HK1250711B - Polycyclic-carbamoylpyridone compounds and their pharmaceutical use - Google Patents

Description

Polycyclic-carbamoylpyridone compounds and their pharmaceutical uses

This application is a divisional application of the Chinese patent application (application number 201380073134.X, application date December 19, 2013, invention title “Polycyclic-carbamoylpyridone compounds and their pharmaceutical uses”) which has entered the Chinese national phase of international application PCT/US2013/076367.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/745,375, filed December 21, 2012, U.S. Provisional Patent Application No. 61/788,397, filed March 15, 2013, and U.S. Provisional Patent Application No. 61/845,803, filed July 12, 2013. The entire contents of the foregoing applications are incorporated herein by reference.

Background Art

Field of the Invention

Disclosed are compounds, compositions, and methods for treating human immunodeficiency virus (HIV) infection. In particular, disclosed are novel polycyclic carbamoylpyridone compounds, methods for their preparation, and uses as therapeutic or prophylactic agents.

Description of related technologies

Human immunodeficiency virus infection and related diseases are major public health problems worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have been shown to be effective, especially when used in combination, toxicity and the development of resistant strains have limited their usefulness (Palella, et al. N. Engl. J Med. (1998) 338: 853-860; Richman, D.D. Nature (2001) 410: 995-1001).

The pregnane X receptor (PXR) is a nuclear receptor that is one of the key regulators of enzymes involved in the metabolism and elimination of small molecules from the body. Activation of PXR is known to upregulate or induce the production of metabolic enzymes such as cytochrome P450 3A4 (CYP3A4) and enzymes involved in transport, such as OATP2, in the liver and intestine (Endocrine Reviews (2002) 23(5):687-702). When a drug causes these and other enzymes to be upregulated by PXR activation, this can reduce the absorption and/or exposure of the co-administered drug to which the upregulated enzymes are sensitive. To minimize the risk of this type of drug-drug interaction, it is desirable to minimize PXR activation. Furthermore, PXR is known to be activated by many different types of molecules (Endocrine Reviews (2002) 23(5):687-702). Therefore, it is important to test for and minimize PXR activation for drugs that are to be co-administered with other drugs.

Transporters have been identified as playing a role in the pharmacokinetic, safety, and efficacy properties of drugs, and some drug-drug interactions are mediated by transporters. See, Giacomini KM, et al. “Membrane transporters in drug development,” Nat. Rev Drug Discov. 9:215-236, 2010; Zhang L, et al. “Transporter-Mediated Drug-Drug Interactions,” Clin. Pharm. Ther. 89(4):481-484 (2011). One transporter, organic cation transporter 2 (OCT2; SLC22A2), is a member of the solute carrier (SLC) superfamily of transporters and is primarily localized on the basolateral membrane of the renal proximal tubule. OCT2, involved in apically expressed multidrug and toxin excretion (MATE) transporters 1 and 2-K, is thought to form the major cation secretion pathway in the kidney and has been shown to transport endogenous compounds including creatinine and xenobiotics including metformin. Therefore, inhibition of OCT2 may lead to increased levels of serum creatinine and potentially increased levels of other OCT2 substances. It is also important to test and minimize OCT2 inhibition by drugs.

The goal of antiretroviral therapy is to obtain viral suppression in patients infected with HIV. The treatment guidelines published by the U.S. Department of Health and Human Services provide that obtaining viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes. (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Section accessed March 14, 2013.). In addition, when patients need to treat other medical conditions, the treatment decision-making for HIV-infected patients is very complicated (Id., in E-12). Because the standard of care requires the use of multiple different drugs to suppress HIV, as well as other conditions that the patient may experience, the possibility of drug interactions is the standard for selecting a drug regimen. In this way, it is necessary to have an antiretroviral therapy with a reduced possibility of drug interactions. Therefore, there is a need for new agents that inhibit HIV replication and minimize PXR activation when co-administered with other drugs.

Summary of the Invention

The present invention relates to novel polycyclic carbamoylpyridone compounds having antiviral activity, including stereoisomers and pharmaceutically acceptable salts thereof, and the use of such compounds in treating HIV infection. The compounds of the present invention can be used to inhibit the activity of HIV integrase and can be used to reduce HIV replication.

In one embodiment of the present invention, there is provided a compound having the following formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are taken together to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, or -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, wherein at least one of Z ¹ and Z ² or Z ¹ and Z ^{3 are} taken together to form -L-;

Z ⁴ is a bond, -CH ₂ - or -CH ₂ CH ₂ -;

^Y1 and ^Y2 are each independently hydrogen, _C1-3 alkyl or _C1-3 haloalkyl;

^R1 is phenyl substituted by one to three halogens; and

Each ^Ra is independently hydrogen, halogen, hydroxy or _C1-4 alkyl.

In another embodiment of the present invention, there is provided a compound having the following formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -O- or -NZ ² - or -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) _{2 -} , -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^{a )} ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ -or-C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -;

Z ⁴ is a bond or -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ NR ^a CH ₂ -, -CH ₂ SCH ₂ -, -CH ₂ S(O)CH ₂ - or -CH ₂ SO ₂ CH ₂ -;

Y ¹ and Y ² are each independently hydrogen, C _1-3 alkyl or C _1-3 haloalkyl, or Y ¹ and Y ^2, together with the carbon atom to which they are attached, form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more ^Ra ;

R ¹ is optionally substituted aryl or optionally substituted heteroaryl; and

Each ^Ra is independently hydrogen, halogen, hydroxy or _C1-4 alkyl, or two ^Ra groups together with the carbon atom to which they are attached form C=O, and

wherein at least one of the following: (i) Z ¹ and Z ² or Z ¹ and Z ³ together form -L-; or (ii) Y ¹ and Y ² together with the carbon atoms to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

In another embodiment, a pharmaceutical composition is provided which includes a compound having formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

The present invention also provides the use of a pharmaceutical composition as described above for treating HIV infection in a human suffering from or at risk of suffering from the infection.

In another embodiment, methods of using a compound of formula (I) in therapy are provided. In particular, methods of treating HIV viral proliferation, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human) are provided, comprising administering to the mammal a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

In another embodiment, disclosed is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for treating HIV infection in a human having or at risk of having the infection.

In another embodiment, disclosed is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of HIV infection in a human having or at risk of having the infection.

In another embodiment, an article of manufacture is disclosed, comprising a composition effective for treating HIV infection; and packaging material comprising a label indicating that the composition can be used to treat HIV infection. An exemplary composition comprises a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof.

In yet another embodiment, a method of inhibiting HIV replication is disclosed. The method comprises exposing the virus to an effective amount of a compound of formula (I) or a salt thereof under conditions wherein HIV replication is inhibited.

In another embodiment, disclosed is the use of a compound of formula (I) for inhibiting the activity of HIV integrase.

In another embodiment, disclosed is the use of a compound of formula (I) or a salt thereof for inhibiting HIV replication.

Other embodiments, objects, features and advantages will be set forth in the detailed description of the embodiments that follows, and in part will be obvious from the description of the claimed invention or may be learned by practicing the claimed invention. These objects and advantages will be realized and attained by the methods and compositions particularly pointed out in the written description and claims. The foregoing summary should be understood as it is to be considered a brief and general summary of some embodiments disclosed herein, provided solely for the benefit and convenience of the reader, and is not intended in any way to limit the scope of the appended claims as legally entitled or the scope of equivalents.

Detailed description

In the following description, in order to provide a detailed understanding of the various embodiments of the present invention, certain details have been set forth. However, it will be understood by those skilled in the art that the present invention can be implemented without these details. It should be understood that the following description of several embodiments is intended to be an example of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments set forth. The titles used throughout the specification are provided only for convenience and are not to be construed in any way as limiting the claims. The embodiment set forth under any title may be combined with the embodiment set forth under any other title.

definition

Unless the context requires otherwise, throughout the specification and claims, the term "comprise" and variations such as "comprises" and "comprising" should be interpreted in an open-ended inclusive sense, that is, to mean "including, but not limited to."

Reference throughout this specification to "one embodiment" or "an embodiment" indicates that a particular feature, structure, or characteristic described with respect to that embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

Unless the context requires otherwise, reference throughout this specification to a "compound of Formula (I)" or "a compound of Formula (I)" refers to all embodiments of Formula (I), including, for example, compounds of the following formulae: (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH), as well as the specific compounds disclosed herein.

"Amino" refers to a _-NH2 group.

"Cyano" refers to a -CN group.

"Hydroxy" refers to an -OH group.

"Imino" refers to a =NH substituent.

"Nitro" refers to a _-NO2 group.

"Oxo" refers to a =0 substituent.

"Thio" refers to a =S substituent.

"Alkyl" refers to a straight or branched chain hydrocarbon consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), has one to twelve carbon atoms ( _Ci - _Ci2 alkyl), preferably one to eight carbon atoms (Ci _{- Cs} alkyl) or one to six carbon atoms (Ci- _{C6 alkyl} ), and is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless specifically stated otherwise in the specification, an alkyl group may be optionally substituted.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds) and has from one to twelve carbon atoms, for example, methylene, ethenyl, propenyl, n-butenyl, ethenylene, propenylene, n-butenyl, propynyl, n-butynyl, etc., which connects the rest of the molecule to a radical group. The alkylene chain is connected to the rest of the molecule and to the radical group through a single bond or a double bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, the alkylene chain may be optionally substituted.

"Alkoxy" refers to a radical of the formula -OR _A , where _RA is an alkyl radical as defined above containing from one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy radical may be optionally substituted.

"Alkylamino" refers to a radical of the formula -NHR _A or -NR _A R _A , wherein each _RA is independently an alkyl radical as defined above containing from one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino radical may be optionally substituted.

"Thioalkyl" refers to a radical of the formula -SR _A , wherein _RA is an alkyl radical as defined above containing from one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl radical may be optionally substituted.

"Aryl" refers to a monocyclic hydrocarbon ring system radical containing hydrogen and 6 to 18 carbon atoms. Aryl groups include, but are not limited to, aryl groups derived from benzene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include optionally substituted aryl groups.

"Aralkyl" refers to a radical of the formula _-RB - _RC , where _RB is an alkylene chain as defined above, and _RC is one or more aryl groups as defined above, for example, benzyl. Unless stated otherwise specifically in the specification, an aralkyl radical may be optionally substituted.

"Cycloalkyl" or "carbocycle" refers to a stable, non-aromatic, monocyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, preferably from three to ten carbon atoms, and being saturated or unsaturated and connected to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specifically stated in the specification, cycloalkyl groups may be optionally substituted.

"Cycloalkylalkyl" refers to a radical of _the formula _-RBRD , wherein _RB is an alkylene chain as defined above and _RD is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl radical may be optionally substituted.

"Halo" or "halogen" refers to bromine, chlorine, fluorine or iodine.

"Haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromomethyl, etc. Unless specifically stated otherwise in the specification, a haloalkyl group may be optionally substituted.

"Heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 18-membered non-aromatic ring radical consisting of two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. In the embodiments disclosed herein, the heterocyclyl is a monocyclic ring system; and the heterocyclyl may be partially or fully saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, thienyl, [1,3]dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, thiophene ... The heterocyclic group may be optionally substituted, unless otherwise specifically stated in the specification, or substituted.

"N-heterocyclyl" refers to a heterocyclyl as defined above that contains at least one nitrogen atom and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through the nitrogen atom in the heterocyclyl. Unless specifically stated otherwise in the specification, an N-heterocyclyl group may be optionally substituted.

"Heterocyclylalkyl" refers to a radical of the _{formula -RBRE} , wherein _RB is an alkylene chain as defined above and _RE is a heterocyclyl radical as defined above, and if the heterocyclyl radical is a nitrogen-containing heterocyclyl radical, the heterocyclyl radical may be attached to the alkyl radical at the nitrogen atom. Unless specifically stated otherwise in the specification, the heterocyclylalkyl radical may be optionally substituted.

"Heteroaryl" refers to a 5- to 14-membered monocyclic ring system radical containing hydrogen atoms, one to thirteen carbon atoms, and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Examples include, but are not limited to, azepine, furanyl, furanonyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, 2-oxoazepine, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thiophenyl, and thienyl. Unless otherwise specifically stated in the specification, heteroarylalkyl groups may be optionally substituted.

"N-heteroaryl" refers to a heteroaryl group as defined above that contains at least one nitrogen and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. Unless specifically stated otherwise in the specification, an N-heteroaryl group may be optionally substituted.

"Heteroarylalkyl" refers to a radical of _the formula _-RBRF , wherein _RB is an alkylene chain as defined above, and _RF is a heteroaryl group as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl radical may be optionally substituted. As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, such as, but not limited to: a halogen atom, such as F, Cl, Br and I; an oxygen atom in groups such as hydroxy, alkoxy and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides and enamines; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher valent bond (e.g., a double bond or a triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, _hydrazones , and nitriles _. For example, "substituted _" includes any of the above groups in which one or more hydrogen atoms are replaced _{by -NRGRH , -NRGC} (= _O ) _{RH , -NRGC} (=O) _NRGRH , -NRGC(=O) _ORH , _-NRGC (=NRg) _NRGRH , _{-NRGSO2RH , -OC} ( _{= O )NRGRH , -ORG} , _-SRG , _-SORG , _-SO2RG , _{-OSO2RG , -SO2ORG} , = _{NSO2RG ,} and _-SO2NRGRH . "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by -C(=O) _RG , -C(=O) _ORG , -C( _{= O ) NRRGRH} , _-CH2SO2RG , _{-CH2SO2NRRGRH} . In the foregoing, _RG and _RH are _the same or different and are independently hydrogen, alkyl, _alkoxy , alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, _N -heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. "Substituted" further means any of the above groups wherein one or more hydrogen atoms are replaced by a bond to amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and/or heteroarylalkyl. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

As used herein, the term "protecting group" refers to an unstable chemical moiety that is known in the art to protect reactive groups (including but not limited to hydroxyl and amino groups) from undesirable reactions during the synthesis process. Hydroxyl and amino groups protected with protecting groups are referred to herein as "protected hydroxyl" and "protected amino," respectively. Protecting groups are typically used selectively and/or orthogonally to protect sites during reactions at other reactive sites and can then be removed while leaving the unprotected group intact or participating in further reactions. Protecting groups as known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Typically, the group is protected or exists as a precursor that is inert to reactions that modify other regions of the parent molecule at the appropriate time to convert them into their final groups. Other representative protecting groups or precursor groups are discussed in Agrawal, et al., Protocols for Oligonucleotide Conjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72. Examples of “hydroxy protecting groups” include, but are not limited to, tert-butyl, tert-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenyl-methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyl-diphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate, p-phenylbenzoate, 9-fluorenylmethyl carbonate, methanesulfonate, and tosylate. Examples of “amino protecting groups” include, but are not limited to, carbamate protecting groups such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)-ethoxy-carbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl and nitrophenylacetyl; sulfonamide-protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimido and dithiasuccinyl.

The invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of formula (I) that are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, 15 O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I. These radiolabeled compounds can be used to determine or ^measure the effectiveness of the compound by characterizing, for example, the site of action or mode of action or the affinity for binding to a pharmacologically important site of action. Certain isotope-labeled compounds of formula (I), such as those incorporating radioisotopes, are used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (ie, ³ H) and carbon-14 ( ¹⁴ C) are particularly useful for this purpose in view of their ease of incorporation and alternative means of detection.

Substitution with heavier isotopes such as deuterium (ie, ² H) may confer certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may be increased or dosage requirements may be reduced. Thus, in some circumstances, heavier isotopes may be preferred.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples below, using an appropriate isotopically labeled reagent in place of the unlabeled reagent used above.

The present invention disclosed herein is also meant to cover the in vivo metabolites of the disclosed compounds. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, for example, mainly due to enzyme catalysis. Therefore, the present invention includes compounds produced by a method comprising administering a compound of the present invention to a mammal for a period of time sufficient to produce its metabolites. Such products are generally obtained by administering the radiolabeled compound of the present invention to an animal (such as, rat, mouse, guinea pig, monkey or human) with a detectable dose sufficient to allow metabolism to occur, and isolating its conversion products from urine, blood or other biological samples to identify.

"Stable compound" and "stable structure" are meant to refer to a compound that is sufficiently robust (reinforced) to be isolated to a useful degree of purity from a reaction mixture and formulated into an efficacious therapeutic agent. "Mammal" includes humans and livestock, such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-livestock animals, such as wild animals, etc.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups without substitution.

"Pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

"Pharmaceutically acceptable salts" refer to salts of compounds that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound (or can be converted into a form that possesses the pharmacological activity of the parent compound). Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX ₄ ⁺ (wherein X is C ₁ -C ₄ alkyl). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, salts of organic carboxylic acids, organic sulfonic acids, and inorganic acids, such as acetic acid, benzoic acid, camphorsulfonic acid, citric acid, glucoheptonic acid, gluconic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, succinic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, and trimethylacetic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and sulfamic acid. Pharmaceutically acceptable salts of compounds of hydroxy groups include combinations of anions of the compounds with suitable groups such as Na ⁺ and _NX4 ⁺ (wherein X is independently selected from H or _C1 - _C4 alkyl). Pharmaceutically acceptable salts also include salts formed by substitution of acidic protons in the parent compound with metal ions, such as alkali metal ions, alkaline earth metal ions, aluminum ions, when present; or salts formed by coordination with organic bases such as diethanolamine, triethanolamine, N-methylglucamine, and the like. Also included within this definition are ammonium and substituted or quaternized ammonium salts. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are incorporated herein by reference.

For therapeutic use, salts of the active ingredients of the compounds disclosed herein are generally pharmaceutically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, it has been found that salts of acids or bases that are not pharmaceutically acceptable may also be useful, for example, in the preparation or purification of compounds of formula (I) or other compounds of the present invention. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the present invention.

Metal salts are generally prepared by reacting metal hydroxides with the compounds of the present invention. Examples of metal salts prepared in this manner are salts containing Li ⁺ , Na ⁺ , and K ⁺ . Less soluble metal salts can be precipitated from solutions of more soluble salts by adding a suitable metal compound.

Additionally, salts can be formed by the addition _of certain organic and inorganic acids, such as HCl, HBr, _H2SO4 , _H3PO4 , or organic sulfonic acids, _to a basic center, typically an amine. Finally, it is understood that the compositions herein include the compounds disclosed herein in non-ionized as well as zwitterionic form and in hydrated form in combination with a stoichiometric amount of water.

Crystallization generally produces a solvate of the compound of the present invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compound of the present invention may exist as a hydrate, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms. The compound of the present invention may be a true solvate, while in other cases, the compound of the present invention may retain only adventitious water or be a mixture of water and some adventitious solvent.

"Pharmaceutical composition" refers to a formulation of a compound of the present invention and a generally accepted medium for delivering biologically active compounds to mammals, such as humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients thereof. "Effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the present invention that, when administered to a patient in need thereof, is sufficient to produce an effective treatment for the disease-state, condition, or disorder for which the compound has an effect. Such an amount is sufficient to elicit the biological or medical response of the tissue system or patient sought by the researcher or clinician. The amount of the compound according to the present invention that constitutes a therapeutically effective amount should vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the excretion rate of the compound, the duration of treatment, the type of disease-state or condition to be treated and its severity, the drugs used in combination with or in conjunction with the compound of the present invention, and the patient's age, weight, general health, sex, and diet. Such a therapeutically effective amount can be routinely determined by one of ordinary skill in the art, taking into account their own knowledge, the state of the art, and this disclosure.

As used herein, the term "treating" is used to refer to the administration of a compound or composition according to the present invention to alleviate or eliminate the symptoms of HIV infection and/or reduce the viral load of a patient. The term "treating" also encompasses the administration of a compound or composition according to the present invention after an individual has been exposed to the virus, but before symptoms of the disease appear, and/or before the virus is detected in the blood, to prevent the onset of symptoms of the disease and/or to prevent the virus from reaching detectable levels in the blood, as well as the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the child during the first days after birth.

As used herein, the term "antiviral agent" refers to an agent (compound or organism) that effectively inhibits the establishment and/or replication of a virus in humans, including but not limited to agents that interfere with host or viral mechanisms required for the establishment and/or replication of a virus in humans.

As used herein, the term "inhibitor of HIV replication" is meant to refer to an agent that is capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo, or in vivo.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined by absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be prepared using conventional methods such as chromatography and fractional crystallization. Conventional methods for preparing/isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, it is intended that the compounds include both E and Z geometric isomers. Furthermore, all tautomeric forms are also intended to be included.

"Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

"Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of the described compounds.

"Prodrug" refers to a compound chemically designed to effectively release the parent drug after overcoming biological barriers to oral delivery. In some embodiments, the present invention includes prodrugs of compounds of formula (I).

Compound

As mentioned above, in one embodiment of the present invention, there is provided a compound having antiviral activity, said compound having the following formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are combined together to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, or -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, wherein at least one group of Z ¹ and Z ² or Z ¹ and Z ³ are combined together to form -L-;

Z ⁴ is a bond, -CH ₂ - or -CH ₂ CH ₂ -;

^Y1 and ^Y2 are each independently hydrogen, _C1-3 alkyl or _C1-3 haloalkyl;

^R1 is phenyl substituted by one to three halogens; and

Each ^Ra is independently hydrogen, halogen, hydroxy or _C1-4 alkyl.

In another embodiment, a compound having the following formula (II-A) is provided:

In another embodiment, a compound having the following formula (II-B) is provided:

In another embodiment, a compound having the following formula (II-C) is provided:

In another embodiment, L is -C( ^Ra ) _2- . In a further embodiment, L is -C( ^Ra ) _2C (Ra)2-. In yet a further embodiment, L is -C( ^Ra ) _2C ( ^Ra ) _2C ( ^{Ra )} _{2- .} In yet a further embodiment, each ^Ra is hydrogen. In yet a further embodiment, one ^Ra is methyl and each remaining ^Ra is hydrogen. In yet a further embodiment, one ^Ra is halogen and each remaining ^Ra is hydrogen. In yet a further embodiment, two ^Ras are halogen and each remaining ^Ra is hydrogen. In yet a further embodiment, one ^Ra is halogen and each remaining ^Ra is hydrogen.

In another embodiment, X is -O-. In another embodiment, X is -NZ ³ -. In another embodiment, X is -NH-. In another embodiment, X is -CHZ ³ - and Z ¹ and Z ³ are combined to form -L-. In a further embodiment, Z ² is hydrogen. In another embodiment, X is -CH ₂ -.

In another embodiment, Z ⁴ is a bond or -CH ₂ -. In another embodiment, Z ⁴ is -CH ₂ -. In another embodiment, Z ⁴ is a bond.

In another embodiment, Y ¹ and Y ² are each independently hydrogen, methyl or trifluoromethyl.

In another embodiment, R ¹ is substituted with one halogen. In a further embodiment, R ¹ is 4-fluorophenyl or 2-fluorophenyl.

In another embodiment, R ¹ is substituted with two halogens. In a further embodiment, R ¹ is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In yet another further embodiment, R ¹ is 2,4-difluorophenyl.

In another embodiment, R ¹ is substituted with three halogens. In a further embodiment, R ¹ is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. In yet a further embodiment, R ¹ is 2,4,6-trifluorophenyl.

In one embodiment, a pharmaceutical composition is provided, which comprises a compound of any one of Formula (I), (II-A), (II-B) or (II-C) as described above, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Another embodiment is provided, which includes a method of treating HIV infection in a patient having an infection or at risk of having an infection by administering to the human a therapeutically effective amount of a compound of any one of Formula (I), (II-A), (II-B), or (II-C), as described above, or a pharmaceutical composition thereof. Another embodiment is provided, which includes a method of treating or preventing HIV infection in a patient having an infection or at risk of having an infection by administering to the human a therapeutically effective amount of a compound of any one of Formula (I), (II-A), (II-B), or (II-C), as described above, or a pharmaceutical composition thereof.

In another embodiment, there is provided a use of any one of the compounds of Formula (I), (II-A), (II-B) or (II-C) as described above, or a pharmaceutical composition thereof, for treating HIV infection in a patient having an infection or at risk of having an infection. In another embodiment, there is provided a use of any one of the compounds of Formula (I), (II-A), (II-B) or (II-C) as described above, or a pharmaceutical composition thereof, for treating or preventing HIV infection in a patient having an infection or at risk of having an infection. In another embodiment, there is provided a use of any one of the compounds of Formula (I), (II-A), (II-B) or (II-C) as described above, or a pharmaceutical composition thereof, for use in a medical therapy.

In another embodiment, provided is the use of any one of the compounds of Formula (I), (II-A), (II-B) or (II-C) as described above, or a pharmaceutical composition thereof, for the therapeutic treatment of HIV infection. In another embodiment, provided is the use of any one of the compounds of Formula (I), (II-A), (II-B) or (II-C) as described above, or a pharmaceutical composition thereof, for the prophylactic or therapeutic treatment of HIV infection.

As further described above, in one embodiment of the present invention, there is provided a compound having antiviral activity, said compound having the following formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -O- or -NZ ² - or -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen, C _1-3 alkyl or C _1-3 haloalkyl, or Z ¹ and Z ² or Z ¹ and Z ³ are taken together to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^{a )} _{2 -} , -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ -or-C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -;

Z ⁴ is a bond or -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ NR ^a CH ₂ -, -CH ₂ SCH ₂ -, -CH ₂ S(O)CH ₂ - or -CH ₂ SO ₂ CH ₂ -;

Y ¹ and Y ² are each independently hydrogen or C _1-3 alkyl, or Y ¹ and Y ^2, together with the carbon atom to which they are attached, form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more ^Ra ;

R ¹ is optionally substituted aryl or optionally substituted heteroaryl; and

Each ^Ra is independently hydrogen, halogen, hydroxy or _C1-4 alkyl, or two ^Ra groups together with the carbon atom to which they are attached form =0, and

wherein at least one of the following: (i) Z ¹ and Z ² or Z ¹ and Z ³ together form -L-; or (ii) Y ¹ and Y ² together with the carbon atoms to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

In another embodiment, W is -CHZ ² -.

In another embodiment, Z ¹ and Z ² or Z ¹ and Z ³ taken together form -L-.

In another embodiment, a compound having one of the following formulae (II-A), (II-B), or (II-C) is provided:

where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^{a )} ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

In another embodiment, Y ¹ and Y ² together with the carbon atom to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

In another embodiment, a compound having one of the following formulae (III-A), (III-B), (III-C), or (III-D) is provided:

wherein Z ¹ and Z ³ are each independently hydrogen or C _1-3 alkyl.

In another embodiment, a compound having one of the following formulae (III-E), (III-F), (III-G), or (III-H) is provided:

wherein Z ¹ and Z ³ are each independently hydrogen or C _1-3 alkyl.

In another embodiment, (i) Z ¹ and Z ² or Z ¹ and Z ³ together form -L-, and (ii) Y ¹ and Y ² together with the carbon atoms to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

In another embodiment, a compound having one of the following formulae (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), or (IV-AH) is provided:

where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^{a )} ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

In another embodiment, a compound having one of the following formulae (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), or (IV-BH) is provided:

where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^{a )} ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

In another embodiment, L is -C( ^Ra ) _2- , -C(Ra) _2C(Ra)2- ^, _-C ( ^Ra ) _2C ( ^Ra )2C( ^Ra ) _2- , or -C( ^Ra )2C( ^Ra ) _2C ( ^Ra ) _2C ( ^Ra ) _2C ( ^Ra ) _2- . In a further embodiment, L is -C(Ra) _2- . In yet a further embodiment, L is -C(Ra)2C( ^Ra ) _2- . In yet a further embodiment, L is -C( ^Ra ) _2C ( ^Ra ) _2- . In yet a further embodiment, L is -C( ^Ra ) _2C ( ^Ra ) _2C ( ^Ra ) _2- . In yet a further embodiment, each ^Ra is hydrogen. In yet a further embodiment, one ^Ra is methyl and each remaining ^Ra is hydrogen. In yet a further embodiment, one ^Ra is halogen and each remaining ^Ra is hydrogen. In yet a further embodiment, two ^Ra are halogen and each remaining ^Ra is hydrogen. In yet a further embodiment, one ^Ra is halogen and each remaining ^Ra is hydrogen.

In another embodiment, L is -C( ^Ra ) _2OC ( ^Ra ) _2- , -C( ^Ra ) ^2NRaC (Ra ⁾ _2- , -C(Ra)2SC( ^Ra ) _2- , -C( ^Ra ) _2S (O)C( ^Ra ) _2- , or -C( ^Ra ) _2SO2C ( ^{Ra )} _{2- .} In a further embodiment, L is -C( ^Ra ) _2OC ( ^Ra ) _2- . In yet a further embodiment, _each ^Ra is hydrogen. In yet a further embodiment, one ^Ra is methyl _and each remaining ^Ra is hydrogen. In yet a further embodiment, one ^Ra is halogen and each remaining ^Ra is hydrogen. In yet a further embodiment, two ^Ras are halogen and each remaining ^Ra is hydrogen. In yet a further embodiment, one ^Ra is halogen and each remaining ^Ra is hydrogen.

In another embodiment, X is -O-. In a further embodiment, Z ² is hydrogen. In another embodiment, X is -NZ ³ -. In another embodiment, X is -NH-. In another embodiment, X is -CHZ ³ -. In another embodiment, X is -CH ₂ -.

In another embodiment, Z ⁴ is a bond or -CH ₂ -. In another embodiment, Z ⁴ is -CH ₂ -. In another embodiment, Z ⁴ is a bond.

In another embodiment, Y ¹ and Y ² are each independently hydrogen, methyl or trifluoromethyl.

In another embodiment, R ¹ is substituted with one halogen. In a further embodiment, R ¹ is 4-fluorophenyl or 2-fluorophenyl.

In another embodiment, R ¹ is phenyl. In another embodiment, R ¹ is pyridinyl.

In another embodiment, R ¹ is substituted with at least one halogen.

In another embodiment, R ¹ is substituted with one halogen. In a further embodiment, R ¹ is 4-fluorophenyl or 2-fluorophenyl.

In another embodiment, R ¹ is substituted with two halogens. In a further embodiment, R ¹ is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In yet another further embodiment, R ¹ is 2,4-difluorophenyl.

In another embodiment, R ¹ is substituted with three halogens. In a further embodiment, R ¹ is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. In yet a further embodiment, R ¹ is 2,4,6-trifluorophenyl.

In another embodiment, R ¹ is 3-trifluoromethyl-4-fluorophenyl or 2-cyclopropyl-4-fluorophenyl.

In one embodiment, a pharmaceutical composition is provided which includes a compound of any one of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH), as described above, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Another embodiment is provided that includes a method of treating HIV infection in a human having or at risk of having the infection by administering to the human a therapeutically effective amount of a compound of any one of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH), as described above, or a pharmaceutical composition thereof. Another embodiment is provided that includes a method of treating or preventing HIV infection in a human having or at risk of having the infection by administering to the human a therapeutically effective amount of a compound of any one of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH), as described above, or a pharmaceutical composition thereof.

In another embodiment, there is provided use of a compound of any one of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH), as described above, or a pharmaceutical composition thereof, for treating an HIV infection in a human having or at risk of having the infection. In another embodiment, provided is the use of a compound of any one of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH), as described above, or a pharmaceutical composition thereof, for treating or preventing HIV infection in a human having or at risk of having the infection.

In another embodiment, provided is a method of treating a patient comprising administering to a patient a compound of any one of Formulae (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) as described above, or a pharmaceutical composition thereof, for use in medical therapy.

In another embodiment, provided is a compound of any one of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) as described above, or a pharmaceutical composition thereof, for the therapeutic treatment of HIV infection. In another embodiment, there is provided a use of any one of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) as described above, or a pharmaceutical composition thereof, for the prophylactic or therapeutic treatment of HIV infection.

It should be understood that any embodiment of the compounds of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) as described above Schemes, and herein for R in compounds of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) as described above Any specific substituents described for ^a , ^R , X, W, Y , ^Y , ^L , ^Z , ^Z , ^Z , or ^Z group can be independently combined with substituents from other embodiments and/or compounds of Formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) to form embodiments of the invention not specifically described above. Additionally, where a list of substituents is listed in a particular embodiment and/or claim for any particular R ¹ , ^Ra , X, W, Y ¹ , Y ² , L, Z ¹ , Z ² , Z ³ , or Z ⁴ , it should be understood that each individual substituent may be deleted from the particular embodiment and/or claim and the remaining list of substituents considered to be within the scope of the invention.

As will be appreciated by those skilled in the art, compounds of Formula (I), (II-A), (II-B), (II-C), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH), wherein Z ¹ and Z ² or Z ¹ and Z ³ together form -L-, can be displayed in several different ways. For example, compound 3 of Example 3 can be displayed as:

Pharmaceutical composition

For the purpose of administration, in some embodiments, the compounds described herein are administered as raw chemicals or formulated into pharmaceutical compositions. Pharmaceutical compositions disclosed herein include a compound of formula (I) and one or more of the following: a pharmaceutically acceptable carrier, a diluent, or an excipient. The compound of formula (I) is present in the composition in an amount effective to treat a particular disease or condition of interest. The activity of the compound of formula (I) can be determined by those skilled in the art, for example, as described below. Suitable concentrations and dosages can be easily determined by those skilled in the art. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in an amount of about 25 mg to about 500 mg. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in an amount of about 100 mg to about 300 mg. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in an amount of about 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or about 500 mg.

Administration of the compound of the present invention or its pharmaceutically acceptable salt in pure form or in a suitable pharmaceutical composition is carried out via any acceptable mode of administration for a reagent for similar purposes. The pharmaceutical composition of the present invention is prepared by mixing the compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and in a specific embodiment, is formulated into a preparation in the form of solid, semisolid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. The exemplary route of administration of such a pharmaceutical composition includes, but is not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal. The pharmaceutical composition of the present invention is prepared so as to allow the active ingredient contained therein to be bioavailable when the composition is administered to the patient. The composition administered to the subject or patient is in the form of one or more dosage units, wherein, for example, a tablet can be a single dosage unit, and the container of the compound of the present invention in the form of an aerosol can accommodate multiple dosage units. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art, for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the composition to be administered contains a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof for treating the disease or condition of interest according to the teachings described herein.

The pharmaceutical compositions disclosed herein are prepared by methods well known in the pharmaceutical art. For example, in some embodiments, a pharmaceutical composition intended for administration by injection is prepared by mixing a compound of the invention with sterile distilled water to form a solution. In certain embodiments, a surfactant is added to facilitate the formation of a uniform solution or suspension. A surfactant is a compound that non-covalently interacts with a compound of the invention, thereby promoting dissolution or uniform suspension of the compound in an aqueous delivery system.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the specific disorder or condition; and the subject's ongoing treatment.

Combination therapy

In one embodiment, a method for treating or preventing HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

In one embodiment, a pharmaceutical composition is provided that includes a compound disclosed herein, a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

In one embodiment, a pharmaceutical medicament is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

In the above embodiments, the additional therapeutic agent can be an anti-HIV agent. For example, in certain embodiments, the additional therapeutic agent is selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 connection inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, compounds targeting HIV capsids ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid destruction compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania) and WO 2013/006792 (Pharma Resources)), pharmacokinetic enhancers, and other drugs for the treatment of HIV, and combinations thereof. In a further embodiment, the additional therapeutic agent is selected from one or more of the following:

(1) HIV protease inhibitors selected from amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brenavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;

(2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355BS, VRX 840773, lesivirine (UK-453061), RDEA806, KM023, and MK-1439;

(3) HIV nucleoside inhibitors of reverse transcriptase selected from zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amidosovir, efavirenz, alovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphine azide, fozivudine tidoxil, apricitibine, (AVX754), KP-1461, GS-9131 (Gilead Sciences), and fosalvudine tidoxil (formerly HDP 99.0003);

(4) HIV nucleotide inhibitors of reverse transcriptase selected from tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate (Gilead Sciences), GS-7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix), or CMX-157 (Chimerix);

(5) HIV integrase inhibitors selected from the group consisting of curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, a derivative of aurintricarboxylic acid, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrphostin, a derivative of a tyrphostin, quercetin, a derivative of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, elvitegravir, dolutegravir, and GSK-744;

(6) HIV non-catalytic site or allosteric integrase inhibitors (NCINIs), including but not limited to BI-224436, CX0516, CX05045, CX14442, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), the entire contents of each of which are incorporated herein by reference;

(7) a gp41 inhibitor selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144;

(8) CXCR4 inhibitor AMD-070;

(9) entry inhibitor SP01A;

(10) gp120 inhibitor BMS-488043;

(11) G6PD and NADH-oxidase inhibitor immunitin;

(12) CCR5 inhibitors selected from apraviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer) and CCR5mAb004;

(13) CD4 ligation inhibitors selected from ibalizumab (TMB-355) and BMS-068 (BMS-663068);

(14) a pharmacokinetic enhancer selected from the group consisting of cobicistat and SPI-452; and

(15) Other drugs for treating HIV selected from the group consisting of: BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040),

and combinations thereof.

In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two, three, four or more additional therapeutic agents. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with four additional therapeutic agents. The two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, or they may be selected from different classes of therapeutic agents. In a specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleotide inhibitors of reverse transcriptase and HIV protease inhibitory compounds of reverse transcriptase. In a further embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase and HIV protease inhibitory compounds. In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.

In some embodiments, when the compounds disclosed herein are combined with one or more additional therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

In some embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, in a solid dosage form for oral administration.

In some embodiments, the compounds disclosed herein are administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of the compound disclosed herein and one or more additional therapeutic agents are both present in the patient's body at the same time.

Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in certain embodiments, a unit dose of a compound disclosed herein is administered first, followed by administering a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administering a unit dose of a compound disclosed herein within seconds or minutes. In certain embodiments, a unit dose of a compound disclosed herein is administered first, followed by administering a unit dose of one or more additional therapeutic agents after a period of several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administering a unit dose of a compound disclosed herein after a period of several hours (e.g., 1-12 hours).

The following examples illustrate the preparation of the compounds of the present invention (ie, compounds of formula (I)):

wherein R ¹ , X, W, Y ¹ , Y ² , Z ¹ , Z ² or Z ⁴ are as defined above. It will be appreciated by those skilled in the art that these compounds may be prepared by similar methods or by a combination of other methods known to those skilled in the art. It will also be appreciated by those skilled in the art that other compounds of formula (I) not specifically described below can be prepared by using suitable starting components and adjusting synthesis parameters as needed, as described below. Typically, starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or synthesized from sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition (Wiley, December 2000)) or prepared as described herein.

For the purpose of example only, the present invention includes but is not limited to the following technical solutions:

Technical solution 1. A compound having the following formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are taken together to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, or -C(R ^a ) ₂ C(R a ) ₂ C(R ^a ) ₂ C(R ^{a )} ₂ -, wherein at least one of Z ¹ and Z ² or Z ¹ and Z ³ are taken together to form -L-;

Z ⁴ is a bond, -CH ₂ - or -CH ₂ CH ₂ -;

^Y1 and ^Y2 are each independently hydrogen, _C1-3 alkyl or _C1-3 haloalkyl;

^R1 is phenyl substituted by one to three halogens; and

Each ^Ra is independently hydrogen, halogen, hydroxy or _C1-4 alkyl.

Technical Solution 2. The compound of Technical Solution 1 has the following formula (II-A):

Technical Solution 3. The compound of Technical Solution 1 has the following formula (II-B):

Technical Solution 4. The compound of Technical Solution 1 has the following formula (II-c):

Technical Solution 5. The compound according to any one of Technical Solutions 1 to 4, wherein L is -C(R ^a ) ₂ -.

Technical Solution 6. The compound according to any one of Technical Solutions 1 to 4, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical Solution 7. The compound according to any one of Technical Solutions 1 to 4, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical Solution 8. The compound according to any one of Technical Solutions 1-7, wherein each ^Ra is hydrogen.

Technical Solution 9. The compound of any one of Technical Solutions 1-7, wherein one ^Ra is methyl and each of the remaining ^Ras is hydrogen.

Technical Solution 10. The compound of any one of Technical Solutions 1-7, wherein at least one ^Ra is halogen and each of the remaining ^Ras is hydrogen.

Technical Solution 11. The compound of any one of Technical Solutions 1-7, wherein two ^Ra are halogen and each remaining ^Ra is hydrogen.

Technical Solution 12. The compound of any one of Technical Solutions 1-7, wherein one ^Ra is halogen and each of the remaining ^Ras is hydrogen.

Technical Solution 13. The compound of any one of Technical Solutions 1-2 or 5-12, wherein X is -O-.

Technical Solution 14. The compound according to any one of Technical Solutions 1-2 or 5-12, wherein X is -NZ ³ -.

Technical Solution 15. The compound according to any one of Technical Solutions 1-2 or 5-12, wherein X is -NH-.

Technical Solution 16. The compound according to any one of Technical Solutions 1-2 or 5-12, wherein X is -CHZ ³ -, and Z ¹ and Z ³ together form -L-.

Technical Solution 17. The compound of Technical Solution 16, wherein Z ² is hydrogen.

Technical Solution 18. The compound according to any one of Technical Solutions 1-2 or 5-12, wherein X is -CH ₂ -.

Technical Solution 19. The compound according to any one of Technical Solutions 1 or 5-18, wherein Z ⁴ is a bond or -CH ₂ -.

Technical Solution 20. The compound according to any one of Technical Solutions 1 or 5-18, wherein Z ⁴ is -CH ₂ -.

Technical Solution 21. The compound of any one of Technical Solutions 1 or 5-18, wherein Z ⁴ is a bond.

Technical Solution 22. The compound of any one of Technical Solutions 1 or 5-21, wherein Y ¹ and Y ² are each independently hydrogen, methyl or trifluoromethyl.

Technical Solution 23. The compound of any one of Technical Solutions 1-22, wherein R ¹ is substituted by a halogen.

Technical Solution 24. The compound of Technical Solution 23, wherein R ¹ is 4-fluorophenyl or 2-fluorophenyl.

Technical Solution 25. The compound according to any one of Technical Solutions 1 to 22, wherein R ¹ is substituted by two halogens.

Technical Solution 26. The compound of Technical Solution 25, wherein R ¹ is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl.

Technical Solution 27. The compound of Technical Solution 26, wherein R ¹ is 2,4-difluorophenyl.

Technical Solution 28. The compound according to any one of Technical Solutions 1-22, wherein R ¹ is substituted by three halogens.

Technical Solution 29. The compound of Technical Solution 28, wherein R ¹ is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

Technical Solution 30. The compound of Technical Solution 29, wherein R ¹ is 2,4,6-trifluorophenyl.

Technical solution 31. The compound of technical solution 1 is selected from:

Technical solution 32. The compound of technical solution 1 is selected from:

Technical solution 33. A pharmaceutical composition comprising the compound of any one of Technical Solutions 1-32 or its stereoisomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient.

Technical Solution 34. The pharmaceutical composition of Technical Solution 33 further comprises one or more additional therapeutic agents.

Technical solution 35. The pharmaceutical composition of technical solution 34, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical solution 36. The pharmaceutical composition of technical solution 35, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

Technical solution 37. A method for treating HIV infection in a human suffering from or at risk of infection, by administering to the human a therapeutically effective amount of the compound of any one of Technical Solutions 1-32 or the pharmaceutical composition of Technical Solution 33.

Technical Solution 38. The method of Technical Solution 37 further comprises administering a therapeutically effective amount of one or more additional therapeutic agents to the human.

Technical solution 39. The method of technical solution 38, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical Solution 40. The method of Technical Solution 39, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

Technical Solution 41. Use of the compound of any one of Technical Solutions 1-32 or the pharmaceutical composition of Technical Solution 33 for treating HIV infection in a person suffering from or at risk of infection.

Technical Solution 42. The use of Technical Solution 41, further comprising administering a therapeutically effective amount of one or more additional therapeutic agents to the human.

Technical solution 43. The use of technical solution 42, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical solution 44. The use of technical solution 43, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

Technical Solution 45. The compound or pharmaceutically acceptable salt thereof according to any one of Technical Solutions 1-32, for use in medical treatment.

Technical Solution 46. A compound or a pharmaceutically acceptable salt thereof according to any one of Technical Solutions 1-32, for use in the therapeutic treatment of HIV infection.

Technical solution 47. A compound having the following formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -O- or -NZ ² - or -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) _{2 -} , -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^{a )} ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -;

Z ⁴ is a bond or -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ NR ^a CH ₂ -, -CH ₂ SCH ₂ -, -CH ₂ S(O)CH ₂ - or -CH ₂ SO ₂ CH ₂ -;

Y ¹ and Y ² are each independently hydrogen, C _1-3 alkyl or C _1-3 haloalkyl, or Y ¹ and Y ^2, together with the carbon atom to which they are attached, form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more ^Ra ;

R ¹ is optionally substituted aryl or optionally substituted heteroaryl; and

Each ^Ra is independently hydrogen, halogen, hydroxy or _C1-4 alkyl, or two ^Ra groups together with the carbon atom to which they are attached form C=O, and

wherein at least one of the following: (i) Z ¹ and Z ² or Z ¹ and Z ³ together form -L-; or (ii) Y ¹ and Y ² together with the carbon atoms to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

Technical solution 48. The compound of Technical Solution 47, wherein W is -CHZ ² -.

Technical Solution 49. The compound of Technical Solution 47 or 48, wherein ^Z1 and ^Z2 or ^Z1 and ^Z3 together form -L-.

Technical solution 50. The compound of technical solution 49 has one of the following formulas (II-A), (II-B) or (II-C):

Where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^{a )} ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

Technical Solution 51. The compound of Technical Solution 47 or 48, wherein ^Y1 and ^Y2 together with the carbon atoms to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

Technical Solution 52. The compound of Technical Solution 51 has one of the following formulas (III-A), (III-B), (III-C) or (III-D):

wherein Z ¹ and Z ³ are each independently hydrogen or C _1-3 alkyl.

Technical Solution 53. The compound of Technical Solution 51 has one of the following formulas (III-E), (III-F), (III-G) or (III-H):

wherein Z ¹ and Z ³ are each independently hydrogen or C _1-3 alkyl.

Technical Solution 54. The compound of Technical Solution 47 or 48, wherein (i) Z ¹ and Z ² or Z ¹ and Z ³ together form -L-, and (ii) Y ¹ and Y ² together with the carbon atoms to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

Technical solution 55. The compound of technical solution 54 has one of the following formulas: (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG) or (IV-AH):

where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^{a )} ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

Technical solution 56. The compound of technical solution 54 has one of the following formulas: (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) or (IV-BH):

where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^{a )} ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

Technical solution 57. The compound of any one of technical solutions 47-50 or 54-56, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, or -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical solution 58. The compound of Technical Solution 57, wherein L is -C(R ^a ) ₂ -.

Technical Solution 59. The compound of Technical Solution 57, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical Solution 60. The compound of Technical Solution 57, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical Solution 61. The compound of any one of Technical Solutions 47-50 or 54-60, wherein each ^Ra is hydrogen.

Technical Solution 62. The compound of any one of Technical Solutions 47-50 or 54-60, wherein one ^Ra is methyl and each of the remaining ^Ras is hydrogen.

Technical Solution 63. The compound of any one of Technical Solutions 47-50 or 54-60, wherein at least one ^Ra is halogen and each of the remaining ^Ras is hydrogen.

Technical Solution 64. The compound of any one of Technical Solutions 47-50 or 54-60, wherein two ^Ra are halogen and each remaining ^Ra is hydrogen.

Technical Solution 65. The compound of any one of Technical Solutions 47-50 or 54-60, wherein one ^Ra is halogen and each of the remaining ^Ras is hydrogen.

Technical solution 66. The compound of any one of technical solutions 47-50 or 54-56, wherein L is -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, or -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -.

Technical Solution 67. The compound according to any one of Technical Solutions 47-50 or 54-56, wherein L is -C(R ^a ) ₂ OC(R ^a ) ₂ -.

Technical Solution 68. The compound of Technical Solution 66 or 67, wherein each ^Ra is hydrogen.

Technical Solution 69. The compound of Technical Solution 66 or 67, wherein one ^Ra is methyl and each of the remaining ^Ras is hydrogen.

Technical Solution 70. The compound of Technical Solution 66 or 67, wherein at least one ^Ra is halogen and each of the remaining ^Ras is hydrogen.

Technical Solution 71. The compound of Technical Solution 66 or 67, wherein two ^Ra are halogen and each remaining ^Ra is hydrogen.

Technical Solution 72. The compound of Technical Solution 66 or 67, wherein one ^Ra is halogen and each of the remaining ^Ras is hydrogen.

Technical Solution 73. The compound of any one of Technical Solutions 47-55 or 57-72, wherein X is -O-.

Technical Solution 74. The compound of Technical Solution 73, wherein Z ² is hydrogen.

Technical solution 75. The compound according to any one of Technical Solutions 47-72, wherein X is -NZ ³ -.

Technical solution 76. The compound of any one of Technical Solutions 47-72, wherein X is -NH-.

Technical Solution 77. The compound according to any one of Technical Solutions 47-55 or 57-72, wherein X is -CHZ ³ -.

Technical Solution 78. The compound according to any one of Technical Solutions 47-55 or 57-72, wherein X is -CH ₂ -.

Technical Solution 79. The compound according to any one of Technical Solutions 47-49, 51, 54 or 57-78, wherein Z ⁴ is a bond or -CH ₂ -.

Technical solution 80. The compound according to any one of Technical Solutions 47-49, 51, 54 or 57-78, wherein Z ⁴ is -CH ₂ -.

Technical Solution 81. The compound of any one of Technical Solutions 47-49, 51, 54 or 57-78, wherein Z ⁴ is a bond.

Technical Solution 82. The compound of any one of Technical Solutions 47-49 or 57-81, wherein Y ¹ and Y ² are each independently hydrogen, methyl or trifluoromethyl.

Technical Solution 83. The compound of any one of Technical Solutions 47-82, wherein R ¹ is phenyl.

Technical Solution 84. The compound of any one of Technical Solutions 47-82, wherein R ¹ is pyridyl.

Technical Solution 85. The compound of any one of Technical Solutions 47-84, wherein R ¹ is substituted by at least one halogen.

Technical Solution 86. The compound of any one of Technical Solutions 47-84, wherein R ¹ is substituted by a halogen.

Technical solution 87. The compound of technical solution 86, wherein R ¹ is 4-fluorophenyl or 2-fluorophenyl.

Technical Solution 88. The compound of any one of Technical Solutions 47-84, wherein R ¹ is substituted by two halogens.

Technical Solution 89. The compound of Technical Solution 88, wherein R ¹ is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl.

Technical Solution 90. The compound of Technical Solution 89, wherein R ¹ is 2,4-difluorophenyl.

Technical Solution 91. The compound of any one of Technical Solutions 47-84, wherein R ¹ is substituted by three halogens.

Technical Solution 92. The compound of Technical Solution 91, wherein R ¹ is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

Technical Solution 93. The compound of Technical Solution 92, wherein R ¹ is 2,4,6-trifluorophenyl.

Technical Solution 94. The compound of Technical Solution 85, wherein R ¹ is 3-trifluoromethyl-4-fluorophenyl or 2-cyclopropyloxy-4-fluorophenyl.

Technical solution 95. A pharmaceutical composition comprising a compound according to any one of technical solutions 47 to 94 or a stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

Technical Solution 96. The pharmaceutical composition of Technical Solution 95 further comprises one or more additional therapeutic agents.

Technical Solution 97. The pharmaceutical composition of Technical Solution 96, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical Solution 98. The pharmaceutical composition of Technical Solution 97, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

Technical Solution 99. A method for treating HIV infection in a human having or at risk of having the infection, by administering to the human a therapeutically effective amount of a compound of any one of Technical Solutions 47-94 or a pharmaceutical composition of Technical Solution 95.

Technical Solution 100. The method of Technical Solution 99 further comprises administering a therapeutically effective amount of one or more additional therapeutic agents to the human.

Technical solution 101. The method of technical solution 100, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical Solution 102. The method of Technical Solution 101, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and other drugs used to treat HIV, and combinations thereof.

Technical Solution 103. Use of the compound of any one of Technical Solutions 47-94 or the pharmaceutical composition of Technical Solution 95 for treating HIV infection in a person suffering from or at risk of infection.

Technical Solution 104. The use of Technical Solution 103, further comprising administering a therapeutically effective amount of one or more additional therapeutic agents to the human.

Technical solution 105. The use of technical solution 104, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical Solution 106. The use of Technical Solution 105, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and other drugs used to treat HIV, and combinations thereof.

Technical Solution 107. A compound or a pharmaceutically acceptable salt thereof as described in any one of Technical Solutions 47-94, for use in medical treatment.

Technical Solution 108. A compound or a pharmaceutically acceptable salt thereof as described in any one of Technical Solutions 47-94, for use in the therapeutic treatment of HIV infection.

The following examples are offered for purposes of illustration and not limitation.

Example

General synthetic scheme

Schemes 1-3 are provided as further embodiments of the invention and illustrate general methods for preparing compounds of formula (I) and can be used to prepare additional compounds of formula (I).

Solution 1

A1 can be converted to amide A2 using a suitable amine and coupling reagents such as HATU or EDCI. A2 can be converted to A3 using a strong acid such as methanesulfonic acid. A3 can be converted to A5 or A4 by heating with a suitable cyclic diamine or cyclic amino alcohol followed by methyl deprotection using reagents such as magnesium bromide.

Alternatively, A1 can be converted to A6 by treatment with a strong acid such as methanesulfonic acid. A6 can be condensed with a suitable cyclic diamine or cyclic amino alcohol, followed by methyl deprotection with a reagent such as magnesium bromide to form A7 or A8, respectively. A7 or A8 can be converted to amides A5 and A4 by treatment with a suitable amine and a coupling reagent such as HATU or EDCI, followed by methyl deprotection with a reagent such as magnesium bromide. Scheme 2

B1 (as described in WO2012/018065) is condensed with a diamine under reflux conditions to give B2. B2 is hydrolyzed and coupled with an amine via an amide formation method to give the product when the benzyl protecting group is removed.

Object B3.

Representative compounds

Example 1

Preparation of compound 1

N-(2,4-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

Will

1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.300 g, 0.95 mmol), prepared as described in WO2011/119566A1, was evaporated once from anhydrous toluene, suspended in acetonitrile (4 mL), and treated with N,N-diisopropylethylamine (DIPEA) (0.329 mL, 1.90 mmol), 2,4-difluorobenzylamine (0.125 mL, 1.05 mmol), and HATU (0.433 g, 1.14 mmol). The reaction mixture was stirred for 10 minutes and concentrated. The residue was purified by flash chromatography on silica gel (10 to 60% ethyl acetate:dichloromethane) to give compound 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester, 1-B. ¹ H-NMR (400 MHz, DMSO-d6) δ 10.28 (t, J = 6.0 Hz, 1H), 8.46 (s, 1H), 7.42 (dd, J = 15.4, 8.6 Hz, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 4.52 (m, 3H), 4.22 (d, J = 4.4 Hz, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.29 (d, 6H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₀ H ₂₃ F ₂ N ₂ O ₇ : 441.15; Found: 441.2.

Step 2

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-B, 0.106 g, 0.24 mmol) in acetonitrile (0.9 mL) and acetic acid (0.1 mL) was treated with methanesulfonic acid (0.005 mL, 0.072 mmol), sealed with a yellow cap, and heated to 70° C. After 16 hours, the mixture was cooled to give a crude solution of methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyacetoxy)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 1-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₈ H ₁₉ F ₂ N ₂ O ₇ : 413.12; Found: 413.1.

Steps 3 and 4

5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (1-C, 0.65 mL of the crude mixture from the previous step, 0.17 mmol) was treated with acetonitrile (0.65 mL) and cis-3-aminocyclopentanol (0.06 mL). The reaction mixture was sealed and heated to 90 ° C. After 30 minutes, the reaction mixture was cooled and magnesium bromide (0.063 g, 0.34 mmol) was added. The mixture was resealed and heated to 50 ° C. After 10 minutes, the reaction mixture was partitioned between dichloromethane and hydrochloric acid (0.2 Maq). The organic layer was removed and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Preparative-HPLC purification (30-70% acetonitrile: water, 0.1% TFA) gave compound 1 as a racemic mixture. ¹ H-NMR (400MHz, DMSO-d6) δ12.45(brs,1H),10.35(t,J＝5.8Hz,1H),8.45(s,1H),7.37(dd,J＝15.4,8.6 Hz,1H),7.23(dt,J＝2.5,9.9Hz,1H),7.05(dt,J＝2.2,8.7Hz,1H),5.43(dd,J＝9.6,4.0Hz,1H),5.09(br s,1H),4.68(dd,J＝13.2,4.0Hz,1H),4.59(br s,1H),4.53(m,2H),4.02(dd,J＝12.6,9.4Hz),1.93(br s, 4H), 1.83 (d, J = 12.0 Hz), 1.57 (dt, J = 12.2, 3.2 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.14; Found: 432.2.

Examples 2 and 3

Preparation of compounds 2 and 3

(2R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (2) and (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (3)

Compound 1 (16 mg) was separated by chiral HPLC using a Chiralpak AS-H with 100% ethanol as the eluent to provide enantiomerically enriched compounds 2 and 3. For compound 2: LCMS-ESI ⁺ (m/z): [M+H] ⁺ (m/ _z ): Calculated _{for C₂₁H₂O₂N₃O₅} : _432.14 ; Found: 432.2, chiral HPLC retention time = 4.50 min (Chiralpak AS-H, 150 x _{4.6 mm} , 1 mL/min EtOH). For compound 3: LCMS-ESI ⁺ (m/z): [M+H] ⁺ (m/ _{z )} : Calculated _{for C₂₁H₂O₂N₃O₅} : 432.14; Found: 432.2, chiral HPLC retention time = 6.84 min (Chiralpak AS-H, 150 x 4.6 mm, 1 mL/min EtOH). ¹ H-NMR(400MHz,DMSO-d6)δ12.45(br s,1H),10.35(t,J＝5.8Hz,1H),8.44(s,1H),7.37(dd,J＝15.2,8.4Hz,1H),7 .23(m,1H),7.05(dt,J＝1.8Hz,8.7Hz,1H),5.44(dd,J＝9.6,4.0Hz),5.09(br s,1H),4.68(dd,J＝12.8,4.0Hz,1H),4.59(br s,1H),4.53(m,2H),4.02(dd,J＝12.6,9.4Hz,1H),1.93(br s, 4H), 1.83 (d, J = 12.4Hz, 1H), 1.57 (m, 1H).

Alternatively, compound 3 is prepared as follows:

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 1.2 mmol in 5 mL of 9:1 acetonitrile:acetic acid containing 0.026 mL of methanesulfonic acid) was treated with acetonitrile (5.0 mL) and cis-3-aminocyclopentanol (0.24 g, 2.4 mmol). The reaction mixture was sealed and heated to 90°C. After 30 minutes, the reaction mixture was cooled, treated with potassium carbonate (0.332 g, 2.4 mmol), sealed, and heated to 90°C again. After 15 minutes, the mixture was cooled and partitioned between dichloromethane and hydrochloric acid (0.2 M aqueous solution). The organic layer was removed, and the aqueous solution was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate (anhydrous), filtered, and concentrated. The residue _was purified by flash chromatography (0-8% ethanol in dichloromethane containing 11% saturated aqueous ammonium hydroxide) to provide Intermediate 1-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _{Required for C22H22F2N3O5 : 446.15 ;} Found: 446.2.

Intermediate 1-D (270 mg) was separated on a 50 mm Chiralpak AD-H column by chiral SFC using 50% (1:1 methanol:acetonitrile) in supercritical carbon dioxide as the eluent to provide intermediates 3-A (first eluting peak) and 3-B (second eluting peak) in enantiomerically enriched form. For 3-A: LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required: C ₂₂ H ₂₂ F ₂ N ₃ O ₅ : 446.15; Found: 446.2. For 3-B: LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required: C ₂₂ H ₂₂ F ₂ N ₃ O ₅ : 446.15; Found: 446.2.

Intermediate 3-A (0.110 g, 0.247 mmol) in acetonitrile (5 mL) was treated in portions with magnesium bromide (0.091 g, 0.494 mmol), sealed and heated to 50° C. After 10 minutes, the mixture was cooled and partitioned between dichloromethane and hydrochloric acid (0.2 M aqueous solution). The organic layer was separated and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Preparative HPLC purification (30-70% acetonitrile: water, 0.1% TFA) gave compound 3 in enantiomerically enriched form. Chiral HPLC retention time = 6.51 min (Chiralpak AS-H, 150x found: 432.2. ¹ H-NMR (44.6 mm, 1 mL/min EtOH). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.14; 00 MHz, DMSO-d 6 ) δ 12.45 (br s,1H),10.35(t,J＝5.8Hz,1H),8.44(s,1H),7.37(dd,J＝15.2,8.4Hz,1H),7.23(m,1H),7.05(dt,J ＝1.8Hz,8.7Hz,1H),5.44(dd,J＝9.6,4.0Hz),5.09(brs,1H),4.68(dd,J＝12.8,4.0Hz,1H),4.59(br s,1H),4.53(m,2H),4.02(dd,J＝12.6,9.4Hz,1H),1.93(br s,4H),1.83(d,J＝12.4Hz,1H),1.57(m,1H).

Example 4

Preparation of compound 4

(1S,4R)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-3,4,6,8,12,12a-hexahydro

-2H-1,4-methanopyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 0.12 mmol in 0.53 mL of 9:1 acetonitrile:acetic acid containing 0.002 mL of methanesulfonic acid) was treated first with acetonitrile and then with (R)-pyrrolidin-3-amine (0.032 mL, 0.36 mmol). The reaction mixture was capped and heated to 90°C for 5.5 hours. After cooling, the mixture was partitioned between dichloromethane and sodium bicarbonate (1 M aqueous solution). The organic layer was separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate (anhydrous), filtered, and concentrated. The residue was dissolved in acetonitrile (1 mL), treated with magnesium bromide (0.022 g, 0.12 mmol), capped, and heated to 50°C for 10 minutes. After cooling, the mixture was distributed between dichloromethane and ammonium chloride (saturated). The organic layer was separated and the aqueous layer was extracted again with dichloromethane. The aqueous layer was adjusted to pH = 1 with HCl (aq) and extracted again with dichloromethane. The aqueous layer was adjusted to pH = 3 with NaOH (aq) and extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Preparative HPLC purification (10-55% acetonitrile: water, 0.1% TFA) gave compound 4. ¹ H-NMR (400MHz, CD ₃ OD-d4) δ8.42 (s, 1H), 7.42, (q, J = 7.7Hz, 1H), 6.99-6.90 (m, 2H), 5.07 (br s, 1H), 4.73 (br d,J＝10.8Hz,1H),4.62(s,2H),4.51(br d,J＝12.8Hz,1H),4.07(t,J＝11.8Hz,1H),3.4-3.0(m,3H),2.76(br d,J＝8.8Hz,1H),2.15-2.0(m,1H),1.9-1.8(m,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₀ H ₁₉ F ₂ N ₄ O ₄ : 417.14; Found: 417.2.

Example 5

Preparation of compound 5

(4R,12aS)-N-(1-(2,4-Difluorophenyl)cyclopropyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide

Step 1

(4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxylic acid (Intermediate 5-A) was prepared in a manner similar to that described for (3S,11aR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-d]pyrido[1,2-a]pyrazine-8-carboxylic acid in WO2011/119566, substituting (R)-3-aminobutan-1-ol for (S)-2-aminopropan-1-ol. The entire contents of WO2011/119566 are incorporated herein by reference. A suspension of intermediate 5-A (24.8 mg, 0.080 mmol), 1-(2,4-difluorophenyl)cyclopropylamine HCl salt (5-B, 21.9 mg, 0.107 mmol) and HATU (48 mg, 0.126 mmol) in CH ₂ Cl ₂ (2 mL) was stirred at ambient temperature while N,N-diisopropylethylamine (DIPEA) (0.1 mL, 0.574 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and then washed with 10% aqueous citric acid (x 1) and saturated aqueous NaHCO ₃ (x 1). After the aqueous fraction was extracted with ethyl acetate (x 1), the organic fractions were combined, dried (MgSO ₄ ) and concentrated. The residue was purified by combiflash (12 g column) using hexanes, ethyl acetate, and 20% methanol in ethyl acetate to afford (4R,12aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-7-methoxy-4 _- methyl- _6,8 -dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a _] pyrazine-9-carboxamide, Intermediate 5-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required _{for C23H24F2N3O5} : 460.17; Found: 460.2.

Step 2

A suspension of Intermediate 5-C (39 mg, 0.080 mmol) and magnesium bromide (42 mg, 0.2282 mmol) in acetonitrile (2 mL) was stirred at 50°C. After 1 hour, the reaction mixture was stirred in a 0°C bath while 1N HCl (2 mL) was added. After diluting the resulting mixture with water (~20 mL), the product was extracted with dichloromethane (x3), and the combined extracts were dried ( _MgSO4 ) and concentrated. The residue was purified by preparative HPLC to yield (4R,12aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide, Compound 5, as a TFA salt. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.72 (br s, 1H), 8.37 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 6.71-6.81 (m, 2H), 5.23 (dd, J = 5.6 and 4.4 Hz, 1H), 4.98 (br quint, J = ∼6.5 Hz, 1H), 4.26 (dd, J = 13.6 and 4.4 Hz, 1H), 4.12 (dd, J = 13.6 and 5.6 Hz, 1H), 4.00-4.06 (m, 2H), 2.16-2.25 (m, 1H), 1.55 (br dd, J = 13.8 and 1.8 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.22-1.31 (m, 4H). ¹⁹ F NMR (376.1 MHz, CDCl ₃ ) δ -76.38 (s, 3F), -111.69 to -111.645 (m, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₂₂ F ₂ N ₃ O ₅ : 446.15; Found: 446.2.

Example 6

Preparation of compound 6

(1R,4S)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-3,4,6,8,12,12a-hexahydro

-2H-1,4-methanopyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 0.100 g, 0.243 mmol), (S)-pyrrolidin-3-amine (0.043 mL, 0.485 mmol), and potassium carbonate (0.067 g, 0.485 mmol) were suspended in acetonitrile (1.9 mL) and acetic acid (0.1 mL) and heated to 90°C for 1.5 hours. After cooling, the mixture was treated with magnesium bromide (0.090 g) and heated to 50°C for 30 minutes. After cooling, the mixture was partitioned between dichloromethane and 0.2 M HCl. The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate (anhydrous), filtered, and concentrated. Preparative HPLC purification (25-50% acetonitrile:water, 0.1% TFA) afforded compound 6. ¹ H-NMR (400MHz, DMSO-d ₆ )δ10.33(t,J＝6.0Hz,1H),8.44(s,1H),7.48-7.32(m,1H),7.31-7.15(m,1H),7.14-6.97(m,1H),4.86(d,J＝2.9Hz,1H),4.62- 4.54(m,1H),4.52(d,J＝5.9Hz,1H),4.01(d,J＝13.0Hz,1H),2.99-2.76(m,3H),1.96-1.81(m,1H),1.71-1.53(m,1H).LCMS-ESI ⁺ (m/z):[M+H] of C ₂₀ H ₁₉ F ₂ N ₄ O ₄ ⁺ Theoretical value: 417.14; measured value: 417.2.

Example 7

Preparation of compound 7

(2S,6R)-N-(2,4-Difluorobenzyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro-2H-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 0.050 g, 0.121 mmol), (1S,3R)-3-aminocyclohexanol (0.028 g, 0.243 mmol) and potassium carbonate (0.034 g, 0.243 mmol) were suspended in acetonitrile (0.95 mL) and heated to 90°C for 0.5 hours. After cooling, acetic acid (0.050 mL) was added, and the mixture was heated to 90°C for another 2 hours. After cooling, the mixture was treated with magnesium bromide (0.044 g) and heated to 50°C for 1 hour. After cooling, a second portion of magnesium bromide (0.044 g) was added, and the mixture was heated to 50°C for another 15 minutes. After cooling, the mixture was partitioned between dichloromethane and 0.2M HCl. The organic layer was separated and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate (anhydrous), filtered and concentrated. Preparative HPLC purification (40-80% acetonitrile: water, 0.1% TFA) gave compound 7. ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.40(s,1H),10.36(t,J=6.1Hz,1H),8.45(s,1H),7.48-7.29(m,1H),7. 31-7.13(m,1H),7.13-6.97(m,1H),5.56(dd,J＝10.0,4.1Hz,1H),4.70(dd, J＝12.7,4.1Hz,1H),4.52(d,J＝5.5Hz,2H),4.40-4.29(m,2H),4.06(dd,J＝1 2.5,10.2Hz,1H),2.46-2.36(m,1H),1.98-1.63(m,4H),1.57-1.30(m,3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₂₂ F ₂ N ₃ O ₅ : 446.15; Found: 446.2.

Example 8

Preparation of compound 8

(2R,6S)-N-(2,4-Difluorobenzyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro-2H-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

Compound 8 was prepared by a method similar to that of compound 7, except that (1R, 3S)-3-aminocyclohexanol was used instead of (1S, 3R)-3-aminocyclohexanol. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (s, 1H), 10.36 (t, J = 6.1 Hz, 1H), 8.45 (s, 1H), 7.48-7.30 (m, 1H), 7.23 (td, J = 10.6, 2.7 Hz, 1H), 7.05 (td, J = 8.3, 2.3 Hz, 1H), 5.56 (dd, J = 10.1, 4.1 Hz, 1H), 4.7 0 (dd, J = 12.8, 3.9 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H), 4.39-4.27 (m, 2H), 4.06 (dd, J = 12.6, 10.0 Hz, 1H), 2.47-2.35 (m, 1H), 2.00-1.64 (m, 4H), 1.58-1.30 (m, 3H) _. LCMS-ESI ⁺ ( _m / _{z )} : [M+H] ⁺ requires for _C22H22F2N3O5 : 446.15; found: 446.2.

Examples 9 and 10

Preparation of compounds 9 and 10

(2S,5R,13aS)-N-((R)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide 9 and (2R,5S,13aR)-N-((R)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide 10

Step 1

1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.500 g, 1.59 mmol) was suspended in acetonitrile (6 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.550 mL, 3.17 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.242 mg, 1.74 mmol) and HATU (0.661 g, 1.74 mmol). The reaction mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic layer was separated and washed with HCl (10% aq), sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to give crude (R)-methyl 1-(2,2-dimethoxyethyl)-5-(1-(4 _- fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate, which was used _in the next step without purification: LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required: _C21H26FN2O7 : _437.17 ; Found: 437.1.

Step 2

(R)-methyl 1-(2,2-dimethoxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate was suspended in acetonitrile (5.7 mL) and acetic acid (0.6 mL) and treated with methanesulfonic acid (0.031 mL, 0.477 mmol). The mixture was capped and heated to 75° C. After 7 hours, the mixture was cooled and used in the next step without purification: LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required: C ₁₉ H ₂₂ FN ₂ O ₇ : 409.14; Found: 409.0.

Step 3

(R)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (3.6 mL of the crude mixture from Step 2, 0.8 mmol) was diluted with acetonitrile (3.6 mL) and treated with cis-3-aminocyclopentanol, the HCl salt (0.219 g, 1.6 mmol) and potassium carbonate (0.276 g, 2.0 mmol). The mixture was capped and heated to 90°C. After 20 minutes, the reaction mixture was cooled and partitioned between dichloromethane and HCl (0.2 mAq). The layers were separated and the aqueous layer was extracted again with dichloromethane. The combined organic layers were treated with a small amount of acetonitrile, dried over sodium sulfate, filtered and concentrated.

The residue was suspended in acetonitrile (4 mL) and treated with magnesium bromide (0.177 g). The mixture was capped and heated to 50° C. After 10 minutes, the reaction mixture was cooled and partitioned between dichloromethane and HCl (0.2 mAq). The organic layer was separated and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0-8% ethanol: DCM) to give the desired diastereoisomer mixture of 9 and 10.

The mixture was separated by chiral HPLC using Chiralpak AD-H with 100% ethanol as eluent to afford compounds 9 and 10 in enantiomerically enriched form.

For compound 9: LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₂ H ₂₃ FN ₃ O ₅ : 428.16; found: 428.1. Chiral HPLC retention time = 10.177 minutes (Chiralpak AD-H, 150 x 4.6 mm, 1 mL/min EtOH). ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.45(s,1H),10.45(d,J＝7.7Hz,1H),8.40(s,1H),7.37(dd,J＝8.6,5.6H z,2H),7.15(t,J＝8.9Hz,2H),5.44(dd,J＝9.5,4.2Hz,1H),5.17-5.04(m,2H) ,4.73-4.62(m,1H),4.59(s,1H),4.00(dd,J＝12.7,9.5Hz,1H),1.93(s,4H), 1.83(d,J＝11.8Hz,1H), 1.56(dt,J＝12.1,3.4Hz,1H), 1.44(d,J＝6.9Hz,3H).

For compound 10: LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₂ H ₂₃ FN ₃ O ₅ : 428.16; found: 428.1. Chiral HPLC retention time = 14.061 minutes (Chiralpak AD-H, 150 x 4.6 mm, 1 mL/min EtOH). ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.44(s,1H),10.46(d,J＝7.8Hz,1H),8.41(s,1H),7.37(dd,J＝8.6,5.6Hz,2 H),7.15(t,J＝8.9Hz,2H),5.42(dd,J＝9.6,4.1Hz,1H),5.18-5.02(m,2H),4.67 (dd,J＝12.8,4.2Hz,1H),4.59(s,1H),4.02(dd,J＝12.7,9.6Hz,1H),1.93(s,4H ), 1.83 (d, J = 12.0Hz, 1H), 1.57 (dt, J = 13.0, 3.5Hz, 1H), 1.44 (d, J = 6.9Hz, 3H).

Example 11

Preparation of compound 11

(2S,5R,13aS)-N-((R)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.315 g, 1.00 mmol) was suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.348 mL, 2.00 mmol), (R)-1-(2,4-difluorophenyl)ethanamine HCl salt (0.213 mg, 1.10 mmol) and HATU (0.418 g, 1.10 mmol). The reaction mixture was stirred for 1 hour and partitioned between dichloromethane and HCl (10% aq). The organic layer was separated and washed with sodium bicarbonate (1 mL), dried over sodium sulfate, filtered, and concentrated to give crude (R)-methyl 5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine- ₂ -carboxylate, which was used in the next step without purification. LCMS-ESI ⁺ (m/ _{z )} : [M+H] ⁺ Required for _C21H25F2N2O7 : _455.16 ; Found: 455.1.

Step 2

(R)-methyl 5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate was suspended in acetonitrile (3.6 mL) and acetic acid (0.4 mL) and treated with methanesulfonic acid (0.020 mL). The mixture was capped and heated to 75°C. _After 16 _hours , the crude mixture _was cooled and used in the next step without purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required: _C19H21F2N2O7 : _427.13 ; Found: 427.1.

Step 3

(R)-5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (half of the crude mixture from step 2, about 0.5 mmol) was diluted with acetonitrile (2.5 mL) and treated with (1S,3R)-3-aminocyclopentanol (0.110 g, 1.09 mmol) and potassium carbonate (0.069 g, 0.50 mmol). The mixture was capped and heated to 90 ° C. After 15 minutes, the reaction mixture was cooled and magnesium bromide (0.184 g) was added. The reaction mixture was heated to 50 ° C. After 10 minutes, the mixture was cooled and treated with another portion of magnesium bromide (0.184 g). The reaction mixture was reheated to 50 ° C and stirred for 10 minutes. After cooling, the mixture was partitioned between dichloromethane and HCl (0.2M aq). The layers were separated and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Preparative HPLC purification (30-60% acetonitrile:water, 0.1% TFA) gave the desired compound 11. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₂₂ F ₂ N ₃ O ₅ : 446.15; Found: 446.1. ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.46(s,1H),10.53(d,J＝7.5Hz,1H),8.38(s,1H),7.39(q,J＝8.5Hz,1H),7.29-7.1 2(m,1H),7.13-6.93(m,1H),5.44(dd,J＝9.8,4.2Hz,1H),5.28(p,J＝7.3,6.8Hz,1H),5. 09(s,1H),4.66(dd,J＝13.2,4.3Hz,1H),4.59(s,1H),3.99(dd,J＝13.1,9.6Hz,1H),1. 93 (s, 4H), 1.83 (d, J = 12.4Hz, 1H), 1.56 (dt, J = 12.5, 2.9Hz, 1H), 1.45 (d, J = 6.9Hz, 3H).

Example 12

Preparation of compound 12

(2R,5S,13aR)-N-((R)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 12 was prepared by a method similar to that of compound 11, except that (1R,3S)-3-aminocyclopentanol was used instead of (1S,3R)-3-aminocyclopentanol. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.43 (s, 1H), 10.52 (d, J=8.2 Hz, 1H), 8.38 (s, 1H), 7.39 (q, J=8.4 Hz, 1H), 7.28-7.12 (m, 1H), 7.11-6.97 (m, 1H), 5.41 (dd, J=10.0, 4.0 Hz, 1H), 5.35-5.20 (m, 1H), 5.08 (s, 1H), 4.65 (dd, J = 13.1, 3.8 Hz, 1H), 4.58 (s, 1H), 4.01 (dd, J = 12.8, 9.5 Hz, 1H), 1.92 (s, 4H), 1.83 (d, J = 11.5 Hz, 1H), 1.61-1.51 (m, 1H), 1.44 (d, J = _6.9 Hz, 3H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires _{for C22H22F2N3O5} : _446.15 ; found: 446.1.

Example 13

Preparation of compound 13

(2S,5R,13aS)-N-((S)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 13 was prepared in a manner similar to compound 11, using ((S)-1-(2,4-difluorophenyl)ethanamine instead of (R)-1-(2,4-difluorophenyl)ethanamine and using only a single portion of magnesium bromide (0.184 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.44 (s, 1H), 10.53 (d, J=7.8 Hz, 1H), 8.39 (s, 1H), 7.39 (q, J=8.5 Hz, 1H), 7.32-7.14 (m, 1H), 7.05 (t, J=9.1 Hz, 1H), 5.42 (dd, J=9.5, 4.2 Hz, 1H), 5.29 (p, J=6.9 Hz, 1H), 5. 09 (s, 1H), 4.65 (dd, J = 12.9, 4.3 Hz, 1H), 4.59 (s, 1H), 4.02 (dd, J = 12.6, 9.8 Hz, 1H), 1.92 (s, 4H) _, 1.83 (d, J = 12.1 Hz, 1H), 1.61-1.52 (m, 1H), 1.44 (d, J = _6.9 Hz, 3H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires for _C22H22F2N3O5 : _446.15 ; found: 446.2.

Example 14

Preparation of compound 14

(2R,5S,13aR)-N-((S)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 14 was prepared by a method similar to that of compound 11, except that ((S)-1-(2,4-difluorophenyl)ethanamine was used instead of (R)-1-(2,4-difluorophenyl)ethanamine, and (1R,3S)-3-aminocyclopentanol was used instead of (1S,3R)-3-aminocyclopentanol. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.46 (s, 1H), 10.53 (d, J=7.6 Hz, 1H), 8.38 (s, 1H), 7.39 (q, J=8.6 Hz, 1H), 7.28-7.14 (m, 1H), 7.05 (t, J=8.5 Hz, 1H), 5.44 (dd, J=9.8, 3.8 Hz, 1H), 5.28 (p, J=8.0 Hz, 1H), 5.09 (s , 1H), 4.66 (dd, J = 12.9, 4.0 Hz, 1H), 4.59 (s, 1H), 3.99 (dd, J = 12.5, 9.6 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 12.6 Hz, 1H), 1.56 (dt, J = 13.0, 3.3 Hz, 1H), 1.45 (d, J = _6.9 Hz, _3H ) _. LCMS-ESI ⁺ (m/z): [M+H] ₊ requires ^for _C22H22F2N3O5 : 446.15; found: 446.1.

Example 15

Preparation of compound 15

(2S,5R,13aS)-N-(4-Fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 3.15 g, 10.0 mmol) suspended in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesulfonic acid (0.195 mL). The mixture was heated to 75°C. After 7 hours, the crude mixture was cooled and stored at -10°C for three days. _The crude mixture was heated to 75°C for another 2 hours, cooled, and _used in the next step _without purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for _C19H21F2N2O7 : _288.07 ; Found: 288.1.

Step 2

Crude 1-(2,2-dihydroxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (16.8 mL of the crude mixture from step 1, about 4 mmol) was mixed with (1S, 3R)-3-aminocyclopentanol (0.809 g, 8 mmol), diluted with acetonitrile (16.8 mL), and treated with potassium carbonate (0.553 g, 4 mmol). The reaction mixture was heated to 85 ° C, stirred for 15 minutes, cooled to ambient temperature and stirred for another 16 hours. HCl (50 mL, 0.2 Maq) was added, and the transparent yellow solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to a yellow solid. The crude material was precipitated from dichloromethane/hexane to obtain the desired intermediate 15-B as a light beige powder. ^1H -NMR (400 MHz, DMSO- _d6 ) δ 8.72 (s, 1H), 5.42 (dd, J = 9.6, 4.1 Hz, 1H), 5.09 (s, 1H), 4.72 (dd, J = 13.0, 3.7 Hz, 1H), 4.57 (s, 1H), 4.09 (dd, J = 12.5, 9.6 Hz, 1H), 3.83 (s, 3H), 1.92 (s, 3H), 1.78 (m, 2H), 1.62-1.47 (m, 1H). _LCMS -ESI ⁺ (m/z): [M+H] ⁺ requires _{for C15H17N2O6} : 321.11 _; found: 321.2.

Step 3

Intermediate 15-B (0.040 g, 0.125 mmol) and (4-fluorophenyl)methanamine (0.017 g, 0.137 mmol) were suspended in acetonitrile (1 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.033 mL, 0.187 mmol) and HATU (0.052 g, 0.137 mmol). After stirring for 30 minutes, the reaction mixture was treated with magnesium bromide (0.046 g, 0.25 mmol) and heated to 50°C. After 10 minutes, the reaction mixture was cooled and treated with HCl (2 mL, 10% aq). After a few minutes, the precipitate was filtered and washed with HCl (10% aq) and water. The precipitate was purified by preparative HPLC (20-65% acetonitrile:water, 0.1% TFA) to give the desired compound 15. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.44(s,1H),10.36(t,J＝6.0Hz,1H),8.46(s,1H),7.37-7.28(m,2H), 7.19-7.09(m,2H),5.43(dd,J＝9.6,4.0Hz,1H),5.08(s,1H),4.68(dd,J＝ 12.8,4.1Hz,1H),4.59(s,1H),4.58-4.42(m,3H),4.02(dd,J＝12.7,9.6H z, 1H), 1.92 (s, 5H), 1.83 (d, J = 12.2Hz, 1H), 1.56 (dt, J = 12.0, 3.4Hz, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₁ FN ₃ O ₅ : 414.15; Found: 414.2.

Example 16

Preparation of compound 16

(2S,5R,13aS)-N-(2,3-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 16 was prepared in a similar manner to compound 15 using (2,3-difluorophenyl)methanamine instead of (4-fluorophenyl)methanamine. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.46(s,1H),10.41(t,J＝6.1Hz,1H),8.45(s,1H),7.43-7.25(m,1H), 7.25-7.05(m,2H),5.44(dd,J＝9.5,3.9Hz,1H),5.09(s,1H),4.68(dd,J＝ 12.8,4.0Hz,1H),4.65-4.53(m,3H),4.02(dd,J＝12.7,9.8Hz,1H),3.56( s, 1H), 1.93 (s, 4H), 1.83 (d, J = 11.9Hz, 1H), 1.57 (dt, J = 11.5, 3.0Hz, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.14; Found: 432.2.

Example 17

Preparation of compound 17

(2S,5R,13aS)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 17 was prepared in a similar manner to Compound 15, using (4-chloro-2-fluorophenyl)methanamine instead of (4-fluorophenyl)methanamine. ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.46(s,1H),10.45-10.29(m,1H),8.44(s,1H),7.42(dd,J＝10.0,2.0Hz,1H), 7.33(t,J＝8.1Hz,1H),7.26(dd,J＝8.4,1.8Hz,1H),5.50-5.38(m,1H),5.09(s,1H) ,4.68(dd,J＝13.0,4.0Hz,1H),4.59(s,1H),4.54(m,2H),4.02(dd,J＝12.8,9.7Hz ,1H),1.93(s,4H),1.83(d,J＝12.0Hz,1H),1.57(dt,J＝11.9,3.4Hz,1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ ClFN ₃ O ₅ : 448.11; Found: 448.2.

Example 18

Preparation of compound 18

(2S,5R,13aS)-N-(3,4-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 18 was prepared in a similar manner to Compound 15 using (3,4-difluorophenyl)methanamine instead of (4-fluorophenyl)methanamine. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.46(s,1H),10.51-10.27(m,1H),8.46(s,1H),7.50-7.23(m,2H),7 .23-7.03(m,1H),5.44(dd,J＝9.5,3.6Hz,1H),5.09(s,1H),4.75-4.63(m ,1H),4.60(s,1H),4.57-4.44(m,2H),4.02(dd,J＝12.6,9.8Hz,1H),1.93(s,4H),1.83(d,J＝12.0Hz,1H),1.57(dt,J＝12.0,3.4Hz,1H).LCMS-ESI ⁺ (m/z):C Theoretical value of [M+H] ⁺ for ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.14; found: 432.2.

Example 19

Preparation of compound 19

(1R,5S)-N-(2,4-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-1,5-methanopyrido[1',2':4,5]pyrazino[1,2-a][1,3]diazepine-10-carboxamide

Steps 1 and 2

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 97.5 mg, 0.236 mmol) was treated with acetonitrile (1.9 mL), acetic acid (0.1 mL), potassium carbonate (145 mg, 1.05 mmol) and (S)-piperidin-3-amine dihydrochloride (82 mg, 0.472 mmol). The reaction mixture was sealed and heated to 90°C. After 60 minutes, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane, and the combined organic phases were combined, dried over _MgSO4 , filtered, and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (89.1 mg, 0.48 mmol) was added. The mixture was resealed and heated to 50°C. After 80 minutes, the reaction mixture was quenched with -5 mL of 0.2 M HCl (aq), adjusted to pH -10, diluted with brine, and extracted three times into DCM. HPLC (acetonitrile:water, 0.1% TFA) gave compound 19. ¹ H-NMR (400MHz, chloroform-d) δ10.43(t,J＝5.9Hz,1H),8.43(s,1H),7.39-7.30(m,1H),6 .81(q,J＝8.1Hz,2H),4.89(dd,J＝11.6,3.8Hz,1H),4.69(s,1H),4.64(d,J＝5.8H z,2H),4.26(dd,J＝12.6,3.8Hz,1H),3.91(t,J＝12.1Hz,1H),3.20-3.10(m,2H), 3.06(s,2H),2.14-2.02(m,1H),1.96-1.81(m,2H),1.81-1.70(m,1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₄ O ₄ : 431.15; Found: 431.2.

Example 20

Preparation of compound 20

(1S,5R)-N-(2,4-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-1,5-methanopyrido[1',2':4,5]pyrazino[1,2-a][1,3]diazepine-10-carboxamide

Steps 1 and 2

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 103.3 mg, 0.25 mmol) was treated with 4-nitropropane (1.9 mL), acetic acid (0.1 mL), potassium carbonate (159.8 mg, 1.16 mmol) and (R)-piperidin-3-amine dihydrochloride (90 mg, 0.52 mmol). The reaction mixture was sealed and heated to 90°C. After 40 minutes, the reaction mixture was partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane, and the combined organic phases were combined, dried over _MgSO4 , filtered, and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (96.5 mg, 0.52 mmol) was added. The mixture was resealed and heated to 50°C. After 80 minutes, the reaction mixture was quenched with -5 mL of 0.2 M HCl (aq), adjusted to pH -10, diluted with brine, and extracted three times into DCM. HPLC (acetonitrile:water, 0.1% TFA) gave compound 20. ¹ H-NMR (400MHz, DMSO-d ₆ )δ10.35(t,J＝6.0Hz,1H),8.48(s,1H),7.45-7.33(m,1H),7.29-7.18(m,1H),7.05(td,J＝8.5,2.4Hz,1H),5.06(dd,J＝11.4,3.5H LCMS-ESI ⁺ (m/z):[M+H] of C ₂₁ H ₂₀ F ₂ N ₄ O ₄ ⁺ Theoretical value: 431.15; measured value: 431.2.

Example 21

Preparation of compound 21

(2S,5R,13aS)-N-((S)-1-(4-Fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

(S)-methyl 1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (21-A, 1 mL, 0.23 M solution in 19:1 acetonitrile:acetic acid, prepared according to (R)-methyl 1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 9-A from Example 9 using (S)-1-(4-fluorophenyl)ethanamine instead of (R)-1-(4-fluorophenyl)ethanamine) was treated with (1S,3R)-3-aminocyclopentanol (62 mg, 0.61 mmol) and potassium carbonate (34 mg, 0.25 mmol). The reaction mixture was sealed and heated to 90°C. After 60 minutes, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted into dichloromethane three times, and the combined organic phases were mixed, dried over MgSO ₄ , filtered and concentrated. The crude product was dissolved in acetonitrile (2 mL) and magnesium bromide (74 mg, 0.4 mmol) was added. The mixture was resealed and heated to 50° C. After 100 minutes, the reaction mixture was quenched with 0.2 M HCl (aq), diluted with brine, and extracted into DCM three times. HPLC purification (acetonitrile: water, 0.1% TFA) gave compound 21. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.42 (br s,1H),10.45(d,J＝7.9Hz,1H),8.40(s,1H),7.36(dd,J＝8.6,5.5Hz,2H),7 .14(t,J＝8.9Hz,2H),5.42(dd,J＝9.6,4.2Hz,1H),5.15-5.04(m,2H),4.72 -4.55(m,2H),4.02(dd,J＝12.7,9.7Hz,1H),1.97-1.89(m,4H),1.82(d,J＝ 12.2Hz,1H),1.56(dt,J＝11.9,3.3Hz,1H),1.43(d,J＝6.9Hz,3H).LCMS-ESI ⁺ (m/z):C ₂₂ H ₂₂ FN ₃ O [M+H] ⁺ Required value for ₅ : 428.16; Found: 428.1.

Example 22

Preparation of compound 22

(2R,5S,13aR)-N-((S)-1-(4-Fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

(S)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (21-A, 1 mL, 0.23 M solution in 19:1 acetonitrile:acetic acid) was treated with (1R, 3S)-3-aminocyclopentanol (52 mg, 0.51 mmol) and potassium carbonate (31 mg, 0.22 mmol). The reaction mixture was sealed and heated to 90 ° C. After 60 minutes, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted into dichloromethane three times, and the combined organic phases were mixed, dried over MgSO ₄ , filtered and concentrated. The crude product was dissolved in acetonitrile (2 mL) and magnesium bromide (91 mg, 0.49 mmol) was added. The reaction mixture was sealed and heated to 50 ° C. After 100 minutes, the reaction mixture was quenched with 0.2 M HCl (aq), diluted with brine, and extracted into DCM three times. HPLC purification (acetonitrile: water, 0.1% TFA) gave compound 22. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.44 (br s,1H),10.45(d,J＝7.7Hz,1H),8.39(s,1H),7.36(dd,J＝8.5,5.6Hz,2H),7.1 4(t,J＝8.9Hz,2H),5.43(dd,J＝9.6,4.0Hz,1H),5.15-5.06(m,2H),4.66(dd, J＝12.8,3.9Hz,1H),4.58(s,1H),3.99(dd,J＝12.6,9.5Hz,1H),1.93(s,4H), 1.82(d,J＝12.0Hz,1H), 1.56(dt,J＝12.0,3.0Hz,1H), 1.44(d,J＝6.9Hz,3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₂₂ FN ₃ O ₅ : 428.16; Found: 428.1.

Example 23

Preparation of compound 23

(2S,5R,13aS)-N-(2-Fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

15-B (41 mg, 0.13 mmol) was treated with acetonitrile (1 mL), (2-fluorophenyl)methanamine (17 mg, 0.14 mmol), HATU (67 mg, 0.18 mmol) and N,N-diisopropylethylamine (DIPEA) (24 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (47 mg, 0.26 mmol) was added. The mixture was sealed and heated to 50°C. After 60 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted into DCM three times. HPLC purification (acetonitrile: water, 0.1% TFA) gave compound 23. ¹ H-NMR (400MHz, chloroform-d) δ10.42(s,1H),8.34(s,1H),7.36(t,J＝7.9Hz,1H),7.24-7.17(m,1H),7.12-6.97(m,2H),5.40-5.32(m,1H),5.29(t,J＝ 3.5Hz,1H),4.67(s,3H),4.28-4.20(m,1H),4.06-3.95(m,1H),2.20-1.96(m,4H),1.95-1.84(m,1H),1.59(dt,J＝12.4,3.3Hz,1H).LCMS-ESI ⁺ (m/z):[M+H] of C ₂₁ H ₂₀ FN ₃ O ₅ ⁺ Theoretical value: 414.15; measured value: 414.2.

Example 24

Preparation of compound 24

(2S,5R,13aS)-N-(3,5-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

15-B (44 mg, 0.14 mmol) was treated with acetonitrile (1 mL), (3,5-difluorophenyl)methanamine (32 mg, 0.23 mmol), HATU (54 mg, 0.14 mmol) and N,N-diisopropylethylamine (37 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (57 mg, 0.31 mmol) was added. The mixture was sealed and heated to 50°C. After 60 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted into DCM three times. HPLC purification (acetonitrile: water, 0.1% TFA) gave compound 24. ¹ H-NMR (400MHz, chloroform-d) δ10.39(s,1H),8.42(s,1H),6.82(d,J＝7.9Hz,2H),6.65(t,J＝8.8Hz,1H),5.38(d,J＝7.7Hz,1H),5.28(s,1H) ,4.78-4.41(m,3H),4.32(d,J＝12.1Hz,1H),4.02(t,J＝10.9Hz,1H),2.30-1.97(m,4H),1.97-1.81(m,1H),1.59(d,J＝12.3Hz,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₁₉ F ₂ N ₃ O ₅ : 432.14; Found: 432.2.

Example 25

Preparation of compound 25

(2S,5R,13aS)-N-(4-Fluoro-3-(trifluoromethyl)benzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

15-B (43 mg, 0.13 mmol) was treated with acetonitrile (1 mL), (4-fluoro-3-(trifluoromethyl)phenyl)methanamine (29 mg, 0.15 mmol), HATU (62 mg, 0.16 mmol) and N,N-diisopropylethylamine (26 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (62 mg, 0.34 mmol) was added. The mixture was sealed and heated to 50°C. After 60 minutes, the reaction mixture was quenched with 0.2M HCl(aq), diluted with brine, and extracted into DCM three times. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 25. ¹ H-NMR (400MHz, chloroform-d) δ10.44(s,1H),8.29(s,1H),7.56-7.38(m,2H),7.06(t,J＝9.2Hz,1H),5.30(dd,J＝9.3,3.5Hz,1H),5.21(s,1H),4.65-4.45 LCMS-ESI ⁺ (m/z):C ₂₂ H ₁₉ F ₄ N ₃ O [M+H] ⁺ Required value for ₅ : 482.14; Found: 482.2.

Example 26

Preparation of compound 26

(2S,5R,13aS)-N-(4-chloro-3-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

15-B (41 mg, 0.13 mmol) was treated with acetonitrile (1 mL), (4-chloro-3-fluorophenyl)methanamine (40 mg, 0.25 mmol), HATU (60 mg, 0.16 mmol) and N,N-diisopropylethylamine (28 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (48 mg, 0.26 mmol) was added. The mixture was sealed and heated to 50°C. After 60 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted into DCM three times. HPLC purification (acetonitrile: water, 0.1% TFA) gave compound 26. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.41 (s, 1H), 8.30 (s, 1H), 7.24 (t, J = 6.1 Hz, 1H), 7.13-6.90 (m, 2H), 5.30 (dd, J = 9.1, 3.2 Hz, 1H), 5.22 (s, 1H), 4.61 (s, 1H), 4.51 (s, 2H), 4.20 (d, J = 9.4 Hz, 1H), 3.95 (d, J = 12.0 Hz, 1H), 2.11-1.90 (m, 4H), 1.90-1.76 (m, 1H), 1.53 (d, J = 12.2 _Hz , 1H) _. LCMS-ESI ⁺ (m/z): [M+H] _{for C21H19ClFN3O5} ⁺ Theoretical value: 448.11; measured value: 448.2.

Example 27

Preparation of compound 27

(2S,5R)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

A suspension of compound 1-A (1.004 g, 3.19 mmol), amine 27-A (688 mg, 3.35 mmol), and HATU (1.453 g, 3.82 mmol) in CH ₂ Cl ₂ (20 mL) was stirred in a 0° C. bath while N,N-diisopropylethylamine (DIPEA) (2 mL, 11.48 mmol) was added. After 1 hour at 0° C., the reaction mixture was concentrated to a slurry, diluted with ethyl acetate, and washed with water (×2). After the aqueous fraction was extracted with ethyl acetate (×1), the organic fractions were combined, dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by CombiFlash (120 g column) using hexane-ethyl acetate as eluent. The major peaks were combined and concentrated to give 1.082 g (73%) of product 27-B. After combining the minor peaks and concentrating, the concentrated residue was dissolved in CH ₂ Cl ₂ , and some insoluble material was filtered off. _The filtrate was concentrated to give 361 mg (24%) of additional product 27-B. LCMS-ESI ⁺ (m/ _{z )} : [M+H] ⁺ Required for _C22H25F2N2O7 : _467.16 ; Found: 467.1.

Steps 2 and 3

Compound 27-B (81 mg, 0.174 mmol) was dissolved in a mixture (1 mL) of acetonitrile (22 mL), AcOH (2 mL) and methanesulfonic acid (0.14 mL, 2.16 mmol) at room temperature, and the resulting solution was stirred at 65° C. for 20 hours.

After the resulting solution was cooled to room temperature, amino alcohol 27-D (50 mg, racemic, 0.363 mmol), K ₂ CO ₃ (50 mg, 0.362 mmol) and acetonitrile (2 mL) were added to the solution. The resulting mixture was stirred in a 65° C. bath for 1 hour. After the reaction mixture was cooled to room temperature, it was acidified with 1N HCl (~2 mL), diluted with water (~8 mL), and extracted with CH ₂ Cl ₂ (× 3). The combined extracts were dried (Na ₂ SO ₄ ), concentrated, and purified by CombiFlash to give 67 mg (82%) of compound 27-E. ¹ H-NMR (400MHz, CDCl ₃ )δ10.53(s,1H),8.25(s,1H),7.60(td,J＝8.5,6.5Hz,1H),6.85-6.57(m,2H),5.33(br,1H),5.26(dd,J＝9.6,3.9Hz,1H),4.60(t,J＝3.0Hz,1H ),4.18-4.06(m,1H),4.01(s,3H),3.92(dd,J＝12.7,9.6Hz,1H),2.11-1.91(m,4H),1.88-1.71(m,1H),1.60-1.49(m,1H),1.31-1.10(m,4H). ¹⁹ F-NMR (376.1 MHz, CDCl ₃ ) δ -111.80 (q, J = 8.8 Hz, 1F), -112.05 (p, J = 7.9 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₄ H ₂₄ F ₂ N ₃ O ₅ : 472.17; Found: 472.1.

Step 4

A mixture of compound 27-E (67 mg, 0.142 mmol) and MgBr ₂ (66 mg, 0.358 mmol) in MeCN (3 mL) was stirred at 50° C. for 30 minutes and cooled to 0° C. before being treated with 1N HCl (3 mL). After diluting the mixture with water (˜30 mL), the product was extracted with CH ₂ Cl ₂ (×3), and the combined extracts were dried (Na ₂ SO ₄ ) and concentrated. The product was purified by preparative HPLC and freeze-dried to give product 27 as a 1:1 mixture with trifluoroacetic acid. ¹ H-NMR (400MHz, CDCl ₃ )δ10.70(s,1H),8.35(s,1H),7.57(q,J＝8.2Hz,1H),6.91-6.56(m,2H),5.31(dt,J＝14.3,4.0Hz,2H),4.68(s,1H),4.22(dd,J＝13.2,3 .9Hz,1H),3.99(dd,J＝12.8,9.3Hz,1H),2.28-1.96(m,5H),1.88(ddt,J＝12.1,8.6,3.7Hz,1H),1.71-1.49(m,1H),1.38-1.11(m,4H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ )δ-76.37 (s, 3F), -111.6～-111.75 (m, 2F). LCMS-ESI ⁺ (m/ _z ): [M+H] ⁺ Required _{for C23H22F2N3O5} : _{458.15 ;} Found: 458.1.

Example 28

Preparation of compound 28

(2S,6R)-N-(1-(2,4-Difluorophenyl)cyclopropyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro-2H-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

Steps 1 and 2

Compound 27-B (87 mg, 0.187 mmol) was dissolved in a mixture (2 mL) of acetonitrile (22 mL), AcOH (2 mL) and methanesulfonic acid (0.14 mL, 2.16 mmol) at room temperature, and the resulting solution was stirred at 65° C. for 20 hours.

After the resulting solution was cooled to room temperature, amino alcohol 28-A (44 mg, racemic, 0.382 mmol) and acetonitrile (2 mL) were added to the solution. After the resulting mixture was stirred in a 65°C bath for 30 minutes, K ₂ CO ₃ (41 mg, 0.297 mmol) was added and the mixture was stirred at 65°C for 21 hours. The reaction mixture was cooled to room temperature, acidified with 1N HCl (~2 mL), diluted with water (~8 mL), and extracted with CH ₂ Cl ₂ (×3). The combined extracts were dried (Na ₂ SO ₄ ), concentrated, and purified by preparative HPLC, and the fractions containing the product were freeze-dried. After the residue was dissolved in ethyl acetate, the solution was washed with saturated NaHCO ₃ (×1), dried (Na ₂ SO ₄ ) and concentrated to give 18 mg (20%) of compound 28-B as a 1:1 mixture with trifluoroacetic acid. ¹ H-NMR (400 MHz, CDCl ₃ )δ10.54(s,1H),8.26(s,1H),7.63(td,J＝8.6,6.6Hz,1H),6.76(dddd,J＝21.9,11.2,8. 7,2.3Hz,2H),5.39(dd,J＝9.6,3.7Hz,1H),4.53-4.36(m,2H),4.09(dd,J＝12.8,3.7Hz, 1H),4.03(s,3H),3.99(dd,J＝12.7,9.7Hz,1H),2.41-2.20(m,2H),1.84(dtd,J＝19.7,9 .3,8.8,4.4Hz,2H),1.74(dd,J＝14.6,2.5Hz,1H),1.62-1.35(m,2H),1.34-1.14(m,5H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ ) δ -111.75 (q, J=8.9Hz, 1F), -112.01 (p, J=7.9Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₅ H ₂₆ F ₂ N ₃ O ₅ : 486.18; Found: 486.2.

Step 3

As described in step 4 of the synthesis of compound 27-E, compound 28-B (18 mg, 0.037 mmol) was treated with MgBr ₂ to give compound 28. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.66 (s, 1H), 8.29 (s, 1H), 7.59 (td, J = 8.5, 6.6 Hz, 1H), 6.89-6.60 (m, 2H), 5.51 (dd, J = 9.9, 4.0 Hz, 1H), 4.55 (s, 1H), 4.48 (t, J = 4.2 Hz, 1H), 4.21 (dd, J = 12.9, 4.1 Hz, 1H). 3H), 1.66-1.37 (m, 3H), 1.28 (d, J=4.4 Hz, 2H), 1.26-1.19 (m ^, 2H). 19 F-NMR (376.1 MHz, CDCl ₃ ) δ -76.41 (s, 3F), -111.79 (m, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₄ H ₂₃ F ₂ N ₃ O ₅ : 472.17; Found: 472.1.

Example 29

Preparation of compound 29

(2R,6S)-N-(1-(2,4-difluorophenyl)cyclopropyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro-2H-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

Steps 1 and 2

Compound 29-B (13 mg, 14%) was prepared from compound 27-B (87 mg, 0.187 mmol) and amino alcohol 29-A (45 mg, 0.391 mmol) in a manner similar to that described in step 1 of the synthesis of compound 28-B. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.54 (s, 1H), 8.26 (s, 1H), 7.63 (td, J = 8.6, 6.6 Hz, 1H), 6.76 (dddd, J = 21.9, 11.2, 8.7, 2.3 Hz, 2H), 5.39 (dd, J = 9.6, 3.7 Hz, 1H), 4.53-4.36 (m, 2H), 4.09 (dd, J = 12.8, 3.7 Hz, 1H),4.03(s,3H),3.99(dd,J＝12.7,9.7Hz,1H),2.41-2.20(m,2H),1.84(dtd,J＝19.7,9 .3,8.8,4.4Hz,2H),1.74(dd,J＝14.6,2.5Hz,1H),1.62-1.35(m,2H),1.34-1.14(m,5H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ ) δ -111.75 (q, J=8.9Hz, 1F), -112.01 (p, J=7.9Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₅ H ₂₆ F ₂ N ₃ O ₅ : 486.18; Found: 486.2.

Step 3

Compound 29 was prepared from compound 29-B in a manner similar to that described in step 2 of the synthesis of compound 16. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.66 (s, 1H), 8.29 (s, 1H), 7.59 (td, J=8.5, 6.6 Hz, 1H), 6.89-6.60 (m, 2H), 5.51 (dd, J=9.9, 4.0 Hz, 1H), 4.55 (s, 1H), 4.48 (t, J=4.2 Hz, 1H), 4.21 (dd, J=12.9, 4.1 Hz, 1H) 3H), 1.66-1.37 (m, 3H), 1.28 (d, J=4.4 Hz, 2H), 1.26-1.19 (m ^, 2H). 19 F-NMR (376.1 MHz, CDCl ₃ ) δ -76.41 (s, 3F), -111.79 (m, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₄ H ₂₃ F ₂ N ₃ O ₅ : 472.17; Found: 472.1.

Example 30

Preparation of compound 30

(2S,5R,13aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

Compound 27-B (150 mg, 0.322 mmol) was dissolved in acetonitrile (2 mL), AcOH (0.2 mL), and methanesulfonic acid (0.007 mL, 0.108 mmol) at room temperature, and the resulting solution was stirred at 65°C for 20 hours. After the resulting solution was cooled to room temperature, _amino alcohol 30-A (72.1 mg, chiral, 0.713 mmol), _K₂CO₃ (89.4 mg, 0.647 mmol), and acetonitrile (2 mL) were added to the solution. The resulting mixture was stirred in a 65°C bath for 0.5 hours. After the reaction mixture was cooled to room temperature, it was acidified with 1N HCl (~3 mL), diluted with water (~12 mL), and extracted with _CH₂Cl₂ (× ₃ ). The combined extracts were dried ( _{Na₂SO₄ )} , concentrated, and purified by CombiFlash to yield 128 mg (84%) of compound 30-B. ¹ H-NMR (400MHz, CDCl ₃ )δ10.52(s,1H),8.24(s,1H),7.61(td,J＝8.6,6.6Hz,1H),6.85-6.65(m,2 H),5.33(t,J＝4.1Hz,1H),5.25(dd,J＝9.5,3.9Hz,1H),4.61(d,J＝3.4Hz,1 H),4.18-4.08(m,1H),4.02(s,3H),3.99-3.87(m,1H),2.12-1.91(m,4H), 1.85-1.69(m,1H),1.55(ddd,J＝12.3,4.1,2.8Hz,1H),1.31-1.14(m,4H). ¹⁹ F-NMR (376.1 MHz, CDCl ₃ ) δ −111.79 (q, J=8.8 Hz, 1F), −112.05 (p, J=7.9 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₄ H ₂₄ F ₂ N ₃ O ₅ : 472.17; Found: 472.2.

Step 3

A mixture of compound 30-B (128 mg, 0.272 mmol) and MgBr ₂ (130 mg, 0.706 mmol) in MeCN (5 mL) was stirred at 50° C. for 30 minutes and cooled to 0° C. before being treated with 1N HCl (4 mL). After diluting the mixture with water, the product was extracted with CH ₂ Cl ₂ (×3), and the combined extracts were dried (Na ₂ SO ₄ ) and concentrated. The product was purified by CombiFlash to afford product 30. ¹ H-NMR (400MHz, CDCl ₃ )δ12.27(s,1H),10.52(s,1H),8.16(s,1H),7.61(td,J＝8.6,6.6Hz,1H),6.96-6.54(m,2H),5.36-5.23(m,2H),4.66(t,J＝3.1Hz,1H),4.1 8-4.06(m,1H),3.94(dd,J＝12.8,9.4Hz,1H),2.20-1.95(m,4H),1.89(td,J＝11.4,9.8,6.7Hz,1H),1.70-1.54(m,1H),1.32-1.15(m,4H). ¹⁹ F-NMR (376.1 MHz, CDCl ₃ ) δ −111.87 (q, J=8.9 Hz, 1F), −112.21 (p, J=7.9 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₃ H ₂₂ F ₂ N ₃ O ₅ : 458.15; Found: 458.2.

Example 31

Preparation of compound 31

(2R,5S)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

Compound 31-B (123 mg, 81%) was prepared from compound 27-B (150 mg, 0.322 mmol) and amino alcohol 31-A (70.3 mg, 0.695 mmol) in a manner similar to that described in steps 1 and 2 of the synthesis of compound 30-B. ¹ H-NMR (400 MHz, CDCl ₃ )δ10.52(s,1H),8.24(s,1H),7.62(td,J＝8.6,6.6Hz,1H),6.91-6.63(m,2H) ,5.33(t,J＝4.1Hz,1H),5.25(dd,J＝9.5,3.9Hz,1H),4.61(d,J＝3.4Hz,1H),4 .14-4.07(m,1H),4.03(s,3H),3.93(dd,J＝12.7,9.5Hz,1H),2.12-1.91(m,4 H),1.85-1.69(m,1H),1.55(ddd,J＝12.3,4.1,2.8Hz,1H),1.31-1.14(m,4H). ¹⁹ F-NMR (376.1 MHz, CDCl ₃ ) δ −111.79 (q, J=9.2, 8.7 Hz, 1F), −112.03 (h, J=8.1, 7.5 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₄ H ₂₄ F ₂ N ₃ O ₅ : 472.17; Found: 472.1.

Step 3

Compound 31 was prepared from compound 31-B in a manner similar to that described in step 3 of the synthesis of compound 30. ¹ H-NMR (400MHz, CDCl ₃ )δ12.26(s,1H),10.49(s,1H),8.13(s,1H),7.58(td,J＝8.6,6.5Hz,1H), 6.90-6.56(m,2H),5.32(dd,J＝9.4,4.1Hz,1H),5.27-5.22(m,1H),4.64(t ,J＝3.1Hz,1H),4.11(dd,J＝12.8,4.0Hz,1H),4.01-3.79(m,1H),2.28-1.9 5(m,4H),1.95-1.80(m,1H),1.71(m,1H),1.56(m,1H),1.42-1.08(m,4H). ¹⁹ F-NMR (376.1 MHz, CDCl ₃ ) δ −111.95 (q, J=8.9 Hz, 1F), −112.22 (p, J=7.9 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₃ H ₂₂ F ₂ N ₃ O ₅ : 458.15; Found: 458.1.

Example 32

Preparation of compound 32

(2S,5R)-N-(1-(2,4-Difluorophenyl)cyclobutyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

A solution of compound 32-A (22.2 mg, 0.069 mmol), compound 32-B (18.7 mg, 0.102 mmol) and HATU (43 mg, 0.113 mmol) in CH ₂ Cl ₂ (2 mL) was stirred at room temperature while N,N-diisopropylethylamine (DIPEA) (0.075 mL, 0.431 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with water (×2). After the aqueous fraction was extracted with EA (×1), the organic fractions were combined, dried, concentrated, and dried in vacuo.

A mixture of the above crude product and MgBr ₂ (35 mg, 0.190 mmol) in MeCN (2 mL) was stirred in a 50°C bath for 1 hour and cooled to 0°C before being treated with 1N HCl (-1 mL). The resulting solution was diluted with water and extracted with CH ₂ Cl ₂ (×3). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated. The product was purified by preparative HPLC and freeze-dried to afford compound 32. ¹ H-NMR (400 MHz, CDCl ₃ )δ10.87(s,1H),~9.3(br,1H),8.35(s,1H),7.50(td,J＝8.7,6.3Hz,1H),6.8 9-6.78(m,1H),6.72(ddd,J＝11.2,8.9,2.6Hz,1H),5.48-5.12(m,2H),4.72- 4.60(m,1H),4.22(dd,J＝13.0,4.1Hz,1H),3.98(dd,J＝12.9,9.4Hz,1H),2.6 8(m,4H),2.33-1.98(m,6H),1.90(m,2H),1.60(ddd,J=12.4,4.1,2.7Hz,1H). ¹⁹ F-NMR (376.1 MHz, CD ₃ CN) δ -76.39 (s, 3F), -110.50 (q, J = 9.2 Hz, 1F), -112.65 (p, J = 7.8 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ for C ₂₄ H ₂₄ F ₂ N ₃ O ₅ : 472.17; found: 472.0.

Example 33

Preparation of compound 33

(2S,5R)-N-(1-(2,4-difluorophenyl)cyclopentyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

As described in the synthesis of compound 32, compound 33 was obtained from compound 32-A and compound 33-A. ¹ H-NMR (400 MHz, CDCl ₃ )δ10.70(s,1H),~9.5(br,1H),8.41(s,1H),7.43(td,J＝8.9,6.4Hz,1H),6.85-6 .76(m,1H),6.72(ddd,J＝11.5,8.8,2.6Hz,1H),5.48-5.18(m,2H),4.68(t,J＝3.2 Hz,1H),4.26(dd,J＝13.0,4.1Hz,1H),4.00(dd,J＝13.0,9.4Hz,1H),2.72-2.45( m,2H),2.22-1.96(m,6H),1.96-1.75(m,5H),1.60(ddd,J＝12.5,4.1,2.7Hz,1H). ¹⁹ F-NMR (376.1 MHz, CD ₃ CN) δ -76.41 (s, 3F), -107.86 (q, J=9.4 Hz, 1F), -113.13 (p, J=8.0 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₅ H ₂₆ F ₂ N ₃ O ₅ : 486.18; Found: 485.9.

Example 34

Preparation of compound 34

(2S,5R)-N-(1-(2,4-difluorophenyl)cyclohexyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 34 was obtained from compound 32-A and compound 34-A as described in the synthesis of compound 32. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.83 (s, 1H), 9.6 (br, 1H), 8.44 (s, 1H), 7.37 (td, J = 9.0, 6.4 Hz, 1H), 6.97-6.76 (m, 1H), 6.69 (ddd, J = 11.9, 8.8, 2.7 Hz, 1H), 5.48-5.18 (m, 2H), 4.68 (t, J = 3.0 Hz, 1H), 4.28 (dd, J = 3.0 Hz, 1H). ＝13.1,4.1Hz,1H),4.03(dd,J＝13.0,9.4Hz,1H),2.60(d,J＝13.1Hz,2H),2.29-1.96(m,4H ),1.95-1.77(m,4H),1.77-1.65(m,4H),1.61(ddd,J＝12.5,4.1,2.7Hz,1H),1.30(br,1H). ¹⁹ F-NMR (376.1 MHz, CD ₃ CN) δ -76.41 (s, 3F), -107.86 (q, J=9.4 Hz, 1F), -113.13 (p, J=8.0 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₆ H ₂₈ F ₂ N ₃ O ₅ : 500.20; Found: 500.0.

Example 35

Preparation of compound 35

(2S,5R)-N-(4-(2,4-Difluorophenyl)tetrahydro-2H-pyran-4-yl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 35 was obtained from compound 32-A and compound 35-A as described in the synthesis of compound 32. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.95 (s, 1H), 8.33 (s, 1H), 7.6 (br, 1H), 7.38 (td, J = 9.0, 6.3 Hz, 1H), 6.85 (td, J = 8.4, 2.6 Hz, 1H), 6.73 (ddd, J = 11.7, 8.6, 2.6 Hz, 1H), 5.32 (dt, J = 14.4, 4.0 Hz, 2H), 4.68 (t,J＝3.1Hz,1H),4.24(dd,J＝13.0,3.9Hz,1H),4.11-3.81(m,5H),2.60(d,J＝13.7Hz, 2H),2.33-2.17(m,2H),2.18-1.97(m,4H),1.87(m,1H),1.61(dt,J=12.5,3.3Hz,1H). ¹⁹ F-NMR (376.1 MHz, CD ₃ CN) δ −76.40 (s, 3F), −108.78 (q, J=10.3, 9.8 Hz, 1F), −112.63 (p, J=8.0 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₅ H ₂₆ F ₂ N ₃ O ₆ : 502.18; Found: 502.0.

Example 36

Preparation of compound 36

(2S,5R)-N-((S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 36 was obtained from compound 32-A and compound 36-A as described in the synthesis of compound 32. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.31 (d, J = 9.4 Hz, 1H), 8.41 (s, 1H), 7.65-7.44 (m, 1H), 6.95 (ddd, J = 9.6, 5.6, 2.0 Hz, 1H), 6.92-6.79 (m, 1H), 6.15 (h, J = 7.4 Hz, 1H), ∼6 (br, 1H), 5.41 (dd, J = 9.5, 4.0 Hz ,1H),5.31(t,J＝4.0Hz,1H),4.70(s,1H),4.34(dd,J＝12.8,3.9Hz,1H),4.05(dd,J＝1 2.9, 9.4Hz, 1H), 2.26-1.99 (m, 4H), 1.99-1.87 (m, 1H), 1.62 (dt, J = 12.6, 3.4Hz, 1H). ¹⁹ F-NMR (376.1 MHz, CDCl ₃ ) δ -75.23 (t, J=6.9 Hz, 3F), -76.33 (s, 3F), -108.31 (m, 1F), -112.30 (p, J=8.0 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₁₉ F ₅ N ₃ O ₅ : 500.12; Found: 500.1.

Example 37

Preparation of compound 37

(3S,11aR)-N-(1-(2,4-difluorophenyl)cyclopropyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

Step 1

Methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (27-B, 0.150 g, 0.32 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treated with methanesulfonic acid (0.05 mL), sealed with a yellow cap, and heated to 70° C. After 16 hours, the mixture was cooled to give a crude solution of methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 27-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₈ H ₁₉ F ₂ N ₂ O ₇ : 439; Found: 439.

Steps 2 and 3

Methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (27-C, 0.32 mmol, crude mixture from the previous step) was dissolved in acetonitrile (1.5 mL) and acetic acid (0.2 mL). To the reaction mixture were added (S)-2-aminopropan-1-ol (0.048 g, 0.64 mmol) and K ₂ CO ₃ (0.088 g, 0.64 mmol). The reaction mixture was sealed and heated to 70° C. After 3 hours, the reaction mixture was cooled and magnesium bromide (0.081 g, 0.44 mmol) was added. The mixture was resealed and heated to 50° C. After 10 minutes, the reaction mixture was cooled to 0° C. and 1N hydrochloric acid (0.5 mL) was added. The reaction mixture was then diluted with MeOH (2 mL). After filtration, the crude material was purified by prep-HPLC (30-70% acetonitrile:water, 0.1% TFA) to afford compound 37 as a TFA salt. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ 8.31 (s, 1H), 7.62 (td, J = 9.2, 8.7, 6.5 Hz, 1H), 7.02-6.78 (m, 2H), 5.53-5.20 (m, 1H), 4.68 (dd, J = 12.3, 4.2 Hz, 1H), 4.40 (dq, J = 19.1, 6.7 Hz, 2H), 3.98 (dd, J = 12.2, 10.0 Hz, 1H), 3.71 (dd, J = 8.3, 6.3 Hz, 1H), 1.41 (d, J = 6.1 Hz, 3H), 1.22 (s, 4H). ¹⁹ F-NMR (376 MHz, methanol-d ₄ )δ-113.66--113.95 (m, 1F), -113.94--114.29 (m, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.; Found: 432.

Example 38

Preparation of compound 38

(1S,4R,12aR)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A solution of compound 38-A (1562 mg, 5.799 mmol) (see Example 41b in WO97/05139) in THF (10 mL) was stirred at -78°C while 2.0 M _LiBH₄ in THF (3.2 mL) was added and the resulting mixture was stirred at room temperature. After 3 hours, additional 2.0 M _LiBH₄ in THF (3.2 mL) was added and the solution was stirred at room temperature for 17.5 hours. After diluting the reaction mixture with ethyl acetate and slowly adding water, the two phases were separated and the separated aqueous fraction was extracted with ethyl acetate (×1). The two organic fractions were washed with water (×1), combined, dried ( _Na₂SO₄ ) and concentrated. The residue was purified by CombiFlash ( ₄₀ g column) using hexane-ethyl acetate as eluent to give compound 38-B. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 4.11 (s, 1H), 3.65-3.52 (m, 2H), 3.45 (m, 1H), 2.32 (d, J = 4.1 Hz, 1H), 2.20 (s, 1H), 1.75-1.64 (m, 2H), 1.61 (m, 2H), 1.49-1.41 (m, 1H), 1.47 (s, 9H), 1.28-1.23 (d, J = 10 Hz, 1H). ^LCMS -ESI ⁺ (m/z): [M+H] _{+ for C12H22NO3} requires: 228.16; found: 227.7.

Step 2

A solution of compound 38-B (589 mg, 2.591 mmol) and NEt ₃ (0.47 mL, 3.369 mmol) in CH ₂ Cl ₂ (6 mL) was stirred at 0° C. while MsCl (0.22 mL, 2.842 mmol) was added. After 1 hour at room temperature, the mixture was diluted with ethyl acetate and then with water (×2). The aqueous fraction was extracted with ethyl acetate (×1), and the organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as eluent to give compound 38-C. ¹ H-NMR (400MHz, chloroform-d) δ4.39-4.28(m,1H),4.16(s,0.4H),4.06(s,0.6H),3.98 (dd,J＝10.0,8.7Hz,0.6H),3.86(t,J＝9.6Hz,0.4H),3.51(dd,J＝9.3,3.7Hz,0 .6H),3.43(dd,J＝9.3,3.6Hz,0.4H),3.02(s,3H),2.59(m,1H),1.82-1.58(m, 4H), 1.51-1.44 (m, 9H), 1.41 (d, J = 14.8Hz, 1H), 1.31 (s, 0.6H), 1.29 (s, 0.4H).

Step 3

To a solution of compound 38-C (769 mg, 2.518 mmol) in DMF (5 mL) was added sodium azide (819 mg, 12.6 mmol). The reaction mixture was stirred at 50°C for 15 hours, at 80°C for 5 hours, and at 100°C for 19 hours. The reaction mixture was diluted with 5% LiCl solution, and the product was extracted with ethyl acetate (×2). After washing the organic fraction with water (×1), the two organic fractions were combined, dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as the eluent to obtain compound ³⁸ -D. H-NMR (400MHz, chloroform-d) δ4.16 (s, 0.4H), 4.06 (s, 0.6H), 3.61 (dd, J = 12.2, 3.6Hz, 0.6H), 3 .51(dd,J＝12.1,3.2Hz,0.4H),3.38(dd,J＝9.4,3.4Hz,0.6H),3.26(dd,J＝9.8,3.3Hz,0 .4H),3.06(dd,J＝12.2,9.4Hz,0.6H),3.01-2.92(m,0.4H),2.48(d,J＝5.2Hz,1H),1.82 -1.57(m,4H),1.46(d,J=3.0Hz,9H),1.42(m,1H),1.28(m,0.6H),1.27-1.23(m,0.4H).

Step 4

To a solution of compound 38-D (507 mg, 2.009 mmol) in ethyl acetate (10 mL) and EtOH (10 mL) was added 10% Pd/C (52 mg). The reaction mixture was stirred under an _H atmosphere for _{1.5 hours. The mixture was filtered through Celite, and the filtrate was concentrated to provide crude compound 38-E. LCMS-ESI (m/z): [M+H] Required for C₁₂H₂N₂O :} ^227.18 _; ^Found _: 226.8.

Step 5

A mixture of crude compound 38-E (206 mg, 0.910 mmol), compound 38-F (330 mg, 0.953 mmol) and NaHCO ₃ (154 mg, 1.833 mmol) in water (3 mL) and EtOH (3 mL) was stirred at room temperature for 20 hours. After the reaction mixture was diluted with water and extracted with ethyl acetate (×2), the extracts were washed with water (×1), combined, dried (Na ₂ SO ₄ ) and concentrated to give the crude pyridine product.

The crude residue (388 mg) was dissolved in _CH2Cl2 (4 mL) and 4N HCl in _dioxane (4 mL). After 1.5 hours, additional 4N HCl in dioxane (4 mL) was added and stirred at room temperature for 1 hour. The mixture was brought to dryness, co-evaporated with toluene (×1) and dried in vacuo for 30 minutes.

The crude residue and 1,8-diazabicycloundec-7-ene (DBU) (1.06 mL, 7.088 mmol) in toluene (10 mL) were stirred in a 110° C. bath. After 30 minutes, the mixture was concentrated and the residue was purified by a CombiFlash 40 g column using ethyl acetate-20% MeOH/ethyl acetate as the eluent to give compound 38-G. ¹ H-NMR (400 MHz, chloroform-d) δ 8.03 (s, 1H), 7.68-7.58 (m, 2H), 7.36-7.27 (m, 3H), 5.53 (d, J=9.9 Hz, 1H), 5.11 (d, J=9.9 Hz, 1H), 4.93 (s, 1H), 4.43-4.30 (m, 2H), 3.89 (dd, J=12.2, 3.3 Hz , 1H), 3.73 (t, J = 12.0 Hz, 1H), 3.59 (dd, J = 11.9, 3.3 Hz, 1H), 2.53 (d, J = 2.8 Hz, 1H), 1.87-1.67 (m, 4H) _, 1.55 (d, J = 10.0 Hz, 1H), 1.51-1.45 (m, 1H), 1.38 (t, J = _7.1 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires for _C23H25N2O5 : _409.18 ; found: 409.2.

Step 6

A mixture of compound 38-G (232 mg, 0.568 mmol) in THF (3 mL) and MeOH (3 mL) was stirred at room temperature while 1N KOH (3 mL) was added. After 1 hour, the reaction mixture was neutralized with 1N HCl (~3.1 mL), concentrated, and the residue was concentrated with toluene (×3). After drying the residue in vacuo for 30 minutes, a suspension of the crude residue, 2,4-difluorobenzylamine (86 mg, 0.601 mmol), and HATU (266 mg, 0.700 mmol) in CH ₂ Cl ₂ (4 mL) and DMF (4 mL) was stirred at 0° C. while N,N-diisopropylethylamine (DIPEA) (0.7 mL, 4.019 mmol) was added. After 45 minutes, additional 2,4-difluorobenzylamine (86 mg, 0.559 mmol), HATU (266 mg, 0.700 mmol), and N,N-diisopropylethylamine (DIPEA) (0.7 mL, 4.019 mmol) were added at room temperature. After 1.25 hours, the mixture was concentrated to remove most of the CH ₂ Cl ₂ , diluted with ethyl acetate, and washed with 5% LiCl (×2). After the aqueous fraction was extracted with ethyl acetate (×1), the organic fractions were combined, dried (Na ₂ SO ₄ ), and concentrated. The residue was purified by CombiFlash (40 g column) using ethyl acetate-20% MeOH/ethyl acetate as eluent to provide compound ³⁸ -H. H-NMR (400 MHz, chloroform-d) δ 10.48 (t, J = 6.0 Hz, 1H), 8.33 (s, 1H), 7.62-7.51 (m, 2H), 7.40-7.27 (m, 4H), 6.87-6.75 (m, 2H), 5.39 (d, J = 10.0 Hz, 1H), 5.15 (d, J = 10.0 Hz, 1H), 4.92 ( s, 1H), 4.68-4.53 (m, 2H), 3.97 (dd, J = 12.5, 3.4 Hz, 1H), 3.77 (t, J = 12.2 Hz, 1H), 3.55 (dd, J = 12.1, 3.3 Hz, 1H), 2.53 (d, J = 3.1 Hz, 1H), 1.88-1.62 (m, 4H), 1.59-1.42 (m, 2H). ¹⁹ F-NMR (376 MHz, CHLOROFORM-d) δ -112.17 (q, J = 7.6 Hz, 1F), -114.79 (q, J = 8.6 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C28H26F2N3O4: 506.19; Found: 506.2.

Step 7

Compound 38-H (240 mg, 0.475 mmol) was dissolved in TFA (3 mL) at room temperature for 30 minutes, and the solution was concentrated. The residue _was purified _by CombiFlash (40 g column) using _CH2Cl2-20 % MeOH in _CH2Cl2 as the eluent. After concentration of the collected product fractions, the residue was triturated in MeCN (~2 mL) at 0°C for 15 minutes, the solid was filtered and washed with MeCN. The collected solid was dried in vacuo to give Compound 38.

The filtrate was concentrated and the residue was dissolved in MeCN (-1 mL) and water (-1 mL) by heating. The solution was slowly cooled to room temperature and then cooled in an ice bath for 15 minutes. The solid was filtered and washed with MeCN and dried in vacuo to give another compound 38. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 11.68 (s, 1H), 10.42 (s, 1H), 8.27 (s, 1H), 7.41-7.31 (m, 1H), 6.86-6.73 (m, 2H), 4.90 (d, J = 2.5 Hz, 1H), 4.71-4.53 (m, 2H), 4.07 (d, J = 10.6 Hz, 1H), 3.90-3.67 (m, 2H), 2.68 (s, 1H), 2.01 (s, 1H), 1.97-1.80 (m, 3H), 1.80-1.62 (m, 2H). ¹⁹ F-NMR (376 MHz, CHLOROFORM-d) δ -112.28 (m, 1F), -114.74 (m, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₁₉ F ₂ N ₃ O ₄ : 416.14; Found: 416.3.

Examples 39 and 40

Preparation of compounds 39 and 40

(2R,3S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-3-methyl-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide 39 and (2S,3R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-3-methyl-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide 40

Step 1

Cuprous cyanide (290 mg, 3.27 mmol) was suspended in 3.3 mL of THF and cooled to -78° C. A 1.6 M solution of MeLi (4.1 mL, 6.56 mmol) in diethyl ether was added dropwise, and the reaction solution was allowed to warm to room temperature over 2 hours and then cooled to -78° C. Tert-butyl (1R,3R,5S)-6-oxobicyclo[3.1.0]hexan-3-ylcarbamate (330 mg, 1.66 mmol) in 3.3 mL of THF was added dropwise, followed by boron trifluoride diethyl etherate (0.25 mL, 1.99 mmol), and the mixture was allowed to warm to -30° C. over 30 minutes and stirred between -35° C. and -25° C. for 1 hour. The reaction solution was then warmed to room temperature and quenched with a saturated mixture of _NH3 (aq)/ _NH4 (aq), extracted with EtOAc, washed with brine, dried over _MgSO4 , filtered, concentrated, and purified by SGC (0-10% EtOH/DCM) to give racemic tert-butyl (1S,3S,4S)-3-hydroxy-4-methylcyclopentylcarbamate. ¹ H-NMR (400MHz, chloroform-d) δ5.16(s,1H),3.98(s,1H),3.74(q,J＝4.3Hz,1H),3.65(q,J＝7.0Hz,1H),2.23(dt,J＝14.0,7.0Hz,1H),1 .98(dt,J＝13.3,7.0Hz,1H),1.89-1.79(m,1H),1.58-1.44(m,1H),1.38(s,9H),1.18(t,J＝7.0Hz,1H),0.91(d,J＝7.0Hz,3H).

Step 2

3 mL of HCl/dioxane (4 M, 12 mmol) was added to a solution of racemic tert-butyl (1S,3S,4S)-3-hydroxy-4-methylcyclopentylcarbamate (182 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated, and chased twice with toluene to give racemic (1S,2S,4S)-4-amino-2-methylcyclopentanol.

Step 3

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 310 mg, 0.75 mmol), racemic (1S,2S,4S)-4-amino-2-methylcyclopentanol (115 mg, 0.76 mmol) and potassium carbonate (232 mg, 1.68 mmol) were dissolved in 3.8 mL of acetonitrile/0.2 mL of acetic acid and stirred at 90 °C for 2 h, after which the reaction mixture was partitioned between DCM and brine, the aqueous phase was extracted into DCM, and the combined organic phases were dried over _MgSO4 , filtered, concentrated and purified by SGC (0-10% EtOH/DCM) to give Intermediate 39-A.

Step 4

Intermediate 39-A (190 mg) was separated by chiral preparative HPLC on a Lux Cellulose-2 column using 9:1 ACN:MeOH as the eluent to provide enantiomerically enriched intermediates 39-B (first eluting peak) and 40-A (second eluting peak). For intermediate 39-B: (absolute stereochemistry confirmed by X-ray crystallography), chiral HPLC retention time = 3.98 minutes (Lux Cellulose-2 IC, 150 x 4.6 mm, 2 mL/min 9:1 ACN:MeOH). For intermediate 40-A: (absolute stereochemistry confirmed by X-ray crystallography), chiral HPLC retention time = 6.35 minutes (Lux Cellulose-2 IC, 150 x 4.6 mm, 2 mL/min 9:1 ACN:MeOH).

Step 5a

Magnesium bromide (68 mg, 0.37 mmol) was added to a solution of intermediate 39-B (83 mg, 0.18 mmol) in 2 mL of acetonitrile. The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous solution and dichloromethane, and the aqueous phase extracted into dichloromethane. The combined organic phases were dried over _MgSO4 , filtered, concentrated, and purified by silica gel chromatography (0-10% EtOH/DCM) to provide compound 39 ^. H-NMR (400MHz, chloroform-d) δ12.32(s,1H),10.36(s,1H),8.29(s,1H),7.44-7.33(m,1H),6.88-6.76(m,2H),5.37(dd,J＝ 9.5,4.1Hz,1H),5.28(t,J＝5.3Hz,1H),4.63(d,J＝5.9Hz,2H),4.23(d,J＝23.0Hz,2H),3.99(dd,J＝12.7,9.5Hz,1H) , 3.72 (q, J = 7.0 Hz, 1H), 2.51 (dq, J = 13.7, 6.8, 6.1 Hz, 1H), 2.15 (ddd, J = 14.7, 8.3, 2.3 Hz, 1H), 1.94 (d, J = 12.7 Hz, 1H), 1.77 (ddd, J = 12.7, 4.0, 2.9 Hz, 1H), 1.61 (dt, J = 14.6, 5.2 Hz, 2H), 1.24 (t, J = 7.0 Hz, 1H), 1.09 (d, J = _7.2 Hz, _3H ) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires for _C22H22F2N3O5 : _446.15 ; found: 446.2.

Step 5b

Magnesium bromide (59 mg, 0.32 mmol) was added to a solution of intermediate 40-A (70 mg, 0.15 mmol) in 2 mL of acetonitrile. The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous solution and dichloromethane, and the aqueous phase extracted into dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated, and purified by silica gel chromatography (0-10% EtOH/DCM) to provide compound 40 ^. H-NMR (400MHz, chloroform-d) δ12.32(s,1H),10.36(s,1H),8.29(s,1H),7.44-7.33(m,1H),6.88-6.76(m,2H),5.37(dd,J＝ 9.5,4.1Hz,1H),5.28(t,J＝5.3Hz,1H),4.63(d,J＝5.9Hz,2H),4.23(d,J＝23.0Hz,2H),3.99(dd,J＝12.7,9.5Hz,1H) , 3.72 (q, J = 7.0 Hz, 1H), 2.51 (dq, J = 13.7, 6.8, 6.1 Hz, 1H), 2.15 (ddd, J = 14.7, 8.3, 2.3 Hz, 1H), 1.94 (d, J = 12.7 Hz, 1H), 1.77 (ddd, J = 12.7, 4.0, 2.9 Hz, 1H), 1.61 (dt, J = 14.6, 5.2 Hz, 2H), 1.24 (t, J = 7.0 Hz, 1H), 1.09 (d, J = _7.2 Hz, _3H ) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires for _C22H22F2N3O5 : _446.15 ; found: 446.2.

Example 41

Preparation of compound 41

(1R,4S,12aR)-7-Hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A solution of 41-A (2020 mg, 7.463 mmol) (prepared by the same method as 38-A) in THF (14 mL) was stirred at 0°C while 2.0 M _LiBH₄ in THF (7.5 mL, 15 mmol) was added. After stirring the resulting mixture at room temperature for 21 h, it was cooled at 0°C and diluted with EA, after which it was slowly quenched by the addition of water. After separation of the two phases, the aqueous fraction was extracted with EA (×1), and the two organic fractions were washed with water (×1), combined, dried _{( Na₂SO₄} ), and concentrated. The residue was purified by CombiFlash (120 g column) using hexane-EA as _the eluent to give ₄₁ - _B . LCMS- ^ESI⁺ (m/z): [ _M₄H₈H ] ^⁺ calcd for _{C₈H₁₄NO₃} : 172.10; found: 171.95.

Step 2

A 100-mL round-bottom flask was charged with reactant 41-B (1.6 g, 7.05 mmol) and triethylamine (0.94 g, 9.3 mmol) in DCM (20 mL). Methanesulfonyl chloride (0.91 g, 8.0 mmol) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 3 hours. The mixture was diluted with EA (100 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and _the organic fractions were combined, dried ( _Na2SO4 ) and concentrated. The residue was purified by CombiFlash (120 g column, used cartridge) using hexane-EA as eluent _to give 41-C. LCMS-ESI ⁺ (m/z ₎ : [M+ _{H ]} ⁺ Required: _C18H19F2N2O7 : 306; Found: 306.

Step 3

A 100-mL round-bottom flask was charged with reactant 41-C (2.1 g, 6.9 mmol) and sodium azide (2.3 g, 34.5 mmol) in DMF (10 mL). The reaction mixture was then stirred at 100°C overnight. The mixture was diluted with EA (100 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and the organic fractions were combined, dried ( _Na2SO4 ), and concentrated. The residue was purified by CombiFlash _{(120 g column, used cartridge) using hexane-EA as the eluent to provide 41-D. LCMS-ESI+ (m/z): [M+H]+ Required for C18H19F2N2O7 : 253 ; Found} ^{: 253} _.

Step 4

To a solution of reactant 41-D (1.3 g) in EA (20 mL) and EtOH (20 mL) (purged with N ₂ ) was added Pd/C (130 mg). The mixture was stirred under H ₂ for 3 h. The mixture was filtered through Celite and the filtrate was concentrated to afford compound 41-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₈ H ₁₉ F ₂ N ₂ O ₇ : 227; Found: 227.

Step 5

A 100-mL round-bottom flask was charged with 41-E (1.05 g, 4.62 mmol) and reactant 38-F (1.6 g, 4.62 mmol) in ethanol (20 mL). Sodium bicarbonate (0.77 g, 9.2 mmol) in water (20 mL) was added to the reaction mixture. The reaction mixture was then stirred overnight at room temperature. The mixture was diluted with EA (100 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x ₎ , and the organic fractions were combined, dried ( _Na2SO4 ), and concentrated. The crude product (2.4 _g ) was used in the next step _{without further} purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required _{for C18H19F2N2O7} : 556; Found: 556.

A 100-mL round-bottom flask was charged with the crude product from the previous reaction in 4N HCl/dioxane (24.7 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, the intermediate (2.1 g) and DBU (3.27 g, 21.5 mmol) in toluene (30 mL) were heated to 110° C. and stirred for 1 hour. After concentration, the residue was purified by CombiFlash (120 g column) using hexane-ethyl acetate as eluent to obtain 41-F. LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₁₈ H ₁₉ F ₂ N ₂ O ₇ : 409; found: 409.

Step 6

A 100-mL round-bottom flask was charged with reactant 41-F (0.5 g, 1.22 mmol) in THF (5 mL) and MeOH (5 mL). 1N KOH (3.7 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by the addition of 1N HCl (3.7 mL), concentrated to remove most of the organic solvent, and extracted with EtOAc ( _2X ). The organic layers were combined, dried ( _Na2SO4 ), and concentrated to provide compound 41-G.

Step 7

A 100-mL round-bottom flask was charged with reactants 41-G (0.14 g, 0.37 mmol), (2,4,6-trifluorophenyl)methanamine (0.12 g, 0.73 mmol), N,N-diisopropylethylamine (DIPEA) (0.24 g, 1.84 mmol), and HATU (0.28 g, 0.74 mmol) dissolved in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl ( _2x ), and dried over _Na₂SO₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford compound 41-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₈ H ₁₉ F ₂ N ₂ O ₇ : 524.5; Found: 524.5.

Step 8

A 50-mL round-bottom flask was charged with reactant 41-H (0.13 g, 0.25 mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to obtain compound 41. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 11.61 (s, 1H), 10.70-10.01 (m, 1H), 8.26 (s, 1H), 6.65 (t, J = 8.1 Hz, 2H), 4.88 (s, 1H), 4.65 (dd, J = 6.1, 2.4 Hz, 2H), 4.07 (d, J = 10.9 Hz, 1H), 3.93-3.58 (m, 2H), 2.67 (d, J = 3.1 Hz, 1H), 2.08-1.41 (m, 7H). ¹⁹ F-NMR (376 MHz, CHLOROFORM-d) δ -109.22 (d, J = 11.6 Hz, 1F), -111.04 - -112.79 (m, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 434.; Found: 434.

Example 42

Preparation of compound 42

(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (3.15 g, 10 mmol) in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesulfonic acid (0.195 mL, 3 mmol) and placed in a 75° C. bath. The reaction mixture was stirred for 7 hours, cooled and stored at −10° C. for 3 days, and then heated to 75° C. for an additional 2 hours. The material was cooled and carried on crude to the next step.

Step 2

The crude reaction mixture from step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (1R,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol), and heated to 85°C. After 2 hours, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2 M HCl (50 mL) was added, and the clear yellow solution was extracted with dichloromethane ( ₂ x ₁₅₀ mL ₎ . The combined organic layers were dried over sodium sulfate, filtered, and concentrated to 1.49 g of a light orange solid. Recrystallization from dichloromethane:hexanes gave the desired intermediate 42A: LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for _C15H17N2O6 : 321.11; Found: 321.3.

Step 3

Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6-trifluorophenyl)methanamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, 0.294 g, 0.774 mmol ₎ . After 1.5 hours, the crude reaction mixture was carried on to _the next step. LCMS-ESI ⁺ (m/z): [M+ _H ] ⁺ Required: _C22H21F3N3O5 : _464.14 ; Found: 464.2.

Step 4

To the crude reaction mixture of the previous step was added MgBr ₂ (0.258 g, 1.40 mmol). The reaction mixture was stirred at 50° C. for 10 minutes, acidified with 10% aqueous HCl, and extracted twice with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated, and purified by silica gel chromatography (EtOH/dichloromethane) followed by HPLC (ACN/H ₂ O with 0.1% TFA as a modifier) to afford compound 42: ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.43(s,1H),10.34(t,J＝5.7Hz,1H),8.42(s,1H),7.19(t,J＝8.7Hz,2H),5.43(dd,J＝9.5,4.1Hz,1H),5.08(s,1H),4.66(dd,J＝12.9,4. 0Hz,1H),4.59(s,1H),4.56-4.45(m,2H),4.01(dd,J＝12.7,9.7Hz,1H),1.93(s,4H),1.83(d,J＝12.0Hz,1H),1.56(dt,J＝12.0,3.4Hz,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₁₉ F ₃ N ₃ O ₅ : 450.13; Found: 450.2.

Example 43

Preparation of compound 43

(12aR)-N-((R)-1-(2,4-difluorophenyl)ethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 100-mL round-bottom flask was charged with reactants 41-G (0.14 g, 0.37 mmol), (R)-1-(2,4-difluorophenyl)ethanamine (0.12 g, 0.74 mmol), N,N-diisopropylethylamine (0.24 g, 1.84 mmol), and HATU (0.28 g, 0.74 mmol) and dissolved in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl (2x), and dried _{over Na₂SO₄} . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to provide compound 43-A. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₈ H ₁₉ F ₂ N ₂ O ₇ : 520; Found: 520.

Step 2

A 50-mL round-bottom flask was charged with reactant 43-A (0.14 g, 0.27 mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to yield compound 43. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 11.65 (s, 1H), 10.57 (s, 1H), 8.22 (s, 1H), 7.31 (m, 1H), 6.99-6.62 (m, 2H), 5.64-5.32 (m, 1H), 4.90 (d, J = 2.7 Hz, 1H), 4.04 (d, J = 11.5 Hz, 1H), 3.93-3.63 (m, 2H), 2.67 (s, 1H), 2.08-1.40 (m, 9H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -113.09 (m, 1F), -115.01 (m, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 430; Found: 430.

Example 44

Preparation of compound 44

(13aS)-8-Hydroxy-7,9-dioxo-N-(2,3,4-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

Compound 15-B (40 mg, 0.12 mmol) was dissolved in 1 mL of acetonitrile and treated with 2,3,4-trifluorobenzylamine (29 mg, 0.18 mmol), HATU (53 mg, 0.14 mmol), and N,N-diisopropylethylamine (DIPEA) (20 mg, 0.16 mmol). The mixture was stirred at room temperature for 2 hours, after which LCMS analysis showed complete consumption of compound 15-B and formation of intermediate 44-A. The reaction mixture was carried on to the next step.

Step 2

To the crude reaction solution from the previous step was added _MgBr2 (63 mg, 0.34 mmol). The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous solution and dichloromethane, and the aqueous phase extracted into dichloromethane. The combined organic phases were dried over _MgSO4 , filtered, concentrated, and purified by HPLC (ACN/ _H2O with 0.1% TFA as a modifier) to afford compound 44. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.45(s,1H),10.38(t,J＝6.0Hz,1H),8.43(s,1H),7.27(q,J＝9.2Hz,1H),7.16(q,J＝8.5Hz,1H),5.42(dd,J＝9.5,4.0Hz,1H), 5.08(s,1H),4.76-4.47(m,4H),4.01(dd,J＝12.8,9.7Hz,1H),1.92(s,4H),1.82(d,J＝12.1Hz,1H),1.55(dt,J＝12.2,2.9Hz,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₁₉ F ₃ N ₃ O ₅ : 450.13; Found: 450.2.

Example 45

Preparation of compound 45

(13aS)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

Compound 15-B (38 mg, 0.12 mmol) was dissolved in 1 mL of acetonitrile and treated with 2,4,6-trifluorobenzylamine (34 mg, 0.21 mmol), HATU (50 mg, 0.13 mmol), and N,N-diisopropylethylamine (DIPEA) (23 mg, 0.18 mmol). The mixture was stirred at room temperature for 2 hours, after which LCMS analysis showed that compound 15-B was completely consumed and intermediate 45-A was formed. The reaction mixture was carried on to the next step.

Step 2

To the crude reaction solution from the previous step was added _MgBr2 (55 mg, 0.30 mmol). The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over _MgSO4 , filtered, concentrated, and purified by HPLC (ACN/ _H2O with 0.1% TFA as a modifier) to afford Compound 45. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.37(s,1H),10.37-10.25(m,1H),8.37(s,1H),7.14(t,J＝8.7Hz,2H),5.37(dd,J＝9.5,4.0Hz,1H),5.02(s,1H), 4.66-4.40(m,4H),3.95(dd,J＝12.8,9.6Hz,1H),1.87(s,4H),1.77(d,J＝11.9Hz,1H),1.50(dt,J＝11.8,3.2Hz,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₁₉ F ₃ N ₃ O ₅ : 450.13; Found: 450.2.

Example 46

Preparation of compound 46

(13aS)-N-(2,6-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

Compound 15-B (38 mg, 0.12 mmol) was dissolved in 1 mL of acetonitrile and treated with 2,6-difluorobenzylamine (19 mg, 0.14 mmol), HATU (56 mg, 0.15 mmol), and N,N-diisopropylethylamine (DIPEA) (20 mg, 0.15 mmol). The mixture was stirred at room temperature for 90 minutes, after which LCMS analysis showed that compound A was completely consumed and intermediate 46-A was formed. The reaction mixture was carried on to the next step.

Step 2

To the crude reaction solution from the previous step was added _MgBr2 (50 mg, 0.27 mmol). The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over _MgSO4 , filtered, concentrated, and purified by HPLC (ACN/ _H2O with 0.1% TFA as a modifier) to afford compound 46. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.37(s,1H),10.33-10.26(m,1H),8.37(s,1H),7.39-7.29(m,1H),7.05(t,J＝7.9Hz,2H),5.37(dd,J＝9.5,4.1Hz,1H),5.0 2(s,1H),4.66-4.45(m,4H),3.95(dd,J＝12.7,9.6Hz,1H),1.87(s,4H),1.77(d,J＝12.0Hz,1H),1.50(dt,J＝12.2,3.5Hz,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.14; Found: 432.2.

Example 47

Preparation of compound 47

(1R,4S,12aR)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

Crude acid 41-G (0.45 g, 1.18 mmol), 2,4-difluorobenzylamine (0.35 g, 2.44 mmol), N,N-diisopropylethylamine (DIPEA) (0.79 g, 6.11 mmol), and HATU (0.93 g, 2.44 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl ( _2x ), and dried over _Na₂SO₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give compound ₄₇ -A. _{LCMS-ESI+ (m/z): [M+H]+ Required for C₁₈H₁₉F₂N₂O₇ :} ^{506 ;} _{Found :} 506.

Step 2

To a 50-mL round-bottom flask was placed the reactant 47-A (0.5 g, 0.99 mmol) in TFA (6 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 47. ^1H NMR (400 MHz, CHLOROFORM-d) δ 11.70 (s, 1H), 10.44 (s, 1H), 8.29 (s, 1H), 7.60-7.29 (m, 1H), 6.95-6.58 (m, 2H), 4.10 (s, 1H), 4.02-3.54 (m, 3H), 2.68 (d, J=3.1 Hz, 1H), 2.00-1.40 (m, 8H). ^19F NMR (376 MHz, CHLOROFORM-d) δ -112.31 (d, J=8.0 Hz, 1F), -114.77 (d, J= _{8.4 Hz} , 1F). LCMS- _ESI ⁺ (m/ _z ): [M+H] ⁺ requires for _C21H20F2N3O5 : 416; found: 416.

Example 48

Preparation of compound 48

(1S,4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

48-B was prepared by substituting 48-A for 55-A in analogy to 55-H in Example 55. Compound 48 was prepared as described for compound 38 in Example 38 by substituting 48-B for 38-B to give compound 48. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 11.79 (s, 1H), 10.44 (m, 1H), 8.33 (s, 1H), 7.42-7.31 (m, 1H), 6.86-6.74 (m, 2H), 4.74 (s, 1H), 4.63 (d, J=5.8 Hz, 2H), 4.19 (m, 1H), 4.07-4.03 (m, 2H), 2.83 (s, 1H), 1.92-1.68 (m, 6H). ¹⁹ F NMR (376 MHz, chloroform-d) δ -112.3 (m, 1F), -114.8 (m, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₄ : 416.14; Found: 416.07.

Example 49

Preparation of compound 49

(2S,5R,13aS)-8-Hydroxy-7,9-dioxo-N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

Compound 15-B (44 mg, 0.11 mmol) was dissolved in 1 mL of acetonitrile and treated with (3-(trifluoromethyl)pyridin-2-yl)methanamine (38 mg, 0.18 mmol, HCl salt), HATU (69 mg, 0.18 mmol), N,N-diisopropylethylamine (DIPEA) (0.07 mL, 0.40 mmol), and stirred at room temperature for 1 hour, after which LCMS analysis showed complete consumption of compound 15-B and formation of intermediate 49-A. The reaction mixture was carried on to the next step.

Step 2

To the crude reaction solution from the previous step was added MgBr ₂ (51 mg, 0.28 mmol). The reaction mixture was stirred at 50°C for 90 minutes, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated, and triturated with methanol, followed by trituration with diethyl ether to afford compound 49. ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.42(s,1H),10.80-10.70(m,1H),8.83(d,J＝5.0Hz,1H),8.44(s,1H),8.19 (d,J＝8.6Hz,1H),7.56(dd,J＝7.7,5.2Hz,1H),5.43(dd,J＝9.5,4.0Hz,1H),5.0 8(s,1H),4.86-4.80(m,2H),4.67(dd,J＝12.9,4.0Hz,1H),4.59(s,1H),4.02(d d,J＝12.6,9.8Hz,1H),1.93(s,4H),1.82(d,J＝12.1Hz,1H),1.60-1.52(m,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₃ N ₄ O ₅ : 465.14; Found: 465.2.

Examples 50 and 51

Preparation of compounds 50 and 51

N-(2,4-Difluorobenzyl)-9-hydroxy-8,10-dioxo-2,3,5,6,8,10,14,14a-octahydro-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,6,3]dioxazocine-11-carboxamide 50 and 51

Step 1

Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 392 mg, 0.95 mmol) (Example 87), racemic cis-5-aminotetrahydro-2H-pyran-3-ol (WO 2012/145569 Bennett, BL et al., filed April 20, 2012) (112 mg, 0.95 mmol) and potassium carbonate (134 mg, 0.97 mmol) were dissolved in 3.8 mL acetonitrile/0.2 mL acetic acid and stirred at 90° C. for 90 min, after which the reaction mixture was partitioned between DCM and brine, the aqueous phase was extracted with DCM, the combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by SGC (0-10% EtOH/DCM) to give Intermediate 50-A.

Step 2

Intermediate 50-A (40 mg) was separated by chiral SFC on a Chiralpak IC column using 10% DMF in supercritical carbon dioxide as the eluent to provide enantiomerically enriched intermediates 50-B (first eluting peak) and 51-A (second eluting peak). For intermediate 50-B: (absolute stereochemistry unknown), chiral HPLC retention time = 11.48 minutes (Chiralpak IC, 150 x 4.6 mm, 1 mL/min MeOH). For intermediate 51-A: (absolute stereochemistry unknown), chiral HPLC retention time = 14.35 minutes (Chiralpak IC, 150 x 4.6 mm, 1 mL/min MeOH).

Step 3a

Magnesium bromide (12 mg, 0.06 mmol) was added to a solution of intermediate 50-B (10.5 mg, 0.02 mmol, absolute stereochemistry unknown) in 1 mL of acetonitrile. The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over _MgSO₄ , filtered, concentrated, and purified by HPLC (ACN/ _H₂O containing 0.1% TFA as a modifier) to provide compound 50. ¹ H-NMR (400MHz, chloroform-d) δ10.47(t,J＝5.8Hz,1H),8.42(s,1H),7.35(q,J＝8.6,8. 2Hz, 1H), 6.81 (q, J＝8.7, 8.0Hz, 2H), 6.41 (dd, J＝10.0, 3.6Hz, 1H), 4.79 (s, 1H) ,4.65(s,2H),4.36-4.26(m,2H),4.20-4.08(m,2H),3.98(dd,J＝12.4,10.2Hz ,1H),3.88(t,J＝11.8Hz,2H),2.27(dt,J＝13.3,3.1Hz,1H),2.15-2.06(m,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₆ : 448.40; Found: 448.2.

Step 3b

Magnesium bromide (13 mg, 0.07 mmol) was added to a solution of intermediate 51-A (13.2 mg, 0.03 mmol, absolute stereochemistry unknown) in 1 mL of acetonitrile. The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous solution and dichloromethane, and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over _MgSO4 , filtered, concentrated, and purified by HPLC (ACN/ _H2O with 0.1% TFA as a modifier) to provide compound 51. ¹ H-NMR (400MHz, chloroform-d) δ10.47(t,J＝5.8Hz,1H),8.42(s,1H),7.35(q,J＝8.6,8. 2Hz, 1H), 6.81 (q, J＝8.7, 8.0Hz, 2H), 6.41 (dd, J＝10.0, 3.6Hz, 1H), 4.79 (s, 1H) ,4.65(s,2H),4.36-4.26(m,2H),4.20-4.08(m,2H),3.98(dd,J＝12.4,10.2Hz ,1H),3.88(t,J＝11.8Hz,2H),2.27(dt,J＝13.3,3.1Hz,1H),2.15-2.06(m,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₀ F ₂ N ₃ O ₆ : 448.40; Found: 448.2.

Example 52

Preparation of compound 52

(2S,5R,13aS)-N-(2-Cyclopropyloxy-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

A solution of cyclopropanol (1.9 g, 29 mmol) in 20 mL of dioxane was added dropwise to a 0°C solution of sodium hydride (60% dispersion in mineral oil, 1.04 g, 26 mmol) in 80 mL of dioxane. The reaction mixture was allowed to warm to room temperature, 2,4-difluorobenzonitrile (3.48 g, 25 mmol) was added portionwise, and the reaction temperature was raised to 95°C. After stirring for 18 hours, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed twice with water and twice with brine, dried over _MgSO₄ , filtered, and concentrated onto silica gel. Purification by silica gel chromatography (0-10% EtOAc/hexane) gave 2-cyclopropyloxy-4-fluorobenzonitrile. ¹ H-NMR (400MHz, chloroform-d) δ7.52 (dd, J = 8.6, 6.2 Hz, 1H), 7.05 (dd, J = 10.5, 2.3 Hz, 1H), 6.73 (td, J = 8.2, 2.3 Hz, 1H), 3.87-3.76 (m, 1H), 0.87 (m, 4H).

Step 2

To a 0°C suspension of lithium aluminum hydride in THF (1M, 15 mL, 15 mmol) was added dropwise 2-cyclopropyloxy-4-fluorobenzonitrile in 14 mL of ether. The reaction solution was stirred for 3 hours and gradually warmed to room temperature, at which point it was recooled to 0°C, an additional 8 mL of lithium aluminum hydride in THF (1M, 8 mmol) was added, and stirred for an additional 90 minutes. The reaction was quenched by the sequential addition of 0.9 mL of water, 0.9 mL of 15% NaOH _(aq) , and 2.7 mL of water. The reaction was filtered through celite, rinsed with ether, dried over MgSO ₄ , and concentrated to give 2-cyclopropyloxy-4-fluorobenzylamine of sufficient purity as a crude material. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 7.17-7.08 (m, 1H), 6.96 (dd, J=10.9, 2.4 Hz, 1H), 6.61 (td, J=8.3, 2.5 Hz, 1H), 3.78-3.66 (m, 3H), 0.89-0.72 (m, 4H).

Step 3

Compound 15-B (46 mg, 0.14 mmol) was dissolved in 1 mL of acetonitrile and treated with 2-cyclopropyloxy-4-fluorobenzylamine (32 mg, 0.18 mmol), HATU (62 mg, 0.16 mmol), and N,N-diisopropylethylamine (DIPEA) (0.04 mL, 0.22 mmol). The mixture was stirred at room temperature for 2 hours, after which LCMS analysis showed complete consumption of compound 15-B and formation of intermediate 52-A. The reaction mixture was carried on to the next step.

Step 4

To the crude reaction solution from the previous step was added MgBr ₂ (56 mg, 0.30 mmol). The reaction mixture was stirred at 50° C. for 90 minutes, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated, and purified by HPLC (ACN/H ₂ O containing 0.1% TFA as a modifier) to afford Compound 52. ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.44(s,1H),10.21(t,J＝5.8Hz,1H),8.41(s,1H),7.22-7.15(m,1H),7.12(dd,J＝11.2,2.5H z,1H),6.72(td,J＝8.5,2.5Hz,1H),5.42(dd,J＝9.6,4.1Hz,1H),5.07(s,1H),4.66(dd,J＝12.8,4 , 1H), 4.54 (s, 1H), 4.33 (dd, J = 5.6, 2.4 Hz, 2H), 4.02 (m, 2H), 1.96 (s, 4H), 1.80 (d, J = 11.9 Hz, 1H), 1.50 (dt, J = 12.4, 3.5 Hz, 1H), 0.83 (q, J = 6.3, 5.7 Hz, 2H), 0.72 (q, J = 6.0, 4.9 _{Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ requires for C24H25FN3O6 : 470.17} ^{; found} _: 470.1.

Example 53

Preparation of compound 53

(2R,5S,13aR)-N-(2-cyclopropyloxy-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

Compound 42-A (46 mg, 0.14 mmol) was dissolved in 1 mL of acetonitrile and treated with 2-cyclopropyloxy-4-fluorobenzylamine (33 mg, 0.18 mmol), HATU (61 mg, 0.16 mmol), and N,N-diisopropylethylamine (DIPEA) (0.04 mL, 0.24 mmol). The mixture was stirred at room temperature for 2 hours, after which LCMS analysis showed complete consumption of compound 42-A and formation of intermediate 53-A. The reaction mixture was carried on to the next step.

Step 2

To the crude reaction solution from the previous step was added MgBr ₂ (55 mg, 0.30 mmol). The reaction mixture was stirred at 50° C. for 90 minutes, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated, and purified by HPLC (ACN/H ₂ O containing 0.1% TFA as a modifier) to afford Compound 53. ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.44(s,1H),10.21(t,J＝5.8Hz,1H),8.41(s,1H),7.22-7.15(m,1H),7.12(dd,J＝11.2,2.5H z,1H),6.72(td,J＝8.5,2.5Hz,1H),5.42(dd,J＝9.6,4.1Hz,1H),5.07(s,1H),4.66(dd,J＝12.8,4 , 1H), 4.54 (s, 1H), 4.33 (dd, J = 5.6, 2.4 Hz, 2H), 4.02 (m, 2H), 1.96 (s, 4H), 1.80 (d, J = 11.9 Hz, 1H), 1.50 (dt, J = 12.4, 3.5 Hz, 1H), 0.83 (q, J = 6.3, 5.7 Hz, 2H), 0.72 (q, J = 6.0, 4.9 _{Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ requires for C24H25FN3O6 : 470.17} ^{; found} _: 470.1.

Example 54

Preparation of compound 54

(2R,5S)-N-((S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

A 50-mL round-bottom flask was charged with 54-A (0.02 g, 0.06 mmol), (S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamine (0.019 g, 0.09 mmol), N,N-diisopropylethylamine (DIPEA) (0.048 g, 0.38 mmol), and HATU (0.036 g, 0.09 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl , and dried over _Na₂SO₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc _to afford 54-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₈ H ₁₉ F ₂ N ₂ O ₇ : 514; Found: 514.

Step 2

A 50-mL round-bottom flask was charged with reactant 54-B (0.03 g, 0.058 mmol) and magnesium bromide (0.03 g, 0.15 mmol) in acetonitrile (2 mL). The reaction mixture was heated to 50°C. After 10 minutes, the reaction mixture was cooled to 0°C and 1N hydrochloric acid (0.5 mL) was added. The reaction mixture was then diluted with MeOH (2 mL). After filtration, the crude material was purified by preparative HPLC (30-70% acetonitrile:water, 0.1% TFA) to afford compound 54 as a TFA salt. ¹ H-NMR (400MHz, chloroform-d) δ11.28(d,J＝9.4Hz,1H),8.39(s,1H),7.54(q,J＝7.8Hz,1H),7.12-6.76(m,2H),6.40-5.98(m,1H),5.57-5.18(m,2H),4. 68(s,1H),4.29(dd,J＝13.1,4.0Hz,1H),4.05(dd,J＝12.9,9.3Hz,1H),2.39-1.94(m,4H),1.86(t,J＝10.5Hz,1H),1.60(dt,J＝12.6,3.4Hz,1H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -75.30 (t, J = 6.8 Hz, 3F), -108.33 (dd, J = 8.6, 6.3 Hz, 1F), -111.56 to -113.23 (m, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ requires: 500; found: 500.

Example 55

Preparation of compound 55

(1R,4S,12aS)-7-Hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A mixture of compound 55-A (40.60 g, 150 mmol) and Pd(OH)/C (12 g) in _EtOH (400 mL) was stirred overnight at room temperature under an atmosphere _of H. The reaction mixture was filtered and treated with HCl/EtOH (400 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford compound 55-B, which was used in the next step without purification. LCMS- ^ESI (m/z): [M+H] ^Required for _C9H16NO : 170.1 _; Found: 170.2.

Step 2

To a solution of compound 55-B (92.25 g, 0.45 mol) and K ₂ CO ₃ (186.30 g, 1.35 mol) in CH ₃ CN (1 L) was added benzyl bromide (76.50 g, 0.45 mol) at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, concentrated, and the residue was purified by silica gel chromatography to give compound 55-C.

Step 3

Under _N₂ atmosphere, at -78°C, to a mixture of diisopropylamine (50 g, 0.50 mol) in THF (400 mL) was added n-BuLi (200 mL, 0.50 mol). After 0.5 hours, the reaction mixture was warmed to 20°C and stirred for 0.5 hours. The mixture was cooled to -78°C and under _N₂ atmosphere, a solution of compound 55-C (64.75 g, 0.25 mol) in THF (600 mL) was added. The mixture was stirred for 4 hours and quenched with a saturated _NH₄Cl solution. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried _{over Na₂SO₄} , filtered and concentrated. The residue was purified by silica gel chromatography to obtain compound 55-D.

Step 4

A mixture of compound 55-D (129.50 g, 0.50 mol) in 4N HCl (1.30 L) was refluxed for 4 hours. The mixture was concentrated and the residue was purified by HPLC to give compound 55-E.

Step 5

A mixture of compound 55-E (47 g, 176 mmol) and Pd(OH) ₂ /C (9 g) in EtOH (400 mL) was stirred at room temperature under H ₂ atmosphere overnight. The reaction mixture was concentrated to give compound 55-F, which was used in the next step without purification. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.22 (s, 1H), 4.06 (s, 1H), 2.98-2.95 (d, J=11.2 Hz, 1H), 1.96-1.93 (d, J=11.2 Hz, 1H), 1.86-1.82 (m, 2H), 1.76-1.74 (d, J=9.2 Hz, 2H), 1.49 (s, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₇ H ₁₂ NO ₂ : 142.1.; Found: 142.1.

Step 6

To a mixture of compound 55-F (29.20 g, 165 mmol) and 2N NaOH solution (330 mL, 0.66 mol) in dioxane (120 mL) was added Boc ₂ O (39.60 g, 181 mmol) at 0°C. The reaction mixture was stirred overnight at room temperature. The mixture was adjusted to pH 5-6 with 3N HCl and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to afford 55-G. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.40 (s, 1H), 4.26 (s, 1H), 2.89 (s, 1H), 1.76-1.74 (s, 1H), 1.69-1.59 (m, 4H), 1.50 (s, 1H), 1.47 (s, 9H). LCMS-ESI ⁺ (m/z): [M+Na] ⁺ Required for C ₁₂ H ₁₉ NNaO ₄ : 264.1; Found: 264.1.

Step 7

To a mixture of compound 55-G (500 mg, 2.07 mmol) in THF (10 mL) chilled to 0°C was slowly added _BH3 -DMS THF complex (2N in THF, 8.23 mmol, 4.1 mL). Gas evolution occurred. The internal temperature was monitored to ensure there was no significant exotherm. The reaction was allowed to warm to room temperature overnight. By LC/MS, some starting material remained, and an additional 2 mL of _BH3 -DMS THF complex was added, and the mixture was stirred for an additional 3 hours, then cooled to 0°C and slowly quenched with methanol (gas evolution occurred). The internal temperature was monitored to ensure the exotherm was less than 25°C. The mixture was concentrated and then purified by silica gel chromatography (20-40% EtOAc/hexanes) to afford 55-H.

Step 8

Compound 55 was prepared as described in Example 41, substituting 55-H for 41-B to give compound 55. ¹ H-NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.40 (t, J = 5.8 Hz, 1H), 8.39 (s, 1H), 7.19 (t, J = 8.6 Hz, 2H), 4.59-4.48 (m, 4H), 4.16 (t, J = 12.2 Hz, 1H), 4.03 (d, J = 12.2 Hz, 1H), 2.69 (s, 1H), 1.75 (d, J = 10.1 Hz, 1H), 1.69-1.55 (m, 5H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -109.3 (m, 1F), -112.5 (m, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₁₉ F ₃ N ₃ O ₄ : 434.13; Found: 434.32.

Example 56

Preparation of compound 56

(1R,2S,4R,12aR)-2-Fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A solution of 56-A (5 g, 19.43 mmol) in tetrahydrofuran (65 mL) was cooled in an ice bath while 0.5 M 9-borabicyclo[3.3.1]nonane (48.58 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature. After 18 hours, the reaction was cooled to 0°C and a mixture of 2 M sodium hydroxide (34 mL) and hydrogen peroxide (9.34 mL, 97.15 mmol) was added dropwise. After 2 hours at 0°C, the reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with EtOAc and washed with water. The aqueous fraction was extracted with EtOAc, and the combined organic fractions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica column chromatography (50-70% EtOAc/hexane) to give 56-B (3.05 g, 57%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₆ H ₂₁ NO ₃ : 275.34; Found: 276.122.

Step 2

To a solution of 56-B (1.45 g, 5.27 mmol) in N,N-dimethylformamide (12 mL) was added tert-butylchlorodiphenylsilane (1.51 mL, 5.79 mmol) and imidazole (1.08 g, 15.8 mmol). After 18 hours, the mixture was diluted with water and extracted into EtOAc (2x). The organic fractions were combined, dried ( _Na2SO4 ), and concentrated. The residue was purified by silica column chromatography (10-20% EtOAc/hexanes) _to afford 56-C ( _2.6 g, 96.1%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required _{for C32H39NO3Si :} 513.74; Found: 514.625.

Step 3

To a solution of 56-C (3.27 g, 6.36 mmol) in EtOH (26 mL) and acetic acid (3 mL) was added 10% PdOH/C (0.52 g, 3.7 mmol), and the suspension was shaken in a Parr apparatus at 50 atm for 20 hours. After filtering through diatomaceous earth, the filter cake was washed with EtOH and the filtrate was concentrated under vacuum. The residue was dissolved in ethanol (26 mL) and acetic acid (3 mL, 52.4 mmol), treated with 10% PdOH/C (0.52 g, 3.7 mmol), and shaken in a Parr apparatus at 50 atm for 20 hours. Filtered through diatomaceous earth, the filter cake was washed with EtOH, and the filtrate was concentrated to dryness under vacuum to give a crude deprotected product (2.07 g, 79.4%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₄ H ₃₁ NO ₃ Si: 409.59; Found: 410.485.

To the crude residue (2 g, 4.88 mmol) and di-tert-butyl dicarbonate 97% (2.14 g, 9.79 mmol) in THF (20 mL) was added N,N-diisopropylethylamine (DIPEA) (2.14 mL, 12.27 mmol). After 20 hours, the reaction mixture was diluted with water and extracted into EtOAc (2x), and the two organic fractions were washed with water, combined, _dried ( _Na2SO4 ), and concentrated. The residue was purified by silica column chromatography (10-20% EtOAc/hexanes) to _{afford 56} -D (2.13 g, 86.14%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for _C30H41NO5Si : 523.74; Found: 523.922.

Step 4

A solution of 56-D (2.07 g, 4.06 mmol) in THF (20 mL) was stirred in an ice bath while 2.0 M _LiBH₄ in THF (4.07 mL) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate and slowly treated with water. The two phases were separated, and the aqueous fraction was extracted again with ethyl acetate. The two organic fractions were washed with water, combined, dried _{( Na₂SO₄} ), and concentrated. The residue was purified by silica _{column chromatography (20-40% EOAc/hexane) to afford 56-E (1.59 g, 81.3%). LCMS-ESI⁺ (m/z): [M+H]⁺ Required for C₂₈H₃NO₄Si :} ^{481.7 ;} _Found : 482.337.

Step 5

A mixture of 56-E (1.58 g, 3.28 mmol), phthalimide (0.79 g, 5.38 mmol) and triphenylphosphine (1.93 g, 7.37 mmol) in THF (90 mL) was cooled in an ice bath. 95% diisopropyl azodicarboxylate (1.46 mL, 7.42 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 20 hours. Afterwards, the reaction mixture was concentrated, and the residue was dissolved in ether, cooled in an ice bath and stirred for 1.5 hours. The solid was filtered out, and the filtrate was concentrated. The residue was purified by silica column chromatography (10-30% EtOAc/hexane) to give the protected amino compound (1.86 g, 92.8%).

A solution of protected amino compound 56-F (1.85 g, 3.03 mmol) and hydrazine hydrate (0.6 mL, 12.39 mmol) in ethanol (19 mL) was stirred at 70°C for 2 hours. The reaction mixture was cooled in an ice bath, ether (10 mL) was added, and the mixture was stirred for 30 minutes. The solid formed was filtered, and the filtrate was concentrated to dryness under vacuum.

Step 6

A mixture of crude amino compound 56-F (991 mg, 2.06 mmol), compound 38-F (Example 38) (714 mg, 2.06 mmol) and NaHCO₃ ₍ 347 mg, 4.12 mmol) in water (15 mL) and EtOH (15 mL) was stirred for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, and _the combined organic layers were dried ( _Na₂SO₄ ) and concentrated. The residue (1.5 g) was dissolved in _CH₂Cl₂ (5 mL), and 4N HCl in _dioxane (18.6 mL) was added. After 1.5 hours, the mixture was concentrated to dryness, co-evaporated with toluene, and dried in vacuo.

The crude residue (1.38 g) and DBU (1.4 mL, 9.38 mmol) were stirred in toluene (25 mL) at 110° C. After 35 minutes, the mixture was concentrated and the residue was purified by silica column chromatography (5-15% MeOH/EtOAc) to afford 56-G (450 mg, 72.3%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₃₉ H ₄₂ N ₂ O ₆ Si: 662.85; Found: 663.766.

Step 7

A mixture of 56-G (890 mg, 1.34 mmol) in MeOH (14 mL) and THF (14 mL) was stirred at room temperature while 1 M KOH (7.09 mL) was added. After 30 min, the reaction mixture was neutralized with 1 N HCl, extracted into EtOAc (2x), and _the combined organic extracts were dried ( _Na2SO4 ) and concentrated.

A suspension of the crude residue (850 mg), 2,4,6-trifluorobenzylamine (248 mg, 1.54 mmol) and HATU (662 mg, 1.74 mmol) in dichloromethane (5 mL) was stirred at room temperature while N,N-diisopropylethylamine (DIPEA) (1.63 mL, 9.37 mmol) was added. After 1 hour, additional 2,4,6-difluorobenzylamine (32 mg, 0.2 mmol), HATU (153 mg, 0.4 mmol) and N,N-diisopropylethylamine (DIPEA) (0.12 mL, 0.67 mmol) were added. After 30 minutes, the mixture was diluted with water and extracted into EtOAc (3x), _the combined organic phases were dried ( _Na2SO4 ), concentrated, and the residue was purified by silica column chromatography (50-75% EtOAc/hexanes _{) to afford} 56-H (919 mg, 88.23%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for _{C44H42F3N3O5Si} : _777.9 ; Found: 778.409.

Step 8

A solution of 56-H (915 mg, 1.18 mmol) in THF (5 mL) was stirred in an ice bath. Simultaneously, 1.0 M tetrabutylammonium fluoride in THF (1.18 mL) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc, washed with water, dried _{( Na₂SO₄} ), concentrated, and purified by silica column chromatography (50-75% EtOAc/hexanes, then 5% MeOH/EtOAc). The resulting material (248 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL) cooled to -78°C, and diethylaminosulfurtrifluoride (0.07 mL, 0.55 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was cooled in an ice bath and quenched with saturated _NaHCO₃ . The two phases were separated and the separated aqueous fraction _was extracted with _CH₂Cl₂ . The two organic fractions were combined, dried _{( Na₂SO₄} ) and _{concentrated. The residue was purified by silica column chromatography (1% MeOH/EtOAc) to give 56-J (75 mg) (LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₃F₄N₃O₄ :} ^{541.49 ;} _{found :} 542.320) and 56-I (30 mg) (LCMS- ^ESI⁺ (m/ _z ): [M+ _H ] ^⁺ calcd _{for C₂₈H₂₂F₃N₃O₄} : 521.49 _; found _: 522.05).

Step 9

Compound 56-J (75 mg, 139 mmol) was dissolved in TFA (1 mL), stirred at room temperature for 10 minutes, and the solution was concentrated. The residue was purified by reverse phase HPLC (Gemini, 15 to 43% ACN/H ₂ O+0.1% TFA) to give Compound 56. ¹ H-NMR (400MHz, DMSO-d6) δ10.67(s,1H),7.80(s,1H),7.17(t,J＝8.6Hz,2H),5.45-5.18(m,1H),4.70-4.39(m,3H),4.2 3(d,J＝11.5Hz,1H),4.11-3.85(m,2H),2.85(dd,J＝4.2,2.0Hz,1H),2.34-2.13(m,1H),1.81(s,1H),1.55-1.33(m,2H). ¹⁹ F-NMR (376MHz, DMSO-d ₆ )δ-74.20(m),-106.95--116.45(m),-190.65--194.54(m).

Example 57

Preparation of compound 57

(1R,4R,12aR)-2,2-difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A solution of 57-A (1.45 g, 5.34 mmol) in dichloromethane (30 mL) was cooled in an ice bath while Dess-Martin periodinane ₍ 4.53 g, 10.69 mmol) was added portionwise. The reaction was stirred at room temperature for 18 hours. The reaction was quenched by adding water, _the precipitate was filtered, and saturated _{Na₂S₂O₃} solution was added. The mixture was stirred until the biphasic solution turned to saturated NaHCO₃, then saturated _NaHCO₃ was added and the aqueous layer was extracted with _CH₂Cl₂ . _The combined organic fractions were dried ( _Na₂SO₄ ) and concentrated. The residue was purified by silica column chromatography (30-50% EtOAc/hexanes) _to afford 57-B (1.13 g, 78.2%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₃ H ₁₉ NO ₅ : 269.29; Found: 269.722.

Step 2

A solution of 57-B (0.5 g, 1.86 mmol) in dichloromethane (10 mL) was cooled to -78°C and diethylaminosulfur trifluoride (0.52 mL, 3.91 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was cooled in an ice bath and quenched with saturated _NaHCO₃ . The two phases were separated, and the separated aqueous fraction was extracted _{with CH₂Cl₂} . The two organic fractions were combined, dried ( _Na₂SO₄ ), and concentrated. The residue was purified by silica column chromatography (20-50% EtOAc/hexanes) _to afford 57-C (518 mg, 95.39%). ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 4.43 (s, 1H), 4.36-4.27 (m, 1H), 4.22 (s, 1H), 3.75 (s, 3H), 2.95 (t, J=8.1 Hz, 1H), 2.30-1.98 (m, 2H), 1.85-1.71 (m, 1H), 1.44 (m, 9H).

Step 3

A solution of 57-C (935 mg, 3.21 mmol) in THF (10 mL) was stirred in an ice bath while 2.0 M _LiBH₄ in THF (3.22 mL) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate and water was slowly added. The two phases were separated, and the separated aqueous fraction was extracted with ethyl acetate. The two organic fractions were washed with water, combined, dried ( _Na₂SO₄ ), and concentrated. The residue was purified by silica column chromatography (20-40% EtOAc/hexanes) _to afford 57-D (724 mg, 85.67%). ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 4.30-3.48 (m, 5H), 2.75-2.56 (m, 1H), 2.24-1.90 (m, 3H), 1.86-1.65 (m, 1H), 1.47 (s, 9H).

Step 4

A mixture of 57-D (720 mg, 2.74 mmol), phthalimide (402 mg, 2.73 mmol), and triphenylphosphine (1.61 g, 6.15 mmol) in THF (45 mL) was cooled in an ice bath. 95% diisopropyl azodicarboxylate (1.22 mL, 6.19 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then concentrated, and the residue was dissolved in diethyl ether, cooled in an ice bath, and stirred for 1.5 hours. After filtering out the solid, the filtrate was concentrated. The residue was purified by silica column chromatography (40-60% EtOAc/hexane) to give the phthalimide adduct (1.07 g, 99.7%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₀ H ₂₂ F ₂ N ₂ O ₄ : 392.4; Found: 393.204.

A solution of phthalimide adduct (1.07 g, 2.73 mmol) and hydrazine hydrate (0.54 mL, 11.15 mmol) in ethanol (10 mL) was stirred at 70 ° C for 2 hours. The reaction mixture was cooled in an ice bath and diethyl ether (10 mL) was added. The mixture was stirred for 30 minutes. The solid formed was filtered and the filtrate was concentrated in vacuo to give crude 57-E.

Step 5

A mixture of crude 57-E (709 mg, 2.7 mmol), compound 38-F (Example 38) (936 mg, 2.7 mmol), and NaHCO₃ ₍ 454 mg, 5.41 mmol) in water (15 mL) and EtOH (15 mL) was stirred for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, and _the combined organic layers were dried ( _Na₂SO₄ ) and concentrated. The residue (1.5 g) was dissolved in _CH₂Cl₂ (7 mL), and 4N HCl in _dioxane (26.9 mL) was added. After 1.5 hours, the mixture was concentrated to dryness, co-evaporated with toluene, and dried under vacuum. The crude residue (1.3 g) and DBU (2 mL, 13.4 mmol) were stirred in toluene (25 mL) at 110°C. After ₃₅ minutes, the mixture was concentrated and the residue was purified by silica column chromatography (5-15% MeOH/EtOAc ₎ to give 57-F (426 mg, 36.17%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required _{for C23H22F2N2O5 : 444.43} ; Found: 445.280.

Step 6

A mixture of compound 57-F (426 mg, 0.96 mmol) in MeOH (7 mL) and THF (7 mL ₎ was stirred at room temperature while 1 M KOH (5.06 mL) was added. After 30 minutes, the reaction mixture was neutralized with 1 N HCl and extracted into EtOAc (2x). The combined organic extracts were dried ( _Na2SO4 ) and concentrated to crude 57-G.

Step 7

A suspension of the crude residue 57-G (189 mg), 2,4,6-trifluorobenzylamine (95 mg, 0.59 mmol), and HATU (276 mg, 0.73 mmol) in dichloromethane (3 mL) was stirred at room temperature while N,N-diisopropylethylamine (DIPEA) (0.59 mL, 3.4 mmol) was added. After 1 hour, the mixture was diluted with water and extracted into EtOAc ( _3x ). The combined organic phases were dried ( _Na2SO4 ) and concentrated to ₅₇ - _{H .} LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for _C28H22F5N3O4 : _559.48 ; Found: 560.24.

Step 8

Compound 57-H (150 mg, 0.27 mmol) was dissolved in TFA (2 mL), stirred at room temperature for 10 minutes, and the solution was concentrated. The residue was purified by reverse-phase HPLC (Gemini, 15 to 60% ACN/ _H₂O + 0.2% TFA ₎ to afford compound ₅₇ (85 _mg , 67.5%). LCMS- ^ESI⁺ (m/z): [M+H] ^⁺ Required for _{C₂₁H₁₆F₅N₃O₄} : _469.36 ; Found: 470.229. ¹ H-NMR (400MHz, DMSO-d ₆ )δ10.41(t,J＝5.6Hz,1H),8.20(s,1H),7.12(t,J＝8.7Hz,2H),4.79(s,1H),4.48(m,3H),4.10(m, 2H),3.02(d,J＝5.7Hz,1H),2.33(m,1H),2.22-1.97(m,2H),1.85(d,J＝11.0Hz,1H),1.21(s,1H). ¹⁹ F NMR (376MHz, DMSO-d ₆ )δ-69.88,-71.77,-74.09,-88.33(dd,J＝222.6,23.8Hz),-109.15--109.60(m),-110.04,-112.44(t,J＝7.6Hz).

Example 58

Preparation of compound 58

(1R,4R,12aR)-N-(3-chloro-2,4-difluorobenzyl)-2,2-difluoro-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A suspension of the crude residue 57-G (120 mg), 3-chloro, 2,4-difluorobenzylamine (67 mg, 0.38 mmol), and HATU (175 mg, 0.46 mmol) in dichloromethane (3 mL) was stirred at room temperature while N,N-diisopropylethylamine (DIPEA) (0.38 mL, 0.28 mmol) was added. After 1 hour, the mixture was diluted with water and extracted into EtOAc (3x). The combined organic phases _were dried ( _Na2SO4 ) and concentrated _to afford 58-A. _LCMS -ESI ⁺ (m/z): [M ^+H]+ _Required for _{C28H22ClF4N3O4} : _575.94 ; Found: 576.394.

Step 2

Compound 58-A (166 mg) was dissolved in TFA (2 mL), stirred at room temperature for 10 minutes, and the solution was concentrated. The residue was purified by reverse phase HPLC (Gemini, 15 to 70% ACN/H ₂ O+0.1% TFA) to give Compound 57 (60 mg, 42.8%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required _{for C21H16ClF4N3O4 :} 485.82; Found: 486.135. ^1H -NMR (400 MHz, DMSO-d6) δ 10.77 ₍ t, J ₌ 6.0 Hz, 1H), 7.77 (s, 1H), 7.28 (m, 2H), 4.77 (s, 1H), 4.64-4.40 (m, 2H), 4.27 (d, J = 9.1 Hz, 1H), 3.93 (m, 2H), 2.95 (d, J = 5.8 Hz, 1H), 2.51 (s, 1H), 2.42-2.17 (m, 1H), 2.14-1.89 (m, 2H), 1.77 (m, 1H). ¹⁹ F-NMR (376MHz, DMSO-d ₆ ) δ -87.63, -88.23, -108.67, -109.27, -116.42 (t, J = 7.0Hz), -118.48 (d, J = 7.8Hz).

Example 59

Preparation of compound 59

(1R,2R,4R,12aR)-2-Fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A solution of 57-B (1.9 g, 7.06 mmol) in methanol (35 mL) was stirred at 0°C while sodium borohydride (667 mg, 17.64 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath, quenched by the addition of water, and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, and the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica column chromatography (30-60% EtOAc/hexane) to give 59-A (1.49 g). ¹ H-NMR (400 MHz, chloroform-d) δ 4.57 (s, 1H), 4.52-4.42 (m, 2H), 4.28 (s, 1H), 4.14 (s, 1H), 3.72 (d, J = 2.1 Hz, 3H), 2.74 (s, 1H), 2.08-1.87 (m, 2H), 1.43 (d, J = 23.1 Hz, 10H) and 57-A (96 mg): ¹ H-NMR (400 MHz, chloroform-d) δ 4.65-4.40 (m, 2H), 4.34-4.02 (m, 1H), 3.73 (d, J = 2.3 Hz, 3H), 2.74 (t, J = 5.3 Hz, 1H), 2.12-1.55 (m, 3H), 1.52-1.18 (m, 11H).

Step 2

To a solution of 59-A (686 mg, 2.53 mmol) in N,N-dimethylformamide (5 mL) was added tert-butylchlorodiphenylsilane (0.723 mL, 2.78 mmol) and imidazole (516 mg, 7.56 mmol). After 18 hours, the mixture was diluted with water and extracted into EtOAc (2x). _The organic fractions were combined, dried ( _Na2SO4 ), and concentrated. The residue was purified by silica column chromatography (10-20% EtOAc/hexanes) to give 59-C. _LCMS - _ESI ⁺ (m/z): [M+H] ⁺ Required for _C29H39NO5Si : 509.71; Found: 510.793.

Step 3

A solution of 59-C (1.23 g, 2.41 mmol) in THF (13 mL) was stirred in an ice bath while 2.0 M _LiBH₄ in THF (2.42 mL, 4.84 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. After diluting the reaction mixture with ethyl acetate, water was slowly added, the two phases separated, and the separated aqueous fraction was extracted with ethyl acetate. The two organic fractions were washed with water, combined, dried _{( Na₂SO₄} ), and _concentrated . The residue was purified by silica column chromatography (20-40% EtOAC/hexanes) to afford 59-D. LCMS- ^ESI⁺ (m/z): [M+H] ^⁺ Required _{for C₂₈H₃NO₄Si :} 481.7; Found: 482.741.

Step 4

A mixture of 59-D (963 mg, 2.0 mmol), phthalimide (482 mg, 3.28 mmol), and triphenylphosphine (1.18 g, 4.49 mmol) in THF (50 mL) was cooled in an ice bath. Diisopropyl azodicarboxylate, 95% (0.89 mL, 4.52 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then concentrated, and the residue was dissolved in diethyl ether, cooled in an ice bath, and stirred _{for 1.5 hours. The solid was then filtered, and the filtrate was concentrated. The residue was purified by silica column chromatography (10-30% EtOAc/hexanes) to yield the phthalimide adduct. LCMS-ESI+ (m/z): [M+H]+ Required for C36H42N2O5Si : 610.81} ^{; Found} _: 611.935.

A solution of the phthalimide adduct (1.2 g, 1.97 mmol) and hydrazine hydrate (0.4 mL, 8.03 mmol) in ethanol (12 mL) was stirred at 70°C for 2 hours. The reaction mixture was cooled in an ice bath, and diethyl ether (10 mL) _was added and stirred for 30 minutes. The resulting solid was filtered, and the filtrate was concentrated to dryness under vacuum to afford ₅₉ -E _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for _C28H40N2O3Si : 480.71; Found: 481.356.

Step 5

A mixture of crude 59-E (770 mg, 1.60 mmol), compound 38-F (Example 38) (555 mg, 1.60 mmol) and NaHCO ₃ (269 mg, 3.20 mmol) in water (12 mL) and EtOH (12 mL) was stirred for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, and the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated.

The residue (1.29 g) was dissolved in CH ₂ Cl ₂ (4 mL) and 4N HCl in dioxane (15.6 mL) was added. After 1.5 h, the mixture was concentrated to dryness, co-evaporated with toluene, and dried in vacuo. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₄₁ H ₄₈ N ₂ O ₇ Si: 708.91; Found: 709.782.

The crude residue (1.09 mg) and DBU (1.17 mL, 7.8 mmol) were stirred in toluene (20 mL) at 110° C. After 35 minutes, the mixture was concentrated and the residue was purified by silica column chromatography (5-15% MeOH/EtOAc) to afford 59-F. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₃₉ H ₄₂ N ₂ O ₆ Si: 662.85; Found: 663.677.

Step 6

A mixture of 59-F (680 mg, 1.03 mmol) in MeOH (10 mL) and THF (10 mL) was stirred at room temperature, and 1 M KOH (5.42 mL) was added. After 30 minutes, the reaction mixture was _neutralized with 1 N HCl and extracted into ^{EtOAc (2x). The combined organic extracts were dried (Na2SO4) and concentrated. LCMS-ESI+ (m/z): [M+H]+} _{for C37H38N2O6Si} ^: _{634.79 ; found} : 635.466.

A suspension of the crude residue (650 mg), 2,4,6-trifluorobenzylamine (214 mg, 1.33 mmol) and HATU (623 mg, 1.64 mmol) in dichloromethane (6 mL) was stirred at room temperature while N,N-diisopropylethylamine (DIPEA) (1.34 mL, 7.68 mmol) was added. After 2 h, the mixture was diluted with water and extracted into EtOAc ( _3x ), the combined organic phases were dried ( _Na2SO4 ), concentrated, and the residue was purified by silica column chromatography ( _50-75 % EtOAc/hexanes) to give 59-G. LCMS-ESI ⁺ ( _m / _z ): [M+H] ⁺ Required for _{C44H42F3N3O5Si} : _777.9 ; Found: 778.566.

Step 7

A solution of 59-G (648 mg, 0.83 mmol) in THF (10 mL) was stirred in an ice bath while 1.0 M tetrabutylammonium fluoride in THF (0.83 mL) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. Additional 1.0 M tetrabutylammonium fluoride in THF (0.1 mL) was added dropwise. After 30 minutes, the reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc, washed with water, dried ( _Na₂SO₄ ), concentrated, and purified by silica column chromatography (5% MeOH/EtOAc). _A solution of the residue (290 mg, 0.54 mmol) in dichloromethane (3 mL) was cooled to -78°C while diethylaminosulfur trifluoride (0.09 mL, 0.65 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 2.5 hours. The reaction was cooled in an ice bath, quenched with saturated _NaHCO₃ , the two phases separated, and _the separated aqueous fraction extracted with _CH₂Cl₂ . The two organic fractions were combined, dried ( _Na₂SO₄ ), and concentrated _. The residue was purified by _{silica column chromatography (1% MeOH/EtOAc) to afford 59-H. LCMS-ESI⁺ (m/z): [M+H]⁺ Required for C₂₈H₂₃F₄N₃O₄ :} ^{541.49 ;} _{Found :} 542.320.

Step 8

Compound 59-H (103 mg, 0.19 mmol) was dissolved in TFA (1.4 mL) at room temperature for 15 minutes, and the solution was concentrated. The residue was suspended in DMF, filtered, and the precipitated product was washed with water and dried under vacuum to obtain compound 59. LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₁ H ₁₇ F ₄ N ₃ O ₄ : 451.37, found: 452.226 ^. H-NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.35(t,J＝5.8Hz,1H),8.34(s,1H),7.18(t,J＝8.6Hz,2H),5.15-4.88(m,1H),4.73(d,J＝3. 3Hz,1H),4.49(m,3H),4.04(t,J＝12.4Hz,1H),3.65(dd,J＝12.4,3.7Hz,1H),2.95-2.76(m,1H),2.26-2.03(m,1H),1.96-1.64(m,3H). ¹⁹ F-NMR (376MHz, DMSO-d ₆ ) δ -73.93, -74.74 (d, J = 28.8Hz), -109.31 (m), -112.51 (m), -165.65 (m).

Example 60

Preparation of Compound 60

(1R,4S,12aR)-N-(2,3-Dichlorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

To a solution of dimethyl 3-methoxy-4-oxo-4H-pyran-2,5-dicarboxylate (5.5 g, 23 mmol) in MeOH (100 mL) was added 41-E (Example 41) (5 g, 22 mmol) and sodium bicarbonate (3.6 g, 43 mmol). The solution was stirred at room temperature for 1.5 hours. 4M HCl (in dioxane, 55 _mL , 221 mmol) was added and the solution was heated to 50°C for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The resulting oil was dissolved in sodium bicarbonate and washed with EtOAc. The aqueous layer was then extracted with _CH2Cl2 ( _4x ). The combined _CH2Cl2 extracts were dried over _Na2SO4 and concentrated _to afford 60-A. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₆ H ₁₉ N ₂ O ₅ : 319.13; Found: 319.20.

Step 2

To a suspension of 60-A (3.7 g, 11.6 mmol) in MeOH (12 mL) and THF (23 mL) was added aqueous KOH (2 M, 15.7 mL, 31.4 mmol). The resulting solution was stirred at room temperature for 10 minutes. Volatiles were removed in vacuo, and the resulting aqueous layer was acidified with 1N HCl. The resulting white solid was filtered, washed with water, and dried in vacuo to yield 60-B. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 8.36 (s, 1H), 5.01 (d, J = 2.7 Hz, 1H), 4.12 (s, 4H), 3.90 (t, J = 12.2 Hz, 1H), 3.78 (dd, J = 12.1, 3.1 Hz, 1H), 2.69 (s, 1H), 1.95-1.71 (m, 4H), 1.70-1.54 (m, 2H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₅ H ₁₇ N ₂ O ₅ : 305.11; Found: 305.15.

Step 3

To a solution of 60-B (0.10 g, 0.33 mmol) in _CH₂Cl₂ (3.5 _mL ) was added (2,3-dichlorophenyl)methanamine (0.12 g, 0.70 mmol), HATU (0.25 g, 0.66 mmol), and N,N-diisopropylethylamine (DIPEA) (0.29 mL, 1.64 mmol). The resulting solution was stirred at room temperature until the reaction was judged complete by LC/ _MS . The reaction mixture was diluted with _CH₂Cl₂ and washed with 1N HCl. The aqueous layer was _back -extracted with _CH₂Cl₂ , and _the combined organic layers were dried over _Na₂SO₄ and concentrated in vacuo. The crude material was dissolved in hot DMF and allowed to precipitate upon cooling. Filtration afforded 60-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C _{2 2} H _{2 2} Cl ₂ N ₃ O ₄ : 462.10; Found: 462.14.

Step 4

To a slurry of 60 _- C (0.11 g, 0.24 mmol) in acetonitrile (4.5 mL) was added magnesium bromide (0.089 g, 0.48 mmol). The reaction mixture was heated to 45°C for 2.5 hours and then cooled to room temperature _. The slurry was diluted with _CH2Cl2 and washed with 1N HCl and brine. The aqueous layer was back extracted with _CH2Cl2 (2x), and the combined organic layers were dried _{over Na2SO4} and dried in vacuo. The crude solid was triturated with methanol and filtered to afford 60. ^1H -NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 10.50 (t, 1H), 8.34 (s, 1H), 7.55 (dd, 1H), 7.40-7.24 (m, 2H), 4.67 (s, 1H), 4.61 (d, 2H), 4.45 (dd, 1H), 3.95 (t, 1H), 3.84-3.73 (m ^{, 1H), 1.86-1.67 (m, 3H), 1.66-1.40 (m, 4H). LCMS-ESI+ (m/z): [M+H]+} _{for C21H20Cl2N3O4} ^: _{448.08 ; found} : 448.18.

Example 61

Preparation of compound 61

(1R,4S,12aS)-N-(3-chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

61 was prepared analogously to Example 60, using (1S,3S,4R)-3-(aminomethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (prepared in Example 55) instead of 41-E, and using (3-chloro-2,4-difluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ¹ H-NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 10.45 (t, 1H), 8.40 (s, 1H), 7.37 (td, 1H), 7.27 (td, 1H), 4.63-4.46 (m, 4H), 4.17 (t, 1H), 4.04 (dt, 1H), 1.76 (d, 1H), _{1.73-1.54 (} m, 5H) _. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ Required for _{C21H19ClF2N3O4} : 450.10; Found: 450.15.

Example 62

Preparation of compound 62

'(2R,5S,13aR)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 62 was prepared in a similar manner to compound 42 using (4-fluoro-2-(trifluoromethyl)phenyl)methanamine instead of (2,4,6-trifluorophenylphenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.50 (s, 1H), 8.38 (s, 1H), 7.57 (dd, 1H), 7.36 (dd, 1H), 7.19 (td, 1H), 5.40-5.28 (m, 2H), 4.79 (t, 2H), 4.69 (s, 1H), 4.25 (dd, 1H), 4.03 (dd, 1H), 2.17-1.98 (m, 4H), 1.96-1.84 (m, _1H ), 1.61 (dt, _1H ) _. LCMS-ESI ⁺ (m/z): [M ^+H]+ _requires for _C22H20F4N3O5 : 482.13; found: 482.145.

Example 63

Preparation of compound 63

(2R,5S,13aR)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 63 was prepared in a similar manner to compound 42 using (2-chloro-4-fluorophenyl)methanamine instead of (2,4,6-trifluorophenylphenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.48 (s, 1H), 8.45 (s, 1H), 7.39 (dd, 1H), 7.12 (dd, 1H), 6.93 (td, 1H), 5.37 (d, 1H), 5.31 (t, 1H), 4.68 (s, 3H), 4.29 (d, 1H), 4.04 (t, 1H), 2.21-2.01 (m, 4H), 1.97-1.82 (m, _1H ), _1.67-1.56 (m, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required _{for C21H20ClFN3O5} : 448.10; Found: 448.143.

Example 64

Preparation of compound 64

(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,5-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 64 was prepared in a similar manner to compound 42 using (2,4,5-trifluorophenyl)methanamine instead of (2,4,6-trifluorophenylphenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.42 (s, 1H), 8.42 (s, 1H), 7.19 (ddd, 1H), 6.91 (td, 1H), 5.38 (dd, 1H), 5.31 (t, 1H), 4.69 (s, 1H), 4.61 (d, 2H), 4.29 (dd, 1H), 4.05 (dd, 1H), 2.18-2.02 (m, 4H), 1.96-1.84 (m, _1H ), _1.66-1.56 (m, 1H) _. LCMS-ESI ⁺ (m/z): [M ^+H]+ _{for C21H19F3N3O5} requires: 450.12; found: 450.119.

Example 65

Preparation of compound 65

(2R,5S,13aR)-N-(5-chloro-2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 65 was prepared in a similar manner to compound 42 using (5-chloro-2,4-difluorophenyl)methanamine instead of (2,4,6-trifluorophenylphenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.47 (t, 1H), 8.41 (s, 1H), 7.40 (dd, 1H), 6.90 (t, 1H), 5.37 (dd, 1H), 5.31 (t, 1H), 4.69 (s, 1H), 4.62 (d, 2H), 4.28 (d, 1H), 4.04 (dd, 1H), 2.17-2.02 (m, 4H), 1.94-1.86 (m, _1H ), _1.61 (dt, _1H ). LCMS-ESI ⁺ (m/z): [M ^+H]+ _Required for _{C21H19ClF2N3O5} : 466.09; Found: 466.107.

Example 66

Preparation of compound 66

(1R,4S,12aR)-N-(3,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 66 was prepared by a method analogous to compound 60 using (3,4-difluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 10.59 (s, 1H), 7.24-7.16 (m, 2H), 7.14-7.04 (m, 2H), 4.91 (s, 1H), 4.58 (d, 3H), 3.94-3.82 (m, 1H), 3.79 (d, 1H), 1.99-1.81 (m, 4H), 1.76 (d, 1H), _1.70-1.60 (m, _3H ) _. LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ Required for _C21H20F2N3O4 : 416.13; Found: 416.415.

Example 67

Preparation of compound 67

(1R,4S,12aR)-N-(4-Fluoro-2-(trifluoromethyl)benzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 67 was prepared in a similar manner to compound 60 using (4-fluoro-2-(trifluoromethyl)phenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 11.72 (s, 1H), 10.55 (s, 1H), 8.29 (s, 1H), 7.61 (s, 1H), 7.36 (dd, 1H), 7.18 (td, 1H), 4.91 (s, 1H), 4.80 (d, 3H), 4.11 ₍ s, 1H), 1.99-1.80 (m, 4H), 1.76 (d, 1H), 1.71-1.47 (m, 3H). LCMS-ESI ⁺ ₍ m/ _z ): [M+H] ⁺ Required _{for C22H20F4N3O4} : 466.13; Found: 466.297.

Example 68

Preparation of compound 68

(1R,4S,12aR)-N-(2-chloro-4-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 68 was prepared in a similar manner to compound 60 using (2-chloro-4-fluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 11.68 (s, 1H), 10.52 (s, 1H), 8.27 (s, 1H), 7.44-7.37 (m, 1H), 7.11 (dd, 1H), 6.93 (td, 1H), 4.90 (s, 1H), 4.68 (d, 2H), 4.16-4.01 (m, 1H), 3.88-3.70 (m, 2H), 2.00-1.79 (m, 4H), 1.75 (d, _1H ), _1.70-1.57 (m, 2H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for _{C21H20ClFN3O4} : 432.10; Found: 432.214.

Example 69

Preparation of compound 69

(1R,4S,12aR)-N-(3-chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 69 was prepared in a similar manner to compound 60 using (3-chloro-2,4-difluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 11.71 (s, 1H), 10.48 (s, 1H), 8.26 (s, 1H), 7.27 (s, 1H), 6.92 (td, 1H), 4.90 (s, 1H), 4.66 (d, 2H), 4.08 (s, 1H), 3.91-3.69 ₍ m, 2H), 2.01-1.79 (m, 3H), 1.75 (d, 1H), 1.71-1.44 (m, _2H ). LCMS-ESI ⁺ (m/ _z ): [M+H] ⁺ Required _{for C21H19ClF2N3O4} : 450.10; Found: 450.27.

Example 70

Preparation of Compound 70

(1R,4S,12aR)-N-(2-Fluoro-3-methylbenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 70 was prepared in a similar manner to compound 60 using (2-fluoro-3-methylphenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 11.62 (s, 1H), 10.39 (s, 1H), 8.30 (s, 1H), 7.19 (t, 1H), 7.07 (t, 1H), 6.96 (t, 1H), 4.89 (d, 1H), 4.67 (d, 2H), 4.08 (s, 1H), 3.88-3.67 (m, 2H), 2.26 (d, 3H), 1.97-1.79 (m, _3H ), _1.78-1.39 (m, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires _{for C22H23FN3O4} : 412.16; found: 412.26.

Example 71

Preparation of compound 71

(1R,4S,12aR)-N-(3,6-dichloro-2-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 71 was prepared by a method analogous to compound 60 using (3,6-dichloro-2-fluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 11.62 (s, 1H), 10.47 (t, 1H), 8.29 (s, 1H), 7.13 (dd, 1H), 4.88 (s, 1H), 4.85-4.73 (m, 2H), 4.09 (d, 1H), 3.88-3.68 (m, _2H ), _1.99-1.53 (m, 8H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required _{for C21H19Cl2FN3O4} : 466.07; Found: 466.257.

Example 72

Preparation of compound 72

(1R,4S,12aR)-N-(3-chlorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 72 was prepared in a similar manner to compound 60 using (3-chlorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ^1H -NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.44 (t, 1H), 8.38 (s, 1H), 7.42-7.22 (m, 4H), 4.68 (s, 1H), 4.54 (d, 2H), 4.48 (dd, 1H), 3.97 (t, 1H), 3.81 (dd, 1H), 2.58 (s, 1H), 1.87-1.69 (m, 3H), 1.68-1.51 (m, 2H), _1.46 (d, 1H) _. LCMS-ESI ⁺ (m/z): [M ⁺ H] ₊ Required for _C21H21ClN3O4 : 414.11; Found: 414.21.

Example 73

Preparation of compound 73

(1R,4S,12aR)-N-(3-chloro-2,6-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 73 was prepared in a similar manner to Compound 60 using (3-chloro-2,6-difluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ^1H -NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.46 (t, 1H), 8.34 (s, 1H), 7.60 (td, 1H), 7.19 (td, 1H), 4.67 (s, 1H), 4.62 (d, 2H), 4.44 (dd, 1H), 3.95 (t, 1H), 3.78 (dd, 1H), 2.57 (s, 1H), 1.86-1.68 (m, 3H), 1.67-1.49 (m, 2H), 1.45 (d, 1H) _. LCMS-ESI ⁺ ( _m / _z ): _[ M+H] ⁺ Required for _{C21H19ClF2N3O4} : 450.10; Found: 450.16.

Example 74

Preparation of Compound 74

(1R,4S,12aR)-N-(2-Fluoro-3-(trifluoromethyl)benzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 74 was prepared in a similar manner to compound 60 using (2-fluoro-3-(trifluoromethyl)phenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ^1H -NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.48 (t, 1H), 8.36 (s, 1H), 7.68 (q, 2H), 7.38 (t, 1H), 4.68 (s, 1H), 4.65 (d, 2H), 4.47 (dd, 1H), 3.96 (t, 1H), 3.80 (dd, 1H), 2.57 (s, 1H), 1.88-1.69 (m, 3H), 1.67-1.50 (m, 2H), 1.45 (d, 1H) _. LCMS-ESI ⁺ ( _m / _{z )} : [M+H] ⁺ Required for _C22H20F4N3O4 : 466.13; Found: 466.142.

Example 75

Preparation of compound 75

(1R,4S,12aR)-N-(3-chloro-4-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 75 was prepared in a similar manner to compound 60 using (3-chloro-4-fluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ^1H -NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.43 (t, 1H), 8.38 (s, 1H), 7.51 (dd, 1H), 7.42-7.28 (m, 2H), 4.68 (s, 1H), 4.51 (d, 2H), 4.47 (dd, 1H), 3.97 (t, 1H), 3.80 (dd, 1H), 2.58 (s, 1H), 1.86-1.68 (m, 3H), 1.68-1.52 (m, 2H), _1.46 (d, 1H) _. LCMS-ESI ⁺ (m/ _z ): [M+H] ⁺ Required for _{C21H20ClFN3O4} : 432.10; Found: 432.159.

Example 76

Preparation of Compound 76

(1R,4S,12aR)-N-((3,5-difluoropyridin-2-yl)methyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 76 was prepared in a similar manner to compound 60 using (3,5-difluoropyridin-2-yl)methanamine instead of (2,3-difluoropyridinylphenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.80 (s, 1H), 8.81 (s, 1H), 8.33 (d, 1H), 7.20 (td, 1H), 4.90 (s, 1H), 4.82 (s, 2H), 4.28 (d, 1H), 3.92-3.75 (m, 2H), 3.48 ₍ s, 2H), 1.98-1.80 (m, 3H), 1.77 (d, 1H), 1.71-1.58 (m, _2H ). LCMS-ESI ⁺ (m/ _z ): [M+H] ⁺ Required _{for C20H19F2N4O4} : 417.13; Found: 417.189.

Example 77

Preparation of compound 77

(1R,4S,12aR)-7-Hydroxy-6,8-dioxo-N-((R)-1-(2,4,6-trifluorophenyl)ethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 50-mL round-bottom flask was charged with 77-A (0.15 g, 0.39 mmol), (R)-1-(2,4,6-trifluorophenyl)ethanamine (0.14 g, 0.78 mmol), N,N-diisopropylethylamine (DIPEA) (0.25 g, 1.97 mmol), and HATU (0.29 g, 0.79 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with saturated _NaHCO (2x), saturated _NH4Cl , and dried _{over Na2SO4} . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 77-B as a white solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ , found: 538.

Step 2

A 50-mL round-bottom flask was charged with 77-B (0.20 g, 0.27 mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by column chromatography on silica gel using EtOAc-20% MeOH in EtOAc as the eluent to give compound 77. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.67 (d, J = 8.2 Hz, 1H), 8.22 (s, 1H), 6.61 (t, J = 8.4 Hz, 2H), 5.60 (dd, J = 8.1, 6.9 Hz, 1H), 4.85 (s, 1H), 3.82 (t, J = 12.2 Hz, 1H), 3.71 (dd, J = 12.4, 3.4 Hz, 1H), 2.75-2.55 (m, 3H), 1.97-1.57 (m, 9H). ^19F -NMR (376 MHz, CHLOROFORM-d) δ -109.65'--111.29 (m), -111.76--113.09 (m). LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 448.

Example 78

Preparation of Compound 78

(2R,13aR)-8-Hydroxy-7,9-dioxo-N-((R)-1-(2,4,6-trifluorophenyl)ethyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

A 50-mL round-bottom flask was charged with 78-A (0.30 g, 0.94 mmol), (R)-1-(2,4,6-trifluorophenyl)ethanamine (0.39 g, 1.87 mmol), N,N-diisopropylethylamine (DIPEA) (0.61 g, 4.87 mmol), and HATU (0.71 g, 1.87 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with saturated _NaHCO (2x), saturated _NH4Cl , and dried _{over Na2SO4} . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 78-B as a white solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ ; Found: 478.

Step 2

A 50-mL round-bottom flask was charged with 78-B (0.4 g, 0.84 mmol) and magnesium bromide (0.4 g, 2.2 mmol) in acetonitrile (5 mL). The reaction mixture was heated to 50°C. After 10 minutes, the reaction mixture was cooled to 0°C and 1N hydrochloric acid (4 mL) was added. More water (~5 mL) was added, the solid was filtered, washed with water and dried to give compound 78. ¹ H-NMR (400MHz, chloroform-d) δ12.30(s,1H),10.59(d,J＝8.3Hz,1H),8.21(s,1H),6.60(t,J＝8.4Hz,2H),5.59(t,J＝7.4Hz,1H),5.37(dd,J＝9.4,4.1Hz, 1H),5.31-5.09(m,1H),4.64(t,J＝3.0Hz,1H),4.20(dd,J＝12.9,4.1Hz, 2H), 3.96 (dd, J=12.8, 9.4Hz, 2H), 2.21-1.85 (m, 4H), 1.71-1.43 (m, 3H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -110.37 (tt, J = 8.7, 6.1 Hz), -112.19 (t, J = 7.2 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 464.

Example 79

Preparation of compound 79

(1R,4S,12aR)-7-Hydroxy-6,8-dioxo-N-(2,4,5-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 50-mL round-bottom flask was charged with 79-A (0.12 g, 0.32 mmol), (2,4,5-trifluorophenyl)methanamine (0.10 g, 0.63 mmol), N,N-diisopropylethylamine (DIPEA) (0.20 g, 1.58 mmol), and HATU (0.24 g, 0.63 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with saturated _NaHCO (2x), saturated _NH4Cl , and dried _{over Na2SO4} . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 79-B as a white solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ ; Found: 524.

Step 2

A 50-mL round-bottom flask was charged with 79-B (0.15 g, 0.29 mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by column chromatography on silica gel using EtOAc-20% MeOH in EtOAc as the eluent to give compound 79. ¹ H-NMR (400MHz, chloroform-d) δ11.70(s,1H),10.65-10.18(m,1H),8.27(s,1H),7.26(m,1H),6.90(td,J＝9.7,6.4Hz,1H),4 .89(s,1H),4.60(d,J＝6.0Hz,2H),4.09(dd,J＝11.4,2.6Hz,1H),3.96-3.66(m,2H),2.68(s,1H),2.15-1.43(m,6H). ¹⁹ F-NMR (376 MHz, CHLOROFORM-d) δ 120.53-120.85 (m), -134.68-136.79 (m), -142.26-144.11 (m). LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 434.

Example 80

Preparation of Compound 80

(1R,4S,12aR)-N-(5-chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 50-mL round-bottom flask was charged with 80-A (0.12 g, 0.32 mmol), (5-chloro-2,4-difluorophenyl)methanamine (0.11 g, 0.63 mmol), N,N-diisopropylethylamine (DIPEA) (0.20 g, 1.58 mmol), and HATU (0.24 g, 0.63 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with saturated _NaHCO (2x), saturated _NH4Cl , and dried _{over Na2SO4} . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 80-B as a white solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ ; Found: 541.

Step 2

A 50-mL round-bottom flask was charged with 80-B (0.14 g, 0.26 mmol) in TFA (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was purified by column chromatography on silica gel using EtOAc-20% MeOH in EtOAc as the eluent to give compound 80. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.46 (s, 1H), 8.27 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 6.89 (t, J = 9.1 Hz, 1H), 4.90 (s, 1H), 4.78-4.48 (m, 2H), 4.08 (dd, J = 11.3, 2.5 Hz, 1H), 3.95-3.63 (m, 2H), 2.68 (s, 1H), 2.22-1.51 (m, 7H). ^19F -NMR (376 MHz, CHLOROFORM-d) δ -113.37 (q, J = 8.1 Hz), -116.37 (q, J = 8.0 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 451.

Example 81

Preparation of compound 81

(1R,3S,4S,12aS)-3-Fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 100-mL round-bottom flask was charged with 81-A (1.0 g, 3.7 mmol) in DCM (10 mL). The reaction mixture was cooled to 0°C. Diethylaminosulfur trifluoride (DAST) (0.58 mL, 4.1 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 1 hour. The mixture was cooled back to 0°C. Saturated _NaHCO₃ (5 mL) was added dropwise to quench the reaction. The reaction mixture was then diluted with EtOAc (100 mL), washed with saturated _NaHCO₃ , brine, and dried _{over Na₂SO₄} . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to give 81-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 274.

Step 2

A 100-mL round-bottom flask was charged with 81-B (0.8 g, 3.0 mmol) in THF (10 mL). The reaction mixture was stirred at -78°C. 2.0 M LiBH ₄ in THF (3.2 mL, 6.4 mmol) was slowly added. The reaction mixture was then allowed to warm and stirred at room temperature for 3 hours. The reaction mixture was then diluted with EtOAc (100 mL) and slowly treated with water (releasing H ₂ ). After phase separation, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over Na ₂ SO _4. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 81-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 246.

Step 3

A 100-mL round-bottom flask was charged with 81-C (0.57 g, 2.3 mmol), triphenylphosphine (1.3 g, 5.1 mmol) and phthalimide (0.55 g, 3.7 mmol) in THF (15 mL). The reaction mixture was then cooled to 0°C while stirring. Diisopropyl azodicarboxylate (DIAD) (1.0 mL, 5.1 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 81-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 375.

Step 4

To a solution of 81-D (0.8 g, 2.1 mmol) in EtOH (40 mL) was added hydrazine monohydrate (0.6 mL). The reaction mixture was heated to 70°C and stirred for 3 hours. After filtering to remove the solid, the filtrate was concentrated to afford 81-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 245.

Step 5

A 100-mL round-bottom flask was charged with 81-E (0.49 g, 2.0 mmol) and 81-F (0.7 g, 2.0 mmol) in ethanol (7 mL). Sodium bicarbonate (0.34 g, 4.0 mmol) in water (7 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc (50 mL) and washed with water (2x). The aqueous fraction was extracted with EtOAc (1x), and the organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The crude material 81-G was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 573.

Step 6

A 100-mL round-bottom flask was charged with 81-G (1.1 g, 1.9 mmol) in 4N HCl/dioxane (11 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 1.0 g of an intermediate was obtained. The intermediate and DBU (1.3 g, 8.8 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110° C. and stirred for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 81-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 413.

Step 7

A 100-mL round-bottom flask was charged with 81-H (0.56 g, 1.4 mmol) in THF (5 mL) and MeOH (5 mL). 1N KOH (4 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by the addition of 1N HCl (4 mL). After concentration, the residue was co-evaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylamine (0.2 g, 1.3 mmol), N,N-diisopropylethylamine (DIPEA) (0.41 g, 3.1 mmol), and HATU (0.48 g, 1.25 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for ₂ hours. The mixture was diluted with EtOAc (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl (2x), and dried over _Na₂SO₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 81-1. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 542.

Step 8

A 50 mL round-bottom flask was charged with reactant 81-1 (0.31 g, 0.58 mmol) in TFA (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to obtain compound 81. ¹ H-NMR (400MHz, chloroform-d) δ10.29(s,1H),8.31(s,1H),6.65(dd,J＝8.7,7.5Hz,2H),5.05-4.75(m,2H),4.65(d,J＝5.6Hz,2H),4.11(d,J＝12.2Hz ,1H),3.83(t,J＝12.3Hz,1H),3.56(dd,J＝12.3,3.3Hz,1H),2.77(s,1H),2.25-1.97(m,2H),1.95(d,J＝11.0Hz,2H),1.77(d,J＝11.2Hz,1H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -108.98 (t, J=8.2 Hz), -112.03 (t, J=7.2 Hz), -168.00. LCMS-ESI ⁺ (m/z): found: 452.

Example 82

Preparation of Compound 82

(1S,3R,4R,12aR)-3-Fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 100-mL round-bottom flask was charged with 82-A (0.6 g, 2.1 mmol) in DCM (6 mL). The reaction mixture was cooled to 0°C. DAST (0.35 mL, 3.0 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 1 hour. The mixture was cooled back to 0°C. Saturated _NaHCO₃ (5 mL) was added dropwise to quench the reaction. The reaction mixture was then diluted with EtOAc (100 mL), washed with saturated _NaHCO₃ , brine, and dried _{over Na₂SO₄} . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to give 82-B. LCMS- ^ESI⁺ (m/z): [M+H] ^⁺ found: 274.

Step 2

A 100-mL round-bottom flask was charged with 82-B (0.4 g, 1.5 mmol) in THF (10 mL). The reaction mixture was stirred at -78°C. 2.0 M LiBH ₄ in THF (1.6 mL, 3.2 mmol) was slowly added. The reaction mixture was then allowed to warm and stirred at room temperature for 3 hours. The reaction mixture was then diluted with EtOAc (100 mL) and water was slowly added (H ₂ was released). After the two phases were separated, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over Na ₂ SO _4. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 82-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 246.

Step 3

A 100-mL round-bottom flask was charged with 82-C (0.25 g, 1.0 mmol), triphenylphosphine (0.59 g, 2.2 mmol) and phthalimide (0.24 g, 1.6 mmol) in THF (10 mL). The reaction mixture was then cooled to 0°C while stirring. DIAD (0.44 mL, 2.2 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 82-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 375.

Step 4

To a solution of 82-D (0.35 g, 0.9 mmol) in EtOH (20 mL) was added hydrazine monohydrate (0.3 mL). The reaction mixture was heated to 70°C and stirred for 3 hours. After filtering to remove the solid, the filtrate was concentrated to afford 82-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 245.

Step 5

A 100-mL round-bottom flask was charged with 82-E (0.21 g, 0.87 mmol) and 82-F (0.3 g, 0.87 mmol) in ethanol (7 mL). Sodium bicarbonate (0.15 g, 1.7 mmol) in water (7 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc (50 mL) and washed with water (2x). The aqueous fraction was extracted with EtOAc, and the organic fractions were combined, dried (Na ₂ SO ₄ ), and concentrated. The crude 82-G was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 573.

Step 6

A 100-mL round-bottom flask was charged with 82-G (0.49 g, 0.86 mmol) in 4N HCl/dioxane (5 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 0.4 g of an intermediate was obtained. The intermediate and DBU (0.6 g, 4.0 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110° C. and stirred for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 82-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 413.

Step 7

A 100-mL round-bottom flask was charged with 82-H (0.2 g, 0.49 mmol) in THF (5 mL) and MeOH (5 mL). The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by the addition of 1N HCl (1.5 mL). After concentration, the residue was co-evaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylamine (0.15 g, 0.95 mmol), N,N-diisopropylethylamine (DIPEA) (0.31 g, 2.4 mmol), and HATU (0.36 g, 0.95 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl (2x), and _dried over _Na₂SO₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 82-1. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 542.

Step 8

A 50 mL round-bottom flask was charged with reactant 82-I (0.22 g, 0.41 mmol) in TFA (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to provide compound 82. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 10.25 (s, 1H), 8.28 (s, 1H), 6.65 (s, 2H), 5.15-4.77 (m, 2H), 4.65 (s, 2H), 4.32-3.41 (m, 2H), 2.78 (s, 1H), 1.86 (dd, J=144.8, 72.3 Hz, 6H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -108.98 (t, J=8.2 Hz), -112.03 (t, J=7.2 Hz), -168.00. LCMS-ESI ⁺ (m/z): found: 452.

Example 83

Preparation of compound 83

(1S,4R,12aS)-3,3-Difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 100-mL round-bottom flask was charged with 83-A (1.0 g, 3.7 mmol) in DCM (20 mL). The reaction mixture was cooled to 0°C. Dess-Martin periodinane (1.8 g, 4.2 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 3 hours. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 83-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 270.

Step 2

A 100-mL round-bottom flask was charged with 83-B (0.85 g, 3.2 mmol) in DCM (15 mL). The reaction mixture was cooled to 0°C. DAST (1.5 mL, 11.3 mmol) was slowly added. The reaction mixture was then stirred at room temperature overnight. The mixture was cooled back to 0°C. Saturated _NaHCO₃ (5 mL) was added dropwise to quench the reaction. The reaction mixture was then diluted with EtOAc (100 mL), washed with saturated _NaHCO₃ , brine, and dried _{over Na₂SO₄} . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to give 83-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 292.

Step 3

A 100-mL round-bottom flask was charged with 83-C (0.44 g, 1.5 mmol) in THF (6 mL). The reaction mixture was stirred at -78°C. 2.0 M LiBH ₄ in THF (1.6 mL, 3.2 mmol) was slowly added. The reaction mixture was then allowed to warm and stirred at room temperature for 3 hours. The reaction mixture was then diluted with EtOAc (100 mL) and water was slowly added (releasing H ₂ ). After the two phases were separated, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over Na ₂ SO _4. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 83-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 264.

Step 4

A 100-mL round-bottom flask was charged with 83-D (0.17 g, 0.65 mmol), triphenylphosphine (0.37 g, 1.4 mmol) and phthalimide (0.15 g, 1.0 mmol) in THF (10 mL). The reaction mixture was then cooled to 0°C while stirring. DIAD (0.28 mL, 1.4 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 83-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 393.

Step 5

To a solution of 83-E (0.25 g, 0.64 mmol) in EtOH (20 mL) was added hydrazine monohydrate (0.3 mL). The reaction mixture was heated to 70°C and stirred for 3 hours. After filtering to remove the solid, the filtrate was concentrated to afford 83-F. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 263.

Step 6

A 100-mL round-bottom flask was charged with 83-F (0.18 g, 0.69 mmol) and 83-G (0.324 g, 0.69 mmol) in ethanol (7 mL). Sodium bicarbonate (0.12 g, 1.4 mmol) in water (7 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc (50 mL) and washed with water. The aqueous fraction was extracted with EtOAc, and the organic fractions were combined, dried (Na ₂ SO ₄ ), and concentrated. The crude 83-H was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 591.

Step 7

A 100-mL round-bottom flask was charged with 83-H (0.4 g, 0.68 mmol) in 4N HCl/dioxane (3.8 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 0.35 g of an intermediate was obtained. The intermediate and DBU (0.51 g, 3.3 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110° C. and stirred for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 83-I. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 431.

Step 8

A 100-mL round-bottom flask was charged with 83-I (0.2 g, 0.47 mmol) in THF (5 mL) and MeOH (5 mL). 1N KOH (1.4 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by the addition of 1N HCl (1.4 mL). After concentration, the residue was co-evaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylamine (0.14 g, 0.91 mmol), N,N-diisopropylethylamine (DIPEA) (0.29 g, 2.2 mmol), and HATU (0.35 g, 0.91 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for ₂ hours. The mixture was diluted with EtOAc (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl (2x), and dried over _Na₂SO₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexanes-EtOAc to give 83-J. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 560.

Step 9

To a 50 mL round-bottom flask was placed the reactant 83-J (0.18 g, 0.32 mmol) in TFA (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to obtain compound 83 as a white solid. ¹ H-NMR (400 MHz, chloroform-d) δ 10.29 (d, J = 6.1 Hz, 1H), 8.34 (s, 1H), 6.65 (dd, J = 8.7, 7.5 Hz, 2H), 4.83 (s, 1H), 4.72-4.58 (m, 2H), 4.36-4.10 (m, 2H), 4.05 (t, J = 11.5 Hz, 1H), 2.97 (d, J = 4.4 Hz, 1H), 2.49-2.08 (m, 3H), 2.12-1.94 (m, 2H). ¹⁹ F-NMR (376 MHz, CHLOROFORM-d) δ -92.32 (ddd, J = 225.6, 22.5, 9.1 Hz), -107.64 - 109.54 (m), -112.05 (t, J = 7.0 Hz), -114.67 (d, J = 226.7 Hz). LCMS-ESI ⁺ (m/z): found: 470.

Example 84

Preparation of compound 84

(1S,2R,4S,12aR)-7-Hydroxy-2-methyl-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 100-mL round-bottom flask was charged with 84-A (1.6 g, 5.9 mmol) in DCM (20 mL). The reaction mixture was cooled to 0°C. Dess-Martin periodinane (4.9 g, 11.7 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 3 hours. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 84-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 270.

Step 2

A 100-mL round-bottom flask was charged with 84-B (1.3 g, 4.8 mmol) in THF (30 mL). The reaction mixture was cooled to 0°C. Tebbe reagent (0.5 M in toluene, 19.4 mL, 9.7 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 2 hours. The mixture was cooled back to 0°C. Saturated NaHCO ₃ (5 mL) was added dropwise to quench the reaction. The reaction mixture was stirred for another 15 minutes at room temperature and filtered through celite. The filter cake was washed with DCM (2x). The combined filtrate was concentrated in vacuo, and the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 84-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 268.

Step 3

To a solution of 84-C (0.9 g, 3.4 mmol) in EtOH (20 mL) purged with _N was added Pd/C (0.18 g). The mixture was stirred _under H for 3 h. The mixture was filtered through Celite, and the filtrate was concentrated to afford 84-D. LCMS- ^ESI (m/z): [M+H] ^Found : 270.

Step 4

A 100-mL round-bottom flask was charged with 84-D (0.9 g, 3.3 mmol) in THF (6 mL). The reaction mixture was stirred at -78°C. 2.0 M LiBH ₄ in THF (13.2 mL, 26.4 mmol) was slowly added. The reaction mixture was then allowed to warm and stirred at room temperature for 3 hours. The reaction mixture was then diluted with EtOAc (100 mL) and water was slowly added (releasing H ₂ ). After the two phases were separated, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over Na ₂ SO _4. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 84-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 242.

Step 5

A 100-mL round-bottom flask was charged with 84-E (0.4 g, 1.66 mmol), triphenylphosphine (0.96 g, 3.6 mmol) and phthalimide (0.39 g, 2.7 mmol) in THF (15 mL). The reaction mixture was then cooled to 0°C while stirring. DIAD (0.7 mL, 3.6 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 84-F. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 371.

Step 6

To a solution of 84-F (0.55 g, 1.5 mmol) in EtOH (20 mL) was added hydrazine monohydrate (0.3 mL). The reaction mixture was heated to 70°C and stirred for 3 hours. After filtering to remove the solids, the filtrate was concentrated to afford 84-G. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 241.

Step 7

A 100-mL round-bottom flask was charged with 84-G (0.35 g, 1.4 mmol) and 84-H (0.5 g, 1.4 mmol) in ethanol (10 mL). Sodium bicarbonate (0.24 g, 2.8 mmol) in water (10 mL) was slowly added to the reaction mixture. The reaction mixture was then stirred overnight at room temperature. The mixture was diluted with EtOAc (50 mL) and washed with water (2x). The aqueous fraction was extracted with EtOAc, and the organic fractions were combined, dried (Na ₂ SO ₄ ), and concentrated. The crude 84-I was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 583.

Step 8

A 100-mL round-bottom flask was charged with 84-I (0.84 g, 1.4 mmol) in 4N HCl/dioxane (8.2 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 0.74 g of an intermediate was obtained. The intermediate and DBU (1.1 g, 7.2 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110 ° C and stirred for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to obtain 84-J. LCMS-ESI ⁺ (m / z): [M + H] ⁺ found: 409.

Step 9

A 100-mL round-bottom flask was charged with 84-J (0.4 g, 0.98 mmol) in THF (5 mL) and MeOH (5 mL). 1N KOH (3.0 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (3.0 mL). After concentration, the residue was co-evaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylamine (0.32 g, 1.96 mmol), N,N-diisopropylethylamine (DIPEA) and 1,2-difluorobenzylamine (DIPEA) were added.

(DIPEA) (0.63 g, 4.9 mmol) and HATU (0.74 g, 1.96 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl (2x), and dried _{over Na₂SO₄} . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to provide 84-K. LCMS- ^ESI⁺ (m/z): [M+H] ^⁺ found: 538.

Step 10

A 50-mL round-bottom flask was charged with 84-K (0.5 g, 0.93 mmol) in TFA (6 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to obtain compound 84. ¹ H-NMR (400 MHz, chloroform-d) δ 10.37 (s, 1H), 8.28 (s, 1H), 6.65 (t, J = 8.1 Hz, 2H), 4.80 (s, 1H), 4.77-4.52 (m, 3H), 4.08 (d, J = 13.1 Hz, 1H), 3.88 (d, J = 12.3 Hz, 1H), 2.47 (d, J = 3.2 Hz, 1H), 2.35 (s, 1H), 2.16 (ddd, J = 14.3, 11.2, 3.6 Hz, 1H), 1.93-1.57 (m, 3H), 1.29-1.19 (m, 1H), 1.17 (d, J = 7.0 Hz, 3H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ −109.24, −111.98. LCMS-ESI ⁺ (m/z): found: 448.

Example 85

Preparation of compound 85

(6aS,7R,11S)-1-Hydroxy-2,13-dioxo-N-(2,4,6-trifluorobenzyl)-6,6a,7,8,9,10,11,13-octahydro-2H-7,11-methanopyrido[1',2':4,5]pyrazino[1,2-a]azepine-3-carboxamide

Step 1

A solution of 85-A (1100 mg, 3.855 mmol) in DMSO (6 mL) and water (0.75 mL) was stirred at room temperature while N-iodosuccinimide (885 mg, 3.934 mmol) was added. After 2 hours, additional N-iodosuccinimide (88 mg, 0.391 mmol) was added and the resulting mixture was stirred at room temperature for 1.5 hours. The dark brown reaction mixture was diluted with EtOAc and washed with a mixture of 10% aq. _{Na 2} S ₂ O ₃ solution and aq. NaHCO ₃ solution (~1:4 mixture), followed by water (containing some brine). After extraction of the aqueous fraction with EtOAc, the organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to give 85-B. ¹ H-NMR (400 MHz, CDCl ₃ )δ7.51-7.44(m,2H),7.33-7.17(m,3H),4.22-4.05(m,2H),4.02-3.86(m,2H),3.77( d,J＝5.3Hz,1H),3.54-3.44(m,1H),3.27(t,J＝4.5Hz,1H),2.75-2.66(m,1H),2.30(dd d, J = 8.9 Hz, 1H), 1.58-1.46 (m, 1H), 1.45-1.34 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ _requires for _C18H25INO3 : _430.1 ; found: 430.0.

Step 2

A solution of 85-B (993 mg, 2.313 mmol), AIBN (305 mg, 1.857 mmol) and tributyltin hydride (1392 mg, 4.799 mmol) in toluene (15 mL) was stirred at 100°C. After 2 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. After the aqueous fraction was extracted with EtOAc, _the organic fractions were combined, dried ( _Na2SO4 ) and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to give 85-C. ^1H -NMR (400 MHz, _CDCl3 )δ7.57-7.49(m,2H),7.32-7.23(m,2H),7.23-7.15(m,1H),4.24-4.02(m,2H),3.97(q,J＝6.7Hz ,1H),3.83(d,J＝5.1Hz,1H),3.48(t,J＝4.6Hz,1H),3.19-3.04(m,1H),2.58(p,J＝4.0Hz,1H),2.3 3H). HPLC-MS/MS: 40.34 (0.977), 4.27 (0.917), 1.24 (d, J = 1.0 Hz, 3H). HPLC-MS/MS: 40.34 (0.977), 4.27 (0.917), 1.24 (d, J = 1.0 Hz, 3H). HPLC-MS/MS: 40.34 (0.977), 4.27 (0.917), 1.24 (d, J = 1.0 Hz, 3H). HPLC-MS/MS: 40.34 (0.977), 4.27 ₍ 0.917), _1.24 (d, J _{= 1.0} Hz, 3H). HPLC ^- MS/MS: 40.34 (0.977), 4.27 ⁽ 0.917), 1.24 (d, J = 1.0 Hz, 3H).

Step 3

Under an _H₂ atmosphere, a mixture of 85-C (725 mg, 2.39 mmol) and 20% Pd(OH) _₂ /C (351 mg) in EtOH (25 mL) with 4N HCl in dioxane (0.9 mL) was stirred. After 2 hours, the reaction mixture was filtered and the filtrate was concentrated. _LCMS - ^ESI⁺ (m/z): [M+H] ^⁺ Required: _{C₁₀H₁₈NO₃} : _200.13 ; Found: 200.1. The residue was co-evaporated with toluene (×2), and the residue was stirred in THF (15 mL) with _Boc₂O (720 mg, 3.299 mmol) at room temperature while N,N-diisopropylethylamine (DIPEA) (1.2 mL, 6.889 mmol) was added. After 1 hour, the reaction mixture was diluted with water and extracted with EtOAc (×2). After washing the organic extracts with water, the combined extracts were dried ( _Na2SO4 ) and concentrated. The residue was purified by flash chromatography using hexanes-EtOAc as eluent _to give 85-D as a mixture of rotamers. ^1H -NMR (400 MHz, CDCl ₃ ) δ 4.42-3.97 (m, 5H), 2.62 (d, J=5.6 Hz, 1H), 2.45-2.26 (m, 1H), 2.25-2.15 (m, 1H), 1.80 (td, J=13.7, 6.7 Hz, 1H), 1.66 (dd, J=12.3, 6.6 Hz, 2H), 1.55-1.70 (m, 2H), 1.47 (s, 2H), 1.42 (s, 7H), 1.28 (dt, J=9.5, 7.1 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₅ H ₂₆ NO ₅ : 300.2; Found: 299.7.

Step 4

To a solution of 85-D (568 mg, 1.897 mmol) and pyridine (0.25 mL, 3.091 mmol) in THF (5 mL) at 0°C was added phenylchlorothioformate (0.3 mL, 2.169 mmol), which quickly produced insoluble material. After ~30 minutes at 0°C, additional pyridine (0.3 mL, 3.709 mmol) and phenylchlorothioformate (0.3 mL, 2.169 mmol) were added. After 1.5 hours at 0°C and 1 hour at room temperature, the mixture was concentrated and the residue was dissolved in EtOAc and water. After separation of the two layers, the organic fraction was washed with ~0.1N HCl, saturated aqueous _NaHCO3 , and _brine . After extraction of the aqueous fraction with EtOAc, the combined organic fractions were dried ( _Na2SO4 ) and concentrated. The residue was purified by flash chromatography using EtOAc/hexanes as eluent to afford 85-E. ¹ H-NMR (400 MHz, CDCl ₃ )δ7.47-7.37(m,2H),7.30(t,J＝6.9Hz,1H),7.11(dd,J＝8.0,4.0Hz,2H),5.54 (dt,J＝9.0,4.9Hz,1H),4.50(dt,J＝9.8,5.3Hz,1H),4.35(dd,J＝21.4,5.0Hz, 1H),4.30-4.14(m,2H),2.71(s,1H),2.54(s,1H),2.14-2.00(m,1H),1.82(m, 3H), 1.54 (m, 1H), 1.48 (s, 4.5H), 1.45 (s, 4.5H), 1.30 (dt, J = 9.4, 7.1Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₃₀ NO ₆ S: 436.2; Found: 435.8.

Step 5

A mixture of 85-E (602 mg, 1.382 mmol), AIBN (182 mg, 1.108 mmol), and tributyltin hydride (608 mg, 2.096 mmol) in toluene (8 mL) was stirred at 100° C. After 1 hour, the reaction mixture was concentrated, and the residue was dissolved in EtOAc, then washed with water and brine. After the aqueous fraction was extracted with EtOAc, the combined organic fractions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using EtOAc/hexanes as eluent to provide 85-F as a mixture of rotamers. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.37-4.06 (m, 4H), 2.69-2.53 (m, 1H), 2.11 (m, 1H), 1.97 (m, 0.65H), 1.93-1.80 (m, 1.35H), 1.54 (s, 5H), 1.46 (s, 3.15H), 1.42 (s, 5.85H), 1.27 (m, 3H). LCMS-ESI ⁺ (m/z): [MC ₄ H ₈ +H] ⁺ for C ₁₁ H ₁₈ NO ₄ requires: 228.1; found: 227.9.

Step 6

85-F (420 mg) was repurified and the purified 85-F in THF (1.5 mL) was stirred at 0°C while 2.0 M LiBH ₄ in THF (1.5 mL) was added. After 5 minutes, the mixture was stirred at room temperature for 17 hours, and additional 2.0 M LiBH ₄ in THF (1.5 mL) was added at room temperature. After 23 hours at room temperature, additional 2.0 M LiBH ₄ in THF (3 mL) was added, and the resulting mixture was stirred for ~72 hours. The reaction mixture was stirred at 0°C while water was slowly added and further diluted with water, and the product was extracted with EtOAc (×2). The extracts were washed with water, combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to provide 85-G. ^1H -NMR (400 MHz, CDCl ₃ ) δ 4.12 (t, J = 5.3 Hz, 1H), 3.99 (dd, J = 12.0, 7.9 Hz, 1H), 3.85 (dd, J = 8.0, 4.7 Hz, 1H), 3.73 (dd, J = 11.9, 1.4 Hz, 1H), 2.28 (d, J = 4.6 Hz, 1H), 1.90-1.73 (m, 2H), 1.68-1.45 (m, 6H), 1.47 (s, 9H), 1.43-1.33 (m, 1H). LCMS-ESI ⁺ (m/z): [MC ₄ H ₈ +H] ⁺ for C ₉ H ₁₆ NO ₃ requires: 186.1; found: 186.0.

Step 7

A solution of 85-G (198 mg, 0.820 mmol), phthalimide (200 mg, 1.359 mmol), and PPh ₃ (488 mg, 1.861 mmol) in THF (10 mL) was stirred in a 0° C. bath and DIAD (0.36 mL, 1.828 mmol) was added. After 30 minutes at 0° C., the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 85-H as a mixture of rotamers. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.82 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.4, 3.1 Hz, 2H), 4.46 (s, 1H), 4.19 (m, 2H), 3.95 (s, 1H), 2.31-2.14 (m, 1H), 2.05 (d, J = 16.5 Hz, 1H), 1.84 (m, 2H), 1.79-1.70 (m, 1H), 1.66 (m, 1H), 1.61-1.30 (m, 12H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires: C ₂₁ H ₂₇ N ₂ O ₄ : 371.2; found: 370.8.

Step 8

At room temperature, hydrazine hydrate (0.145 mL, 3.083 mmol) was added to a solution of 85-H (270 mg, 0.729 mmol) in EtOH (12 mL), and the resulting solution was stirred at 70°C. After 1.5 hours, the mixture was cooled to 0°C and diluted with ether (30 mL), then stirred at 0°C for 1 hour. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH ₂ Cl ₂ and filtered to remove some insoluble material. The resulting filtrate was concentrated. At room temperature, the residue was stirred with 85-I (257 mg, 0.742 mmol) and NaHCO ₃ (131 mg, 1.559 mmol) in water (3 mL) and EtOH (3 mL). After 1 hour, the mixture was diluted with water and extracted with EtOAc (x2). After washing the extract with water, the organic extracts were combined, dried (Na ₂ SO ₄ ) and concentrated. To a solution of the residue in CH ₂ Cl ₂ (2 mL) was added 4N HCl in dioxane (6 mL). After 1.5 hours at room temperature, the solution was concentrated and co-evaporated with toluene. A mixture of the residue and DBU (0.6 mL, 4.012 mmol) in toluene (5 mL) was stirred in a 100° C. bath. After 1 hour, additional DBU (0.3 mL, 2.006 mmol) was added, and the mixture was stirred at 100° C. for another hour. After concentrating the mixture, the residue was purified by flash chromatography using EtOAc-20% MeOH/EtOAc as eluent to give 85-J. ¹ H-NMR (400 MHz, CDCl ₃ )δ8.08(s,1H),7.71-7.62(m,2H),7.36-7.29(m,2H),7.29-7.23(m,1H),5.44(d,J＝9.8Hz,1H),5 .10(d,J＝9.8Hz,1H),4.44-4.28(m,3H),4.23(t,J＝13.0Hz,1H),3.99(ddt,J＝10.2,6.3,3.6Hz,2 3H), 1.57 (d, J = 11.7 Hz, 1H), 1.48 (ddd, J = 20.9, 12.3, 5.5 Hz, 1H), 1.38 (t _, J = 7.1 _Hz , 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires _{for C24H27N2O5} : 423.2; found: 423.3.

Step 9

A mixture of 85-J (214 mg, 0.507 mmol) in THF (4 mL) and MeOH (4 mL) was stirred at room temperature while 1N KOH (1.1 mL) was added. After 30 minutes, the reaction mixture was concentrated to ~1 mL, acidified with 1N HCl (~1.2 mL), diluted with brine, and extracted with _{CH2Cl2 (} 20 mL x ₂ ). The combined extracts were dried ( _Na2SO4 ) and concentrated to give the crude acid. LCMS- _ESI ⁺ (m/z): [M+H] ⁺ Required _{for C22H23N2O5} : _395.2 ; Found: 395.3.

A mixture of the crude acid (199 mg, 0.505 mmol), 2,4,6-trifluorobenzylamine (130 mg, 0.807 mmol) and HATU (304 mg, 0.800 mmol) in CH ₂ Cl ₂ (6 mL) was stirred at room temperature while N,N-diisopropylethylamine (DIPEA) (0.62 mL, 3.559 mmol) was added. After 30 minutes, the reaction mixture was concentrated and the residue was dissolved in EtOAc and washed with saturated aqueous NH ₄ Cl solution (x2), saturated aqueous NaHCO ₃ solution (x2) and brine. After extraction of the aqueous fraction with EtOAc, the two organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH/EA as eluent to give 85-K. ¹ H-NMR (400 MHz, CDCl ₃ )δ10.40(t,J＝5.7Hz,1H),8.42(s,1H),7.68-7.54(m,2H),7.33(ddd,J＝7.7,6.3,1.5Hz,2H),7.30-7.26(m,1H),6.74- 6.60(m,2H),5.37(d,J＝10.0Hz,1H),5.17(d,J＝10.0Hz,1H),4.76-4.57(m,2H),4.46(dd,J＝6.0,4.3Hz,1H),4.34(t,J＝ 12.4Hz,1H),4.07(dd,J＝12.4,3.6Hz,1H),3.91(dt,J＝12.4,3.9Hz,1H),2.52-2.44(m,1H),2.32(dd,J＝11.8,6.2Hz,1H ),1.92(dt,J＝10.7,5.4Hz,1H),1.83-1.70(m,3H),1.67(d,J＝11.7Hz,1H),1.52(dddt,J＝25.5,17.0,11.8,5.3Hz,2H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ −109.15 (dq, J=15.0, 7.5, 7.1 Hz, 1F), −111.85 (t, J=6.8 Hz, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₉ H ₂₇ F ₃ N ₃ O ₄ : 538.2; Found: 538.3.

Step 10

At room temperature, 85-K (187 mg, 0.348 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature. After 1 hour, the solution was concentrated and the residue was dissolved in CH ₂ Cl _2. After washing the solution with 0.1N HCl, the aqueous fraction was extracted with CH ₂ Cl ₂ (x2). The organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using CH ₂ Cl _2-20 % MeOH in CH ₂ Cl ₂ as eluent to obtain 150 mg (96%) of compound 85. Compound 85 was further purified by recrystallization from methanol (10 mL) to obtain compound 85. ¹ H-NMR (400MHz, CDCl ₃ )δ12.09(s,1H),10.39(t,J＝5.7Hz,1H),8.36(s,1H),6.74-6.48(m,2H),4.64(d,J＝5.7Hz,2H),4.59(dd,J＝6.1,4.4Hz,1H),4.36-4.1 8(m,2H),4.12(dt,J＝12.4,4.1Hz,1H),2.68-2.47(m,1H),2.25-2.10(m,1H),2.10-1.98(m,1H),1.98-1.66(m,4H),1.66-1.48(m,2H). ¹⁹ F-NMR (376MHz, CDCl ₃ )δ-109.23 (ddd, J=15.1, 8.6 _{, 6.0 Hz, 1F), -112.02 (t, J=6.9 Hz, 2F). LCMS-ESI+ (m/z): [M+H]+ Required for C22H21F3N3O4 : 448.2} ^{; Found} _{: 448.3} .

Example 86

Preparation of Compound 86

(1R,3S,4R,12aS)-7-hydroxy-3-methyl-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

At room temperature, a solution of 86-A (10.160 g, 39.48 mmol) in DMSO (52 mL) and water (6.5 mL) was stirred and N-iodosuccinimide (8.888 g, 39.50 mmol) was added. After 30 minutes, the dark brown reaction mixture was diluted with EtOAc and washed with a saturated aqueous _NaHCO solution, a 10% _{aqueous Na2S2O3} solution _, and brine. After the aqueous fraction was extracted with EtOAc, the organic fractions were combined, dried ( _Na2SO4 ), and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent _to obtain 86-B as a white solid. ¹ H-NMR (400MHz, CDCl ₃ )δ7.33-7.19(m,5H),4.25-4.12(m,1H),3.79(q,J＝1.6Hz,1H),3.72(q,J＝6.5Hz,1H),3.51(s,1H),3.47(s,3H),3.31(dd,J＝3.9,1.6Hz,1H), 2.76-2.69(m,1H),2.13(ddd,J＝14.3,7.8,1.7Hz,1H),2.08-1.97(m,1H),1.91(dtd,J＝14.1,4.0,1.5Hz,1H),1.42(d,J＝6.5Hz,3H).LCMS-ESI ⁺ (m/z):C ₁₆ H ₂₁ Theoretical value of [M+H] ⁺ for INO ₃ : 402.1; found: 402.0.

Step 2

A solution of 86-B (12.468 g, 31.07 mmol), azobisisobutyronitrile (AIBN) (4.082 g, 24.86 mmol) and tributyltin hydride (18.047 g, 62.22 mmol) in toluene (150 mL) was stirred at 100° C. After 30 minutes, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The aqueous fraction was extracted with EtOAc, and the organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified twice by flash chromatography using hexane-EtOAc as the eluent to give 86-C. ¹ H-NMR (400MHz, CDCl ₃ )δ7.39-7.31(m,2H),7.31-7.24(m,2H),7.24-7.17(m,1H),4.11(s,1H ),3.72(s,1H),3.49(s,3H),3.33(d,J＝3.4Hz,1H),3.27(d,J＝6.4Hz,1H ), 2.65-2.51(m,1H),1.92(ddd,J＝13.6,6.8,2.4Hz,1H),1.69-1.50(m,2H),1.47(d,J＝10.1Hz,1H),1.41(d,J＝6.6Hz,3H),1.21-1.07(m,1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₆ H ₂₂ NO ₃ : 276.2; Found: 276.1.

Step 3

A mixture of 86-C (4.187 g, 15.21 mmol), 20% Pd(OH)/ _C (1.022 g) in EtOH (100 mL), and 4 N HCl in dioxane (5.7 mL) was stirred under an _H atmosphere. After 1.5 hours, the reaction mixture was filtered, and the filtrate was concentrated. The residue was co _{-evaporated with toluene and used in the next step. LCMS-ESI (m/z): [M+H] Required for C₈H₁₄NO₃} ^: _172.1 ^; _Found : 172.1.

After the residue was co-evaporated with toluene, the residue and Boc ₂ O (5.712 g, 26.17 mmol) in THF (45 mL) were stirred at room temperature while N,N-diisopropylethylamine (DIPEA) (8 mL, 45.93 mmol) was added. After 30 minutes, the reaction mixture was diluted with water and extracted with EtOAc (x2). After washing the organic extracts with water, the combined extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to give 86-D. ¹ H NMR spectroscopy showed a mixture of rotamers. ^1H -NMR (400 MHz, CDCl ₃ ) δ 4.20 (d, J = 7.6 Hz, 1H), 4.19-4.10 (m, 2H), 4.08 (d, J = 3.5 Hz, 1H), 3.72 (s, 3H), 2.74 (d, J = 5.6 Hz, 1H), 1.97 (ddd, J = 13.6, 6.9, 2.8 Hz, 1H), 1.88-1.78 (m, 1H), 1.79-1.50 (m, 1H), 1.46 (s, 3H), 1.38 (s, 6H), 1.31 (d, J = 13.3 Hz, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₃ H ₂₂ NO ₅ : 272.2; Found: 271.6.

Step 4

A solution of 86-D (1659 mg, 6.115 mmol) in CH ₂ Cl ₂ (35 mL) was stirred in a 0° C. bath while Dess-Martin periodinane (5.183 g, 12.22 mmol) was added portionwise. After 5 minutes, the mixture was stirred at room temperature. After 2 hours, the reaction mixture was cooled in an ice bath, quenched with water, and filtered. The filtrate was washed with saturated NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to give 86-E. ¹ H NMR chromatograms showed two rotamers. ¹ H-NMR (400 MHz, CDCl ₃ )δ4.43(d,J＝3.8Hz,0.5H),4.39(s,1H),4.26(s,0.5H),3.75(s,3H),3.10(s,1H) ,2.24(d,J＝4.5Hz,0.5H),2.19(d,J＝4.4Hz,0.5H),2.12(d,J＝4.4Hz,0.5H),2.07 5H), 1.77 (s, 0.5H), 1.46 (s, 4.5H), 1.40 (d, J = 2.8 Hz, 4.5H). LCMS-ESI ⁺ (m/z): [ _MC4H8 +H] ⁺ _{for C9H12NO5 requires} : 214.1; found _{: 213.8} .

Step 5

A solution of 86-E (528 mg, 1.961 mmol) in THF (12 mL) was stirred at 0°C while a 0.5 M solution of Tebbe's reagent in toluene (7.9 mL, 3.95 mmol) was added dropwise. After the addition, the brown solution was slowly warmed to room temperature and stirred at room temperature for 2.5 hours. The reaction mixture was stirred in a 0°C bath while being quenched by the careful addition of a saturated aqueous _NaHCO solution. After the mixture was _diluted with _CH₂Cl₂ and stirred at room temperature for 15 minutes, the resulting mixture was filtered through a pad of _Celite , and the filter cake was washed with _CH₂Cl₂ . After separating the two fractions in the filtrate, the aqueous fraction was extracted with _CH₂Cl₂ , and the organic fractions were combined, dried ( _Na₂SO₄ ) _, and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as _the eluent to give 86-F. ^1H NMR spectroscopy showed two rotamers. ¹ H-NMR (400MHz, CDCl ₃ )δ5.13(s,0.6H),5.04(s,0.4H),4.82-4.71(m,1H),4.55(s,0.6H),4.43(s,0.4H),4.29(d,J＝3.7Hz,0.4H),4.24(d,J＝3.7Hz,0.6H LCMS-ESI ⁺ (m/z):[M+H] of C ₁₄ H ₂₂ NO ₄ ⁺ Theoretical value: 268.2; measured value: 267.6.

Step 6

A mixture of 86-F (333 mg, 1.246 mmol) and 20% Pd(OH) ₂ /C (53 mg) in EtOH (5 mL) was stirred under H ₂ atmosphere. After 30 minutes, the mixture was filtered and the filtrate was concentrated to give 86-G. ¹ H NMR spectrum showed two rotamers. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.20 (m, 1H), 4.08 (m, 1H), 3.71 (two s, 3H), 2.68 (m, 1H), 2.06 (m, 1H), 1.80-1.63 (m, 2H), 1.63-1.51 (m, 1H), 1.44 (s, 4H), 1.38 (s, 5H), 1.13 (m, 3H), 0.92 (m, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₄ H ₂₄ NO ₄ : 270.2; Found: 269.7.

Step 7

At 0 ℃, stir 86-G (336mg, 1.482mmol) solution in THF (5mL), add 2.0M LiBH ₄ in THF (1.5mL) simultaneously. After 5 minutes, the mixture was stirred at room temperature. After 2 hours, add another 2.0M LiBH 4 in THF (1.5mL). After 21 hours, add another 2.0M LiBH ₄ in THF (3mL). After 3 hours at room temperature, heat the solution at 35 ℃ for 18 hours. The reaction mixture is cooled to 0 ℃, and quenched carefully with water. After the mixture is extracted with EtOAc (x2), the _two organic fractions are washed with water, merged, dried (Na ₂ SO ₄ ) and concentrated. By using the flash chromatography purification residue of hexane-EtOAc, 86-H is obtained. ¹ H-NMR (400MHz, CDCl ₃ )δ4.95-4.09(br,1H),4.05(s,1H),3.82(dd,J＝11.5,7.7Hz,1H),3.76-3.6 9(m,1H),3.66(d,J＝11.5Hz,1H),2.45(d,J＝4.1Hz,1H),2.03(dqdd,J＝11.4, 7.0,4.5,2.6Hz,1H),1.77-1.57(m,2H),1.48(dd,J＝10.1,1.8Hz,1H),1.45 (s,9H),1.00(d,J＝6.9Hz,3H),0.93(ddd,J＝13.2,4.7,2.6Hz,1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₃ H ₂₄ NO ₃ : 242.2; Found: 241.7.

Step 8

A solution of 86-H (218 mg, 0.903 mmol), phthalimide (218 mg, 1.482 mmol), and PPh ₃ (535 mg, 2.040 mmol) in THF (10 mL) was stirred in a 0° C. bath, and DIAD (0.40 mL, 2.032 mmol) was added. After 10 minutes at 0° C., the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 86-I. ¹ H NMR showed two rotamers. ^1H -NMR (400 MHz, CDCl ₃ ) δ 7.82 (dt, J=7.3, 3.6 Hz, 2H), 7.70 (d, J=5.3 Hz, 2H), 4.53-4.26 (m, 1H), 4.26-3.89 (m, 2H), 3.89-3.65 (m, 1H), 2.28 (m, 1H), 2.04 (m, 1H), 1.82-1.65 (m, 2H), 1.66-1.43 (m, 7H), 1.38 (s, 4H), 1.19-1.01 (m, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₂₇ N ₂ O ₄ : 371.2; Found: 370.8.

Step 9

To a solution of 86-I (319 mg, 0.861 mmol) in EtOH (12 mL) was added hydrazine hydrate (0.17 mL, 3.494 mmol) at room temperature, and the resulting solution was stirred in a 70°C bath. After 1.5 hours, the mixture was cooled to 0°C and diluted with diethyl ether (25 mL), then stirred at 0°C for 1 hour. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved _{in CH2Cl2} and filtered to remove some insoluble material. _The resulting filtrate was concentrated _to afford _the crude amine. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for _C13H25N2O2 : 241.2; Found: 240.9.

After the crude amine was co-evaporated with toluene, a mixture of crude amine 85-I (300 mg, 0.866 mmol) and NaHCO₃ ₍ 150 mg, 1.845 mmol) in water (3 mL) and EtOH (3 mL) was stirred at _room temperature. After 2 hours, the mixture was diluted with water and extracted with EtOAc (x2). After washing the extracts with water, the organic extracts were combined, dried ( _Na₂SO₄ ) and concentrated. To a solution of the residue in _CH₂Cl₂ (2 _mL ) was added 4N HCl in dioxane (6 mL). After 1.5 hours at room temperature, the solution was concentrated and co-evaporated with toluene. At 100° C., a mixture of the residue and DBU (0.65 mL, 4.347 mmol) in toluene (6 mL) was stirred. After 1 hour, additional DBU (0.65 mL, 4.347 mmol) was added and the mixture was stirred again at 100° C. After 1 hour, additional DBU (0.65 mL, 4.347 mmol) was added and the mixture was stirred at 100° C. for an additional 2.5 hours. The mixture was diluted with CH ₂ Cl ₂ and washed with water containing 3 mL of 1N HCl. The organic fraction was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH/EtOAc as eluent to give 86-J. ¹ H-NMR (400 MHz, CDCl ₃ )δ8.09(s,1H),7.70-7.62(m,2H),7.37-7.27(m,3H),5.48(d,J＝9.9Hz,1H),5.16(d,J＝9.9H z,1H),4.53(s,1H),4.38(m,2H),4.11(m,1H),3.97(dd,J＝12.2,3.0Hz,1H),3.88(dt,J＝12.2 , 3.0 Hz, 1H), 2.63 (d, J = 4.2 Hz, 1H), 2.28 (qd, J = 7.2, 3.1 Hz, 1H), 2.00-1.88 (m, 1H), 1.80-1.56 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.04 (dd, J = 5.0, _{2.5 Hz} , 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires for _C24H27N2O5 : _423.2 ; found: 423.2.

Step 10

A mixture of 86-J (83 mg, 0.196 mmol) in THF (2 mL) and EtOH (2 mL) was stirred at room temperature while 1N KOH (0.4 mL) was added. After 30 minutes, the reaction mixture was diluted with water and _washed with _CH₂Cl₂ . After the aqueous fraction was acidified with 1N HCl (0.45 mL), the product was extracted _{with CH₂Cl₂} (x2). The combined extracts were dried ( _Na₂SO₄ ) _and concentrated _to give _the crude acid. LCMS- ^ESI⁺ (m/z): [M+H] ^⁺ Required: _{C₂H₂N₂O₅} : _395.2 ; Found: 395.2.

A mixture of the crude acid (69 mg, 0.175 mmol), 2,4,6-trifluorobenzylamine (42 mg, 0.261 mmol) and HATU (106 mg, 0.279 mmol) in CH ₂ Cl ₂ (3 mL) was stirred at room temperature while N,N-diisopropylethylamine (DIPEA) (0.25 mL, 1.435 mmol) was added. After 30 minutes, the reaction mixture was concentrated and the residue was dissolved in EtOAc and washed with saturated aqueous NH ₄ Cl solution (x2), saturated aqueous NaHCO ₃ solution (x2) and brine. After extraction of the aqueous fraction with EtOAc, the two organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH/EtOAc as eluent to give 86-K. ¹ H-NMR (400 MHz, CDCl ₃ )δ10.40(t,J=5.7Hz,1H),8.40(s,1H),7.66-7.51(m,2H),7.36-7.29(m,2H),7.29-7.23(m,1H),6.71-6.61 (m,2H),5.36(d,J＝10.0Hz,1H),5.18(d,J＝10.0Hz,1H),4.73-4.58(m,2H),4.53(s,1H),4.22-4.11(m,1H),4 .03(dd,J＝12.4,3.1Hz,1H),3.81(dt,J＝12.3,3.1Hz,1H),2.68-2.59(m,1H),2.29(dddd,J＝11.4,7.1,4.7,2 .4Hz, 1H), 1.94 (ddd, J＝13.5, 11.2, 4.6Hz, 1H), 1.88-1.67 (m, 2H), 1.06 (d, J＝7.0Hz, 3H), 1.03-1.09 (m, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ −109.14 (ddd, J=15.2, 8.7, 6.2 Hz, 1F), −111.86 (t, J=7.0 Hz, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₉ H ₂₇ F ₃ N ₃ O ₄ : 538.2; Found: 538.1.

Step 11

86-K (61 mg, 0.113 mmol) was dissolved in trifluoroacetic acid (2 mL) at room temperature. After 1 hour, the solution was concentrated and the residue was dissolved in CH ₂ Cl _2. After washing the solution with 0.1 N HCl, the aqueous fraction was extracted with CH ₂ Cl ₂ (x2). The organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using CH ₂ Cl ₂ -20% MeOH in CH ₂ Cl ₂ as eluent to give compound 86. ¹ H-NMR (400 MHz, CDCl ₃ )δ12.02(s,1H),10.40(t,J＝5.7Hz,1H),8.35(s,1H),6.63(t,J＝8.1Hz,2H),4.6 2(d,J＝5.7Hz,2H),4.59(s,1H),4.22(dd,J＝12.2,3.5Hz,1H),4.13(t,J＝11.9Hz, 1H),4.05(dt,J＝12.0,3.1Hz,1H),2.77-2.70(m,1H),2.31m,1H),2.09-1.93(m,1 H),1.93-1.81(m,2H),1.10(ddd,J＝13.9,5.0,2.1Hz,1H),1.02(d,J＝6.9Hz,3H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ −109.22 (ddd, J=15.1, 8.7, 6.1 Hz, 1F), −112.05 (t, J=6.9 Hz, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₂₁ F ₃ N ₃ O ₄ : 448.2; Found: 448.3.

Example 87

Preparation of cis-5-aminotetrahydro-2H-pyran-3-ol

Step 1

A solution of benzyl (5-oxotetrahydro-2H-pyran-3-yl)carbamate (740 mg, 3.0 mmol) and cerium (III) chloride heptahydrate (1.12 g, 3.0 mmol) in 20 mL of methanol was cooled to 0°C, followed by the addition of sodium borohydride (120 mg, 3.2 mmol) in portions. The reaction mixture was stirred at 0°C for 45 minutes, then quenched by the slow addition of 1 mL of acetone and stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and dichloromethane, and the aqueous phase was extracted into dichloromethane and then into 2-butanol. The combined organic phases were dried over magnesium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (0-100% EtOAc/hexane) to yield the desired benzyl cis-((3R,5S)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 7.39-7.26 (m, 5H), 6.06 (br s, 1H), 5.07 (s, 2H), 3.86-3.70 (m, 2H), 3.69-3.47 (m, 4H), 2.00-1.89 (m, 1H), 1.76 (d, J=13.5 Hz, 1H). The undesired trans isomer was also isolated.

Step 2

To cis-((3R, 5S)-5-hydroxytetrahydro-2H-pyrans-3-yl) benzyl carbamate (290mg, 1.16mmol) in 5mL 1:1DCM:10wt%Pd/C (255mg) is added.Under balloon pressure hydrogen, stir the mixture 18 hours, and pass through diatomite and remove palladium, rinse with ethanol.When concentrated filtrate, obtain cis-5-aminotetrahydro-2H-pyrans-3-ol, and carry out as thick material.

Example 88

Preparation of compound 88

'(2R,5S,13aR)-N-(3-chloro-2-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 88 was prepared in a similar manner to compound 15 using (3-chloro-2-fluorophenyl)methanamine instead of (4-fluorophenyl)methanamine. ¹ H-NMR (400MHz, chloroform-d) δ10.43 (br s, 1H), 8.34 (br s,1H),7.32-7.24(m,2H),7.02(t,J＝7.9Hz,1H),5.36(d,J＝9.4Hz,1H),5.30(s,2H),4.70(d,J＝6.0Hz,3H),4.24(d,J＝1 2.0Hz,1H),4.00(dd,J＝12.7,9.5Hz,1H),2.18-1.96(m,4H),1.96-1.83(m,1H),1.60(dt,J＝12.4,3.1Hz,1H).LCMS-ESI ⁺ (m/z):[M+H] of C ₂₁ H ₁₉ ClFN ₃ O ₅ ⁺ Theoretical value: 448.11; measured value: 448.2.

Example 89

Preparation of compound 89

(2R,5S,13aR)-N-(2,5-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 89 was prepared in a similar manner to compound 15 using (2,5-difluorophenyl)methanamine instead of (4-fluorophenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.32 (t, J = 5.8 Hz, 1H), 8.31 (br s, 1H), 7.15-6.89 (m, 2H), 6.86 (d, J = 8.5 Hz, 1H), 5.40 (d, J = 9.3 Hz, 1H), 5.24 (s, 1H), 4.67-4.51 (m, 3H), 4.35-4.28 (m, 1H), 3.99-3.90 (m, 1H), 2.16-1.85 (m, 5H), _1.60-1.50 (m, 1H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _requires for _C21H19F2N3O5 : _432.14 ; found: 432.2.

Example 90

Preparation of Compound 90

(1R,4S,12aR)-N-(3-chloro-2-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 90 was prepared by a procedure analogous to compound 41 using (3-chloro-2-trifluorophenyl)methanamine instead of (2,4,6-trifluorophenyl)methanamine. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 9.22 (s, 1H), 8.79 (s, 1H), 7.39-7.28 (m, 2H), 7.06 (t, J=8.0 Hz, 1H), 4.89 (s, 1H), 4.70-4.56 (m, 3H), 4.06-3.83 (m, 2H), 3.04-2.88 (m, 1H), 2.77 ( _s , 1H), 1.97-1.58 (m, 6H). LCMS-ESI ⁺ (m/ _z ): [M+H] ⁺ Required _{for C21H19ClFN3O4} : 432.11; Found: 432.2.

Example 91

Preparation of Compound 91

(1R,4S,12aR)-7-Hydroxy-6,8-dioxo-N-(2,3,4-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 91 was prepared in a similar manner to compound 41 using (2,3,4-trifluorophenyl)methanamine instead of (2,4,6-trifluorophenyl)methanamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.25 (s, 1H), 8.45 (s, 1H), 7.10 (d, J = 5.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.89 (s, 1H), 4.63 (s, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.93-3.73 (m, 2H), 2.71 (s, 1H), 1.97-1.57 (m, 6H). LCMS-ESI ⁺ ₍ m/ _{z )} : [M+H] ⁺ requires for _C21Hi8F3N3O4 : _434.13 ; found: 434.2.

Example 92

Preparation of Compound 92

(1R,4S,12aR)-N-(4-chloro-2-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 92 was prepared by a method analogous to compound 41 using (4-chloro-2-trifluorophenyl)methanamine instead of (2,4,6-trifluorophenyl)methanamine. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 10.28 (s, 1H), 8.41 (s, 1H), 7.29 (s, 1H), 7.11-6.95 (m, 2H), 4.85 (s, 1H), 4.57 (s, 2H), 4.22 (d, J=10.2 Hz, 1H), 3.81 (q, J=13.9, 13.1 Hz, 2H), 2.68 (s, 1H), 1.99-1.50 (m, 6H). _LCMS - _ESI ⁺ (m/z): [M+H] ⁺ Required _{for C21H19ClFN3O4 :} 432.11; Found: 432.2.

Example 93

Preparation of compound 93

(1R,4S,12aR)-N-(2-chloro-4,6-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 5 mL microwave vial was charged with 2-bromo-1-chloro-3,5-difluorobenzene (540 mg, 2.4 mmol), cuprous cyanide (436 mg, 4.87 mmol), and tetrakis(triphenylphosphine)palladium (63 mg, 0.05 mmol), sealed, and evacuated/backfilled with nitrogen. 5 mL of degassed DMF was added. The sealed vial was heated at 110°C for 18 hours, diluted with ethyl acetate, and washed sequentially with 9:1 _NH₄OH : _NH₄Cl (aq) twice, 5% LiCl(aq) twice, and brine twice. The organic phase was then dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (100% hexanes) to yield 2-chloro-4,6-difluorobenzonitrile. ¹ H-NMR (400 MHz, chloroform-d) δ 7.13 (dt, J=8.0, 1.9 Hz, 1H), 6.93 (td, J=8.5, 2.3 Hz, 1H).

Step 2

To a solution of 2-chloro-4,6-difluorobenzonitrile (210 mg, 1.2 mmol) in 2.4 mL of THF was added a 2 M solution of borane-DMS in THF (0.6 mL). The reaction mixture was stirred at reflux temperature for 18 hours, resulting in the loss of all solvent. It was redissolved in 3 mL of THF, cooled to 0 ° C, a 6 M solution of HCl (aq) was carefully added, and the mixture was restored to reflux for 30 minutes. The reaction mixture was cooled to 0 ° C again and treated with 4 M NaOH (aq). The aqueous phase was extracted with DCM, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography (0-10% MeOH/DCM) to obtain (2-chloro-4,6-difluorophenyl)methylamine. ¹ H-NMR (400 MHz, chloroform-d) δ 6.95 (dt, J = 8.3, 2.1 Hz, 1H), 6.76 (td, J = 9.4, 2.5 Hz, 1H), 3.94 (d, J = 1.9 Hz, 2H).

Steps 3 and 4

A solution of 93-A (74 mg, 0.11 mmol), (2-chloro-4,6-difluorophenyl)methanamine (48.5 mg, 0.27 mmol), HATU (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) in 1 mL of dichloromethane was stirred at room temperature for 1 hour, at which point LCMS observed the complete disappearance of 93-A and the formation of 93-B. TFA (0.65 M) was added, and the mixture was stirred at room temperature for 1 hour, at which point 1 mL of DMF was added. The reaction mixture was then concentrated and purified by preparative HPLC (ACN/ _H₂O + 0.1% TFA) to provide compound 93. ^1H -NMR (400 MHz, DMSO- _d6 ) δ 10.41 (t, J = 5.7 Hz, 1H), 8.33 (s, 1H), 7.41-7.26 (m, 2H), 4.72-4.57 (m, 3H), 4.43 (dd, J = 12.5, 3.6 Hz, 1H), 3.94 (t, J = 12.4 Hz, 2H), 3.77 (dd, J = 12.4, 3.6 Hz, 3H), 1.87-1.67 (m, 3H), 1.67-1.45 (m, 2H), 1.43 (d, J = _{10.4 Hz} , _1H ) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ requires for _{C21Hi8ClF2N3O4} : 450.10; found: 450.2.

Example 94

Preparation of Compound 94

(1R,4S,12aR)-N-Benzyl-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 94 was prepared in a similar manner to compound 41 using phenylmethylamine instead of (2,4,6-trifluorophenyl)methylamine. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 10.37 (s, 1H), 8.26 (s, 1H), 7.37-7.19 (m, 5H), 4.55 (d, J = 4.8 Hz, 1H), 4.34 (d, J = 5.7 Hz, 1H), 4.23 (d, J = 9.8 Hz, 1H), 4.09 (d, J = _28.2 Hz, 1H), 3.78 (d, J = 10.9 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H), 3.14-3.01 (m, 1H), 1.91-1.49 (m, 4H). LCMS-ESI ⁺ (m/ _{z )} : [M+H] ⁺ requires for _C21H21N3O4 : 380.16; found: 380.2.

Example 95

Preparation of Chiral tert-butyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 95-A and 95-B

Step 1

To a 0°C solution of racemic tert-butyl 3-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (285 mg, 1.34 mmol), triphenylphosphine (425 mg, 1.62 mmol), and phthalimide (240 mg, 1.62 mmol) in 9 mL of THF was added dropwise a solution of diisopropyl azodicarboxylate (0.35 mL, 1.8 mmol) in 1 mL of THF. The reaction mixture was allowed to warm to room temperature, stirred for 90 minutes, concentrated onto silica, and purified by flash chromatography (0-25% EtOAc/hexanes) to afford tert-butyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate as a racemic mixture. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₉ H ₂₃ N ₂ O ₄ : 343.2; Found: 342.8.

Step 2

Racemic tert-butyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (655 mg, 1.91 mmol) was separated by chiral HPLC on a Lux Cellulose-2 column using acetonitrile as the eluent to provide enantiomerically enriched chiral 95-A (first eluting peak) and 95-B (second eluting peak). For 95-A: 144 mg, 98% ee (absolute stereochemistry unknown). For 95-B: 242 mg, 49% ee (absolute stereochemistry unknown).

Example 96

Preparation of Compound 96

(1R,3R,11aS)-6-Hydroxy-5,7-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,5,7,11,11a-hexahydro-1H-1,3-methanopyrido[1,2-a]pyrrolo[1,2-d]pyrazine-8-carboxamide

Step 1

To a solution of intermediate 95-A (141 mg, 0.41 mmol, 98% ee, unknown absolute stereochemistry) in 9 mL of ethanol was added hydrazine hydrate (0.5 mL, 10.3 mmol) and stirred at 70 ° C for 18 hours to give 96-A of unknown absolute stereochemistry. The solid was removed by filtration and the filtrate was concentrated and carried forward crude.

Step 2

A mixture of crude 96-A (0.41 mmol assumed), 96-B (430 mg, 1.25 mmol) and sodium bicarbonate (69 mg, 0.82 mmol) in 2 mL of water and 2 mL of ethanol was stirred at room temperature for 18 hours, after which the reaction mixture was diluted with water and extracted three times into ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude residue (222 mg) was dissolved in 1.5 mL of DCM, 4N HCl in dioxane (4 mL) was added, and stirred at room temperature for 90 minutes. The mixture was concentrated to dryness and co-evaporated with toluene. The crude residue and DBU (0.3 mL, 2.0 mmol) in 6 mL of methanol were stirred at 50° C. for 90 minutes. The reaction mixture was then concentrated on silica gel and purified by flash chromatography (0-10% MeOH/DCM) to give 96-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₂₂ N ₂ O ₅ : 395.16; Found: 395.2.

Step 3

At room temperature, a mixture of 96-C (112 mg, 0.28 mmol), 1 M potassium hydroxide aqueous solution (1 mL), 4 mL methanol and 4 mL THF was stirred for 3 hours. The mixture was then diluted with dichloromethane, acidified by adding 1 M aqueous hydrogen chloride solution, and the organic phase was extracted into dichloromethane. The combined organics were dried, filtered, and concentrated from toluene. After drying under vacuum, the residue was suspended in 1.5 mL of DCM and trifluorobenzylamine (62 mg, 0.38 mmol), HATU (220 mg, 0.58 mmol) and N,N-diisopropylethylamine (DIPEA) (0.15 mL, 0.86 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours to obtain 96-D, which was carried out to the next step as a crude material.

Step 4

Trifluoroacetic acid (1.7 mL, 22.2 mmol) was added to the crude reaction solution containing 96-D from the previous step, and the reaction mixture was stirred at room temperature for 90 minutes. Then, 1 mL of DMF was added, and the reaction mixture was concentrated to 1 mL, filtered, and purified by preparative HPLC (ACN/water + 0.1% TFA) to give compound 96 (unknown absolute stereochemistry). ¹ H-NMR (400MHz, DMSO-d ₆ )δ10.45-10.35(m,1H),8.39(s,1H),7.23-7.09(m,2H),4.67(dd,J＝12.6,4.8Hz,2H),4.53(d,J＝5.5Hz,2H),4.20(dd,J＝11.9,3.8Hz,1 LCMS-ESI ⁺ (m/z):C ₂₀ H ₁₆ F ₃ N ₃ O [M+H] ⁺ Required value for ₄ : 420.12; Found: 420.2.

Example 97

Preparation of Compound 97

(1S,3S,11aR)-6-Hydroxy-5,7-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,5,7,11,11a-hexahydro-1H-1,3-methanopyrido[1,2-a]pyrrolo[1,2-d]pyrazine-8-carboxamide

Compound 97 (49% ee, unknown absolute stereochemistry) was prepared in a manner analogous to compound 96 using intermediate 95-B (49% ee, unknown absolute stereochemistry) instead of enantiomerically opposite intermediate 95-A. ¹ H-NMR (400MHz, DMSO-d ₆ )δ10.39(t,J＝5.7Hz,1H),8.42(s,1H),7.25-7.13(m,2H),4.73-4.66(m, 2H),4.54(d,J＝5.7Hz,2H),4.20(dd,J＝12.3,3.9Hz,1H),4.01(t,J＝12.4H LCMS-ESI ⁺ (m/z):C Theoretical value of [M+H] ⁺ for ₂₀ H ₁₆ F ₃ N ₃ O ₄ : 420.12; found: 420.2.

Example 98

Preparation of Compound 98

(1S,4R,12aR)-3,3-Difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

98-A (0.5 g, 1.87 mmol) was dissolved in DCM (20 mL) and cooled to 0°C under nitrogen. Dess-Martin periodinane (1.59 g, 3.74 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours, quenched with a saturated aqueous solution _{of Na2S2O3} / _NaHCO3 (7: ₁ ) (160 mL), and stirred vigorously until the two layers separated. The crude product was extracted twice with DCM. The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel with 0-20% MeOH/DCM to give 98-B. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 4.34-4.05 (m, 1H), 3.97-3.75 (m, 1H), 3.69 (s, 3H), 2.89 (dd, J=4.4, 2.1 Hz, 1H), 2.30-1.97 (m, 3H), 1.56 (d, J=11.3 Hz, 1H), 1.35 (s, 9H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₃ H ₁₉ NO ₅ : 269.13; Found: 270.78.

Step 2

A solution of 98-B (504 mg, 1.87 mmol) in DCM (15 mL) was stirred at 0°C. DAST (1 ml) was added dropwise to the reaction mixture. After stirring overnight at room temperature, the reaction mixture was cooled back to 0°C. Saturated _NaHCO₃ (10 mL) was slowly added. The mixture was extracted twice with DCM and dried over _Na₂SO₄ . After concentration, the residue was purified by flash chromatography 0-50% EtOAc/hexane _to give 98-C. ¹ H-NMR (400 MHz, chloroform-d) δ 4.45-4.18 (m, 1H), 3.85 (m, 1H), 3.72 (d, J = 1.5 Hz, 3H), 2.72 (ddd, J = 5.1, 3.2, 1.6 Hz, 1H), 2.27-1.52 (m, 4H), 1.41 (d, J = 21.9 Hz, 9H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -91.72-93.99 (m), -113.65-115.98 (m). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₃ H ₁₉ F ₂ NO ₄ : 291.13; Found: 291.55.

Step 3

98-C (476 mg, 1.634 mmol) in THF (20 mL) was stirred at 0°C while 2.0 M _LiBH₄ in THF (2.4 mL, 4.8 mmol) was added. The mixture was allowed to warm to room _temperature and stirred for 4 hours. The reaction mixture was quenched with ice and diluted with EtOAc and saturated _NH₄Cl (some _H₂ evolved). After separation of the two phases, the organic fraction was washed with brine, dried ( _Na₂SO₄ ), and concentrated. The crude product of 98- _D was used as is in the next step. _{LCMS-ESI⁺ (m/z): [M+H]⁺ Required for C₁₂H₁₆F₂NO₃} ^{: 263.13} _{; Found} : 164.10.

Step 4

98-D (1.634 mmol), phthalimide (0.36 g, 2.45 mmol), and _PPh₃ (0.855 g, 3.26 mmol) in THF (10 mL) were stirred in a 0°C bath, and DIAD (0.642 mL, 3.26 mmol) was added. After the addition, the mixture was stirred at 0°C for 30 minutes and then at room temperature for 16 _hours . It was diluted with EtOAc and saturated _NH₄Cl . After stirring for 5 minutes, the solid was filtered and the two phases were separated. The organic phase was washed with brine, dried ( _Na₂SO₄ ), and concentrated. The crude product was purified by flash chromatography using 0-50% EA/Hex as the eluent to give 98-E. ^1H -NMR showed a mixture of two rotamers. ¹ H-NMR (400 MHz, chloroform-d) δ7.89-7.80 (m, 2H), 7.78-7.66 (m, 2H), 5.02 (ddt, J=16.6, 12.5, 6.3 Hz, 1H), 4.24 (d, J=71.8 Hz, 1H), 4.10-3.92 (m, 1H), 3.83-3.51 (m, 2H), 2.46 (s, 1H), 2.21-1.98 (m, 2H), 1.87-1.62 (m, 2H), 1.31 (d, J=8.5 Hz, 9H); ¹⁹ F-NMR (376 MHz, chloroform-d) δ-91.22--93.58 (m), -113.20--115.45 (m). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₀ H ₂₂ F ₂ N ₂ O ₄ : 392.15; Found: 393.3.

Step 5

To a solution of 98-E (696 mg, 1.774 mmol) in EtOH (10 mL) was added hydrazine hydrate (1 mL) at room temperature, and the resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with diethyl ether (30 mL) and stirred at 0°C for 60 minutes before filtering. The filtrate was concentrated, and the residue was dissolved _{in CH2Cl2} and filtered. The filtrate was concentrated and purified by flash chromatography on silica gel with 0-20% MeOH (0.2% TEA)/DCM to provide 98-F. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 4.91 (p, J = 6.2 Hz, 1H), 4.29-3.97 (m, 1H), 3.36-2.93 (m, 2H), 2.49 (qt, J = 8.8, 5.2 Hz, 2H), 2.08 (dddd, J = 25.5, 14.0, 7.1, 4.9 Hz, 1H), 1.89-1.49 (m, 4H), 1.41 and 1.21 (d, J = 6.2 Hz, 9H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -91.63--93.16 (m), -113.11--115.08 (m). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₁₂ H ₂₀ F ₂ N ₂ O ₂ : 262.15; Found: 262.8.

Steps 6, 7, and 8

A mixture of 98-G (375.8 mg, 1.55 mmol), 98-E (370 mg, 1.41 mmol) and NaHCO-3 (261 mg, 3.10 mmol) in water (5 mL) and EtOH (5 mL) was stirred at room temperature for 2 hours. The mixture was diluted with saline and extracted with EtOAc (x2). The extracts were combined, dried (Na ₂ SO ₄ ), concentrated, and dried in vacuo to give crude A. LCMS-ESI ⁺ (m/z): [M+H] ⁺ 591.59. 4N HCl in dioxane (5 mL) was added to crude A (1.38 mmol) in CH ₂ Cl ₂ (5 mL). After 2 hours at room temperature, the mixture was concentrated to dryness. It was co-evaporated once with toluene and dried in vacuo to give crude B. A solution of B (1.38 mmol + 0.442 mmol) and DBU (3 mL, 11 mmol) in anhydrous MeOH (15 mL) was stirred for 40 minutes in a 50°C bath. The mixture was concentrated. The residue was purified by flash chromatography (80 g column) using 0-20% MeOH/DCM as the eluent to afford 98-H. LCMS ^{- ESI} (m/z): [M+H _] Required _{for C₂₃H₂F₂N₂O₅} : _444.15 ; Found: 445.36 (90%), 431.18 (10 _% ).

Steps 9, 10, and 11

The remaining steps were carried out using a method similar to that of Example 41 to give the desired compound 98. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 10.29 (d, J = 6.1 Hz, 1H), 8.34 (s, 1H), 6.65 (dd, J = 8.7, 7.5 Hz, 2H), 4.83 (s, 1H), 4.72-4.58 (m, 2H), 4.36-4.10 (m, 2H), 4.05 (t, J = 11.5 Hz, 1H), 2.97 (d, J = 4.4 Hz, 1H), 2.49-2.08 (m, 3H), 2.12-1.94 (m, 1H). ^{1 9} F-NMR (376 MHz, chloroform-d) δ -92.08--93.57 (m, 1F), -108.92 (ddd, J=15.1, 8.8, 6.3 Hz, 1F), -109.30--110.65 (m, 1F), -112.16 (p, J=7.3 Hz, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₁ H ₁₆ F ₅ N ₃ O ₄ : 469.11; Found: 470.23.

Example 99

Preparation of Compound 99

(1R,3S,4R,12aR)-7-hydroxy-3-methyl-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

To a stirred solution of 99-A (1 g, 3.71 mmol) in THF (20 mL) was added a solution of Tebbe reagent (0.5 M in toluene, 14.85 mL, 7.42 mmol) at 0 ° C. After the addition, the brown solution was slowly warmed to room temperature and stirred at room temperature for 2 hours. At 0 ° C, the reaction was carefully quenched by adding a saturated NaHCO ₃ solution, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered through celite, and the filter cake was washed twice with ether and DCM (1: 1). After separation of the layers, the organic layers were combined, concentrated in vacuo, and the residue was purified by column chromatography on silica gel with 0-50% EtOAc/hexane to give 99-B. ¹ H-NMR (400MHz, chloroform-d) δ5.06 (dt, J＝48.6, 2.6Hz, 1H), 4.73 (d, J＝7.0Hz, 1H), 4 .42(d,J＝61.8Hz,1H),3.81(d,J＝48.2Hz,1H),3.73(d,J＝1.6Hz,3H),2.74(d d,J＝9.4,4.4Hz,1H),2.38(ddt,J＝13.5,4.5,2.5Hz,1H),2.18-2.06(m,1H), 1.99(dt,J＝10.2,2.4Hz,1H),1.58(s,1H),1.42(d,J＝25.5Hz,9H).LCMS-ESI ⁺ (m/z):C ₁₄ H ₂₁ NO Theoretical value of [M+H] ⁺ for ₄ : 267.15; found: 267.65.

Step 2

A mixture of 99-B (675 mg, 2.506 mmol) and 20% Pd(OH) ₂ /C (500 mg) in EtOH (50 mL) was stirred under an atmosphere of H _2. The mixture was filtered through celite, and the filtrate was concentrated to give 99-C. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 4.23-3.99 (m, 1H), 3.77-3.64 (m, 4H), 2.55 (d, J = 4.8 Hz, 1H), 2.14-1.86 (m, 3H), 1.42 (d, J = 24.2 Hz, 9H), 0.96 (d, J = 6.6 Hz, 3H), 0.85 (ddd, J = 12.5, 4.8, 2.4 Hz, 1H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required _{for C14H23NO4 :} 269.16; Found: 269.69.

Step 3

99-C (670 mg, 2.488 mmol) in THF (20 mL) was stirred at 0°C while 2.0 _M LiBH₄ in THF (3.7 mL, 7.46 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with ice and _diluted with EtOAc and saturated _NH₄Cl (some _{H₂ evolved ). After separation of the two phases, the organic fraction was washed with brine, dried (Na₂SO₄) and concentrated. The crude alcohol 99-D was used as is in the next step. LCMS-ESI⁺ (m/z): [M+H]⁺ Required for C₁₃H₂NO₃ :} ^{241.17 ;} _Found : 241.76.

Steps 4 and 5

Using a procedure analogous to that in Example 41, steps 4 and 5 were carried out to give 99-F _{. LCMS-ESI+ (m/z): [M+H]+ Required for Ci3H24N2O2 :} ^{240.18 ;} _{Found :} 241.2.

Steps 6, 7, and 8

Using a procedure analogous to that in Example 41, steps 6, 7, and 8 were performed to give 99-G _{. LCMS-ESI+ (m/z): [M+H]+ Required for C24H26N2O5 : 422.18} ^{; Found} _: 423.21.

Steps 9, 10, and 11

The remaining steps were carried out using a method similar to that of Example 41 to give the desired compound 99. ¹ H-NMR (400 MHz, chloroform-d) δ 11.71 (s, 1H), 10.36 (t, J = 5.7 Hz, 1H), 8.28 (s, 1H), 6.63 (t, J = 8.1 Hz, 2H), 4.63 (t, J = 5.4 Hz, 3H), 4.12 (dd, J = 12.3, 3.5 Hz, 1H), 3.83 (t, J = 12.3 Hz, 1H), 3.67 (dd, J = 12.3,3.4Hz,1H),2.64-2.52(m,1H),2.30(ddq,J＝10.5,7.2,3.6Hz,1H),2.13(td,J＝12.1,4. 4Hz, 1H), 1.82-1.63 (m, 2H), 1.24 (d, J = 3.3Hz, 1H), 1.04 (d, J = 6.9Hz, 4H), 0.90-0.79 (m, 1H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -109.20 (ddd, J=15.0, 8.8, 6.2 Hz), -112.03 (t, J=7.0 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Required for C ₂₂ H ₂₀ F ₃ N ₃ O ₄ : 447.14; Found: 448.32.

Example 100

Preparation of Compound 100

(1R,4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-ethanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 100-mL round-bottom flask was charged with 100-A (2.0 g, 7.8 mmol) in THF (20 mL). The reaction mixture was cooled to 0 ° C. Borane dimethyl sulfide (2N in THF, 17.6 mL) was slowly added. Then, the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled back to 0 ° C. Methanol (8 mL) was added dropwise to quench the reaction. After concentration, the residue was purified by CombiFlash (40 g column, used cartridge) using hexane-EA as eluent to obtain 100-B. LCMS-ESI ⁺ (m / z): [M + H] ⁺ found: 242.

Step 2

A 100-mL round-bottom flask was charged with 100-B (1.8 g, 7.4 mmol), triphenylphosphine (4.3 g, 16.2 mmol) and phthalimide (1.8 g, 12.2 mmol) in THF (30 mL). The reaction mixture was then cooled to 0°C while stirring. DIAD (3.2 mL, 16.2 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After concentration, the residue was purified by CombiFlash (80 g column, cartridge used) using hexane-EA as eluent to obtain 100-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 371.

Step 3

To a solution of 100-C (2.5 g, 6.8 mmol) in EtOH (50 mL) was added hydrazine monohydrate (1.7 mL). The reaction mixture was heated to 70°C and stirred for 3 hours. After filtering to remove the solids, the filtrate was concentrated to afford 100-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 241.

Step 4

A 100-mL round-bottom flask (rbf) was charged with 100-D (1.6 g, 6.7 mmol) and 100-E (2.3 g, 6.7 mmol) in ethanol (30 mL). Sodium bicarbonate (1.2 g, 1.4 mmol) in water (30 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EA (200 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and the organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated. The crude 100-F was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 569.

Step 5

100-F (3.7 g, 6.5 mmol) in 4N HCl/dioxane (38 mL) was loaded into a 100-mL rbf. The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 3.2 g of the intermediate was obtained. The intermediate and DBU (5.1 g, 33.8 mmol) were dissolved in toluene (100 mL). The reaction mixture was heated to 110° C. and stirred for 1 hour. After concentration, the residue was purified by CombiFlash (80 g column, used column) using hexane-EA as eluent to obtain 100-G. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 423.

Step 6

In a 100-mL rbf was loaded 100-G (2.0 g, 4.7 mmol) in THF (20 mL) and MeOH (20 mL). 1N KOH (18.9 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour and acidified by adding 1N HCl (18.9 mL). After concentration, the residue was co-evaporated with toluene (3x). Crude acid (0.28 g, 0.72 mmol), 2,4-difluorobenzylamine (0.2 g, 1.44 mmol), N,N-diisopropylethylamine (DIPEA) (0.47 g, 3.6 mmol) and HATU (0.55 g, 1.44 mmol) were dissolved in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL) and washed with saturated NaHCO ₃ (2×), saturated NH ₄ Cl (2×), and dried over Na ₂ SO _4. After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 100-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 520.

Step 7

A 50-mL rbf was charged with 100-H (0.36 g, 0.69 mmol) in TFA (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 100. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 12.25 (m, 1H), 10.47 (t, J = 5.9 Hz, 1H), 8.30 (s, 1H), 7.58-7.29 (m, 1H), 6.98-6.50 (m, 2H), 4.62 (dd, J = 14.8, 4.9 Hz, 3H), 4.22 (t, J = 12.2 Hz, 1H), 4.14-4.07 (m, 1H), 3.96 (dd, J = 12.2, 3.1 Hz, 1H), 2.26-1.44 (m, 9H). ^19F -NMR (376 MHz, CHLOROFORM-d) δ -112.38 (t, J = 7.7 Hz), -114.78 (q, J = 8.5 Hz). LCMS-ESI ⁺ (m/z): found: 430.

Example 101

Preparation of Compound 101

(1R,4R,12aS)-7-Hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-ethanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 100-mL rbf was charged with 101-A (0.3 g, 0.72 mmol) in THF (2 mL) and MeOH (2 mL). 1N KOH (2.1 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by the addition of 1N HCl (2.1 mL). After concentration, the residue was co-evaporated with toluene (3x). The crude acid (0.72 mmol), 2,4,6-trifluorobenzylamine (0.23 g, 1.44 mmol), N,N-diisopropylethylamine (DIPEA) (0.47 g, 3.6 mmol), and HATU (0.55 g, 1.44 mmol) were dissolved in DCM (20 mL). The reaction mixture was stirred at room temperature for ₂ hours. The mixture was diluted with EA (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl (2x), and dried over _Na₂SO₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 101-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 538.

Step 2

A 50-mL rbf was charged with 101-B (0.36 g, 0.67 mmol) in TFA (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 101. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 12.11 (s, 1H), 10.40 (t, J = 5.8 Hz, 1H), 8.28 (s, 1H), 6.91-6.39 (m, 2H), 4.62 (ddd, J = 25.0, 6.5, 2.8 Hz, 3H), 4.21 (t, J = 12.2 Hz, 1H), 4.09 (dd, J = 12.5, 3.0 Hz, 1H), 3.93 (dd, J = 12.2, 3.1 Hz, 1H), 2.35-1.39 (m, 9H). ¹⁹ F NMR (376 MHz, CHLOROFORM-d) δ -112.38 (t, J = 7.7 Hz), -114.78 (q, J = 8.5 Hz). LCMS-ESI ⁺ (m/z): found: 448.

Example 102

Preparation of Compound 102

(1S,4S,12aR)-7-Hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-ethanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

A 100-mL round-bottom flask was charged with 102-A (2.0 g, 7.8 mmol) in THF (20 mL). The reaction mixture was cooled to 0°C. Borane dimethyl sulfide (2N in THF, 17.6 mL) was slowly added. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was cooled back to 0°C. Methanol (8 mL) was added dropwise to quench the reaction. After concentration, the residue was purified by CombiFlash (40 g column, cartridge used) using hexane-EA as eluent to obtain 102-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 242.

Step 2

A 100-mL rbf was charged with 102-B (1.8 g, 7.4 mmol), triphenylphosphine (4.3 g, 16.2 mmol) and phthalimide (1.8 g, 12.2 mmol) in THF (30 mL). The reaction mixture was then cooled to 0°C while stirring. DIAD (3.2 mL, 16.2 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. After concentration, the residue was purified by CombiFlash (80 g column, used cartridge) using hexane-EA as eluent to obtain 102-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 371.

Step 3

To a solution of 102-C (2.5 g, 6.8 mmol) in EtOH (50 mL) was added hydrazine monohydrate (1.7 mL). The reaction mixture was heated to 70°C and stirred for 3 hours. After filtering to remove the solid, the filtrate was concentrated to afford 102-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 241.

Step 4

A 100-mL rbf was charged with 102-D (1.6 g, 6.7 mmol) and 102-E (2.3 g, 6.7 mmol) in ethanol (30 mL). Sodium bicarbonate (1.2 g, 1.4 mmol) in water (30 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EA (200 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and _the organic fractions were combined, dried ( _Na2SO4 ), and concentrated. The crude material 102-F was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 569.

Step 5

A 100-mL rbf was charged with 102-F (3.7 g, 6.5 mmol) in 4N HCl/dioxane (38 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 3.2 g of the intermediate was obtained. The intermediate and DBU (5.1 g, 33.8 mmol) were dissolved in toluene (100 mL). The reaction mixture was heated to 110° C. and stirred for 1 hour. After concentration, the residue was purified by CombiFlash (80 g column, used column) using hexane-EA as eluent to obtain 102-G. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 423.

Step 6

102-G (0.3 g, 0.72 mmol) in THF (2 mL) and MeOH (2 mL) was loaded into a 100-mL rbf. 1N KOH (2.1 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by the addition of 1N HCl (2.1 mL). After concentration, the residue was co-evaporated with toluene (3x). Crude acid (0.72 mmol), 2,4,6-trifluorobenzylamine (0.23 g, 1.44 mmol), N,N-diisopropylethylamine (DIPEA) (0.47 g, 3.6 mmol), and HATU (0.55 g, 1.44 mmol) were dissolved in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated _NaHCO₃ (2x), saturated _NH₄Cl (2x), and _dried over _Na₂SO₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexanes-EtOAc to give 102-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ found: 538.

Step 7

A 50-mL rbf was charged with 102-H (0.36 g, 0.67 mmol) in TFA (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 102. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 12.13 (s, 1H), 10.40 (t, J = 5.8 Hz, 1H), 8.28 (s, 1H), 6.64 (t, J = 8.1 Hz, 2H), 4.89-4.41 (m, 3H), 4.22 (t, J = 12.2 Hz, 1H), 4.09 (dd, J = 12.3, 3.1 Hz, 1H), 3.95 (dd, J = 12.1, 4.1 Hz, 1H), 2.45-1.60 (m, 9H). ¹⁹ F-NMR (376 MHz, CHLOROFORM-d) δ -109.26 (ddd, J = 15.1, 8.8, 6.3 Hz), -111.99 (t, J = 6.9 Hz). LCMS-ESI ⁺ (m/z): Found: 448.

Example 103

Preparation of Compound 103

(1R,4R,12aR)-2,3-Difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Step 1

In a dry ice / acetone bath, a solution of (1R, 3R, 4R, 5R, 6S) -5,6- dihydroxy -2- ((S) -1- phenylethyl) -2- azabicyclo [2.2.1] heptane -3- carboxylic acid methyl ester (2.0 g, 6.9 mmol) in DCM (27 mL) was cooled to -78 ° C. DAST (2.18 mL, 16.48 mmol) was added to the solution via a plastic tipped pipette. The solution was stirred for 30 minutes at -78 ° C, after which it was removed from the bath, slowly warmed to room temperature, and stirred at room temperature for 1 hour. The reaction was quenched by slowly adding the reaction mixture to a stirred solution of saturated sodium bicarbonate (150 mL) via a plastic tipped pipette. The layers were separated and the aqueous layer was back-extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (7-28% ethyl acetate/hexanes) to give 103-A. ¹ H-NMR (400 MHz, chloroform-d) δ 7.43-7.16 (m, 5H), 5.01-4.60 (m, 2H), 3.85 (q, J = 7.1, 6.6 Hz, 1H), 3.55 (s, 2H), 3.53-3.42 (m, 2H), 2.76 (dq, J = 5.1, 2.0 Hz, 1H), 2.19-2.07 (m, 1H), 2.03-1.88 (m, 1H), 1.39 (d, J = 6.7 Hz, 3H).

Steps 2 and 3

To a solution of 103-A (0.96 g, 3.24 mmol) in ethanol (36.01 mL) and 1.25 M HCl in ethanol (4.09 mL) was added 20% PdOH/C (1.14 g, 1.62 mmol). The suspension was stirred under a hydrogen atmosphere for 22 hours. After filtration through celite, the filter cake was washed with EtOH, and the filtrate was concentrated _to dryness in vacuo to _give the crude deprotected product, which was used in the next step at an estimated mass of 3.24 mmol _. LCMS- ^ESI (m/z): [M+H] Required ^for _C8H12F2NO2 : 192.08; Found: 192.110.

To the crude residue (0.62 g, 3.24 mmol) and di-tert-butyl dicarbonate (1.06 g, 4.86 mmol) in 2-methyltetrahydrofuran (32.43 mL) was added N,N-diisopropylethylamine (0.56 mL, 0 mol). Upon completion, the reaction mixture was diluted with water and extracted into EtOAc (2x), and the organic fractions were washed with water, combined, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica column chromatography (0-55% EtOAc/hexanes) to afford 103-B. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ 5.12-5.01 (m, 1H), 4.92 (s, 1H), 4.49 (s, 1H), 4.14 (d, J=14.7 Hz, 1H), 3.75 (s, 3H), 2.91 (s, 1H), 2.24-1.98 (m, 2H), 1.47 (s, 5H), 1.38 (s, 5H) _. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _requires : _C13H20F2NO4 : _292.13 ; found: 291.75.

Step 4

A solution of 103-B (0.68 g, 2.33 mmol) in THF (15 mL) was stirred in an ice bath while 1.0 M LiBH ₄ in THF (4.65 mL) was added. The resulting mixture was stirred at 0° C. for 30 minutes, at which point TLC indicated completion. The reaction mixture was carefully treated with water (0.3 mL), then with NaOH (~15%, 3.5 M, 0.3 mL), and finally with additional water (0.9 mL). The mixture was stirred at room temperature for 15 minutes, and the resulting ppt was filtered, washed with ether, and the supernatant was concentrated to provide 103-C. ¹ H-NMR (400 MHz, chloroform-d) δ 4.83 (s, 1H), 4.56 (d, J=10.5 Hz, 1H), 4.37 (s, 1H), 3.78-3.47 (m, 3H), 2.76 (s, 1H), 2.36-2.18 (m, 1H), 2.17-1.98 (m, 1H), 1.55 (s, 1H), 1.48 (s, 9H).

Steps 5 and 6

A mixture of 103-C (0.59 g, 2.25 mmol), phthalimide (0.53 g, 3.6 mmol), and triphenylphosphine (1.3 g, 4.95 mmol) in THF (11 mL) was cooled in an ice bath. Diisopropyl azodicarboxylate (0.97 mL, 4.95 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 14 hours before being concentrated in vacuo. The residue was dissolved in diethyl ether and stirred for 1 hour, after which the solid was filtered off and the filtrate was concentrated. The residue _{was purified by silica column chromatography (10-31-91% EtOAc/hexanes) to afford the protected amino compound (assuming 2.25 mmol of product). LCMS-ESI+ (m/z): [M+H]+ Required for C20H23F2N2O4 :} ^393.15 _; ^Found _{: 392.77} .

A solution of the protected amino compound (0.88 g, 2.25 mmol) and hydrazine hydrate (0.46 mL, 9.52 mmol) in ethanol (22 mL) was stirred at 60°C for 2 hours. The reaction mixture was cooled in an ice bath, ether (10 mL) was added, and the mixture was stirred for 30 minutes. The solid formed was filtered, and the filtrate was concentrated to dryness under vacuum to provide 103-D. ^1H -NMR (400 MHz, CHLOROFORM-d) δ 5.17-4.61 (m, 2H), 4.37 (s, 1H), 3.80 (s, 1H), 3.11-2.77 (m, 1H), 2.01 (s, 2H), 1.87 (s, 1H), 1.83 (d, J=7.4 Hz, 1H), 1.46 (s, 9H), 1.30 (d, J=6.4 Hz, 1H), 1.27 (d, J=6.3 Hz, 3H). LCMS-ESI ⁺ (m/ _{z )} : [M+H] ⁺ requires _{for C12H20F2N2O2} : _263.15 ; found: 262.86.

Steps 7, 8, and 9

Compound 103 was prepared by a procedure analogous to compound 60, using 103-D instead of 41-E and (2,4,6-trifluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. A single diastereomer was produced. The stereochemistry of fluorine is unknown. ¹ H-NMR (400MHz, chloroform-d) δ8.08(s,1H),6.46-6.27(m,2H),4.95(d,J＝53.5Hz,1H),4.65(d,J＝54.9Hz,1H),4.45(s,1H),4.33(d,J＝5.6H LCMS-ESI ⁺ (m/z):[M+H] of C ₂₁ H ₁₇ F ₅ N ₃ O ₄ ⁺ Theoretical value: 470.11; measured value: .470.13.

Antiviral assay

Example 104

Antiviral assay in MT4 cells

For antiviral assays using MT4 cells, 0.4 μL of 189X test concentration of 3-fold serially diluted compounds in DMSO was added to 40 μL of cell growth medium (RPMI 1640, 10% FBS, 1% penicillin/streptomycin, 1% L-glutamine, 1% HEPES) in quadruplicate in each well of a 384-well assay plate (10 concentrations).

A 1 mL aliquot of 2×10 ⁶ MT4 cells was pre-infected for 1 hour and 3 hours at 37° C. with 25 μL (MT4) of cell growth medium (mock infection) or fresh 1:250 dilution of HIV-IIIb concentrated ABI stock (0.004 moi for MT4 cells). Infected and uninfected cells were diluted in cell growth medium, and 35 μL of 2000 (for MT4) cells were added to each well of the assay plate.

The assay plate was then incubated in a 37°C incubator. After 5 days of incubation, 25 μL of 2X concentrated CellTiter-Glo ^™ reagent (Catalog # G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cells were lysed by incubation at room temperature for 2-3 minutes, and chemiluminescence was then read using an Envision reader (PerkinElmer).

In this assay, compounds of the invention demonstrated antiviral activity as described below in Table 1. Therefore, compounds of the invention may be used to treat the proliferation of HIV virus, treat AIDS, or delay the onset of AIDS or ARC symptoms.

Table 1

Example 105

Human PXR activation assay

Luciferase reporter gene assay: A stably transformed tumor cell line (DPX2) was plated in 96-well microtiter plates. DPX2 cells harbor the human PXR gene (NR1I2) and luciferase reporter genes linked to two promoters identified in the human CYP3A4 gene, namely, XREM and PXRE. Cells were treated with six concentrations of various compounds (0.15 to 50 μM) and cultured for 24 hours. The number of viable cells was determined and reporter gene activity was assessed. Positive control: rifampicin at six concentrations (0.1 to 20 μM). The % Emax relative to the maximum fold induction of RIF at 10 or 20 μM is the theoretical value of the test compound adjusted for DMSO background according to the following equation: % Emax = (fold induction - 1) / (maximum fold induction of RIF - 1) × 100%.

Table 2

Example 106

OCT2 inhibition assay

Dose-dependent inhibition of OCT2-mediated uptake of the model substrate ¹⁴ C-tetraethylammonium (TEA) by test compounds was studied in wild-type and OCT2-transfected MDCKII cells at seven concentrations ranging from 0.014 μM to 10 μM.

MDCKII cells are set at 37 ℃, 90% humidity and 5%CO ₂ in the incubator, maintain in the minimum essential medium (MEM) with 1% Pen/Strep, 10% fetal bovine serum and 0.25mg/mL hygromycin (hygromycin) B. 24 hours before measuring, the culture medium containing 5mM sodium butyrate is added to the MDCKII cells in the flask, and the cells are grown to 80-90% fusion. On the same day of measuring, cells are trypsinized and resuspended in Krebs-Henseleit buffer (KHB), pH 7.4, at 5 × 10 ⁶ million cells/mL. Before adding test compound or matrix, cells are pre-cultured 15 minutes in the assay plate.

The test compound was serially diluted in DMSO and then incorporated (2 μL) into 0.4 mL of KHB buffer containing wild-type or OCT2-transfected cells and cultured for 10 minutes. 0.1 mL of 100 μM ¹⁴ C-TEA (20 μM final concentration after mixing) in KHB buffer was added to start the assay. The concentration of TEA was based on Km. After 10 minutes of culture, 0.5 mL of ice-cold 1X PBS buffer was added to quench the assay mixture. The sample was then centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed. The rinse step was repeated 4 times with ice-cold PBS. Finally, the cell clumps were dissolved with 0.2 N NaOH and allowed to stand at room temperature for at least 30 minutes to ensure complete dissolution. The samples were then counted on a liquid scintillation counter and the following calculations were performed using dpm counting. The % inhibition was calculated as follows: % inhibition = [1-{[OCT2] _i- [WT] _ni }/{[OCT2] _ni- [WT] _ni }]*100, where [OCT2] _i represents the dpm counts of OCT2 cells in the presence of the test compound, [OCT2] _ni represents the dpm counts of OCT2 cells in the absence of the test compound, and [WT] _ni represents the dpm counts of wild-type cells in the absence of the test compound, respectively.

Table 3

The data in Tables 1, 2, and 3 represent the average over time of the individual measurements for each compound. For some compounds, multiple measurements were performed during the planned period. Therefore, the data reported in Tables 1, 2, and 3 include the data reported in the priority document, as well as data from measurements performed during the intervening period.

Example 107

Pharmacokinetic analysis after oral or intravenous administration to beagle dogs

Pharmacokinetic analysis of various test compounds was performed following intravenous or oral administration to beagle dogs.

For pharmacokinetic analysis of intravenously administered compounds, the test compounds were formulated in 5% ethanol, 55% PEG 300, and 40% water at 0.1 mg/mL for IV infusion. For pharmacokinetic analysis of orally administered compounds, the test compounds were formulated in an aqueous suspension of 0.1% Tween 20, 0.5% HPMC LV100 in Di Water at 1 mg/kg.

Each drug group is made up of 3 male, adult (non-naive) purebred beagle dogs.When administering, animal weighs between 10 and 13kg.Before and after dosing, up to 4 hours, animals are fasted overnight.For intravenous administration research, test article is administered to animal by intravenous infusion 30 minutes.According to the body weight of each animal, the infusion rate is regulated to send the dosage of 0.5mg/kg.For the research of oral administration, according to the body weight administration test article of each animal, the dosage of 1mg/kg is sent.

For the pharmacokinetic analysis of the compound of intravenous administration, after dosage administration, 0, 0.250, 0.483, 0.583, 0.750, 1.00, 1.50, 2.00, 4.00, 8.00, 12.0 and 24.0 hours from each animal collection continuous venous blood sample (about 1mL each).Blood sample is collected in the Vacutainer containing EDTA-K2 as anticoagulant ^TM tube, and is immediately placed on wet ice until centrifuged for blood plasma.The concentration of test compound in blood plasma is measured using LC/MS/MS method.The aliquot of each plasma sample of 100 μ L is added in clean 96 orifice plates, and adds in the cold acetonitrile/internal standard solution (ACN)/(ISTD) of 400 μ L.After protein precipitation, the aliquot of the supernatant of 110 μ L is transferred in clean 96 orifice plates, and with the water dilution of 300 μ L. A 25 μL aliquot of the above solution was injected into a TSQ Quantum Ultra LC/MS/MS system utilizing a Hypersil Gold C ₁₈ HPLC column (50×3.0 mm, 5 μm; Thermo-Hypersil Part #25105-053030). An Agilent 1200 Series Binary Pump (P/N G1312A Bin Pump) was used for elution and separation, and an HTSPal autosampler (LEAP Technologies, Carrboro, NC) was used for sample injection. A TSQ Quantum Ultra triple quadrupole mass spectrometer (Thermo Finnigan, San Jose, CA) was used in selected reaction monitoring mode. Liquid chromatography was performed using two mobile phases: mobile phase A contained 1% acetonitrile in 2.5 mM aqueous ammonium formate, pH 3.0; and mobile phase B contained 90% acetonitrile in 10 mM ammonium formate, pH 4.6. Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The resulting data are shown in the first three columns of Table 4. In Table 4, CL refers to clearance, which characterizes the rate at which a drug is cleared from plasma. The lower the drug clearance, the longer the in vivo elimination half-life. _Vss refers to the steady-state volume of distribution and indicates how well a drug is distributed in tissues. The larger the Vss, the longer the in vivo elimination half-life. MRT refers to mean residence time, which is a measure of the average time a molecule remains in the body.

For pharmacokinetic analysis of orally administered compounds, serial venous blood samples (approximately 0.3 mL each) were collected from each animal at 0, 0.25, 0.50, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after dosing. Blood samples were collected, prepared, and analyzed in a manner similar to the intravenous studies described above. Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The resulting data are shown in the last three columns of Table 4. In Table 4, F (%) refers to oral bioavailability. _Cmax refers to the peak plasma concentration of the compound after dosing. AUC refers to the area under the curve and is a measure of the total plasma exposure of the indicated compound.

Table 4

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety to the extent not inconsistent with this specification.

From the foregoing, it should be understood that although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not to be limited except as in the appended claims.

Claims (14)

1. Compounds having the following formula (I): Or its stereoisomers or medicinal salts. in: X is -O-; W is -CHZ ² -; ^Z1 and ^Z2 combine to form -L-, where L is -C( ^Ra ) _2C ( ^Ra ) _2- ; Z ⁴ is -CH ₂ -; ^Y1 and ^Y2 are each independently hydrogen, _C1-3 alkyl, or _C1-3 haloalkyl; ^R1 is a phenyl group substituted with one to three halogens; and Each ^Ra is independently hydrogen, halogen, hydroxyl, or _C1-4 alkyl. 2. The compound of claim 1, having the following formula (II-A): Wherein X, L and ^R1 are as defined in claim 1. 3. The compound of any one of claims 1-2, wherein each ^Ra is hydrogen. 4. The compound of any one of claims 1-2, wherein ^Y1 and ^Y2 are each independently hydrogen, methyl or trifluoromethyl. 5. The compound of any one of claims 1-2, wherein ^R1 is substituted with three halogens. 6. The compound of claim 5, wherein ^R1 is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. 7. The compound of claim 6, wherein ^R1 is 2,4,6-trifluorophenyl. 8. The compound of claim 1, selected from: 9. A pharmaceutical composition comprising a compound of any one of claims 1-8 or a stereoisomer thereof or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient. 10. The pharmaceutical composition of claim 9, further comprising one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are anti-HIV agents. 11. The pharmaceutical composition of claim 10, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof. 12. A pharmaceutical composition, comprising a compound: Or its stereoisomers or pharmaceutically acceptable salts and pharmaceutically acceptable carriers, diluents or excipients; and one or more other therapeutic agents selected from: lamivudine, abacavir, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, and combinations thereof. 13. The pharmaceutical composition of claim 12, wherein the one or more additional therapeutic agents are selected from emtricitabine, tenofovir alafenamide, and combinations thereof. 14. Use of a compound of any one of claims 1-8 or a pharmaceutical composition of any one of claims 9-13 in the preparation of a medicament for treating HIV infection in a person who has or is at risk of having an infection.