, and G protein-coupled receptor 84, is a medium-chain fatty acid receptor that is primarily expressed in immune cells and upregulated in inflammatory disorders.

As a result of an expression sequence tagging data mining strategy, GPR84 was isolated from and characterized from human B cells (Wittenberger et al., 2001. J. Mol. Biol. 307, 799-813.), and a novel chemokine receptor expressed in neutrophils was identified using degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) (Yousefi S et al., 2001. J. Leukoc. Biol. 69, 1045-1052.). GPR84 remained an orphan GPCR until medium-chain free fatty acids (FFAs) with carbon chain lengths of 9-14 were identified as ligands for this receptor (Wang J et al., 2006. J. Biol. Chem. 281, 34457-34464.). GPR84 has been described as being activated via decanoic acid (C10:0), undecanoic acid (C11:0), and lauric acid (C12:0), with efficacies of 5 μM, 9 μM, and 11 μM, respectively. Three small molecules have also been described as possessing some GPR84 agonist activity: 3,3′-diindolemethane (DIM) (Wang et al., 2006), embelin (Hakak Y et al., 2007. WO2007027661(A2).), and 6-n-octylaminouracil (6-OAU) (Suzuki M et al., 2013. J. Biol. Chem. 288, 10684-10691.).

GPR84 has been shown to be expressed on immune cells, at least but not limited to polymorphonuclear leukocytes (PMNs), neutrophils, monocytes, T cells, and B cells. (Hakak et al., 2007; Venkataraman C, Kuo F. 2005. Immunol. Lett. 101, 144-153; Wang et al., 2006; Yousefi et al., 2001). GPR84 levels in neutrophils and eosinophils have been measured to be higher than in T cells and B cells. GPR84 expression has been confirmed in tissues that may play a role in the spread of inflammatory responses, such as the lungs, spleen, and bone marrow.

For example, in a recent review, du Bois reported on the current state of treatment for interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF). Interstitial lung diseases that can cause diffuse pulmonary scarring have nearly 300 different damaging or inflammatory causes, and the initial stages of IPF pathology are highly likely to involve inflammation (du Bois RM.. 2010. Nat. Rev. Drug Discov. 9, 129-140.), and combination therapies involving anti-inflammatory treatments can be advantageously used.

Following LPS stimulation, GPR84 expression was highly upregulated in monocytes/macrophages (Wang et al., 2006).

GPR84 knockout (KO) mice survive and are indistinguishable from wild-type littermate controls (Venkataraman and Kuo 2005). T and B cell proliferation in response to various mitogens has been reported to be normal in GPR84-deficient mice (Venkataraman and Kuo 2005). T cells differentiated from T helper cells 2 (Th2) in GPR84 KO mice secrete higher levels of IL4, IL5, and IL13, the three major _Th2 cytokines, compared to wild-type littermate controls. In contrast, Th1 cytokine (INFγ) production is similar in Th1-differentiated T cells from GPR84 KO mice and wild-type littermates (Venkataraman and Kuo 2005).

Furthermore, decanoic acid, undecanoic acid, and lauric acid dose-dependently increased the secretion of interleukin-12p40 subunits (IL-12p40) from LPS-stimulated RAW264.7 mouse macrophage-like cells. The pro-inflammatory cytokine IL-12 plays a crucial role in promoting cell-mediated immunity to eradicate pathogens by inducing and maintaining T helper cell 1 (Th1) responses and inhibiting T helper cell 2 (Th2) responses. Medium-chain FFAs can affect the Th1/Th2 balance through their direct action on GPR84.

Berry et al. identified the transcriptional signature of 393 genes in whole blood from active pulmonary tuberculosis (TB) (Berry MPR et al., 2010. Nature 466, 973-977.). GPR84 is part of this transcriptional signature of 393 genes in whole blood from active TB, suggesting a potential role for GPR84 in infectious diseases.

GPR84 expression has also been described in microglia, primary immune effector cells of the central nervous system (CNS) of myeloid-monocyte origin (Bouchard C et al., 2007. Glia55, 790-800.). As observed in peripheral immune cells, GPR84 expression in microglia is highly inducible in inflammatory disorders, such as those treated with TNFα and IL1, but is also evident in endotoxemia and experimental autoimmune encephalomyelitis (EAE), suggesting a role in neuroinflammatory processes. These results indicate that GPR84 will be upregulated in the CNS not only during endotoxemia and multiple sclerosis, but also in all neurological disorders that produce pro-inflammatory cytokines such as TNFα or IL-1β, including brain injury, infection, Alzheimer's disease (AD), and Parkinson's disease (PD).

GPR84 expression was also observed in adipocytes and showed to be enhanced by inflammatory stimulation (Nagasaki H et al., 2012. FEBS Lett. 586, 368-372.). These results suggest that GPR84 expression is triggered by TNFα from infiltrating macrophages and exacerbates the vicious cycle between obesity and diabetes/obesity, and therefore, inhibition of GPR84 activity may be beneficial for the treatment of endocrine and/or metabolic diseases.

Following nerve injury, GPR84 expression is also upregulated in microglia surrounding neurons (Gamo et al., 2008. J. Neurosi. 28(46), 11980-11988.). Furthermore, in GPR84 knockout mice, hypersensitivity to mechanical stimuli is significantly reduced or completely absent in mouse models of inflammatory and neuropathic pain (Nicol LSC et al., 2015. J. Neurosci. 35, 8959-8969.). Molecules that block GPR84 activation may therefore have the potential to deliver broad-spectrum analgesia.

Compared to hematopoietic stem cells from healthy donors, human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML) show increased GPR84 expression. GPR84 simultaneously enhances β-catenin signaling and establishes the oncogenic transcriptional program essential for MLL leukemia (Dietrich et al., 2014. Blood 124(22), 3284-3294). Inhibition of GPR84 significantly suppressed pre-LSC cell growth, reduced LSC frequency, and attenuated the recovery of stem cell-derived MLL leukemia, which represents a particularly aggressive and drug-resistant subtype of AML. Targeting the oncogenic GPR84/β-catenin signaling axis could represent a novel therapeutic strategy for AML and potentially other leukemias.

GPR84 expression was increased 49.9-fold in M1 macrophages isolated from atherosclerotic lesions of the aorta in LDLR-/- mice fed a Western diet (Kadl A et al., 2010. Circ. Res. 107, 737-746.). Therefore, molecules targeting GPR84 may have potential therapeutic benefits for atherosclerosis.

In experimental esophagitis, GPR84 was upregulated in esophageal tissue, primarily in epithelial cells, and was significantly reduced in rats treated with omeprazole (a proton pump inhibitor) or STW5 (an herbal preparation that showed improvement in esophagitis without affecting reflux pH) (Abdel-Aziz H et al., 2015. Mol. Med. 21, 1011-1024.). Western blots and immunohistochemistry in rat tissue and HET-1A cells (a human esophageal squamous cell line) supported this finding. GPR84 was also found to be significantly upregulated in esophageal biopsies from patients with grade B reflux esophagitis. Molecules that block GPR84 receptor activity could therefore represent a novel therapeutic paradigm for treating esophagitis.

Therefore, the identification and development of novel compounds, their preparation methods, and their uses in pharmaceutical preparations will be of great need for patients suffering from inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia, and/or diseases involving impaired immune cell function.

In addition, there remains a great need to identify and develop novel compounds suitable for the preparation of agents for the prevention and/or treatment of one or more fibrotic diseases, and more particularly NASH and/or IPF.

Summary of the Invention

It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective antagonists of GPR84. In some embodiments, the present invention provides compounds having the formula presented herein.

The compounds of this invention and pharmaceutically acceptable compositions thereof can be used to treat a variety of diseases, conditions, or disorders associated with GPR84. Such diseases, conditions, or disorders include those described herein.

The compounds provided by this invention are also applicable to the study of GPR84 in biological and pathological phenomena; the study of fibrotic processes occurring in body tissues; and the comparative evaluation of novel GPR84 inhibitors or other regulators of neutrophil and macrophage chemotaxis in vitro or in vivo.

Detailed Implementation

1. General description of certain embodiments of the present invention:

In some respects, the present invention provides compounds of formula I:

Or a pharmaceutically acceptable salt thereof, wherein each of ring A, ring B, ^L1 , ^L2 , ^L3 , ^R1 , ^R2 , ^R3 , X, m and n is individually and in combination as defined below and described in the embodiments herein.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

In some embodiments, the present invention provides a method for treating GPR84-mediated diseases, conditions, or disorders, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need.

2. Compounds and definitions:

The compounds of this invention include those generally described herein and further illustrated by the classes, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999; and “March’s Advanced Organic Chemistry,” 5th edition, edited by Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain (which is fully saturated or contains one or more unsaturated units) or a monocyclic or bicyclic hydrocarbon (which is fully saturated or contains one or more unsaturated units) with a single connection point to the rest of the molecule, but which is not aromatic (also referred to herein as "carbocyclic,""cycloaliphatic," or "cycloalkyl"). Unless otherwise stated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclic" or "cycloalkyl") refers to a fully saturated or containing one or more unsaturated units, but not aromatic, monocyclic _C3 - _C6 hydrocarbon with a single connection point to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term "bridging bicyclic" refers to any saturated or partially unsaturated bicyclic system having at least one bridging bond, i.e., a carbocyclic or heterocyclic ring. As defined by IUPAC, a "bridging bond" is a non-branched or valence bond connecting two bridgeheads of multiple atoms or a single atom, wherein a "bridgehead" is any skeletal atom of a ring system bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, the bridging bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridging bicyclic groups are well known in the art and include those groups set forth below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise specified, the bridging bicyclic group is optionally substituted with one or more substituents as set forth with respect to aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridging bicyclic group is optionally substituted. Exemplary bridging bicyclic groups include:

The term "lower alkyl" refers to a _C1-4 straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term "lower haloalkyl" refers to a _C1-4 straight-chain or branched alkyl group that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any quaternized form of basic nitrogen; or substituted nitrogen of heterocycles, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl) or NR ⁺ (as in N-substituted pyrrolealkyl)).

As used in this article, the term "unsaturated" means that a part has one or more unsaturated units.

As used herein, the term “divalent _C1-8 (or _C1-6 ) saturated or unsaturated straight or branched hydrocarbon chain” refers to a straight or branched divalent alkylene, alkenyl, or alkyne chain as defined herein.

The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -( _CH₂ ) _n- , where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

The term "alkenyl" refers to a divalent alkenyl group. The substituted alkenyl chain is a polymethylene containing at least one double bond and one or more hydrogen atoms replaced by a substituent. Suitable substituents include those described below with respect to the substituted aliphatic group.

The term "halogen" refers to F, Cl, Br, or I.

The term "aryl," used alone or as part of a larger portion of "aralkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and each ring in the system contains three to seven ring members. The term "aryl" is used interchangeably with the term "aromatic ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system capable of carrying one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracene, etc. As used herein, the scope of the term "aryl" also includes groups fused with one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthylimide, phenanthridine, or tetrahydronaphthyl.

The terms “heteroaryl” and “heteroaryl-” (e.g., “heteroarylalkyl” or “heteroarylalkoxy”) used alone or as part of a larger part refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in the cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur; and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, indazinyl, purinyl, naphthidyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups fused to one or more aryl, cycloaliphatic, or heterocyclic rings, wherein, unless otherwise specified, the group or connecting point is on the heteroaryl ring or on one of the rings to which the heteroaryl ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaryl," any of which includes optionally substituted rings. The term "heteroaryl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

As used herein, the terms “heterocycle,” “heterocyclic group,” “heterocyclic ring,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When used with respect to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolidinyl), or ⁺ NR (as in N-substituted pyrrolidinyl).

Heterocycles can be attached to their side groups at any heteroatom or carbon atom to produce a stable structure, and any ring atom can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolyl, piperazine, dioxyl, dioxazolidinyl, dioxazolidinyl, diazaspirolyl, diazaspirolyl, oxazolidinyl, thioazolidinyl, morpholinyl, 2-oxa-6-azaspirol[3.3]heptane, and quininecycloyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which the heterocyclic ring is fused with one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3H-indolyl, chromanyl, phenanthridineyl, or tetrahydroquinolinyl. The heterocyclic group can be monocyclic or bicyclic. The term “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic moieties are independently and optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but not to include aryl or heteroaryl moieties.

As described herein, the compounds of the present invention may contain an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the specified portion are replaced by a suitable substituent. Unless otherwise indicated, the "optionally substituted" group may have a suitable substituent at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably combinations that form stable or chemically viable compounds. The term "stable" as used herein means a compound that remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and in some embodiments recovered, purified, and used for the purposes disclosed herein.

The suitable monovalent substituents on the substituted carbon atoms of the "optionally substituted" groups are independently halogens; -( _CH2 ) _0-4Ro ; -(CH2)0-4ORo; -O( _CH2 ) ^0-4Ro , -O-(CH2) _0-4C (O ^)ORo ; -( _CH2 ) _0-4CH (ORo) ² ; -( _CH2 ) _0-4SRo ; -( _CH2 ) _0-4Ph , which can be substituted with Ro; -( ^CH2 )0-4O( ^CH2 ) _0-1Ph , which can be _substituted with ^Ro ; -CH=CHPh, which can be substituted with Ro; -( _CH2 ) _0-4O ( _CH2 ) _0-1 -pyridyl, which can be substituted with ^Ro ; -NO2; -CN; _-N3 ... _4O ( _CH2 ) _0-1- pyridyl, which can be substituted with ^Ro ; -NO2; -CN; -N3; -( _CH2 )0-4O(CH2) _0-4O ( _CH2 ) _0-1 -pyridyl, which can be substituted with ^Ro ; -NO2; -CN; -N3; -(CH2)0-4O(CH2)0-4O(CH2)0-1-pyridyl, which can be substituted with ^Ro ; _-NO2 ; -CN; _{-N3 ;} ) _0-4 N(R ^o ) ₂ ;-(CH ₂ ) _0-4 N(R ^o )C(O)R ^o ;-N(R ^o )C(S)R ^o ;-(CH ₂ ) _0-4 N(R ^o )C(O)NR ^o ₂ ;-N(R ^o )C(S)NR ^o ₂ ;-(CH ₂ ) _0-4 N(R ^o )C(O)OR ^o ;-N(R ^o )N(R ^o )C(O)R ^o ;-N(R ^o )N(R ^o )C(O)NR ^o ₂ ;-N(R ^o )N(R ^o )C(O)OR ^o ;-N(R ^o )C(NR ^o )N(R ^o ) ₂ ;-(CH ₂ ) _0-4 C(O)R ^o ;-C(S)R ^o ;-(CH ₂ ) _0-4 C ₍ O)OR ^o ;-(CH ₂ ) _0-4 C(O)SR ^o ;-(CH ₂ ) _0-4 C(O)OSiR ^o ₃ ;-(CH ₂ ) _0-4 OC(O)R ^o ;-OC(O)(CH ₂ ) _0-4 SR ^o ;-SC(S)SR ^o ;-(CH ₂ ) _0-4 SC(O)R ^o ;-(CH ₂ ) _0-4 C(O)NR ^o ₂ ;-C(S)NR ^o ₂ ;-C(S)SR ^o ;-SC(S)SR ^o ,-(CH ₂ ) _0-4 OC(O)NR ^o ₂ ;-C(O)N(OR ^o )R ^o ;-C(O)C(O)R ^o ;-C(O)CH ₂ C(O)R ^o ;-C(NOR ^o )R ^o ;-(CH ₂ ) _0-4 SSR ^o ;-(CH ₂ ) _0-4 S(O) ₂ R ^o ;-(CH ₂ ) _0-4 S(O) ₂ OR ^o ;-(CH ₂ ) _0-4 OS(O) ₂ R ^o ;-S(O) ₂ NR ^o ₂ ;-(CH ₂ ) _0-4 S(O)R ^o ;-N(R ^o )S(O) ₂ NR ^o ₂ ;-N(R ^o )S(O) ₂ R ^o ;-N(OR ^o )R ^o ;-C(NH)NR ^o ₂ ;-P(O) ₂ R ^o ;-P(O)R ^o ₂ ;-OP(O)R ^o ₂ ;-OP(O)(OR ^o ) ₂ ;-SiR ^o ₃ ;-(C _-(C1-4 straight-chain or branched alkylene)ON( ^Ro ) ₂ ; or -( _C1-4 straight-chain or branched alkylene)C(O)ON( ^Ro ) ₂ , wherein each ^Ro may be substituted as defined below (e.g., by one, two or more substituents) and is independently hydrogen, _C1-6 aliphatic, _-CH2Ph , -O( _CH2 ) _0-1Ph , _-CH2- (5-6-membered heteroaryl ring) or a 5-6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definitions, two independently occurring ^Ros together with one or more intercalary atoms form a 3-12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on ^Ro (or a ring formed by two independently occurring ^Ro atoms bonded together with their intervening atoms) are independently halogens, -( _CH₂ ) _O₻₂R ^· , -(halo R ^· ), -( _CH₂ ) _O₻₂OH , -( _CH₂ ) _O₻₂OR ^· , -( _CH₂ ) _O₻₂CH (OR ^· ) _₂ ; -O(halo R ^· ), -CN, _-N₃ , -( _CH₂ ) _O₻₂C (O)R ^· , -( _CH₂ ) _O₻₂C (O)OH, -( _CH₂ ) _O₻₂C (O)OR ^· , -( _CH₂ ) _O₻₂SR ^· , -( _CH₂ ) _O₻₂SH , -( _{CH₂ ) O₻₂NH₂} , -( _CH₂ ) _O₻₂NHR ^· -( _CH₂ ) _₀- 2NR ^· ₂ , _-NO₂ , -SiR ^· ₃ , -OSiR ^· ₃ , -C(O)SR ^· , -(C₁ _-4 straight-chain or branched alkylene)C(O)OR ^· or -SSR ^· , wherein each R ^· is unsubstituted or, if preceded by a "halogen group", substituted by only one or more halogens, and is independently selected from C₁ _-4 aliphatic groups, _-CH₂Ph , -O( _CH₂ ) _₀- 1Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents for the saturated carbon atom of ^R₀ include =O and =S.

Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) _2R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3O- or -S(C(R ^* ₂ )) _2-3S- , wherein each R ^* is independently selected from hydrogen, a _C1-6 aliphatic group that may be substituted as defined below, or an unsubstituted 5-6 saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents for adjacent substituted carbons of the "optionally substituted" group include: -O(CR ^* ₂ ) _2-3O- , wherein R ^* is independently selected each time it appears from hydrogen, _C1-6 aliphatic groups that may be substituted as defined below, or unsubstituted 5-6 saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group of R ^* include halogens, -R ^· , -(halogen R ^· ), -OH, -OR ^· , -O(halogen R ^· ), -CN, -C(O)OH, -C(O)OR ^· , _-NH2 , -NHR ^· , -NR ^· ₂ or _-NO2 , wherein each R ^· is unsubstituted or, if preceded by "halogen", is substituted by only one or more halogens, and is independently a _C1-4 aliphatic group, _-CH2Ph , -O( _CH2 ) _0-1Ph , or a 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the substituted nitrogen of the "optionally substituted" group include, or wherein each is independently hydrogen, a _C1-6 aliphatic group that may be substituted as defined below, an unsubstituted -OPh, or an unsubstituted 5-6 saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independently occurring groups together with one or more intervening atoms to form a 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group are independently halogens, -R ^· , -(halogen R ^· ), -OH, -OR ^· , -O(halogen R ^· ), -CN, -C(O)OH, -C(O)OR ^· , _-NH2 , -NHR ^· , -NR ^· ₂ or _-NO2 , wherein each R ^· is unsubstituted or substituted by only one or more halogens if preceded by "halogen", and is independently _C1-4 aliphatic groups, _-CH2Ph , -O( _CH2 ) _0-1Ph or a 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with human and lower animal tissues within the bounds of reasonable medical judgment without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N ⁺ ( _C1-4 alkyl) ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate).

Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformations)) of said structures; for example, R and S configurations, Z and E double bond isomers, and Z and E conformational isomers for each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or conformations), are within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention, including those in which hydrogen is replaced by deuterium or tritium or carbon is replaced by carbon enriched in ^13C- or ^14C- , are within the scope of the present invention. Such compounds are suitable as, for example, analytical tools, probes in bioassays, or therapeutic agents according to the present invention.

In some embodiments, ^R1 of the provided compound contains one or more deuterium atoms. In some embodiments, ^R2 of the provided compound contains one or more deuterium atoms. In some embodiments, ^R3 of the provided compound contains one or more deuterium atoms. In some embodiments, ^R4 of the provided compound contains one or more deuterium atoms. In some embodiments, ^R5 of the provided compound contains one or more deuterium atoms. In some embodiments, ^L1 of the provided compound contains one or more deuterium atoms. In some embodiments, ^L2 of the provided compound contains one or more deuterium atoms. In some embodiments, ^L3 of the provided compound contains one or more deuterium atoms. In some embodiments, ring A of the provided compound contains one or more deuterium atoms. In some embodiments, ring B of the provided compound contains one or more deuterium atoms. In some embodiments, ring C of the provided compound contains one or more deuterium atoms. In some embodiments, R of the provided compound may be substituted with one or more deuterium atoms. In some embodiments, ^Rz of the provided compound may be substituted with one or more deuterium atoms. In some embodiments, X of the provided compound may be substituted with one or more deuterium atoms.

The drawn structures represent relative configurations unless marked as absolute configurations. This invention covers individual enantiomers and racemic mixtures.

As used herein, a “GPR84 antagonist” or “GPR84 inhibitor” is a molecule that reduces, inhibits, or otherwise mitigates one or more of the biological activities of GPR84 (e.g., Gαi signaling, increased immune cell migration, and secretion of pro-inflammatory cytokines). Antagonism with a GPR84 antagonist does not necessarily indicate complete elimination of GPR84 activity. In fact, activity can be reduced by statistically significant amounts, including, for example, a reduction in GPR84 activity of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% compared to a suitable control. In some embodiments, the GPR84 antagonist reduces, inhibits, or otherwise diminishes the activity of GPR84. The compounds disclosed in this invention bind directly to GPR84 and inhibit its activity.

"Specific antagonist" means an agent that reduces, inhibits, or otherwise diminishes the activity of a defined target to a greater extent than an unrelated target. For example, a GPR84 specific antagonist reduces the biological activity of at least one GPR84 by a statistically greater amount than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In some embodiments, the _IC50 of the antagonist against the target _is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001%, or less of the IC50 of the antagonist against the non-target. The compounds disclosed in this invention may or may not be specific GPR84 antagonists. Specific GPR84 antagonists reduce the biological activity of GPR84 by a statistically greater amount than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In some embodiments, the GPR84 antagonist specifically inhibits the activity of GPR84. In some of these embodiments, the _IC50 of the GPR84 antagonist against GPR84 is approximately 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or lower than the IC50 of the _GPR84 antagonist against closely related GPCRs (e.g., free fatty acid receptors (FFARs), such as GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), or GPR120 (FFAR4)) or other types of GPCRs (e.g., type A GPCRs).

The compounds of the present invention can be tethered to a detectable moiety. It should be understood that such compounds are suitable as developing agents. Those skilled in the art will recognize that the detectable moiety can be linked to the provided compound via suitable substituents. As used herein, the term "suitable substituent" refers to a moiety capable of covalently linking to the detectable moiety. Such moieties are well known to those skilled in the art and include the group containing, for example, carboxylic acid ester moieties, amino moieties, thiol moieties, or hydroxyl moieties, etc. It should be understood that such moieties can be linked directly or via tethering groups (e.g., divalent saturated or unsaturated hydrocarbon chains). In some embodiments, such moieties can be linked via click chemistry. In some embodiments, such moieties can be linked via azide-alkyne 1,3-cycloaddition optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described in Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem. 2006, 17, 52-57. In some embodiments, such portions may be connected via strained alkynes. Methods for achieving rapid Cu-free click chemistry using strained alkynes are known in the art and include those described in: Jewett et al., J. Am. Chem. Soc. 2010, 132(11), 3688-3690.

As used herein, the terms “detectable portion” and “label” are used interchangeably and refer to any portion that can be detected (e.g., primary and secondary labels). Primary labels, such as radioisotopes (e.g., tritium, ^32P , ^33P , ^35S , or ^14C ), mass tags, and fluorescent labels, are signals that can be detected without further modification to generate reporter genes. Detectable portions also include luminescent and phosphorescent groups.

As used herein, the term "secondary label" refers to a portion that requires the presence of a second intermediate to generate a detectable signal (e.g., biotin and various protein antigens). In the case of biotin, the secondary intermediate may include an antibiotic streptavidin-enzyme conjugate. In the case of antigen labeling, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group via non-radiative fluorescence resonance energy transfer (FRET), and the second group generates a detection signal.

As used herein, the terms “fluorescent label,” “fluorescent dye,” and “fluorophore” refer to the portion that absorbs light energy at a defined excitation wavelength and emits light energy at different wavelengths. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, and BODI. PY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), carboxy-rhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, C Ascade Yellow, Coumarin 343, Anthocyanin Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl Acetate, Dapoxyl, DialkylaminoCoumarin, 4′,5′-Dichloro-2′,7′-Dimethoxy-Fluorescence, DM-NERF, Eosin, Erythrosin, Fluorescence, FAM, Hydroxycoumarin, IRDye (IRD40, IRD700, IRD800), JOE, Rhodamine B, Ma Marina Blue, Methoxycoumarin, Naphthalene Fluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, RhodolGreen, 2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-Rhodamine (TMR), CarboxytetramethylRhodamine (TAMRA), Texas Red, Texas Red-X.

As used herein, the term "quality tag" refers to any portion that can be specifically detected by mass spectrometry (MS) techniques by virtue of its mass. Examples of quality tags include electrophoretic release tags, such as N-[3-[4′-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglycero]isopiperidinecarboxylic acid, 4′-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone and derivatives thereof. The synthesis and utility of these quality tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of quality tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers having varying lengths and base compositions. A wide variety of organic molecules (neutral and charged (biomolecules or synthetic compounds)) with appropriate mass ranges (100-2000 Daltons) can also be used as quality labels.

The compounds of this invention can be tethered to the E3 ligase-binding moiety. It should be understood that such compounds are suitable as degrading agents (see, for example, Kostic and Jones, Trends Pharmacol. Sci., 2020, 41(5), 305-31; Ottis and Crews, ACS Chem. Biol. 2017, 12(4), 892-898.). Those skilled in the art will recognize that the E3 ligase-binding moiety can be linked to the provided compounds via suitable substituents as defined above. Such degrading agents have been found suitable for targeted degradation of G protein-coupled receptors (Li et al., Acta Pharm. Sin. B. 2020, 10(9), 1669-1679.).

As used herein, the term “E3 ligase-binding moiety” is used interchangeably with the term “E3 ligase binder” and refers to any moiety capable of binding to and/or recruiting E3 ligases (e.g., cIAP1, MDM2, cereblon, VHL, APC/C) for targeted degradation.

The compounds of this invention can be tethered to lysosomal targeting moieties. It should be understood that such compounds are suitable as degrading agents (see, for example, Banik et al., 2020. Nature 584, 291-297.). Those skilled in the art will recognize that lysosomal targeting moieties can be linked to the provided compounds via suitable substituents as defined above. Such degrading agents have been found suitable for the targeted degradation of secretory and membrane proteins (Banik et al., 2020).

As used herein, the term “lysosome-targeting portion” may be used interchangeably with the term “lysosome-binding portion” and refers to any portion capable of binding to and/or recruiting cell surface lysosome-targeting receptors (e.g., cation-independent mannose-6-phosphate receptor, CI-M6PR) for targeted degradation.

As used herein, the terms “measurable affinity” and “measurable inhibition” refer to a measurable change in GPR84 activity between a sample containing the compound of the present invention or a combination thereof and a GPR84 GPCR and an equivalent sample containing the GPR84 GPCR in the absence of said compound or combination thereof.

3. Description of exemplary implementation schemes:

As described above, in some embodiments, the present invention provides a compound of formula I:

Or its pharmaceutically acceptable salt, wherein:

Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; an 8-10 membered bicyclic heteroaryl ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;

Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

^R1 is selected from (i) 3-7 membered saturated or partially unsaturated monocyclic carbon rings; 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and _C1-6 aliphatic groups; each of which is substituted by p instances of ^R4 ; and (ii) hydrogen;

Each instance of ^R2 , ^R4 , and ^R5 is independently hydrogen, deuterium, ^Rz , halogen, -CN, _-NO2 , -OR, -SR, ^-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S( _O ) _NR2 , -CF2R, _-CF3 , -CR2(CN), _-CR2 (OR), _-CR2 ( _NR2 ), _-C (O)R, -C( _O )OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 , -N(R)S(O) ₂ NR ₂ , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ ; or

Two ^R2 groups may optionally combine to form =O;

Two ^R4 groups may optionally combine to form =O;

Two ^R5 groups may optionally combine to form =O;

The two ^R2 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur;

The two ^R4 groups optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or

The two ^R5 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur;

Each instance of R ^z is independently selected from optionally substituted groups selected from the following: _C1-6 aliphatic groups; phenyl groups; 3-7 membered saturated or partially unsaturated monocyclic carbon rings; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

^R3 is hydrogen or an optionally substituted _C1-6 aliphatic group; or

Two ^R3 groups may optionally combine to form =O; or

The ^R2 and ^R3 groups, together with their intermediary atoms, optionally form 5-8 member saturated or partially unsaturated fused rings with 0-3 independent heteroatoms selected from nitrogen, oxygen or sulfur.

^L1 is one of the following:

(a) A _C1-6 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units in the chain are independently and optionally replaced by: -O-, -Cy-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- ; or

(b) Covalent bond;

Each -Cy- is independently a divalent ring optionally substituted from the following: phenylene; 3-7 membered saturated or partially unsaturated carbocyclic group; 4-7 membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

^L2 is a covalent or _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CR(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)-, -CH( _CR3 )-, -C=( _CH2 )- or -S(O) _2- ;

^L3 is one of the following:

(a) A _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)-, or -S(O) _2- ; or

(b) Covalent bond;

X is one of the following:

(a) A 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 member saturated or partially unsaturated bridging or spirocyclic, bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 member saturated or partially unsaturated bridging tricyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member partially aromatic or heteroaromatic bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbocyclic ring; or a phenyl ring; each of which is substituted by q R ⁵ examples; or

(b) -CH ₂ (OR), -CH(R)(OR) or -C(R) ₂ (OR);

Each instance of R is independently hydrogen or optionally substituted with a group selected from: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

Two R groups on the same atom may optionally be together with the atom to form a 3-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having 0-3 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur in addition to the atom.

m can be 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3, 4, or 5; and

q can be 0, 1, 2, 3, 4 or 5.

As generally defined above, ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; an 8-10 membered bicyclic heteroaryl ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.

In some embodiments, ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a phenyl group. In some embodiments, ring A is an 8-10 membered bicyclic heteroaryl ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, ring A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.

In some implementations, ring A is

In some embodiments, the left side of ^ring A is connected to ^L1 and the right side of ring A is connected to ^{L2 .}

In some implementations, ring A is selected from those depicted in Table 1 below.

As generally defined above, ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ring B is a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some implementation schemes, ring B is

In some embodiments, the two ^R3 groups are bonded together to form =O, and ring B is... In some embodiments, the left side of ring ^B is connected to L2 and the right side of ring ^B is connected to ^L3 . In some embodiments, the right side of ring B is connected to ^L2 and the left side of ring B is connected to ^{L3 .}

In some implementations, ring B is selected from those depicted in Table 1 below.

As generally defined above, ^R1 is selected from (i) 3-7 membered saturated or partially unsaturated monocyclic carbon rings; 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 7-11 membered saturated or partially unsaturated spirobicyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and _C1-6 aliphatic groups; each of which is substituted by p instances of ^R4 ; and (ii) hydrogen.

In some embodiments, ^R1 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with p ^R4 examples. In some embodiments, ^R1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with p ^R4 examples. In some embodiments, ^R1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with p ^R4 examples. In some embodiments, ^R1 is a 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with p ^R4 examples. In some embodiments, ^R1 is a _C1-6 aliphatic group substituted with p ^R4 examples. In some embodiments, ^R1 is a phenyl group substituted with p ^R4 examples. In some embodiments, ^R1 is hydrogen.

In some implementations, ^R1 is

In some embodiments, the two ^R4 groups combine to ^{form =} O, and ^{R1 is ...}

In some embodiments, the two sets of ^R4 groups combine to form =O, and ^R1 is...

In some implementations, ^R1 is... In some implementations, ^-L1 - ^R1 is...

In some implementations, ^R1 is selected from those described in Table 1 below.

As generally defined above, each instance of ^R2 , ^R4 , and ^R5 is independently hydrogen, deuterium, ^Rz , halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O) _R , -S(O) _NR2 , -CF2R, _-CF3 , -CR2(CN), _-CR2 (OR ₎ , _-CR2 ( _NR2 ), _-C (O)R, -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O) ₂ R , -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ .

In some implementations, ^R2 is hydrogen, deuterium, ^Rz , halogen, -CN, -NO2, _-OR , -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S(O) _NR2 , _-CF2R , _-CF3 , _-CR2 (CN), _-CR2 (OR), _-CR2 (NR2), -C( _O ) _R , -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 -N(R)S(O) _₂NR₂ , _-N (R)S(O) _₂R , -N=S(O) _R₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR) _R₂ , _-SiR₃ , -P(O)(R) _NR₂ , -P(O)(R)OR, or -P(O) _R₂ . In some embodiments, ^R₂ is hydrogen. In some implementations, ^R2 can be ^Rz , halogen, -CN, -NO2, _-OR , -SR, -NR2, -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S(O) _{NR2 , -CF2R} , _-CF3 , _-CR2 (CN), _-CR2 (OR), _-CR2 ( _NR2 ), _-C (O)R, -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 , -N(R)S(O) _{2NR 2} , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ .

In some embodiments, ^R2 is methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, _-CF3 , _-OCH3 , -N( _CH3 ) ₂ , _-OCH2CH2OH , -CH2CF3, -C(O) _CH3 , _-S (O) _CH3 , -S(O) _2CH3 , _-OiPr , -SCH3, _-CN , -C(O) _NH2 , _-C (O) _OCH3 , _-CH2OH , _-CH2CN , _-CO2H , _-OCF3 , _{-OCHF2 ,}

In some implementations, ^R2 is selected from those depicted in Table 1 below.

As generally defined above, ^R4 represents hydrogen, deuterium, ^Rz , halogens, -CN, -NO2, _-OR , -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S(O) _NR2 , _-CF2R , _-CF3 , -CR2(CN), _-CR2 (OR), _-CR2 ( _NR2 ), -C( _O )R, -C( _O )OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 -N(R)S(O) _₂NR₂ , _-N (R)S(O) _₂R , -N=S(O) _R₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR) _R₂ , _-SiR₃ , -P(O)(R) _NR₂ , -P(O)(R)OR, or -P(O) _R₂ . In some embodiments, ^R₄ is hydrogen. In some implementations, ^R4 is ^Rz , halogen, -CN, -NO2, _-OR , -SR, -NR2, -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S(O) _{NR2 , -CF2R} , _-CF3 , _-CR2 (CH), _-CR2 (OR), _-CR2 (NR2), _-C ( _O )R, -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 , -N(R)S(O) _{2NR 2} , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ .

In some embodiments, ^R4 is methyl, fluorine, _-OCH3 , -N( _CH3 ) ₂ , -OH, _-CF3 , -C(O) _NH2 , -CN,

In some implementations, ^R4 is selected from those described in Table 1 below.

As generally defined above, ^R₅ represents hydrogen, deuterium, ^R₂ , halogens, -CN, -NO₂, _-OR , -SR, _-NR₂ , -S(O) _₂R , -S(O) _₂NR₂ , -S(O)R, -S(O) _NR₂ , _-CF₂R , _-CF₃ , -CR₂(CN), _-CR₂ (OR), _-CR₂ ( _NR₂ ), -C( _O )R, -C( _O )OR, -C(O) _NR₂ , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR₂ , -C(S) _NR₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR₂ , -N(R)C(NR) _NR₂ , -N(R) _NR₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ .

In some embodiments, ^R5 is methyl or fluorine; in other embodiments, ^R5 is hydrogen. In some implementations, ^R5 is ^Rz , halogen, -CN, -NO2, _-OR , -SR, -NR2, -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S(O) _{NR2 , -CF2R} , _-CF3 , _-CR2 (CN), _-CR2 (OR), _-CR2 (NR2), _-C ( _O )R, -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 , -N(R)S(O) _{2NR 2} , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ .

In some implementations, ^R5 is selected from those depicted in Table 1 below.

As defined above, two ^R2 groups may optionally combine together to form =O.

In some implementations, the two ^R2 groups combine to form =O.

As defined above, two ^R4 groups may optionally combine to form =O.

In some implementations, the two ^R4 groups combine to form =O.

As defined above, two ^R5 groups may optionally combine together to form =O.

In some implementations, the two ^R5 groups combine to form =O.

As generally defined above, two ^R2 groups may optionally be together with their intermediary atoms to form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, the two ^R2 groups together with their intermediary atoms form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

As generally defined above, two ^R4 groups may optionally be together with their intermediary atoms to form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, the two ^R4 groups together with their intermediary atoms form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

As generally defined above, two ^R5 groups may optionally be together with their intermediary atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, the two ^R5 groups together with their intermediary atoms form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

As generally defined above, each instance of ^Rz is independently selected from optionally substituted groups selected from the following: _C1-6 aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, Rz is selected from groups optionally substituted from the following: C 1-6  aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some implementations, R ^_z is selected from those described in Table 1 below.

As generally defined above, ^R3 is hydrogen or an optionally substituted _C1-6 aliphatic group. In some embodiments, R3 is hydrogen. In some embodiments, ^R3 is an optionally substituted _C1-6 aliphatic group. In some embodiments, ^R3 is methyl. In some embodiments, ^R3 is selected ^from those depicted in Table 1 below.

As generally defined above, two ^R3 groups are optionally bonded together to form =O. In some embodiments, two ^R3 groups are bonded together to form =O.

As generally defined above, the ^R2 and ^R3 groups are optionally combined with their intermediary atoms to form a 5-8 member saturated or partially unsaturated fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen or sulfur.

In some embodiments, the ^R2 and ^R3 groups, together with their intermediary atoms, form a 5-8 member saturated or partially unsaturated fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

As generally defined above, ^L1 is one of the following: (a) a _C1-6 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units in the chain are independently and optionally replaced by: -O-, -Cy-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- ; or (b) a covalent bond.

In some embodiments, ^L1 is a _C1-6 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units in the chain are independently and optionally replaced by: -O-, -Cy-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- .

In some implementations, ^L1 is a covalent bond.

In some implementations, ^L1 is

In some embodiments, the left side of ^L1 is connected to ^R1 and the right side of ^L1 is connected to ring A. In some embodiments, the right side of ^L1 is connected to ^R1 and the left side of ^L1 is connected to ring A.

In some implementations, ^L1 is selected from those depicted in Table 1 below.

As generally defined above, each -Cy- is independently a divalent ring optionally substituted from the following: phenylene; 3-7 membered saturated or partially unsaturated carbocyclic group; 4-7 membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, -Cy- is a divalent ring optionally substituted from the following: phenylene; 3-7 membered saturated or partially unsaturated carbocyclic group; 4-7 membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some implementations, -Cy- is selected from those depicted in Table 1 below.

As generally defined above, ^L2 is a covalent or _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CR(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)-, -CH( _CR3 ), -C＝( _CH2 )- or -S(O) _2- .

In some implementations, ^L2 is a covalent bond.

In some embodiments, ^L2 is _{a C1-4} divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CR(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)-, -CH( _CR3 ), -C=( _CH2 )- or -S(O) _2- .

In some implementations, ^L2 is

In some implementations, ^L2 is selected from those depicted in Table 1 below.

As generally defined above, ^L3 is one of the following: (a) a _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- ; or (b) a covalent bond.

In some embodiments, ^L3 is _{a C1-4} divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- .

In some implementations, ^L3 is a covalent bond.

In some embodiments, ^L3 is connected to ring B on ^its left side and to X on ^{its right} side ^.

In some implementations, ^L3 is selected from those depicted in Table 1 below.

As generally defined above, X is one of the following: (a) a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 member saturated or partially unsaturated bridging or spirocyclic, bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 member saturated or partially unsaturated bridging tricyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member partially aromatic or heteroaromatic bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbocyclic ring; or a phenyl ring; each of which is substituted by q instances of ^R ; or (b) _-CH₂ (OR), -CH(R)(OR), or -C(R) _₂ (OR).

In some embodiments, X is a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 member saturated or partially unsaturated bridging or spirocyclic, bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 member saturated or partially unsaturated bridging tricyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member partially aromatic or heteroaromatic bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbocyclic ring; or a phenyl ring; each of which is substituted by q R ⁵ examples.

In some implementations, X is -CH ₂ (OR), -CH(R)(OR), or -C(R) ₂ (OR).

In some implementation schemes, X is

In some embodiments, the two ^R5 groups combine to form =O, and X is

In some embodiments, the two sets of ^R5 groups combine to form =O, and X is

In some implementations, X is selected from those depicted in Table 1 below.

As generally defined above, each instance of R is independently hydrogen or optionally substituted with a group selected from: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen may optionally be together with nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, excluding nitrogen.

In some embodiments, R is hydrogen. In some embodiments, R is a group optionally substituted from the following: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, the two R groups on the same nitrogen atom are together with the nitrogen to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 independently selected heteroatoms other than nitrogen, oxygen, and sulfur.

In some implementations, R is selected from those described in Table 1 below.

As generally defined above, m is 0, 1, 2, 3, or 4.

In some implementations, m is 0, 1, 2, 3, or 4. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4.

In some implementations, m is selected from those depicted in Table 1 below.

As generally defined above, n is 0, 1, 2, 3, or 4.

In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

In some implementations, n is selected from those described in Table 1 below.

As generally defined above, p is 0, 1, 2, 3, 4 or 5.

In some implementations, p is 0, 1, 2, 3, 4, or 5. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4. In some implementations, p is 5.

In some implementations, p is selected from those described in Table 1 below.

As defined above, q is 0, 1, 2, 3, 4, or 5.

In some implementations, q is 0, 1, 2, 3, 4, or 5. In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2. In some implementations, q is 3. In some implementations, q is 4. In some implementations, q is 5.

In some implementations, q is selected from those described in Table 1 below.

In some embodiments, the present invention provides a compound of formula I, wherein ring A is phenyl, ring B is triazolyl, and ^L2 is covalently bonded, to provide a compound of formula Ia:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L3 , R1, ^R2 , ^R3 , ^X , m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ring A is pyridyl, ring B is triazolyl, and ^L2 is covalently bonded, to provide compounds of formula Ib-1, Ib-2, or Ib-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L3 , R1, ^R2 , ^R3 , ^X , m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ring A is a thiophene group, ring B is a triazolyl group, and L2 is a covalent bond, to provide compounds of formula I-c:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L3 , R1, ^R2 , ^R3 , ^X , m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ^L1 is ethynyl, L2 is covalently bonded, ring A is phenyl, thiophene, or pyridyl, and ring B is triazolyl, to provide compounds of formula If-1, If-2, If-3, If-4, If-5, If-6, If-7, If-8, or If-9:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L3 , ^R1 , ^R2 , ^R3 , X, m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ring B is a triazolyl group, ^L3 is a methylene group, and X is an oxacyclobutyl group, to provide compounds of formula Ig-1, Ig-2, or Ig-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L2 , R1, ^R2 , ^R3 , ^R5 , ^m , n and q is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ring B is a triazolyl group, ^L3 is a methylene group, and X is a furanyl group, to provide compounds of formula Ih-1, Ih-2, or Ih-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L2 , R1, ^R2 , ^R3 , ^R5 , ^m , n and q is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ring B is a triazolyl group, ^L3 is a methylene group, and X is a tetrahydropyranyl group, to provide compounds of formula Ii-1, Ii-2, or Ii-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L2 , R1, ^R2 , ^R3 , ^R5 , ^m , n and q is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ring B is a triazolyl group, ^L3 is a methylene group, and X is a 1,4-dioxanealkyl group, to provide compounds of formula Ij-1, Ij-2, or Ij-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L2 , R1, ^R2 , ^R3 , ^R5 , ^m , n and q is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I, wherein ring B is a triazolyl group, ring A is a phenyl group, and ^L2 is selected from -O-, -N(H)-, -N(Ac)-, -N( _CH3 )-, -S-, -S(O)-, or -S(O) _2- to provide a compound of formula Ik-1:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L3 , R1, ^R2 , ^R3 , ^X , m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the compound of formula I is a compound of formula I-k-2:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L3 , ^R1 , ^R3 , X and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the compound is a compound of formula I-k-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L3 , ^R2 , ^R3 , X, m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the compound of formula I is a compound of formula I-k-4, I-k-5, or I-k-6:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , R1, ^R2 , ^R3 , ^R5 , ^m , q, and n is individually and in combination as defined above and described in the embodiments herein. In some embodiments, in Ik-5 and Ik-6, q is not 0 and ^R5 is not hydrogen.

In some embodiments, the compound of formula I is a compound of formula I-l-1, I-l-2, or I-l-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^R1 and ^R2 is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the compound of formula I is a compound of formula I-m-1, I-m-2, or I-m-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^R1 , ^R2 , ^R3 , ^L3 and X is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the compound of formula I is a compound of formula I-n-1, I-n-2, or I-n-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the compound of formula I is a compound of formula I-o-1, I-o-2, or I-o-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 , individually and in combination, is as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side of the formula in this paragraph is H, and ^R2 alternating with the nitrogen of pyridine (ring B) is not H.

In some embodiments, the compound of formula I is a compound of formula I-p-1, I-p-2, or I-p-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 , individually and in combination, is as defined above and described in the embodiments herein. In some embodiments, in the formula of the paragraphs of this invention, ^R2 alternating with the triazole junction (and opposite the N of pyridine) is not H.

In some embodiments, the compound of formula I is a compound of formula I-q-1, I-q-2, or I-q-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 , individually and in combination, is as defined above and described in the embodiments herein. In some embodiments, ^R2 on the left-hand side of ^R2 in this paragraph is H.

In some embodiments, the compound of formula I is a compound of formula I-r-1, I-r-2, or I-r-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side of the formula in this paragraph (in parentheses) is H, and the ^R2 adjacent to the nitrogen of pyridine (ring B) is not H. In some embodiments, ^R2 adjacent to the N of pyridine in the formula in this paragraph is methyl.

In some embodiments, the compound of formula I is a compound of formula I-s-1, I-s-2, or I-s-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, the upper (downward) ^R2 to the right of R2 in the formula of this paragraph is ^H. In some embodiments, the upper (upward) R2 to the left of ^R2 in the ^formula of this paragraph is not H.

In some embodiments, the compound of formula I is a compound of formula I-t-1, I-t-2, or I-t-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side of ^R2 in the formula of this paragraph is H. In some embodiments, ^R2 alternating with the triazole junction in the formula of this paragraph is not H.

In some embodiments, the compound of formula I is a compound of formula I-u-1, I-u-2, or I-u-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, ^R1 is cyclopropyl or _-CH2OR . In some embodiments, this R is H or methyl. In some embodiments, ^R2 on the right-hand side of the formula in this paragraph is H, and ^R2 adjacent to the triazole junction is not H.

In some embodiments, the compound of formula I is a compound of formula I-v-1, I-v-2, or I-v-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, ^R1 is cyclopropyl or -CH2OR. In some embodiments, this R is H or methyl. In some embodiments, ^R2 on the right-hand side of the formula in this paragraph is H, and ^R2 alternating with the nitrogen atom of pyridine (ring B) is not H.

In some embodiments, the compound of formula I is a compound of formula I-w-1, I-w-2, or I-w-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, ^R1 is cyclopropyl or _-CH2OR . In some embodiments, this R is H or methyl. In some embodiments, ^R2 on the right-hand side of the formula in this paragraph is H, and ^R2 opposite to the nitrogen of pyridine is not H.

In some embodiments, the compound of formula I is a compound of formula I-x-1, I-x-2, or I-x-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side of this paragraph is H. In some embodiments, ^R1 is cyclopropyl or _-CH2OR . In some embodiments, this R is H or methyl.

In some embodiments, the compound of formula I is a compound of formula I-y-1, I-y-2, or I-y-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side of the formula in this paragraph is H, and ^R2 adjacent to the nitrogen of pyridine is not H. In some embodiments, ^R1 is cyclopropyl or _-CH2OR . In some embodiments, this R is H or methyl.

In some embodiments, the compound of formula I is a compound of formula I-z-1, I-z-2, or I-z-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, R2 on the right-hand side (face down ⁾ of ^R2 in this paragraph is ^H. In some embodiments, ^R1 is cyclopropyl or _-CH2OR . In some embodiments, this R is H or methyl.

In some embodiments, the compound of formula I is a compound of formula I-aa-1, I-aa-2, or I-aa-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side of ^R2 in this paragraph is H. In some embodiments, ^R1 is cyclopropyl or _-CH2OR . In some embodiments, this R is H or methyl.

In some embodiments, the compound of formula I is a compound of formula I-bb-1, I-bb-2, or I-bb-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 , individually and in combination, is as defined above and described in the embodiments herein. In some embodiments, ^R2 to the right of ^R2 adjacent to the triazole linker in the formula of this paragraph is H.

In some embodiments, the compound of formula I is a compound of formula I-cc-1, I-cc-2, or I-cc-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the compound of formula I is a compound of formula I-dd-1, I-dd-2, or I-dd-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the compound of formula I is a compound of formula I-ee-1, I-ee-2, or I-ee-3:

Or a pharmaceutically acceptable salt thereof, wherein each of the ^R2s , individually and in combination, is as defined above and described in the embodiments herein. In some embodiments, the 0-2 ^R2s to the right of the pyridine nitrogen ortho position in the formula of this paragraph are ^H.

In some embodiments, the compound of formula I is a compound of formula I-ff-1, I-ff-2, or I-ff-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 , individually and in combination, is as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side (face down) of the formula in this paragraph is ^H.

In some embodiments, the compound of formula I is a compound of formula I-gg-1, I-gg-2, or I-gg-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 , individually and in combination, is as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side of the formula in this paragraph is ^H.

In some embodiments, the compound of formula I is a compound of formula I-hh-1, I-hh-2, or I-hh-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 , individually and in combination, is as defined above and described in the embodiments herein. In some embodiments, ^R2 on the right-hand side of ^R2 in the formula of this paragraph is H, and ^R2 adjacent to the triazole linker is not H.

In some embodiments, the compound of formula I is a compound of formula I-hh-1, I-hh-2, or I-hh-3:

Or a pharmaceutically acceptable salt thereof, wherein each of ^R2 is individually and in combination as defined above and described in the embodiments herein. In some embodiments, 0-3 ^R2 on the right side of the formula in this paragraph ( ^R2 adjacent to the phenyl at the ring B junction) are H. In some embodiments, the ^R2 adjacent to the phenyl at the ring B junction is not H. In some embodiments, ring B is

In some embodiments, the compound of formula I is a compound of either formula I-ii-1 or I-ii-2:

Or a pharmaceutically acceptable salt thereof, wherein ^R2 ′ is ^R2 . In some embodiments, ^R2 ′ is _-NR2 . In some embodiments, ^R2 ′ is -N( _CH3 ) ₂ .

In some embodiments, the compound of formula I is a compound of either formula I-jj-1 or I-jj-2:

Or its pharmaceutically acceptable salt.

In some embodiments, the compound of formula I is a compound of either formula I-kk-1 or I-kk-2:

Or its pharmaceutically acceptable salt.

Where ^R2 ′ is ^R2 . In some embodiments, ^R2 ′ is _-NR2 . In some embodiments, ^R2 ′ is -N( _CH3 ) ₂ .

In some embodiments, the compound of formula I is a compound of either formula I-ll-1 or I-ll-2:

Or a pharmaceutically acceptable salt thereof. In some embodiments, one ^R2 is F.

In some embodiments, the present invention provides a compound of formula I-1*:

Or its pharmaceutically acceptable salt, wherein:

Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or a 3-7 membered saturated or partially unsaturated monocyclic carbide ring;

Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

^R1 is selected from (i) 3-7 membered saturated or partially unsaturated monocyclic carbon rings; 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 7-11 membered saturated or partially unsaturated spirobicyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and _C1-6 aliphatic groups; each of which is substituted by p instances of ^R4 ; and (ii) hydrogen;

Each instance of ^R2 , ^R4 , and ^R5 is independently hydrogen, deuterium, ^Rz , halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S( _O ) _NR2 , -CF2R, _-CF3 , -CR2(CN), _-CR2 (OR), _-CR2 ( _NR2 ), _-C (O)R, -C( _O )OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 , -N(R)S(O) ₂ NR ₂ , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ ; or

Two ^R2 groups may optionally combine to form =O;

Two ^R4 groups may optionally combine to form =O;

Two ^R5 groups may optionally combine to form =O;

The two ^R2 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur;

The two ^R4 groups optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or

The two ^R5 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur;

Each instance of R ^z is independently selected from optionally substituted groups selected from the following: _C1-6 aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

^R3 is hydrogen or an optionally substituted _C1-6 aliphatic group; or

Two ^R3 groups may optionally combine to form =O; or

The ^R2 and ^R3 groups may optionally form, together with their intervening atoms, a 5-8 member saturated or partially unsaturated fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen or sulfur;

^L1 is one of the following:

(a) A _C1-6 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units in the chain are independently and optionally replaced by: -O-, -Cy-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- ; or

(b) Covalent bond;

Each -Cy- is independently a divalent ring optionally substituted from the following: phenylene; 3-7 membered saturated or partially unsaturated carbocyclic group; 4-7 membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 7-11 membered saturated or partially unsaturated spirobicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

^L2 is a covalent or _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- ;

^L3 is one of the following:

(a) A _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)-, or -S(O) _2- ; or

(b) Covalent bond;

X is one of the following:

(c) A 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a phenyl ring; each of which is substituted by q R ⁵ examples; or

(d) -CH ₂ (OR), -CH(R)(OR) or -C(R) ₂ (OR);

Each instance of R is independently hydrogen or optionally substituted with a group selected from: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

Two R groups on the same nitrogen atom are optionally together with nitrogen to form a 4-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having 0-3 independently selected heteroatoms other than nitrogen, oxygen and sulfur.

m can be 0, 1, 2, 3, or 4;

n can be 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, 4, or 5; and

q can be 0, 1, 2, 3, 4 or 5.

Compounds of Formula I-1* can be defined more specifically. For example, in some embodiments, ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a phenyl group. In some embodiments, ring A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.

In some implementations, ring A is

In some implementations, ring A is selected from those depicted in Table 1 below.

In some embodiments, ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some implementation schemes, ring B is

In some embodiments, the two ^R3 groups combine to form =O, and ^ring B ^is ...

In some implementations, ring B is selected from those depicted in Table 1 below.

In some embodiments, ^R1 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with p ^R4 examples. In some embodiments, ^R1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with p ^R4 examples. In some embodiments, ^R1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with p ^R4 examples. In some embodiments, ^R1 is a 7-11 membered saturated or partially unsaturated spirobicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with p ^R4 examples. In some embodiments, ^R1 is a _C1-6 aliphatic group substituted with p ^R4 examples. In some embodiments, ^R1 is a phenyl group substituted with p ^R4 examples. In some embodiments, ^R1 is hydrogen.

In some implementations, ^R1 is

In some embodiments, the two ^R4 groups combine to ^{form =} O, and ^{R1 is ...}

In some embodiments, the two sets of R4 groups combine to form =O, and ^R1 is...

In some implementations, ^R1 is selected from those described in Table 1 below.

In some implementations, ^R2 is hydrogen, deuterium, ^Rz , halogen, -CN, -NO2, _-OR , -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S(O) _NR2 , _-CF2R , _-CF3 , _-CR2 (CN), _-CR2 (OR), _-CR2 (NR2), -C( _O ) _R , -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 , -N(R)S(O) ₂ NR ₂ , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ .

In some embodiments, ^R2 is methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, _-CF3 , _-OCH3 , -N( _CH3 ) ₂ , _-OCH2CH2OH , -CH2CF3, -C( _O ) _CH3 , _-S (O) _CH3 , -S(O) _2CH3 , _-OiPr , -SCH3, _-CN , -C(O) _NH2 , -C(O) _OCH3 , _-CH2OH , _-CH2CN , _-CO2H , _-OCF3 , _{-OCHF2 .} In some embodiments, ^R2 is selected from those described in Table 1 below.

In some implementations, ^R4 is hydrogen, deuterium, ^Rz , halogen, -CN, -NO2, _-OR , -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S(O) _NR2 , _-CF2R , _-CF3 , _-CR2 (CN), _-CR2 (OR), _-CR2 (NR2), -C( _O ) _R , -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 -N(R)S(O) _₂NR₂ , _-N (R)S(O) _₂R , -N=S(O) _R₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR) _R₂ , _-SiR₃ , -P(O)(R) _NR₂ , -P(O)(R)OR, or -P(O) _R₂ . In some embodiments, ^R₄ is methyl, fluorine, _-OCH₃ , -N( _CH₃ ) _₂ , -OH, _-CF₃ , -C(O) _NH₂ , -CN, or in some embodiments, ^R₄ is selected from those depicted in Table 1 below.

In some implementations, ^R5 is hydrogen, deuterium, ^Rz , halogen, -CN, -NO2, _-OR , -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S(O) _NR2 , _-CF2R , _-CF3 , _-CR2 (CN), _-CR2 (OR), _-CR2 (NR2), -C( _O ) _R , -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 -N(R)S(O) _₂NR₂ , _-N (R)S(O) _₂R , -N=S(O) _R₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR) _R₂ , _-SiR₃ , -P(O)(R) _NR₂ , -P(O)(R)OR, or -P(O) _R₂ . In some embodiments, ^R₅ is methyl, fluorine,

In some implementations, ^R5 is selected from those depicted in Table 1 below.

In some embodiments, two ^R2 groups are bonded together to form =O. As generally defined above, two ^R4 groups are optionally bonded together to form =O. In some embodiments, two ^R4 groups are bonded together to form =O. As generally defined above, two ^R5 groups are optionally bonded together to form =O. In some embodiments, two ^R5 groups are bonded together to form =O.

In some embodiments, the two ^R2 groups together with their intermediary atoms form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, the two ^R4 groups together with their intermediary atoms form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, the two ^R5 groups together with their intermediary atoms form a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, Rz is selected from groups optionally substituted from the following: C 1-6  aliphatic groups; phenyl groups; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some implementations, R ^_z is selected from those described in Table 1 below.

In some embodiments, ^R3 is hydrogen. In some embodiments, ^R3 is an optionally substituted _C1-6 aliphatic group.

In some implementations, ^R3 is methyl.

In some implementations, ^R3 is selected from those described in Table 1 below.

In some implementations, the two ^R3 groups combine to form =O.

In some embodiments, the ^R2 and ^R3 groups, together with their intermediary atoms, form a 5-8 member saturated or partially unsaturated fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

In some embodiments, ^L1 is one of the following: (a) a _C1-6 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units in the chain are independently and optionally replaced by: -O-, -Cy-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- ; or (b) a covalent bond. In some embodiments, ^L1 is a _C1-6 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units in the chain are independently and optionally replaced by: -O-, -Cy-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- .

In some implementations, ^L1 is a covalent bond.

In some implementations, ^L1 is

In some implementations, ^L1 is selected from those depicted in Table 1 below.

In some embodiments, -Cy- is a divalent ring optionally substituted from the following: phenylene; 3-7 membered saturated or partially unsaturated carbocyclic groups; 4-7 membered saturated or partially unsaturated heterocyclic groups having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7-11 membered saturated or partially unsaturated spirobicyclic heterocyclic groups having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 5-6 membered heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is selected from those depicted in Table 1 below.

In some embodiments, ^L2 is a covalent bond or a _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)-, or -S(O) _2- . In some embodiments, ^L2 is a covalent bond. In some embodiments, ^L2 is _{a C1-4} divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- .

In some implementations, ^L2 is

In some implementations, ^L2 is selected from those depicted in Table 1 below.

In some embodiments, ^L3 is _{a C1-4} divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- .

In some implementations, ^L3 is a covalent bond.

In some implementations, ^L3 is

In some implementations, ^L3 is selected from those depicted in Table 1 below.

In some embodiments, X is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a phenyl ring; each of which is substituted by q R ⁵ examples. In some embodiments, X is -CH ₂ (OR), -CH(R)(OR), or -C(R) ₂ (OR).

In some implementation schemes, X is

In some embodiments, the two ^R5 groups combine to form =O, and X is

In some embodiments, the two groups of ^R5 groups combine to form =O, and X is selected from those depicted in Table 1 below in some embodiments.

In some embodiments, R is hydrogen. In some embodiments, R is a group optionally substituted from the following: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, the two R groups on the same nitrogen atom are together with the nitrogen to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 independently selected heteroatoms other than nitrogen, oxygen, and sulfur.

In some implementations, R is selected from those described in Table 1 below.

In some implementations, m is 0, 1, 2, 3, or 4. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is selected from those depicted in Table 1 below.

In some implementations, n is 0, 1, 2, 3, or 4. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is selected from those depicted in Table 1 below.

In some implementations, p is 0, 1, 2, 3, 4, or 5. In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4. In some implementations, p is 5. In some implementations, p is selected from those depicted in Table 1 below.

In some implementations, q is 0, 1, 2, 3, 4, or 5. In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2. In some implementations, q is 3. In some implementations, q is 4. In some implementations, q is 5. In some implementations, q is selected from those described in Table 1 below.

In some embodiments, the present invention provides a compound of formula I-1*, wherein ring A is phenyl, ring B is triazolyl, and L2 is covalently bonded, to provide a compound of formula I-a*:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L3 , R1, ^R2 , ^R3 , ^X , m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I-1*, wherein ring A is pyridyl, ring B is triazolyl, and ^L2 is covalently bonded, to provide compounds of formula Ib-1*, Ib-2*, or Ib-3*:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L3 , R1, ^R2 , ^R3 , ^X , m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I-1*, wherein ring A is a thiophene group, ring B is a triazolyl group, and ^L2 is a covalent bond, to provide a compound of formula Ic*:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L3 , R1, ^R2 , ^R3 , ^X , m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I-1*, wherein ^L1 is ethynyl, ^L2 is covalently bonded, ring A is phenyl, thiophene, or pyridyl, and ring B is triazolyl, to provide compounds of formula If-1*, If-2*, If-3*, If-4*, If-5*, If-6*, If-7*, If-8*, or If-9*:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L3 , ^R1 , ^R2 , ^R3 , X, m and n is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I-1*, wherein ring B is a triazolyl, ^L3 is a methylene, and X is an oxacyclobutane, to provide compounds of formula Ig-1*, Ig-2*, or Ig-3*:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L2 , R1, ^R2 , ^R3 , ^R5 , ^m , n and q is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I-1*, wherein ring B is a triazolyl group, ^L3 is a methylene group, and X is a furanyl group, to provide compounds of formula Ih-1*, Ih-2*, or Ih-3*:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L2 , R1, ^R2 , ^R3 , ^R5 , ^m , n and q is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I-1*, wherein ring B is a triazolyl group, ^L3 is a methylene group, and X is a tetrahydropyranyl group, to provide compounds of formula Ii-1*, Ii-2*, or Ii-3*:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L2 , R1, ^R2 , ^R3 , ^R5 , ^m , n and q is individually and in combination as defined above and described in the embodiments herein.

In some embodiments, the present invention provides a compound of formula I-1*, wherein ring B is a triazolyl group, ^L3 is a methylene group, and X is a 1,4-dioxanealkyl group, to provide compounds of formula Ij-1*, Ij-2*, or Ij-3*:

Or a pharmaceutically acceptable salt thereof, wherein each of ^L1 , ^L2 , R1, ^R2 , ^R3 , ^R5 , ^m , n and q is individually and in combination as defined above and described in the embodiments herein.

Exemplary compounds of the present invention are listed in Table 1 below.

Table 1. Selected Compounds

In some embodiments, the present invention provides the compounds set forth in Table 1 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides the compounds set forth in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds set forth in Table 1 above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

In some embodiments, the present invention provides a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator, which is used as a pharmaceutical agent.

In the chemical structures in Table 1 above and the examples below, the stereoisomer centers are described according to the enhanced stereo representation format (MDL/Biovia, e.g., using the notation "or1", "or2", "abs", "and1").

In some embodiments, the present invention also provides compounds of Formula I or pharmaceutical compositions described herein for use in methods of inhibiting GPR84 as described herein, for modulating the immune response of a subject in need as described herein, and/or for treating GPR84 dependence as described herein.

In some embodiments, the present invention also provides compounds of formula I or pharmaceutical compositions described herein for use in methods of inhibiting GPR84 as described herein.

In some embodiments, the present invention also provides a compound of formula I or a pharmaceutical composition described herein for use in methods of modulating an immune response in a subject in need, as described herein.

In some embodiments, the present invention also provides a compound of formula I or a pharmaceutical composition described herein for use in a method of treating GPR84 dependence as described herein.

In some embodiments, the present invention also provides the use of the Formula I compound or the pharmaceutical composition described herein for the manufacture of agents for inhibiting GPR84, agents for modulating the immune response of a subject in need, and/or agents for treating GPR84 dependence.

In some embodiments, the present invention also provides the use of the compound of formula I described herein or the pharmaceutical composition described herein for the manufacture of an agent for inhibiting GPR84.

In some embodiments, the present invention also provides the use of the Formula I compound or the pharmaceutical composition described herein for the manufacture of an agent for modulating the immune response of a subject in need.

In some embodiments, the present invention also provides the use of the compound of formula I described herein or the pharmaceutical composition described herein for the manufacture of an agent for treating GPR84 dependence.

In some embodiments, the present invention also provides the use of the Formula I compound or pharmaceutical composition described herein in methods for inhibiting GPR84 as described herein, in methods for modulating the immune response of a subject in need as described herein, and/or in methods for treating GPR84 dependence as described herein.

In some embodiments, the present invention also provides the use of the Formula I compound or pharmaceutical composition described herein for use in a method of inhibiting GPR84 as described herein.

In some embodiments, the present invention also provides the use of the Formula I compound or pharmaceutical composition described herein in a method for modulating the immune response of a subject in need, as described herein.

In some embodiments, the present invention also provides the use of the compound of formula I or the pharmaceutical composition described herein in a method of treating GPR84 dependence as described herein.

4. A general method for providing the compounds of the present invention.

The compounds of the present invention can generally be prepared or isolated by methods known to those skilled in the art for the synthesis and/or semi-synthesis of similar compounds and by methods described in detail in the examples herein.

5. Use, preparation and application

Pharmaceutically acceptable compositions

According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or mediator. The amount of the compound in the composition of the present invention is such that it can effectively inhibit GPR84 or a mutant thereof in a measurable manner in a biological sample or patient. In some embodiments, the amount of the compound in the composition of the present invention is such that it can effectively inhibit GPR84 or a mutant thereof in a measurable manner in a biological sample or patient. In some embodiments, the composition of the present invention is formulated for administration to a patient requiring such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant, or mediator" refers to a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of saturated vegetable fatty acids in the form of glycerides; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polypropylene oxide block polymers; polyethylene glycol; and lanolin.

"Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of ester or other derivative of the compound of the present invention that can directly or indirectly provide, when administered to a recipient, the compound of the present invention or its inhibitory metabolites or residues.

As used herein, the term "its inhibitory metabolite or residue" refers to the metabolite or residue of an inhibitor that is also an inhibitor of GPR84 or its mutants.

The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of the compounds of the present invention. Metabolites include compounds produced by methods comprising exposing the compounds of the present invention to mammals for a duration sufficient to produce their metabolites. If the compounds of the present invention are bases, the desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside amino acids (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc. If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, such as treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (e.g., glycine and arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (e.g., piperidine, morpholine, and piperazine), as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The compounds of this invention may be in the form of "prodrugs," which comprise compounds having a portion that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo via esterases or other mechanisms that activate the drug. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al., (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66: 1-19). Prodrugs may be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound, in its free acid form or with a suitable esterifying agent, respectively. The hydroxyl group may be converted to an ester via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionates), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), amide lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., methyl, halogenated, or methoxy-substituted) aryl and aryl-lower alkyl esters, amides, lower alkylamides, di-lower alkylamides, and hydroxyamides. Prodrugs that are converted into their active form in vivo via other mechanisms are also included. In all respects, the compounds of the present invention are prodrugs of any formula herein.

The compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implantable receptacle. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathic, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of this invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media.

For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. For example, fatty acids of oleic acid and their glycerol derivatives are suitable for preparing injectable formulations, such as pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylene form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants (such as Tween, Span, and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of the present invention can be used for administration in the form of rectal suppositories. These suppositories can be prepared by mixing the pharmaceutical agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

The pharmaceutically acceptable compositions of the present invention can also be applied topically, especially when the therapeutic target includes areas or organs easily accessible by topical application (including diseases of the eyes, skin, or lower intestine). Suitable topical formulations for each of these areas or organs are readily prepared.

For local application to the lower intestine, it can be achieved in the form of rectal suppositories (see above) or in the form of suitable enemas. Topical transdermal patches may also be used.

For topical application, the pharmaceutically acceptable compositions provided may be formulated as suitable ointment forms containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated as suitable lotions or creams containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, cetyl octadecanol, 2-octyl dodecanol, benzyl alcohol, and water.

For ocular use, the pharmaceutically acceptable composition provided may be formulated as a micron-sized suspension, with or without a preservative (e.g., benzylalkonium chloride), in isotonic pH-adjusted sterile saline solution, or preferably as a solution in isotonic pH-adjusted sterile saline solution. Alternatively, for ocular use, the pharmaceutically acceptable composition may be formulated as an ointment, such as paraffin oil.

The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in pharmaceutical formulation and can be prepared into solutions in physiological saline using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons and/or other conventional solvents or dispersants.

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

The amount of the compounds of the present invention that can be combined with carrier materials to produce compositions in a single dosage form will vary depending on the host being treated and the specific mode of administration. Preferably, the provided compositions are formulated as inhibitors that can be administered to patients receiving these compositions at doses between 0.01 and 100 mg/kg body weight/day.

It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

Use of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein are generally suitable for inhibiting the signal transduction activity of one or more GPCRs. In some embodiments, the GPCR inhibited by the compounds and methods of the present invention is GPR84.

The compounds disclosed in this invention can be used to inhibit the activity of GPR84. GPR84 is a Gi-coupled G protein-coupled receptor (GPCR) expressed on the surface of immune cells. GPR84 regulates innate immune responses in diseases such as fibrosis.

Multiple studies have shown that GPR84 may be a potential target for the treatment of obesity and/or metabolic dysfunction.

GPR84 gene expression in cultured human differentiated adipocytes was highly upregulated by the major pro-inflammatory cytokines TNF-α and IL-1β (Muredda et al., 2017. Arch. Physiol. Biochem. 124(2), 97-108). These data confirm that activation of pro-inflammatory GPR84 signaling in inflammatory conditions in adipocytes was first described by Nagasaki in 2012 (Nagasaki et al., 2012, FEBS Letters, 586, 368-372).

IL-33 (a member of the IL-1β superfamily) strongly upregulates GPR84 mRNA expression in human differentiated adipocytes via an autocrine pathway, which is associated with enhanced production of pro-inflammatory cytokines and chemokines such as IL-1β, CCL2, IL6, CXCL2, and CSF3 (Zaibi et al., 2018. Cytokine, 110, 189-193). This suggests that GPR84 activation in adipocytes, induced by pro-inflammatory stimuli, leads to further release of pro-inflammatory cytokines and identifies the existence of a hypothetical autocrine positive feedback loop.

GPR84 expression is upregulated in the liver of patients with NASH and is associated with disease severity. GPR84 is upregulated in activated human and mouse macrophages and neutrophils. GPR84 mediates myelocellular infiltration that promotes steatotic hepatitis and fibrosis. Pharmacological inhibition of GPR84 in a NASH model significantly reduced macrophage accumulation, inflammation, and fibrosis, similar to selonsertib (an ASK1 inhibitor). These findings suggest that GPR84 promotes myelocellular infiltration in liver injury and is an effective therapeutic target for steatotic hepatitis and fibrosis in NAFLD/NASH (Puengel et al., 2020. J. Clin. Med. 9(4), 1140).

GPR84 deficiency in mice is associated with reduced NAFLD-induced liver injury. Treatment with PBI-4547 (a putative GPR84 antagonist) reduced NAFLD-induced injury in the liver and adipose tissue and promoted fatty acid oxidation (Simard et al., 2020. Sci. Rep. 10(1), 12778).

Mice with total Gpr84 deletion [Gpr84 knockout (KO)] exhibited mild impairment of glucose tolerance when fed a diet rich in MCFAs. Studies have shown that mitochondrial metabolism in rodent skeletal muscle is regulated by the medium-chain fatty acid receptor GPR84 (a key player in glycemic control) (Montgomery MK et al., 2019. FASEB J.33(11), 12264-12276).

Nutrient-sensing receptors located on enteroendocrine (EEC) cells regulate appetite by detecting luminal contents. Peiris et al. evaluated the effects of obesity and gastric bypass-induced weight loss on the expression of nutrient-sensing G protein-coupled receptors (GPCRs) and found that GPR84 expression was increased in obese mice. Furthermore, obesity-induced GPR84 overexpression was further increased after Roux-en-Y gastric bypass surgery (RYGB). Several nutrient-sensing receptors, including GPR84, induce activation of the colonic EEC. Profound adaptive changes in the expression of these receptors occur in response to diet and weight loss induced by RYGB or calorie restriction. (Peiris M et al., 2018. Nutrients. 10(10), 1529)

Du Toit et al. investigated the effects of GPR84 deficiency on the development of obesity and diabetes in mice fed diets rich in long-chain fatty acids (LCFA) or medium-chain fatty acids (MCFA), and found no effect on body weight or glucose tolerance in mice fed diets high in MCFA or LCFA. GPR84 can affect lipid metabolism because GPR84 KO mice had smaller livers and increased myocardial triglyceride accumulation when fed an LCFA diet, and increased hepatic triglyceride accumulation in response to increased dietary MCFA. (Du Toit et al., 2018 Eur. J. Nutr. 57(5), 1737-1746)

Hara et al.’s review indicates that GPR84 and other free fatty acid receptors (FFARs) primarily involved in energy metabolism are considered key therapeutic targets in the pathology of obesity and type 2 diabetes. (Hara et al., 2014. Biochim. Biophys. Acta. 1841(9), 1292-300)

In a study conducted in mice, Nagasaki et al. showed that a high-fat diet upregulated GPR84 expression in the fat pad. These results suggest that GPR84 appears in adipocytes in response to TNFα from infiltrating macrophages and exacerbates the vicious cycle between obesity and diabetic obesity. (Nagasaki H. et al., 2012. FEBS Lett. 586(4), 368-72)

Fibrosis is a process that can be triggered by chronic tissue damage attributable to toxic substances, viral infection, inflammation, or mechanical stress (Nanthakumar et al., 2015. Nature Reviews Drug Discovery 14, 693-720); and can be defined as the abnormal or excessive preparation and accumulation of the extracellular matrix (ECM).

In particular, fibrosis is a key driver of organ dysfunction in many inflammatory and metabolic diseases, including idiopathic pulmonary fibrosis (IPF), advanced liver diseases (such as nonalcoholic steatosis hepatitis (NASH)), and advanced kidney diseases. Treatment for these conditions remains inadequate, but progress has been made in understanding the disease mechanisms, and the increasing number of clinical trials in recent years reflects the need to identify novel treatments, particularly in IPF (Nanthakumar et al., 2015).

Nonalcoholic fatty liver disease (NAFLD) initially manifests as pure steatosis, progressing to nonalcoholic steatohepatitis (NASH), primarily caused by excessive energy intake and low physical activity, excluding genetic defects, and is closely associated with obesity, insulin resistance, and other related metabolic complications (Neuschwander-Tetri BA and Caldwell SH, 2003, Hepatology 37, 1202-1219). If left untreated, NASH leads to fatal liver failure.

The mechanisms that promote the progression from NAFLD to NASH and end-stage liver disease are complex and can be triggered by acute inflammatory damage and oxidative stress. (Day and James 1998, Hepatology 27, 1463-1466).

GPR84 (also known as EX33) has been isolated from and characterized in human B cells (Wittenberger et al., 2001, J. Mol. Biol. 307, 799-813) and also using degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) (Yousefi et al., 2001). It remains an orphan GPCR until medium-chain fatty acids (FFAs) with carbon chain lengths of 9-14 were identified as ligands for this receptor (Wang et al., 2006).

GPR84 is activated by medium-chain FFAs, such as decanoic acid (Cl0:0), undecanoic acid (C11:0) and lauric acid (12:0), which amplify the production of lipopolysaccharide-stimulated pro-inflammatory cytokines/chemokines (TNFα, IL-6, IL-8, CCL2 and others) and is highly expressed in neutrophils and monocytes (macrophages) (Miyamoto et al., 2016, Int. J. Mol. Sci. 17(4) 450).

In contrast, GPR84-ligand-mediated chemotaxis of neutrophils and monocytes/macrophages was inhibited by GPR84 antagonists (Suzuki M et al., 2013. J. Biol. Chem. 288, 10684-10691.).

Although the recruitment of monocytes/macrophages to the liver appears to occur concurrently with fibrosis in patients with chronic liver disease (Marra et al., 1998. Am. J. Pathol. 152, 423-430; Zimmermann et al., 2010. PLOS ONE 5, el1049), this has not yet yielded novel therapies.

There are currently no approved drugs for the treatment of NASH, and therefore liver transplantation remains a last resort for end-stage disease. For example, in the case of IPF, only two drugs have been approved despite unwanted side effects (Brunnemer et al., 2018. Respiration 95, 301-309; Lancaster et al., 2017. Eur. Respir. Rev. 26, 170057; Richeldi et al., 2014. N. Engl. J. Med. 370, 2071-2082), and therefore there is a clear need for improved therapies (Raghu, 2015. Am J Respir Crit Care Med 191(3)252-4).

In a mouse model of chronic inflammatory bowel disease induced by sodium dextran sulfate, the potent and selective GPR84 inhibitor GLPG1205, administered at once-daily doses of 3 and 10 mg/kg, reduced disease activity index scores and neutrophil infiltration with efficacy similar to the positive control compound sulfasalazine. (Labéguère F et al., 2020. J Med Chem. 63(22), 13526-13545)

The study by Nguyen et al. showed that PBI-4050 (a GPR84 antagonist/GPR40 agonist) reduced right ventricular dysfunction in pulmonary hypertension, pulmonary fibrosis, and heart failure. This points to GPR84 antagonists as a novel and promising therapy for targeting lung remodeling in group II pulmonary hypertension (Nguyen et al., 2020. Cardiovasc Res. 116(1), 171-182).

Studies by Gagnon et al. have shown that GPR40 and GPR84 can represent promising molecular targets in the fibrotic pathway. Administration of PBI-4050 (a GPR84 antagonist and a GPR40 agonist) significantly attenuates fibrosis in many injury scenarios, as evidenced by its antifibrotic activity observed in fibrosis of the kidney, liver, heart, lung, pancreas, and skin (Gagnon et al., 2018. Am J Pathol. 188(5)).

Studies have also linked GPR84 to acute lung injury and/or inflammation.

Alavi et al.'s review summarizes studies on GPR17, GPR30, GPR37, GPR40, GPR50, GPR54, GPR56, GPR65, GPR68, GPR75, GPR84, GPR97, GPR109, GPR124, and GPR126, reporting significant effects in the prevention and/or treatment of multiple sclerosis (MS) in preclinical studies (Alavi et al., 2019. Life Sci. 224, 33-40).

GPR84 expression in several murine tissues is enhanced under inflammatory stimuli, such as in endotoxemia, hyperglycemia, and hypercholesterolemia. These stimuli also increase GPR84 expression in macrophages, and a selective GPR84 receptor agonist (6-OAU) triggers increased secretion of pro-inflammatory cytokines and phagocytosis in macrophages (Recio et al., 2018. Front. Immunol. 9, 1419). These results suggest that GPR84 acts as an enhancer of inflammatory signaling in macrophages once inflammation occurs, and molecules antagonizing the GPR84 receptor may be potential therapeutic tools in inflammatory and metabolic diseases.

Compared with other GPR84 ligands, DL-175 was discovered, a novel structural molecule with potent and selective effects that produce different functionalities in macrophages (Lucy et al., 2019. ACS Chem. Biol. 14(9), 2055-2064). This study confirms that GPR84 agonism induces enhanced chemotaxis and/or phagocytosis in macrophages (also known as macrophage activation).

GPR84 is one of the pro-inflammatory neutrophil-associated genes that are highly enriched in RNA-seq dataset analysis of BALF cells from COVID-19 patients (Didangelos, A.2020.mSphere.5(3), e00367-20).

In an acute pneumonia model, LPS induces a shift of alveolar macrophages from ^{a low} CD11 state to a ^higher , more inflammatory CD11 state, which exacerbates the lung injury process (Yin et al., 2020. Mucosal Immunol. 13(6), 892-907). GPR84 is highly expressed in diseased lung tissue and is involved in cytokine release, phagocytosis, and alveolar macrophage state transitions. GPR84 may represent a potential therapeutic target for acute respiratory distress syndrome.

et al. prepared a first GPR84 agonist radioligand (tritylated) for studying the binding affinity of receptor ligands. They noted that GPR84 was found to be involved in inflammatory processes associated with gastroesophageal reflux disease, inflammatory bowel disease, multiple sclerosis, neuropathic pain, and Alzheimer's disease. In addition, GPR84 has been associated with obesity and diabetes. Preliminary evidence suggests that GPR84 may be associated with leukemia, osteoclastogenesis, and organ fibrosis, which are pathological outcomes of many inflammatory and metabolic diseases. (M et al., 2020. J. Med. Chem. 63(5), 2391-2410).

Müller et al. identified endotoxin-tolerant monocytes and GPR84 as markers of TNFα expression regulators through a holistic analysis of glycoproteins. (Müller et al., 2017 Sci Rep. 7(1), 838).

Studies by Venkataraman et al. have shown that GPR84 regulates the production of IL-4 by T lymphocytes in response to CD3 crosslinking, revealing a novel role of GPR84 in regulating early IL-4 gene expression in activated T cells (Venkataraman C et al., 2005. Immunol Lett. 101(2), 144-53).

In addition, GPR84 has been associated with neuropathic pain and/or neuropathy.

Gao et al. have demonstrated that DOK3 is involved in microglial activation in neuropathic pain through its interaction with GPR84, revealing a physical association between DOK3 and GPR84 in inducing inflammatory responses. They hypothesize that targeting the transferor protein DOK3 could open new avenues for pharmacological approaches to alleviate neuropathic pain in the spinal cord (Gao WS et al., 2020. Aging (Albany NY). 12.).

The study by Kozela et al. on the behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration showed that CBD reversed KET-induced transcriptional changes, including those in the Gpr84 gene (Kozela et al., 2020. Mol Neurobiol. 57(3), 1733-1747).

The study by Wei et al. demonstrated that agonists of G protein-coupled receptor 84 (GPR84) alter cell morphology and activity, but do not induce pro-inflammatory responses in microglia. This research suggests that microglia GPR84 could be a therapeutic target for microglia-related diseases such as multiple sclerosis and Alzheimer's disease (Wei L et al., 2017. J Neuroinflammation. 14(1), 198).

Nicol et al. investigated the role of GPR84 in experimental neuropathic pain and showed that GPR84 is a pro-inflammatory receptor that promotes nociceptive signaling through macrophage regulation, and that these cells respond less to inflammatory damage in its absence (Nicol LS et al., 2015. J Neurosci. 35(23), 8959-69).

Mededdu et al. found that Gpr84 expression was induced in both microglia and astrocytes and was upregulated in the CNS after viral infection, suggesting that Gpr84 expression could be a suitable measure of glial activation during CNS damage or injury (Madeddu S et al., 2015. PLoS One. 10(7), e0127336).

Bouchard et al. found that mice with endotoxemia expressed GPR84 in microglia in a strong and persistent manner, making GPR84 a sensitive marker of microglia activation. It can play an important regulatory role in the neuroimmune process and acts downstream of pro-inflammatory mediators (Bouchard C et al., 2007. Glia. 55(8), 790-800).

GPR84 is also associated with inflammatory bowel disease, which is a potential disease target.

Planell et al. identified GPR84 as a transcriptional blood biomarker suitable as a non-invasive alternative marker of mucosal healing and endoscopic response in ulcerative colitis. At 14 weeks of treatment, response to anti-TNF therapy induced alterations in blood HP, CD177, GPR84, and S100A12 transcripts associated with changes in endoscopic activity (Planell N et al., 2017. J Crohns Colitis. 11(11), 1335-1346).

The study by Abdel-Aziz et al. found that GPR84 and TREM-1 signaling caused the pathogenesis of reflux esophagitis, indicating that GPR84 plays an important role in the pathogenesis of gastroesophageal reflux disease (GERD) (Abdel-Aziz et al., 2016 Mol Med. 21(1), 1011-1024).

Dietrich et al. demonstrated that GPR84 plays a role in the aberrant β-catenin signaling in leukemia stem cells (LSCs) to maintain stem cell-derived mixed lineage leukemia (MLL) leukemia generation, a previously unrecognized role of GPR84 in maintaining well-developed acute myeloid leukemia (AML) by enabling aberrant β-catenin signaling in LSCs, and showed that targeting the oncogenic GPR84/β-catenin signaling axis could represent a novel therapeutic strategy for AML (Dietrich PA et al., 2014. Blood. 124(22), 3284-94).

By exploring tumor microenvironment-related genes for prognostic values in hepatocellular carcinoma (HCC) using the Cancer Genome Atlas (TCGA) database, Deng et al. identified GPR84 among a group of differentially expressed genes (DEGs) suitable as candidate biomarkers for HCC prognosis (Deng Z et al., 2019. Biomed Res Int. 2019, 2408348).

GeneChip expression analysis by Wang et al. revealed changes in energy metabolism-related genes, including GPR84, in osteocytes under high gradient magnetic fields. Identifying genes sensitive to specific environments (such as GPR84) could provide some potential targets for the prevention and treatment of bone loss or osteoporosis (Wang et al., 2015. PLoS One. 10(1), e0116359).

Park et al.’s research showed that GPR84 controls osteoclastogenesis by inhibiting the NF-κB and MAPK signaling pathways, indicating that GPR84 acts as a negative regulator of osteoclastogenesis and could be a potential therapeutic target for osteoclast-mediated bone destruction (Park JW et al., 2018. J Cell Physiol. 233(2), 1481-1489).

Zhu et al. identified aberrant gene regulatory pathways in systemic lupus erythematosus (SLE) through genome-wide transcription and DNA methylation analysis of peripheral blood mononuclear cells. Compared with SLE LN- patients, the gene expression of MX1, GPR84, and E2F2 was increased in SLE-LN+ patients (Zhu H et al., 2016. Arthritis Res Ther. 18, 162).

In one embodiment, the subject matter disclosed herein relates to a method for inhibiting GPR84, the method comprising contacting GPR84 with an effective amount of the compound or pharmaceutical composition of the present invention described herein.

In some embodiments, the subject matter disclosed herein relates to a method for modulating the immune response of a subject in need, wherein the method comprises administering to the subject an effective amount of the compound or pharmaceutical composition of the invention described herein.

The compounds disclosed in this invention bind directly to GPR84 and inhibit its signaling activity. In some embodiments, the compounds disclosed in this invention reduce, inhibit, or otherwise attenuate GPR84-mediated inflammatory responses.

The compounds disclosed in this invention may or may not be specific GPR84 antagonists. Specific GPR84 antagonists reduce the biological activity of GPR84 by a statistically higher amount than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In some embodiments, the compounds disclosed in this invention specifically inhibit the signaling activity of GPR84. In some of these embodiments, the _IC50 of the GPR84 antagonist against GPR84 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC50 of the _GPR84 antagonist against another GPCR activated by free fatty acids (FFA) or other GPCR types (e.g., class A GPCRs).

The compounds disclosed in this invention can be used in methods for inhibiting GPR84. Such methods involve contacting GPR84 with an effective amount of the compounds disclosed in this invention. "Contact" means bringing the compound into sufficient proximity with isolated GPR84 GPCRs or cells expressing GPR84 (e.g., T cells or B cells) such that the compound can bind to GPR84 and inhibit its activity. Contact with GPR84 can be achieved in vitro or in vivo by administering the compound to a subject.

Any method known in the art for measuring the signal transduction activity of GPR84 can be used to determine whether GPR84 has been inhibited, including in vitro determination or measurement of downstream biological effects of GPR84 signal transduction activity.

The compounds disclosed in this invention can be used to treat GPR84-dependent conditions. As used herein, "GPR84-dependent condition" is a pathological condition in which GPR84 activity is required to cause or maintain the pathological condition. In some embodiments, GPR84-dependent condition is an inflammatory condition.

The compounds disclosed in this invention can also be used to modulate the immune response of subjects in need. Such methods include administering an effective amount of the compounds of this invention.

As used in this article, “regulation of immune response” refers to the regulation of any immunogenic response to an antigen.

In another aspect of the invention, the invention provides novel compounds of the invention for use in therapeutic applications.

In another aspect of the invention, the invention provides a method for treating mammals susceptible to or suffering from the diseases listed herein, particularly those diseases that may be associated with abnormal GPR84 activity and/or abnormal GPR84 expression and/or abnormal GPR84 distribution, such as inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia and/or diseases involving impaired immune cell function, the method comprising administering a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions of the invention described herein.

In another aspect, the present invention provides a compound suitable for the treatment or prevention of diseases selected from those listed herein, specifically, such diseases may be associated with abnormal GPR84 activity and/or abnormal GPR84 expression and/or abnormal GPR84 distribution, such as inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia and/or diseases involving impaired immune cell function.

In an additional aspect, the present invention provides methods for synthesizing the compounds of the present invention using the representative synthetic schemes and routes disclosed herein.

Therefore, the main objective of this invention is to provide compounds of this invention that can alter the activity of GPR84 and thus prevent or treat any disease that may be causally related to it.

Another object of the present invention is to provide a compound of the present invention that can treat or alleviate a disease or ailment or its symptoms that may be causally related to the activity and/or expression and/or distribution of GPR84, such as inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia and/or diseases involving impaired immune cell function.

Another object of the present invention is to provide pharmaceutical compositions that can be used to treat or prevent various disease states, including diseases that may be associated with abnormal GPR84 activity and/or abnormal GPR84 expression and/or abnormal GPR84 distribution, such as inflammatory disorders, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia and/or diseases involving impaired immune cell function.

Other objectives and advantages will become apparent to those skilled in the art from the following detailed implementation.

This disclosure provides a method for modulating (e.g., inhibiting) GPR84 activity, the method comprising administering to a patient a compound provided herein or a pharmaceutically acceptable salt thereof.

In one aspect, this article provides a method for treating cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

In the methods described herein, the compounds of the present invention or pharmaceutical compositions thereof are administered to a subject suffering from cancer.

In some embodiments, the subject matter disclosed herein relates to a method for treating GPR84 dependence, the method comprising administering to a subject in need an effective amount of the compound or pharmaceutical composition of the invention described herein. In some aspects of this embodiment, GPR84 dependence is cancer.

In some embodiments, the subject matter disclosed herein relates to a method for treating chronic viral infections. In some embodiments, the subject matter disclosed herein relates to using GPR84 inhibitors as adjunctive therapy to enhance the efficacy of vaccination.

In some embodiments, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

In some respects, the present invention provides a method for treating cell proliferation disorders, including cancer.

In one aspect, the present invention provides a method for treating a subject with a cell proliferation disorder, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

In some implementations, cell proliferation disorder is referred to as cancer.

Examples of cancers that can be treated with the compounds disclosed herein include, but are not limited to, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, and combinations of said cancers.

In some embodiments, the cancers that can be treated with the compounds of this disclosure include, but are not limited to, blood cancers (e.g., lymphomas, leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, and combinations of said cancers).

In some implementations, the cancer is leukemia. In another implementation, the cancer is selected from the group consisting of acute myeloid leukemia and chronic myeloid leukemia.

In some embodiments, the cancer is selected from leukemia and blood cancers. In certain embodiments, the cancer is present in an adult patient; in other embodiments, the cancer is present in a pediatric patient. In certain embodiments, the cancer is AIDS-related.

In a specific implementation, the cancer is selected from leukemia and blood cancers. In a specific implementation, the cancer is selected from the group consisting of: myelodysplastic neoplasms, myelodysplastic syndrome, myelodysplastic/myelodysplastic neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myelodysplastic neoplasms (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high-risk MDS or AML, blastocyst-stage chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasmacytoma including plasmacytoma and multiple myeloma. The leukemia mentioned herein may be acute or chronic.

In some embodiments, diseases and indications for which the compounds disclosed herein can be used for treatment include, but are not limited to, hematologic cancers.

Exemplary hematologic cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, and myeloproliferative disorders (such as primary myelofibrosis). Polycythemia vera (PMF), polycythemia vera (PV), essential thrombocythemia (ET), spinal dysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, pilocellular lymphoma, chronic myeloma, and Burkitt's lymphoma.

As used herein, the term "inflammatory disease" refers to a group of diseases including: inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, vasculitis, lung diseases (e.g., chronic obstructive pulmonary disease (COPD) and interstitial lung disease (e.g., idiopathic pulmonary fibrosis (IPF))), psoriasis, gout, allergic airway diseases (e.g., asthma, rhinitis), and endotoxin-driven disease states (e.g., complications following bypass surgery or chronic endotoxin states causing, for example, chronic heart failure). Specifically, the term refers to rheumatoid arthritis, allergic airway diseases (e.g., asthma), and inflammatory bowel disease. In another specific aspect, the term refers to uveitis, periodontitis, esophagitis, neutrophilic dermatitis (e.g., pyoderma gangrenosa, Sweet's syndrome), severe asthma, and inflammation of the skin and/or colon caused by oncology treatments designed to activate an immune response.

As used herein, the term "pain" refers to a disease or condition characterized by a feeling of discomfort, usually caused by a severe or damaging stimulus, and includes, but is not limited to, nociceptive pain, inflammatory pain (associated with tissue damage and inflammatory cell infiltration), and neuropathic or functional pain (as caused by damage or dysfunction of the nervous system) and/or pain associated with or caused by the disorders mentioned herein. Pain can be acute or chronic.

As used herein, the term “neuroinflammatory disorder” refers to a disease or condition characterized by sudden neurological deficits associated with inflammation, demyelination, and axonal injury, and includes, but is not limited to, disorders such as Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

As used herein, the term "neurodegenerative disorder" refers to a disease or condition characterized by progressive loss of neuronal structure or function (including neuronal death), and includes, but is not limited to, the following: dementia, degenerative dementia, Alzheimer's disease, vascular dementia, dementia associated with intracranial space-occupying lesions, age-related mild cognitive impairment, age-related memory impairment, and/or peripheral neuropathy. Specifically, the term refers to retinopathy, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), spinocerebellar ataxia (SCA), and/or spinal muscular atrophy (SMA). More specifically, the terms refer to retinopathy, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and/or amyotrophic lateral sclerosis (ALS).

As used herein, the term “infectious disease” refers to a bacterial infectious disease, and includes, but is not limited to, diseases such as: sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving species such as Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacteriaceae.

As used herein, the term "autoimmune disease" refers to a group of diseases including: obstructive airway diseases (including, for example, COPD (chronic obstructive pulmonary disease)), psoriasis, asthma (e.g., intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma), particularly chronic or refractory asthma (e.g., delayed-onset asthma and airway hyperresponsiveness), bronchitis (including bronchial asthma), systemic lupus erythematosus (SLE), multiple sclerosis, type 1 diabetes mellitus and its associated complications, atopic eczema (atopic dermatitis), contact dermatitis and other eczematous dermatitis, vasculitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. Specifically, the term refers to COPD, asthma, psoriasis, systemic lupus erythematosus, type 1 diabetes mellitus, vasculitis, and inflammatory bowel disease.

As used in this article, the term "endocrine and/or metabolic disorders" refers to a group of conditions involving an overproduction or underproduction of certain hormones in the body, while metabolic disorders affect the body's ability to process certain nutrients and vitamins. Endocrine disorders include hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal disorders (including Cushing's syndrome and Addison's disease), and ovarian dysfunction (including polycystic ovary syndrome), among others. Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. A specific example of a metabolic disorder is obesity.

As used herein, the term "cardiovascular disease" refers to a disease affecting the heart or blood vessels, or both. Specifically, cardiovascular disease includes arrhythmias (atrial or ventricular, or both); atherosclerosis and its sequelae; angina; arrhythmias; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis; stroke; peripheral obstructive arterial disease of the limbs, organs, or tissues; reperfusion injury following local ischemia of the brain, heart, kidneys, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraines); vascular abnormalities, inflammation, and dysfunction limited to a single organ or tissue. In particular, the term refers to atherosclerosis.

As used herein, the term "leukemia" refers to a neoplastic disease of the blood and blood-forming organs. Such diseases can cause dysfunction of the bone marrow and immune system, making the host highly susceptible to infection and bleeding. Specifically, the term leukemia refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

As used herein, the term "disease involving impaired immune cell function" includes conditions with symptoms such as recurrent and persistent viral and bacterial infections and slow recovery. Other invisible symptoms may prevent the elimination of parasites, yeast, and bacterial pathogens in the gut or throughout the body.

As used herein, the term "fibrotic disease" refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of the extracellular matrix, and associated with abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased recruitment of fibroblasts, including but not limited to fibrosis of individual organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneum, skin, cornea, retina, musculoskeletal system, and digestive tract. Specifically, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis; other diffuse solid lung diseases of various etiologies, including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcomatoid diseases, hypersensitivity pneumonia), collagen vascular diseases, pulmonary alveolar proteinosis, Langerhans cell granulomatosis, lymphangiomyomatosis, and genetic diseases (Hepp syndrome). Rmansky-Pudlak Syndrome; tuberous sclerosis; neurofibromatosis; metabolic storage disease; familial interstitial lung disease; radiation-induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos-induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); renal fibrosis; tubulointerstitial fibrosis; glomerulonephritis; diabetic nephropathy; focal segmental glomerulosclerosis; IgA nephropathy; hypertension; Allport syndrome Alport syndrome; intestinal fibrosis; liver fibrosis; cirrhosis; alcohol-induced liver fibrosis; toxic/drug-induced liver fibrosis; hemochromatosis; alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NASH), non-alcoholic fatty liver disease (NAFLD); cholestasis, bile duct injury; primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC); infection-induced liver fibrosis; virus-induced liver fibrosis; and autoimmune hepatitis; corneal scarring; proliferative... Scarring; Dupuytren's disease, keloids, cutaneous fibrosis; scleroderma; systemic sclerosis, spinal cord injury/fibrosis; myelofibrosis; musculoskeletal fibrosis associated with Duchenne muscular dystrophy (DMD), restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease or chronic lymphocytic fibrosis. More specifically, the term "fibrotic disease" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, nonalcoholic fatty liver disease (NASH), nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (ASH), portal hypertension, systemic sclerosis, renal fibrosis, and cutaneous fibrosis. Most specifically, the term "fibrotic disease" refers to nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic fatty liver disease (NAFLD). Or, most specifically, the term "fibrotic disease" refers to IPF.

In some embodiments, the compounds of the present invention are suitable for preventing or reducing the risk of any of the diseases mentioned herein; for example, preventing individuals who may be susceptible to a disease, ailment, or condition but have not yet experienced or exhibited the pathology or symptomology of the disease from developing or reducing the risk of developing the disease, ailment, or condition.

The compounds disclosed in this invention may be administered in any suitable manner known in the art. In some embodiments, the compounds of this invention, or their pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives, may be administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorally, intraorally, by inhalation, intrathecally, intratumorally, or intranasally.

In some embodiments, the GPR84 antagonist is administered continuously. In other embodiments, the GPR84 antagonist is administered intermittently. Furthermore, treating a subject with an effective amount of the GPR84 antagonist may include monotherapy or a series of treatments.

It should be understood that the appropriate dosage of an active compound depends on a number of factors within the knowledge of a physician or veterinarian with general skills. The dosage of an active compound will vary, for example, depending on the subject's age, weight, general health condition, sex and diet, time of administration, route of administration, excretion rate, and any combination of drugs.

It should also be understood that the effective dose of the compound of the present invention or its pharmaceutically acceptable salt, prodrug, metabolite, or derivative used for treatment may increase or decrease over a specific treatment course. Dosage variations may be caused by and become apparent from diagnostic assays.

In some embodiments, the GPR84 antagonist is administered to the subject at doses between about 0.001 μg/kg and about 1000 mg/kg, including but not limited to about 0.001 μg/kg, 0.01 μg/kg, 0.05 μg/kg, 0.1 μg/kg, 0.5 μg/kg, 1 μg/kg, 10 μg/kg, 25 μg/kg, 50 μg/kg, 100 μg/kg, 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg, and 200 mg/kg.

In the methods described herein, the method may further include administering a chemotherapeutic agent to a subject. In some aspects of this embodiment, the chemotherapeutic agent and a compound or composition are administered to the subject simultaneously. In some aspects of this embodiment, the chemotherapeutic agent is administered to the subject prior to the administration of the compound or composition. In some aspects of this embodiment, the chemotherapeutic agent is administered to the subject after the administration of the compound or composition.

As used herein, the term "treatment/treat/treating" refers to reversing or alleviating a disease or condition or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered when symptoms are absent. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

The term "administration/administering" refers to the route by which a compound is introduced into a subject to exert its intended function. Examples of possible routes of administration include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

The term "effective amount" refers to the amount that effectively achieves the desired outcome at the required dose and time period. The effective amount of a compound can be varied based on factors such as the subject's disease state, age, weight, and the compound's ability to elicit the desired response in the subject. Dosing regimens can be adjusted to provide the optimal therapeutic response.

As used in this article, the phrases “systemic administration,” “systemic application,” “peripheral application,” and “peripheral application” refer to the administration of a compound, drug, or other substance to the patient’s system, where it undergoes metabolism and other similar processes.

The phrase "therapeutic effective amount" means the amount of the compound of the present invention that achieves the following effects: (i) treating or preventing a specific disease, ailment, or condition; (ii) alleviating, improving, or eliminating one or more symptoms of a specific disease, ailment, or condition; or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, ailment, or condition described herein. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., to some extent slow down and preferably terminate) the invasion of cancer cells into surrounding organs; inhibit (i.e., to some extent slow down and preferably terminate) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate one or more of the symptoms associated with cancer to some extent. The drug may have cell growth inhibitory and/or cytotoxic effects to the extent that it can prevent the growth of existing cancer cells and/or kill existing cancer cells. For cancer therapies, efficacy may be measured, for example, by assessing time to progression (TTP) and/or determining response rate (RR).

The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some implementations, the subject is a human.

In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for the prevention and/or treatment of one or more fibrotic diseases. In a particular embodiment, the fibrotic disease is NASH and/or NAFLD. In a most particular embodiment, the fibrotic disease is NASH. In another most particular embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of an agent for the prevention and/or treatment of one or more fibrotic diseases. In a particular embodiment, the fibrotic disease is NASH and/or NAFLD. In a most particular embodiment, the fibrotic disease is NASH. In another most particular embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

In terms of additional treatment methods, the present invention provides methods for preventing and/or treating mammals suffering from fibrotic diseases, the methods comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention described herein to treat or prevent said disease. In one particular embodiment, the fibrotic disease is NASH and/or NAFLD. In one most particular embodiment, the fibrotic disease is NASH. In another most particular embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a fibrotic disease treatment agent. In a particular embodiment, the fibrotic disease is NASH and/or NAFLD. In a most particular embodiment, the fibrotic disease is NASH. In another most particular embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for the prevention and/or treatment of subjects with a NAS score of at least 3, at least 4, at least 5, at least 6, or at least 7.

In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the prevention and/or treatment of subjects with a NAS score >5.

In terms of additional treatment methods, the present invention provides a method for preventing and/or treating mammals with a NAS score >5, the method comprising administering an effective amount of one or more of the compounds of the present invention described herein, or pharmaceutical compositions, for the treatment or prevention of said fibrotic disease, particularly NASH, and/or NAFLD, more particularly NASH.

In other implementations of the treatment method, the method of preventing and/or treating mammals includes measuring the subject's forced vital capacity (FVC), wherein the FVC does not decrease after treatment. In one particular implementation, the FVC does not decrease during a treatment period of 12, 16, 20, or 26 weeks. In another implementation, the method includes measuring the subject's FVC, wherein the FVC increases by at least 1 mL, at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 6 mL, at least 7 mL, or at least 8 mL. In one particular implementation, the FVC increases by at least 1 mL, at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 6 mL, at least 7 mL, or at least 8 mL during a treatment period of 12, 16, 20, or 26 weeks.

In one embodiment, the method includes measuring airway volume, wherein the airway volume reduction does not exceed 5 mL/L, 4 mL/L, or 3 mL/L. In a particular embodiment, the airway volume reduction does not exceed 5 mL/L, 4 mL/L, or 3 mL/L after 12, 16, 20, or 26 weeks of treatment.

Combination therapy

Depending on the specific ailment or disease to be treated, additional therapeutic agents typically administered to treat said ailment may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents typically administered to treat a specific ailment or disease are referred to as “the ailment or disease to be treated”.

In some embodiments, the provided combination or composition thereof is administered in combination with another therapeutic agent.

The compounds of the present invention can be used as therapeutic agents for treating diseases in mammals that are causally related to or attributable to abnormal GPR84 activity and/or abnormal GPR84 expression and/or abnormal GPR84 distribution.

Therefore, the compounds and pharmaceutical compositions of the present invention are suitable as therapeutic agents for the prevention and/or treatment of inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia and/or diseases involving impaired immune cell function in mammals, including humans.

Therefore, in one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention, which are suitable as pharmaceutical agents.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention, which are suitable for manufacturing pharmaceutical preparations.

In another aspect, the present invention provides a method for treating mammals suffering from or at risk of developing the diseases disclosed herein. In one particular aspect, the present invention provides a method for treating mammals, including humans, suffering from or at risk of developing inflammatory disorders, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia, and/or diseases involving impaired immune cell function, said method comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention described herein.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of inflammatory disorders. In one specific embodiment, the inflammatory disorder is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory disorder is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatitis (e.g., pyoderma gangrenosa, Sweet's syndrome), severe asthma, and inflammation of the skin and/or colon caused by oncology treatments aimed at activating an immune response.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of inflammatory disorders. In one specific embodiment, the inflammatory disorder is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory disorder is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatitis (e.g., pyoderma gangrenosa, Sweet's syndrome), severe asthma, and inflammation of the skin and/or colon caused by oncology treatments aimed at activating an immune response.

In another aspect, the present invention provides a method for a mammal suffering from or at risk of suffering from a disease selected from inflammatory diseases (e.g., inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis), lung diseases (e.g., chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (e.g., idiopathic pulmonary fibrosis (IPF))), neuroinflammatory diseases, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases and/or diseases involving impaired immune cell function), said method comprising administering an effective amount of one or more of the compounds of the present invention described herein, or pharmaceutical compositions thereof.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from inflammatory diseases, the methods comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions described herein. In one specific embodiment, the inflammatory disease is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory disease is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatitis (e.g., pyoderma gangrenosa, Sweet's syndrome), severe asthma, and inflammation of the skin and/or colon caused by oncology treatments aimed at activating an immune response.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of pain. In one specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of pain. In one specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing pain in mammals susceptible to or suffering from pain, the methods comprising administering an effective amount of one or more of the compounds of the present invention described herein, or pharmaceutical compositions. In one specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention, which are suitable for manufacturing agents for the prevention and/or treatment of neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, or autoimmune encephalomyelitis, said methods comprising administering an effective amount of one or more of the compounds of the present invention described herein, or pharmaceutical compositions thereof.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of infectious diseases. In one specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving species such as Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacteriaceae.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of infectious diseases. In one specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving species such as Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacteriaceae.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from infectious diseases, said methods comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions described herein. In one specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving species such as Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacteriaceae.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of autoimmune diseases and/or diseases involving impaired immune cell function. In one specific embodiment, the autoimmune diseases and/or diseases involving impaired immune cell function are selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of autoimmune diseases and/or diseases involving impaired immune cell function. In one specific embodiment, the autoimmune diseases and/or diseases involving impaired immune cell function are selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from autoimmune diseases and/or diseases involving impaired immune cell function, said methods comprising administering an effective amount of one or more of the compounds of the present invention described herein, or pharmaceutical compositions. In one specific embodiment, the autoimmune disease and/or disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type 1 diabetes, vasculitis, and inflammatory bowel disease.

In one aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for the prevention and/or treatment of endocrine and/or metabolic disorders. In one specific embodiment, the endocrine and/or metabolic disorders are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

In another aspect, the present invention provides compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention for use in the manufacture of agents for the prevention and/or treatment of endocrine and/or metabolic disorders. In one specific embodiment, the endocrine and/or metabolic disorders are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

In terms of additional treatment methods, the present invention provides methods for treating and/or preventing mammals susceptible to or suffering from endocrine and/or metabolic disorders, said methods comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention described herein. In one specific embodiment, the endocrine and/or metabolic disorders are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

As another aspect of the invention, a compound of the invention is provided, which is used particularly as a medicament in the treatment or prevention of the aforementioned diseases and ailments. The use of the compound in the manufacture of a medicament for the treatment or prevention of one of the aforementioned diseases and ailments is also provided herein.

One specific embodiment of the method of the present invention includes administering an effective amount of the compound of the present invention to a subject suffering from an inflammatory disease for a period of time sufficient to reduce the inflammation level of the subject and preferably terminate the process causing the inflammation. Another specific embodiment of the method includes administering an effective amount of the compound of the present invention to a subject susceptible to or developing an inflammatory disease for a period of time sufficient to reduce or prevent inflammation in the patient and preferably terminate the process causing the inflammation.

Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, lasting from about 1 to about 120 h, and especially 24 to 96 h. Preloaded pellets of about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady-state levels. For human patients weighing 40 to 80 kg, the maximum total dose is expected not to exceed about 2 g/day.

Transdermal delivery is often chosen to provide blood levels similar to or lower than those achieved with injectable delivery.

When used to prevent the onset of a disease, the compounds of the present invention should generally be administered to patients at risk of having the disease at the dosage levels described above, as advised by and under the supervision of a physician. Patients at risk of having a particular disease generally include those with a family history of the disease, or those identified by genetic testing or screening as particularly susceptible to the disease.

The compounds of the present invention can be administered as a single active agent or in combination with other therapeutic agents, including those exhibiting the same or similar therapeutic activity and proven safe and effective for such combinations. In one specific embodiment, co-administration of two (or more) agents allows for a significant reduction in the dosage of each agent to be used, thereby mitigating observed side effects.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory disorders; the specific agent includes, but is not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, for example), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g., rheumatoid arthritis); the specific agent includes, but is not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDs (e.g., but not limited to methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiouralate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporin) and biological DMARDs (e.g., but not limited to infliximab, etanercept, adalimumab, rituximab, golimumab, pegylated cetuzumab, tosilimumab, interleukin-1 blockers, and abatacept).

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of autoimmune diseases; the specific agent includes, but is not limited to: glucocorticoids, cell growth inhibitors (e.g., purine analogs), alkylating agents (e.g., nitrogen mustard (cyclophosphamide), nitrosourea, platinum compounds, etc.), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., actinomycin anthracycline, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, and), cyclosporine, tacrolimus, rapamycin (sirolimus), interferon (e.g., IFN-β), TNF-binding proteins (e.g., infliximab, etanercept, or adalimumab), mycophenolate mofetil, fingolimod, and myriocin.

In one embodiment, the compound of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of infectious diseases; the specific agent includes, but is not limited to, antibiotics. In one specific embodiment, the compound of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of infection of any organ in the human body; the specific agent includes, but is not limited to: aminoglycosides, anesamcinolone, carbapenems, cephalosporins, glycopeptides, lincosamides, macrolides, monoamides, nitrofurans, penicillins, polypeptides, quinolinones, sulfonamides, tetracyclines, anti-mycobacterial agents, and chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycin, thiamphenicol, and tinidazole.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of vasculitis, the specific agent including but not limited to steroids (e.g., prednisone, prednisolone), cyclophosphamide, and a final antibiotic (e.g., cephalexin) in cases of skin infection.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of esophagitis; the specific agent includes, but is not limited to: antacids (e.g., formulations containing aluminum hydroxide, magnesium hydroxide and/or polydimethicone), H2- antagonists (e.g., cimetidine, ranitidine, famotidine), proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole), and glucocorticoids (e.g., prednisone, budesonide).

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of IPF; specific agents include, but are not limited to, pirfenidone and bosentan.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD; specific agents include, but are not limited to: β2-adrenergic receptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), adrenaline (inhaled or tablet form), anticholinergic agents (e.g., ipratropium bromide), long-acting β2-agonists of glucocorticoids (oral or inhaled) (e.g., salmeterol, formoterol, bamboolol, and sustained-release oral salbutamol), and combinations of inhaled steroids with long-acting bronchodilators (e.g., fluticasone/salmeterol, budesonide). Nidone/formoterol, leukotriene antagonists and synthesis inhibitors (e.g., montelukast, zafirlukast, and zileuton), mediator release inhibitors (e.g., cromoglycate and ketotifen), phosphodiesterase-4 inhibitors (e.g., roflurane), biological modulators of IgE response (e.g., omalizumab), antihistamines (e.g., cetirizine, cinnarizine, and fexofenadine), and vasoconstrictors (e.g., oxymethazoline, xylomethazoline, nafazoline, and tramazoline).

Additionally, the compounds of the present invention can be administered in combination with emergency therapies for asthma and/or COPD, including oxygen or helium-oxygen mixtures, nebulized salbutamol or terbutaline (optionally in combination with an anticholinergic agent such as ipratropium), systemic steroids (oral or intravenous, such as prednisone, prednisolone, methylprednisolone, dexamethasone, or corticosteroids), intravenous salbutamol, nonspecific beta-agonists, and injectable or inhaled formulations (such as epinephrine, isoetharine, etc.). Adrenaline, meprocarline, anticholinergic agents (IV or nebulized, such as glycopyrrolate, atropine, ipratropium), methylxanthine (theophylline, aminophylline, bamiphylline), inhaled anesthetics with bronchodilatory effects (such as isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory bowel disease (IBD); the specific agents include, but are not limited to: glucocorticoids (e.g., prednisone, budesonide); synthetic disease modifiers and immunomodulators (e.g., methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine) and biological disease modifiers and immunomodulators (infliximab, adalimumab, rituximab, and abatacept).

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of pain, such as non-anesthetic and anesthetic analgesics; specific agents include, but are not limited to: acetaminophen, acetylsalicylic acid, NSAID, codeine, dihydrocodeine, tramadol, tebuconazole, meperidine, tetridin, buprenorfine, fentanyl, hydromorfon, methadone, morphine, oxycodone, piperonitrile, tapentadol, or combinations thereof.

The treatment process for leukemia includes chemotherapy, biological therapy, targeted therapy, radiotherapy, bone marrow transplantation, and/or combinations thereof.

Examples of other therapeutic agents used for acute lymphoblastic leukemia (ALL) include methotrexate, nerabine, asparaginase, Erwinia chrysanthemi, blinatumomab, daunorubicin, clofarapine, cyclophosphamide, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib, vincristine, mercaptopurine, pegaspargase, and/or prednisone.

Examples of other therapeutic agents used for acute myeloid leukemia (AML) include arsenic trioxide, donomycin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and/or vincristine.

Examples of other therapeutic agents used for chronic lymphocytic leukemia (CLL) include alemtuzumab, chlorambucil, ovarumumab, bendamustine, cyclophosphamide, fludarabine, atoruzumab, ibrutinib, idelalisib, nitrogen mustard, prednisone, and/or rituximab.

Examples of other therapeutic agents used for chronic myeloid leukemia (CML) include besutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, nitrogen mustard, nilotinib, and/or omaltazine.

Examples of other treatments for hairy cell leukemia include cladiribine, pentostatin, and/or interferon alpha-2b.

As will be apparent to those skilled in the art, co-administration includes any method of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. It is not necessary that the two or more agents be administered simultaneously in a single formulation. The agents may be in different formulations and administered at different times.

In one embodiment, the compound of the present invention is co-administered with one or more other therapeutic agents for the treatment and/or prevention of fibrotic diseases. In a particular embodiment, the compound of the present invention is co-administered with one or two other therapeutic agents for the treatment and/or prevention of fibrotic diseases. In a more particular embodiment, the compound of the present invention is co-administered with another therapeutic agent for the treatment and/or prevention of fibrotic diseases.

In one implementation, other therapeutic agents for treating and/or preventing fibrotic diseases include, but are not limited to, 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone); nintedanib (or); STX-100 (ClinicalTrials.gov identifier NCT01371305), FG-3019 (ClinicalTrials.gov identifier NCT01890265), raprecizumab (CAS n#953400-68-5); tarozinumab (CAS n#1044515-88-9), CC-90001 (ClinicalTrials.gov identifier NCT03142191), and tyrosine (MN-001; ClinicalTrials.gov identifier NCT03142191). The following are listed: s.gov identifier NCT02503657, ND-L02-s0201 (ClinicalTrials.gov identifier NCT03538301), KD025 (ClinicalTrials.gov identifier NCT02688647), TD139 (ClinicalTrials.gov identifier NCT02257177), VAY736 (ClinicalTrials.gov identifier NCT03287414), PRM-151 (ClinicalTrials.gov identifier NCT02550873), and PBI-4050 (ClinicalTrials.gov identifier NCT02538536). In one particular implementation, another therapeutic agent for treating and/or preventing fibrotic diseases is an autocrine motor factor (or exonucleic acid pyrophosphatase/phosphodiesterase 2 or NPP2 or ENPP2) inhibitor, examples of which are described in WO 2014/139882, such as GLPG1690.

In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and/or prevention of NASH. Specific agents include, but are not limited to, weight-loss therapeutic agents (e.g., sibutramine or orlistat), insulin sensitizers (e.g., metformin, thiazolidinedione, rosiglitazone, or pioglitazone), lipid-lowering agents (e.g., gemfibrozil), antioxidants (e.g., vitamin E, N-acetylcysteine, betaine, or pentoxifylline), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, monounsaturated fatty acids, or polyunsaturated fatty acids. FXR agonists (e.g., obeticholic acid), LOXL2 antagonists (e.g., cintuzumab), ASK1 antagonists (e.g., seloselte), PPAR agonists (e.g., clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, thiazolidinedione, ibuprofen, GW-9662, agliflozin, moggliflozin, or ticaggliflozin), acetyl-CoA-carboxylase (ACC) antagonists (e.g., NDI-010976, PF-05221304), CCR2/CCR5 (e.g., denivilol), and VAP1 antagonists.

Examples of pharmaceutical agents that can also be combined with the present invention include, but are not limited to: those for the treatment of Alzheimer's disease, such as ritonavir, and those for the treatment of HIV; and those for the treatment of Parkinson's disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, and trihexyphenidyl. Trihexephendyl and amantadine; agents used to treat multiple sclerosis (MS), such as beta-interferon (e.g., and mitoxantrone); agents used to treat asthma, such as salbutamol; and agents used to treat schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids. Steroids, TNF blockers, IL-1RAs, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's agents; agents used to treat cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, and calcium. Ion channel blockers and statins; agents used to treat liver diseases, such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents used to treat blood disorders, such as corticosteroids, antileukemic agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir); and agents used to treat immunodeficiency disorders, such as gamma globulin.

In some embodiments, the combination therapy of the present invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

These additional agents may be administered separately from the provided combination therapy as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the present invention to form a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or at intervals between each other (typically within five hours).

As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, a combination of the invention may be administered simultaneously or sequentially with another therapeutic agent in a single unit dosage form or together in a single unit dosage form.

The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would normally be applied in the form of a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed in the present invention will be in the range of about 50% to 100% of the amount normally present in a composition containing said pharmaceutical agent as the sole active agent.

In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent may be administered together with the compound of formula I, or may be administered before or after the administration of the compound of formula I. Suitable therapeutic agents are described in more detail below. In some embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

In another embodiment, the present invention provides a method for treating an inflammatory disease, condition, or disorder by administering a compound of formula I and one or more additional therapeutic agents to a patient in need. Such additional therapeutic agents may be small molecule or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin, and celecoxib, colchicine, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat, sulfasalazine, antimalarial drugs such as hydroxychloroquine and chloroquine, methotrexate gold salts such as glucosinolate gold, thiomalate gold, and auronoxine, D-penicillamine (or azathioprine, cyclophosphamide, chlorambucil, cyclosporine) Flumex and "anti-TNF" agents such as etanercept, inliximab, golimumab, pegylated cetuzumab and adalimumab; "anti-IL-1" agents such as anaprost and linacip, canalimumab; anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab; "anti-T cell" agents such as abatacept; "anti-IL-6" agents such as tocilizumab, diclofenac, cortisone, hyaluronic acid (or), monoclonal antibodies such as tanizumab, anticoagulants such as heparin (or) and warfarin; antidiarrheal drugs such as diphenhydramine and loperamide; bile acid conjugates such as cholestyramine, allosetron, rubiprostone; mild laxatives such as emulsifiable concentrate. Inhaled corticosteroids, such as β-2 agonists like salbutamol (HFA, L-salbutamol), mesoproterenol, pibuterol acetate, terbutaline sulfate, salmeterol and formoterol, anticholinergics like ipratropium bromide and tiotropium, inhaled corticosteroids like beclomethasone dipropionate (and), triamcinolone acetonide, mometasone, budesonide and flunisolone, sodium cromoglycate, methylxanthines like theophylline and aminophylline, IgE antibodies like omalizumab, nucleoside reverse transcriptase inhibitors like zidovudine, abacavir, abacavir/lamivudine, abacavir/lamivudine Fudovudine/zidovudine, didanofin, emtricitabine, lamivudine, lamivudine/zidovudine, stavudine and zalcitabine, non-nucleoside reverse transcriptase inhibitors such as deraviridine, efavirenz, lavin, and travirine, nucleotide reverse transcriptase inhibitors such as tenofovir, protease inhibitors such as ampravir, atazanavir, darunavir, fazanavir, indinavir, lopinavir and ritonavir, nefenavir, ritonavir, saquinavir (or) and telanavir, entry inhibitors such as enfvirdi and maraviro, integrase inhibitors such as raltegravir, doxorubicin, vincristine, bortezomib and dexamethasone with lenalidomide or any combination thereof.

In another embodiment, the present invention provides a method for treating rheumatoid arthritis, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin, and celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; sulfasalazine antimalarial drugs such as hydroxychloroquine and chloroquine; methotrexate gold salts such as glucosinolate gold, thiomalate gold, and auronoxine; D-penicillamine (or), azathioprine, cyclophosphamide, chlorambucil, cyclosporine, leflunomide, and "anti-TNF" agents such as etanercept, inliximab, golimumab, pegylated sertuzumab, and adalimumab; "anti-IL-1" agents such as anaerobiculin and linaccept; antibodies such as rituximab; "anti-T cell" agents such as abatacept; and "anti-IL-6" agents such as tocilizumab.

In some embodiments, the present invention provides a method for treating osteoarthritis, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin and celecoxib, diclofenac, cortisone, hyaluronic acid (or) and monoclonal antibodies such as tanizumab.

In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin, and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarial drugs such as hydroxychloroquine and chloroquine, cyclophosphamide, methotrexate, azathioprine, and anticoagulants such as heparin (or) and warfarin.

In some embodiments, the present invention provides a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: mesalamine, sulfasalazine, antidiarrheals such as diphenoxylate and loperamide, cholic acid conjugates such as cholestyramine, allosetronil, lubiprostone, laxatives such as magnesium oxide emulsion, polyethylene glycol, and anticholinergics or antispasmodics such as bicyclic amine, anti-TNF agents, steroids, and antibiotics such as metronidazole (Flagyl) or ciprofloxacin.

In some embodiments, the present invention provides a method for treating asthma, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: β-2 agonists such as salbutamol (HFA, HFA), levosalbutamol, mesodeoxycholine, pibuterol acetate, terbutaline sulfate, salmeterol hydroxynaphthenic acid, and formoterol; anticholinergics such as ipratropium bromide and tiotropium; inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (and), triamcinolone acetonide, mometasone acetate, budesonide, and flunisolone; sodium cromoglycate; methylxanthines such as theophylline and aminophylline; and IgE antibodies such as omalizumab.

In some embodiments, the present invention provides a method for treating COPD, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: β-2 agonists such as salbutamol (HFA, levosabutamol), mesoproterenol acetate, pibuterol sulfate, terbutaline, salmeterol and formoterol; anticholinergics such as ipratropium bromide and tiotropium; methylxanthines such as theophylline and aminophylline; inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate, triamcinolone acetonide, mometasone acetate, budesonide, and flunisolone.

In another embodiment, the present invention provides a method for treating hematological malignancies, the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof to a patient in need.

In another embodiment, the present invention provides a method for treating solid tumors, the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from the group consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof to a patient in need.

In another embodiment, the present invention provides a method for treating a hematological malignancy, the method comprising administering a compound of formula I and a hedgehog (Hh) signaling pathway inhibitor to a patient in need. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al., “Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, hedgehog signaling inhibitors, and combinations thereof to a patient in need.

In another embodiment, the present invention provides a method for treating multiple myeloma, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: bortezomib and dexamethasone hedgehog signaling inhibitors, BTK inhibitors, JAK/pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and lenalidomide.

In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, the method comprising administering a compound of formula I and a BTK inhibitor to a patient in need, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune diseases, etc. Thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lymeneuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, strabismus-clonic myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic nervous system dysfunction, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromuscular rigidity, scleroderma, vulvar pain, hyperplastic diseases, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, infusion, systemic allergic reactions, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect toxins, animal hair, animal dander, dust mites, or cockroach calyxes). Type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, allergic purpura (Henoch-Schonlein purpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritoneum Inflammation, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma/Wald's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasmacytoma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma). Marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma/leukemia, or lymphoma-like granuloma, breast cancer, prostate cancer), or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mast cell hyperplasia), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including but not limited to rheumatoid arthritis, serologically negative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behcet's disease, Hughley's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic diseases (e.g.) Such conditions include myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass grafting, restenosis after aortocoronary artery bypass grafting, stroke, transient ischemic attack, peripheral artery occlusion, pulmonary embolism, deep vein thrombosis, inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Hugh Lane's disease, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), and autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome). (Symptoms), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpassuia syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative arthritis, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (e.g., acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves' disease.

In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising administering a compound of formula I and a PI3K inhibitor to a patient in need, wherein the disease is selected from cancer, neurodegenerative diseases, angiogenic diseases, viral diseases, autoimmune diseases, inflammatory diseases, hormone-related diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune disorders involving T-cell activation, cardiovascular diseases, and CNS diseases.

In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising administering a compound of formula I and a PI3K inhibitor to a patient in need, wherein the disease is selected from benign or malignant tumors; cancers or solid tumors of the brain, kidneys (e.g., renal cell carcinoma (RCC)), liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, endometrium, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland; sarcomas; glioblastoma; neuroblastoma; multiple bone tumors. Myeloma or gastrointestinal cancer, especially colon cancer or colorectal adenoma or head and neck tumors; epidermal hyperplasia; psoriasis; benign prostatic hyperplasia; tumor formation; epithelial-characteristic tumor formation; adenoma; adenocarcinoma; keratoacanthoma; epidermoid carcinoma; large cell carcinoma; non-small cell lung cancer; lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin's or Hodgkin's disease)); breast cancer; follicular carcinoma; undifferentiated carcinoma; papillary carcinoma; seminoma; melanoma or leukemia, including diseases such as Cowden syndrome, Lermit-Dudor... Lhermitte-Dudos disease and Bannayan-Zonana syndrome; or diseases involving abnormal activation of the PI3K/PKB pathway; asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced by bacterial infection; acute lung injury (ALI); adult/acute respiratory distress syndrome (ARDS); Chronic obstructive pulmonary, airway, or lung disease (COPD, COAD, or COLD), including chronic bronchitis or related dyspnea, emphysema, and exacerbations of airway hyperresponsiveness caused by other drug therapies, particularly other inhaled drug therapies; bronchitis of any type or origin, including but not limited to acute, peanut inhalation, catarrhal, croupus, chronic, or tuberculous bronchitis; and pneumoconiosis of any type or origin (inflammatory, usually occupational lung disease, whether chronic or acute, often accompanied by...). Airway obstruction caused by repeated inhalation of dust, including, for example, aluminum deposition, carbon deposition, asbestos deposition, stone deposition, eyelash loss, iron deposition, silica deposition, tobacco deposition, and cotton wool deposition; Loffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polynodular arteritis (including Churg-Strauss syndrome), eosinophilic... Granulomas and eosinophilic disorders affecting the airways caused by drug reactions; psoriasis; contact dermatitis; atopic dermatitis; alopecia areata; erythema multiforme; herpetic dermatitis; scleroderma; vitiligo; hypersensitivity vasculitis; urticaria; bullous pemphigoid; lupus erythematosus; pemphigus; acquired epidermolysis bullosa; conjunctivitis; dry eye; and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases with autoimmune reactions or autoimmune components or etiologies, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia). Allergic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura; cutaneous lupus erythematosus; systemic lupus erythematosus; rheumatoid arthritis; polychondritis; scleroderma; Wegener's granulomatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Stevens-Johnson syndrome; idiopathic stomatitis; autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease); endocrine ophthalmopathy; Graves' disease; sarcoidosis; alveolitis; chronic... Allergic pneumonia; multiple sclerosis; primary biliary cirrhosis; uveitis (anterior and posterior); dry eye and vernal keratoconjunctivitis; interstitial pulmonary fibrosis; psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy); restenosis; cardiac hypertrophy; atherosclerosis; myocardial infarction; ischemic stroke and congestive heart failure; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; and cerebral ischemia; as well as neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

In some embodiments, the present invention provides a method for treating or reducing the severity of a disease, the method comprising administering a compound of formula I and a Bcl-2 inhibitor to a patient in need, wherein the disease is an inflammatory condition, an autoimmune condition, a proliferative condition, an endocrine condition, a neurological condition, or a transplant-related condition. In some embodiments, the condition is a proliferative condition, lupus, or lupus nephritis. In some embodiments, the proliferative condition is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematuria, or a solid tumor.

In some embodiments, the disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplant-related disease. In some embodiments, the JH2-binding compound is a compound of formula I. Other suitable JH2-domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1-domain-binding compounds include those described in WO2015131080A1, the entire of which is incorporated herein by reference.

The compounds and compositions according to the method of the present invention can be administered in any effective dose and via any effective route of administration for treating or reducing the severity of autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases. The precise amount required will vary depending on the individual subject, including species, age and general condition, severity of infection, specific agent, mode of administration, etc. The compounds of the present invention are preferably formulated in unit dosage forms for ease of administration and dose uniformity. As used herein, “unit dosage form” refers to a physically discrete unit of the agent suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disease to be treated and its severity; the activity of the specific compound used; the specific composition used; the patient’s age, weight, general health condition, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), or buccally (e.g., orally or via nasal spray), depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention can be administered orally or parenterally at the following dosage levels to achieve the desired therapeutic effect: about 0.01 mg to about 50 mg per kg of subject body weight per day, preferably about 1 mg to about 25 mg, once or more daily.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol; and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

Injectable formulations can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents include water, Ringer's solution (U.S.P.), and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids, such as oleic acid, are used in the preparation of injectable formulations.

Injectable formulations can be sterilized, for example, by filtration via a bacterial trapping filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

To prolong the effects of the compounds of this invention, it is generally necessary to slow the absorption of compounds injected subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. Therefore, the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered compounds can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable reservoir forms are manufactured by forming microcapsule matrices of the compound in a biodegradable polymer, such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

Compositions for rectal or vaginal application are preferably suppositories prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; e) solvent inhibitors, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well-known in the field of pharmaceutical formulation. They may optionally contain emulsifiers and may also have compositions that release the active ingredient only or preferentially in a portion of the intestine or optionally in a delayed manner. Examples of usable encapsulation compositions include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

The active compound may also be present in microencapsulation form with one or more excipients as noted above. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). As is customary, such dosage forms may also contain additional substances besides inert diluents, such as tablet-making lubricants and other tablet-making aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer. It may optionally contain an emulsifier and may also have a composition that releases or optionally releases the active ingredient only or preferentially in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

Dosage forms for topical or transdermal application of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops are also covered within the scope of this invention. Additionally, this invention covers the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

According to one embodiment, the present invention relates to a method for inhibiting GPR84 activity in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

According to another embodiment, the present invention relates to a method for inhibiting the activity of GPR84 or its mutants in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

Inhibition of GPR84 (or its mutants) activity in biological samples is suitable for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and bioassay.

Another embodiment of the invention relates to a method for inhibiting GPR84 activity in a patient, the method comprising the step of administering the compound of the invention or a composition comprising the compound to the patient.

According to another embodiment, the present invention relates to a method for inhibiting the activity of GPR84 or its mutants in a patient, the method comprising the step of administering a compound of the present invention or a composition comprising the compound to the patient. According to some embodiments, the present invention relates to a method for reversibly or irreversibly inhibiting one or more of GPR84 or its mutants in a patient, the method comprising the step of administering a compound of the present invention or a composition comprising the compound to the patient. In other embodiments, the present invention provides a method for treating a condition mediated by GPR84 or its mutants in a patient in need, the method comprising the step of administering a compound of the present invention or a pharmaceutically acceptable composition thereof to the patient. Such conditions are described in detail herein.

Depending on the specific ailment or disease to be treated, additional therapeutic agents typically used to treat said ailment may also be present in the compositions of the present invention. As used herein, additional therapeutic agents typically used to treat a specific ailment or disease are referred to as “the ailment or disease to be treated”.

The compounds of the present invention can also be used in combination with other therapeutic compounds for an advantageous position. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-proliferative antimetabolites; platinum compounds; compounds that target/reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparinase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematologic malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors, such as those from Conforma. Therapeutics' 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; temozolomide kinin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and formyltetrahydrofolate. As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, such as the conversion of substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane; and particularly non-steroids, particularly aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letr ozole. Exemestane is marketed under the brand name Aromasin ^™ . Formestane is marketed under the brand name Lentaron™ ^{. Fadrozole is marketed under the brand name Afema™ .} Anastrozole is marketed under the brand name Arimidex ^™ . Letrozole is marketed under the brand names Femara ^™ or Femar ^™ . Aminoglutethimide is marketed under the brand name Orimeten ^™ . Combinations of the present invention containing chemotherapeutic agents as aromatase inhibitors are particularly suitable for treating hormone receptor-positive tumors, such as breast tumors.

As used herein, the term "anti-estrogenic" refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, ranoxifene, and ranoxifene hydrochloride. Tamoxifen is marketed under the brand name Nolvadex ^™ . Ranoxifene hydrochloride is marketed under the brand name Evista ^™ . Fulvestrant can be administered under the brand name Faslodex ^™ . Combinations of the present invention comprising chemotherapeutic agents as anti-estrogens are particularly suitable for treating estrogen receptor-positive tumors, such as breast tumors.

As used herein, the term "anti-androgen" refers to any substance capable of inhibiting the biological effects of androgens, and includes, but is not limited to, bicalutamide (Casodex ^™ ). The term "gonadotropin-releasing hormone agonist" as used herein includes, but is not limited to, abalex, goserelin, and goserelin acetate. Goserelin can be administered under the brand name Zoladex ^™ .

As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecian and the macrocamptothecian conjugate PNU-166148. Irinotecan may be administered, for example, in its marketed form, such as under the trademark Camptosar ^™ . Topotecan is marketed under the trade name Hycamptin ^™ .

As used herein, the term "topoisomerase II inhibitor" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx ^™ ), doxorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones mitoxantrone and losoxantrone; and podophyllotoxins etoposide and teniposide. Etoposide is marketed under the brand name Etopophos ^™ . Teniposide is marketed under the brand name VM 26-Bristol. Doxorubicin is marketed under the brand names Acriblastin ^™ or Adriamycin ^™ . Epirubicin is marketed under the brand name Farmorubicin ^™ . Idarubicin is marketed under the brand name Zavedos ^™ . Mitorubicin is marketed under the brand name Novantron.

The term "microtubule activator" refers to microtubule stabilizing, microtubule destabilizing, and microtubule polymerization inhibitors, including but not limited to taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vincaine or vinca sulfate, vincristine or vinca sulfate and vinorelbine; discormolide; colchicine and epothilone and their derivatives. Paclitaxel is marketed under the trade name Taxol ^™ . Docetaxel is marketed under the trade name Taxotere ^™ . Vinca sulfate is marketed under the trade name Vinblastin RP ^™ . Vinca sulfate is marketed under the trade name Farmistin ^™ .

As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin ^™ . Ifosfamide is marketed under the trade name Holoxan ^™ .

The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylases and have antiproliferative activity. This includes, but is not limited to, succinyl aniline oxime acid (SAHA).

The term "anti-metabolic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (such as 5-azacytidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (such as pemetrexed). Capecitabine is marketed under the brand name Xeloda ^™ . Gemcitabine is marketed under the brand name Gemzar ^™ .

As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin, and oxaliplatin. Carboplatin may be administered, for example, in its marketed form, such as under the trademark Carboplat ^™ . Oxaliplatin may be administered, for example, in its marketed form, such as under the trademark Eloxatin ^™ .

As used herein, the term "compounds that target/reduce the activity of protein or lipid kinases, or protein or lipid phosphatases; or other anti-angiogenic compounds" includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as: a) compounds that target, reduce, or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, reduce, or inhibit the activity of PDGFR, especially compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidinylamine derivatives, such as imatinib, SU101, SU6668, and GFB-111; b) compounds that target, reduce, or inhibit the activity of fibroblast growth factor receptor (FGFR). c) Compounds that target, reduce, or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce, or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factor; d) Compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or apirelin B4 inhibitors; e) Compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; f) Compounds that target, reduce, or inhibit the activity of Ret receptor tyrosine kinase; g) Compounds that target, reduce, or inhibit the activity of Kit/SCFR receptor tyrosine kinase, such as imatinib; h) Compounds that target, reduce, or inhibit the activity of c-kit receptor tyrosine kinases, wherein the c-kit receptor tyrosine kinase is part of the PDGFR family, such as compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, particularly compounds that inhibit c-Kit receptors, such as imatinib; i) compounds that target, reduce, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase), and mutants, such as compounds that target, reduce, or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidinylamine derivatives, such as imatinib or nilotinib (AMN4107) from Parke Davis. PD180970, AG957, NSC680410, PD173955; or dasatinib (BMS-354825); j) compounds that target, reduce, or inhibit the activity of serine/threonine kinases, members of the protein kinase C (PKC) and Raf family, MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK, and TEC family and/or members of the cyclin-dependent kinase family (CDK), including astrocytocin derivatives such as midostaurin; other examples include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) Compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec ^™ ) or tyrosine phosphorylation inhibitors (Tyrphostin), such as tyrosine phosphorylation inhibitors A23/RG-50810; AG 99; tyrosine phosphorylation inhibitor AG213; tyrosine phosphorylation inhibitor AG 1748; Tyrosine phosphorylation inhibitor AG 490; Tyrosine phosphorylation inhibitor B44; Tyrosine phosphorylation inhibitor B44(+) enantiomer; Tyrosine phosphorylation inhibitor AG 555; AG 494; Tyrosine phosphorylation inhibitors AG 556, AG 957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino)-adaphostin benzoate; NSC 680410, adaphostin); l) Compounds that target, reduce or inhibit the activity of the epidermal growth factor family (EGFR ₁ ErbB2, ErbB3, ErbB4, in homodimer or heterodimer form) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially those that inhibit EGF receptor tyrosine kinase family members such as EGF receptor, ErbB2, ErbB3 and ErbB4 or EGF or EGF-associated ligand CP. Compounds, proteins, or antibodies bound to 358774, ZD1839, and ZM 105180; trastuzumab (Herceptin ^™ ), cetuximab (Erbitux ^™ ), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, or E7.6.3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, reduce, or inhibit the activity of c-Met receptors, such as compounds that target, reduce, or inhibit the activity of c-Met, especially those that inhibit the kinase activity of c-Met receptors. Compounds that target the extracellular domain of c-Met or antibodies that bind to HGF; n) compounds that target, reduce, or inhibit the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG -101348, tofacitmib and ruxolitinib; o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL -719, dactolisib, XL-147, XL-765 and idelalisib; and q) compounds that target, reduce or inhibit signal transduction of the hedgehog protein (Hh) or smooth receptor (SMO) pathway, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors suitable for use in this invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupazoxib, picotecoxib, PF-4691502, BYL-719, dartoxib, XL-147, XL-765, and adelali.

As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including but not limited to AVL-292 and ibrutinib.

As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds with inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, AB%737, apogossypol, pan-Bcl-2 inhibitors of Ascenta, curcumin (and its analogues), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), and Genase. The following compounds are listed: nse)(G3139), HA14-1 (and its analogues; see WO2008118802), navitoclax (and its analogues, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogues, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptide mimic.

Other examples of BTK inhibitory compounds and diseases that can be treated by combination of such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

Other examples of SYK inhibitory compounds and diseases that can be treated by combination of such compounds with compounds of the present invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

Other examples of PI3K inhibitory compounds and diseases that can be treated by combination of such compounds with compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WP2002088112, WP2007084786, WP2007129161, WP2006122806, WP2005113554 and WP2007044729, the entire contents of which are incorporated herein by reference.

Other examples of JAK inhibitory compounds and diseases that can be treated by combination of such compounds with compounds of the present invention can be found in WP2009114512, WP2008109943, WP2007053452, WP2000142246 and WP2007070514, the entire contents of which are incorporated herein by reference.

Other anti-angiogenic compounds include those with a different mechanism of activity (e.g., independent of protein or lipid kinase inhibition), such as thalidomide (Thalomid ^™ ) and TNP-470.

Examples of proteasome inhibitors suitable for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), halosporin A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases include, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors, or CDC25 inhibitors, such as okadaic acid or its derivatives.

Compounds that induce cell differentiation include, but are not limited to, retinoic acid, α-tocopherol, γ-tocopherol or δ-tocopherol, or α-tocotrienol, γ-tocotrienol or δ-tocotrienol.

As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex ^™ ), rofecoxib (Vioxx ^™ ), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2′-chloro-6′-fluoroaniline)phenylacetic acid, lumiracoxib.

As used herein, the term "bisphosphonate" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos ^™ . Tiludronic acid is marketed under the trade name Skelid ^™ . Pamidronic acid is marketed under the trade name Aredia ^™ . Alendronic acid is marketed under the trade name Fosamax ^™ . Ibandronic acid is marketed under the trade name Bondranat ^™ . Risedronic acid is marketed under the trade name ^{Actonel™ .} Zoledronic acid is marketed under the trade name Zometa ^™ . The term “mTOR inhibitor” refers to compounds that inhibit mammalian rapamycin target (mTOR) and have antiproliferative activity, such as sirolimus everolimus (Certican ^™ ), CCI-779, and ABT578.

As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

As used herein, the term "inhibitor of Ras oncogenic isoforms" (e.g., H-Ras, K-Ras, or N-Ras) refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors," such as L-744832, DK8G557, or R115777 (Zamestra ^™ ). The term "telomerase inhibitor," as used herein, refers to compounds that target telomerase, reduce, or inhibit its activity. Compounds that target telomerase, reduce, or inhibit its activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets methionine aminopeptidase and reduces or inhibits its activity. Compounds that target methionine aminopeptidase and reduce or inhibit its activity include, but are not limited to, bengamide or its derivatives.

As used herein, the term "proteasome inhibitor" refers to a compound that targets the proteasome and reduces or inhibits its activity. Compounds that target, reduce, or inhibit proteasome activity include, but are not limited to, bortezomib (Velcade ^™ ) and MLN341.

As used herein, the term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) includes, but is not limited to, collagen peptide mimics and non-peptide mimics, tetracycline derivatives, such as the hydrooxaloyl ester peptide mimics inhibitor batimastat and its oral bioavailable analogues marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

As used herein, the term "compound for the treatment of hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arasulfuran cytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, reduce or inhibit polymorphic lymphoma kinase and Bcl-2 inhibitors.

Compounds that target the FMS-like tyrosine kinase receptor (Flt-3R), reduce or inhibit its activity, especially compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, astrocytocin derivatives, SU11248 and MLN518.

As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity, particularly compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldmycin (17AAG) (a geldmycin derivative); other geldmycin-related compounds; radicicol; and HDAC inhibitors.

As used herein, the term "antiproliferative antibody" includes, but is not limited to, trastuzumab (Herceptin ^™ ), trastuzumab-DM1, erbitux, bevacizumab (Avastin ^™ ), rituximab PRO64553 (anti-CD40), and 2C4 antibody. Antibody means intact monoclonal antibody, polyclonal antibody, multispecific antibody formed from at least two intact antibodies, and antibody fragments, provided they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly those for the treatment of AML. Specifically, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and/or other drugs suitable for the treatment of AML, such as donomycin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, and PKC412. In some embodiments, the present invention provides a method of treating AML associated with ITD and/or D835Y mutations, the method comprising administering the compounds of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), astrocytocin derivatives (e.g., midotulin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midotulin, lestaurtinib, sorafenib, and sunitinib.

Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2′-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogues of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Histone deacetylase (HDAC) inhibitors, such as sodium butyrate and salinomycin oxime acid (SAHA), and compounds that reduce or inhibit their activity, inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A, and compounds disclosed in US 6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, especially lactates. Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damage methods refer to methods such as ionizing radiation. The term "ionizing radiation" as used above and below means ionizing radiation occurring in the form of electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha particles and beta particles). Ionizing radiation is provided in, but not limited to, radiotherapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, eds. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

This also includes EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C to resist ALL), and/or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

This also includes, in particular, compounds, proteins, or monoclonal antibodies against VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof; 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin ^™ ; Endostatin ^™ ; o-aminobenzoic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab; VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin ^™ ).

As used in this article, photodynamic therapy refers to the use of certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatments using compounds such as Visudyne ^™ and porfimer sodium.

As used in this article, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as anecocave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, estrone, and dexamethasone.

Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or hybrid compounds or compounds with other or unknown mechanisms of action.

The compounds of this invention are also suitable as adjunctive therapeutic compounds for use in combination with other drugs, such as anti-inflammatory drugs, bronchodilators, or antihistamines, particularly for the treatment of obstructive or inflammatory airway diseases, such as those mentioned above, for example, as therapeutic enhancers of such drugs or as a method of reducing the required dosage or potential side effects of such drugs. The compounds of this invention can be mixed with other active pharmaceutical ingredients in a fixed pharmaceutical composition or can be administered alone before, simultaneously with, or after other active pharmaceutical ingredients. Therefore, this invention includes combinations of the compounds of this invention as described above with anti-inflammatory, bronchodilator, antihistamine, or antitussive pharmaceutical substances, wherein the pharmaceutical compositions of the compounds and the pharmaceutical substances of this invention may be the same or different.

Suitable anti-inflammatory drugs include steroids, especially glucocorticoids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; and LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, and SC-53228. BIIL 284, ONO 4057, SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast (GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-P1ough), Arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM)CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists, such as salbutamol (hydroxymethyltert-butyladrenergic), mesoproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and their pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxytropium bromide, tiotropium salts, and CHF 4226 (Chiesi) and glycopyrrolate.

Suitable antihistamine active pharmaceutical ingredients include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefenadine.

Other suitable combinations of the compounds of the present invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-hydro-2-(4-methylphenyl)-5H-benzo-cycloheptene-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

The structures of active compounds identified by code number, class, or trade name can be obtained from the official standard summary "The Merck Index" or from databases such as Patents International (e.g., IMS World Publications).

Exemplary immuno-oncology agents

In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that effectively enhances, stimulates, and/or upregulates the immune response of a subject. In some embodiments, the immuno-oncology agent, when administered together with the compounds of the present invention, has a synergistic effect in the treatment of cancer.

Immuno-oncology agents can be, for example, small molecule drugs, antibodies, or biomolecules or small molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized or human antibody.

In some implementations, immuno-oncology agents are (i) agonists that stimulate (including co-stimulate) receptors or (ii) antagonists that inhibit (including co-inhibitory) signals on T cells, both of which induce an amplified antigen-specific T cell response.

Some stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family, which binds to molecules that are members of the homologous TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, and RANKL. , TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, ITβR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3 , EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

In some implementations, immuno-oncology agents are cytokines that inhibit T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or cytokines that stimulate T cell activation to stimulate an immune response.

In some embodiments, the combination of the compounds of the present invention with immuno-oncology agents can stimulate T cell responses. In some embodiments, the immuno-oncology agents are: (i) antagonists (e.g., immune checkpoint inhibitors) of proteins that inhibit T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galactoglobulin 9, CEACAM-1, BTLA, CD69, galactoglobulin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

In some embodiments, the immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonist of activating receptors on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirilumab.

In some implementations, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonistic antibodies, including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249, WO13169264, WO14/036357).

In some embodiments, immuno-oncology agents are selected from agonists that link positive costimulatory receptors; blockers that attenuate signal transduction by inhibiting receptors, antagonists, and one or more agents that systematically increase the frequency of anti-tumor T cells; agents that overcome unique immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1/PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., dalizumab) or by depletion via in vitro anti-CD25 beads), inhibiting metabolic enzymes such as IDO, or reversing/preventing T cell energy or depletion); and agents that trigger innate immune activation and/or inflammation at the tumor site.

In some implementations, the tumor immunotherapy agent is a CTLA-4 antagonist. In some implementations, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some implementations, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or its antigen-binding moiety that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein, termed AMP-224, composed of the fusion of the extracellular domain (B7-DC) of PD-L2 and the Fc moiety of IgG1.

In some embodiments, the tumor immunotherapy agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).

In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218) or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12/32433).

In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116) or MK-4166 (WO11/028683).

In some implementations, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some implementations, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS: F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); kynuronine-degrading enzymes (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonist CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonist CD40 antibody. In some embodiments, the CD40 antibody is lucarumumab or dacetuzumab.

In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

In some implementations, the immuno-oncology agent is MGA271 (targeting B7H3) (WO11/109400).

In some implementation schemes, immuno-oncology agents include abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimusab, avelumab, bonatetumab, BMS-936559, catumaxomab, durvalumab, icardostat, epratuzumab, indomod, and others. Inotuzumab, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, olatatumab, pembrolizumab, rituximab, ticilimumab, samalizumab, or trimetumab.

In some implementations, immuno-oncology agents are immunostimulants. For example, antibodies that block the PD-1 and PD-L1 inhibitory axes release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses and increase the number of tumor tissue structures, including some tumor types not conventionally considered sensitive to immunotherapy. See, for example, Okazaki, T. et al., (2013) Nat. Immunol. 14, 1212, 1218; Zou et al., (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who experience disease progression during or after prior anti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis in tumor cells. Approved immunomodulatory therapeutic agents that can be used in this invention include pomalidomide (Celgene); lenalidomide (Celgene); and ingenol mebutate (LEO Pharma).

In some implementations, the tumor immunotherapy agent is a cancer vaccine. In some implementations, the cancer vaccine is selected from sipuleucel-T (Den dreon/Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene lahe rparepvec (BioVex/Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodular lesions of melanoma. In some implementations, the immuno-oncology agent is selected from oncolytic virus therapies, such as pexastimogenedevacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-)-deficient vaccinia virus engineered to express GM-CSF for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); and Oncolytics. Biotech, a respiratory enteric-coated orphan virus variant (reovirus), which does not replicate in RAS-unactivated cells in a wide range of cancers, including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT00861627); Enasire (NG-348, PsiOxus, formerly known as ColoAd1), an engineered variant for use in ovarian cancer ( NCT02028117), an adenovirus that expresses full-length CD80 and antibody fragments specific to the T-cell receptor CD3 protein in metastatic or advanced epithelial tumors, such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland carcinoma (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676) and peritoneal diseases, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC 1 (GLV-1h68/GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal)/β-glucuronidase or β-gal/human sodium iodide transporter (hNIS), respectively, in peritoneal carcinoma (NCT01443260), fallopian tube cancer, and ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

In some implementations, the immuno-oncology agents are selected from JX-929 (SillaJen/formerly JennerexBiotherapeutics), a vaccinia virus engineered to express cytosine deaminase lacking TK and vaccinia growth factor, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapeutic agents targeting refractory RAS mutations; and TILT-123 (TILTBiotherapeutics), an engineered adenovirus named Ad5/3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to produce antigen-specific CD8 ⁺ T cell responses.

In some implementations, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor, or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

A CAR has been constructed that consists of a binding domain derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for cell surface antigens, and an intracellular domain serving as the functional terminus of the T cell receptor (TCR), such as a CD3-ζ signaling domain from the TCR capable of generating activation signals in T lymphocytes. Upon antigen binding, this type of CAR links to endogenous signaling pathways in effector cells and generates activation signals similar to those induced by the TCR complex.

For example, in some embodiments, the CAR-T cells are those described in U.S. Patent 8,906,682 (June et al.; hereby incorporated in its entirety by reference), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (e.g., a domain that binds to CD19) and an intracellular signaling domain fused to the ζ chain of the T cell antigen receptor complex (e.g., CD3ζ). When expressed in T cells, the CAR is able to redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, more than 200 clinical trials using CAR-T in various indications are underway. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, the immunostimulant is an activator of retinoic acid receptor-associated orphan receptor γ (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of IL-17-expressing innate immune cell subsets (e.g., NK cells). In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in a clinical trial for the treatment of solid tumors (NCT02929862).

In some embodiments, the immunostimulant is an agonist or activator of a Toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG being investigated for use in B-cell lymphoma, follicular lymphoma, and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in this invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being investigated for use in head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

Other immuno-oncology agents that can be used in this invention include varlilumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; and lirilumab (IPH2102/BMS-9). 86015 (Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; molizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

In some implementations, the immunostimulant is selected from elotuzumab, mifamurtide, agonists or activators of Toll-like receptors, and activators of RORγt.

In some embodiments, the immunostimulatory agent is recombinant human interleukin-15 (rhIL-15). rhIL-15 has been tested clinically as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulator is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunostimulator is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex (IL15: sIL-15RA) consisting of a synthetic form of endogenous IL-15 and the α chain of the soluble IL-15-binding protein IL-15 receptor, which has been tested in a phase 1 clinical trial for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some implementations, recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

In some embodiments, the immuno-oncology agent is selected from the immuno-oncology agents described in Jerry L. Adams et al., “Bigopportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule targeting immuno-oncology targets selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the tumor immunotherapy agent is a small molecule agent selected from the small molecule agents listed in Table 2 of Jerry L. Adams et al.

In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent that targets pathways as described in Peter L. Toogood.

In some embodiments, the immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T-cell engaging rantibody constructs can immediately by standard tumor cell killing,” PLoS ONE 12(8): e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T-cell engaging rantibody construct. In some embodiments, the bispecific T-cell engaging rantibody construct is a CD19/CD3 bispecific antibody construct. In some embodiments, the bispecific T-cell engaging rantibody construct is an EGFR/CD3 bispecific antibody construct. In some embodiments, the bispecific T-cell engaging rantibody construct activates T cells. In some embodiments, the bispecific T-cell engaging rantibody construct activates T cells, which release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on neighboring cells. In some embodiments, a bispecific T-cell conjugate antibody construct activates T cells, leading to induced lysis of neighboring cells. In some embodiments, the neighboring cells are in a solid tumor. In some embodiments, the lysed neighboring cells are adjacent to the activated T cells. In some embodiments, the neighboring cells contain tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the neighboring cells contain EGFR-negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1/PD1 axis and/or CTLA4. In some embodiments, the immuno-oncology agent is ex vivo expanded tumor-infiltrating T cells. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAAs).

Exemplary immune checkpoint inhibitors

In some implementations, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

As used in this article, the term "checkpoint inhibitor" refers to agents designed to prevent cancer cells from evading a patient's immune system. One of the main mechanisms of antitumor immune destruction is called "T-cell exhaustion," which is caused by prolonged exposure to antigens that induce upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuation factor (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223), and other receptors are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to indicate whether cell cycle progression and other intracellular signaling processes will continue.

In some implementations, the immune checkpoint inhibitor is an antibody against PD-1. PD-1 binds to the planned cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby suppressing the tumor's ability to suppress the host's anti-tumor immune response.

In some embodiments, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a whole-human antibody, a fusion protein, or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits checkpoint proteins selected from the following: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with ligands selected from the following checkpoint proteins: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some embodiments, the checkpoint inhibitor is an immunostimulant, T-cell growth factor, interleukin, antibody, vaccine, or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits a suppressive pathway of the immune system in a statistically significant manner. Such inhibitors may include small molecule inhibitors or may include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blockade or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 molecule family and expressed on all NK, γδ, and memory CD8 ⁺ (αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or their antigen-binding fragments, other binding proteins, biological therapeutics, or small molecules that bind to and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, tramemumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

In some embodiments, the immune checkpoint inhibitor is selected from PD-1 antagonists, PD-L1 antagonists, and CTLA-4 antagonists. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab, ipilimumab, and pembrolizumab. In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Merck); ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Genentech).

In some implementations, the checkpoint inhibitors are selected from the group consisting of: lanizumab (MK-3475), nivolumab (BMS-936558), pilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirelizumab, IPH2101, pembrolizumab, and trametumab.

In some implementations, the immune checkpoint inhibitors are REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); and pilithumab (CureTech), also known as CT-011, a drug in clinical trials for diffuse large B-cell lymphoma and... Antibodies that bind to PD-1 for multiple myeloma; Averuma (Pfizer/Merck KGaA, also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody used in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, kidney cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1 used in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Trimetazaprine (CP-675, 206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been investigated in clinical trials for multiple indications, including: mesothelioma, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, non-small cell lung cancer, pancreatic duct adenocarcinoma, pancreatic cancer, germ cell carcinoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic liver cancer, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic undifferentiated thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody investigated in a phase 1 clinical trial for advanced solid tumors (NCT02694822).

In some embodiments, the checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors available in this invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody studied in advanced malignant disease (NCT02608268).

In some embodiments, the checkpoint inhibitor is an inhibitor of a T-cell immune receptor having an Ig domain and an ITIM domain, or of TIGIT (an immune receptor on certain T cells and NK cells). TIGIT inhibitors that can be used in this invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and an anti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in this invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, has been studied in glioblastoma and glioma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and has been studied in malignant diseases (NCT03005782). IMP321 (Immutcp S.A.) is a LAG-3-Ig fusion protein and has been studied in melanoma (NCT02676869), adenocarcinoma (NCT02614833), and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that can be used in this invention include OX40 agonists. OX40 agonists investigated in clinical trials include: PF-04518600/PF-8600 (Pfizer), an agonist anti-OX40 antibody in metastatic renal cell carcinoma (NCT03092856) and advanced cancer and necrozoomas (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonist anti-OX40 antibody in a phase 1 cancer trial (NCT02528357); and MEDI0562 (Medimmune/AstraZeneca), an antibody in advanced solid tumors (NCT0231839). 4. Active anti-OX40 antibody in NCT02705482; MEDI6469, active anti-OX40 antibody in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705) (Medimmune/AstraZeneca); and BMS-986178 (Bristol-Myers Squibb), active anti-OX40 antibody in advanced cancer (NCT02737475).

Checkpoint inhibitors that can be used in this invention include CD137 (also known as 4-1BB) agonists. CD137 agonists currently being investigated in clinical trials include utomilumab (PF-05082566, Pfizer), an agonist anti-CD137 antibody in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and lesions (NCT02554812 and NCT05082566); utomilumab (BMS-663513, Bristol-Myers Squibb), an agonist anti-CD137 antibody in melanoma and skin cancer (NCT02652455) and glioblastoma and glioma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonist anti-CD137 antibody in metastatic or locally advanced malignant disease (NCT03881488).

Checkpoint inhibitors that can be used in this invention include CD27 agonists. CD27 agonists investigated in clinical trials include: valimumab (CDX-1127, CelldexTherapeutics), an agonistic anti-CD27 antibody in head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

Checkpoint inhibitors that can be used in this invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists investigated in clinical trials include: TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody in solid tumors and lymphoma (NCT 02740270); and INCAGN01876 (Incyte/Age). The following are listed: activating anti-GITR antibodies in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), activating anti-GITR antibody in solid tumors (NCT02132754); and MEDI1873 (Medimmune/AstraZeneca), an activating hexameric GITR-ligand molecule with a human IgG1 Fc domain in advanced solid tumors (NCT02583165).

Checkpoint inhibitors that can be used in this invention include inducible T-cell co-stimulatory (ICOS, also known as CD278) agonists. ICOS agonists investigated in clinical trials include: MEDI-570 (Medimmune), an agonistic anti-ICOS antibody in lymphoma (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody in phase 1 (NCT02723955); and JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody in phase 1 (NCT02904226).

Checkpoint inhibitors that can be used in this invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include: lireuromab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti-KIR antibody in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody (KIR3DL2) that binds to three domains of the long cytoplasmic tail region in lymphoma (NCT02593045).

Checkpoint inhibitors that can be used in this invention include CD47 inhibitors that address the interaction between CD47 and signal regulatory protein α (SIRPa). CD47/SIRPa inhibitors investigated in clinical trials include: ALX-148 (AlexoTherapeutics), an antagonistic variant of SIRPa that binds to CD47 and prevents CD47/SIRPa-mediated signal transduction in a phase 1 trial (NCT03013218); and TTI-621 (SIRPa-Fc, TrilliumTherapeutics), which, in phase 1 clinical trials (NCT02890368 and NCT02663518), binds to the N-terminal CD47-binding domain of SIRPa and... A soluble recombinant fusion protein produced by the Fc domain of human IgG1, which functions by binding to human CD47 and preventing it from delivering its "do not eat" signal to macrophages; CC-90002 (Celgene), an anti-CD47 antibody in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal cysts and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

Checkpoint inhibitors that can be used in this invention include CD73 inhibitors. CD73 inhibitors investigated in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

Checkpoint inhibitors that can be used in this invention include agonists of interferon gene-stimulating protein (STING, also known as transmembrane protein 173 or TMEM173). Agonists of STING investigated in clinical trials include: MK-1454 (Merck), an agonist of synthetic cyclic dinucleotides in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonist of synthetic cyclic dinucleotides in phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that can be used in this invention include CSF1R inhibitors. CSF1R inhibitors investigated in clinical trials include: pexidartinib (PLX3397, Plexxikon), a small molecule CSF1R inhibitor in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710), as well as melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855). Lilly), an anti-CSF-1R antibody in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and Novartis, an orally effective inhibitor of CSF1R in advanced solid tumors (NCT02829723).

Checkpoint inhibitors that can be used in this invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors investigated in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody in head and neck sarcoma (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

In some implementations, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pilizumab.

The compounds of the present invention can also be used in combination with known treatment methods (e.g., administration of hormones or radiation). In some embodiments, the provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

The compounds of this invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of a fixed combination or alternating or independent administration of the compounds of this invention and one or more other therapeutic compounds, or a fixed combination combined with one or more other therapeutic compounds. Furthermore, the compounds of this invention may be combined with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly for oncology. As described above, long-term therapy is also possible, similar to adjuvant therapy in the context of other treatment strategies. Other possible treatments include maintenance therapy after tumor regression, or even chemopreventive therapy (e.g., for patients at risk).

These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of the present invention to form a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or at intervals between each other (typically within five hours).

As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the invention. For example, the compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in a single unit dosage form or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising the compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

The amounts of the compounds of the invention that can be combined with a carrier substance to produce a single dosage form and additional therapeutic agents (in those compositions containing additional therapeutic agents as described above) will vary depending on the host being treated and the specific administration method. Preferably, the compositions of the invention should be formulated such that the compounds of the invention can be administered at a dose between 0.01 and 100 mg/kg body weight/day.

In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention can act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions will be less than that required in a single therapy using only the therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dose between 0.01 and 1,000 μg/kg body weight/day.

The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would normally be applied in the form of a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed in the present invention will be in the range of about 50% to 100% of the amount normally present in a composition containing said pharmaceutical agent as the sole active agent.

The compounds of the present invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Intravascular stents have been used, for example, to overcome restenosis (restriction of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a GPR84 inhibitor. Implantable devices coated with the compounds of the present invention are another embodiment of the invention.

example

As depicted in the following examples, in some exemplary embodiments, the compounds are prepared according to the following general procedure. It should be understood that while the general approach describes the synthesis of certain compounds of the present invention, the following general approach and other methods known to those skilled in the art can be applied to all compounds as described herein and to subclasses and types of each of these compounds. Other compounds of the present invention are prepared by methods substantially similar to those described in the examples herein and by methods known to those skilled in the art.

General Information: All evaporations were performed in vacuum using a rotary evaporator. Samples were dried for analysis in vacuum (1–5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, with spots observed under UV light (214 and 254 nm). Column and rapid chromatography purification was performed using silica gel (200–300 mesh). Solvent systems are reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. ¹H chemical shifts are reported as δ values (ppm), with deuterated solvents used as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad peak, m = multiplet), coupling constant (Hz), and integral value. LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization, and unless otherwise specified, the general LCMS conditions were as follows: Waters X Bridge C18 column (50 mm * 4.6 mm * 3.5 μm); flow rate: 2.0 mL/min; column temperature: 40 °C.

*Other methods:

“A” = Acquity BEH C18 1.7μm column (2.1nn x 50mm); flow rate: 0.8mL/min, column temperature: 50℃. Elute with MeCN containing 0.1% TFA in water containing 0.1% TFA; 1% to 100% in 5 min.

"B" = same column and flow rate in "A". Elute with MeCN in 10 mM ammonium acetate aqueous solution; 0 to 100% over 5 min.

“C” = CSH C18, 3.5 μm column (4.6 mm x 30 mm); flow rate: 0.8 mL/min, column temperature: 40 °C. Elution with MeCN in 10 mM ammonium formate aqueous solution; 5% MeCN for 0.5 min, 5% to 100% MeCN for 5 min; maintain 100% MeCN for 1.5 min.

General Procedure A (Formation of Triazole Derivatives from Acylhydrazides and Primary Amines): An amine hydrochloride (1.0 equivalent) was added to a mixture of 4-methyl-N′-(1-phenylethylene)benzenesulfonylhydrazide (1.0 equivalent), Cu(OAc) _₂ (2.0 equivalent), NaOAc (2.0 equivalent), and N-acetylglycine (2.0 equivalent) in toluene. The reaction mixture was stirred at 110 °C for 24 hours until complete (by LCMS). The suspension was diluted with _H₂O and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired triazole intermediate.

General Procedure B (cyclization reaction, yielding triazole derivatives via click reaction): Sodium ascorbate (0.2 equivalents) was added to a solution of _CuSO₄ · _5H₂O (0.05–0.1 equivalents) in water. The resulting mixture was added to a solution of terminal alkyne (1.0 equivalent) and alkyl azide (1.5 equivalent) in DMF. The reaction mixture was stirred overnight at room temperature, then diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by preparative TLC to obtain the desired triazole intermediate.

General Procedure C (Formation of Alkyl Azide Derivatives from Primary/Secondary Alcohols): Sodium azide (1.2 equivalents) is added to a solution of primary/secondary alcohol (1.0 equivalents) in DMSO. The reaction mixture is heated to 50–90 °C for 24 hours until the reaction is complete (by LCMS), then cooled to room temperature, diluted with water, and extracted with dichloromethane. The combined organic phases are washed with water and brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness to give the desired alkyl azide, which is used directly in the next step.

General Procedure D (Formation of Alkyl Azide Derivatives from Primary Amines): _K₂CO₃ (2.0 equivalents), CuSO₄ _{· 5H₂O} (0.2 equivalents), and imidazole-1-sulfonyl azide hydrochloride (1.0 equivalent) were added to a solution of primary _amine (1.0 equivalent) in MeOH. The reaction mixture was stirred at room temperature for 5 h. After depletion of the starting material (by LCMS), water was added, and the reaction mixture was extracted with ethyl acetate, washed with water, dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired alkyl azide intermediate.

General Procedure E (formation of terminal alkynes via Seyferth-Gilbert homologation): A mixture of aldehyde (1.0 equivalent), dimethyl 1-diazo-2-oxopropylphosphonate (1.1 equivalent), and potassium carbonate (2.0 equivalent) in methanol was stirred at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated to dryness. The crude product was purified by C.C. to obtain the desired terminal alkyne intermediate.

General Procedure F (Pogostemon cablin coupling, Method 1): K₂CO₃ (2.0 equivalents) was added to a mixture of aromatic bromide/iodide (1.0 equivalents), ethynylcyclopropane (2.0–6.0 equivalents), X-phos (0.1 equivalents), and bis(acetonitrile)dichloropalladium(II) (0.1 equivalents) in acetonitrile. The reaction mixture was heated to ₉₀ ° _C overnight until complete (by LCMS), then cooled to room temperature, diluted with water, and extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by cc and preparative HPLC to obtain the desired product.

General Procedure G (Pogostemon cablin coupling, Method 2): PdCl₂(PPh₃ _)₂ (0.1 equivalent) and CuI (0.05–0.10 equivalent) were added to a stirred solution of aromatic bromide/iodide (1.0 equivalent), ethynylcyclopropane ( _2.0–6.0 equivalent), and _TEA (5.0 equivalent) in DMF. The reaction mixture was stirred at 80 °C for 16 hours until complete (by LCMS), then cooled to room temperature, diluted with water, and extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by cc and preparative HPLC to obtain the desired product.

General Procedure H (Suzuki Coupling): Pd(dppf)Cl₂ (0.1 equivalent) was added to a stirred solution of aromatic bromide (1.0 equivalent), boric acid/boronic acid ester ( _1.2–1.5 equivalent), and _K₂CO₃ (2.0 equivalent) in _dioxane . The reaction mixture was stirred at 100 °C for 5 hours until complete (by LCMS), then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by preparative HPLC to obtain the desired product.

General Procedure I: (Buchwald Coupling): Pd₂(dba)₃ (0.1 equivalent) and Cs₂CO₃ (3.0 equivalent) were added to a stirred solution of aromatic bromide/iodide (1.0 equivalent), _3,3- dimethylazine hydrochloride (1.5 equivalent), _BINAP (0.1 equivalent), and _X -Phos (0.1 equivalent) in DMF. The reaction mixture was stirred at ₁₀₀ °C for 16 hours until complete (by LCMS), then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude material was purified by preparative HPLC to obtain the desired product.

General Procedure J: (Esterification of alcohol derivatives to methanesulfonates with _Ms₂O ): _Ms₂O (1.5 equivalents) is added to a solution of alcohol derivative (1.0 equivalents) and _Et₃N (3.0 equivalents) in DCM at 0°C. The mixture is stirred at room temperature for 30 to 90 minutes, then quenched with water and extracted with DCM. The combined organic phases are washed with water and brine, dried over anhydrous _{Na₂SO₄ ,} and concentrated to obtain crude methanesulfonates, which are used directly in the next step.

General procedure K: (replacing primary/secondary amines with methanesulfonate): Add _K₂CO₃ (3.0 equivalents) to a stirred solution of _{methanesulfonate} (1.0 equivalents) and primary/secondary amine (1.0 equivalents) in DMF. Stir the reaction mixture overnight at room temperature. Add _H₂O and EA, and collect the organic phase and evaporate under reduced pressure. Purify the residue by preparative HPLC to obtain the desired product.

Example 1: Synthesis of I-45

I-45 synthesis scheme

1. Synthetic intermediates 1.2

DIPEA (12.9 g, 100 mmol) and HATU (9.5 g, 25 mmol) were added to a solution of 1.1 (5.4 g, 25 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 15 min, then N,O-dimethylhydroxylamine hydrochloride (2.4 g, 25 mmol) was added and the mixture was stirred at room temperature for 2 h. After depletion of the starting material (by LCMS), water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with water (30 mL x ₃ ), dried over anhydrous _Na₂SO₄ , and concentrated. The crude product was purified by preparative HPLC to give 1.2 (4.0 g, 62% yield) as a yellow oil. LC-MS m/z: 258.11 [M+H] ^⁺ .

2. Synthetic intermediate 1.3

Ethyl magnesium bromide (2.0 M/THF, 15.5 mL, 31.0 mmol) was slowly added to a stirred solution of 1.2 (4.0 g, 15.6 mmol) in anhydrous THF (20 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h. Saturated _NH₄Cl (aqueous solution) was added and the mixture was extracted with EA (30 mL x 2). The organic layer was washed with water, dried over anhydrous _{Na₂SO₄ ,} and evaporated to dryness. The crude product was purified by preparative HPLC to give 1.3 (3.0 g, yield: 86%) as a yellow oil. LC-MS m/z: 227.1 [M+H] ^⁺ .

3. Synthetic intermediate 1.4

4-Methylbenzenesulfonylhydrazine (2.5 g, 13.3 mmol) was added to a solution of compound 1.3 (3.0 g, 13.3 mmol) in MeOH (20 mL). The mixture was stirred at room temperature for 12 hours. After the reaction was complete (by LC-MS), the mixture was concentrated to dryness. The crude product was purified by preparative HPLC to give 1.4 (3.0 g, 57% yield) as a white solid. LC-MS m/z: 395.31 [M+H] ⁺ .

4. Synthetic intermediate 1.5

To a stirred solution of 1.4 (1.0 g, 2.5 mmol), Cu(OAc) _₂ (0.90 g, 5.0 mmol), AcONa (0.40 g, 5.0 mmol), and N-acetylglycine (0.60 g, 5.0 mmol) in PhMe ( ₂₀ mL), (tetrahydro-2H-pyran-2-yl)methylamine hydrochloride (0.40 g, 2.5 mmol) was added. The reaction mixture was stirred at 110 °C for 24 h until complete (by LC-MS). The suspension was diluted with H₂O (20 mL) and extracted with EA (20 mL x 2), and the concentrated organic layers were combined. The crude product was purified by preparative HPLC to give 1.5 (0.40 g, yield: 46%) as a white solid. LC-MS m/z: 350.25 [M+H] ^⁺ .

5. Synthesize I-45

PdCl₂( _PPh₃ ) _{₂ (} 80 mg) and CuI (80 mg) were added to a stirred solution of 1.5 (0.40 g, 1.2 mmol), ethynylcyclopropane (0.30 g, 4 mmol), and TEA (0.50 g, 5 mmol) in DMF (5 mL). The reaction mixture was stirred at 80 °C for 16 hours until the reaction was complete (by LCMS). The suspension was diluted with _H₂O (20 mL) and extracted with EA (20 mL x 2), and the concentrated organic layers were combined. The crude product was purified by preparative HPLC to give I-45 (23 mg, yield: 6%) as a yellow oil.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 2: Characterization data of additional exemplary compounds

Example 2: Synthesis of I-315

I-315 synthesis scheme

1. Synthetic intermediate 2-Int-4

Sodium azide (1.5 g, 22 mmol) was added to a solution of compound 2-Int-2 (5.0 g, 18.5 mmol) in DMSO (20 mL). The reaction mixture was heated to 50 °C for 24 h and then cooled to room temperature, diluted with water (80 mL), and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with water (3 × 10 mL) and brine ( ₁₀ mL), dried over _Na₂SO₄ , and concentrated to dryness to give 2-Int-4 (2.6 g) as a brown oil. ¹ H NMR (400MHz, CDCl ₃ )δ: 3.99-4.06 (m, 1H), 3.41-3.52 (m, 2H), 3.24-3.32 (m, 1H), 3.16-3.22 (m, 1H), 1.83-1.91 (m, 1H), 1.45-1.62 (m, 4H), 1.30-1.40 (m, 1H).

2.2 Synthetic intermediates

A mixture of 2.1 (500 mg, 2.3 mmol), dimethyl 1-diazo-2-oxopropylphosphonate (482 mg, 2.5 mmol), and potassium carbonate (630 mg, 4.6 mmol) in methanol (5 mL) was stirred at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated to give 2.2 (450 mg, yield: 92%) as a grayish-white solid. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.59 (d, J = 1.2 Hz, 1H), 7.35–7.40 (m, 2H), 3.42 (s, 1H).

3. Synthetic intermediates 2.3

Sodium ascorbate (37 mg, 0.19 mmol) was added to a solution of CuSO₄ _{· 5H₂O} (24 mg, 0.096 mmol) in water (1 mL). The resulting mixture was added to a solution of compounds 2.2 (200 mg, 0.9 mmol) and 2.4 (197 mg, 1.4 mmol) in DMF (4 mL). The reaction mixture was stirred overnight at room temperature and then diluted with water (16 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with brine (10 _mL ), dried over _Na₂SO₄ , and concentrated to dryness. The crude product was purified by preparative TLC (petroleum ether/ethyl acetate = 3/1) to give 2.3 (331 mg, yield: 100%) as a white solid. ¹ HNMR (400MHz, CDCl ₃ )δ8.30 (s, 1H), 8.14 (d, J=8.8Hz, 1H), 7.63 (d, J=2.0Hz, 1H), 7.50 (dd, J=8.4, 2.0Hz, 1H), 4.49-4.55 (m, 1H), 4.31-4.39 (m, 1H), 3. 97-4.03 (m, 1H), 3.68-3.76 (m, 1H), 3.36-3.44 (m, 1H), 1.84-1.93 (m, 1H), 1.65-1.72 (m, 1H), 1.49-1.60 (m, 3H), 1.22-1.34 (m, 1H).

4. Synthetic intermediate I-315

A solution of 2.3 (331 mg, 0.9 mmol), ethynylcyclopropane (369 mg, 5.6 mmol), X-phos (56 mg, 0.12 mmol), bis(acetonitrile)dichloropalladium(II) (24 mg, 0.09 mmol), and potassium carbonate (257 mg, 1.9 mmol) in acetonitrile (10 mL) was heated to 90 °C overnight. The reaction mixture was cooled to room temperature and then filtered through diatomaceous earth and washed with ethyl acetate. The concentrated filtrate was purified by column chromatography (petroleum ether, petroleum ether/ethyl acetate = 3/1) and preparative HPLC to give I-315 (24.4 mg, yield: 8%) as a white solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 3: Characterization data of additional exemplary compounds

Example 3: Synthesis of I-77

I-77 synthesis scheme

1. Synthetic intermediates 3.2

PdCl₂( _PPh₃ ) _₂ (50 mg) and CuI (100 mg) were added to a stirred solution of 3.1 (500 mg, 1.6 mmol), ethynyltrimethylsilane ( ₄₇₀ mg, 4.8 mmol), and TEA (5 mL) in DMF (5 mL). The reaction mixture was stirred at 80 °C for 16 hours until the reaction was complete. The suspension was diluted with _H₂O (20 mL) and extracted with EA (20 mL x 2), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 100:1) to give 3.2 (420 mg, yield: 93.7%) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 7.03-7.11 (m, 3H), 2.57 (q, J = 7.6Hz, 2H), 1.02-1.09 (m, 3H), 0.06 (s, 9H).

2. Synthetic intermediates 3.3

TBAF (10 mL) was added to a stirred solution of 3.2 (420 mg, 1.5 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 0.5 h until the reaction was complete. The reaction mixture was poured into water and extracted with DCM (20 mL x 2). The reaction mixture was concentrated and the crude product was purified by rapid column chromatography (silica gel, PE/EA = 100:1) to give 3.3 (280 mg, yield: 89.7%) as a yellow oil.

3.4 Synthetic intermediates

To a stirred solution of 3.3 (280 mg, 1.3 mmol) in DMF (10 mL), 2-(azidomethyl)tetrahydro-2H-pyran 2-Int-4 (182 mg, 1.3 mmol), _CuSO₄ (26 mg, 0.13 mmol), and sodium ascorbate (52 mg, 0.26 mmol) were added. The reaction mixture was stirred at room temperature for 12 h until complete. The reaction mixture was poured into ice water and extracted with DCM (20 mL x 2). The reaction mixture was concentrated and the crude product was purified by rapid column chromatography (silica gel, PE/EA = 2:1) to give 3.4 (270 mg, yield: 59.5%) as a yellow oil.

4. Synthesis of I-77

Pd(ACN)₂Cl₂ ( ₃₀ mg), _X- Phos (60 mg), and _H₂O (5 mL) were added to a stirred solution of 3.4 (270 mg, 0.77 mmol), _{ethynylcyclopropane} (153 mg, 2.31 mmol), and _Cs₂CO₃ (753 mg, 2.31 mmol) in _CH₃CN (10 mL). The reaction mixture was stirred at 90 °C for 16 hours until the reaction was complete. The suspension was diluted with _H₂O (20 mL) and extracted with EA (20 mL x 2) and concentrated. The crude product was purified by preparative HPLC to give I-77 (53.02 mg, yield: 20.5%) as a yellow solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 4: Characterization data of additional exemplary compounds

Example 4: Synthesis of I-69

I-69 synthesis scheme

1. Synthetic intermediates 4.2

PdCl₂( _PPh₃ ) _{₂ (} 2.9 g) and CuI (455 mg) were added to a stirred solution of 4.1 (9 g, 45.45 mmol), ethynylcyclopropane ( ₉ g, 136.35 mmol), and TEA (20 mL) in DMF (10 mL). The reaction mixture was stirred at 80 °C for 16 hours until the reaction was complete. The suspension was diluted with _H₂O (20 mL) and extracted with EA (200 mL x 2), and concentrated. The crude product was purified by preparative HPLC to give 4.2 (7.3 g, yield: 87%) as a brown oil. LC-MS m/z: 185.4 [M+H] ^⁺ .

2. Synthetic intermediates 4.3

To a solution of 4.2 (7.3 g, 39.45 mmol) in MeOH (50 mL) _{, K₂CO₃} (11 g, 79 mol) and dimethyl 1-diazo-2-oxopropylphosphonate (7.57 g, 39.45 mmol) were added. The mixture was stirred at room temperature under a _nitrogen atmosphere for 8 h. The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was washed with brine and dried. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 2:1) to give 4.3 (6.5 g, yield: 91.5%) as a brown oil. LC-MS m/z: 181.7 [M+H] ^⁺ .

3. Synthesis of I-69

SM-2 (123 mg, 0.7 mmol), CuSO₄ _{· 5H₂O} (50 mg, 0.2 mmol), and sodium ascorbate (40 mg, 0.2 mmol) were added to a stirred solution of 100 mg (0.7 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. After depletion of the starting material (by LCMS), water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with water (10 mL x 3), dried, and concentrated. The crude product was purified by preparative HPLC to give I-69 (55 mg, yield: 23%) as a white solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 5: Characterization data of additional exemplary compounds

Example 5: Synthesis of I-75

I-75 synthesis scheme

1. Synthetic intermediates 5.2

To a solution of 5.1 (5.0 g, 25 mmol) in MeOH (50 mL) _{, K₂CO₃} (6.9 g, 50 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (5.0 g, 25 mmol) were added. The reaction mixture was stirred at room temperature for 8 hours. After depletion of the starting material (by LC-MS), water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with water (30 mL x 3), dried, and concentrated. The crude product was purified by preparative HPLC to give 5.2 (4.5 g, yield: 90%) as a yellow solid. LC-MS m/z: 195.1 [M+H] ^⁺ .

2. Synthetic intermediate 5.3

2-Int-4 (3.3 g, 23 mmol), CuSO₄ _{· 5H₂O} (1.3 g, 5 mmol), and sodium ascorbate (1.3 g, 6 mmol) were added to a stirred solution of 5.2 (4.5 g, 23 mmol) in DMF (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. After depletion of the starting material (by LCMS), water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with water (30 mL x 3), dried, and concentrated. The crude product was purified by preparative HPLC to give 5.3 (4.5 g, yield: 60%) as a brown solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.36 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 7.55 (s, 1H), 7.48 (dd, J=8.4Hz, 1.6Hz, 1H), 4.38-4.50 (m, 2H), 3.72-3.87 ( m, 2H), 3.29-3.32 (m, 1H), 2.44 (s, 3H), 1.78-1.81 (m, 1H), 1.63-1.66 (m, 1H), 1.40-1.51 (m, 3H), 1.19-1.25 (m, 1H).

3. Synthesize I-75

Under nitrogen atmosphere, Pd₂(dba) _₃ (15 mg), Cs₂CO₃ (440 mg, 1.35 mmol), and BINAP (30 mg) were added to a stirred solution of 5.3 (150 mg, 0.45 mmol), _{3,3- dimethylazetane} hydrochloride ( ₈₈ mg, 0.72 mmol), and X-Phos (30 mg) in DMF (10 mL). The reaction mixture was stirred at 100 °C for 16 hours until complete (by LCMS). The suspension was diluted with _H₂O (20 mL) and extracted with EA (30 mL x 3), and concentrated. The crude product was purified by preparative HPLC to give I-75 (49.98 ng, yield: 33%) as a white solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 6: Characterization data of additional exemplary compounds

Example 6: Synthesis of I-86

I-86 synthesis scheme

1. Synthetic intermediate 6.2

Pd(ACN)₂Cl₂ (60 mg), X-Phos (120 mg), and H₂O ( ₅ mL) were added to a stirred solution of _6.1 (600 mg, 3 mmol), tert-butyldimethyl(propane-2-alkynoxy)silane ( _1.5 g, 9 mmol), and Cs₂CO₃ ( _2.9 g, ₉ mmol) in _CH₃CN (10 mL). The reaction mixture was stirred at 90 °C for 16 hours until the reaction was complete (by LCMS). The suspension was diluted with _H₂O (20 mL) and extracted with EA (20 mL x 2) and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 20:1) to give 6.2 (300 mg, yield: 34%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ): δ10.06 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.22 (d, J=8.0Hz, 1H), 7.13 (s, 1H), 4.38 (s, 2H), 2.46 (s, 3H), 0.74 (s, 9H), 0.007 (s, 6H).

2. Synthetic intermediate 6.3

To a stirred solution of 6.2 (300 mg, 1.04 mmol) in MeOH (5 mL) _{, K₂CO₃} (217 mg, 1.56 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (200 mg, 1.04 mmol) were added. The reaction mixture was stirred at room temperature for 8 h until complete (by LCMS). The reaction mixture was poured into ice water and extracted with DCM (20 mL x 2). The reaction mixture was concentrated and the crude product was purified by rapid column chromatography (silica gel, PE/EA = 50:1) to give 6.3 (280 mg, yield: 94%) as a yellow oil.

3. Synthetic intermediates 6.4

To a stirred solution of 6.3 (280 mg, 0.98 mmol) in DMF (5 mL), 2-Int-4 (138 mg, 0.98 mmol), _CuSO₄ (20 mg, 0.098 mmol), and sodium ascorbate (40 mg, 0.196 mmol) were added. The reaction mixture was stirred at room temperature for 12 h until complete (by LCMS). The reaction mixture was poured into ice water and extracted with DCM (20 mL x 2). The reaction mixture was concentrated and the crude product was purified by rapid column chromatography (silica gel, PE/EA = 1:1) to give 6.4 (300 mg, yield: 72%) as a yellow oil.

4. Synthetic intermediate 6.5

TBAF (1.0 N, 5 mL) was added to a stirred solution of 6.4 (300 mg, 0.7 mmol) in THF (5 mL). The reaction mixture was stirred overnight at room temperature until complete (by LCMS). The reaction mixture was poured into water and extracted with DCM (20 mL x 2). The reaction mixture was concentrated and the crude product was purified by rapid column chromatography (silica gel, PE/EA = 1:1) to give 6.5 (200 mg, yield: 91.8%) as a yellow oil.

5. Synthetic intermediates 6.6

TEA (79 mg, 0.78 mmol) and _Ms₂O (68 mg, 0.39 mmol) were added to a stirred solution of 6.5 (80 mg, 0.26 mmol) in DCM (10 mL). The reaction mixture was stirred at RT for 2 h. _H₂O (15 mL) and DCM (10 mL) were added, and the organic phase was collected and evaporated under reduced pressure to give 6.6 (90 mg, crude substance) as a yellow oil.

6. Synthesize I-86

_K₂CO₃ ( ₉₆ mg, 0.69 mmol) was added to a stirred solution of 6.6 (90 mg, 0.23 mmol) and phenylmethylamine (25 mg, 0.23 mmol) in DMF (3 mL). The reaction mixture was stirred overnight at room temperature. _H₂O (20 mL) and EA (20 mL) were added, and the organic phase was collected and evaporated under reduced pressure. The residue was purified by preparative HPLC to give I-86 (33.52 mg, yield: 36.4%) as a white solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 7: Characterization data of additional exemplary compounds

Example 7: Synthesis of I-344

I-344 synthesis scheme

1. Synthetic intermediate 7.2

_AlCl₃ (0.1 g, 1 mmol), _NaN₃ (0.7 g, 10 mmol), and SM₂ (0.75 g, 10 mmol) were added to a solution of 7.1 (2.3 g, 10 mmol) in DMSO (10 mL). The reaction mixture was stirred at 70 °C for 8 hours. After depletion of the starting material (by LC-MS), water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with water (30 mL x 3), dried, and concentrated. The crude product was purified by preparative HPLC to give 7.2 (1.0 g, 35% yield) as a yellow oil. LC-MS m/z: 285.08 [M+H] ^⁺ .

2. Synthetic intermediate 7.3

_K₂CO₃ (1.0 g, 7.0 mmol) and 2-Int₂ (1.0 mg, 3.5 mmol) were added to a stirred solution of _7.2 (1.0 g, 3.5 mmol) in DMF (10 mL) at room temperature. The mixture was stirred overnight at 80 °C. _H₂O was added, and the mixture was extracted with EA (10 mL x ₂ ). The organic layer was washed with water, dried over _Na₂SO₄ , and evaporated to dryness. The crude product was purified by preparative HPLC to give 7.3 (0.3 g, yield: 22%) as a yellow oil. LC-MS m/z: 383.23 [M+H] ^⁺ .

3. Synthesize I-344

PdCl₂( _PPh₃ ) _₂ (80 mg) and CuI (80 mg) were added to a stirred solution of 7.3 (300 mg, 0.8 mmol), cyclopropylacetylene ( ₂₆₄ mg, 4.0 mmol), and TEA (505 mg, 5.0 mmol) in DMF (5 mL). The reaction mixture was stirred at 80 °C for 16 hours until the reaction was complete. The suspension was diluted with _H₂O (20 mL) and extracted with EA (20 mL x 2), and concentrated. The crude product was purified by preparative HPLC to give I-344 (60 mg, yield: 24%) as a yellow oil.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 8: Characterization data of additional exemplary compounds

Example 8: Synthesis of I-74

I-74 synthesis scheme

1. Synthetic intermediate 8.2

Morpholine (87 mg, 1.0 mmol) and _NaBHAc3 (820 mg, 5.0 mmol) were added to a solution of 8.1 (198 mg, 1.0 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 4 hours. After depletion of the starting material (by LC-MS), water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with water (10 mL x 3), dried, and concentrated. The crude product was purified by preparative HPLC to give 8.2 (100 mg, 37% yield) as a yellow oil. LC-MS m/z: 270.2 [M+H] ⁺ .

2. Synthetic intermediate 8.3

PdCl₂( _PPh₃ ) _₂ (40 mg) and CuI (40 mg) were added to a stirred solution of 8.2 (100 mg, 0.4 mmol), ethynyltrimethylsilane (80 mg, 0.8 mmol), and TEA (200 mg, ₂ mmol) in DMF (5 mL). The reaction mixture was stirred at 80 °C for 16 hours until the reaction was complete. The suspension was diluted with _H₂O (20 mL) and extracted with EA (20 mL x 2), and concentrated. The crude product was purified by preparative HPLC to give 8.3 (110 mg, yield: 87%) as a yellow oil. LC-MS m/z: 288.4 [M+H] ^⁺ .

3. Synthetic intermediate 8.4

TBAF (1M/THF, 2 mL) was added to a stirred solution of 8.3 (110 mg, 0.3 mmol) in THF (3 mL) at room temperature. The mixture was stirred for 0.5 h at room temperature. After depletion of the starting material (by LC-MS), water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3), washed with water (5 mL x 3), dried, and concentrated. The crude product was purified by preparative HPLC to give 8.4 (70 mg, yield: 70%) as a brown oil. LC-MS m/z: 216.4 [M+H] ⁺ .

4. Synthetic intermediate I-74

2-(azidomethyl)tetrahydro-2H-pyran (2-Int-4, 42 mg, 0.3 mmol), CuSO₄ _· 5H₂O (25 mg, 0.1 mmol), and sodium ascorbate (20 mg, 0.1 mmol) were added to a stirred solution of ₇₀ mg (0.3 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. After depletion of the starting material (by LCMS), water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with water (10 mL x 3), dried, and concentrated. The crude product was purified by preparative HPLC to give I-74 (8 mg, yield: 8%) as a yellow oil.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 9: Characterization data of additional exemplary compounds

Example 9: Synthesis of I-269

I-269 synthesis scheme

1. Synthetic intermediate 9.2

Dimethyl 1-diazo- ₂ -oxopropylphosphonate (576 mg, 3.0 mmol) was added to a stirred solution of 9.1 (384 mg, 3.0 mmol) and _K₂CO₃ (828 Mg, 6.0 mmol) in MeOH (15 mL). The reaction mixture was stirred at room temperature for 4 hours until the reaction was complete. The suspension was concentrated and diluted with _H₂O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by preparative HPLC to give 9.2 (200 mg, yield: 54%) as a yellow oil.

2. Synthetic intermediate 9.4

To a solution of 9.3 (185 mg, 1.0 mmol) in MeOH (10 mL), _K₂CO₃ (276 _mg , 2.0 mmol), _{CuSO₄ ·5H₂O} (50 mg, 0.2 mmol), and imidazole-1-sulfonyl azide hydrochloride (208 mg, 1 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. After depletion of the starting material (by LCMS), water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by preparative HPLC to give 9.4 (100 mg, 47% yield) as a colorless oil.

3. Synthetic intermediate 9.5

Add 9.2 (124 mg, 1.0 mmol), CuSO₄ _{·5H₂O (} 50 mg, 0.20 mmol), and sodium ascorbate (40 mg, 0.20 mmol) to a stirred solution of 9.4 (100 mg, 0.47 mmol) in DMF (5 mL) at room temperature. Stir for 12 h at room temperature. After depletion of the starting material (by LC-MS), add water (10 mL), extract with ethyl acetate (10 mL x 3), wash with water (10 mL x 3), dry and concentrate. The crude product was purified by preparative HPLC to give 9.5 (70 mg, yield: 45%) as a yellow oil. LC-MS m/z: 336.0 [M+H] ^⁺ .

4. Synthetic target I-269

PdCl₂(ACN) _₂ (10 mg) was added to a stirred solution of 9.5 g (70 mg, 0.21 mmol), _{ethynylcyclopropane} (40 mg, 0.60 mmol), X- _Phos (10 mg), and _Cs₂CO₃ (324 mg, 1.0 mmol) in CAN/H₂O ( ₁₀ mL/1 mL). The reaction mixture was stirred at 90 °C for 16 hours until the reaction was complete. The suspension was diluted with _H₂O (10 mL) and extracted and concentrated with EA (10 mL x 2). The crude product was purified by preparative HPLC to give I-269 (28 mg, yield: 42%) as a grayish-white solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 10: Characterization data of additional exemplary compounds

Example 10: Synthesis of I-333

I-333 synthesis scheme

1. Synthetic intermediate 10.2

A solution of 10.1 (5.00 g, 18.11 mmol) in formamide (30 mL) was stirred at 140 °C for 8 hours until the reaction was complete (by LC-MS). The suspension was diluted with _NaHCO3 (aqueous solution), extracted with EtOAc (30 mL x 3), washed with NaCl (aqueous solution) and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 1:1) to give 10.2 (3.5 g, 87% yield) as a yellow solid. LC-MS m/z: 223.1 [M+H] ⁺ .

2. Synthetic intermediate 10.3

_K₂CO₃ ( ₄₆₆ mg, 3.37 mmol) was added to a stirred solution of 10.2 (500 mg, 2.25 mmol) and 2-Int-2 (730 mg, 2.71 mmol) in DMF (6 mL). The reaction mixture was stirred overnight at 120 °C until the reaction was complete. The suspension was diluted with _H₂O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layer was washed with NaCl (aqueous solution) and concentrated. The residue was purified by rapid column chromatography (silica gel, PE/EA = 1:2) to give 10.3 (600 mg, 69% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.54 (d, J=8.4Hz, 2H), 7.42 (s, 1H), 7.37 (d, J=8.4Hz, 2H), 7.14 (s, 1H), 3.86-3.89 (m, 1H), 3.79-3.81 (m, 2H), 3.38-3.44 (m, 1H), 3.24-3.30 (m, 1H), 1.73-1.77 (m, 1H), 1.33-1.46 (m, 4H), 1.09-1.18 (m, 1H).

3. Synthesize I-333

Pd( _PPh₃ ) _₂Cl₂ (66 mg, 0.09 mmol) was added to a stirred solution of 10.3 (300 mg, 0.94 mmol), ethynylcyclopropane (186 mg, 2.81 mmol), _CuI (18 mg, 0.09 mmol), and TEA (0.39 mL, 2.81 mmol) in DMF (10 mL). The reaction mixture was stirred overnight at 80 °C under N₂ until the reaction was complete. The suspension was diluted with _H₂O (25 mL) and extracted with EtOAc (25 mL x 3). The organic layer was washed with NaCl (aqueous solution) and concentrated. The residue was purified by preparative HPLC to give I-333 (60 mg, 21% yield) as a pink oil.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 11: Characterization data of additional exemplary compounds

Example 11: Synthesis of I-338

I-338 synthesis scheme

1. Synthetic intermediate 11.2

TsOH _·H₂O (570 mg, 3.0 mmol) was added to a mixture of compound 11.1 (636 mg, 3.0 mmol) and NBS (587 mg, 3.3 mmol) in _CH₃CN (20 mL), and the mixture was heated to reflux for 6 h. The reaction mixture was cooled to room temperature, diluted with _H₂O (40 mL), and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by column chromatography (petroleum/ethyl acetate = 10/1) to give 11.2 (770 mg, yield: 88%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.81 (d, J=8.4Hz, 1H), 7.62 (s, 1H), 7.57 (dd, J=1.6Hz, 8.4Hz, 1H), 4.86 (s, 2H), 2.39 (s, 3H).

2. Synthetic intermediate 11.3

DIPEA (774 mg, 6.0 mmol) was added to a mixture of compound 11.2 (580 mg, 2.0 mmol) and 2-(tetrahydro-2H-pyran-2-yl)acetic acid (288 mg, 2.0 mmol) in _CH3CN (20 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with _H2O (40 mL) and extracted with EtOAc (25 mL x ₃ ). The combined organic phases were washed with brine (20 mL), dried over anhydrous _Na2SO4 , and concentrated to dryness. The crude product was purified by column chromatography (petroleum/ethyl acetate = 6/1) to give 11.3 (600 mg, yield: 85%) as a yellow oil. LC-MS m/z: 355.1 [M+H] ⁺ .

3. Synthetic intermediate 11.4

A mixture of 11.3 (300 mg, 0.9 mmol) and _NH₄OAc (776 mg, 12.7 mmol) in toluene (15 mL) was heated to 100 °C for 16 h. The mixture was concentrated and purified by column chromatography (petroleum/ethyl acetate = 5/1, 3/1) to give 11.4 (110 mg, yield: 39%) as a yellow solid. LC-MS m/z: 335.0 [M+H] ^⁺ .

4. Synthesis of I-338

A solution of 11.4 (110 mg, 0.3 mmol), ethynylcyclopropane (119 mg, 2.0 mmol), X-Phos (15 mg, 0.03 mmol), bis(acetonitrile)dichloropalladium(II) (8 mg, 0.03 mmol), and cesium carbonate (213 mg, 0.7 mmol) in MeCN (6 mL) and H₂O ( ₂ mL) was heated to 80 °C for 16 h and cooled to room temperature. The mixture was extracted with EtOAc (10 mL x 3). The organic phase was concentrated and purified by column chromatography (petroleum/ethyl acetate = 3/1) followed by preparative HPLC to give I-338 (15 mg, yield: 14%) as a gray solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 12: Characterization data of additional exemplary compounds

Example 12: Synthesis of I-316

I-316 synthesis scheme

1. Synthetic intermediate 12.2

DMF-DMA (952 mg, 8.0 mmol) was added to a solution of 12.1 (852 mg, 4.0 mmol) in DMF (10 mL), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with _H₂O (40 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine ( ₂₀ mL), dried over anhydrous _Na₂SO₄ , and concentrated to dryness to give 12.2 (800 mg, yield: 75%) as a yellow solid. LC-MS m/z: 267.8 [M+H] ^⁺

2. Synthetic intermediate 12.3

To a solution of 12.2 (800 mg, 2.99 mmol) in EtOH (10 mL), _{N₂H₄ · H₂O} (746 mg, 14.93 mmol) was added and the mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with _H₂O (30 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (20 mL), dried over _Na₂SO₄ , and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 1/1) to give 12.3 (660 mg, 94% yield) as a yellow solid. _LC -MS m/z: 236.9 [M+H] ^⁺

3. Synthetic intermediate 12.4

2-Int- ₂ (573 mg, 2.1 mmol) was added to a mixture of 12.3 (501 mg, 2.1 mmol) and _Cs₂CO₃ (1374 mg, 4.2 mmol) in DMF (15 mL). The reaction mixture was stirred at 60 °C for 5 h, then diluted with _H₂O (30 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (20 mL), dried over _{Na₂SO₄ ,} and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 1/3) to give 12.4 (500 mg, 71% yield) as a colorless oil. LC-MS m/z: 334.9 [M+H] ^⁺ .

4. Synthesis of I-316

Ethynylcyclopropane (237 mg, 3.6 mmol) was added to a _mixture of 12.4 (200 mg, 0.6 mmol), _Cs₂CO₃ (585 mg, 1.8 mmol), X-Phos _{(28 mg, 0.06 mmol), and Pd(ACN)₂Cl₂ (} 15 mg, 0.06 mmol) in MeCN/ _H₂O (3/1, 4 mL). The reaction mixture was stirred at 90 °C for 35 min under microwave irradiation. The reaction mixture was diluted with _H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over _Na₂SO₄ , and concentrated to dryness. The residue was purified by preparative HPLC to give I-316 (70 mg, 36% yield) as _a gray solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 13: Characterization data of additional exemplary compounds

Example 13: Synthesis of I-299

I-299 synthesis scheme

1. Synthetic intermediate 13.2

Magnesium ethynyl bromide (15 mL, 7.50 mmol) was added to a stirred solution of 13.1 (1.20 g, 6.03 mmol) in 15 mL of THF at 0 °C. The reaction mixture was stirred at 40 °C for 4 hours until complete, _NH₄Cl (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with _H₂O (20 mL) and extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by preparative HPLC to give 13.2 (1.0 g, yield: 74%) as a brown oil.

2. Synthetic intermediate 13.3

A solution of CuSO₄· _{H₂O (111} mg, 0.44 mmol) in water (1 mL) was added to a stirred solution of 13.2 (500 mg, 2.22 mmol) and 2-Int-4 (313 mg, 2.22 mmol) in DMF (15 mL), and water (1 mL) containing sodium ascorbate (176 mg, 0.88 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours until the reaction was complete. The reaction mixture was diluted with _H₂O (20 mL) and extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous _{Na₂SO₄ ,} and concentrated to dryness. The crude product was purified by preparative HPLC to give 13.3 (600 mg, yield: 73%) as a yellow solid.

3. Synthetic intermediate 13.4

Triethylsilane (380 mg, 3.27 mmol) was added to a stirred solution of 13.3 (400 mg, 1.09 mmol) in _CF3COOH (5 mL). The reaction mixture was stirred at room temperature for 4 hours until complete. The reaction mixture was diluted with _H2O (10 mL) and extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (10 mL), _dried over _Na2SO4 , and concentrated to dryness. The crude product was purified by preparative HPLC to give 13.4 (300 mg, yield: 78%) as a yellow oil.

4. Synthetic target I-299

_Cs₂CO₃ ( ₃₇₁ mg, 1.14 mmol), PdCl₂( _CH₃CN ) _₂ (20 mg), and X-phos (40 mg) were added to a stirred solution of 13.4 (200 mg, 0.57 mmol) in CH₃CN ( _{10 mL} ) and _H₂O (1 mL), and then backfilled with argon (three times). Ethynylcyclopropane (75 mg, 1.14 mmol) was added to the resulting suspension, and the reaction mixture was stirred at 90 °C for 3 hours until the reaction was complete. The reaction mixture was diluted with _H₂O (10 mL) and extracted with DCM (10 mL × 2). The combined organic phases were washed with brine (10 mL), _dried over _Na₂SO₄ , and concentrated to dryness. The crude product was purified by preparative HPLC to give I-299 (75 mg, yield: 39%) as a white solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 14: Characterization data of additional exemplary compounds

Example 14: Synthesis of I-10

Synthesis scheme of I-10

1. Synthetic intermediate N′-(4-bromophenyl)-2-(1,4-dioxane-2-yl)acetylhydrazine (14.1)

At 0 °C, (4-bromophenyl)hydrazine hydrochloride (224 mg, 1.0 mmol, 1.0 equivalent) was added to a mixture of 2-(1,4-dioxane-2-yl)acetic acid (146 mg, 1.0 mmol, 1.0 equivalent), hydroxybenzotriazole (189 mg, 1.4 mmol, 1.4 equivalent), and N,N′-dicyclohexylcarbodiimide (248 mg, 1.2 mmol, 1.2 equivalent) in DCM (5 mL). The mixture was heated to room temperature and stirred at room temperature for 48 hours. DCM and 1N HCl were added, and the organic layer was separated, washed twice successively with 1N HCl and brine, dried over _Na₂SO₄ , _filtered , and concentrated. The residue was purified by silica gel chromatography (30-100% EtOAc/hexane) to give N′-(4-bromophenyl)-2-(1,4-dioxane-2-yl)acetylhydrazine (14.1) (84 mg, 27%) as a beige solid.

2. Synthetic intermediate 5-((1,4-dioxan-2-yl)methyl)-3-(4-bromophenyl)-1,3,4-oxadiazol-2(3H)-one (14.2)

1,1′-carbonyldiimidazole (65 mg, 0.40 mmol, 1.5 equivalence) was added to a solution of N′-(4-bromophenyl)-2-(1,4-dioxan-2-yl)acetylhydrazine (14.1, 84 mg, 0.267 mmol, 1.0 equivalence) in DCE (3 mL). The mixture was stirred at 80 °C for 18 hours. Once at room temperature, the mixture was purified by silica gel chromatography (30-100% EtoAc/hexane) to give 5-((1,4-dioxan-2-yl)methyl)-3-(4-bromophenyl)-1,3,4-oxadiazol-2(3H)-one (14.2) (29 mg, 32%) as a yellow solid.

3. Synthesis of 5-((1,4-dioxane-2-yl)methyl)-3-(4-(cyclopropylethynyl)phenyl)-1,3,4-oxadiazol-2(3H)-one (I-10)

Cyclopropylacetylene (104 μL, 1.23 mmol, 10 equivalents) was added to a bubbling solution of 5-((1,4-di-oxan-2-yl)methyl)-3-(4-bromophenyl)-1,3,4-oxadiazol-2(3H)-one 14.2 (42 mg, 0.12 mmol, 1.00 equivalents), Pd( _PPh3 ) ₄ (14 mg, 0.012 mmol, 0.1 equivalents), and CuI (5 mg, 0.012 mmol, 0.1 equivalents) in _Et3N (1.2 mL) of N2. After bubbling with _N2 for 5 minutes, the reaction mixture was stirred at 90 °C for 24 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and MTBE was added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (20-100% EtOAc/hexane) to give 5-((1,4-dioxan-2-yl)methyl)-3-(4-(cyclopropylethynyl)phenyl)-1,3,4-oxadiazol-2(3H)-one (I-10) (34 mg, 85%) as a yellow solid. Melting point 64-70 °C.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 15: Characterization data of additional exemplary compounds

Example 15: Synthesis of I-18

Synthesis scheme of I-18

1. Synthetic intermediate tert-butyl 2-(2-(tetrahydro-2H-pyran-2-yl)acetyl)-hydrazine-1-carboxylate

At 0 °C, DIPEA (1.81 mL, 10.4 mmol, 3.0 equivalence) was added to a mixture of 2-(tetrahydro-2H-pyran-2-yl)acetic acid (500 mg, 3.47 mmol, 1.0 equivalence), tert-butyl hydrazide (687 mg, 5.20 mmol, 1.5 equivalence), and HATU (1.58 g, 10.4 mmol, 3.0 equivalence) in dichloromethane (14 mL). The mixture was stirred at 0 °C for 1 hour, and then _H₂O and dichloromethane were added. The organic layer was separated, washed with _H₂O and brine, dried over _Na₂SO₄ , _filtered , and concentrated. The residue was purified on silica gel (10–80% EtOAc/hexane) to obtain impurities, which were used as is in the next step.

2. Synthetic intermediate 2-(tetrahydro-2H-pyran-2-yl)acetylhydrazine, trifluoroacetate

Trifluoroacetic acid (4 mL) was added to a mixture of tert-butyl 2-(2-(tetrahydro-2H-pyran-2-yl)acetyl)hydrazide-1-carboxylate (896 mg, 3.47 mmol, 1.0 equivalent) in dichloromethane (10 mL). After stirring at room temperature for 2 hours, the mixture was concentrated and used as is for the next step.

3. Synthetic intermediate (E, Z)-N′-(3-bromophenylmethylene)-2-(tetrahydro-2H-pyran-2-yl)acetylhydrazine

3-Bromobenzaldehyde (0.80 mL, 6.94 mmol, 2.0 equivalent) was added to a mixture of 2-(tetrahydro-2H-pyran-2-yl)acetylhydrazine trifluoroacetate (944 mg, 3.47 mmol, 1.0 equivalent) in ethanol (7 mL). The mixture was stirred at room temperature for 4 hours. Methanol (7 mL) was added and the mixture was cooled to 0 °C. Sodium borohydride (394 mg, 10.4 mmol, 3.0 equivalent) was added fractionally, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0 °C, and sodium borohydride (394 mg, 10.4 mmol, 3.0 equivalent) was added fractionally _again . The mixture was warmed to room temperature and stirred at room temperature for 18 hours. The mixture was concentrated and dissolved in dichloromethane, and _H₂O was added. The organic layer was separated, washed with _H₂O and brine, dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified on silica gel (10-80% EtOAc/hexane) to give (EZ)-N′-(3-bromophenylmethylene)-2-(tetrahydro-2H-pyran-2-yl)acetylhydrazine (729 mg, 65%) as a white solid.

4. Synthetic intermediate N′-(3-bromophenylmethyl)-2-(tetrahydro-2H-pyran-2-yl)-acetylhydrazine

Triethylsilane (0.72 mL, 4.48 mL, 2 equivalents) was added dropwise to a mixture of (E,Z)-N′-(3-bromophenylmethylene)-2-(tetrahydro-2H-pyran-2-yl)acetylhydrazine (729 mg, 2.24 mmol, 1.0 equivalent) in trifluoroacetic acid ( _3.4 mL). After stirring for 20 minutes, the reaction mixture was slowly poured into a saturated aqueous solution of _NaHCO3 , and dichloromethane and MTBE were added. The organic layer was separated, washed with brine, dried over _Na2SO4 , filtered, and concentrated. The residue was purified on silica gel (30-90% EtOAc/hexane) to give N′-(3-bromophenylmethylene)-2-(tetrahydro-2H-pyran-2-yl)acetylhydrazine (325 mg, 44%) as a grayish-white solid.

5. Synthetic intermediate 3-(3-bromophenylmethyl)-5-((tetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one

At 0 °C, phosgene (20% in toluene, 2.62 mL, 4.97 mmol, 5.0 equivalent) was added dropwise to a mixture of N′-(3-bromophenylmethyl)-2-(tetrahydro-2H-pyran-2-yl)acetylhydrazine (325 mg, 0.99 mmol, 1.0 equivalent) in DCM (7.5 mL). The mixture was heated to room temperature and stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was dissolved in MTBE and water. The organic layer was separated, washed with brine, dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give _3- (3-bromophenylmethyl)-5-((tetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one (327 mg, 94%) as a colorless oil.

6. Synthesis of 3-(3-(cyclopropylethynyl)benzyl)-5-((tetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one (I-18)

Cyclopropylacetylene (391 μL, 4.61 mmol, 10 equivalents) was added to 3-(3-bromophenylmethyl)-5-((tetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one (163 mg, 0.461 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (53 mg, 0.046 mmol, 0.1 equivalent), and CuI (9 mg, 0.046 mmol, 0.1 equivalent) in a _N2 bubbling solution in _Et3N (2.3 mL) and DME (2.3 mL). After bubbling with _N2 for 1 minute, the reaction mixture was stirred at 90 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and MTBE was added. The organic layer was separated, dried over _Na2SO4 , filtered _, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give 3-(3-(cyclopropylethynyl)benzyl)-5-((tetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one (I-18) (132 mg, 85%), which was an orange oil.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 16: Characterization data of additional exemplary compounds

Example 16: Synthesis of I-406 and I-407

Synthesis schemes for I-406 and I-407

1. Synthetic intermediate 2-(4-bromo-2-methylphenyl)ethylene oxide

Sodium hydride (118 mg, 4.92 mmol) and trimethylsulfonium iodide (1.03 g, 4.92 mmol) were added to a solution of 4-bromo-2-methylbenzaldehyde (500 mg, 2.46 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 2 h 30 and partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed, dried over MgSO4, and concentrated to give crude 2-(4-bromo-2-methylphenyl)ethylene oxide (500 mg) as is used in the next step. HPLC (Method C): 1.04 min

2. Synthetic intermediates 1-(4-bromo-2-methylphenyl)-2-(((tetrahydro-2H-pyran-2-yl)methyl)amino)ethanol and 2-(4-bromo-2-methylphenyl)-2-(((tetrahydro-2H-pyran-2-yl)methyl)amino)ethanol

Bismuth(III) trifluoromethanesulfonate (77.0 mg, 117 μmol) and (tetrahydro-2H-pyran-2-yl)methylamine (284 mg, 2.35 mmol) were added to a solution of 2-(4-bromo-2-methylphenyl)ethylene oxide (500 mg, 2.35 mmol) in MeOH (4 mL). The reaction mixture was stirred overnight at 60 °C, cooled to room temperature, and partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed, dried over _MgSO4 , concentrated, and purified by reverse-phase FCC (30 g C18 cylinder, 5% to 40% ACN/10 mM AmF) to give the desired mixture of 1-(4-bromo-2-methylphenyl)-2-(((tetrahydro-2H-pyran-2-yl)methyl)amino)ethanol (58 mg) and 2-(4-bromo-2-methylphenyl)-2-(((tetrahydro-2H-pyran-2-yl)methyl)amino)ethanol (58 mg). HPLC (Method C): 0.85 and 0.90 min.

3. Synthetic intermediates 5-(4-bromo-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one, 4-(4-bromo-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one

At 0 °C, 1,1-carbonylimidazole (32.2 mg, 194 μmol) and imidazole (6.08 mg, 88.3 μmol) were added to a solution of 1-(4-bromo-2-methylphenyl)-2-(((tetrahydro-2H-pyran-2-yl)-methyl)amino)ethanol (58.0 mg, 177 μmol) in DCM (504 μL). The reaction mixture was stirred at room temperature for 2 h 30 and diluted with dichloromethane. The reaction mixture was washed, dried over _MgSO₄ , concentrated, and purified by reverse-phase FCC (30 g C18 cartridge, 5% to 70% ACN/10 mM ammonium formate gradient) to give a mixture of isomers 5-(4-bromo-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one (53 mg) and 4-(4-bromo-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one (53 mg). HPLC (Method C): 1.32 and 1.34 min.

4. Synthesis of 5-(2-methyl-4-(6-methylpyridin-3-yl)phenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one (I-406) and 4-(2-methyl-4-(6-methylpyridin-3-yl)phenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one (I-407)

5-(4-bromo-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one (53.0 mg, 150 μmol), 4-(4-bromo-2-methylphenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one (53.0 mg, ₁₅₀ μmol), _K₂CO₃ (62.0 mg, 449 μmol), and pinacol 2-methylpyridin-5-boronate (51.2 mg, 224 μmol) were added to a microwave-safe vial. Then, a degassed mixture of dioxane (389 μL) and water (43.2 μL) was added, and the mixture was degassed with nitrogen. The reaction mixture was stirred at 100 °C for 16 h and partitioned between ethyl acetate and an aqueous ammonium chloride solution. The layers were separated, and the organic layer was washed, dried over _MgSO₄ , and concentrated. The crude product was purified by reverse-phase FCC (30 g C18 cartridge, 5% to 70% ACN/10 mM ammonium formate gradient) and by reverse-phase LC-MS (C18 OBD cartridge, 20% to 100% ACN/10 mM ammonium formate gradient) to give 5-(2-methyl-4-(6-methylpyridin-3-yl)phenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one I-406 (4.5 mg) and 4-(2-methyl-4-(6-methylpyridin-3-yl)phenyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)oxazolidin-2-one I-407 (7.1 mg).

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 17: Characterization data of additional exemplary compounds

Example 17: Synthesis of I-7

I-7 Synthesis Scheme

1. Synthetic intermediate 17.2

Tributyltin azide (4.1 g, 12.3 mmol) was added to a stirred solution of 17.1 (2.2 g, 11.2 mmol) in toluene (30 mL). The reaction mixture was heated to 110 °C for 16 h and concentrated to give 17.2 (2.5 g, crude product) as a brown oil. LC-MS m/z: 239.0 [M+H] ⁺ .

2. Synthetic intermediate 17.3

2-Int-2 (1.7 g, 6.3 mmol) was added to a stirred solution of 17.2 (1.0 g, 4.2 mmol, crude) and _2CO3 (1.2 g, 8.4 mmol) in anhydrous DMF (30 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with _H2O (20 mL) and extracted with EA (50 mL x 2), and concentrated to dryness. The crude product was purified by preparative HPLC to 17.3 (250 mg, yield for both steps: 6.6%) as a yellow oil. LC-MS m/z: 337.0 [M+H] ⁺ .

3. Synthesis of I-7

X-Phos (48 mg, 0.10 mmol) and Pd(ACN)₂Cl₂ ( ₁₃ mg, 0.05 mmol) were added to a stirred solution of 17.3 (200 mg, 0.59 mmol), _K₂CO₃ (163 mg, 1.18 mmol), _{and ethynylcyclopropane (} 103 mg, 1.53 mmol) in MeCN (30 mL). The reaction mixture was stirred at 90 °C for 16 hours. The suspension was concentrated and purified by preparative HPLC to give I-7 (45 mg, yield: 23%) as a yellow oil.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 18: Characterization data of additional exemplary compounds

Example 18: Synthesis of I-342

I-342 synthesis scheme

1. Synthetic intermediate 4-bromo-2-methylbenzoylhydrazide

1,1′-carbonyldiimidazole (5.66 g, 34.9 mmol, 1.5 equivalents) was added to a mixture of 4-bromo-2-methylbenzoic acid (5.0 g, 23.3 mmol, 1.0 equivalents) in DMF (50 mL). After stirring at room temperature for 2 hours, hydrazine hydrate (5.7 mL, 116 mmol, 5.0 equivalents) was slowly added. The mixture was stirred at room temperature for 2 hours, then poured into a saturated aqueous ammonium chloride solution and the precipitate was filtered to give 4-bromo-2-methylbenzoylhydrazine (4.01 g, 75%).

2. Synthetic intermediate 4-bromo-2-methyl-N′-(2-(tetrahydro-2H-pyran-2-yl)-acetyl)benzoylhydrazide

A mixture of 2-(tetrahydro-2H-pyran-2-yl)acetic acid (755 mg, 5.24 mmol, 1.2 equivalents) and _SOCl₂ (1.4 mL, 21.8 mmol, 5.0 equivalents) was stirred under reflux for 1 hour. Once at room temperature, the mixture was concentrated and dissolved in DMF (1 mL). At 0 °C, the resulting solution was added to a mixture of 4-bromo-2-methylbenzoylhydrazine (1.0 g, 4.37 mmol, 1.0 equivalents) and _Et₃N (3.04 mL, 21.8 mmol, 5.0 equivalents) in DMF (12 mL). The mixture was heated to room temperature and stirred at room temperature for 4 hours. The mixture was poured into a saturated aqueous solution of _NH₄Cl and the precipitate was filtered to give 4-bromo-2-methyl-N′-(2-(tetrahydro-2H-pyran-2-yl)acetyl)benzoylhydrazine (1.25 g, 81%) as a grayish-white solid.

3. Synthetic intermediate 2-(4-bromo-2-methylphenyl)-5-((tetrahydro-2H-pyran-2-yl)-methyl)-1,3,4-oxadiazole

Methyl N-(triethylammonium sulfonyl)carbamate [Burgess reagent] (101 mg, 0.422 mmol, 1.5 equivalence) was added to a mixture of 4-bromo-2-methyl-N′-(2-(tetrahydro-2H-pyran-2-yl)acetyl)benzoylhydrazine (100 mg, 0.282 mmol, 1.0 equivalence) in THF (3 mL). The mixture was stirred under reflux for 18 hours. Once at room temperature, the mixture was concentrated, and the residue was dissolved in MTBE and _H₂O . The organic layer was separated, washed with brine, dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give _2- (4-bromo-2-methylphenyl)-5-((tetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazole (56 mg, 59%) as a pale yellow oil.

4. Synthesis of I-342

Cyclopropylacetylene (138 μL, 1.63 mmol, 10 equivalents) was added to a solution of 2-(4-bromo-2-methylphenyl)-5-((tetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazole (55 mg, 0.163 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (19 mg, 0.016 mmol, 0.1 equivalent), and CuI (3 mg, 0.016 mmol, 0.1 equivalent) in a bubbling solution of _Et3N (0.8 mL) and DME (0.8 mL) in _N2 . After bubbling with _N2 for 1 minute, the reaction mixture was stirred at 90 °C for 3 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and MTBE was added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give 2-(4-(cyclopropylethynyl)-2-methylphenyl)-5-((tetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazole I-342 (47 mg, 89%) as an orange oil.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 19: Characterization data of additional exemplary compounds

Example 19: Synthesis of I-330, I-331 and I-328

Synthesis schemes of I-330, I-331 and I-328

1. Synthetic intermediate 19.2

(Bromomethyl)benzene (2.4 g, 13.8 mmol) was added to a stirred solution of 19.1 (1.5 g, 9.2 mmol) and _K₂CO₃ (3.8 g, 27.7 mmol) in _acetone (100 mL). The reaction mixture was heated to 60 °C for 16 hours. The reaction mixture was diluted with _H₂O (50 mL) and extracted with EA (200 mL x 2). The concentrated organic layers were combined to give 19.2 (2.0 g, crude substance) as a brown oil.

2. Synthetic intermediate 19.3

DMF-DMA (19.0 g, 15.8 mmol) was added to a stirred solution of 19.2 (2.0 g, 7.9 mmol) in toluene (30 mL). The reaction mixture was heated to 110 °C for 40 h until the reaction was complete (by LCMS). The reaction mixture was concentrated to give 19.3 (2.0 g, crude substance) as a brown solid.

3. Synthetic intermediate 19.4

_{N₂H₄ - H₂O} (4.0 g, 65.0 mmol, 80%) was added to a stirred solution of 19.3 (2.0 g, 6.5 mmol) in EtOH (30 mL). The reaction mixture was stirred at 80 °C for 16 hours until the reaction was complete (by LCMS). The suspension was concentrated and diluted with _H₂O (50 mL), and extracted with EA (100 mL x 2). The concentrated organic layers were combined to give 19.4 (1.6 g, crude material) as a yellow solid.

4. Synthesis of intermediates/targets I-330 and I-331

To a stirred solution of 19.4 g (1.6 g, 5.8 mmol) _{and Cs₂CO₃} (4.7 g, 14.5 mmol) in DMF (50 mL), methyl 4-methylbenzenesulfonic acid (tetrahydro-2H-pyran-2-yl) ester (1.9 g, 6.9 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h. The suspension was diluted with _H₂O (100 mL) and extracted with EA (200 mL x 2), and the concentrated organic layers were combined. The crude product was purified by CC (silica gel, PE/EA = 2:1) and chiral-HPLC to give I-330 (1.5 g, yield: 69%) and I-331 (450 mg, yield: 21%) as yellow oils.

5. Synthetic intermediate 19.5

A stirred solution of I-330 (1.0 g, 2.67 mmol) and Pd/C (10% palladium/activated carbon, 400 mg) in MeOH (20 mL) was stirred at room temperature under a _H₂ atmosphere (1.0 atm) for 16 h until the reaction was complete (by LCMS). Hydrogen was removed under vacuum and Ar was introduced. The reaction mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to give 19.5 g (650 mg, crude matter) as a yellow oil.

6. Synthetic intermediate 19.6

A solution of 19.5 (300 mg, 1.06 mmol), trifluoromethanesulfonyl chloride (214 mg, 1.27 mmol), and _Et3N (268 mg, 2.65 mmol) in _CH2Cl2 (15 _mL ) was stirred at room temperature for 3 h. The solvent was removed under vacuum to give 19.6 (450 mg, crude substance) as a yellow oil.

7. Synthetic Target I-328

Ethynylcyclopropane (140 mg, 2.1 mmol), _K₂CO₃ (194 mg, 1.4 mmol), X-Phos (67 mg, 0.14 mmol), and PdCl₂(ACN) _₂ (19 mg, 0.07 mmol) were added to a stirred solution of 19.6 _g (200 mg, 0.7 mmol) _in MeCN (20 mL). The reaction mixture was stirred at 90 °C for 16 h until the reaction was complete (by LCMS). _H₂O (10 mL) and EA (20 mL) were added, and the organic phase was collected and evaporated under reduced pressure. The residue was purified by preparative HPLC to give I-328 (39.5 mg, yield: 17%) as a yellow oil.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 20: Characterization data of additional exemplary compounds

Example 20: Synthesis of I-332

I-332 synthesis scheme

1. Synthetic intermediate (5-bromo-2-iodophenethoxy)(tert-butyl)dimethylsilane

2-(5-bromo-2-iodophenyl)ethanol (1.40 g, 4.28 mmol), anhydrous DMF (4.28 mL), imidazole (471 mg, 6.85 mmol), and tert-butyldimethylchlorosilane (1.05 g, 6.85 mmol) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (15 mL) and heptane (15 mL), washed with semi-saturated _NH₄Cl (2 x 15 mL) and water (2 x 15 mL), dried over sodium sulfate, and concentrated to dryness. Co-evaporation with heptane (1 x 30 mL) gave (5-bromo-2-iodophenylethoxy)(tert-butyl)dimethylsilane (1.80 g, 95%) as a colorless oil.

¹ H NMR (400MHz, CDCl ₃ )δ7.63 (d, J=8.4Hz, 1H), 7.39 (d, J=2.4Hz, 1H), 7.02 (dd, J=8.4, 2.45Hz, 1H), 3.78 (t , J=6.6Hz, 2H), 2.90 (t, J=6.6Hz, 2H), 0.85 (s, J=2.9Hz, 9H), -0.05 (s, J=3.1Hz, 6H).

2. Synthetic intermediate (5-bromo-2-((trimethylsilyl)ethynyl)phenethoxy)(tert-butyl)dimethylsilane

A reaction flask was filled with (5-bromo-2-iodophenethoxy)(tert _{-butyl)dimethylsilane (1.75 g, 3.97 mmol), PdCl₂(PPh₃)₂ ( 84.4} mg, 119 μmol), and copper iodide (I) (22.8 mg, 119 μmol), and purged with nitrogen. Anhydrous THF (7.93 mL) was added, and the mixture was further degassed with nitrogen for 2 minutes. The flask was cooled to 0 °C in an ice bath, and triethylamine (1.68 mL, 11.9 mmol) and (trimethylsilyl)acetylene (623 μL, 4.36 mmol) were added, followed by degassed for 1 minute. The flask was then sealed with a diaphragm and a nitrogen balloon. The reaction mixture was allowed to warm to room temperature over 18 hours. The reaction mixture was diluted with EtOAc (40 mL), washed with semi-saturated _NH₄Cl (2 x 30 mL), dried over sodium sulfate, and concentrated. Purification by normal-phase FCC (50 g cartridge, 0 to 5% DCM/hexane gradient) yielded (5-bromo-2-((trimethylsilyl)ethynyl)phenethoxy)(tert-butyl)dimethylsilane (1.23 g, 57%), a pale yellow oil. LCMS(C): Rt = 2.65 min; 97% purity, non-ionized.

3. Synthetic intermediate (5-bromo-2-ethynylphenethoxy)(tert-butyl)dimethylsilane

A reaction flask was filled with (5-bromo-2-((trimethylsilyl)ethynyl)phenethoxy)(tert-butyl)dimethylsilane (1.23 g, 2.99 mmol), THF (7.40 mL), _H₂O (148 μL), MeOH (7.40 mL), and potassium carbonate (413 mg, 2.99 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with semi-saturated _NH₄Cl (20 mL) and extracted with 1:1 EtOAc:heptane (2 x 25 mL). The mixture was dried over sodium sulfate and concentrated to dryness to give a colorless oily product of (5-bromo-2-ethynylphenethoxy)(tert-butyl)dimethylsilane (0.970 g, 96%), which was used directly in the next step.

4. Synthetic intermediate 3-(4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-phenyl)propynate

(5-Bromo-2-ethynylphenylethoxy)(tert-butyl)dimethylsilane (970 mg, 2.86 mmol), anhydrous THF (9.53 mL), and cooled to -78 °C were added dropwise to a flame-dried flask. A solution of lithium bis(trimethylsilyl)amino (4.29 mL, 4.29 mmol) (1 M/THF) was added dropwise, and the reaction mixture was stirred at the stated temperature for 35 minutes. Methyl chloroformate (339 μL, 4.34 mmol) was added, and the mixture was stirred at -78 °C for 30 minutes, quenched by the addition of saturated _NH₄Cl (5 mL). Once heated to room temperature, the reaction mixture was extracted with EtOAc (30 mL), dried over sodium sulfate, and concentrated to give a crude mixture of methyl 3-(4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)propynate (1.29 g, crude substance), which was used directly in the next step.

5. Synthetic intermediate 5-(4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-phenyl)-1H-pyrazole-3-ol

Methyl 3-(4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)propynate (1.18 g, 2.86 mmol), anhydrous EtOH (14.3 mL), and hydrazine hydrate solution (302 μL, 5.72 mmol) (60 wt%) were added to a reaction flask under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 2 h. The reaction mixture was concentrated to dryness, co-evaporated with heptane (4 mL), and purified by reverse-phase FCC (30 g C18 cylinder, 10% to 70% ACN/10 mM ammonium formate gradient) to give 5-(4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-1H-pyrazole-3-ol (580 mg, 48%) as a brown solid. LCMS(C): Rt＝1.96min(M+H)+: 399.2; >98% purity.

6. Synthetic intermediate 5-(4-bromo-2-(2-hydroxyethyl)phenyl)-1H-pyrazole-3-ol

Add 5-(4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-1H-pyrazole-3-ol (580 mg, 1.46 mmol), anhydrous MeOH (14.6 mL), and concentrated hydrochloric acid (120 μL, 1.46 mmol) to a flask. Stir the reaction mixture at room temperature for 30 minutes. Concentrate the reaction mixture to dryness and co-evaporate it with MeOH and heptane. Wet mill the residue with DCM (15 mL) and filter to give 5-(4-bromo-2-(2-hydroxyethyl)phenyl)-1H-pyrazole-3-ol (445 mg, crude) (HCl salt) as a pink solid, which is used directly in the next step.

7. Synthetic intermediate 8-bromo-5,6-dihydropyrazolo[5,1-a]isoquinoline-2-ol

To a reaction flask, 5-(4-bromo-2-(2-hydroxyethyl)phenyl)-1H-pyrazole-3-ol (400 mg, 1.41 mmol) (HCl salt), triphenylphosphine (561 mg, 2.12 mmol), anhydrous THF (10.6 mL), and triethylamine (197 μL, 1.40 mmol) were added. The mixture was then cooled to 0 °C in an ice bath, and diisopropyl azodicarbonate (426 μL, 2.12 mmol) was added. After 5 minutes, the ice bath was removed, and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with semi-saturated _NH₄Cl (30 mL) and extracted with EtOAc (3 x 15 mL) and (CHCl₃ ∶IPA ( ₄ ∶ 1), 25 mL), dried over sodium sulfate, and concentrated to dryness. The residue was wet-milled with MeOH (8 ml) at 4 °C, the supernatant was aspirated, and the residue was dried under vacuum to give 8-bromo-5,6-dihydropyrazolo[5,1-a]isoquinoline-2-ol (257 mg, 62%) as a white solid. ^¹NMR (400 MHz, DMSO- _d⁶ ) δ 9.81 (s, 1H), 7.56 (d, J = 1.4 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 5.97 (s, 1H), 4.00 (t, J = 7.0 Hz, 2H), 3.13 (t, J = 7.0 Hz, 2H). LCMS(C): Rt = 1.43 min(M+H)+H: 267.0, 90% purity at 220 nm.

8. Synthetic intermediate 8-bromo-5,6-dihydropyrazolo[5,1-a]isoquinoline-2-ol

8-Bromo-5,6-dihydropyrazolo[5,1-a]isoquinoline-2-ol (80.0 mg, 302 μmol), methyl methanesulfonate (1,4-dioxane-2-yl) ester (118 mg, 604 μmol), and potassium carbonate (125 mg, 905 μmol) were added to a reaction vial. The vial was purged with nitrogen, and anhydrous DMF (1.00 mL) was added. The reaction mixture was stirred overnight at 60 °C. The second portion of methyl methanesulfonate (1,4-dioxane-2-yl) ester (118 mg, 604 μmol) and potassium carbonate (125 mg, 905 μmol) were added, and the reaction mixture was heated at 80 °C for 6 h. The reaction mixture was diluted with EtOAc (25 mL), washed with water (4 x 15 mL), dried over sodium sulfate, and concentrated to dryness. Wet milling with MeOH (2 x 3 ml) yielded 2-((1,4-dioxane-2-yl)methoxy)-8-bromo-5,6-dihydropyrazolo[5,1-a]isoquinoline (67.0 mg, 61%) as a white solid. LCMS (C): Rt = 1.63 min, >95% purity; (M+H+): 367.1

9. Synthesis of I-332

2-((1,4-dioxane-2-yl)methoxy)-8-bromo-5,6-dihydropyrazolo[5,1-a]isoquinoline (30.0 mg, 82.1 μmol), copper iodide (I) (1.56 mg, 8.21 μmol), and PdCl2(PPh3)2 (5.88 mg, 8.21 μmol) were added to a reaction vial, and the vial was purged with nitrogen. THF (479 μL) and triethylamine (92.5 μL, 657 μmol) were added, and the reaction mixture was further degassed with nitrogen for 2 min. Cyclopropylacetylene (57.3 μL, 657 μmol) was then added, and the reaction mixture was heated to 60 °C for 18 h. The reaction mixture was concentrated overnight. It was directly purified by reverse-phase FCC (30g C18 tube, 5% to 50% ACN/10mM ammonium formate gradient), and after lyophilization, 2-((1,4-dioxane-2-yl)methoxy)-8-(cyclopropylethynyl)-5,6-dihydropyrazolo[5,1-a]isoquinoline I-332 (15.0 mg, 52%) was obtained as a light brown powder.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 21: Characterization data of additional exemplary compounds

Example 21: Synthesis of I-303

I-303 synthesis scheme

1. Synthetic intermediate 7-bromo-3-((tetrahydro-2H-pyran-2-yl)methyl)-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazole

6-Bromo-3,4-dihydro-2(1H)-naphthol (80.0 mg, 355 μmol), (tetrahydro-2H-pyran-2-yl)methylamine (60.3 mg, 498 μmol), 1-azido-4-nitrobenzene (58.3 mg, 355 μmol), and 80 mg of 4A molecular sieve (briefly flame-dried under vacuum) were added to a flame-dried reaction vial, and the mixture was purged with nitrogen. Anhydrous toluene (800 μL) was added, and the reaction mixture was heated at 100 °C for 90 minutes. Once cooled, the reaction mixture was diluted with DCM (20 mL), washed with 1 M HCl (20 mL), dried over sodium sulfate, and concentrated. Purified by reverse-phase FCC (30 g C18 cartridge, 10% to 60% ACN/10 mM ammonium formate gradient), and lyophilized, 7-bromo-3-((tetrahydro-2H-pyran-2-yl)methyl)-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazole (71.0 mg, 57%) was obtained as a brown powder. ¹ H NMR (400MHz, CDCl3) δ7.86-7.78 (m, 1H), 7.42 (dd, J=8.1, 1.9Hz, 1H), 7.38 (d, J=1.9Hz, 1H), 4.40 (dd, J=14.2, 3.3Hz, 1H), 4.20 (dd, J=14.2, 7.7Hz, 1H), 3.93-3.84(m, 1H), 3.75-3.66(m, 1H), 3.39-3.27(m, 1H), 3.09-2.88(m, 4H), 1.90-1.83 (m, 1H), 1.73-1.64 (m, 1H), 1.59-1.43 (m, 3H), 1.35-1.19 (m, 1H). LCMS(C): Rt = 1.76 min(M+H)+: 350.1. 95% purity.

2. Synthesis of I-303

7-Bromo-3-((tetrahydro-2H-pyran-2-yl)methyl)-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazole (30.0 mg, 86.1 μmol), bis(acetonitrile)dichloropalladium(II) (2.26 mg, 8.61 μmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (10.8 mg, 25.8 μmol), and cesium carbonate (56.7 mg, 172 μmol) were added to a reaction vial and the mixture was purged with nitrogen. ACN (137 μL) was added and the reaction mixture was further degassed with nitrogen for 2 min. Cyclopropylacetylene (60.1 μL, 689 μmol) was then added and the reaction mixture was heated to 60 °C overnight. Semi-saturated NH₄Cl ( ₄ mL) was added and the mixture was extracted with EtOAc (2 x 5 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reversed-phase chromatography (30 g C18 cartridge; 5% to 50% ACN/10 mM ammonium formate gradient), and then purified by normal-phase chromatography (10 g SiO2 cartridge; 0 to 5% MeOH/DCM gradient) to obtain 7-(cyclopropylethynyl)-3-((tetrahydro-2H-pyran-2-yl)methyl)-4,5-dihydro-3H-naphtho[1,2-d][1,2,3]triazole I-303 (5 mg, 17%) as a white powder.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided below.

Table 22: Characterization data of additional exemplary compounds

Example 22: Synthesis of I-447

1. Synthetic intermediate 22.2

To a stirred solution of 5.3 (1 g, 3 mmol), methyl 3-methylazacyclobutane-3-carboxylate hydrochloride (742 _mg , 4.5 mmol), and _Cs₂CO₃ (2.9 g, 9 mmol) in toluene (20 mL), _RuPhosPdG₂ (100 mg) and X-Phos (200 mg) were added. The reaction mixture was stirred at 90 °C for 2 hours until complete (by LCMS). The suspension was diluted with _H₂O (40 mL), extracted with EA (40 mL x 2), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 1:1) to give 22.2 (1.1 g, yield: 95%) as a yellow oil.

2. Synthetic intermediate 22.3

To a stirred solution of 22.2 (1.1 g, 2.8 mmol) in anhydrous THF (20 mL) _{, NaBH₄} (319 mg, 8.4 mmol) and MeOH (10 mL) were added. The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with _H₂O (40 mL), extracted with EA (50 mL x 2), and concentrated to dryness. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 1:1) to give 22.3 (800 mg, yield: 80%) as a yellow oil.

3. Synthetic intermediate 22.4

Add Et3N (667 mg, 6.6 mmol) and _Ms2O (766 mg, 4.4 mmol) to a stirred solution of 22.3 g (800 mg, 2.2 mmol) in DCM (20 mL). Stir the reaction mixture at room temperature for 2 h until the reaction is complete. Dilute the suspension with _H2O (30 mL), extract with DCM (30 mL x 2), and concentrate. Use the crude product directly in the next step.

4. Synthetic intermediate 22.5

22.4 (900 mg, 2.1 mmol) was stirred overnight at room temperature in a stirred solution of _NH3 (20 mL, 7 N/ _CH3OH ) until the reaction was complete. The suspension was concentrated to give 22.5 (400 mg, yield: 54%) as a yellow oil. LC-MS m/z: 356.2 [M+H] ⁺ .

5. Synthesis of I-447

Add _Et₃N (85 mg, 0.84 mmol) and _Ac₂O (57 mg, 0.56 mmol) to a stirred solution of 22.5 g (100 mg, 0.28 mmol) in DCM (5 mL). Stir the reaction mixture at room temperature for 1 h until the reaction is complete. Dilute the suspension with _H₂O (30 mL), extract with DCM (30 mL x 2), and concentrate. The crude product was purified by preparative HPLC to give I-447 (54.44 mg, yield: 49%) as a white solid.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 23: Synthesis of I-609

1. Synthetic intermediate 23.2

L-proline (483 mg) and CuI (382 mg) were added to a stirred solution of 23.1 (6.0 g, _20.1 mmol), 3,3-dimethylazetane hydrochloride (2.4 g, 20.1 mmol), and _K₂CO₃ (5.5 g, 40.2 mmol) in DMSO (150 mL). The reaction mixture was stirred at 60 °C for 16 h until complete (by LCMS). The suspension was diluted with _H₂O (100 mL) and extracted with EA (50 mL x 2), and the concentrated organic layers were combined. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 2:1) to give 23.2 (900 mg, yield: 17%) as a yellow oil.

2. Synthetic intermediate 23.3

Pd( _PPh3 ) _2Cl2 ( ₃₈₂ mg) was added to a stirred solution of 23.2 (900 mg, 3.5 mmol) and 4-(tributyltinyl)-1-triphenylmethyl-1H-imidazole (2.3 g, 3.85 mmol) in dioxane (60 mL). The reaction mixture was stirred under reflux for 2 hours until complete (by LC-MS). The suspension was diluted with _H2O (100 mL) and extracted with EA (50 mL x 2), and the concentrated organic layers were combined. The crude product was purified by rapid column chromatography (silica gel, DCM/MeOH = 10:1) to give 23.3 (592 mg, yield: 35%) as a yellow solid. LC-MS m/z: 485.0 [M+H] ⁺ .

2. Synthetic intermediate 23.4

TFA (8 mL) was added to a stirred solution of 23.3 (592 mg, 1.2 mmol) in DCM (40 mL). The reaction mixture was stirred at room temperature for 2 hours until complete (by LC-MS). The suspension was diluted with _H₂O (100 mL) and extracted with DCM (50 mL x 2), and the concentrated organic layers were combined. The crude product was purified by rapid column chromatography (silica gel, DCM/MeOH = 10:1) to give 23.4 (261 mg, yield: 90%) as a yellow solid. LC-MS m/z: 243.1 [M+H] ^⁺ .

3. Synthetic target I-609

_K₂CO₃ (303 mg, 2.2 mmol) was added to a stirred solution of 23.4 g (261 mg, 1.1 mmol) of tetrahydro-2H-pyran-2-yl)methyl ₄ -methylbenzenesulfonic acid (2-Int-2, 297 mg, 1.1 mmol) in DMF (20 mL). The reaction mixture was stirred at 120 °C for 16 h until the reaction was complete (by LCMS). The suspension was diluted with _H₂O (100 mL) and extracted with EA (100 mL x 2), and the concentrated organic layers were combined. The crude product was purified by preparative HPLC to give I-609 (295 mg, yield: 79%) as a white solid.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 24: Synthesis of I-425

1. Synthetic intermediate 24.2

Magnesium ethynyl bromide (2.4 mL, 2.4 mmol) was added to a stirred solution of 24.1 g (400 mg, 2.02 mmol) in 5 mL of THF at 0 °C. The reaction mixture was stirred overnight at 40 °C until complete (by LCMS), 5 mL of aqueous _NH₄Cl solution was added, and the mixture was stirred at room temperature for another 30 minutes. The reaction mixture was diluted with 10 mL of _H₂O and extracted with DCM (10 mL x ₂ ). The combined organic phases were dried over anhydrous _Na₂SO₄ and concentrated to dryness. The crude product was used directly in the next step without further purification.

2. Synthetic intermediate 24.3

A solution of _CuSO₄ · _5H₂O (50 mg, 0.20 mmol) in water (0.5 mL) was added to a stirred solution of 24.2 (450 mg, 2.0 mmol) and 24.2.1 (283 mg, 2.02 mmol) in DMF (5 mL), and water containing sodium ascorbate (80 mg, 0.40 mmol) (0.5 mL) was added. The reaction mixture was stirred overnight at room temperature until complete (by LC-MS). The reaction mixture was diluted with _H₂O (10 mL) and extracted with EA (15 mL x 3). The combined organic layers were washed with brine (15 mL x ₃ ), dried over anhydrous _Na₂SO₄ , and concentrated to dryness. The crude product was purified by preparative HPLC to give 24.3 (450 mg, yield: 61%, in two steps) as a yellow solid. LC-MS m/z: 366.0 [M+H] ^⁺ .

3. Synthetic intermediate 24.4

Triethylsilane (429 mg, 3.70 mmol) was added to a stirred solution of 24.3 (450 mg, 1.23 mmol) in _CF3COOH (2 mL). The reaction mixture was stirred overnight at room temperature until complete (by LC-MS). The reaction mixture was diluted with _H2O (10 mL) and neutralized to pH 7–8 with _NaHCO3 , then extracted with EA (15 mL x ₃ ). The combined organic phases were dried over anhydrous _Na2SO4 and concentrated to dryness. The crude product was purified by preparative HPLC to 24.4 (300 mg, yield: 70%) as a yellow oil. LC-MS m/z: 350.0 [M+H] ⁺ .

4. Synthetic intermediate 24.5

_Cs₂CO₃ ( ₄₀ mg, 1.29 mmol), Pd(dppf) _Cl₂ (30 mg), and X-phos (30 mg) were added to a stirred solution of 24.4 (300 mg, 0.86 mmol) in DMF (5 mL) and _H₂O (0.5 mL), followed by backfilling with argon (three times). Tert-butyldimethyl(propane-2-alkynoxy)silane (438 mg, 2.58 mmol) was added to the resulting suspension, and the reaction mixture was stirred in a microwave at 80 °C for 30 min until complete (by LCMS). The reaction mixture was diluted with _H₂O (10 mL) and extracted with EA (15 mL x 3). The combined organic phases were washed with brine (10 mL x ₃ ), dried over anhydrous _Na₂SO₄ , and concentrated to dryness. The crude product was purified by preparative HPLC to give 24.5 (340 mg, yield: 90%) as a white solid. LC-MS m/z: 440.2[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ7.32 (s, 1H), 7.21-7.29 (m, 4H), 4.51 (s, 2H), 4.34-4.39 (m, 1H), 4.16-4.25 (m, 2H), 3.92-3.95 (m, 1H), 3.60-3.65 (m, 1H) ), 3.34-3.37(m, 1H), 1.82-1.86(m, 1H), 1.48-1.67(m, 4H), 1.45-1.48(m, 3H), 1.22-1.25(m, 1H), 0.92(s, 9H), 0.12(s, 6H).

5. Synthetic intermediate 24.6

Add _K₂CO₃ ( ₅₃₄ mg, 3.87 mmol) to a stirred solution of 24.5 g (340 mg, 0.77 mmol) in MeOH (3 mL). Stir the reaction mixture at 50 °C for 5 hours until complete (by LCMS). Concentrate the reaction mixture to dryness. Dilute the crude product with _H₂O (10 mL) and extract with EA (15 mL x 3). Combine the organic phases, dry them over _{anhydrous Na₂SO₄} and concentrate to dryness, then use them directly in the next step without further purification.

6. Synthetic intermediate 24.7

_Ms₂O (270 mg, 1.55 mmol) was added to a stirred solution of 24.6 (252 mg, 0.77 mmol) and TEA (235 mg, 2.32 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 0.5 h until the reaction was complete (by LCMS). The reaction mixture was diluted with _H₂O (10 mL) and extracted with DCM (15 mL x ₃ ). The combined organic phases were dried over anhydrous _Na₂SO₄ and concentrated to dryness, and then used directly in the next step without further purification.

7. Synthetic Target I-425

3,3-Dimethylazacyclobutane hydrochloride (141 mg, 1.16 mmol) was added to a stirred solution of 24.7 _g (312 mg, 0.77 mmol) and _K₂CO₃ (321 mg, 2.32 mmol) in DMF (3 mL). The reaction mixture was stirred overnight at room temperature until complete (by LCMS). The reaction mixture was diluted with _H₂O (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (10 mL x ₃ ), dried over anhydrous _Na₂SO₄ , and concentrated to dryness. The crude product was purified by preparative HPLC to give I-425 (32.1 mg, yield: 11%, in three steps) as a yellow oil.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 25: Synthesis of I-443

1. Synthetic target I-443

To a stirred solution of 13.4 (300 mg, 0.86 mmol) in toluene (10 mL) _, 3,3-dimethylazetane hydrochloride (104 mg, 0.86 mmol), _Cs₂CO₃ (836 mg, 2.57 mmol), X-Phos (82 mg, 0.17 mmol), and _RuPhosPdG₂ (130 mg) were added. The reaction mixture was stirred overnight at 90 °C. After depletion of the starting material (by LCMS), the reaction mixture was concentrated to an oily state, then water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layer was washed with water (10 mL x 3), dried, and concentrated. The crude material was purified by preparative HPLC to give I-443 (69 mg, 23% yield) as a white solid.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 26: Synthesis of I-469

1. Synthetic intermediate 26.2

KI (50 mg) was added to a stirred solution of 26.1 (500 mg, 3.7 mmol), 5-(chloromethyl)-3-methyl-1,2,4- _oxadiazole (528 mg, 4 mmol), and _Cs₂CO₃ (3.6 g, 11 mmol) in DMF (10 mL). The reaction mixture was stirred at 50 °C for 2 hours until complete (by LCMS). The suspension was diluted with _H₂O (20 mL), extracted with EA (20 mL x 2), and concentrated. The crude product was purified by preparative HPLC to give 26.2 (150 mg, yield: 18%) as a yellow oil.

2. Synthetic intermediate 26.3

A mixture of 26.2 mg (150 mg, 0.7 mmol), dimethyl 1-diazo-2-oxopropylphosphonate (192 mg, 1.0 mmol), and potassium carbonate (276 mg, 2 mmol) in methanol (5 mL) was stirred at 40 °C for 16 hours. The mixture was concentrated and used directly in the next step.

3. Synthetic target I-469

A solution of CuSO₄ _{· 5H₂O} (50 mg, 0.2 mmol) was dissolved in water (1 mL) and sodium ascorbate (60 mg, 0.3 mmol) was added. The resulting mixture was added to a solution of compound 26.3 (150 mg, 0.7 mmol) and 2-Int-4 (141 mg, 1.0 mmol) in DMF (4 mL). The reaction mixture was stirred overnight at room temperature, then diluted with water (8 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with brine (10 _mL ), dried over _Na₂SO₄ , and concentrated to dryness. The crude product was purified by preparative HPLC to give I-469 (40 mg, yield: 17%) as a yellow oil.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 27: Synthesis of I-461

1. Synthetic intermediate 27.2

To a solution of 27.1 (10.0 g, 49.2 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane (10.0 g, 59.1 mmol) in dioxane (500 mL) and water (50 mL ₎ , _K₃PO₄ (31.3 g, 147.6 mmol) and Pd(dppf) _Cl₂ (1.8 g, 2.46 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen. The suspension was diluted with _H₂O (300 mL), extracted with EA (500 mL x 2), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 3:1) to give 27.2 (7.5 g, yield: 93%) as a yellow oil.

2. Synthetic intermediate 27.3

A stirred solution of 27.2 (7.5 g, 45.7 mmol), Pd/C (10%/activated carbon, 3.0 g), and MeOH (200 mL) was stirred overnight at 30 °C under a _H₂ atmosphere (1.0 atm) until the reaction was complete (by LCMS). Hydrogen was removed under vacuum and Ar was introduced. The reaction mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to give 27.3 (5.5 g, 88%) as a grayish-white solid.

3. Synthetic intermediate 27.4

NBS (8.0 g, 44.4 mmol) was added to a solution of 27.3 (5.5 g, 40.4 mmol) in dioxane (150 mL) and _H₂O (50 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 2 hours. After depletion of the starting material (by LCMS), the reaction mixture was quenched with sodium thiosulfate solution, extracted and concentrated with EA (200 mL x 2). The crude product was purified by rapid column chromatography (silica gel, PE/EA = 3:1) to give 27.4 (5.5 g, yield: 63%) as a brown solid.

4. Synthetic intermediate 27.5

To a solution of 27.4 (5.5 g, 25.5 mmol) in THF (100 mL) _, tert-butyl nitrite (7.9 g, 76.5 mmol), CuI (7.3 g, 38.3 mmol), and _CH₂I₂ (13.7 g, 51.0 mmol) were added. The reaction mixture was stirred at 65 °C for 16 h and quenched with sodium thiosulfate solution. The mixture was extracted with EA (200 mL x 2) and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE) to give 27.5 (5.0 g, approximately 60% purity) as a yellow oil.

5. Synthetic intermediate 27.6

Ethynyltrimethylsilane (1.4 g, 13.8 mmol) was added to a nitrogen-bubbled solution of 27.5 (4.5 g, 13.8 mmol), Pd( _PPh3 ) _2Cl2 ( _9.67 mg, 1.38 mmol), CuI (526 mg, 2.76 mmol), and _Et3N (4.2 g, 41.4 mmol) in DMF (50 mL). The reaction mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The mixture was quenched with _H2O (100 mL), extracted with EA (100 mL x 2), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE) to give 27.6 (3.0 g, approximately 50% purity) as a brown oil.

6. Synthetic intermediate 27.7

_CuSO₄ (170 mg, 0.68 mmol) and sodium ascorbate (270 mg, 1.36 mmol) were added to a stirred solution of 27.6 (2.0 g, purity: approx. 50%, 3.4 mmol), _K₂CO₃ (940 mg, 6.8 mmol), 2-Int- ₄ (480 mg, 3.4 mmol) in DMF (20 mL) and H₂O ( ₂ mL). The reaction mixture was stirred at room temperature for 2 h until the reaction was complete (by LCMS). The mixture was quenched with _H₂O (50 mL), extracted with EA (100 mL x 3), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 1:2) to give 27.7 (1.1 g, yield: 89%) as a yellow solid.

7. Synthetic Target I-461

X-Phos (80 mg, 0.164 mmol) and _RuPhosPdG2 (64 mg, 0.082 mmol) were added to a stirred solution of _27.7 g (300 mg, 0.82 mmol), 3,3-dimethylazine hydrochloride (120 mg, 0.98 mmol), and _Cs₂CO₃ (802 mg, 2.46 mmol) in toluene (30 mL). The reaction mixture was stirred overnight at 90 °C under nitrogen until complete (by LCMS). The suspension was diluted with _H₂O (50 mL), extracted with EA (100 mL x 2), and concentrated. The crude product was purified by preparative HPLC to give I-461 (65 mg, yield: 21%) as a white solid.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 28: Synthesis of I-462

1. Synthetic intermediate 28.2

Pd(ACN)₂Cl₂ (43 mg, 0.164 mmol) and X- _Phos (157 mg, 0.328 mmol) were added to a stirred solution of 27.7 (600 mg, 1.64 mmol), tert-butyldimethyl(propane-2-alkynoxy) _silane (336 mg, 1.97 mmol), and _Cs₂CO₃ ( _1.6 g, 4.92 mmol) in _CH₃CN (40 mL) and _H₂O (5 mL). The reaction mixture was stirred overnight at 80 °C until complete (by LCMS). The suspension was diluted with _H₂O (50 mL), extracted with EA (100 mL x 2), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 1:4) to give 28.2 (300 mg, yield: 54%) as a yellow oil.

2. Synthetic intermediate 28.3

TEA (270 mg, 2.64 mmol) and _Ms₂O (300 mg, 1.76 mmol) were added to the stirred solution of 28.2 (300 mg, 0.88 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 3 min. Then _H₂O (15 mL) and DCM (10 mL) were added and the organic phase was collected and evaporated under reduced pressure to give 28.3 (350 mg, crude substance) as a yellow oil, which was used directly in the next step.

3. Synthetic target I-462

_K₂CO₃ ( ₃₅₀ mg, 2.51 mmol) was added to a stirred solution of 28.3 (350 mg, 0.836 mmol) and 3,3-dimethylazacyclobutane (122 mg, 1.0 mmol) in DMF (10 mL). The reaction mixture was stirred overnight at room temperature. The suspension was diluted with _H₂O (30 mL), extracted with EA (100 mL x 2), and concentrated. The residue was purified by preparative HPLC to give I-462 (64 mg, yield: 19%) as a white solid.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 29: Synthesis of I-483

1. Synthetic intermediate 29.2

Et3N (1.4 g, 14.1 mmol), PdCl2( _PPh3 ) _{2 (} 180 mg), CuI (89 mg, 0.47 mmol), and ethynyltrimethylsilane (921 mg, 9.4 mmol) were added to a stirred solution of 29.1 (1.3 g, 4.7 mmol) in DMF (20 mL). The reaction mixture was stirred at 40 °C for 16 h until complete (by LC-MS), then cooled to room temperature, diluted with water, and extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over anhydrous _{Na2SO4 ,} and concentrated to dryness. The crude product was purified by column chromatography (silica gel, PE/EA = 5:1) to give 29.2 (750 mg, yield: 68%) as a white solid. LC-MS m/z: 234.1 [M+H]+ ^.

2. Synthetic intermediate 29.3

CuSO₄ _{· 5H₂O} (75 mg, 0.3 mmol) and sodium ascorbate (119 mg, 0.9 mmol) were added to a stirred solution of 29.2 (0.7 g, 3.0 mmol) in MeOH (5 mL) and water (3 mL). The resulting mixture was added to a solution of 2-Int-4 (0.42 g, 3.0 mmol) and _K₂CO₃ (621 _mg , 4.5 mmol) in DMF (5 mL). The reaction mixture was stirred overnight at room temperature, then diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over _{anhydrous Na₂SO₄} , and concentrated to dryness. The crude product was purified by preparative TLC to 29.3 (450 mg, yield: 49%) as a brown oil. LC-MS m/z: 303.2 [M+H] ^⁺ .

3. Synthetic intermediate 29.4

Pd/C (10% w/w, 45 mg) was added to a stirred solution of 29.3 (450 mg, 1.49 mmol) in EA (10 mL). The reaction mixture was stirred at room temperature under a _H₂ atmosphere (1.0 atm) for 5 h until the reaction was complete (by LC-MS). The suspension was filtered and concentrated. The crude product was purified by preparative HPLC to 29.4 (146 mg, yield: 23%) as a brown oil. LC-MS m/z: 273.2 [M+H] ^⁺ .

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

4. Synthesize I-483

DIPEA (279 mg, 2.16 mmol) and HATU (205 mg, 0.54 mmol) were added to a solution of 29.4 g (146 mg, 0.54 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 15 min, then benzoic acid (62 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 2 h. After depletion of the starting material (by LCMS), water (30 mL) was added, the reaction mixture was extracted with ethyl acetate (30 mL x 3), washed with water (30 mL x ₃ ), dried over anhydrous _Na₂SO₄ and concentrated. The crude product was purified by preparative HPLC to give I-483 (34.78 mg, 17% yield) as a white solid.

Example 30: Synthesis of I-558

1. Synthetic intermediate 30.2

DIPEA (2.6 g, 20 mmol) and HATU (1.7 g, 4.4 mmol) were added to a solution of 30.1 (1.0 g, 4.0 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 15 min, then _NH3 - _H2O (4 mL) was added and the mixture was stirred at room temperature for 16 h. After depletion of the starting material (by LCMS), water (30 mL) was added, the mixture was extracted with ethyl acetate (30 mL x 3), washed with water (30 mL x ₃ ), dried over anhydrous _Na2SO4 , and concentrated. The crude product was purified by preparative HPLC to give 30.2 (0.4 g, 38% yield) as a yellow solid. LC-MS m/z: 262.0 [M+H] ⁺ .

2. Synthetic intermediate 30.3

Add ₆ mL of _B₂H₆ -THF to a solution of 30.2 (0.4 g, 1.5 mmol) in 10 mL of THF. Reflux the reaction mixture for 16 hours. After depletion of the starting material (by LC-MS), add 20 mL of MeOH and concentrate the mixture to dryness. The crude product was purified by preparative HPLC to 30.3 (340 mg, 92% yield) as a yellow oil. LC-MS m/z: 248.2 [M+H] ^⁺ .

3. Synthetic intermediate 30.4

_CH3COONa (1148 mg, 14 mmol) and BrCN (147 mg, 1.4 mmol) were added to a solution of 30.3 (340 mg, 1.4 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature for 2 h. After depletion of the starting material (by LC-MS), the mixture was concentrated to an oil. The crude product was purified by preparative HPLC to give 30.4 (300 mg, 79% yield) as a yellow oil. LC-MS m/z: 273.1 [M+H] ⁺ .

4. Synthetic intermediate 30.5

To a solution of 30.4 (300 mg, 1.1 mmol) in 10 mL of ACN _{, K₂CO₃} (455 mg, 3.3 mmol) and methyl 2-bromoacetate (167 mg, 1.1 mmol) were added. The reaction mixture was stirred at 50 °C for 6 hours. After depletion of the starting material (by LC-MS), the mixture was concentrated to dryness. The crude product was purified by preparative HPLC to give 30.5 (250 mg, 66% yield) as a yellow oil. LC-MS m/z: 345.0 [M+H] ^⁺ .

5. Synthetic intermediate 30.6

_H₂O (5 mL) and _H₂SO₄ ( ₃ mL) were added to a solution of 30.5 (250 mg, 0.7 mmol) in _Et₂O (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then heated to room temperature and stirred for 8 h. After depletion of the starting material (by LC-MS), the mixture was concentrated and the crude product was purified by preparative HPLC to give 30.6 (200 mg, 84% yield) as a yellow oil. LC-MS m/z: 331.0 [M+H] ^⁺ .

6. Synthetic intermediate 30.7

PdCl₂(PPh₃) _₂ ( _{30 mg} ) and CuI (30 mg) were added to a stirred solution of 30.6 (200 mg, 0.6 mmol), ethynyltrimethylsilane ( ₁₇₆ mg, 1.8 mmol), and TEA (3 mL) in DMF (3 mL). The reaction mixture was stirred at 40 °C for 16 hours until the reaction was complete. The suspension was diluted with _H₂O (20 mL), extracted with EA (20 mL x 2), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 100:1) to give 30.7 (150 mg, yield: 93%) as a yellow solid.

7. Synthetic intermediate 30.8

_K₂CO₃ ( ₂₇₆ mg, 2.0 mmol) was added to a stirred solution of 30.7 (150 mg, 0.5 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 2 h until the reaction was complete. The reaction mixture was concentrated and the crude product was purified by preparative HPLC to give 30.8 (70 mg, yield: 61%) as a yellow oil.

8. Synthetic target I-558

Sodium ascorbate (60 mg, 0.3 mmol) was added to a solution of CuSO₄ _{· 5H₂O} (25 mg, 0.1 mmol) in water (0.5 mL). The resulting mixture was added to a solution of compound 30.8 (70 mg, 0.3 mmol) and 2-Int-4 (70 mg, 0.5 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 2 h, then diluted with water (8 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with brine (10 _mL ), dried over _Na₂SO₄ , and concentrated to dryness. The crude product was purified by preparative HPLC to give I-558 (21 mg, yield: 19%) as a pale yellow solid.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 31: Synthesis of I-625

1. Synthetic intermediate 31.2

Pd( _ACN )₂Cl₂ (265 mg, 1.0 mmol) and _X - _Phos (972 mg, 2.0 mmol) were added to a stirred solution of 31.1 (2.0 g, 10.2 mmol), _{ethynylcyclopropane} ( _1.35 g, 20.5 mmol), and Cs₂CO₃ (10.0 g, 30.7 mmol) in CH₃CN (100 mL) and _H₂O (5 mL). The reaction mixture was stirred at 90 °C for 3 h until complete (by LCMS). The suspension was diluted with _H₂O (100 mL), extracted with EA (200 mL x 2), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 100:1) to give 31.2 (890 mg, yield: 48%) as a yellow solid.

2. Synthetic intermediate 31.3

_K₂CO₃ ( _1.9 g, 14.4 mmol) was added to a stirred solution of 31.2 (870 mg, 4.8 mmol) and hydroxylamine hydrochloride (672 mg, 9.6 mmol) in EtOH (50 mL). The reaction mixture was stirred under reflux for 16 hours. The suspension was concentrated, diluted with _H₂O (50 mL), extracted and concentrated with EA (100 mL x 2). The crude product was purified by rapid column chromatography (silica gel, EA) to give 31.3 (350 mg, yield: 34%) as a yellow solid.

3. Synthetic intermediate 31.4

DIPEA (303 mg, 2.34 mmol) was added to a stirred solution of 31.3 (250 mg, 1.17 mmol), 2-(tetrahydro-2H-pyran-2-yl)acetic acid (185 mg, 1.28 mmol), and HATU (533 mg, 1.40 mmol) in DCM (20 mL). The reaction mixture was stirred overnight at room temperature. The suspension was concentrated and diluted with _H₂O (50 mL), extracted with EA (100 mL x 2), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 1:2) to give 31.4 (220 mg, yield: 41%, purity: approx. 74%) as a yellow solid.

4. Synthetic target I-625

_K₂CO₃ (270 mg, 1.98 mmol) was added to a stirred solution of 31.4 _g (220 mg, 0.646 mmol) in dioxane (10 mL). The reaction mixture was stirred overnight at 90 °C. The suspension was concentrated and diluted with _H₂O (20 mL), extracted and concentrated with EA (50 mL x 2). The crude product was purified by preparative HPLC to give I-625 (86.4 mg, yield: 41%) as a white solid.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 32: Synthesis of I-646

1. Synthetic intermediate 32.2

To a stirred solution of 32.1 (2.0 g, 10.3 mmol) in DMF (25 mL) _, methyl 4-methylbenzenesulfonic acid (tetrahydro-2H-pyran-2-yl) ester (2-Int-2, 2.92 g, 10.8 mmol) and _K₂CO₃ (4.26 g, 30.9 mmol) were added. The mixture was stirred at 90 °C for 16 h. After depletion of the starting material (by LCMS), the mixture was concentrated to an oily state, then water (25 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3), washed with water (25 mL _x 3), dried over anhydrous _Na₂SO₄ , and concentrated. The crude material was purified by preparative HPLC to give 32.2 (2.1 g, 70% yield) as a white solid.

2. Synthetic intermediate 32.3

Isopropyl magnesium chloride (5 mL, 5 mmol) was added to a stirred solution of 32.2 (1.0 g, 3.42 mmol) in THF (25 mL). The mixture was stirred at room temperature for 4 h. Then, 5-bromo-2-methylbenzaldehyde (1.0 g, 3.42 mmol) was added to the mixture. The mixture was stirred overnight at 40 °C. After depletion of the starting material (by LCMS), the mixture was concentrated to an oil, and water (25 mL) was added. The mixture was extracted with ethyl acetate (25 mL x 3), washed with water (25 mL x ₃ ), dried over anhydrous _Na₂SO₄ , and concentrated. The crude material was purified by preparative HPLC to give 32.3 (600 mg, 48% yield) as a yellow oil.

3. Synthetic intermediate 32.4

To a stirred solution of 32.3 (600 mg, 1.64 mmol) in DMF (15 mL), NaH (180 mg, 60% w/w, 4.92 mmol) and _CH3I (694 mg, 4.92 mmol) were added. The mixture was stirred at room temperature for 2 h. After depletion of the starting material (by LCMS), water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3), washed with water (15 mL x ₃ ), dried over anhydrous _Na2SO4 , and concentrated. The crude material was purified by preparative HPLC to give 32.4 (500 mg, 80% yield) as a yellow oil.

4. Synthetic target I-646

Add 261 mg (3.96 mmol), _Cs₂CO₃ ( _1.29 g, 3.96 mmol), X-Phos (126 mg, 0.26 mmol), and Pd(ACN) _₂Cl₂ (35 mg) to a stirred solution of 32.4 g (500 mg, 1.32 mmol) in MeCN ( ₁₅ mL). Stir the mixture at 90 °C for 3 hours. After depletion of the starting material (by LCMS), concentrate the mixture to an oily state, add water (15 mL), extract with ethyl acetate (15 mL x 3), wash with water (15 mL x 3), dry over anhydrous _{Na₂SO₄ ,} and concentrate. Purify the crude material by preparative HPLC to give I-646 (111 mg, 23% yield) as a yellow oil.

Example 33: Synthesis of I-671 and I-672

1. Synthetic intermediate 33.2

BINAP (6.0 g, 9.73 mmol) and Pd₂(dba) _₃ (4.4 g, 4.86 mmol) were added to a stirred solution of _33.1 (10.0 g, 48.66 mmol), piperazine-1-carboxylate tert-butyl ester (9.97 g, 53.53 mmol), and _Cs₂CO₃ (31.7 g, 97.32 mmol) _in toluene (300 mL). The reaction mixture was stirred at 60 °C under nitrogen for 16 h until the reaction was complete (by LCMS). The suspension was diluted with _H₂O (500 mL), extracted with EA (500 mL x 3), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 5:1) to give 33.2 (12.0 g, yield: 79%) as a yellow solid.

2. Synthetic intermediate 33.3

33.2 (5.0 g, 16.08 mmol) was dissolved in dioxane (2 M) containing HCl (100 mL). The reaction mixture was stirred overnight at room temperature until the reaction was complete (by LCMS), and then concentrated to give 33.3 (3.5 g, yield: 88%) as a yellow solid.

3. Synthetic intermediate 33.4

_Cs₂CO₃ ( _11.8 g, 36.39 mmol) was added to a stirred solution of 33.3 (3.0 g, 12.13 mmol) and 2-(chloromethyl)pyridine hydrochloride (2.4 g, 1.456 mmol) in DMF (30 mL). The reaction mixture was stirred at 50 °C for 6 h. The suspension was diluted with _H₂O (50 mL), extracted with EA (100 mL x 3), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 3:1) to give 33.4 (3.2 g, yield: 87%) as a light brown solid.

4. Synthetic intermediate 33.5

X-Phos (1.0 g, 2.12 mmol) and Pd₂(dba)₃ (970 mg, 1.06 mmol) were added to a solution of 33.4 (3.2 g, 10.60 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl- _2,2′ -bi(1,3,2-dioxaborane) (3.2 g, 12.72 mmol), KOAc ( _2.1 g, 21.2 mmol) in dioxane (100 mL). The mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The suspension was diluted with _H₂O (100 mL), extracted with EA (100 mL x 3), and concentrated. The crude product was purified by rapid column chromatography (silica gel, PE/EA = 3:1) to give 33.5 (2.5 g, purity: approximately 69%) as a light brown oil.

5. Synthetic intermediates 33.7 and 33.7a

_K₂CO₃ (854 mg, 6.18 mmol) was added to a stirred solution of 33.6 (600 mg, 3.09 mmol) and (R) _-4 -methylbenzenesulfonic acid (tetrahydro-2H-pyran-2-yl)methyl ester (1.0 g, 3.71 mmol) in DMF (10 mL). The reaction mixture was stirred at 90 °C for 16 h. The suspension was diluted with _H₂O (20 mL), extracted with EA (50 mL x 2), and concentrated to give a mixture of 33.7 and 33.7a (900 mg, yield: crude substance) as a yellow semi-solid.

6. Synthetic targets I-672 and I-671

Pd( _PPh3 )4 (132 mg, 0.114 mmol) was added to a solution of 33.5 (450 mg, 1.14 mmol), a mixture of 33.7 and 33.7a ( ₄₀₁ mg, 1.37 mmol), and _Cs2CO3 ( _1.14 g, 3.42 mmol) in DMF (30 mL) and H2O ( ₃ mL). The mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The suspension was diluted with _H2O (50 mL), extracted and concentrated with EA (50 mL x 3). The crude substance was purified by rapid column chromatography (silica gel, EA) to obtain a crude product, which was then further purified sequentially by preparative HPLC and chiral HPLC to obtain I-671 (47.71 mg, yield: 9.1%) and I-672 (37.83 mg, yield: 7.6%) as brown oil.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 following Example 34.

Example 34: Synthesis of I-417

1. Synthetic intermediate 34.2

To a stirred solution of 13.3 (400 mg, 1.09 mmol) in DMF (15 mL), NaH (120 mg, 60% w/w, 3.28 mmol) and _CH3I (464 mg, 3.28 mmol) were added. The mixture was stirred overnight at room temperature. After depletion of the starting material (by LCMS), water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3), washed with water (15 mL x ₃ ), dried over anhydrous _Na2SO4 , and concentrated. The crude material was purified by preparative HPLC to give 34.2 (320 mg, 77% yield) as a yellow oil.

2. Synthetic target I-417

Add ethynylcyclopropane (156 mg, 2.37 mmol), _Cs₂CO₃ (770 _mg , 2.37 mmol), X-Phos (75 mg, 0.16 mmol), and Pd(ACN) _₂Cl₂ (21 mg) to a stirred solution of 34.2 mg (300 mg, _0.79 mmol) in MeCN (15 mL). Stir the mixture at 90 °C for 2 hours. After depletion of the starting material (by LCMS), concentrate the mixture to an oily state, add water (15 mL), extract with ethyl acetate (15 mL x 3), wash with water (15 mL x 3), dry over anhydrous _{Na₂SO₄ ,} and concentrate. Purify the crude material by preparative HPLC to give I-417 (90 mg, 31% yield) as a white solid.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Table 23 below.

Table 23: Characterization data of exemplary compounds

Example 35: Synthesis of I-432

Step 1:

A solution of 3-(3-methyl-4-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)prop-2-yn-1-ol (238.3 mg, 0.76 mmol) and triethylamine (0.13 mL, 0.912 mmol) in anhydrous dichloromethane (3.3 mL) was cooled to 0 °C and treated with methanesulfonyl chloride (59 μL, 0.76 mmol). The reaction mixture was stirred at 0 °C for 1 hour, then poured into 4 mL of water. The organic layer was separated. The aqueous phase was re-extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (0-50% EtOAc/hexane) to obtain 4-(4-(3-chloroprop-1-ynyl)-2-methylphenyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazole (39 mg, 15%).

Step 2:

A solution of 4-(4-(3-chloroprop-1-ynyl)-2-methylphenyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazole (38.5 mg, 0.12 mmol) in DMF (80 μL) was treated with sodium azide (15.6 mg, 0.24 mmol) and sodium iodide (3.6 mg, 0.024 mmol). The reaction mixture was stirred overnight at room temperature to give 4-(4-(3-azidoprop-1-ynyl)-2-methylphenyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazole. This substance will be used directly in the next step.

Step 3:

Under an inert atmosphere, a solution of acetylenebenzene (13.8 mg, 0.132 mmol) in THF (0.78 mL) was added to 4-(4-(3-azidopropyl-1-ynyl)-2-methylphenyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazole (40 mg, 0.12 mmol). Then, a solution of copper sulfate (3.1 mg, 0.012 mmol) in water (0.26 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes, and then ascorbic acid (10.7 mg, 0.06 mmol) was added. The reaction mixture was stirred and heated to 60 °C for 5 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride. The organic layer was separated, and the aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude compound. Purified by silica gel chromatography column (0-2% MeOH/DCM), 1-(3-(3-methyl-4-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)prop-2-ynyl)-4-phenyl-1H-1,2,3-triazole (11 mg, 21%) was obtained as a white solid.

^¹H NMR (400 MHz, chloroform-d) δ 8.07 (s, ¹H), 7.91–7.83 (m, ¹H), 7.84 (d, J = 1.4 Hz, ³H), 7.49–7.36 (m, ³H), 7.39–7.29 (m, ¹H), 5.47 (s, ²H), 4.53 (dd, J = 14.2, 2.9 Hz, ¹H), 4.33 (dd, J = 14.2, 7.6 Hz, ¹H), 3.99 (dd, J = 10.7, 2.0 Hz, ³H). Hz, 1H), 3.71 (ddt, J=10.1, 7.6, 2.6Hz, 1H), 3.57-3.26 (m, 1H), 2.47 (s, 3H), 1. 97-1.83 (m, 1H), 1.67 (t, J=13.7Hz, 2H), 1.41-1.12 (m, 3H), 1.01-0.74 (m, 1H).

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 36: Synthesis of I-494

Step 1

But-3-en-1-ol (5.0 mL, 58.1 mmol, 1.0 equivalent) was added to a mixture of ethyl propynate (6.4 mL, 63.2 mmol, 1.09 equivalent) and N-methylmorpholine (6.8 mL, 61.6 mmol, 1.06 equivalent) in _Et₂O (80 mL). The mixture was stirred at room temperature for 18 hours. The mixture was poured into a 0.5 M AcOH aqueous solution and the organic layer was separated, washed with brine, dried over _Na₂SO₄ , filtered, and concentrated to give (E,Z)-3-(but-3-en-1-yloxy)ethyl acrylate ( _9.1 g, 92%) as a yellow oil.

Step 2

TFA was slowly added over 30 minutes at 0°C to a mixture of (E,Z)-3-(but-3-en-1-yloxy)ethyl acrylate (9.1 g, 53.5 mmol, 1.0 equivalent) in DCM (150 mL). The mixture was stirred at 0°C for 2.5 h, then at 4°C for 3 days. The mixture was concentrated and diluted in EtOAc. The organic layer was washed with cold saturated _NaHCO3 aqueous solution and brine, dried over _Na2SO4 , filtered, and concentrated. The residue was purified on silica gel (0-20% EtOAc/hexane) to give 2,2,2-trifluoroacetic acid _2- (2-ethoxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl ester (11.72 g, 77%) as a colorless oil.

Step 3

A solution _{of K₂CO₃} (5.83 g, 42.2 mmol, 1.2 equivalents) in _H₂O (140 mL) was added to a mixture of 2,2,2-trifluoroacetic acid 2-(2-ethoxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl ester (9.99 g, 35.1 mmol, 1.0 equivalents) in MeOH (56 mL). After stirring at room temperature for 20 minutes, acetic acid was added until pH 7 was reached _. DCM was added and the organic layer was separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated to give ethyl 2-(4-hydroxytetrahydro-2H-pyran-2-yl)acetate (6.4 g, 97%) as a colorless oil.

Step 4

At 0 °C, _Cr₂O₃ ( _2M / _H₂SO₄ , 17 _mL , 34.0 mmol, 1.0 equivalence) was added dropwise to a mixture of ethyl 2-(4-hydroxytetrahydro-2H-pyran-2-yl)acetate (6.4 g, 34.0 mmol, 1.0 equivalence) and acetone (136 mL). After stirring at 0 °C for 30 min, a saturated aqueous solution _{of NaHSO₃} was added, followed by the addition of EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified on silica gel (0-30% EtOAc/hexane) to give ethyl _2- (4-oxotetrahydro-2H-pyran-2-yl)acetate (3.27 g, 52%) as a colorless oil.

Step 5

At 0 °C, DAST (2.84 mL, 21.5 mmol, 4.0 equivalence) was added dropwise to a mixture of ethyl 2-(4-oxotetrahydro-2H-pyran-2-yl)acetate (1.0 g, 5.37 mmol, 1.0 equivalence) and DCE ( _{21 mL). The mixture was stirred at 70 °C for 45 minutes and then cooled to 0 °C. A saturated aqueous solution of NaHCO3 was carefully added dropwise, and the mixture was warmed to room temperature. DCM was added, and the organic layer was separated, washed with brine, dried over Na2SO4 , filtered} , and concentrated. The residue was purified on silica gel (0-20% EtOAc/hexane) to give ethyl 2-(4,4-difluorotetrahydro-2H-pyran-2-yl)acetate (846 mg, 76%) as a colorless oil.

Step 6

A solution of LiOH (554 mg, 13.2 mmol, 3.0 equivalent) in _H₂O (12 mL) was added to a mixture of ethyl 2-(4,4-difluorotetrahydro-2H-pyran-2-yl)acetic acid (916 mg, 4.4 mmol, 1.0 equivalent) in dioxane (24 mL). The mixture was stirred at room temperature for 18 hours. 1 N HCl was added until pH 2 was reached, and then EtOAc was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated to give 2-(4,4-difluorotetrahydro-2H-pyran-2-yl)acetic acid (793 mg, quartet) as a yellow solid.

Step 7 (Purification)

At -40°C, a solution of _KMnO₄ (73 mg, 0.46 mmol, 0.25 equivalents) in _H₂O (1.0 mL) was added dropwise to a mixture of 2-(4,4-difluorotetrahydro-2H-pyran-2-yl)acetic acid (278 mg, 1.54 mmol, 1.0 equivalents) and _MgSO₄ (46 mg, 0.46 mmol, 0.3 equivalents) in EtOH (5.0 mL). The mixture was stirred at -40°C for 1 hour, and then a saturated aqueous solution _{of NaHSO₃} was added. The mixture was warmed to room temperature and then filtered onto diatomaceous earth. The filtrate was concentrated and the residue was acidified to pH 2 with 1N HCl. The resulting mixture was extracted twice with EtOAc. After washing the combined organic layers with brine, drying _{with Na₂SO₄} , filtering and concentrating, 2-(4,4-difluorotetrahydro-2H-pyran-2-yl)acetic acid (250 mg, 90%) was obtained as a yellow solid.

Step 8

A mixture of 2-(4,4-difluorotetrahydro-2H-pyran-2-yl)acetic acid (242 mg, 1.34 mmol, 1.2 equivalents) and sulfonyl chloride (0.72 mL, 11.2 mmol, 10 equivalents) was stirred under reflux for 1 hour. Once at room temperature, the mixture was concentrated and dissolved in DMF (1 mL). The resulting solution was added dropwise to a mixture of (5-bromo-2-methylphenyl)hydrazine hydrochloride (266 g, 1.12 mmol, 1.0 equivalents) and _Et3N (0.94 mL, 6.72 mmol, 6.0 equivalents) in DMF (1.8 mL) at 0 °C. The mixture was heated to room temperature and stirred at room temperature _for 3 hours. The mixture was poured into a saturated aqueous solution of _NH4Cl and EtOAc was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over _Na2SO4 , filtered, and concentrated. The residue was purified on silica gel (20-70% EtOAc/hexane) to give N′-(5-bromo-2-methylphenyl)-2-(4,4-difluorotetrahydro-2H-pyran-2-yl)acetylhydrazine (227 mg, 56%) as a beige solid.

Step 9

At 0 °C, a solution of phosgene (20% in toluene, 1.64 mL, 3.11 mmol, 5.0 equivalent) was added dropwise to a mixture of N′-(5-bromo-2-methylphenyl)-2-(4,4-difluorotetrahydro-2H-pyran-2-yl)acetylhydrazine (226 mg, 0.622 mmol, 1.0 equivalent) in DCM (4.6 mL). The mixture was heated to room temperature and stirred at room temperature for 75 minutes. The mixture was concentrated and the residue was purified by silica gel chromatography (0-30% EtOAc/hexane) to give 3-(5-bromo-2-methylphenyl)-5-((4,4-difluorotetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one (192 mg, 79%) as a pale yellow oil.

Step 10

Cyclopropylacetylene (415 μL, 4.91 mmol, 10 equivalents) was added to a solution of 3-(5-bromo-2-methylphenyl)-5-((4,4-difluorotetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one (191 mg, 0.491 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (57 mg, 0.049 mmol, 0.1 equivalent), and CuI (9 mg, 0.049 mmol, 0.1 equivalent) in a bubbling solution of _Et3N (2.5 mL) and DME (2.5 mL) in _N2 . After bubbling with _N2 for 1 minute, the reaction mixture was stirred at 90 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and MTBE was added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexane) to give a yellow oily substance, 3-(5-(cyclopropylethynyl)-2-methylphenyl)-5-((4,4-difluorotetrahydro-2H-pyran-2-yl)methyl)-1,3,4-oxadiazol-2(3H)-one (163 mg, 89%). ^¹H NMR (400 MHz, CDCl₃ ₎ )δ7.38 (d, J=1.6Hz, 1H), 7.31 (dd, J=7.9, 1.7Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 4.07 (ddd, J= 11.5, 6.1, 2.8Hz, 1H), 4.02-3.91 (m, 1H), 3.64 (td, J=11.9, 2.8Hz, 1H), 2.92-2.78 (m, 2H) , 2.29 (s, 3H), 2.21 (tdt, J=10.6, 5.1, 2.6Hz, 1H), 2.10-1.90 (m, 2H), 1.81 (dddd, J=32.8, 13.3, 11.7, 3.8Hz, 1H), 1.42 (tt, J=8.2, 5.1Hz, 1H), 0.89-0.82 (m, 2H), 0.81-0.75 (m, 2H). ¹³ C NMR (101MHz, CDCl ₃ )δ153.71, 152.05, 134.19, 133.46, 132.24, 131.31, 129.35, 123.16, 122.76, 120.78, 118.33, 94.25, 74.38, 70.9 2, 70.82, 64.39, 64.30, 39.97, 39.76, 39.73, 39.52, 34.48, 34.27, 34.24, 34.03, 32.83, 32.82, 18.02, 8.59, 0.09.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 37: Synthesis of I-522

Step 1:

A solution of (3,3-dimethyloxane-2-yl)methylamine hydrochloride (189 mg, 1 mmol) in methanol (10 mL) was treated with potassium carbonate (276.4 mg, 2 mmol), copper sulfate hydrate (50.9 mg, 0.2 mmol), and imidazole 1-sulfonyl azide hydrochloride (220.6 mg, 1 mmol). The reaction mixture was stirred overnight at room temperature. The blue color of the reaction mixture turned purple. The solvent was evaporated without heating, and the reaction mixture was dissolved in 3.5 mL of methanol and 2 mL of ethyl acetate, and then filtered. The solvent was then evaporated again, and the crude product was dissolved in a minimal amount of water. The pH was adjusted to 3 by adding 3 M HCl aqueous solution. The reaction mixture was then extracted three times with ethyl acetate.

The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated without heating to obtain crude 2-(azidomethyl)-3,3-dimethyltetrahydro-2H-pyran, which was used directly in the next step.

Step 2:

Under an inert atmosphere, a solution of 4-(cyclopropylethynyl)-1-ethynyl-2-toluene (198.3 mg, 1.1 mmol) in THF (6.5 mL) was added to 2-(azidomethyl)-3,3-dimethyltetrahydro-2H-pyran (169 mg, 1.00 mmol). Then, a solution of copper sulfate (25.5 mg, 0.1 mmol) in water (2.2 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes, and then ascorbic acid (88.9 mg, 0.50 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride. The organic layer was separated, and the aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude compound. Purified by silica gel column chromatography (0-40% ethyl acetate/hexane), 4-(4-(cyclopropylethynyl)-2-methylphenyl)-1-((3,3-dimethyltetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazole (223 mg, 64%) was obtained as a white solid.

¹ H NMR (400MHz, chloroform-I) δ7.80 (s, 1H), 7.75 (d, J=8.3Hz, 1H), 7.28 (d, J=7.3Hz, 2H ), 4.70 (d, J=14.1Hz, 1H), 4.10 (dd, J=14.0, 9.8Hz, 1H), 3.97 (dd, J=11.2, 4. 9Hz, 1H), 3.38 (d, J=9.6Hz, 1H), 3.34-3.17 (m, 1H), 2.42 (s, 3H), 1.97-1.73 ( m, 1H), 1.62-1.48 (m, 1H), 1.48-1.35 (m, 3H), 1.04 (s, 6H), 0.95-0.75 (m, 4H).

¹³ C NMR (101 MHz, chloroform-d) δ 146.27, 135.16, 133.97, 129.48, 129.26, 128.53, 123.41, 123.26, 93.87, 84.30, 77.43, 77.12, 76.80, 75.77, 68.72, 51.04, 38.91, 32.35, 27.50, 22.72, 21.34, 19.15, 8.68, 0.27.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 38: Synthesis of I-537

Step 1:

_Cs₂CO₃ ( _1.75 g, 5.37 mmol, 2.0 equivalent) was added to a mixture of bromobenzene (282 μ g, 2.68 mmol, 1.0 equivalent), tert-butyl 3-amino-3-methylazacyclobutane-1-carboxylate (500 mg, 2.68 mmol, 1.0 equivalent), _Pd₂ (dba) _₃ (246 mg, 0.27 mmol, 0.1 equivalent), and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (233 mg, 0.40 mmol, 0.15 equivalent) in dioxane (13.4 mL) bubbling _N₂ . After 1 minute of N₂ bubbling, the mixture was stirred at 100 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of NH₄Cl and EtOAc was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexane) to give tert-butyl 3-methyl-3-(phenylamino)azacyclobutane-1-carboxylate (489 mg, 70%), which was a yellow oil.

Step 2

Add 2.5 mL of TFA to the mixture of tert-butyl 3-methyl-3-(phenylamino)azacyclobutane-1-carboxylate (488 mg, 1.86 mmol, 1.0 equivalent) and DCM (5.0 mL). Stir the mixture at room temperature for 3 hours. Concentrate the mixture and use the residue as is for the next step.

Step 3

_Cs₂CO₃ (485 _mg , 1.49 mmol, 5.0 equivalents) was added to a mixture of 4-(4-bromo-2-methylphenyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazole (100 mg, 0.297 mmol, 1.0 equivalents), 3-methyl-N-phenylazyrazine-3-aminebis(trifluoroacetic acid) (116 mg, 0.297 mmol, 1.0 equivalents), _Pd₂ (dba) _₃ (27 mg, 0.030 mmol, 0.1 equivalents), and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (26 mg, 0.045 mmol, 0.15 equivalents) in dioxane (3.0 mL) bubbling _N₂ . After 1 minute of _N₂ bubbling, the mixture was stirred at 100 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of NH4Cl and EtOAc was added. The organic layer was separated, dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (10-60% EtOAc/hexane) to give 3-methyl-1-(3-methyl- _4- (1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N-phenylazacyclobut-3-amine (55 mg, 44%) as a yellow solid. ^¹H NMR (400 MHz, CDCl3 ₎ )7.70 (s, 1H), 7.67 (d, J=8.3Hz, 1H), 7.20 (dd, J=8.4, 7.4Hz, 2H), 6.75 (t, J=7.3Hz, 1H), 6.60-6.52 (m, 2H), 6.41 (dd, J=8.3, 2.5Hz, 1H), 6.36 (d, J=2.2Hz, 1H), 4.50 (dd, J=14.1, 3.2Hz, 1H), 4.33 (dd, J=14.2 , 7.5Hz, 1H), 4.07-3.92 (m, 6H), 3.71 (dtd, J＝11.1, 5.3, 2.8Hz, 1H), 3.41 (td, J＝11.3, 4.3Hz, 1H), 2.42 (s, 3H), 1.93-1.83 (m, 1H), 1.73 (s, 3H), 1.68 (d, J=12.4Hz, 1H), 1.59-1.45 (m, 3H), 1.34-1.20 (m, 1H). ¹³ C NMR (101MHz, CDCl ₃ )δ150.77, 147.15, 145.17, 136.37, 129.76, 129.34, 122.40, 119.76, 117.85, 114.06, 1 13.34, 109.27, 76.23, 68.45, 63.77, 55.01, 51.11, 28.77, 25.61, 24.83, 22.87, 21.65.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 39: Synthesis of I-570

Step 1:

Trifluoroacetic acid (1.26 mL, 16.5 mmol, 20.0 equivalents) was slowly added to an ice-cold solution of tert-butyl carbamate (340 mg, 0.827 mmol, 1.00 equivalents) in _CH₂Cl₂ ( ₄ mL). The mixture was stirred at room temperature for 2 hours. A saturated solution of _NaHCO₃ was added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain 3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-amine (237 mg, 92%), an amber-colored semi-solid.

Step 2

A saturated solution of _NaHCO3 (0.32 mL) was added to a solution of 3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-amine (100 mg, 0.322 mmol, 1.00 equivalent) in dioxane (0.32 mL). The mixture was stirred for 30 minutes, and then isopropyl chloroformate (0.40 mL, 0.402 mmol, 1.25 equivalent, 1.0 M/PhMe) was added. The mixture was stirred vigorously for 20 hours, then diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, _dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel (15-100%) to give (3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-yl)carbamate (24 mg, 19%) as a pale yellow solid.

¹ H NMR (400MHz, CDCl ₃ )δ8.47 (d, J=1.5Hz, 1H), 8.22 (s, 1H), 7.59 (s, 1H), 5.05-4.90 (m, 2H), 4.49 (dd, J=14 .1, 3.3Hz, 1H), 4.34 (dd, J=14.1, 7.5Hz, 1H), 4.22 (d, J=4.8Hz, 2H), 3.97 (d, J=11.1H z, 1H), 3.70 (dtd, J=10.9, 5.3, 2.7Hz, 1H), 3.38 (td, J=11.3, 3.0Hz, 1H), 2.70 (s, 3H) , 1.95-1.79 (m, 1H), 1.66 (d, J=12.7Hz, 1H), 1.58-1.44 (m, 3H), 1.35-1.20 (m, 7H)ppm. ¹³ C NMR (101MHz, CDCl ₃ )δ149.06, 148.67, 147.80, 141.74, 131.10, 125.48, 117.97, 88.62, 80.09, 75.87, 68.70, 68.39, 55.06, 31.42, 28.77, 25.46, 22.78, 22.10, 20.64ppm.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 40: Synthesis of I-617

Step 1

Sodium azide (0.5 g, 7.72 mmol, 2.0 equivalent) was added to a solution of 4-methylbenzenesulfonic acid (5,5-dimethyl-1,3-dioxane-2-yl)methyl ester (1.16 g, 3.86 mmol, 1.0 equivalent) in DMF ( _7.7 mL ₎ . The mixture was stirred at 90 °C for 18 hours. Once at room temperature, _H₂O and MTBE were added. The organic layer was separated and the aqueous layer was extracted with MTBE. The combined organic layers were washed with 1N NaOH and brine, dried over Na₂SO₄, filtered, and concentrated to give 2-(azidomethyl)-5,5-dimethyl-1,3-dioxane (661 mg, tetrette) as a pale yellow solid.

Step 2

_K₂CO₃ (646 _mg , 4.67 mmol, 5.0 equivalent) was added to a mixture of 2-(azidomethyl)-5,5-dimethyl-1,3-dioxane (160 mg, 0.935 mmol, 1.0 equivalent), 1-(5-(cyclopropylethynyl)-2-methylphenyl)-3-(trimethylsilyl)prop-2-yn-1-ol (264 mg, 0.935 mmol, 1.0 equivalent), _CuSO₄ · _5H₂O (117 mg, 0.47 mmol, 0.5 equivalent), and ascorbic acid (165 mg, 0.935 mmol, 1.0 equivalent) in DMF (6.0 mL). After stirring at room temperature for 2 hours, the mixture was poured into a saturated aqueous solution of _NH₄Cl and EtOAc was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (10-70% EtOAc/hexane) to give a white, foamy (5-(cyclopropylethynyl)-2-methylphenyl)(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (298 mg, 84%).

Step 3

At 0 °C, methanesulfonyl chloride (47 μL, 0.610 mmol, 1.2 equivalents) was added to a solution of (5-(cyclopropylethynyl)-2-methylphenyl)(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (194 mg, 0.509 mmol, 1.0 equivalents) and Et ₃ N (106 μL, 0.763 mmol, 1.5 equivalents) in DCM (2.5 mL). The reaction mixture was heated to room temperature and stirred at room temperature for 4 hours. Water and DCM were added to the mixture and the organic layer was separated. The _mixture was dried over _Na₂SO₄ , filtered, and concentrated to give a yellow solid of methanesulfonic acid (5-(cyclopropylethynyl)-2-methylphenyl)(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl ester (209 mg, 89%).

Step 4

DIPEA (158 μL, 0.907 mmol, 4.0 equivalents) was added to a mixture of methanesulfonic acid (5-(cyclopropylethynyl)-2-methylphenyl)(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl ester (104 mg, 0.226 mmol, 1.0 equivalents) in 2,2,2-trifluoroethane-1-ol (1.0 mL). The mixture was stirred at 80 °C for 100 min. Once at room temperature, the mixture was concentrated and the residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give 4-((5-(cyclopropylethynyl)-2-methylphenyl)(2,2,2-trifluoroethoxy)methyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (86 mg, 82%) as a colorless oil.

¹ H NMR (400MHz, CDCl ₃ )δ7.58 (d, J=1.5Hz, 1H), 7.45 (s, 1H), 7.23 (dd, J=7.8, 1.7Hz, 1H), 7.04 (d, J=7.8Hz , 1H), 5.88 (s, 1H), 4.74 (t, J=4.1Hz, 1H), 4.53-4.38 (m, 2H), 4.04-3.78 (m, 2H), 3.5 9(d, J＝11.2Hz, 2H), 3.40(d, J＝11.3Hz, 2H), 2.21(s, 3H), 1.50-1.41(m, 1H), 1.02(s , 3H), 0.87 (ddd, J=11.3, 5.4, 2.2Hz, 2H), 0.82 (td, J=5.5, 2.6Hz, 2H), 0.70 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ147.30, 137.12, 135.13, 131.27, 130.66, 128.99, 127.98, 125.22, 124.13, 122.45, 121.85, 97.96, 93.1 0, 76.95, 76.93, 75.67, 74.46, 66.54, 66.19, 65.85, 65.51, 53.13, 30.11, 22.66, 21.60, 19.12, 8.55, 0.14.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 41: Synthesis of I-669

Step 1

Concentrated _H₂SO₄ (149 _μL , 2.79 mmol, 0.4 equivalents) was added to a mixture of 2-(5-bromo-2-methylphenyl)acetic acid (1.6 g, 6.98 mmol, 1.0 equivalents) and MeOH (35 mL). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and dissolved in MTBE. Water was added and the organic layer was separated. The mixture was washed twice with water and _brine , dried over _Na₂SO₄ , filtered, and concentrated to give methyl 2-(5-bromo-2-methylphenyl)acetic acid (1.68 g, 99%) as a colorless oil.

Step 2

At 0 °C, a solution of methyl 2-(5-bromo-2-methylphenyl)acetate (1.68 g, 6.91 mmol, 1.0 equivalent) in THF (4.0 mL) was added dropwise to a mixture of LiAlH4 (312 mg, 8.29 mmol, 1.2 equivalent) in THF (10 mL). After stirring at 0 °C for 2.5 hours, a saturated aqueous solution _{of Na₂SO₄} was slowly added dropwise. The mixture was filtered and the filtrate was extracted twice with MTBE. The combined organic layers were washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated to give 2-(5-bromo-2-methylphenyl)ethanol-1-ol (955 mg, 64%) as a colorless oil.

Step 3

Dess-Martin reagent (3.77 g, 8.88 mmol, 2.0 equivalent) was added to a mixture of 2-(5-bromo-2-methylphenyl)ethane-1-ol (955 mg, 4.44 mmol, 1.0 equivalent) and DCM (22 mL). The mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium metabisulfite and DCM were added. The organic layer was separated, washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified on silica gel (0-15% EtOAc/hexane) to give 2-(5-bromo-2-methylphenyl)acetaldehyde (403 mg, 45%) as a colorless oil.

Step 4

Ohira-Bestmann reagent (0.40 mL, 2.64 mmol, 1.4 equivalences) was added to a _mixture of 2-(5-bromo-2-methylphenyl)acetaldehyde (402 mg, 1.89 mmol, 1.0 equivalences) and _Cs₂CO₃ (1.84 g, 5.66 mmol, 3.0 equivalences) in MeOH (19 mL). After stirring at room temperature for 1 hour, hexane and _H₂O were added. The organic layer was separated and the aqueous layer was extracted with hexane. The combined organic layers were washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated to give 4-bromo-1-methyl-2-(prop-2-yn-1-yl)benzene (356 mg, 90%) as a yellow oil.

Step 5

A solution of _CuSO₄ (42 mg, 0.17 mmol, 0.1 equivalent) in _H₂O (4.0 mL) was added to a solution of 2-(azidomethyl)-5,5-dimethyl-1,3-dioxane (291 mg, 1.70 mmol, 1.0 equivalent) and 4-bromo-1-methyl-2-(prop-2-yn-1-yl)benzene (355 mg, 1.70 mmol, _1.0 equivalent) in THF (12 mL). After stirring for 1 minute at room temperature, ascorbic acid (150 mg, 0.85 mmol, 0.5 equivalent) was added. The mixture was stirred at room temperature for 2.5 hours. The mixture was poured into a saturated aqueous solution of NH₄Cl and EtOAc was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to give 4-(5-bromo-2-methylbenzyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (334 mg, 52%), which was a yellow oil.

Step 6

Cyclopropylacetylene (0.25 mL, 2.92 mmol, 10 equivalents) was added to a mixture of 4-(5-bromo-2-methylbenzyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (111 mg, 0.292 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (34 mg, 0.029 mmol, 0.1 equivalent), and CuI (6 mg, 0.029 mmol, 0.1 equivalent) in a N2 bubbling mixture of _Et3N (1.5 mL) and DME (1.5 mL). After bubbling with N2 for 1 minute, the reaction mixture was stirred at 90 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and MTBE was added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to give 4-(5-(cyclopropylethynyl)-2-methylbenzyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (80 mg, 75%), which was a yellow oil.

^1H NMR (400MHz, CDCl3 ₎ )δ7.19 (s, 2H), 7.16 (dd, J=7.7, 1.7Hz, 1H), 7.05 (d, J=7.8Hz, 1H), 4.73 (t, J=4.4Hz, 1H), 4.42 (d, J=4.4Hz, 2H), 4.01 (s, 2H), 3.64-3.55 (m, 2H), 3.39 (d, J=10.6Hz, 2H), 2.24 (s, 3H), 1.42 (tt, J=8.2, 5.1Hz, 1H), 1.08 (s , 3H), 0.84 (ddt, J=8.3, 5.6, 2.8Hz, 2H), 0.81-0.74 (m, 2H), 0.70 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ146.61, 137.29, 136.11, 132.54, 130.30, 129.94, 123.16, 121.49, 98.38, 92.69, 76.97, 75.71, 53.02, 30.16, 29.95, 22.79, 21.65, 19.45, 8.52, 0.13.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 42: Synthesis of I-679

Step 1

A mixture of KOH (574 mg, 10.2 mmol, 4.3 equivalents) in H₂O (0.57 mL) was added to a mixture of 2-(5-bromo-2-methylphenyl)acetonitrile, tetramethylammonium bromide (115 mg, 0.357 mmol, 0.15 equivalents), and 1,2-dibromoethane (0.31 mL, 3.57 mmol, 1.5 equivalents). The mixture was stirred at 50 °C for 18 hours. Once at room temperature, 1 N HCl and MTBE were added. The organic layer was separated, washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified on silica gel (0–10% EtOAc/hexane) to give 1-(5-bromo-2-methylphenyl)cyclopropane-1-carboxynitrile (443 mg, 79%) as a grayish-white solid.

Step 2

At 0 °C, diisobutylaluminum hydride (1 M/DCM, 2.48 mL, 2.48 mmol, 1.5 equivalences) was added dropwise to a mixture of 1-(5-bromo-2-methylphenyl)cyclopropane-1-carboxynitrile (390 mg, 1.65 mmol, 1.0 equivalences) and toluene (8.0 mL). The mixture was heated to room temperature and stirred at room temperature for 30 minutes. 2 N HCl was added and the mixture was stirred at room temperature for 30 minutes. MTBE was added and the organic layer was separated, washed with water and brine, dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified on silica gel (0-7% EtOAc/hexane) to give _1- (5-bromo-2-methylphenyl)cyclopropane-1-carboxaldehyde (311 mg, 79%) as a colorless oil.

Step 3

Ohira-Bestmann reagent (0.30 mL, 1.97 mmol, 1.4 equivalences) was added to a mixture of 1-(5-bromo-2-methylphenyl)cyclopropane-1-carboxaldehyde (337 mg, 1.41 mmol, 1.0 equivalences) and _Cs₂CO₃ (1.38 _g , 4.23 mmol, 3.0 equivalences) in MeOH (7.0 mL). After stirring at room temperature for 2 hours, hexane and _H₂O were added. The organic layer was separated and the aqueous layer was extracted with hexane. The combined organic layers were washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated to give 4-bromo-2-(1-ethynylcyclopropyl)-1-toluene (277 mg, 84%) as a colorless oil.

Step 4

A solution of _CuSO₄ (29 mg, 0.12 mmol, 0.1 equivalent) in _H₂O (3.0 mL) was added to a solution of 2-(azidomethyl)tetrahydro-2H-pyran (182 mg, 1.29 mmol, 1.1 equivalent) and 4-bromo-2-(1-ethynylcyclopropyl)-1-toluene (276 mg, 1.17 mmol, 1.0 equivalent) in THF (9.0 mL). Ascorbic acid (103 mg, 0.59 mmol, 0.5 equivalent) was added, and the mixture was stirred at 60 °C for 48 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of NH₄Cl and MTBE was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give 4-(1-(5-bromo-2-methylphenyl)cyclopropyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazole (407 mg, 92%) as a colorless oil.

Step 5

Cyclopropylacetylene (180 μL, 2.13 mmol, 10 equivalents) was added to a mixture of 4-(1-(5-bromo-2-methylphenyl)cyclopropyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazole (80 mg, 0.213 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (25 mg, 0.021 mmol, 0.1 equivalent), and CuI (4 mg, 0.021 mmol, 0.1 equivalent) in a _N2 bubbling mixture of _Et3N (1.1 mL) and DME (1.1 mL). After bubbling with N2 for 1 minute, the reaction mixture was stirred at 90 °C for 4 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and MTBE was added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give an orange oil, 4-(1-(5-(cyclopropylethynyl)-2-methylphenyl)cyclopropyl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazole (63 mg, 82%). ^¹H NMR (400 MHz, CDCl₃ ₎ )δ7.42 (d, J=1.7Hz, 1H), 7.21 (dd, J=7.8, 1.8Hz, 1H), 7.06 (d, J=7.8Hz, 1H), 6.87 (s, 1H), 4.26 (dd, J=14.1, 3.5Hz, 1H), 4.11 (dd, J=14.1, 7.4Hz, 1H), 3.94-3.85 (m, 1H), 3.63-3.51 (m, 1H), 3.37-3.26 (m, 1H), 2.23 (s, 3H), 1.86-1.78 (m, 1H), 1.73-1.60 (m, 2H), 1.56 (d, J＝ 12.8Hz, 1H), 1.52-1.40 (m, 4H), 1.25-1.09 (m, 3H), 0.89-0.83 (m, 2H), 0.83-0.76 (m, 2H). ¹³ C NMR (101MHz, CDCl ₃ )δ151.60, 141.14, 138.64, 133.75, 130.44, 130.29, 122.48, 121.27, 92.76, 75.99, 75.67, 68.30, 54.89, 28.76, 25.56, 22.80, 21.76, 19.41, 16.67, 16.54, 8.56, 0.13.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 43: Synthesis of I-733

Step 1

Sodium cyanide (22 mg, 0.455 mmol, 2.0 equivalent) was added to a mixture of 5-bromo-2-(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (90 mg, 0.228 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (26 mg, 0.023 mmol, 0.1 equivalent), and copper iodide (9 mg, 0.046 mmol, 0.2 equivalent) in acetonitrile (0.5 mL) bubbling _N2 . After 1 minute of _N2 bubbling, the mixture was stirred at 85 °C for 18 hours. Once at room temperature, the mixture was filtered through diatomaceous earth using EtOAc. The filtrate was washed with a saturated aqueous solution of _NH4Cl , _dried over _Na2SO4 , filtered, and concentrated. The residue was purified on silica gel (0-50% Et0Ac/hexane) to give 4-(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3-(dimethylamino)benzonitrile (60 mg, 77%) as a yellow oil.

¹ H NMR (400MHz, CDCl ₃ )δ8.34 (s, 1H), 8.27 (dd, J=7.9, 0.5Hz, 1H), 7.42-7.35 (m, 2H), 4.80 (t, J=4.5Hz, 1H), 4.58 (d, J=4 .5Hz, 2H), 3.64 (d, J=11.3Hz, 2H), 3.44 (d, J=11.2Hz, 2H), 2.65 (s, 6H), 1.14 (s, 3H), 0.72 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ151.43, 143.57, 129.82, 129.63, 126.62, 125.23, 122.77, 119.13, 111.63, 98.50, 77.10, 53.11, 44.00, 30.23, 22.93, 21.68.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 44: Synthesis of I-743

Step 1

NaOH (116 mg, 2.89 mmol, 1.00 equivalent) was added to a solution of 3-bromophenol (500 mg, 2.89 mmol, 1.00 equivalent) in DMSO (5.0 mL). The mixture was stirred at room temperature for 2 hours, and then 1,1,2-trichloroethylene (253 μL, 2.89 _mmol , 1.00 equivalent) was added. The mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted twice _{with CH₂Cl₂} . The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-15% EtOAc/hexane) to give (E)-1-bromo-3-((1,2-dichlorovinyl)oxy)benzene (520 mg, 67%) as a colorless oil.

Step 2

A solution of (E)-1-bromo-3-((1,2-dichlorovinyl)oxy)benzene (250 mg, 0.936 mmol, 1.00 equivalent) in _Et₂O (5.0 mL) was cooled to -40 °C. nBuLi (1.50 mL, 3.75 mmol, 4.00 equivalent, 2.5 M in hexane) was added dropwise, and the mixture was heated to 0 °C and stirred for 1 hour. Water was added, and the mixture was extracted twice _{with CH₂Cl₂} . The combined organic layers were washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure. The crude mixture (150 mg) was used directly in the next step.

Step 3

The mixture of the previous crude mixture (150 mg), 2-(azidomethyl)-5,5-dimethyl-1,3-dioxane (173 mg, 0.877 mmol, 1.00 equivalent), _CuSO₄ (55 mg, 0.219 mmol, 0.25 equivalent), and ascorbic acid (77 mg, 0.439 mmol, 0.50 equivalent) in DMF (5.0 mL) was stirred at room temperature for 75 minutes. A saturated solution of _NH₄Cl was added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to give 1-((5,5-dimethyl-1,3-dioxane _- 2-yl)methyl)-4-phenoxy-1H-1,2,3-triazole (45 mg, 18%) as an amber oil.

¹ H NMR (400MHz, CDCl ₃ )δ7.37(s, 1H), 7.35-7.28(m, 2H), 7.13-7.04(m, 3H), 4.77(t, J=4.3Hz, 1H), 4.47(d, J =4.3Hz, 2H), 3.63 (d, J = 11.3Hz, 2H), 3.53-3.33 (m, 2H), 1.13 (s, 3H), 0.72 (s, 3H)ppm. ¹³ C NMR (101MHz, CDCl ₃ ) δ 157.73, 157.06, 129.61, 123.62, 117.37, 112.14, 98.18, 77.00, 53.95, 30.16, 22.81, 21.62ppm.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 45: Synthesis of I-759

Step 1

Cyclopropylacetylene (5.7 mL, 67.4 mmol, 10 equivalents) was added to a mixture of 2-bromo-4-iodo-1-toluene (2.0 g, 6.74 mmol, 1.0 equivalents), Pd( _PPh3 ) ₄ (779 mg, 0.674 mmol, 0.1 equivalents), and CuI (128 mg, 0.674 mmol, 0.1 equivalents) in a _N2 bubbling mixture of _Et3N (33 mL) and DME (33 mL). After bubbling with _N2 for 2 minutes, the reaction mixture was stirred at 50 °C for 3 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and hexane and MTBE were added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (100% hexane) to give 2-bromo-4-(cyclopropylethynyl)-1-methylbenzene (1.57 g, 99%) as an orange oil.

Step 2

Diisopropyl azodicarbonate (295 μL, 1.5 mmol, 1.5 equivalents) was added to a mixture of (5,5-dimethyl-1,3-dioxan-2-yl)methanol (219 mg, 1.5 mmol, 1.5 equivalents), 4-nitro-2H-1,2,3-triazole (114 mg, 1.0 mmol, 1.0 equivalents), and triphenylphosphine (393 mg, 1.5 mmol, 1.5 equivalents) in THF (2.5 mL). The mixture was stirred at room temperature for 66 hours. The mixture was concentrated, and the residue was purified on silica gel (0-50% EtOAc/hexane) to give 2-((5,5-dimethyl-1,3-dioxan-2-yl)methyl)-4-nitro-2H-1,2,3-triazole (159 mg, 66%) as a white solid.

Step 3

2-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-4-nitro-2H-1,2,3-triazole (158 mg, 0.652 mmol, 1.0 equivalent) was added to a mixture of palladium/carbon (10% w/w, 69 mg, 0.065 mmol, 0.1 equivalent) in methanol (7 mL) bubbling _N₂ . _{N₂ was removed and H₂ was bubbled in the mixture for 5 minutes. The mixture was stirred under an H₂ atmosphere for 2 hours. H₂ was removed and N₂} was bubbled in the mixture. Diatomaceous earth was added and the mixture was filtered through the diatomaceous earth. The filtrate was concentrated to give 2-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-2H-1,2,3-triazole-4-amine (138 mg, tetrette) as a pale yellow solid.

Step 4

_Cs₂CO₃ (322 _mg , 0.989 mmol, 3.0 equivalents) was added to a mixture of 2-bromo-4-(cyclopropylethynyl)-1-methylbenzene (78 mg, 0.330 mmol, 1.0 equivalents), 2-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-2H-1,2,3-triazol-4-amine (70 mg, 0.330 mmol, 1.0 equivalents), _Pd₂ (dba) _₃ (30 mg, 0.033 mmol, 0.1 equivalents), and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (28 mg, 0.049 mmol, 0.15 equivalents) in dioxane (3.3 mL) bubbling _N₂ . After 1 minute of _N₂ bubbling, the mixture was stirred at 100 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH₄Cl and MTBE was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexane) to give N-(5-(cyclopropylethynyl)-2-methylphenyl)-2-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-2H-1,2,3-triazol-4-amine (74 mg, 61%) as an orange gel.

^1H NMR (400MHz, CDCl3 ₎ )δ7.42 (s, 1H), 7.24 (d, J = 1.3Hz, 1H), 7.03 (d, J = 7.8Hz, 1H), 6.87 (dd, J = 7.7, 1.5Hz, 1H), 5.77 (s, 1H), 4.91 (t, J = 4.9Hz, 1H), 4.49 (d, J = 4.9Hz, 2H ), 3.67 (d, J = 11.3Hz, 2H), 3.44 (d, J = 10.7Hz, 3H), 2.22 (s, 3H), 1.49-1.3 7(m, 1H), 1.19(s, 4H), 0.87-0.81(m, 2H), 0.81-0.76(m, 2H), 0.72(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ148.33, 140.52, 130.57, 124.05, 124.03, 123.87, 122.43, 116.98, 98. 91, 92.55, 77.14, 75.91, 57.57, 30.31, 22.90, 21.75, 17.58, 8.53, 0.15.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 46: Synthesis of I-760

Step 1

At 0 °C, _Et3N (3.1 mL, 22.1 mmol, 2.5 equivalences) was added to a mixture of (5,5-dimethyl-1,3-dioxane-2-yl)methanol (1.29 g, 8.82 mmol, 1.0 equivalences) and toluenesulfonyl chloride (1.85 g, 9.71 mmol, 1.1 equivalences) in DCM (22 mL). The mixture was heated to room temperature and stirred at room temperature for 18 hours. Another portion of toluenesulfonyl chloride (841 mg, 4.41 mmol, 0.5 equivalences) and _Et3N (1.23 mL, 8.82 mmol, 1.0 equivalences) was added, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of _NaHCO3 and DCM were added, the organic layer was separated, washed with brine, dried over _Na2SO4 , filtered _, and concentrated. The residue was purified on silica gel (0-30% EtOAc/hexane) to give 4-methylbenzenesulfonic acid (5,5-dimethyl-1,3-dioxane-2-yl) methyl ester (2.45 g, 92%) as a white solid.

Step 2

At 0 °C, 4-nitro-2H-1,2,3-triazole (228 mg, 2.0 mmol, 1.0 equivalent) was added to a mixture of sodium hydride (60% w/w oil dispersion, 84 mg, 2.1 mmol, 1.05 equivalent) in DMF (10 mL). After stirring at 0 °C for 10 min, methyl 4-methylbenzenesulfonic acid (5,5-dimethyl-1,3-dioxane-2-yl) methyl ester was added. The mixture was stirred at 100 °C for 66 h. Once at room temperature, the mixture was poured into _a saturated aqueous solution of _NH₄Cl and MTBE was added. The organic layer was separated, dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified on silica gel (0-40% EtOAc/hexane) to give 1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-4-nitro-1H-1,2,3-triazole (210 mg, 43%) as a white solid.

Step 3

1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-4-nitro-1H-1,2,3-triazole (209 mg, 0.863 mmol, 1.0 equivalent) was added to a mixture of palladium/carbon (10% w/w, 92 mg, 0.086 mmol, 0.1 equivalent) in methanol (9 mL) and bubbling with _N2 . _N2 was removed and _H2 was bubbled in the mixture for 5 minutes. The mixture was stirred under an _H2 atmosphere for 2 hours. H2 was removed and _N2 was bubbled in the mixture. Diatomaceous earth was added and the mixture was filtered through the diatomaceous earth. The filtrate was concentrated to give 1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole-4-amine (177 mg, 97%) as a pale yellow solid.

Step 4

_Cs₂CO₃ (926 _mg , 2.84 mmol, 3.0 equivalents) was added to a mixture of 2-bromo-4-(cyclopropylethynyl)-1-methylbenzene (223 mg, 0.947 mmol, 1.0 equivalents), 1-((5,5-dimethyl-1,3-dioxan-2-yl)methyl)-1H-1,2,3-triazol-4-amine (201 mg, 0.947 mmol, 1.0 equivalents), _Pd₂ (dba) _₃ (87 mg, 0.095 mmol, 0.1 equivalents), and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (82 mg, 0.142 mmol, 0.15 equivalents) in dioxane (9.5 mL) bubbling _N₂ . After 1 minute of _N₂ bubbling, the mixture was stirred at 100 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH₄Cl and EtOAc was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to give N-(5-(cyclopropylethynyl)-2-methylphenyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-amine (174 mg, 50%) as a yellow solid.

¹ H NMR (400MHz, CDCl ₃ )δ7.53 (s, 1H), 7.06-7.00 (m, 2H), 6.84 (dd, J=7.6, 1.5Hz, 1H), 5.88 (s, 1H), 4.79 (t, J=4.3Hz, 1H), 4.50 (d, J=4.3Hz, 2H), 3.65 (d, J=11.3Hz, 2 H), 3.45 (d, J=10.8Hz, 2H), 2.24 (s, 3H), 1.42 (tt, J=8.2, 5.1Hz, 1H), 1. 17 (s, 3H), 0.87-0.80 (m, 2H), 0.78 (tt, J=5.1, 2.3Hz, 2H), 0.73 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ147.44, 141.10, 130.60, 123.76, 123.55, 122.29, 115.76, 112.71, 98. 43, 92.34, 77.06, 76.07, 53.63, 30.23, 22.95, 21.68, 17.58, 8.50, 0.15.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Synthetic I-793

Step 1

Paraformaldehyde (373 mg, 12.4 mmol, 6.00 equivalents) and NaOMe (1.04 mL, 6.24 mmol, 3.00 equivalents, 25% w/w) were added to a solution of 1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-4-nitro-1H-1,2,3-triazole (440 mg, 2.08 mmol, 1.00 equivalents) in MeOH (7.0 mL). The mixture was stirred at 65 °C for three hours and then cooled to room temperature. _NaBH₄ (196 mg, 5.20 mmol, 2.50 equivalents) was added and the mixture was stirred at room temperature for one hour. Saturated _NaHCO₃ was added dropwise, and the mixture was concentrated under reduced pressure to remove MeOH. The aqueous residue was diluted with brine and extracted twice _{with CH₂Cl₂} . The combined organic layers were dried over _Na₂SO₄ , _filtered , and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20-100% EtOAc/hexane) to give 1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-N-methyl-1H-1,2,3-triazol-4-amine (253 mg, 54%) as a white solid.

Step 2

A mixture of 1-((5,5-dimethyl-1,3-dioxan-2-yl)methyl)-N-methyl-1H-1,2,3-triazol-4-amine (40 mg, 0.177 mmol, 1.00 equivalent), 4-bromobenzonitrile (32 mg, 0.177 _mmol , 1.00 equivalent), _Cs₂CO₃ (144 mg, 0.443 mmol, 2.50 equivalent), XPhos (17 mg, 0.0354 mmol, 0.20 equivalent), and _Pd₂ (dba) _₃ (16 mg, 0.0177 mmol, 0.10 equivalent) in dioxane (1.0 mL) was degassed with _N₂ for 10 min and stirred at 100 °C for 4 h. The mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. _The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20-70% EtOAc/hexane) to give 4-((1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)(methyl)amino)benzonitrile (46 mg, 79%) as an orange oil.

¹ H NMR (400MHz, CDCl ₃ )δ7.59 (s, 1H), 7.47 (d, J = 9.0Hz, 2H), 6.92 (d, J = 9.0Hz, 2H), 4.80 (t, J = 4.1Hz, 1H), 4.52 (d, J = 4.1 Hz, 2H), 3.64 (d, J=11.3Hz, 2H), 3.45 (d, J=10.8Hz, 2H), 3.40 (s, 3H), 1.12 (s, 3H), 0.73 (s, 3H)ppm. ¹³ C NMR (101MHz, CDCl ₃ ) δ 150.63, 150.28, 133.25, 119.89, 117.71, 114.23, 101.01, 97.99, 77.00, 53.61, 39.03, 30.14, 22.76, 21.58ppm.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 47: Synthesis of I-761

Step 1

Sodium hydride (60% w/w oil dispersion, 7 mg, 0.164 mmol, 1.2 equivalents) was added to a mixture of N-(5-(cyclopropylethynyl)-2-methylphenyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-amine (50 mg, 0.136 mmol, 1.0 equivalents) in DMF (1.4 mL). The mixture was stirred at room temperature for 5 hours. The mixture was poured into a saturated aqueous solution of _NH₄Cl and MTBE was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was dissolved in acetonitrile. The resulting solution was washed with heptane and concentrated to give N-(5-(cyclopropylethynyl)-2-methylphenyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-N-methyl-1H-1,2,3-triazol-4-amine (37 mg, 72%), which was an orange gel.

¹ H NMR (400MHz, CDCl ₃ )δ7.21 (s, 1H), 7.17-7.10 (m, 2H), 6.62 (s, 1H), 4.72 (t, J=4.5Hz, 1H), 4.34 (d, J=4.5Hz, 2H), 3.59 (d, J=11.4Hz, 2H), 3.40 (d, J=11.3Hz, 2 H), 3.31 (s, 3H), 2.15 (s, 3H), 1.47-1.38 (m, 1H), 1.12 (s, 3H), 0.85 (ddt, J=8.3, 5.7, 3.2Hz, 2H), 0.77 (tt, J=5.0, 2.8Hz, 2H), 0.71 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ155.55, 146.54, 135.04, 131.33, 128.95, 128.60, 122.58, 108.90, 98.70, 93.04, 76.98, 75.29, 53.45, 39.26, 30.19, 22.86, 21.68, 17.91, 8.55, 0.10.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 48: Synthesis of I-774

Step 1

2-(azidomethyl)-5,5-dimethyl-1,3-dioxane (300 mg, 1.75 mmol, 1.00 equivalent), 1,4-bis(trimethylsilyl)but-1,3-diyne (880 mg, 4.53 mmol, 2.5 equivalent), and _K₂CO₃ (1.2 _g , 8.70 mmol, 5.0 equivalent) were added to a solution of Cu(OAc) _₂ · _H₂O (64 mg, 0.35 mmol, 0.20 equivalent) in MeOH (3.5 mL) and water (3.5 mL). The mixture was stirred at room temperature for 3 hours. A saturated solution of _NH₄Cl was added, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered _, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc/hexane) to give 1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-4-ethynyl-1H-1,2,3-triazole (55 mg, 14%) as a white solid.

Step 2

A mixture of 4-iodotoluene (45 mg, 0.207 mmol, 1.00 equivalent), 1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-4-ethynyl-1H-1,2,3-triazole (55 mg, 0.249 mmol, 1.20 equivalent), Pd( _PPh3 ) ₄ (24 mg, 0.021 mmol, 0.10 equivalent), and CuI (4 mg, 0.021 mmol, 0.10 equivalent) in DME (0.8 mL) and _Et3N (0.2 mL) was degassed with N2 for 10 min and then stirred at 50 °C for 4 h. The mixture was cooled to room temperature, poured into a saturated solution of _NH4Cl , and extracted twice with EtOAc. The combined organic layers were washed with brine, _dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to give 1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-4-(p-tolylethynyl)-1H-1,2,3-triazole (47 mg, 73%) as a yellow solid.

¹ H NMR (400MHz, CDCl ₃ )δ7.84 (s, 1H), 7.43 (d, J=8.0Hz, 2H), 7.15 (d, J=8.0Hz, 2H), 4.75 (t, J=4.4Hz, 1H), 4.52 (d, J=4.4 Hz, 2H), 3.62 (d, J=11.3Hz, 2H), 3.42 (d, J=10.9Hz, 2H), 2.35 (s, 3H), 1.13 (s, 3H), 0.72 (s, 3H)ppm. ¹³ C NMR (101MHz, CDCl ₃ ) δ 138.88, 131.46, 131.03, 129.09, 127.35, 119.26, 98.08, 92.49, 76.97, 53.07, 30.14, 22.83, 21.60, 21.49ppm.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 49: Synthesis of I-781, I-782 and I-783

Step 1

1-[(trimethylsilyl)ethynyl]-1,2-benzoiodocyclopentan-3(1H)-one (559 mg, 1.62 mmol, 1.1 equivalent) was added to a mixture of 5-bromo-2-methylthiophenol (300 mg, 1.48 mmol, 1.0 equivalent) and triazabicyclodecene (205 mg, 1.48 mmol, 1.0 equivalent) in THF (18 mL). After stirring at room temperature for 10 minutes, the mixture was concentrated and the residue was purified on silica gel (0-10% EtOAc/hexane) to give (((5-bromo-2-methylphenyl)thio)ethynyl)trimethylsilane (421 mg, 95%) as a colorless oil.

Step 2

_K₂CO₃ (970 _mg , 7.02 mmol, 5.0 equivalent) was added to a mixture of 2-(azidomethyl)-5,5-dimethyl-1,3-dioxane (240 mg, 1.40 mmol, 1.0 equivalent), (((5-bromo-2-methylphenyl)thio)ethynyl)trimethylsilane (420 mg, 1.40 mmol, 1.0 equivalent), _CuSO₄ · _5H₂O (175 mg, 0.70 mmol, 0.5 equivalent), and ascorbic acid (247 mg, 1.40 mmol, 1.0 equivalent) in DMF (7.0 mL). After stirring at room temperature for 2 hours, the mixture was poured into a saturated aqueous solution of _NH₄Cl and MTBE was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified on silica gel (0-40% EtOAc/hexane) to give 4-((5-bromo-2-methylphenyl)thio)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (393 mg, 70%) as a colorless oil.

Step 3

Cyclopropylacetylene (149 μL, 1.76 mmol, 10 equivalents) was added to a mixture of 4-((5-bromo-2-methylphenyl)thio)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (70 g, 0.176 mmol, 1.0 equivalents), Pd( _PPh3 ) ₄ (21 mg, 0.018 mmol, 0.1 equivalents), and CuI (3 mg, 0.018 mmol, 0.1 equivalents) in a _N2 bubbling mixture of _Et3N (0.9 mL) and DME (0.9 mL). After bubbling with _N2 for 1 minute, the reaction mixture was stirred at 90 °C for 5 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and MTBE was added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give 4-((5-(cyclopropylethynyl)-2-methylphenyl)thio)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (46 mg, 68%), which was a pale yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ7.80 (s, 1H), 7.12-6.98 (m, 3H), 4.79 (t, J=4.2Hz, 1H), 4.55 (d, J=4.2Hz, 2H), 3.64 (d, J=11.3Hz, 2H), 3 .44 (d, J=10.7Hz, 2H), 2.41 (s, 3H), 1.42-1.33 (m, 1H), 1.10 (s, 3H), 0.85-0.78 (m, 2H), 0.77-0.71 (m, 5H). ¹³ C NMR (101MHz, CDCl ₃ )δ137.11, 136.26, 135.01, 131.43, 130.07, 129.79, 129.68, 122.25, 97.97, 93.16, 77.02, 53.34, 30.18, 22.84, 21.65, 20.20, 8.49, 0.11.

Step 1

At 0°C, mCPBA (approximately 70%, 62 mg, 0.251 mmol, 1.0 equivalent) was added to a mixture of 4-((5-bromo-2-methylphenyl)thio)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (100 mg, 0.251 mmol, 1.0 equivalent) in DCM (2.5 mL). The mixture was stirred at 0°C for 15 minutes, and a saturated aqueous solution of _NaHCO3 was added. DCM was added, and the organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified on silica gel (10-60% EtOAc/hexane) to give (RS)-4-((5-bromo-2-methylphenyl)sulfinyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (94 mg, 90%) as a white foam.

Step 2

Cyclopropylacetylene (192 μL, 2.27 mmol, 10 equivalents) was added to a mixture of (RS)-4-((5-bromo-2-methylphenyl)sulfinyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (94 g, 0.227 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (27 mg, 0.023 mmol, 0.1 equivalent), and CuI (4 mg, 0.023 mmol, 0.1 equivalent) in a _N2 bubbling mixture of _Et3N (1.15 mL) and DME (1.15 mL). After bubbling with _N2 for 1 minute, the reaction mixture was stirred at 90 °C for 3 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and EtOAc was added. The organic layer was separated, washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (10-60% EtOAc/hexane) to give a yellow gelatinous substance (RS)-4-((5-(cyclopropylethynyl)-2-methylphenyl)sulfinyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (88 mg, 97%).

¹ H NMR (400MHz, CDCl ₃ )δ8.04 (d, J=1.6Hz, 1H), 7.85 (s, 1H), 7.37 (dd, J=7.8, 1.8Hz, 1H), 7.09 (d, J=7.9Hz, 1H), 4.73 (t, J=4.1Hz, 1H), 4.57-4.42 (m, 2H), 3.63-3 .54 (m, 2H), 3.39 (dd, J=11.2, 3.0Hz, 2H), 2.33 (s, 3H), 1.48-1.40 (m, 1H), 1.00 (s, 3H), 0.92-0.84 (m, 2H), 0.84-0.77 (m, 2H), 0.71 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ151.91, 141.46, 134.63, 133.86, 130.84, 126.68, 125.84, 123.20, 97.52, 94.78, 76.96, 76.93, 74.65, 53.42, 30.10, 22.74, 21.58, 18.26, 8.64, 0.12.

Step 1

At 0 °C, mCPBA (approximately 70%, 124 mg, 0.502 mmol, 2.0 equivalent) was added to a mixture of 4-((5-bromo-2-methylphenyl)thio)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (100 mg, 0.251 mmol, 1.0 equivalent) in DCM (2.5 mL). The mixture was heated to room temperature and stirred at room temperature for 66 hours. A saturated aqueous solution _{of NaHCO3} and DCM were added. The organic layer was separated, washed with brine, dried over _Na2SO4 , filtered, and concentrated to give a white, foamy 4-((5-bromo- ₂ -methylphenyl)sulfonyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (108 mg, tetrette).

Step 2

Cyclopropylacetylene (210 μL, 2.49 mmol, 10 equivalents) was added to a mixture of 4-((5-bromo-2-methylphenyl)sulfonyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (107 g, 0.249 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (29 mg, 0.025 mmol, 0.1 equivalent), and CuI (5 mg, 0.025 mmol, 0.1 equivalent) in a _N2 bubbling mixture of _Et3N (1.25 mL) and DME (1.25 mL). After bubbling with _N2 for 1 minute, the reaction mixture was stirred at 90 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and EtOAc was added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (10-60% EtOAc/hexane) to give 4-((5-(cyclopropylethynyl)-2-methylphenyl)sulfonyl)-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (98 mg, 95%), which was a yellow gel.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.30 (s, 1H), 8.19 (d, J = 1.7Hz, 1H), 7.45 (dd, J = 7.8, 1.8Hz, 1H), 7.17 (d, J = 8.0Hz, 1H), 4.75 (t, J = 4.1Hz, 1H), 4.55 (d, J = 4.1Hz, 2H), 3.62 (d, J=11.4Hz, 2H), 3.42 (d, J=11.1Hz, 2H), 2.65 (s, 3H), 1.48-1.39 (m, 1H), 1.04 (s, 3H), 0.94-0.84 (m, 2H), 0.84-0.77 (m, 2H), 0.72 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ148.73, 138.19, 137.66, 136.47, 132.82, 132.64, 128.08, 122.90, 97. 33, 95.34, 76.99, 74.01, 53.41, 30.13, 22.73, 21.59, 20.39, 8.67, 0.09.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 50: Synthesis of I-790

Step 1

Potassium carbonate (275 mg, 2.00 mmol, 1.50 equivalent) was added to a solution of 4-bromo-2H-1,2,3-triazole (197 mg, 1.33 mmol, 1.00 equivalent) in DMF (7.0 mL). 4-Toluenesulfonic acid (5,5-dimethyl-1,3-dioxane-2-yl) methyl ester (480 mg, 1.60 mmol, 1.20 equivalent) was added, and the mixture was stirred at 50 °C for 3 days. The mixture was cooled to room temperature, poured into a saturated _NH₄Cl solution, and extracted twice with EtOAc. The combined organic layers were washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give 4-bromo-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (110 mg, 30%) as a white solid.

Step 2

A mixture of 4-bromo-1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazole (50 mg, 0.181 _mmol , 1.00 equivalent), Pd(dppf) _Cl₂ · _CH₂Cl₂ (15 mg, 0.0181 mmol, 0.10 equivalent), and CuI (3.4 mg, 0.0181 mmol, 0.10 equivalent) in DME (0.8 mL) and _Et₃N (0.2 mL) was degassed with N₂ for 10 min. 3-ethynyltoluene (35 μL, 0.272 mmol, 1.50 equivalent) was added, and the mixture was stirred at 90 °C for 18 h. The mixture was cooled to room temperature, poured into a saturated _NH₄Cl solution, and extracted twice with EtOAc. The combined organic layers were washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to give a yellow oily substance, 1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-4-(m-tolylethynyl)-1H-1,2,3-triazole (15 mg, 27%).

¹ H NMR (400MHz, CDCl ₃ )δ7.85 (s, 1H), 7.40-7.33 (m, 2H), 7.24 (t, J=7.5Hz, 1H), 7.19-7.12 (m, 1H), 4.76 (d, J=4.4Hz, 1H), 4.53 (d, J=4.4Hz, 2H), 3.73-3.56 (m, 2H), 3.43 (d, J=10.7Hz, 2H), 2.35 (s, 3H), 1.14 (s, 3H), 0.73 (s, 3H)ppm. ¹³ C NMR (101MHz, CDCl ₃ )δ138.04, 132.15, 131.00, 129.61, 128.68, 128.25, 127.47, 122.18, 98.13, 92.54, 78.24, 77.03, 53.12, 30.20, 22.87, 21.65, 21.23ppm.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 51: Synthesis of I-792

Step 1

At 0 °C, _Et3N (1.5 mL, 10.7 mmol, 2.0 equivalent) was added to a mixture of 5-bromo-2-methylaniline (1.0 g, 5.37 mmol, 1.0 equivalent) and acetyl chloride (0.5 mL, 6.99 mmol, 1.3 equivalent) in DCM (8.0 mL). After stirring at 0 °C for 2 hours, the mixture was poured into _H2O and DCM was added. The organic layer was separated, washed with brine, _dried over _Na2SO4 , filtered, and concentrated to give N-(5-bromo-2-methylphenyl)acetamide (1.23 g, quartet) as a brown solid.

Step 2

(Bromoethynyl)triisopropylsilane (0.52 mL, 1.97 mmol, 1.5 equivalents) was added to a mixture of N-(5-bromo-2-methylphenyl)acetamide (300 mg, 1.32 mmol, 1.0 equivalents), _CuSO₄ · _5H₂O (66 mg, 0.263 mmol, 0.2 equivalents), 1,10-phenanthroline (95 mg, 0.526 mmol, 0.4 equivalents), and _K₃PO₄ (558 _mg , 2.63 mmol, 2.0 equivalents) in toluene (5 mL) bubbling _N₂ . After bubbling _N₂ for 1 minute, the reaction mixture was stirred at 110 °C for 18 hours. Once at room temperature, the mixture was filtered through diatomaceous earth using a DCM filter. The concentrated filtrate and residue were purified by silica gel chromatography (0-6% EtOAc/hexane) to give N-(5-bromo-2-methylphenyl)-N-((triisopropylsilyl)ethynyl)acetamide (330 mg, 61%), which was an orange oil.

Step 3

At 0°C, TBAF (1 M/THF, 0.96 mL, 0.964 mmol, 1.2 equivalents) was added dropwise to a mixture of N-(5-bromo-2-methylphenyl)-N-((triisopropylsilyl)ethynyl)acetamide (328 mg, 0.803 mmol, 1.0 equivalents) and THF (10 mL). After stirring at 0°C for 20 minutes, the mixture was poured into an aqueous solution of _NH₄Cl and MTBE was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was dissolved in THF (6 mL), and then a solution of 2-(azidomethyl)-5,5-dimethyl-1,3-dioxane (137 mg, 0.803 mmol, 1.0 equivalent) and _CuSO₄ · _5H₂O (20 mg, 0.080 mmol, 0.1 equivalent) in _H₂O (2 mL) was added, along with 71 mg (0.402 mmol, 0.5 equivalent). The mixture was stirred at 60 °C for 18 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH₄Cl and EtOAc was added. The organic layer was separated, _dried over _Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (10-60% EtOAc/hexane) to give N-(5-bromo-2-methylphenyl)-N-(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)acetamide (52 mg, 15%) as a colorless oil.

Step 4

Cyclopropylacetylene (104 μL, 1.23 mmol, 10 equivalents) was added to a mixture of N-(5-bromo-2-methylphenyl)-N-(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)acetamide (52 mg, 0.123 mmol, 1.0 equivalent), Pd( _PPh3 ) ₄ (14 mg, 0.012 mmol, 0.1 equivalent), and CuI (2 mg, 0.012 mmol, 0.1 equivalent) in a _N2 bubbling mixture of _Et3N (0.6 mL) and DME (0.6 mL). After bubbling with _N2 for 1 minute, the reaction mixture was stirred at 90 °C for 3 hours. Once at room temperature, the mixture was poured into a saturated aqueous solution of _NH4Cl and EtOAc was added. The organic layer was separated, _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel chromatography (10-60% EtOAc/hexane) to give N-(5-(cyclopropylethynyl)-2-methylphenyl)-N-(1-((5,5-dimethyl-1,3-dioxane-2-yl)methyl)-1H-1,2,3-triazol-4-yl)acetamide (36 mg, 72%) as a white solid.

¹ H NMR (400MHz, CDCl ₃ )δ8.31 (s, 1H), 7.36 (d, J=7.7Hz, 1H), 7.30-7.22 (m, 2H), 4.77 (t, J=4.6Hz, 1H), 4.53-4.41 (m, 2H), 3.63 (d, J=11.2Hz, 2H), 3.42 (dd, J=10.4 , 4.9Hz, 2H), 2.14 (s, 3H), 1.92 (s, 3H), 1.42 (ddd, J=13.1, 8.3, 5.2Hz, 1H), 1.16 (s, 3H), 0.89-0.81 (m, 2H), 0.81-0.74 (m, 2H), 0.72 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ168.93, 145.70, 138.95, 136.21, 132.34, 131.46, 123.38, 116.55, 98.46, 94.14, 76.97, 74.70, 53.52, 30.21, 23.15, 22.86, 21.71, 17.55, 8.58, 0.09.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 52: Synthesis of I-826 and I-841

Step 1

A solution of 3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-yl ester (1.36 g, 3.48 mmol, 1 equivalent) in DMF (10 mL) was treated with potassium phthalimide (790 mg, 4.18 mmol, 1.2 equivalent) and stirred overnight at room temperature for 19 hours. The solution was then poured into a saturated aqueous solution of _NH₄Cl and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. Purified by Combi-Flash chromatography using 0-100% EtOAc/hexane, 2-(3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-yl)isoindoline-1,3-dione (810 mg, 53%).

Step 2:

A solution of 2-(3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-yl)isoindoline-1,3-dione (397 mg, 0.90 mmol, 1 equivalent) in THF (3.9 mL) was treated with hydrazine monohydrate (0.17 mL, 3.60 mmol, 4 equivalents) and p-toluenesulfonic acid (12 mg, 0.064 mmol). The reaction mixture was refluxed at 70 °C for 2 h, then poured into a saturated aqueous solution of _NH4Cl and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude substance. Purified by Combi-Flash chromatography using 0-20% MeOH/DCM, 3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-amine (162 mg, 58%) was obtained as an orange solid.

¹H NMR (400 MHz, chloroform-d) δ 8.36 (s, ¹H), 8.20–8.08 (m, ¹H), 7.52 (s, ¹H), 4.50–4.34 (m, ¹H), 4.27 (dd, J = 14.2, 7.5 Hz, ¹H), 3.89 (d, J = 11.5 Hz, ¹H), 3.61 (d, J = 18.1 Hz, 3H), 3.31 (q, J = 11.4, 10.2 Hz, 3H), 2.59 (s, 3H), 1.78 (d, J = 9.2 Hz, 1H), 1.59 (d, J = 13.0 Hz, 1H), 1.43 (s, 3H), 1.20 (q, J = 12.9, 12.2 Hz, 1H).

13C NMR (101MHz, cdcl3) δ148.77, 148.05, 147.31, 141.75, 131.34, 125.50, 118.61, 92.64, 79.59, 77.46, 77.14, 76.82, 75.81, 68.34, 55.00, 49.43, 49.22, 49.00, 48.79, 48.58, 31.54, 28.67, 25.38, 22.69, 20.41.

Step 1:

Add 2,2-dimethoxyacetaldehyde (40 μL, 0.26 mmol, 1 equivalence) to a solution of 4-methylbenzenesulfonyl hydrazine (45 mg, 0.24 mmol, 1 equivalence) in MeOH (0.51 mL). Stir the reaction mixture at room temperature for 3.5 h. Then add 0.5 mL of MeOH containing 3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-amine (80 mg, 0.26 mmol, 1.1 equivalence), followed by glacial acetic acid (13.7 μL, 0.24 mmol, 1.0 equivalence). Heat the reaction mixture at 75 °C for 16 h, then cool to room temperature, concentrate under vacuum, and partition with DCM/water (2 mL/2 mL). The combined organic layers were washed successively with 10 ml of 5% _{K₂CO₃ aqueous} solution and brine, _dried over anhydrous _Na₂SO₄ and concentrated under vacuum. Purification by silica gel chromatography using 0-100% EtOAc/hexane yielded a yellow oily substance, 5-(3-(1H-1,2,3-triazol-1-yl)prop-1-yn-1-yl)-3-methyl-2-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridine (35 mg, 37%).

^¹H NMR (400 MHz, chloroform-d) δ 8.49 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.75 (d, J = 1.1 Hz, 1H), 7.65–7.61 (m, 1H), 5.45 (s, 2H), 4.48 (dd, J = 14.1, 3.2 Hz, 1H), 4.33 (dd, J = 14.1, 7.6 Hz, 1H), 3.95 (dt, J=11.9, 2.3Hz, 1H), 3.69 (ddt, J=10.4, 7.6, 2.8Hz, 1H), 3.36 (td, J=11.2, 3.3Hz, 1H), 2.70 (s, 3H), 2.01 (s, 1H), 1.87-1.82 (m, 1H), 1.65 (d, J=12.9Hz, 1H), 1.54-1.45 (m, 2H), 1.39-1.33 (m, 1H).

¹³ C NMR (101MHz, CDCl ₃ )δ171.26, 149.10, 148.57, 148.35, 142.03, 134.18, 131.40, 125.79, 123.33, 116.82, 83.91, 83.59, 77.38, 77.06, 76. 74, 75.87, 68.41, 60.41, 55.10, 53.43, 50.60, 40.45, 29.66, 28.77, 25.47, 22.78, 21.19, 21.01, 20.66, 17.37, 14.14.

Additional exemplary compounds were prepared according to methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 following Example 53.

Example 53: Synthesis of I-843

Step 1:

Ethyl trifluoroacetate (31 μL, 0.26 mmol, 1 equivalent) was added to 0.5 mL of DCM containing 3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-amine (81 mg, 0.26 mmol, 1 equivalent), followed by the addition of acetic acid (1.4 μL, 0.026 mmol, 0.1 equivalent). After 5 days at room temperature, the solvent was evaporated, and the crude substance was purified by Combi-Flash chromatography using 0-80% EtOAc/hexane to give 2,2,2-trifluoro-N-(3-(5-methyl-6-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)prop-2-yn-1-yl)acetamide (22 mg, 21%) as a grayish-white solid.

¹ H NMR (400MHz, CDCl3) δ8.50 (s, 1H), 8.22 (s, 1H), 7.60 (s, 1H), 7.17 (s, 1H), 4.51 (dd, J=14.1, 3.2Hz, 1H), 4.45-4.27 (m, 3H), 4.07-3.91 (m, 1H), 3 .71 (ddt, J=11.0, 7.8, 2.7Hz, 1H), 3.38 (td, J=11.2, 3.4Hz, 1H), 2.70 (s , 3H), 1.87 (dq, J=9.9, 2.7Hz, 1H), 1.79-1.62 (m, 1H), 1.41-1.16 (m, 4H).

^13C NMR (101MHz, cdcl3) δ157.09, 156.71, 149.13, 148.41, 141.91, 131.31, 125.63, 117.35, 117.09, 114.2 3, 85.83, 81.63, 77.33, 77.01, 76.69, 75.88, 68.44, 55.17, 30.42, 29.69, 28.81, 25.50, 22.82, 20.65.

¹⁹ F NMR (377MHz, CDCl3) δ -75.44, -75.66, -75.69, -75.76, -76.20, -189.55.

Additional exemplary compounds were prepared using methods substantially similar to those described above and herein. Data for these compounds are provided in Table 24 below.

Table 24: Characterization of exemplary compounds of the present invention

Example 54: Preparation of salts of the compounds in Table 1

Table 25: Preparation of Salts of Compounds in Table 1

Example 55: BRET Measurement

Background – The following assays can be used to determine GPR84 activation in live HEK293 cells. _Gαi BRET biosensors (Gagnon et al., 2018; Gales et al., 2006. Nat Struct Mol Biol. 13, 778-86; Saulieres et al., 2012. Nat Chem Biol. 8, 622-30) enable direct monitoring of GPR84-mediated _Gαi activation. The _Gαi biosensor consists of an Rluc8-labeled _Gαi2 subunit, a GFP10-labeled _Gγ2 subunit, and an unlabeled _Gβ1 . Agonistic stimulation and GPR84 activation trigger physical dissociation between the RLuc8- _Gαi donor and the GFP10- _Gγ2 receptor, resulting in a decrease in BRET signal amplitude associated with ligand efficacy (Gales et al., 2006). Furthermore, the signal transduction function of GPCRs is tightly regulated through endoponucleation, receptor targeting of endosomes, and sorting to lysosomes or recycling back to the plasma membrane. Early endosome (EE) migration assay (Namkung et al., 2016. Nat Commun. 7, 12178) used Rluc8-labeled GPR84 and Renilla GFP (rGFP), which attaches to the FYVE domain of protein 16 containing the human endorphin/zinc finger FYVE domain (which binds to phosphatidylinositol 3-phosphate in the EE). Agonistic stimulation of GPR84-Rluc8 caused receptor migration to the EE and subsequently increased donor concentration relative to the rGFP-FYVE receptor anchored in the same cell compartment, thus increasing BRET signaling.

The cDNA clones of the plasmid-human GPR84 receptor, human _Gαi2 , _Gβ1 , and _Gγ2 were obtained from the cDNA Resource Center (www.cdna.org). The GFP10 (F64L, S147P, S202F, and H231L variants of Aequorea victoria green fluorescent protein) gBlocks gene fragment (integrative DNA technology, IA) and adapter were inserted into the N-terminal frame of human _Gγ2 . The Rluc8 (A55T, C124A, S130A, K136R, A143M, M185V, M253L, and S287L variants of Renilla reniformis luciferase) gBlocks gene fragment was inserted together with the adapter between residues 91 and 92 of _Gαi2 or within the frame at the C-terminus of GPR84. The FYVE domain (residues Q739 to K806) of human endorphin linked in the box at the C-terminus of humanized Renal GFP (rGFP) was synthesized into the gBlocks gene fragment.

Bioluminescent Resonance Energy Transfer (BRET) Measurement - HEK293 cells were transfected with GPR84-Rluc8 and rGFP-FYVE for EE transfer biosensors or with GPR84, _Gαi2 -Rluc8, GFP10- _Gγ2 , and _Gβ1 for _Gαi biosensors. The following day, transiently transfected cells were seeded in 96-well white clear-bottomed microplates coated with poly-D-lysine and incubated for 24 hours. Cells were washed once with Tyrode buffer (140 mmol/L NaCl, ₁ mmol/L CaCl2, 2.7 mmol/L KCl, 0.49 mmol/L _MgCl2 , 0.37 mmol/L _NaH2PO4 , 5.6 mmol/L glucose, ₁₂ mmol/L NaHCO3, _and 25 mmol/L HEPES, pH 7.5) and then measured in Tyrode buffer. The test compound was incubated with cells at 37°C for 5 (Gα _i ) or 15 (EE) min, followed by the addition of 200 nmol/L of the GPR84 agonist ZQ-16 (2-(hexylthio)-6-hydroxy-4(3H)-pyrimidinone) for 5 min at room temperature (Gα _i ) or 30 min at 37°C (EE). Rluc8 substrate coelentin 400A (Prolume, Lakeside, AZ) was added at a final concentration of 5 μmol/L, and BRET readings were collected using an Infinite M1000 microplate reader (Tecan, Morrisville, NC). BRET 2 readings between Rluc8 and GFP10 or rGFP were collected by ^sequentially integrating signals detected in the 370–450 nm (Rluc8) and 510–540 nm (GFP10, rGFP) windows. The BRET signal was calculated as the ratio of light emitted by the receptor (GFP10, rGFP) to light emitted by the donor (Rluc8). This value was corrected to net BRET by subtracting the background BRET signal obtained from cells transfected with the Rluc8 construct alone. The ligand-induced net BRET value was calculated by subtracting the mediator-induced net BRET from the ligand-induced net BRET.

Table 26 shows the activity of selected compounds of the present invention in the BRET assay of the Gαi biosensor when tested at a single concentration. The compound numbers correspond to the compound numbers in Table 1. Compounds tested at concentrations below 1 μM are indicated as “A*”; compounds tested at 1 μM are indicated as “A ^o ”; compounds tested at 2 μM are indicated as “A”; compounds tested at 3 μM are indicated as “B”; compounds tested at 3.3 μM are indicated as “C”; compounds tested at 5 μM are indicated as “D”; compounds tested at 6.00 μM are indicated as “D ^o ”; compounds tested at 6.25 μM are indicated as “E”; compounds tested at 10 μM are indicated as “F”; compounds tested at 12.5 μM are indicated as “G”; compounds tested at 15 μM are indicated as “H”; and compounds tested at 25 μM are indicated as “I”. Compounds with activity specified as "*" provide an inhibition percentage of ≤25%; compounds with activity specified as "**" provide an inhibition percentage of >25% to ≤50%; compounds with activity specified as "***" provide an inhibition percentage of >50% to ≤75%; and compounds with activity specified as "****" provide an inhibition percentage of >75%.

Table 26. BRET assay (inhibition %)

Table 27 shows the activities of the selected compounds of the present invention in the BRET assay of the Gαi biosensor. The compound numbers correspond to the compound numbers in Table 1. Compounds with activities designated as "A" provide _IC50 values of ≤0.3 μM; compounds with activities designated as "B" provide _IC50 values of 0.3–1 μM; compounds with activities designated as "C" provide _IC50 values of 1–3 μM; compounds with activities designated as "D" provide _IC50 values of >2 μM but no exact amount was measured; and compounds with activities designated as "D" provide _IC50 values of >3 μM.

Table 27. BRET determination ( _IC50 )

Example 56: Neutrophil Migration Assay

Neutrophil migration assay: After isolation, neutrophils were resuspended in chemoattractant buffer (DMEM supplemented with 10 mM HEPES) at a concentration of 8.9 x 10⁶ cells/mL. In a 96-well plate, 20 μl of the compound solution in the chemoattractant buffer was added to 180 μl of cell suspension. After incubation at 37°C for 30 min, 75 μl of cell suspension was transferred to the upper chamber of a 5 μm Corning HTS transwell. 235 μl of chemoattractant buffer (embelin) was added to the lower chamber of the transwell. After incubation at 37°C in 5% _CO₂ for 60 min, the upper chamber of the transwell was removed, and the plate was centrifuged at 1500 rpm for 6 min. The supernatant was removed, and the cells were resuspended in 100 μl of PBS. ATP content was assessed using an ATPlite luminescence assay according to the manufacturer's instructions (Perkin Elmer, Buckinghamshire, UK). In short, 50 μl of ATPlite buffer and 50 μl of lysis solution were added to the lower chamber of a Transwells. After incubation at room temperature, followed by 5 minutes in the dark with continuous stirring, 150 μl of cell lysate was transferred to a 96-well white plate and incubated in the dark for 10 minutes. The luminescence was read using a TECAN Infinite M1000 plate reader (Tecan, Morrisville, NC).

Table 27 shows the activities of the selected compounds of the present invention in the neutrophil migration assay. The compound numbers correspond to those in Table 1. Neutrophil migration results were normalized relative to the GPR84 antagonistic control compound, which provided a mean _IC50 value of 131 nM and an _IC50 range of 15 nM to 553 nM in the neutrophil migration assay (n=26). Normalization of the results accounted for donor variations. Compounds with activity designated as “A” provided _IC50 values of ≤300 nM; compounds with activity designated as “B” provided _IC50 values of >300–≤1,000 nM; compounds with activity designated as “C” provided _{IC50 values} of >1,000–3,000 nM; and compounds with activity designated as “D” provided _IC50 values of >3,000 nM. Compounds with migration inhibition efficacy relative to the control compound designated as "C" provide an _IC50 of ≤0.5 times that of the control compound; compounds with activity designated as "B" provide an IC50 of >0.5 to ≤1.0 times that of the control compound; and compounds with activity designated as "A" provide an _IC50 of >1.0 times that of the control _compound .

Table 27. Neutrophil migration assay

While we have described several embodiments of the invention, it will be apparent that our embodiments can be modified to provide other embodiments utilizing the compounds and methods of the invention. Therefore, it should be understood that the scope of the invention should be defined by the appended claims rather than the specific embodiments illustrated.

Claims (56)

1. A compound of formula I, Or its pharmaceutically acceptable salt, wherein: Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; an 8-10 membered bicyclic heteroaryl ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. ^R1 is selected from (i) 3-7 membered saturated or partially unsaturated monocyclic carbon rings; 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and _C1-6 aliphatic groups; each of which is substituted by p instances of _R4 ; and (ii) hydrogen; Each instance of ^R2 , ^R4 , and ^R5 is independently hydrogen, deuterium, ^Rz , halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -S( _O ) _NR2 , -CF2R, _-CF3 , -CR2(CN), _-CR2 (OR), _-CR2 ( _NR2 ), _-C (O)R, -C( _O )OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)C(NR) _NR2 , -N(R) _NR2 , -N(R)S(O) ₂ NR ₂ , -N(R)S(O) ₂ R, -N＝S(O)R ₂ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ₂ , -SiR ₃ , -P(O)(R)NR ₂ , -P(O)(R)OR or -P(O)R ₂ ; or Two ^R2 groups may optionally combine to form =O; Two ^R4 groups may optionally combine to form =O; Two ^R5 groups may optionally combine to form =O; The two ^R2 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur; The two ^R4 groups optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated, or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or The two ^R5 groups may optionally form, together with their intermediary atoms, a 5-8 member saturated, partially unsaturated or aryl fused ring having 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur; Each instance of R ^z is independently selected from optionally substituted groups selected from the following: _C1-6 aliphatic groups; phenyl groups; 3-7 membered saturated or partially unsaturated monocyclic carbon rings; 4-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. ^R3 is hydrogen or an optionally substituted _C1-6 aliphatic group; or Two ^R3 groups may optionally combine to form =O; or The ^R2 and ^R3 groups, together with their intermediary atoms, optionally form 5-8 member saturated or partially unsaturated fused rings with 0-3 independent heteroatoms selected from nitrogen, oxygen or sulfur. ^L1 is one of the following: (a) A _C1-6 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units in the chain are independently and optionally replaced by: -O-, -Cy-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)- or -S(O) _2- ; or (b) Covalent bond; Each -Cy- is independently a divalent ring optionally substituted from the following: phenylene; 3-7 membered saturated or partially unsaturated carbocyclic group; 4-7 membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. ^L2 is a covalent or _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CR(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)-, -CH( _CR3 )-, -C=( _CH2 )- or -S(O) _2- ; ^L3 is one of the following: (a) A _C1-4 divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) _2- , -CH(R)-, -CH(OR)-, -C(F) _2- , -N(R)-, -S-, -S(O)-, or -S(O) _2- ; or (b) Covalent bond; X is one of the following: (a) A 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 member saturated or partially unsaturated bridging or spirocyclic, bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 member saturated or partially unsaturated bridging tricyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member partially aromatic or heteroaromatic bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbocyclic ring; or a phenyl ring; each of which is substituted by q R ⁵ examples; or (b) -CH ₂ (OR), -CH(R)(OR) or -C(R) ₂ (OR); Each instance of R is independently hydrogen or optionally substituted with a group selected from: _C1-6 aliphatic group; phenyl; 8-10 membered bicyclic aryl ring; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R groups on the same atom may optionally be together with the atom to form a 3-7 membered monocyclic saturated, partially unsaturated or heteroaryl ring having 0-3 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur in addition to the atom. m can be 0, 1, 2, 3, or 4; n can be 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5. 2. The compound of claim 1, wherein the compound is any one of formula I-a, I-b-1, I-b-2, I-b-3 or I-c: Or its pharmaceutically acceptable salt. 3. The compound of claim 1, wherein the compound is any one of formula I-f-1, I-f-2, I-f-3, I-f-4, I-f-5, I-f-6, I-f-7, I-f-8 or I-f-9: Or its pharmaceutically acceptable salt. 4. The compound of claim 1, wherein the compound is any one of formula I-g-1, I-g-2, or I-g-3: Or its pharmaceutically acceptable salt. 5. The compound of claim 1, wherein the compound is any one of formula I-h-1, I-h-2, or I-h-3: Or its pharmaceutically acceptable salt. 6. The compound of claim 1, wherein the compound is any one of formula I-i-1, I-i-2, or I-i-3: Or its pharmaceutically acceptable salt. 7. The compound of claim 1, wherein the compound is any one of formula I-j-1, I-j-2 or I-j-3: Or its pharmaceutically acceptable salt. 8. The compound of claim 1, wherein ring A is a phenyl ring; a 4-7 member saturated or partially unsaturated monocyclic carbon ring; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8 member saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 9. The compound of claim 1, wherein ring A and its ^R2 substituent are 10. The compound of claim 9, wherein ring A and its ^R2 substituent are 11. The compound of claim 1, wherein ring B is a 5-membered monocyclic partially unsaturated heterocyclic group or heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 12. The compound of claim 1, wherein ring B and its ^R3 substituent are 13. The compound of claim 12, wherein the two ^R3 groups are bonded together to form =O, and ring B is 14. The compound of claim 12, wherein ring B and its ^R3 substituent are 15. The compound of claim 1, wherein ^R1 is a group selected from: _C1-6 aliphatic group; phenyl group; 3-7 membered saturated or partially unsaturated monocyclic carbon ring; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of these is substituted by p instances of ^R4 . 16. The compound of claim 1, wherein ^R1 and its ^R4 substituents are... 17. The compound of claim 16, wherein the two ^R4 groups are bonded together to form =O, and ^R1 is 18. The compound of claim 16, wherein the two groups of ^R4 groups are bonded together to form =O, and ^R1 is 19. The compound of claim 1, wherein ^L1 is a covalent bond, 20. The compound of claim 1, wherein ^L2 is a covalent bond, 21. The compound of claim 1, wherein ^L3 is a covalent bond, 22. The compound of claim 1, wherein m is 1, 2, 3 or 4. 23. The compound of claim 1, wherein n is 1, 2, 3 or 4. 24. The compound of claim 1, wherein p is 1, 2, 3, 4 or 5. 25. The compound of claim 1, wherein ring A is a 5-6 membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen and oxygen; ring B is a 5-membered monocyclic heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen and oxygen; ^R1 is a 3-7 membered saturated monocyclic carbide ring substituted with p instances of ^R4 ; each instance of ^R2 , ^R4 , and ^R5 is independently hydrogen, deuterium, ^Rz , halogen, -CN, _-NO2 , -OR, -SR, or _-NR2 ; each instance of ^Rz is independently an optionally substituted _C1-6 aliphatic group; ^R3 is hydrogen or an optionally substituted _C1-6 aliphatic group; ^L1 is a _C2-4 divalent straight-chain or branched unsaturated hydrocarbon chain; ^L2 is a covalent bond; ^L3 is a C _1-4 divalent straight-chain or branched saturated hydrocarbon chain; X is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the ring is substituted by ^q instances of R; each instance of R is independently hydrogen or optionally substituted _C1-6 aliphatic group; m is 0, 1 or 2; n is 0 or 1; p is 0, 1 or 2; and q is 0, 1 or 2. 26. The compound of claim 1 or 25, wherein X is a 5-7 member saturated monocyclic heterocycle having 1 or 2 oxygen atoms, wherein the ring is substituted by q instances of R ⁵ . 27. The compound of claim 1, wherein the compound is represented by: Or its pharmaceutically acceptable salt. 28. The compound of claim 27, wherein ^R1 is a 3-7 member saturated monocyclic carbon ring substituted with p instances of ^R4 ; each instance of ^R2 and ^R5 is independently hydrogen, deuterium, ^Rz , halogen, -CN, _-NO2 , -OR, -SR, or _-NR2 ; each instance of ^Rz is independently an optionally substituted _C1-6 aliphatic group; ^R3 is hydrogen or an optionally substituted _C1-6 aliphatic group; ^L3 is a _C1-4 divalent straight-chain or branched saturated hydrocarbon chain; X is a 4-8 member saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with q instances ^{of R5} ; each instance of R is independently hydrogen or an optionally substituted _C1-6 aliphatic group; m is 0, 1, or 2; n is 0 or 1; p is 0, 1, or 2; and q is 0, 1, or 2. 29. The compound of claim 27 or 28, wherein X is a 5-7 member saturated monocyclic heterocycle having 1 or 2 oxygen atoms, wherein the ring is substituted by q instances of R ⁵ . 30. The compound of claim 1, wherein the compound is any one of formula I-ii-1 or I-ii-2: Or its pharmaceutically acceptable salt. Where ^R2 ′ is ^R2 . 31. The compound of claim 30, wherein ^R2 ′ is _-NR2 . 32. The compound of claim 30, wherein ^R2 ′ is -N( _CH3 ) ₂ . 33. The compound of claim 1, wherein the compound is any one of formula I-jj-1 or I-jj-2: Or its pharmaceutically acceptable salt. 34. The compound of claim 1, wherein the compound is any one of formula I-kk-1 or I-kk-2: Or its pharmaceutically acceptable salt. Where ^R2 ′ is ^R2 . 35. The compound of claim 34, wherein ^R2 ′ is _-NR2 . 36. The compound of claim 34, wherein ^R2 ′ is -N( _CH3 ) ₂ . 37. The compound of claim 1, wherein the compound is any one of formula I-II-1 or I-II-2: Or its pharmaceutically acceptable salt. 38. The compound of claim 37, wherein one of ^R2 is F. 39. The compound of claim 1, wherein the compound is selected from those compounds depicted in Table 1, or pharmaceutically acceptable salts thereof. 40. A pharmaceutical composition comprising the compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator. 41. The compound of any one of claims 1-39, or the pharmaceutical composition of claim 40, used as a pharmaceutical agent. 42. A method for inhibiting GPR84 in a biological sample, the method comprising contacting the sample with a compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 40. 43. A method of treating a patient with GPR84-mediated symptoms, diseases, or disorders, the method comprising administering to the patient in need a compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 40. 44. The method of claim 43, wherein the condition, disease, or disorder is a proliferative disorder, fibrotic disease, infectious disease, autoimmune disease, endocrine and/or metabolic disease, cardiovascular disease, disease involving impaired immune cell function, neuroinflammatory disorder, neurodegenerative disorder, inflammatory disorder, multiple sclerosis, or pain. 45. The method of claim 43, wherein the condition, disease, or ailment is cancer. 46. The method of claim 45, wherein the cancer is leukemia or hepatocellular carcinoma (HCC). 47. The method of claim 45, wherein the cancer is acute myeloid leukemia (AML). 48. The method of claim 43, wherein the condition, disease, or ailment is a proliferative condition associated with one or more activating mutations in GPR84. 49. The method of claim 43, wherein the condition, disease, or ailment is a chronic viral infection. 50. The method of claim 44, wherein the condition, disease, or disorder is an inflammatory disorder selected from rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis (IPF), psoriasis, Crohn's disease, ulcerative colitis, uveitis, periodontitis, esophagitis, gastroesophageal reflux disease (GERD), inflammatory bowel disease, or pyoderma gangrenosa. 51. The method of claim 43, wherein the condition, disease, or disorder is non-alcoholic steatosis (NASH) or idiopathic pulmonary fibrosis (IPF). 52. The method of claim 43, wherein the condition, disease, or ailment is systemic lupus erythematosus (SLE). 53. The method of claim 43, wherein the condition, disease, or disorder is neuropathic pain. 54. The method of claim 43, wherein the condition, disease, or ailment is Alzheimer's disease. 55. The method of claim 43, wherein the condition, disease, or ailment is idiopathic pulmonary fibrosis (IPF). 56. A method for increasing the efficacy of a vaccine in a patient, the method comprising administering to the patient a compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 40 as an adjuvant.