Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

Abstract

To provide compounds for use in the treatment of human immunodeficiency virus (HIV) infection.SOLUTION: The compounds have the following Formula (I), including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, X, W, Y1, Y2, Z1, and Z4 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Citation of Related Applications This 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, all of which are incorporated herein by reference in their entireties.

[0002] background Field Compounds, compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection are disclosed. In particular, novel polycyclic carbamoylpyridone compounds, and methods for their preparation and use as therapeutic or prophylactic agents, are disclosed. [Background technology]

[0003] 2. Description of Related Art 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. Drugs targeting reverse transcriptase and protease are widely used and have shown efficacy, but toxicity and the emergence of resistant strains, especially when used in combination, limit their usefulness (Palella et al., N. Engl. J Med. (1998) 338:853-860; Richman, DD Nature (2001) 410:995-1001).

[0004] Pregnane X receptor (PXR) is a nuclear receptor that is one of the major regulators of enzymes involved in the metabolism and excretion of small molecules from the body. PXR activation is known to upregulate or induce the production of metabolic enzymes (e.g., cytochrome P450 3A4 (CYP3A4)) and enzymes involved in transport in the liver and intestinal tract (e.g., OATP2) (Endocrine Reviews (2002) 23 (5): 687-702). If a drug causes upregulation of these and other enzymes through PXR activation, the absorption and / or exposure of co-administered drugs that are susceptible to this upregulated enzyme may be reduced. 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 classes of molecules (Endocrine Reviews (2002) 23 (5): 687-702). Therefore, it is important to test for and minimize PXR activation for drugs that are administered in conjunction with other drugs.

[0005] Transporters have been identified to play a role in the pharmacokinetics, safety, and efficacy profiles of drugs, and certain 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 in the basolateral membrane of renal proximal tubules. OCT2, distinct from the apically expressed multidrug and toxin extrusion (MATE) transporters 1 and 2-K, is thought to form the major cation secretory pathway in the kidney and has been shown to transport endogenous compounds (including creatinine) and xenobiotics (including metformin). Therefore, inhibition of OCT2 can result in elevated serum creatinine levels and potentially elevated levels of other OCT2 substrates. It is also important to test drugs for OCT2 inhibition and to reduce OCT2 inhibition.

[0006] The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Treatment guidelines published by the U.S. Department of Health and Human Services stipulate that achieving viral suppression requires combination therapy, i.e., the use of several drugs from at least two or more drug classes (Adult and Adolescent Antiretroviral Guidelines Task Force. Guidelines for the Use of Antiretroviral Agents in Adult and Adolescent HIV-1 Infected Persons. Department of Health and Human Services. Available at http: / / aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf., accessed March 14, 2013). Furthermore, decisions regarding the treatment of HIV-infected patients are complicated when the patient requires treatment for other medical conditions (ibid. E-12). Because the standard of care requires the use of multiple different drugs to suppress HIV and to treat other conditions the patient may be experiencing, the potential for drug interactions is a criterion for the selection of drug regimens. Therefore, there is a need for antiretroviral therapy with a reduced potential for drug interactions.

[0007] Therefore, there is a need for new agents that inhibit HIV replication and minimize activation of PXR when administered concomitantly with other drugs. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Palella et al., N. Engl. J Med. (1998) 338:853-860 [Non-patent document 2] Richman, DDNature (2001) 410:995-1001 [Non-patent document 3] Endocrine Reviews(2002)23(5):687-702 [Non-patent document 4] Giacomini KM et al., “Membrane transporters in drug development”, Nat.Rev Drug Discov.9:215-236, 2010 [Non-Patent Document 5] Zhang L et al., “Transporter-Mediated Drug-Drug Interactions”, Clin.Pharm.Ther.89(4):481-484(2011) [Non-patent document 6] 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, [online], [Retrieved March 14, 2013].<URL:http: / / aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf.> Summary of the Invention [Means for solving the problem]

[0009] A brief summary The present invention relates to novel polycyclic carbamoylpyridone compounds (including their stereoisomers and pharmaceutically acceptable salts) having antiviral activity, and the use of such compounds in the treatment of HIV infection. The compounds of the present invention can be used to inhibit the activity of HIV integrase and to reduce HIV replication.

[0010] In one embodiment of the present invention, the compound of formula (I):

[0011] [ka]

[0012] or a stereoisomer or a pharmaceutically acceptable salt thereof, In formula (I): X is -O- or -NZ 3 -or- CHZ 3 - and; W is -CHZ 2 - and; 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 and together form -L-, where L is -C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, or -C(R a )2C(R a )2C(R a )2C(R a )2-, where Z 1 and Z 2 , or Z 1 and Z 3 at least one of which together form -L-; Z 4 is a bond, -CH2-, or -CH2CH2-; Y 1 and Y 2 are each independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1 is phenyl substituted with 1 to 3 halogens; and Each R a are independently hydrogen, halo, hydroxyl or C1~4 It is alkyl.

[0013] In another embodiment of the present invention, a compound of formula (I):

[0014] [ka]

[0015] or a stereoisomer or a pharmaceutically acceptable salt thereof, In formula (I): X is -O- or -NZ 3 -or- CHZ 3 - and; W is -O- or -NZ 2 -or- CHZ 2 - and; 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 and together form -L-, where L is -C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2C(R a )2-, -C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2-, -C(R a )2SO2C(R a )2-, -C(Ra )2OC(R a )2C(R a )2-, -C(R a )2C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2C(R a )2-, -C(R a )2C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2C(R a )2-, -C(R a )2C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2C(R a )2-, -C(R a )2C(R a )2S(O)C(R a )2-, -C(R a )2SO2C(R a )2C(R a )2-, -C(R a )2C(R a )2SO2C(R a )2-, -C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2- and; Z 4 is a bond or -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2NR a CH2-, -CH2SCH2-, -CH2S(O)CH2- or -CH2SO2CH2-; Y 1 and Y 2 are each independently hydrogen, C 1~3 Alkyl or C 1~3 haloalkyl, or Y 1 and Y 2together 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 ring or heterocyclic ring is a with substitution as necessary; R 1 is optionally substituted aryl or optionally substituted heteroaryl; and Each R a are independently hydrogen, halo, hydroxyl or C 1~4 alkyl or two R a The groups, together with the carbon atoms to which they are attached, form =O, and (i) Z 1 and Z 2 , or Z 1 and Z 3 together form -L-; or (ii) Y 1 and Y 2 are at least one of: together with the carbon atom to which they are attached, a carbocyclic ring having 3 to 6 ring atoms, or a heterocyclic ring having 3 to 6 ring atoms.

[0016] In another embodiment, there is provided a pharmaceutical composition comprising a compound having formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0017] The present invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of HIV infection in a human having or at risk of having HIV infection.

[0018] In another embodiment, methods of using compounds having formula (I) in therapy are provided. Specifically, methods are provided for treating the growth of the HIV virus, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human), comprising administering to the mammal a compound having formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0019] In another embodiment, disclosed is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the treatment of HIV infection in a human having or at risk of having HIV infection.

[0020] In another embodiment, disclosed is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the manufacture of a medicament for the treatment of HIV infection in a human having or at risk of having HIV infection.

[0021] In another embodiment, an article of manufacture is disclosed that includes a composition effective for treating HIV infection; and packaging material with a label indicating that the composition can be used to treat infection by HIV. An exemplary composition contains a compound of formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof.

[0022] In yet another embodiment, a method of inhibiting the replication of HIV is disclosed, comprising exposing the virus to an effective amount of a compound of formula (I) or a salt thereof under conditions such that the replication of HIV is inhibited.

[0023] In another embodiment, the use of a compound of formula (I) for inhibiting the activity of the HIV integrase enzyme is disclosed.

[0024] In another embodiment, the use of a compound of formula (I) or a salt thereof for inhibiting the replication of HIV is disclosed.

[0025] Other embodiments, objects, features and advantages will be set forth in the following detailed description of the embodiments, and in part will be obvious from the description or may be learned by the practice of the invention. These objects and advantages will be realized and attained by the processes and compositions particularly pointed out in the written description and claims thereof. The foregoing summary has been prepared with the understanding that it should be considered a brief, general summary of some of the embodiments disclosed herein, that it is provided merely for the benefit and convenience of the reader, and that it is not intended in any way to limit the scope of the appended claims to which they are legally entitled or to equivalents thereof. DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description In the following description, certain specific details are set forth for the purpose of providing a thorough understanding of various embodiments of the present invention. However, those skilled in the art will understand that the present invention may be practiced without these details. The following description of several embodiments is made with the understanding that this disclosure should be considered an illustration of the subject matter of the present application and is not intended to limit the scope of the appended claims to the specific embodiments described. Headings used throughout this disclosure are provided for convenience only and should not be construed to limit the scope of the claims in any way. Embodiments described under any heading may be combined with embodiments described under any other heading.

[0027] definition Unless the context requires otherwise, throughout this specification and claims, the term "comprise" and variations thereof (e.g., "comprises" and "comprising") are to be interpreted in an open and inclusive sense, i.e., "including but not limited to."

[0028] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the 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, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0029] Unless the context requires otherwise, reference to "a compound of Formula (I)" or "compounds of Formula (I)" refers to all embodiments of Formula (I), including compounds of Formula (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 specific compounds disclosed herein.

[0030] "Amino" refers to the -NH2 radical.

[0031] "Cyano" refers to the -CN radical.

[0032] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0033] "Imino" refers to the =NH substituent.

[0034] "Nitro" refers to the -NO2 radical.

[0035] "Oxo" refers to the =O substituent.

[0036] "Thioxo" refers to the =S substituent.

[0037] "Alkyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, saturated or unsaturated (i.e., containing one or more double or triple bonds), and containing from 1 to 12 carbon atoms (C1 to C 12 "Ci-C alkyl" refers to a straight or branched hydrocarbon chain radical (e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like), preferably having 1 to 8 carbon atoms (Ci-C alkyl), or 1 to 6 carbon atoms (Ci-C alkyl), and attached to the rest of the molecule by a single bond. Unless specifically stated otherwise in the specification, alkyl groups can be optionally substituted.

[0038] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain (e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, and n-butynylene) that connects the rest of the molecule to a radical group, is saturated or unsaturated (i.e., contains one or more double or triple bonds), and has 1 to 12 carbon atoms (e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, and n-butynylene, etc.). The alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or 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, an alkylene chain can be optionally substituted.

[0039] "Alkoxy" means a group of the formula -OR A where R A is an alkyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0040] "Alkylamino" means a group of the formula -NHR A or -NR A R A where each R A is independently an alkyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0041] "Thioalkyl" means a group of the formula -SR A where R A is an alkyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.

[0042] "Aryl" refers to a monocyclic hydrocarbon ring system radical containing a hydrogen atom and 6 to 18 carbon atoms. Aryl radicals include, but are not limited to, aryl radicals derived from benzene. Unless otherwise specifically stated herein, the term "aryl" or the prefix "ar-" (as in aralkyl) is meant to include aryl radicals that are optionally substituted.

[0043] "Aralkyl" means a group of the formula -R B -R C where R B is an alkylene chain as defined above, and R C is one or more aryl radicals as defined above (e.g., benzyl). Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

[0044] "Cycloalkyl" or "carbocyclic ring" refers to a stable non-aromatic monocyclic hydrocarbon radical consisting exclusively of carbon and hydrogen atoms, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or unsaturated, and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless specifically stated otherwise in the specification, cycloalkyl groups can be optionally substituted.

[0045] "Cycloalkylalkyl" means a group of the formula -R B R D where R B is an alkylene chain as defined above, and R D is a cycloalkyl radical, as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.

[0046] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0047] "Haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halo radicals, as defined above (e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). Unless specifically stated otherwise in the specification, a haloalkyl group can be optionally substituted.

[0048] "Heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 18-membered non-aromatic ring radical, which consists of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In embodiments disclosed herein, the heterocyclyl radical is a monocyclic ring system, and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl, [1,3]dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, heterocyclyl groups may be optionally substituted.

[0049] "N-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and wherein the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless specifically stated otherwise in the specification, N-heterocyclyl groups can be optionally substituted.

[0050] "Heterocyclylalkyl" means a group of the formula -R B R E where R B is an alkylene chain as defined above, and R E is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, it may be attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

[0051] "Heteroaryl" refers to a 5- to 14-membered monocyclic ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples include, but are not limited to, azepinyl, furanyl, furanonyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thiophenyl, and thienyl. Unless otherwise specified herein, heteroaryl groups can be optionally substituted.

[0052] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and wherein the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless specifically stated otherwise in the specification, N-heteroaryl groups can be optionally substituted.

[0053] "Heteroarylalkyl" means a group of the formula -R B R F where R B is an alkylene chain as defined above, and R Fis a heteroaryl radical, as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group 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, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl) in which at least one hydrogen atom has been replaced by a bond to a non-hydrogen atom (e.g., halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and heteroatoms in various other groups). "Substituted" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a heteroatom (e.g., oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles). For example, "substituted" refers to any group ... G R H , -NR G C(=O)R H , -NR G C(=O)NR G R H , -NR G C(=O)OR H , -NR G C(=NR g )NR G R H, -NR G SO2R H , -OC(=O)NR G R H , -OR G , -SR G , -SOR G , -SO2R G , -OSO2R G , -SO2OR G , =NSO2R G , and -SO2NR G R H "Substituted" also includes any of the above groups where one or more hydrogen atoms have been replaced with -C(=O)R. G , -C(=O)OR G , -C(=O)NR G R H , -CH2SO2R G , -CH2SO2NR G R H In the above, R G and R H are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms have been replaced by a bond to an amino group, cyano group, hydroxyl group, imino group, nitro group, oxo group, thioxo group, halo group, alkyl group, alkoxy group, alkylamino group, thioalkyl group, aryl group, aralkyl group, cycloalkyl group, cycloalkylalkyl group, haloalkyl group, heterocyclyl group, N-heterocyclyl group, heterocyclylalkyl group, heteroaryl group, N-heteroaryl group, and / or heteroarylalkyl group. Furthermore, each of the above substituents can also be optionally substituted with one or more of the above substituents.

[0054] The term "protecting group," as used herein, refers to a labile chemical moiety known in the art for protecting reactive groups (including, but not limited to, hydroxyl and amino groups) against undesired reactions during synthetic procedures. Hydroxyl and amino groups protected with a protecting group are referred to as "protected hydroxyl groups" and "protected amino groups," respectively. Protecting groups are typically used selectively and / or orthogonally to protect sites during reactions at other reactive sites, and can then be removed to leave unprotected groups intact or available for 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). Generally, groups are protected or exist as precursors, inert to reactions that modify other regions of the parent molecule, for conversion to their final groups at the appropriate time. Further 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 "hydroxyl protecting groups" include, but are not limited to, t-butyl, t-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, t-butyldimethylsilyl, t-butyl-diphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, tri-fluoro-acetate, pivaloate, benzoate, p-phenylbenzoate, 9-fluorenylmethylcarbonate, mesylate, and tosylate.Examples of "amino-protecting groups" include, but are not limited to, carbamate protecting groups (e.g., 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)-ethoxy-carbonyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz)); amide protecting groups (e.g., formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl); sulfonamide protecting groups (e.g., 2-nitrobenzenesulfonyl); and imine and cyclic imide protecting groups (e.g., phthalimide and dithiasuccinoyl).

[0055] The invention disclosed herein is also intended to encompass all pharmaceutically acceptable compounds of formula (I) that are isotopically labeled by replacing one or more atoms with an atom having a different atomic mass or mass number. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine (e.g., 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 may be useful to aid in determining or measuring the effectiveness of these compounds, for example, by characterizing the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of formula (I) (e.g., compounds incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e.3 H, and carbon-14 i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and rapid means of detection.

[0056] Heavier isotopes (e.g., deuterium i.e. 2 Substitution with H may confer certain therapeutic advantages resulting from greater metabolic stability. For example, the in vivo half-life may be increased or the dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some situations.

[0057] Positron-emitting isotopes (e.g., 11 C. 18 F, 15 O and 13 Substitution at N) may be useful in positron emission tomography (PET) studies to examine receptor occupancy by substrates. Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples set forth below, using the appropriate isotopically labeled reagent in place of the previously used unlabeled reagent.

[0058] The invention disclosed herein is also intended to encompass in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the administered compound, primarily due to enzymatic processes. Thus, the invention encompasses compounds produced by a process comprising administering a compound of the invention to a mammal for a period of time sufficient to yield its metabolic products. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the invention to an animal (e.g., a rat, mouse, guinea pig, monkey, or human), allowing metabolism to occur for a sufficient period of time, and isolating the conversion products from urine, blood, or other biological sample.

[0059] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0060] "Mammal" includes both humans and domestic animals, such as laboratory animals and household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals, such as wildlife.

[0061] "Optionally" or "optionally" means that the subsequently described circumstance event may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted and unsubstituted aryl radicals.

[0062] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0063] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted into a form that possesses) the desired pharmacological activity of the parent compound. Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts of compounds containing a suitable base (e.g., alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium, and NX4). +(wherein X is C1-C4 alkyl). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, salts of organic carboxylic acids (e.g., 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 (e.g., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid); and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and sulfamic acid). Pharmaceutically acceptable salts of hydroxy groups of a compound include salts of suitable cations of the compound (e.g., Na + and NX4 + (wherein X is independently selected from H or a C1-C4 alkyl group). Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is replaced by either a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or when coordinated with an organic base (e.g., diethanolamine, triethanolamine, N-methylglucamine, and the like). Ammonium salts, and substituted ammonium salts or quaternary ammonium salts are also included in this definition. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, edited by R. Hendrickson, 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Table 38-5, both of which are incorporated herein by reference.

[0064] For therapeutic use, salts of the active ingredients of the compounds disclosed herein are typically pharmaceutically acceptable. That is, they are salts derived from pharmaceutically acceptable acids or bases. However, salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of formula (I) or another compound of the present invention. All salts, whether derived from pharmaceutically acceptable acids or bases or not, are within the scope of the present invention.

[0065] Metal salts are typically prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts prepared in this manner are Li + , Na + , and K. + A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

[0066] Additionally, salts can be formed by acid addition of certain organic and inorganic acids (e.g., HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids) to a basic center (typically an amine). Finally, it should be understood that the compositions herein contain the compounds disclosed herein in their non-ionized and zwitterionic forms, as well as in combination with a stoichiometric amount of water as hydrates.

[0067] Crystallization often produces solvates of the compounds of the present invention. As used herein, the term "solvate" refers to an aggregate containing one or more molecules of the compounds of the present invention with one or more molecules of solvent. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present invention can exist as hydrates (including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc.) and corresponding solvated forms. The compounds of the present invention can be true solvates, while in other cases, the compounds of the present invention may simply retain incidental water or a mixture of water and incidental solvents.

[0068] A "pharmaceutical composition" refers to a formulation of a compound of the present invention with a medium generally accepted in the art for the delivery of biologically active compounds to mammals (e.g., humans), including any pharmaceutically acceptable carrier, diluent, or excipient therefor.

[0069] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound according to the present invention that, when administered to a patient in need thereof, is sufficient to cause treatment of a disease state, condition, or disorder for which the compound has utility. Such an amount is sufficient to elicit the biological or medical response in a tissue or patient desired by a researcher or clinician. The amount of a compound according to the present invention that constitutes a therapeutically effective amount will vary depending on the compound and its biological activity, the composition used for administration, the number of doses, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, drugs used in conjunction with or concurrently with the compound of the present invention, and factors such as the patient's age, weight, general health, sex, and diet. Such a therapeutically effective amount can be routinely determined by one skilled in the art, taking into account their own knowledge, the state of the art, and this disclosure.

[0070] The term "treatment," as used herein, is intended to mean the administration of a compound or composition according to the invention to reduce or eliminate the symptoms of HIV infection in a patient and / or to reduce the viral load. The term "treatment" also encompasses the administration of a compound or composition according to the invention after an individual's exposure to the virus, but before the appearance of disease symptoms and / or before the virus is detected in the blood, to prevent the appearance of disease symptoms 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 invention to a mother before birth and to a child within the first few days of life, thereby preventing perinatal transmission of HIV from mother to newborn.

[0071] The term "antiviral agent," as used herein, is intended to mean an agent (compound or biological) effective to inhibit the formation and / or replication of a virus in humans, including, but not limited to, an agent that interferes with either the host or viral mechanisms necessary for the formation and / or replication of a virus in humans.

[0072] The term "inhibitor of HIV replication," as used herein, is intended to mean an agent that is capable of reducing or eliminating the ability of HIV to replicate in host cells, whether in vitro, ex vivo, or in vivo.

[0073] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers and diastereomers, as well as other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The present invention is intended to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate, optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) 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 specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0074] "Stereoisomers" refer to compounds composed of the same atoms connected by the same bonds but with different, non-interchangeable three-dimensional structures. 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.

[0075] "Tautomer" refers to the shifting of a proton from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of these compounds.

[0076] "Prodrug" refers to a compound chemically designed to effectively release the parent drug after crossing the biological barrier for oral delivery. In certain embodiments, the present invention encompasses prodrugs of compounds of formula (I).

[0077] compound As noted above, in one embodiment of the present invention, compounds having antiviral activity are provided, which compounds have the following formula (I):

[0078] [ka]

[0079] or a stereoisomer or pharmaceutically acceptable salt thereof; In formula (I): X is -O- or -NZ 3 -or- CHZ 3 - and; W is -CHZ 2 - and; 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 and together form -L-, where L is -C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, or -C(R a )2C(R a )2C(R a )2C(R a )2-, where Z 1 and Z 2 , or Z 1 and Z 3 at least one of which together form -L-; Z4 is a bond, -CH2-, or -CH2CH2-; Y 1 and Y 2 are each independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1 is phenyl substituted with 1 to 3 halogens; and Each R a are independently hydrogen, halo, hydroxyl or C 1~4 It is alkyl.

[0080] In another embodiment, the compound of formula (II-A) below:

[0081] [ka]

[0082] Compounds having the formula:

[0083] In another embodiment, the compound of formula (II-B) below:

[0084] [ka]

[0085] Compounds having the formula:

[0086] In another embodiment, the compound of formula (II-C) below:

[0087] [ka]

[0088] Compounds having the formula:

[0089] In another embodiment, L is -C(R a In a further embodiment, L is -C(R a )2C(Ra )2-. In still further embodiments, L is -C(R a )2C(R a )2C(R a )2-. In still further embodiments, each R a is hydrogen. In still further embodiments, one R a is methyl, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining R a Each of is hydrogen.

[0090] In another embodiment, X is -O-. In another embodiment, X is -NZ 3 In another embodiment, X is -NH-. 16. In another embodiment, X is -CHZ 3 - and Z 1 and Z 3 and together form -L-. In a further embodiment, Z 2 is hydrogen. In another embodiment, X is —CH 2 —.

[0091] In another embodiment, Z 4 is a bond or -CH2-. 4 is -CH2-. In another embodiment, Z 4 is a bond.

[0092] In another embodiment, Y 1 and Y 2 are each independently hydrogen, methyl, or trifluoromethyl.

[0093] In another embodiment, R 1is substituted with one halogen. In a further embodiment, R 1 is 4-fluorophenyl or 2-fluorophenyl.

[0094] 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. 1 is 2,4-difluorophenyl.

[0095] In another embodiment, R 1 is substituted with 3 halogens. In a further embodiment, R 1 is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. 1 is 2,4,6-trifluorophenyl.

[0096] In one embodiment, a pharmaceutical composition is provided comprising 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.

[0097] Another embodiment is provided that includes a method of treating HIV infection in a human having or at risk of having HIV infection by administering to the human a therapeutically effective amount of a compound of any one of Formulas (I), (II-A), (II-B), or (II-C), 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 HIV infection by administering to the human a therapeutically effective amount of a compound of any one of Formulas (I), (II-A), (II-B), or (II-C), as described above, or a pharmaceutical composition thereof.

[0098] In another embodiment, there is provided a use of a compound of any one of formulas (I), (II-A), (II-B), or (II-C), as described above, or a pharmaceutical composition thereof, for the treatment of HIV infection in a human having or at risk of having HIV infection. In another embodiment, there is provided a use of a compound of any one of formulas (I), (II-A), (II-B), or (II-C), as described above, or a pharmaceutical composition thereof, for the treatment or prevention of HIV infection in a human having or at risk of having HIV infection.

[0099] In another embodiment, there is provided a use 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 medical therapy.

[0100] In another embodiment, there is provided a use of a compound of any one of formulas (I), (II-A), (II-B), or (II-C), as described above, or a pharmaceutical composition thereof, for use in the therapeutic treatment of HIV infection. In another embodiment, there is provided a use of a compound of any one of formulas (I), (II-A), (II-B), or (II-C), as described above, or a pharmaceutical composition thereof, for use in the prophylactic or therapeutic treatment of HIV infection.

[0101] As further described above, in another embodiment of the present invention, compounds having antiviral activity are provided, which compounds have the following formula (I):

[0102] [ka]

[0103] or a stereoisomer or pharmaceutically acceptable salt thereof; In formula (I): X is -O- or -NZ 3 -or- CHZ 3 - and; W is -O- or -NZ 2 -or- CHZ 2 - and; 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 and together form -L-, where L is -C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2C(R a )2-, -C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2-, -C(R a)2SO2C(R a )2-, -C(R a )2OC(R a )2C(R a )2-, -C(R a )2C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2C(R a )2-, -C(R a )2C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2C(R a )2-, -C(R a )2C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2C(R a )2-, -C(R a )2C(R a )2S(O)C(R a )2-, -C(R a )2SO2C(R a )2C(R a )2-, -C(R a )2C(R a )2SO2C(R a )2-, -C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2- and; Z 4 is a bond or -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2NR a CH2-, -CH2SCH2-, -CH2S(O)CH2- or -CH2SO2CH2-; Y 1 and Y 2 are each independently hydrogen or C 1~3 alkyl or Y 1 and Y2 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 ring or heterocyclic ring is a with substitution as necessary; R 1 is optionally substituted aryl or optionally substituted heteroaryl; and Each R a are independently hydrogen, halo, hydroxyl or C 1~4 alkyl or two R a The groups, together with the carbon atoms to which they are attached, form =O, and (i)Z 1 and Z 2 , or Z 1 and Z 3 and together form -L-; or (ii) Y 1 and Y 2 means that, together with the carbon atom to which they are attached, they form at least one of a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

[0104] In another embodiment, W is -CHZ 2 -It is.

[0105] In another embodiment, Z 1 and Z 2 , or Z 1 and Z 3 Together with -L-,

[0106] In another embodiment, the compound of formula (II-A), (II-B), or (II-C) below:

[0107] [ka]

[0108] wherein L is —C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2C(R a )2-, -C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2-, -C(R a )2SO2C(R a )2-, -C(R a )2OC(R a )2C(R a )2-, -C(R a )2C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2C(R a )2-, -C(R a )2C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2C(R a )2-, -C(R a )2C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2C(R a )2-, -C(R a )2C(R a )2S(O)C(R a )2-, -C(R a )2SO2C(R a )2C(R a )2-, -C(Ra )2C(R a )2SO2C(R a )2-, -C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2-.

[0109] In another embodiment, 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.

[0110] In another embodiment, the compound of formula (III-A), (III-B), (III-C) or (III-D) below:

[0111] [ka]

[0112] [ka]

[0113] and wherein Z is a substituted or unsubstituted alkyl group; 1 and Z 3 are each independently hydrogen or C 1~3 It is alkyl.

[0114] In another embodiment, the compound of formula (III-E), (III-F), (III-G) or (III-H) below:

[0115] [ka]

[0116] [ka]

[0117] and wherein Z is a substituted or unsubstituted alkyl group; 1 and Z 3 are each independently hydrogen or C 1~3 It is alkyl.

[0118] In another embodiment, (i) Z 1 and Z 2 , or Z 1 and Z 3 and (ii) Y 1 and Y 2 together with the carbon atom to which they are attached to form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

[0119] In another embodiment, a compound of formula (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG) or (IV-AH) below:

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] wherein L is —C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, -C(R a )2C(R a)2C(R a )2C(R a )2-、-C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2-、-C(R a )2OC(R a )2C(R a )2-、-C(R a )2C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2C(R a )2-、-C(R a )2C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2C(R a )2-、-C(R a )2C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2C(R a )2-、-C(R a )2C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NR a C(R a )2-または-C(R a )2NR a SO2C(R a )2-である。

[0124] In another embodiment, a compound of formula (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) or (IV-BH) is selected from the group consisting of:

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] wherein L is —C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2C(R a )2-, -C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2-, -C(R a )2SO2C(R a )2-, -C(R a )2OC(R a )2C(R a )2-, -C(R a )2C(R a )2OC(R a )2-, -C(Ra )2NR a C(R a )2C(R a )2-, -C(R a )2C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2C(R a )2-, -C(R a )2C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2C(R a )2-, -C(R a )2C(R a )2S(O)C(R a )2-, -C(R a )2SO2C(R a )2C(R a )2-, -C(R a )2C(R a )2SO2C(R a )2-, -C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2-.

[0129] In another embodiment, L is —C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, or -C(R a )2C(R a )2C(R a )2C(R a In a further embodiment, L is -C(R a )2-. In still further embodiments, L is -C(R a )2C(R a )2-. In still further embodiments, L is -C(R a)2C(R a )2C(R a )2-. In still further embodiments, each R a is hydrogen. In still further embodiments, one R a is methyl, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining R a Each of is hydrogen.

[0130] In another embodiment, L is —C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2-, or -C(R a )2SO2C(R a In a further embodiment, L is -C(R a )2OC(R a )2-. In still further embodiments, each R a is hydrogen. In still further embodiments, one R a is methyl, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining R a Each of R is hydrogen. a is a halogen, and the remaining Ra Each of is hydrogen.

[0131] In another embodiment, X is -O-. 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 -CH2-.

[0132] In another embodiment, Z 4 is a bond or -CH2-. 4 is -CH2-. In another embodiment, Z 4 is a bond.

[0133] In another embodiment, Y 1 and Y 2 are each independently hydrogen, methyl, or trifluoromethyl.

[0134] In another embodiment, R 1 is substituted with one halogen. In a further embodiment, R 1 is 4-fluorophenyl or 2-fluorophenyl.

[0135] In another embodiment, R 1 is phenyl. In another embodiment, R 1 is pyridinyl.

[0136] In another embodiment, R 1 is substituted with at least one halogen.

[0137] In another embodiment, R 1 is substituted with one halogen. In a further embodiment, R 1 is 4-fluorophenyl or 2-fluorophenyl.

[0138] 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. 1 is 2,4-difluorophenyl.

[0139] In another embodiment, R 1 is substituted with 3 halogens. In a further embodiment, R 1 is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. 1 is 2,4,6-trifluorophenyl.

[0140] In another embodiment, R 1 is 3-trifluoromethyl-4-fluorophenyl or 2-cyclopropoxy-4-fluorophenyl.

[0141] In one embodiment, there is provided a pharmaceutical composition comprising a compound of any one of Formulas (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.

[0142] Another embodiment is provided that includes a method of treating HIV infection in a human having or at risk of having HIV infection by administering to the human a therapeutically effective amount of a compound of any one of Formulas (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 HIV infection by administering to the human a therapeutically effective amount of a compound of any one of Formulas (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.

[0143] In another embodiment, the use of a compound of any one of formulas (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 treatment of HIV infection in a human having or at risk of having HIV infection. In another embodiment, the use of a compound of any one of formulas (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 treatment or prevention of HIV infection in a human having or at risk of having HIV infection.

[0144] In another embodiment, there is provided a compound of any one of formulas (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 treatment.

[0145] In another embodiment, there is provided a use of a compound of any one of formulas (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 the therapeutic treatment of HIV infection. In another embodiment, there is provided a use of a compound of any one of formulas (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 the prophylactic or therapeutic treatment of HIV infection.

[0146] any embodiment of a compound 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; and in 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, R 1 , R a , X, W, Y 1 , Y 2 , L, Z 1 , Z 2 , Z 3 , or Z 4 It is understood that any particular substituent described herein for a group may be independently combined with other embodiments and / or substituents of 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. Furthermore, the listing of substituents may be combined with other embodiments and / or substituents of 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. Furthermore, it is understood that the listing of substituents may be combined with other embodiments and / or substituents of compounds of formula (I), (II-A), (II-B), (II-C), (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 1 , R a , X, W, Y 1 , Y2 , L, Z 1 , Z 2 , Z 3 , or Z 4 When any particular embodiment and / or claim is recited, it is understood that each individual substituent may be deleted from that particular embodiment and / or claim and the recitation of the remaining substituents is considered to be within the scope of the invention.

[0147] As one skilled in the art will appreciate, Z 1 and Z 2 , or Z 1 and Z 3 and (IV-BF), (IV-BG), and (IV-BH), which together form -L-, can be represented in several different ways. For example, compound 3 in Example 3 is:

[0148] [ka]

[0149] It can be shown as follows.

[0150] Pharmaceutical Compositions For administration purposes, in certain embodiments, the compounds described herein are administered as raw chemicals or formulated as pharmaceutical compositions. The pharmaceutical compositions disclosed herein contain a compound of Formula (I) and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compound of Formula (I) is present in the composition in an amount effective to treat the particular disease or condition of interest. The activity of the compound of Formula (I) can be determined by one of ordinary skill in the art, for example, as described in the examples below. Appropriate concentrations and dosages can be readily determined by one of ordinary skill in the art. In certain embodiments, the compound of Formula (I) is present in the pharmaceutical composition in an amount of about 25 mg to about 500 mg. In certain embodiments, the compound of Formula (I) is present in the pharmaceutical composition in an amount of about 100 mg to about 300 mg. In certain 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.

[0151] The administration of the compounds of the present invention or their pharmaceutically acceptable salts in pure form or in suitable pharmaceutical compositions can be carried out by any of the accepted modes of administration for agents that perform similar functions.The pharmaceutical compositions of the present invention are prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents or excipients, and in certain embodiments, are formulated into preparations in solid, semi-solid, liquid or gaseous form (e.g., tablets, capsules, powders, granules, ointments, liquids, suppositories, injections, inhalants, gels, microspheres, and aerosols).Exemplary routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.The pharmaceutical compositions of the present invention are formulated so that the active ingredients contained therein are bioavailable upon administration of the composition to a patient. The composition administered to a subject or patient may take the form of one or more dosage units, where, for example, a tablet may be one dosage unit, and one container of the compound of the present invention in aerosol form may hold multiple dosage units. Actual methods for preparing such dosage forms are known or will become apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the composition to be administered will contain a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for treating the disease or condition of interest, in accordance with the teachings set forth herein.

[0152] The pharmaceutical compositions disclosed herein are prepared by methods well known in the pharmaceutical field.For example, in certain embodiments, the pharmaceutical compositions intended to be administered by injection are prepared by combining the compound of the present invention with sterile distilled water to form a solution.In some embodiments, surfactants are added to facilitate the formation of homogeneous solution or suspension.Surfactants are compounds that interact non-covalently with the compound of the present invention, so as to facilitate the dissolution or homogeneous suspension of the compound in aqueous delivery system.

[0153] The compounds of the present invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the particular compound used; the metabolic stability and length of action of the compound; the patient's age, weight, general health, sex, and diet; the mode and frequency of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject being treated.

[0154] Combination therapy In one embodiment, there is provided a method of treating or preventing HIV infection in a human having or at risk of having HIV infection, 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.

[0155] In one embodiment, a pharmaceutical composition is provided that contains a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0156] In one embodiment, a therapeutic combination is provided that contains a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0157] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an entry inhibitor (e.g., a CCR5 inhibitor, a gp41 inhibitor (i.e., a fusion inhibitor) and a CD4 attachment inhibitor), a CXCR4 inhibitor, a gp120 inhibitor, a G6PD and an NADH-oxidase inhibitor, a compound that targets the HIV capsid ("capsid inhibitor"; e.g., a capsid polymerization inhibitor or a capsid disruption compound (e.g., a compound described in WO 2013 / 006738 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), and WO 2013 / 006792 (Pharmaceuticals In a further embodiment, the additional therapeutic agent is selected from the group consisting of one or more of the following: (1) an HIV protease inhibitor selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, 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) an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase selected from the group consisting of capravirine, emivirine, delavirdine, efavirenz, nevirapine, (+)calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK-453061), RDEA806, KM023, and MK-1439; (3) an HIV nucleoside inhibitor of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxivir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricibine (AVX754), KP-1461, GS-9131 (Gilead Sciences), and fosalvudine tidoxil (formerly HDP 99.0003); (4) an HIV nucleotide inhibitor of reverse transcriptase selected from the group consisting of 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, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, 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, allosteric, integrase inhibitors (NCINI) (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) (each of which is incorporated herein by reference in its entirety); (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) Immunitin, a G6PD and NADH-oxidase inhibitor; (12) a CCR5 inhibitor selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004; (13) a CD4 binding inhibitor selected from the group consisting of idalitumab (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, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040); and combinations thereof.

[0158] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. These 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 certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of transcriptase and an HIV protease inhibitor compound. In further embodiments, 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 an HIV protease inhibitor compound. In further embodiments, 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.

[0159] In certain 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 as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0160] In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient (e.g., as a solid dosage form for oral administration).

[0161] In certain embodiments, the compound disclosed herein is administered together with one or more additional therapeutic agents.The simultaneous administration of the compound disclosed herein and one or more additional therapeutic agents is generally referred to as the simultaneous administration or sequential administration of the compound disclosed herein and one or more additional therapeutic agents, so that both the compound disclosed herein and one or more additional therapeutic agents are present in the patient's body in therapeutically effective amounts.

[0162] Simultaneous administration includes administration of a unit dosage of a compound disclosed herein before or after administration of a unit dosage of one or more additional therapeutic agents (e.g., administration of a compound disclosed herein within seconds, minutes, or hours of administration of one or more additional therapeutic agents). For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by administration of a unit dose of a compound disclosed herein. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of time (e.g., 1 to 12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of time (e.g., 1 hour to 12 hours), by administration of a unit dose of a compound disclosed herein.

[0163] The following examples illustrate compounds of the present invention, i.e., compounds of formula (I):

[0164] [ka]

[0165] and in formula (I), R 1 , X, W, Y 1 , Y 2 , Z 1 , Z 2 , or Z 4 is as defined above. It will be understood that those skilled in the art may be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It will also be understood that those skilled in the art may be able to prepare other compounds of formula (I) not specifically described below by methods similar to those described below, by using appropriate starting components and modifying the synthetic parameters as necessary. In general, the starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or can be synthesized by sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition (Wiley, December 2000)), or can be prepared as described herein.

[0166] The following examples are offered by way of illustration and not by way of limitation. [Example]

[0167] General synthetic scheme Schemes 1-3 are provided as further embodiments of the present invention and illustrate general methods that can be used to prepare compounds having formula (I), as well as general methods that can be used to prepare additional compounds having formula (I).

[0168] Scheme 1

[0169] [ka]

[0170] A1 can be converted to amide A2 using an appropriate amine and a coupling reagent (e.g., HATU or EDCI). A2 can be converted to A3 using a strong acid (e.g., methanesulfonic acid). A3 can be converted to either A5 or A4 by heating with an appropriate cyclic diamine or cyclic amino alcohol, followed by methyl deprotection with a reagent such as magnesium bromide.

[0171] Alternatively, A1 can be converted to A6 by treatment with a strong acid (e.g., methanesulfonic acid). A6 can be condensed with an appropriate cyclic diamine or cyclic amino alcohol, followed by methyl deprotection with a reagent such as magnesium bromide to form either A7 or A8, respectively. A7 or A8 can be converted to amides A5 and A4 by treatment with an appropriate amine and coupling reagent (e.g., HATU or EDCI), followed by methyl deprotection with a reagent such as magnesium bromide.

[0172] Scheme 2

[0173] [ka]

[0174] B1 (as described in WO2012 / 018065) ​​is condensed with a diamine under reflux conditions to give B2, which is hydrolyzed and coupled with an amine via an amide-forming method to remove the benzyl protecting group to give product B3.

[0175] 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

[0176] [ka]

[0177] [ka]

[0178] Process 1 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 / 119566 A1) was evaporated once from dry 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 methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 1-B. 1H-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] + calculated for C 20 H 23 F2N2O7:441.15;found:441.2.

[0179] Process 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 h, the mixture was cooled to give a crude solution of methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 1-C. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 19 F2N2O7:413.12;found:413.1.

[0180] Steps 3 and 4 Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (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 M aq). The organic layer was removed, and the aqueous layer was re-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Prep-HPLC purification (30%-70% acetonitrile:water, 0.1% TFA) afforded compound 1 as a racemic mixture. 1 H-NMR (400 MHz, DMSO-d6) δ 12.45 (br s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.37 (dd, J = 15.4, 8.6 Hz, 1H), 7.23 (dt, J = 2.5, 9.9 Hz, 1H), 7.05 (dt, J = 2.2, 8.7 Hz, 1H), 5.43 (dd, J = 9.6, 4.0 Hz, 1H), 5.09 (br s, 1H), 4.68 (dd, J = 13.2, 4.0 Hz, 1H), 4.59 (br s, 1H), 4.53 (m, 2H), 4.02 (dd, J = 12.6, 9.4 Hz), 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] + calculated for C 21 H 20 F2N3O5:432.14;found:432.2.

[0181] 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).

[0182] [ka]

[0183] Compound 1 (16 mg) was separated by chiral HPLC using Chiralpak AS-H with 100% ethanol as the eluent to give compounds 2 and 3 in enantiomerically enriched form. For compound 2: LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N3O5: 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] + calculated for C 21 H 20 F2N3O5:432.14;found:432.2, Chiral HPLC retention time = 6.84 min (Chiralpak AS-H, 150 x 4.6 mm, 1 mL / min EtOH). 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (br s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.44 (s, 1H), 7.37 (dd, J = 15.2, 8.4 Hz, 1H), 7.23 (m, 1H), 7.05 (dt, J = 1.8 Hz, 8.7 Hz, 1H), 5.44 (dd, J = 9.6, 4.0 Hz), 5.09 (br s, 1H), 4.68 (dd, J = 12.8, 4.0 Hz, 1H), 4.59 (br s, 1H), 4.53 (m, 2H), 4.02 (dd, J = 12.6, 9.4 Hz, 1H), 1.93 (br s, 4H), 1.83 (d, J = 12.4 Hz, 1H), 1.57 (m, 1H).

[0184] Alternatively, compound 3 was prepared as follows:

[0185] [ka]

[0186] 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 reheated to 90° C. After 15 minutes, the mixture was cooled and partitioned between dichloromethane and hydrochloric acid (0.2 M aqueous). The organic layer was removed, and the aqueous solution was re-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate (anhydrous), filtered, and concentrated. The residue was purified by flash chromatography (0% to 8% ethanol in dichloromethane (containing 11% saturated aqueous ammonium hydroxide)) to give intermediate 1-D. LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 22 F2N3O5:446.15;found:446.2.

[0187] Intermediate 1-D (270 mg) was separated by chiral SFC on a 50 mm Chiralpak AD-H column using 50% (1:1 methanol:acetonitrile) in supercritical carbon dioxide as the eluent to give 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] + calculated for C 22 H 22 F2N3O5: 446.15; found: 446.2. For 3-B: LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 22F2N3O5:446.15;found:446.2.

[0188] Intermediate 3-A (0.110 g, 0.247 mmol) in acetonitrile (5 mL) was treated portionwise with magnesium bromide (0.091 g, 0.494 mmol), sealed, and heated to 50 °C. After 10 min, the mixture was cooled and partitioned between dichloromethane and hydrochloric acid (0.2 M aqueous). The organic layer was separated, and the aqueous material was re-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Preparative HPLC purification (30% to 70% acetonitrile:water, 0.1% TFA) afforded compound 3 in enantiomerically enriched form. Chiral HPLC retention time = 6.51 min (Chiralpak AS-H, 150 × 4.6 mm, 1 mL / min EtOH). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N3O5:432.14;found:432.2. 1 H-NMR (400 MHz, DMSO-d6) δ 12.45 (br s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.44 (s, 1H), 7.37 (dd, J = 15.2, 8.4 Hz, 1H), 7.23 (m, 1H), 7.05 (dt, J = 1.8 Hz, 8.7 Hz, 1H), 5.44 (dd, J = 9.6, 4.0 Hz), 5.09 (br s, 1H), 4.68 (dd, J = 12.8, 4.0 Hz, 1H), 4.59 (br s, 1H), 4.53 (m, 2H), 4.02 (dd, J = 12.6, 9.4 Hz, 1H), 1.93 (br s, 4H), 1.83 (d, J = 12.4 Hz, 1H), 1.57 (m, 1H).

[0189] 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

[0190] [ka]

[0191] 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 with acetonitrile followed by (R)-pyrrolidin-3-amine (0.032 mL, 0.36 mmol). The reaction mixture was capped and heated at 90° C. for 5.5 hours. After cooling, the mixture was partitioned between dichloromethane and sodium bicarbonate (1 M aqueous). The organic layer was separated, and the aqueous material was re-extracted 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 at 50° C. for 10 minutes. After cooling, the mixture was partitioned between dichloromethane and ammonium chloride (saturated). The organic layer was separated, and the aqueous material was re-extracted with dichloromethane. The aqueous layer was adjusted to pH=1 with HCl(aq) and re-extracted with dichloromethane. The aqueous solution was adjusted to pH=3 with NaOH(aq) and re-extracted 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. 1H-NMR (400 MHz, CD3OD-d4) δ 8.42 (s, 1H), 7.42, (q, J = 7.7 Hz, 1H), 6.99 - 6.90 (m, 2H), 5.07 (br s, 1H), 4.73 (br d, J = 10.8 Hz, 1H), 4.62 (s, 2H), 4.51 (br d, J = 12.8 Hz, 1H), 4.07 (t, J = 11.8 Hz, 1H), 3.4- 3.0 (m, 3H), 2.76 (br d, J = 8.8 Hz, 1H), 2.15-2.0 (m, 1H), 1.9-1.8 (m, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 20 H 19 F2N4O4:417.14;found:417.2.

[0192] 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

[0193] [ka]

[0194] [ka]

[0195] Process 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 similar manner to (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, as described in WO2011 / 119566, using (R)-3-aminobutan-1-ol instead of (S)-2-aminopropan-1-ol. WO2011 / 119566 is incorporated herein by reference in its entirety. A suspension of intermediate 5-A (24.8 mg, 0.080 mmol), 1-(2,4-difluorophenyl)cyclopropanamine HCl salt (5-B, 21.9 mg, 0.107 mmol), and HATU (48 mg, 0.126 mmol) in CHCl (2 mL) was stirred at ambient temperature, at which time N,N-diisopropylethylamine (DIPEA) (0.1 mL, 0.574 mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and then washed with 10% aqueous citric acid (1×) and saturated aqueous NaHCO (1×). After the aqueous fraction was extracted with ethyl acetate (1×), the organic fractions were combined, dried (MgSO), and concentrated. The residue was purified by combiflash (12 g column) using hexane, ethyl acetate, and 20% methanol in ethyl acetate to give (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] + calculated for C 23 H 24 F2N3O5:460.17;found 460.2.

[0196] Process 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 h, the reaction mixture was stirred in a 0° C. bath, at which time 1 N HCl (2 mL) was added. After diluting the resulting mixture with water (approximately 20 mL), the product was extracted with dichloromethane (3 times), and the combined extracts were dried (MgSO) and concentrated. The residue was purified by preparative HPLC to give (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, CDCl3) 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, CDCl3) δ -76.38 (s, 3F), -111.69 ~ -111.645 (m, 2F). LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 22 F2N3O5:446.15;found:446.2.

[0197] 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

[0198] [ka]

[0199] 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 at 90° C. for 1.5 hours. After cooling, the mixture was treated with magnesium bromide (0.090 g) and heated at 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 material was re-extracted 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) gave compound 6. 1 H-NMR (400 MHz, DMSO-d6) δ 10.33 (t, J = 6.0 Hz, 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 = 2.9 Hz, 1H), 4.62 - 4.54 (m, 1H), 4.52 (d, J = 5.9 Hz, 1H), 4.01 (d, J = 13.0 Hz, 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] + calculated for C 20 H 19 F2N4O4:417.14;found:417.2.

[0200] 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

[0201] [ka]

[0202] 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 at 90°C for 0.5 hours. After cooling, acetic acid (0.050 mL) was added, and the mixture was heated again at 90°C for 2 hours. After cooling, the mixture was treated with magnesium bromide (0.044 g) and heated at 50°C for 1 hour. After cooling, a second portion of magnesium bromide (0.044 g) was added, and the mixture was heated again at 50°C for 15 minutes. After cooling, the mixture was partitioned between dichloromethane and 0.2 M HCl. The organic layer was separated, and the aqueous material was re-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate (anhydrous), filtered, and concentrated. Preparative HPLC purification (40% to 80% acetonitrile:water, 0.1% TFA) gave compound 7. 1H-NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.36 (t, J = 6.1 Hz, 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, 4.1 Hz, 1H), 4.70 (dd, J = 12.7, 4.1 Hz, 1H), 4.52 (d, J = 5.5 Hz, 2H), 4.40 - 4.29 (m, 2H), 4.06 (dd, J = 12.5, 10.2 Hz, 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] + calculated for C 22 H 22 F2N3O5:446.15;found:446.2.

[0203] 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

[0204] [ka]

[0205] Compound 8 was prepared in a manner similar to compound 7, using (1R,3S)-3-aminocyclohexanol instead of (1S,3R)-3-aminocyclohexanol. 1H-NMR (400 MHz, DMSO-d6) 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), 4.70 (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] + calculated for C 22 H 22 F2N3O5:446.15;found:446.2.

[0206] 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

[0207] [ka]

[0208] Process 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 methyl (R)-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] + calculated for C 21 H 26 FN2O7:437.17;found:437.1.

[0209] Process 2 Methyl (R)-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] + calculated for C 19 H 22 FN2O7:409.14;found:409.0.

[0210] Process 3 Methyl (R)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (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, 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 M aq). The layers were separated, and the aqueous layer was re-extracted with dichloromethane. The combined organic layers were treated with a small amount of acetonitrile, dried over sodium sulfate, filtered, and concentrated.

[0211] 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 M aq). The layers were separated, and the aqueous layer was re-extracted 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% to 8% ethanol:DCM) to give the desired diastereomeric mixture of 9 and 10.

[0212] This mixture was separated by chiral HPLC using a Chiralpak AD-H with 100% ethanol as eluent to give compounds 9 and 10 in enantiomerically enriched form: Compound 9: LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 23 FN3O5:428.16;found:428.1. Chiral HPLC retention time = 10.177 min (Chiralpak AD-H, 150 x 4.6 mm, 1 mL / min EtOH). 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.45 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H), 7.37 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 5.44 (dd, J = 9.5, 4.2 Hz, 1H), 5.17 - 5.04 (m, 2H), 4.73 - 4.62 (m, 1H), 4.59 (s, 1H), 4.00 (dd, J = 12.7, 9.5 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 11.8 Hz, 1H), 1.56 (dt, J = 12.1, 3.4 Hz, 1H), 1.44 (dt, J = 6.9 Hz, 3H).

[0213] Compound 10 について:LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 23 FN3O5: 428.16; found: 428.1. Chiral HPLC retention time = 14.061 min (Chiralpak AD-H, 150 × 4.6 mm, 1 mL / min EtOH). 1 H-NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.46 (d, J = 7.8 Hz, 1H), 8.41 (s, 1H), 7.37 (dd, J = 8.6, 5.6 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 5.42 (dd, J = 9.6, 4.1 Hz, 1H), 5.18 - 5.02 (m, 2H), 4.67 (dd, J = 12.8, 4.2 Hz, 1H), 4.59 (s, 1H), 4.02 (dd, J = 12.7, 9.6 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 12.0 Hz, 1H), 1.57 (dt, J = 13.0, 3.5 Hz, 1H), 1.44 (d, J = 6.9 Hz, 3H).

[0214] 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

[0215] [ka]

[0216] [ka]

[0217] Process 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 h and partitioned between dichloromethane and HCl (10% aq). The organic layer was separated and washed with sodium bicarbonate (1M aq), 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] + calculated for C 21 H 25 F2N2O7:455.16;found:455.1.

[0218] Process 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] + calculated for C 19 H 21 F2N2O7:427.13;found:427.1.

[0219] Process 3 Methyl (R)-5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (half of the crude mixture from step 2, approximately 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 additional 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 (0.2 M aq). The layers were separated, and the aqueous layer was re-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Preparative HPLC purification (30%-60% acetonitrile:water, 0.1% TFA) afforded the desired compound 11. LCMS-ESI + (m / z):[M+H] +calculated for C 22 H 22 F2N3O5:446.15;found:446.1. 1 H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.53 (d, J = 7.5 Hz, 1H), 8.38 (s, 1H), 7.39 (q, J = 8.5 Hz, 1H), 7.29 - 7.12 (m, 1H), 7.13 - 6.93 (m, 1H), 5.44 (dd, J = 9.8, 4.2 Hz, 1H), 5.28 (p, J = 7.3, 6.8 Hz, 1H), 5.09 (s, 1H), 4.66 (dd, J = 13.2, 4.3 Hz, 1H), 4.59 (s, 1H), 3.99 (dd, J = 13.1, 9.6 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 12.4 Hz, 1H), 1.56 (dt, J = 12.5, 2.9 Hz, 1H), 1.45 (d, J = 6.9 Hz, 3H).

[0220] 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

[0221] [ka]

[0222] Compound 12 was prepared in a similar manner to compound 11, using (1R,3S)-3-aminocyclopentanol instead of (1S,3R)-3-aminocyclopentanol. 1H-NMR (400 MHz, DMSO-d6) 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] + calculated for C 22 H 22 F2N3O5:446.15;found:446.1.

[0223] 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

[0224] [ka]

[0225] Compound 13 was prepared in a manner similar to that of compound 11, using (S)-1-(2,4-difluorophenyl)ethanamine instead of (R)-1-(2,4-difluorophenyl)ethanamine and using magnesium bromide (0.184 g) only once. 1H-NMR (400 MHz, DMSO-d6) 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] + calculated for C 22 H 22 F2N3O5:446.15;found:446.2.

[0226] 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

[0227] [ka]

[0228] Compound 14 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 (1R,3S)-3-aminocyclopentanol instead of (1S,3R)-3-aminocyclopentanol. 1 H-NMR (400 MHz, DMSO-d6) 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] + calculated for C 22 H 22 F2N3O5:446.15;found:446.1.

[0229] 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

[0230] [ka]

[0231] [ka]

[0232] Process 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 h, the crude mixture was cooled and stored at −10° C. for 3 days. The crude mixture was heated again at 75° C. for 2 h, cooled, and used in the next step without purification. LCMS-ESI + (m / z):[M+H] + calculated for C 19 H 21 F2N2O7:288.07;found:288.1.

[0233] Process 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, approximately 4 mmol) was combined 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 an additional 16 hours. HCl (50 mL, 0.2 M aq) was added, and the clear yellow solution was extracted three times with dichloromethane. The combined organics were dried over sodium sulfate, filtered, and concentrated to a yellow solid. The crude material was precipitated from dichloromethane / hexane to give 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] + calculated for C 15 H 17 N2O6:321.11;found:321.2.

[0234] Process 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 min, the reaction mixture was treated with magnesium bromide (0.046 g, 0.25 mmol) and heated to 50 °C. After 10 min, the reaction mixture was cooled and treated with HCl (2 mL, 10% aq). After several minutes, the precipitate was filtered and washed with HCl (10% aq) and water. Preparative HPLC purification of the precipitate (20%-65% acetonitrile:water, 0.1% TFA) afforded the desired compound 15. 1H-NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.36 (t, J = 6.0 Hz, 1H), 8.46 (s, 1H), 7.37 - 7.28 (m, 2H), 7.19 - 7.09 (m, 2H), 5.43 (dd, J = 9.6, 4.0 Hz, 1H), 5.08 (s, 1H), 4.68 (dd, J = 12.8, 4.1 Hz, 1H), 4.59 (s, 1H), 4.58 - 4.42 (m, 3H), 4.02 (dd, J = 12.7, 9.6 Hz, 1H), 1.92 (s, 5H), 1.83 (d, J = 12.2 Hz, 1H), 1.56 (dt, J = 12.0, 3.4 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 21 FN3O5:414.15;found:414.2.

[0235] 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

[0236] [ka]

[0237] Compound 16 was prepared in a similar manner to compound 15, using (2,3-difluorophenyl)methanamine instead of (4-fluorophenyl)methanamine. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.41 (t, J = 6.1 Hz, 1H), 8.45 (s, 1H), 7.43 - 7.25 (m, 1H), 7.25 - 7.05 (m, 2H), 5.44 (dd, J = 9.5, 3.9 Hz, 1H), 5.09 (s, 1H), 4.68 (dd, J = 12.8, 4.0 Hz, 1H), 4.65 - 4.53 (m, 3H), 4.02 (dd, J = 12.7, 9.8 Hz, 1H), 3.56 (s, 1H), 1.93 (s, 4H), 1.83 (d, J = 11.9 Hz, 1H), 1.57 (dt, J = 11.5, 3.0 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N3O5:432.14;found:432.2.

[0238] 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

[0239] [ka]

[0240] Compound 17 was prepared in a similar manner to compound 15, using (4-chloro-2-fluorophenyl)methanamine in place of (4-fluorophenyl)methanamine. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.45 - 10.29 (m, 1H), 8.44 (s, 1H), 7.42 (dd, J = 10.0, 2.0 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.26 (dd, J = 8.4, 1.8 Hz, 1H), 5.50 - 5.38 (m, 1H), 5.09 (s, 1H), 4.68 (dd, J = 13.0, 4.0 Hz, 1H), 4.59 (s, 1H), 4.54 (m, 2H), 4.02 (dd, J = 12.8, 9.7 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 12.0 Hz, 1H), 1.57 (dt, J = 11.9, 3.4 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 ClFN3O5:448.11;found:448.2.

[0241] 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

[0242] [ka]

[0243] Compound 18 was prepared in a similar manner to compound 15, using (3,4-difluorophenyl)methanamine in place of (4-fluorophenyl)methanamine. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (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, 3.6 Hz, 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, 9.8 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 12.0 Hz, 1H), 1.57 (dt, J = 12.0, 3.4 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N3O5:432.14;found:432.2.

[0244] 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

[0245] [ka]

[0246] 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 min, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted three times with dichloromethane, and the combined organic phases were combined, dried over MgSO, 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 90 min, the reaction mixture was quenched with approximately 5 mL of 0.2 M HCl(aq), the pH adjusted to approximately 10, diluted with brine, and extracted three times with DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 19. 1 H-NMR (400 MHz, chloroform-d) δ 10.43 (t, J = 5.9 Hz, 1H), 8.43 (s, 1H), 7.39 - 7.30 (m, 1H), 6.81 (q, J = 8.1 Hz, 2H), 4.89 (dd, J = 11.6, 3.8 Hz, 1H), 4.69 (s, 1H), 4.64 (d, J = 5.8 Hz, 2H), 4.26 (dd, J = 12.6, 3.8 Hz, 1H), 3.91 (t, J = 12.1 Hz, 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] + calculated for C 21 H 20 F2N4O4:431.15;found:431.2.

[0247] 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

[0248] [ka]

[0249] 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 acetonitrile (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), and the reaction mixture was sealed and heated to 90 °C. After 40 min, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted three times with dichloromethane, and the combined organic phases were combined, dried over MgSO, 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 min, the reaction mixture was quenched with approximately 5 mL of 0.2 M HCl(aq), the pH adjusted to approximately 10, diluted with brine, and extracted three times with DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 20. 1H-NMR (400 MHz, DMSO-d6) δ 10.35 (t, J = 6.0 Hz, 1H), 8.48 (s, 1H), 7.45 - 7.33 (m, 1H), 7.29 - 7.18 (m, 1H), 7.05 (td, J = 8.5, 2.4 Hz, 1H), 5.06 (dd, J = 11.4, 3.5 Hz, 1H), 4.56 - 4.47 (m, 3H), 4.44 (s, 1H), 4.05 (t, J = 11.8 Hz, 1H), 3.07 - 2.89 (m, 4H), 1.85 - 1.73 (m, 3H), 1.54 - 1.46 (m, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N4O4:431.15;found:431.2.

[0250] 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

[0251] [ka]

[0252] [ka]

[0253] Steps 1 and 2 Methyl (S)-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)-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 min, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted three times with 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 (74 mg, 0.4 mmol) was added. The mixture was resealed and heated to 50°C. After 100 min, the reaction mixture was quenched with 0.2 M HCl(aq), diluted with brine, and extracted three times with DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 21. 1H-NMR (400 MHz, DMSO-d6) δ 12.42 (br s, 1H), 10.45 (d, J = 7.9 Hz, 1H), 8.40 (s, 1H), 7.36 (dd, J = 8.6, 5.5 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 5.42 (dd, J = 9.6, 4.2 Hz, 1H), 5.15 - 5.04 (m, 2H), 4.72 - 4.55 (m, 2H), 4.02 (dd, J = 12.7, 9.7 Hz, 1H), 1.97 - 1.89 (m, 4H), 1.82 (d, J = 12.2 Hz, 1H), 1.56 (dt, J = 11.9, 3.3 Hz, 1H), 1.43 (d, J = 6.9 Hz, 3H). LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 22 FN3O5:428.16;found:428.1.

[0254] 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

[0255] [ka]

[0256] Steps 1 and 2 (S)-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) 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 three times with 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 (91 mg, 0.49 mmol) was added. The mixture was resealed and heated to 50° C. After 100 min, the reaction mixture was quenched with 0.2 M HCl(aq), diluted with brine, and extracted three times with DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 22. 1 H-NMR (400 MHz, DMSO-d6) δ 12.44 (br s, 1H), 10.45 (d, J = 7.7 Hz, 1H), 8.39 (s, 1H), 7.36 (dd, J = 8.5, 5.6 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 5.43 (dd, J = 9.6, 4.0 Hz, 1H), 5.15 - 5.06 (m, 2H), 4.66 (dd, J = 12.8, 3.9 Hz, 1H), 4.58 (s, 1H), 3.99 (dd, J = 12.6, 9.5 Hz, 1H), 1.93 (s, 4H), 1.82 (d, J = 12.0 Hz, 1H), 1.56 (dt, J = 12.0, 3.0 Hz, 1H), 1.44 (d, J = 6.9 Hz, 3H). LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 22 FN3O5:428.16;found:428.1.

[0257] 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

[0258] [ka]

[0259] 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 h, and magnesium bromide (47 mg, 0.26 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 min, the reaction mixture was quenched with 0.2 M HCl(aq), diluted with brine, and extracted three times with DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 23. 1 H-NMR (400 MHz, chloroform-d) δ 10.42 (s, 1H), 8.34 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.12 - 6.97 (m, 2H), 5.40 - 5.32 (m, 1H), 5.29 (t, J = 3.5 Hz, 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, 3.3 Hz, 1H). LCMS-ESI + (m / z):[M+H]+ calculated for C 21 H 20 FN3O5:414.15;found:414.2.

[0260] 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

[0261] [ka]

[0262] 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 h, and magnesium bromide (57 mg, 0.31 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 min, the reaction mixture was quenched with 0.2 M HCl(aq), diluted with brine, and extracted three times with DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 24. 1H-NMR (400 MHz, chloroform-d) δ 10.39 (s, 1H), 8.42 (s, 1H), 6.82 (d, J = 7.9 Hz, 2H), 6.65 (t, J = 8.8 Hz, 1H), 5.38 (d, J = 7.7 Hz, 1H), 5.28 (s, 1H), 4.78 - 4.41 (m, 3H), 4.32 (d, J = 12.1 Hz, 1H), 4.02 (t, J = 10.9 Hz, 1H), 2.30 - 1.97 (m, 4H), 1.97 - 1.81 (m, 1H), 1.59 (d, J = 12.3 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 19 F2N3O5:432.14;found:432.2.

[0263] 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

[0264] [ka]

[0265] 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 h, and magnesium bromide (62 mg, 0.34 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 min, the reaction mixture was quenched with 0.2 M HCl(aq), diluted with brine, and extracted three times with DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 25. 1 H-NMR (400 MHz, chloroform-d) δ 10.44 (s, 1H), 8.29 (s, 1H), 7.56 - 7.38 (m, 2H), 7.06 (t, J = 9.2 Hz, 1H), 5.30 (dd, J = 9.3, 3.5 Hz, 1H), 5.21 (s, 1H), 4.65 - 4.45 (m, 3H), 4.21 (dd, J = 12.8, 3.4 Hz, 1H), 3.95 (dd, J = 12.4, 9.7 Hz, 1H), 2.11 - 1.89 (m, 4H), 1.89 - 1.74 (m, 1H), 1.53 (dt, J = 12.4, 3.2 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 19 F4N3O5:482.14;found:482.2.

[0266] 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

[0267] [ka]

[0268] 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 h, and magnesium bromide (48 mg, 0.26 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 min, the reaction mixture was quenched with 0.2 M HCl(aq), diluted with brine, and extracted three times with DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 26. 1 H-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] + calculated for C 21 H 19 ClFN3O5:448.11;found:448.2.

[0269] 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

[0270] [ka]

[0271] Process 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 CHCl (20 mL) was stirred in a 0 °C bath, at which time N,N-diisopropylethylamine (DIPEA) (2 mL, 11.48 mmol) was added. After 1 h at 0 °C, the reaction mixture was concentrated to a syrup, diluted with ethyl acetate, and washed with water (twice). After extracting the aqueous fraction with ethyl acetate (once), the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by CombiFlash (120 g column) using hexane-ethyl acetate as the eluent. The larger peak was combined and concentrated to give 1.082 g (73%) of product 27-B. After combining and concentrating the smaller peak, the concentrated residue was dissolved in CH2Cl2 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] + calculated for C 22 H 25 F2N2O7:467.16;found:467.1.

[0272] 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.

[0273] After the resulting solution was cooled to room temperature, amino alcohol 27-D (50 mg, racemic, 0.363 mmol), K2CO3 (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 h. After the reaction mixture was cooled to room temperature, it was acidified with 1 N HCl (ca. 2 mL), diluted with water (ca. 8 mL), and extracted with CHCl2 (3 times). The combined extracts were dried (Na2SO4), concentrated, and purified by CombiFlash to give 67 mg (82%) of compound 27-E. 1 H-NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.25 (s, 1H), 7.60 (td, J = 8.5, 6.5 Hz, 1H), 6.85 - 6.57 (m, 2H), 5.33 (br, 1H), 5.26 (dd, J = 9.6, 3.9 Hz, 1H), 4.60 (t, J = 3.0 Hz, 1H), 4.18 - 4.06 (m, 1H), 4.01 (s, 3H), 3.92 (dd, J = 12.7, 9.6 Hz, 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, CDCl3) δ -111.80 (q, J = 8.8 Hz, 1F), -112.05 (p, J = 7.9 Hz, 1F). LCMS-ESI + (m / z):[M+H] + calculated for C 24 H 24 F2N3O5:472.17;found:472.1.

[0274] Process 4 A mixture of compound 27-E (67 mg, 0.142 mmol) and MgBr (66 mg, 0.358 mmol) in MeCN (3 mL) was stirred at 50 °C for 30 min and cooled to 0 °C, then treated with 1 N HCl (3 mL). After diluting the mixture with water (approximately 30 mL), the product was extracted with CHCl (3 times), and the combined extracts were dried (NaSO) 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 (400 MHz, CDCl3) δ 10.70 (s, 1H), 8.35 (s, 1H), 7.57 (q, J = 8.2 Hz, 1H), 6.91 - 6.56 (m, 2H), 5.31 (dt, J = 14.3, 4.0 Hz, 2H), 4.68 (s, 1H), 4.22 (dd, J = 13.2, 3.9 Hz, 1H), 3.99 (dd, J = 12.8, 9.3 Hz, 1H), 2.28 - 1.96 (m, 5H), 1.88 (ddt, J = 12.1, 8.6, 3.7 Hz, 1H), 1.71 - 1.49 (m, 1H), 1.38 - 1.11 (m, 4H). 19 F-NMR (376.1 MHz, CDCl3) δ -76.37 (s, 3F), -111.6 ~ -111.75 (m, 2F). LCMS-ESI + (m / z):[M+H] + calculated for C 23 H 22 F2N3O5:458.15;found:458.1.

[0275] 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

[0276] [ka]

[0277] [ka]

[0278] 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.

[0279] 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 stirring the resulting mixture in a 65 °C bath for 30 min, K2CO3 (41 mg, 0.297 mmol) was added, and the mixture was stirred at 65 °C for 21 h. The reaction mixture was cooled to room temperature, acidified with 1 N HCl (ca. 2 mL), diluted with water (ca. 8 mL), and extracted with CHCl2 (3 times). The combined extracts were dried (Na2SO4), concentrated, purified by preparative HPLC, and the product-containing fractions were freeze-dried. After dissolving the residue in ethyl acetate, the solution was washed with saturated NaHCO3 (1 time), dried (Na2SO4), and concentrated to give 18 mg (20%) of compound 28-B as a 1:1 mixture with trifluoroacetic acid. 1H-NMR (400 MHz, CDCl3) 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, 9.7 Hz, 1H), 2.41 - 2.20 (m, 2H), 1.84 (dtd, J = 19.7, 9.3, 8.8, 4.4 Hz, 2H), 1.74 (dd, J = 14.6, 2.5 Hz, 1H), 1.62 - 1.35 (m, 2H), 1.34 - 1.14 (m, 5H). 19 F-NMR (376.1 MHz, CDCl3) δ -111.75 (q, J = 8.9 Hz, 1F), -112.01 (p, J = 7.9 Hz, 1F). LCMS-ESI + (m / z):[M+H] + calculated for C 25 H 26 F2N3O5:486.18;found:486.2.

[0280] Process 3 Compound 28-B (18 mg, 0.037 mmol) was treated with MgBr2 as described in step 4 of the synthesis of compound 27-E to give compound 28. 1H-NMR (400 MHz, CDCl3) 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), 3.99 (dd, J = 12.8, 9.8 Hz, 1H), 2.56 - 2.35 (m, 1H), 2.14 (dd, J = 16.1, 5.9 Hz, 1H), 1.96 - 1.74 (m, 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, CDCl3) δ -76.41 (s, 3F, -111.79 (m, 2F). LCMS-ESI + (m / z):[M+H] + calculated for C 24 H 23 F2N3O5:472.17;found:472.1.

[0281] 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

[0282] [ka]

[0283] Steps 1 and 2 Compound 29-B (13 mg, 14%) was prepared from compound 27-B (87 mg, 0.187 mmol) and aminoalcohol 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, CDCl3) 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, 9.7 Hz, 1H), 2.41 - 2.20 (m, 2H), 1.84 (dtd, J = 19.7, 9.3, 8.8, 4.4 Hz, 2H), 1.74 (dd, J = 14.6, 2.5 Hz, 1H), 1.62 - 1.35 (m, 2H), 1.34 - 1.14 (m, 5H). 19 F-NMR (376.1 MHz, CDCl3) δ -111.75 (q, J = 8.9 Hz, 1F), -112.01 (p, J = 7.9 Hz, 1F). LCMS-ESI + (m / z):[M+H] + calculated for C 25 H 26 F2N3O5:486.18;found:486.2.

[0284] Process 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. 1H-NMR (400 MHz, CDCl3) 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), 3.99 (dd, J = 12.8, 9.8 Hz, 1H), 2.56 - 2.35 (m, 1H), 2.14 (dd, J = 16.1, 5.9 Hz, 1H), 1.96 - 1.74 (m, 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, CDCl3) δ -76.41 (s, 3F, -111.79 (m, 2F). LCMS-ESI + (m / z):[M+H] + calculated for C 24 H 23 F2N3O5:472.17;found:472.1.

[0285] 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

[0286] [ka]

[0287] [ka]

[0288] 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 h. After the resulting solution was cooled to room temperature, amino alcohol 30-A (72.1 mg, chiral, 0.713 mmol), KCO (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 h. After the reaction mixture was cooled to room temperature, it was acidified with 1 N HCl (approximately 3 mL), diluted with water (approximately 12 mL), and extracted with CHCl (three times). The combined extracts were dried (NaSO), concentrated, and purified by CombiFlash to give 128 mg (84%) of compound 30-B. 1 H-NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.24 (s, 1H), 7.61 (td, J = 8.6, 6.6 Hz, 1H), 6.85 - 6.65 (m, 2H), 5.33 (t, J = 4.1 Hz, 1H), 5.25 (dd, J = 9.5, 3.9 Hz, 1H), 4.61 (d, J = 3.4 Hz, 1H), 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, 2.8 Hz, 1H), 1.31 - 1.14 (m, 4H). 19 F-NMR (376.1 MHz, CDCl3) δ -111.79 (q, J = 8.8 Hz, 1F), -112.05 (p, J = 7.9 Hz, 1F). LCMS-ESI + (m / z):[M+H] + calculated for C 24 H 24 F2N3O5:472.17;found:472.2.

[0289] Process 3 A mixture of compound 30-B (128 mg, 0.272 mmol) and MgBr (130 mg, 0.706 mmol) in MeCN (5 mL) was stirred at 50 °C for 30 min and cooled to 0 °C, then treated with 1 N HCl (4 mL). After diluting the mixture with water, the product was extracted with CHCl (3 times), and the combined extracts were dried (NaSO) and concentrated. The product was purified by CombiFlash to give product 30. 1 H-NMR (400 MHz, CDCl3) δ 12.27 (s, 1H), 10.52 (s, 1H), 8.16 (s, 1H), 7.61 (td, J = 8.6, 6.6 Hz, 1H), 6.96 - 6.54 (m, 2H), 5.36 - 5.23 (m, 2H), 4.66 (t, J = 3.1 Hz, 1H), 4.18 - 4.06 (m, 1H), 3.94 (dd, J = 12.8, 9.4 Hz, 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, CDCl3) δ -111.87 (q, J = 8.9 Hz, 1F), -112.21 (p, J = 7.9 Hz, 1F). LCMS-ESI + (m / z):[M+H] + calculated for C 23 H 22 F2N3O5:458.15;found:458.2.

[0290] 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

[0291] [ka]

[0292] Steps 1 and 2 Compound 31-B (123 mg, 81%) was prepared from compound 27-B (150 mg, 0.322 mmol) and aminoalcohol 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, CDCl3) δ 10.52 (s, 1H), 8.24 (s, 1H), 7.62 (td, J = 8.6, 6.6 Hz, 1H), 6.91 - 6.63 (m, 2H), 5.33 (t, J = 4.1 Hz, 1H), 5.25 (dd, J = 9.5, 3.9 Hz, 1H), 4.61 (d, J = 3.4 Hz, 1H), 4.14 - 4.07 (m, 1H), 4.03 (s, 3H), 3.93 (dd, J = 12.7, 9.5 Hz, 1H), 2.12 - 1.91 (m, 4H), 1.85 - 1.69 (m, 1H), 1.55 (ddd, J = 12.3, 4.1, 2.8 Hz, 1H), 1.31 - 1.14 (m, 4H). 19 F-NMR (376.1 MHz, CDCl3) 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] + calculated for C 24 H 24 F2N3O5:472.17;found:472.1.

[0293] Process 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 (400 MHz, CDCl3) δ 12.26 (s, 1H), 10.49 (s, 1H), 8.13 (s, 1H), 7.58 (td, J = 8.6, 6.5 Hz, 1H), 6.90 - 6.56 (m, 2H), 5.32 (dd, J = 9.4, 4.1 Hz, 1H), 5.27 - 5.22 (m, 1H), 4.64 (t, J = 3.1 Hz, 1H), 4.11 (dd, J = 12.8, 4.0 Hz, 1H), 4.01 - 3.79 (m, 1H), 2.28 - 1.95 (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, CDCl3) δ -111.95 (q, J = 8.9 Hz, 1F), -112.22 (p, J = 7.9 Hz, 1F). LCMS-ESI + (m / z):[M+H] + calculated for C 23 H 22 F2N3O5:458.15;found:458.1.

[0294] 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

[0295] [ka]

[0296] [ka]

[0297] 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 CHCl (2 mL) was stirred at room temperature, at which time N,N-diisopropylethylamine (DIPEA) (0.075 mL, 0.431 mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and washed with water (twice). After the aqueous fraction was extracted with EA (once), the organic fractions were combined, dried, concentrated, and dried in vacuo.

[0298] A mixture of the crude product and MgBr (35 mg, 0.190 mmol) in MeCN (2 mL) was stirred in a 50° C. bath for 1 h and cooled to 0° C. before being treated with 1 N HCl (approximately 1 mL). The resulting solution was diluted with water and extracted with CHCl (3×). The combined extracts were dried (NaSO) and concentrated. The product was purified by preparative HPLC and freeze-dried to give compound 32. 1 H-NMR (400 MHz, CDCl3) δ 10.87 (s, 1H), ~9.3 (br, 1H), 8.35 (s, 1H), 7.50 (td, J = 8.7, 6.3 Hz, 1H), 6.89 - 6.78 (m, 1H), 6.72 (ddd, J = 11.2, 8.9, 2.6 Hz, 1H), 5.48 - 5.12 (m, 2H), 4.72 - 4.60 (m, 1H), 4.22 (dd, J = 13.0, 4.1 Hz, 1H), 3.98 (dd, J = 12.9, 9.4 Hz, 1H), 2.68 (m, 4H), 2.33 - 1.98 (m, 6H), 1.90 (m, 2H), 1.60 (ddd, J = 12.4, 4.1, 2.7 Hz, 1H). 19F-NMR (376.1 MHz, CD3CN) 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] + calculated for C 24 H 24 F2N3O5:472.17;found:472.0.

[0299] 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

[0300] [ka]

[0301] Compound 33 was obtained from compound 32-A and compound 33-A as described in the synthesis of compound 32. 1 H-NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), ~9.5 (br, 1H), 8.41 (s, 1H), 7.43 (td, J = 8.9, 6.4 Hz, 1H), 6.85 - 6.76 (m, 1H), 6.72 (ddd, J = 11.5, 8.8, 2.6 Hz, 1H), 5.48 - 5.18 (m, 2H), 4.68 (t, J = 3.2 Hz, 1H), 4.26 (dd, J = 13.0, 4.1 Hz, 1H), 4.00 (dd, J = 13.0, 9.4 Hz, 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, 2.7 Hz, 1H).19 F-NMR (376.1 MHz, CD3CN) 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] + calculated for C 25 H 26 F2N3O5:486.18;found:485.9.

[0302] 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

[0303] [ka]

[0304] [ka]

[0305] Compound 34 was obtained from compound 32-A and compound 34-A as described in the synthesis of compound 32. 1H-NMR (400 MHz, CDCl3) 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 = 13.1, 4.1 Hz, 1H), 4.03 (dd, J = 13.0, 9.4 Hz, 1H), 2.60 (d, J = 13.1 Hz, 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, 2.7 Hz, 1H), 1.30 (br, 1H). 19 F-NMR (376.1 MHz, CD3CN) 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] + calculated for C 26 H 28 F2N3O5:500.20;found:500.0.

[0306] 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

[0307] [ka]

[0308] 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, CDCl3) 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 = 3.1 Hz, 1H), 4.24 (dd, J = 13.0, 3.9 Hz, 1H), 4.11 - 3.81 (m, 5H), 2.60 (d, J = 13.7 Hz, 2H), 2.33 - 2.17 (m, 2H), 2.18 - 1.97 (m, 4H), 1.87 (m, 1H), 1.61 (dt, J = 12.5, 3.3 Hz, 1H). 19 F-NMR (376.1 MHz, CD3CN) 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] + calculated for C 25 H 26 F2N3O6:502.18;found:502.0.

[0309] 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

[0310] [ka]

[0311] 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, CDCl3) 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 = 4.0 Hz, 1H), 4.70 (s, 1H), 4.34 (dd, J = 12.8, 3.9 Hz, 1H), 4.05 (dd, J = 12.9, 9.4 Hz, 1H), 2.26 - 1.99 (m, 4H), 1.99 - 1.87 (m, 1H), 1.62 (dt, J = 12.6, 3.4 Hz, 1H). 19 F-NMR (376.1 MHz, CDCl3) 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] + calculated for C 22 H 19 F5N3O5:500.12;found:500.1.

[0312] 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

[0313] [ka]

[0314] Process 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 h, 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] + calculated for C 18 H 19 F2N2O7:439;found:439.

[0315] 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). (S)-2-Aminopropan-1-ol (0.048 g, 0.64 mmol) and K2CO3 (0.088 g, 0.64 mmol) were added to the reaction mixture. The reaction mixture was sealed and heated to 70 °C. After 3 h, 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 min, the reaction mixture was cooled to 0 °C and 1 N 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 give compound 37 as a TFA salt. 1 H-NMR (400 MHz, methanol-d4) 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-d4) δ -113.66 - -113.95 (m, 1F), -113.94 - -114.29 (m, 1F). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N3O5:432.;found:432.

[0316] 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

[0317] [ka]

[0318] [ka]

[0319] Process 1 A solution of compound 38-A (1562 mg, 5.799 mmol) (see Example 41b of WO 97 / 05139) in THF (10 mL) was stirred at −78° C., at which time 2.0 M LiBH in THF (3.2 mL) was added, and the resulting mixture was stirred at room temperature. After 3 hours, additional 2.0 M LiBH in THF (3.2 mL) was added, and the solution was stirred at room temperature for 17.5 hours. The reaction mixture was diluted with ethyl acetate, and after slow addition of 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 (NaSO), and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as the 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] + calculated for C 12 H 22 NO3:228.16;found:227.7.

[0320] Process 2 A solution of compound 38-B (589 mg, 2.591 mmol) and NEt (0.47 mL, 3.369 mmol) in CHCl (6 mL) was stirred at 0 °C, at which time MsCl (0.22 mL, 2.842 mmol) was added. After 1 h at room temperature, the mixture was diluted with ethyl acetate and washed with water (twice). The aqueous fraction was extracted with ethyl acetate (once), and the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by Combi Flash (40 g column) using hexane-ethyl acetate as eluent to give compound 38-C. 1H-NMR (400 MHz, chloroform-d) δ 4.39 - 4.28 (m, 1H), 4.16 (s, 0.4H), 4.06 (s, 0.6H), 3.98 (dd, J = 10.0, 8.7 Hz, 0.6H), 3.86 (t, J = 9.6 Hz, 0.4H), 3.51 (dd, J = 9.3, 3.7 Hz, 0.6H), 3.43 (dd, J = 9.3, 3.6 Hz, 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 = 14.8 Hz, 1H), 1.31 (s, 0.6H), 1.29 (s, 0.4H).

[0321] Process 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 (twice). After washing the organic fraction with water (once), the two organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as the eluent to give compound 38-D. 1H-NMR (400 MHz, chloroform-d) δ 4.16 (s, 0.4H), 4.06 (s, 0.6H), 3.61 (dd, J = 12.2, 3.6 Hz, 0.6H), 3.51 (dd, J = 12.1, 3.2 Hz, 0.4H), 3.38 (dd, J = 9.4, 3.4 Hz, 0.6H), 3.26 (dd, J = 9.8, 3.3 Hz, 0.4H), 3.06 (dd, J = 12.2, 9.4 Hz, 0.6H), 3.01 - 2.92 (m, 0.4H), 2.48 (d, J = 5.2 Hz, 1H), 1.82 - 1.57 (m, 4H), 1.46 (d, J = 3.0 Hz, 9H), 1.42 (m, 1H), 1.28 (m, 0.6H), 1.27 - 1.23 (m, 0.4H).

[0322] Process 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 give crude compound 38-E. LCMS-ESI + (m / z):[M+H] + calculated for C 12 H 23 N2O2:227.18;found:226.8.

[0323] Process 5 A mixture of crude compound 38-E (206 mg, 0.910 mmol), compound 38-F (330 mg, 0.953 mmol), and NaHCO (154 mg, 1.833 mmol) in water (3 mL) and EtOH (3 mL) was stirred at room temperature for 20 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. After that, the extracts were washed once with water, combined, dried (NaSO), and concentrated to give the crude pyridine product.

[0324] The crude residue (388 mg) was dissolved in CHCl (4 mL) and 4 mL of 4 N HCl in dioxane. After 1.5 h, additional 4 mL of 4 N HCl in dioxane was added and stirred at room temperature for 1 h. The mixture was concentrated to dryness, coevaporated with toluene (1×), and dried in vacuo for 30 min.

[0325] The crude residue and 1,8-diazabicycloundec-7-ene (DBU) (1.06 mL, 7.088 mmol) in toluene (10 mL) were stirred in a bath at 110° C. After 30 min, the mixture was concentrated, and the residue was purified by 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] + calculated for C 23 H 25 N2O5:409.18;found:409.2.

[0326] Process 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, at which time 1N KOH (3 mL) was added. After 1 h, the reaction mixture was neutralized with 1N HCl (ca. 3.1 mL), concentrated, and the residue was co-concentrated with toluene (3 times). After drying the residue in vacuo for 30 min, a suspension of the crude residue, 2,4-difluorobenzylamine (86 mg, 0.601 mmol), and HATU (266 mg, 0.700 mmol) in CHCl (4 mL) and DMF (4 mL) was stirred at 0 °C, at which time N,N-diisopropylethylamine (DIPEA) (0.7 mL, 4.019 mmol) was added. After 45 min, 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 h, the mixture was concentrated to remove most of the CHCl, diluted with ethyl acetate, and washed with 5% LiCl (twice). After extracting the aqueous fraction with ethyl acetate (once), the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by CombiFlash (40 g column) using ethyl acetate-20% MeOH / ethyl acetate as the eluent to give compound 38-H. 1H-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] + calculated for C28H26F2N3O4:506.19;found:506.2.

[0327] Process 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 20% ​​MeOH in CH2Cl2-CH2Cl2 as the eluent. After concentration of the collected product fractions, the residue was triturated with MeCN (ca. 2 mL) at 0 °C for 15 minutes, and the solid was filtered and washed with MeCN. The collected solid was dried in vacuo to give compound 38.

[0328] The filtrate was concentrated, and the residue was dissolved in MeCN (about 1 mL) and water (about 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 additional 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] + calculated for C 21 H 19 F2N3O4:416.14;found:416.3.

[0329] 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

[0330] [ka]

[0331] Process 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 in diethyl ether (4.1 mL, 6.56 mmol) was added dropwise, and the reaction solution was warmed to room temperature over 2 hours and cooled again to −78°C. tert-Butyl (1R,3R,5S)-6-oxabicyclo[3.1.0]hexan-3-ylcarbamate (330 mg, 1.66 mmol) was added dropwise in 3.3 mL of THF. Boron trifluoride diethyl etherate (0.25 mL, 1.99 mmol) was then added, the mixture was warmed to −30°C over 30 minutes, and stirred at −35 to −25°C for 1 hour. The reaction solution was then warmed to room temperature and quenched with a mixture of saturated NH3(aq) / NH4(aq), extracted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated, and purified by SGC (0% to 10% EtOH / DCM) to give racemic tert-butyl (1S,3S,4S)-3-hydroxy-4-methylcyclopentylcarbamate. 1 H-NMR (400 MHz, chloroform-d) δ 5.16 (s, 1H), 3.98 (s, 1H), 3.74 (q, J = 4.3 Hz, 1H), 3.65 (q, J = 7.0 Hz, 1H), 2.23 (dt, J = 14.0, 7.0 Hz, 1H), 1.98 (dt, J = 13.3, 7.0 Hz, 1H), 1.89 - 1.79 (m, 1H), 1.58 - 1.44 (m, 1H), 1.38 (s, 9H), 1.18 (t, J = 7.0 Hz, 1H), 0.91 (d, J = 7.0Hz, 3H).

[0332] Process 2 3 mL of HCl / dioxane (4 M, 12 mmol) was added to a solution of racemic (1S,3S,4S)-tert-butyl 3-hydroxy-4-methylcyclopentylcarbamate (182 mg, 0.85 mmol) in 3 mL of dioxane. The reaction mixture was stirred at room temperature for 2 h, concentrated, and chased twice with toluene to give racemic (1S,2S,4S)-4-amino-2-methylcyclopentanol.

[0333] Process 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 with DCM, and the combined organic phases were dried over MgSO, filtered, concentrated, and purified by SGC (0% to 10% EtOH / DCM) to give intermediate 39-A.

[0334] Process 4 Intermediate 39-A (190 mg) was separated by chiral prep-HPLC on a Lux Cellulose-2 column using 9:1 ACN:MeOH as the eluent to give intermediates 39-B (first-eluting peak) and 40-A (second-eluting peak) in enantioenriched form. For intermediate 39-B: (absolute stereochemistry confirmed by X-ray analysis), chiral HPLC retention time = 3.98 min (Lux Cellulose-2 IC, 150 × 4.6 mm, 2 mL / min 9:1 ACN:MeOH). For intermediate 40-A: (absolute stereochemistry confirmed by X-ray analysis), chiral HPLC retention time = 6.35 min (Lux Cellulose-2 IC, 150 × 4.6 mm, 2 mL / min 9:1 ACN:MeOH).

[0335] 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 h, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by silica gel chromatography (0% to 10% EtOH / DCM) to give compound 39. 1 H-NMR (400 MHz, chloroform-d) δ 12.32 (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, 4.1 Hz, 1H), 5.28 (t, J = 5.3 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 4.23 (d, J = 23.0 Hz, 2H), 3.99 (dd, J = 12.7, 9.5 Hz, 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] + calculated for C 22 H 22 F2N3O5:446.15;found:446.2.

[0336] 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 acidified with 10% aqueous HCl at 50 °C for 1 h, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by silica gel chromatography (0% to 10% EtOH / DCM) to give compound 40. 1 H-NMR (400 MHz, chloroform-d) δ 12.32 (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, 4.1 Hz, 1H), 5.28 (t, J = 5.3 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 4.23 (d, J = 23.0 Hz, 2H), 3.99 (dd, J = 12.7, 9.5 Hz, 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] + calculated for C 22 H 22 F2N3O5:446.15;found:446.2.

[0337] 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

[0338] [ka]

[0339] [ka]

[0340] Process 1 A solution of 41-A (2020 mg, 7.463 mmol) (prepared by the same method as for 38-A) in THF (14 mL) was stirred at 0 °C, at which time 2.0 M LiBH4 in THF (7.5 mL, 15 mmol) was added. After the resulting mixture was stirred at room temperature for 21 h, it was cooled to 0 °C and diluted with EA, then quenched by the slow 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 eluent to give 41-B. LCMS-ESI + (m / z): [M-C4H8+H] + calculated for C8H 14 NO3:172.10;found:171.95.

[0341] Process 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 (twice). The aqueous fraction was extracted with EA (once), and the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by Combi Flash (120 g column, cartridge) using hexane-EA as the eluent to give 41-C. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 19 F2N2O7:306;found:306.

[0342] Process 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 (twice). The aqueous fraction was extracted with EA (once), and the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by Combi Flash (using a 120 g column cartridge) using hexane-EA as the eluent to give 41-D. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 19 F2N2O7:253;found:253.

[0343] Process 4 To a solution of reactant 41-D (1.3 g) in EA (20 mL) and EtOH (20 mL) (purged with N) was added Pd / C (130 mg). The mixture was stirred under H for 3 h. The mixture was filtered through Celite, and the filtrate was concentrated to give compound 41-E. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 19 F2N2O7:227;found:227.

[0344] Process 5 A 100 mL round-bottom flask was charged with reactant 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 at room temperature overnight. The mixture was diluted with EA (100 mL) and washed with water (2 times). The aqueous fraction was extracted with EA (1 time), and the organic fractions were combined, dried (NaSO), and concentrated. The crude product (2.4 g) was used in the next step without further purification. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 19 F2N2O7:556;found:556.

[0345] 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. with stirring for 1 hour. After concentration, the residue was purified by CombiFlash (120 g column) using hexane-ethyl acetate as eluents to give 41-F. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H19 F2N2O7:409;found:409.

[0346] Process 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 adding 1N HCl (3.7 mL), concentrated to remove most of the organic solvent, and extracted with EtOAc (twice). The organic layers were combined, dried (NaSO), and concentrated to give compound 41-G.

[0347] Process 7 A 100 mL round-bottom flask was charged with reactant 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 h. The mixture was diluted with EA (100 mL) and washed with saturated NaHCO (twice), saturated NH Cl (twice), and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give compound 41-H. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 19 F2N2O7:524.5;found:524.5.

[0348] Process 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 give compound 41. 1H-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] + calculated for C 21 H 20 F2N3O5:434.;found:434.

[0349] 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

[0350] [ka]

[0351] [ka]

[0352] Process 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 reheated to 75° C. for an additional 2 hours. The material was cooled and carried on crude to the next step.

[0353] Process 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 h, 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 (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to 1.49 g of a pale orange solid. Recrystallization from dichloromethane:hexane afforded the desired intermediate 42A: LCMS-ESI + (m / z):[M+H] + calculated for C 15 H 17 N2O6:321.11;found:321.3.

[0354] Process 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 h, the crude reaction mixture was carried on to the next step. LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 21 F3N3O5:464.14;found:464.2.

[0355] Process 4 To the crude reaction mixture from the previous step was added MgBr (0.258 g, 1.40 mmol). The reaction mixture was stirred at 50 °C for 10 min, acidified with 10% aqueous HCl, and extracted twice with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by silica gel chromatography (EtOH / dichloromethane) followed by HPLC (ACN / HO (with 0.1% TFA modifier)) to give compound 42: 1H-NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.34 (t, J = 5.7 Hz, 1H), 8.42 (s, 1H), 7.19 (t, J = 8.7 Hz, 2H), 5.43 (dd, J = 9.5, 4.1 Hz, 1H), 5.08 (s, 1H), 4.66 (dd, J = 12.9, 4.0 Hz, 1H), 4.59 (s, 1H), 4.56 - 4.45 (m, 2H), 4.01 (dd, J = 12.7, 9.7 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 12.0 Hz, 1H), 1.56 (dt, J = 12.0, 3.4 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 19 F3N3O5:450.13;found:450.2.

[0356] 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

[0357] [ka]

[0358] Process 1 A 100 mL round-bottom flask was charged with reactant 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 h. The mixture was diluted with EA (100 mL) and washed with saturated NaHCO (twice), saturated NH Cl (twice), and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give compound 43-A. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 19 F2N2O7:520;found:520.

[0359] Process 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 give 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] + calculated for C 21H 20 F2N3O5:430.;found:430.

[0360] 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

[0361] [ka]

[0362] Process 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) and stirred at room temperature for 2 h, after which LCMS analysis revealed complete consumption of compound 15-B and formation of intermediate 44-A. This reaction mixture was carried on to the next step.

[0363] Process 2 To the crude reaction solution from the previous step was added MgBr (63 mg, 0.34 mmol). The reaction mixture was stirred at 50 °C for 1 h, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by HPLC (ACN / H2O (with 0.1% TFA modifier)) to give compound 44. 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.38 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 7.27 (q, J = 9.2 Hz, 1H), 7.16 (q, J = 8.5 Hz, 1H), 5.42 (dd, J = 9.5, 4.0 Hz, 1H), 5.08 (s, 1H), 4.76 - 4.47 (m, 4H), 4.01 (dd, J = 12.8, 9.7 Hz, 1H), 1.92 (s, 4H), 1.82 (d, J = 12.1 Hz, 1H), 1.55 (dt, J = 12.2, 2.9 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 19 F3N3O5:450.13;found:450.2.

[0364] 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

[0365] [ka]

[0366] Process 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) and stirred at room temperature for 2 h, after which LCMS analysis revealed complete consumption of compound 15-B and formation of intermediate 45-A. This reaction mixture was carried on to the next step.

[0367] Process 2 To the crude reaction solution from the previous step was added MgBr (55 mg, 0.30 mmol). The reaction mixture was stirred at 50 °C for 1 h, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by HPLC (ACN / H2O (with 0.1% TFA modifier)) to give compound 45. 1 H-NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 10.37 - 10.25 (m, 1H), 8.37 (s, 1H), 7.14 (t, J = 8.7 Hz, 2H), 5.37 (dd, J = 9.5, 4.0 Hz, 1H), 5.02 (s, 1H), 4.66 - 4.40 (m, 4H), 3.95 (dd, J = 12.8, 9.6 Hz, 1H), 1.87 (s, 4H), 1.77 (d, J = 11.9 Hz, 1H), 1.50 (dt, J = 11.8, 3.2 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 19 F3N3O5:450.13;found:450.2.

[0368] 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

[0369] [ka]

[0370] [ka]

[0371] Process 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) and stirred at room temperature for 90 minutes, after which LCMS analysis revealed complete consumption of compound A and formation of intermediate 46-A. This reaction mixture was carried on to the next step.

[0372] Process 2 To the crude reaction solution from the previous step was added MgBr (50 mg, 0.27 mmol). The reaction mixture was stirred at 50 °C for 1 h, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by HPLC (ACN / H2O (with 0.1% TFA modifier)) to give compound 46. 1 H-NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 10.33 - 10.26 (m, 1H), 8.37 (s, 1H), 7.39 - 7.29 (m, 1H), 7.05 (t, J = 7.9 Hz, 2H), 5.37 (dd, J = 9.5, 4.1 Hz, 1H), 5.02 (s, 1H), 4.66 - 4.45 (m, 4H), 3.95 (dd, J = 12.7, 9.6 Hz, 1H), 1.87 (s, 4H), 1.77 (d, J = 12.0 Hz, 1H), 1.50 (dt, J = 12.2, 3.5 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N3O5:432.14;found:432.2.

[0373] 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

[0374] [ka]

[0375] Process 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 h. The mixture was diluted with EA (100 mL) and washed with saturated NaHCO (twice), saturated NH Cl (twice), and dried over Na SO . 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] + calculated for C 18 H 19 F2N2O7:506;found:506.

[0376] Process 2 A 50 mL round-bottom flask was charged with 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). 19 F 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] + calculated for C 21 H 20 F2N3O5:416.;found:416.

[0377] 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

[0378] [ka]

[0379] 48-B was prepared similarly to 55-H in Example 55, substituting 48-A for 55-A. Compound 48 was prepared as described for compound 38 in Example 38, substituting 48-B for 38-B to give compound 48. 1H-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] + calculated for C 21 H 20 F2N3O4:416.14.;found:416.07.

[0380] 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

[0381] [ka]

[0382] Process 1 Compound 15-B (44 mg, 0.14 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), and N,N-diisopropylethylamine (DIPEA) (0.07 mL, 0.40 mmol) and stirred at room temperature for 1 h, after which LCMS analysis revealed complete consumption of compound 15-B and formation of intermediate 49-A. This reaction mixture was carried on to the next step.

[0383] Process 2 To the crude reaction solution from the previous step was added MgBr (51 mg, 0.28 mmol). The reaction mixture was stirred at 50 °C for 90 min, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and triturated with methanol followed by diethyl ether to give compound 49. 1 H-NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 10.80 - 10.70 (m, 1H), 8.83 (d, J = 5.0 Hz, 1H), 8.44 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 7.7, 5.2 Hz, 1H), 5.43 (dd, J = 9.5, 4.0 Hz, 1H), 5.08 (s, 1H), 4.86 - 4.80 (m, 2H), 4.67 (dd, J = 12.9, 4.0 Hz, 1H), 4.59 (s, 1H), 4.02 (dd, J = 12.6, 9.8 Hz, 1H), 1.93 (s, 4H), 1.82 (d, J = 12.1 Hz, 1H), 1.60 - 1.52 (m, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F3N4O5:465.14;found:465.2.

[0384] 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

[0385] [ka]

[0386] [ka]

[0387] Process 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 of acetonitrile / 0.2 mL of acetic acid and stirred at 90° C. for 90 minutes, after which the reaction mixture was partitioned between DCM and brine, the aqueous phase was extracted with DCM, and the combined organic phases were dried over MgSO, filtered, concentrated, and purified by SGC (0%-10% EtOH / DCM) to provide intermediate 50-A.

[0388] Process 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 give intermediates 50-B (first eluting peak) and 51-A (second eluting peak) in enantiomerically enriched form. For intermediate 50-B: (absolute stereochemistry unknown), chiral HPLC retention time = 11.48 min (Chiralpak IC, 150 × 4.6 mm, 1 mL / min MeOH). For intermediate 51-A: (absolute stereochemistry unknown), chiral HPLC retention time = 14.35 min (Chiralpak IC, 150 × 4.6 mm, 1 mL / min MeOH).

[0389] Process 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 h, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by HPLC (ACN / HO (with 0.1% TFA modifier)) to give compound 50. 1 H-NMR (400 MHz, chloroform-d) δ 10.47 (t, J = 5.8 Hz, 1H), 8.42 (s, 1H), 7.35 (q, J = 8.6, 8.2 Hz, 1H), 6.81 (q, J = 8.7, 8.0 Hz, 2H), 6.41 (dd, J = 10.0, 3.6 Hz, 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, 10.2 Hz, 1H), 3.88 (t, J = 11.8 Hz, 2H), 2.27 (dt, J = 13.3, 3.1 Hz, 1H), 2.15 - 2.06 (m, 1H). LCMS-ESI + (m / z):[M+H] +calculated for C 21 H 20 F2N3O6:448.40;found:448.2.

[0390] Process 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 h, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by HPLC (ACN / HO (with 0.1% TFA modifier)) to give compound 51. 1 H-NMR (400 MHz, chloroform-d) δ 10.47 (t, J = 5.8 Hz, 1H), 8.42 (s, 1H), 7.35 (q, J = 8.6, 8.2 Hz, 1H), 6.81 (q, J = 8.7, 8.0 Hz, 2H), 6.41 (dd, J = 10.0, 3.6 Hz, 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, 10.2 Hz, 1H), 3.88 (t, J = 11.8 Hz, 2H), 2.27 (dt, J = 13.3, 3.1 Hz, 1H), 2.15 - 2.06 (m, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N3O6:448.40;found:448.2.

[0391] Example 52 Preparation of Compound 52 (2S,5R,13aS)-N-(2-Cyclopropoxy-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

[0392] [ka]

[0393] Process 1 A solution of cyclopropanol (1.9 g, 29 mmol) in 20 mL of dioxane was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 1.04 g, 26 mmol) in 80 mL of dioxane at 0 °C. The reaction mixture was warmed to room temperature, and 2,4-difluorobenzonitrile (3.48 g, 25 mmol) was added dropwise, causing the reaction temperature to rise to 95 °C. The reaction solution was cooled to room temperature and stirred for 18 h before being diluted with ethyl acetate, washed twice with water and twice with brine, dried over MgSO, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (0% to 10% EtOAc / hexanes) gave 2-cyclopropoxy-4-fluorobenzonitrile. 1 H-NMR (400 MHz, chloroform-d) δ 7.52 (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).

[0394] Process 2 To a 0°C suspension of lithium aluminum hydride in THF (1 M, 15 mL, 15 mmol) was added dropwise 14 mL of 2-cyclopropoxy-4-fluorobenzonitrile in diethyl ether. The reaction solution was stirred for 3 hours, gradually warming to room temperature, at which point it was recooled to 0°C and an additional 8 mL of lithium aluminum hydride (1 M, 8 mmol) in THF was added and stirred for an additional 90 minutes. The reaction was diluted with 0.9 mL of water, 0.9 mL of 15% NaOH, and the resulting solution was cooled to 0°C for 3 hours. (aq) and 2.7 mL of water, sequentially. The reaction was filtered through Celite, rinsing with diethyl ether, dried over MgSO4, and concentrated to give 2-cyclopropoxy-4-fluorobenzylamine of sufficient purity to be carried forward crude. 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).

[0395] Process 3 Compound 15-B (46 mg, 0.14 mmol) was dissolved in 1 mL of acetonitrile and treated with 2-cyclopropoxy-4-fluorobenzylamine (32 mg, 0.18 mmol), HATU (62 mg, 0.16 mmol), and N,N-diisopropylethylamine (DIPEA) (0.04 mL, 0.22 mmol) and stirred at room temperature for 2 hours, after which LCMS analysis revealed complete consumption of compound 15-B and the formation of intermediate 52-A. This reaction mixture was carried on to the next step.

[0396] Process 4 To the crude reaction solution from the previous step was added MgBr (56 mg, 0.30 mmol). The reaction mixture was stirred at 50 °C for 90 min, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by HPLC (ACN / H2O (with 0.1% TFA modifier)) to give compound 52. 1 H-NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.21 (t, J = 5.8 Hz, 1H), 8.41 (s, 1H), 7.22 - 7.15 (m, 1H), 7.12 (dd, J = 11.2, 2.5 Hz, 1H), 6.72 (td, J = 8.5, 2.5 Hz, 1H), 5.42 (dd, J = 9.6, 4.1 Hz, 1H), 5.07 (s, 1H), 4.66 (dd, J = 12.8, 4.1 Hz, 1H), 4.58 (s, 1H), 4.34 (dd, J = 5.6, 2.4Hz, 2H), 4.04 - 3.91 (m, 2H), 1.92 (s, 4H), 1.82 (d, J = 11.9 Hz, 1H), 1.55 (dt, J = 12.4, 3.5 Hz, 1H), 0.80 (q, J = 6.3, 5.7 Hz, 2H), 0.72 (q, J = 6.0, 4.9 Hz, 2H). LCMS-ESI + (m / z):[M+H] + calculated for C 24 H 25 FN3O6:470.17;found:470.1.

[0397] Example 53 Preparation of Compound 53 (2R,5S,13aR)-N-(2-Cyclopropoxy-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

[0398] [ka]

[0399] Process 1 Compound 42-A (46 mg, 0.14 mmol) was dissolved in 1 mL of acetonitrile and treated with 2-cyclopropoxy-4-fluorobenzylamine (33 mg, 0.18 mmol), HATU (61 mg, 0.16 mmol), and N,N-diisopropylethylamine (DIPEA) (0.04 mL, 0.24 mmol) and stirred at room temperature for 2 hours, after which LCMS analysis revealed complete consumption of compound 42-A and the formation of intermediate 53-A. This reaction mixture was carried on to the next step.

[0400] Process 2 To the crude reaction solution from the previous step was added MgBr (55 mg, 0.30 mmol). The reaction mixture was stirred at 50 °C for 90 min, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by HPLC (ACN / H2O (with 0.1% TFA modifier)) to give compound 53. 1H-NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.21 (t, J = 5.8 Hz, 1H), 8.41 (s, 1H), 7.22 - 7.15 (m, 1H), 7.12 (dd, J = 11.2, 2.5 Hz, 1H), 6.72 (td, J = 8.5, 2.5 Hz, 1H), 5.42 (dd, J = 9.6, 4.1 Hz, 1H), 5.07 (s, 1H), 4.66 (dd, J = 12.8, 4.1 Hz, 1H), 4.58 (s, 1H), 4.34 (dd, J = 5.6, 2.4Hz, 2H), 4.04 - 3.91 (m, 2H), 1.92 (s, 4H), 1.82 (d, J = 11.9 Hz, 1H), 1.55 (dt, J = 12.4, 3.5 Hz, 1H), 0.80 (q, J = 6.3, 5.7 Hz, 2H), 0.72 (q, J = 6.0, 4.9 Hz, 2H). LCMS-ESI + (m / z):[M+H] + calculated for C 24 H 25 FN3O6:470.17;found:470.1.

[0401] 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

[0402] [ka]

[0403] [ka]

[0404] Process 1 A 50 mL round-bottom flask was charged with reactant 54-A (0.02 g, 0.06 mmol), (S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethanamine (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 h. The reaction mixture was concentrated to a low volume, redissolved in EtOAc (50 mL), washed with saturated NaHCO (twice), saturated NH Cl, and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel using hexane-EtOAc to give 54-B. LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 19 F2N2O7:514;found:514.

[0405] Process 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 min, the reaction mixture was cooled to 0 °C, and 1 N 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 pre-HPLC purification (30% to 70% acetonitrile:water, 0.1% TFA) to give compound 54 as a TFA salt. 1H-NMR (400 MHz, chloroform-d) δ 11.28 (d, J = 9.4 Hz, 1H), 8.39 (s, 1H), 7.54 (q, J = 7.8 Hz, 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, 4.0 Hz, 1H), 4.05 (dd, J = 12.9, 9.3 Hz, 1H), 2.39 - 1.94 (m, 4H), 1.86 (t, J = 10.5 Hz, 1H), 1.60 (dt, J = 12.6, 3.4 Hz, 1H). 19 F-NMR (376 MHz, chloroform-d) δ -75.30 (t, J = 6.8 Hz, 3 F), -108.33 (dd, J = 8.6, 6.3 Hz, 1 F), -111.56 - -113.23 (m, 1 F). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 20 F2N3O5:500.;found:500.

[0406] 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

[0407] [ka]

[0408] Process 1 A mixture of compound 55-A (40.60 g, 150 mmol) and Pd(OH) / C (12 g) in EtOH (400 mL) under an atmosphere of H was stirred at room temperature overnight. 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 give compound 55-B, which was used in the next step without purification. LCMS-ESI + (m / z):[M+H] + calculated for C9H 16 NO:170.1.;found:170.2.

[0409] Process 2 To a solution of compound 55-B (92.25 g, 0.45 mol) and KCO (186.30 g, 1.35 mol) in CHCN (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 and concentrated, and the residue was purified by silica gel chromatography to give compound 55-C.

[0410] Process 3 To a mixture of diisopropylamine (50 g, 0.50 mol) in THF (400 mL) was added n-BuLi (200 mL, 0.50 mol) at −78° C. under a N atmosphere. After 0.5 h, the reaction mixture was warmed to 20° C. and stirred for 0.5 h. The mixture was cooled to −78° C., and a solution of compound 55-C (64.75 g, 0.25 mol) in THF (600 mL) was added under a N atmosphere. The mixture was stirred for 4 h and quenched with 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 give compound 55-D.

[0411] Process 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. The residue was purified by HPLC to give compound 55-E.

[0412] Process 5 A mixture of compound 55-E (47 g, 176 mmol) and Pd(OH) / C (9 g) in EtOH (400 mL) was stirred overnight at room temperature under an atmosphere of H. The reaction mixture was concentrated to give compound 55-F, which was used in the next step without purification. 1 H-NMR (400 MHz, CDCl3) 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] + calculated for C7H 12 NO2:142.1.;found:142.1.

[0413] Process 6 To a mixture of compound 55-F (29.20 g, 165 mmol) and 2 N NaOH solution (330 mL, 0.66 mol) in dioxane (120 mL) was added BocO (39.60 g, 181 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The mixture was adjusted to pH = 5-6 with 3 N HCl and extracted with DCM. The organic layer was dried over NaSO, filtered, and concentrated to give 55-G. 1 H-NMR (400 MHz, CDCl3) 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] +calculated for C 12 H 19 NNaO4:264.1.;found:264.1.

[0414] Process 7 To a mixture of compound 55-G (500 mg, 2.07 mmol) in THF (10 mL) cooled to 0 °C, BH3-DMS THF complex (2N in THF, 8.23 ​​mmol, 4.1 mL) was slowly added. 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. LC / MS indicated some starting material remained, so an additional 2 mL of BH3-DMS THF complex was added, and the mixture was stirred for an additional 3 h. The reaction was then cooled to 0 °C and slowly quenched with methanol (gas evolution occurred). The internal temperature was monitored to ensure the exotherm was below 25 °C. The mixture was concentrated and then purified by silica gel chromatography (20% to 40% EtOAc / hexanes) to give 55-H.

[0415] Process 8 Compound 55 was prepared as described for Example 41 using 55-H in place of 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] + calculated for C 21 H19 F3N3O4:434.13.;found:434.32.

[0416] 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

[0417] [ka]

[0418] [ka]

[0419] Process 1 A solution of 56-A (5 g, 19.43 mmol) in tetrahydrofuran (65 mL) was cooled in an ice bath, at which time 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 h, 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 h at 0 °C, the reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with EtOAc and washed with water. The aqueous fraction was extracted with EtOAc, and the combined organic fractions were dried (Na2SO4) and concentrated. The residue was purified by silica column chromatography (50% to 70% EtOAc / hexane) to give 56-B (3.05 g, 57%). LCMS-ESI + (m / z):[M+H] + calculated for C 16 H 21 NO3:275.34;found:276.122.

[0420] Process 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 h, the mixture was diluted with water and extracted with EtOAc (twice), and the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by silica column chromatography (10%-20% EtOAc / hexane) to give 56-C (2.6 g, 96.1%). LCMS-ESI + (m / z):[M+H] + calculated for C 32 H 39 NO3Si:513.74;found:514.625.

[0421] Process 3 To a solution of 56-C (3.27 g, 6.36 mmol) in EtOH (26 mL) and acetic acid (3 mL), 10% PdOH / C (0.52 g, 3.7 mmol) was added, and the suspension was shaken in a Parr apparatus at 50 atm for 20 h. After filtration through Celite, the cake was washed with EtOH, and the filtrate was concentrated under reduced pressure. 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 h. After filtration through Celite, the cake was washed with EtOH, and the filtrate was concentrated to dryness under reduced pressure to give the crude deprotected product (2.07 g, 79.4%). LCMS-ESI + (m / z):[M+H] + calculated for C 24 H 31 NO3Si:409.59;found:410.485.

[0422] To this 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 h, the reaction mixture was diluted with water, extracted with EtOAc (2×), and the two organic fractions were washed with water, combined, dried (NaSO), and concentrated. The residue was purified by silica column chromatography (10% to 20% EtOAc / hexanes) to give 56-D (2.13 g, 86.14%). LCMS-ESI + (m / z):[M+H] + calculated for C 30 H 41 NO5Si:523.74;found:523.922.

[0423] Process 4 A solution of 56-D (2.07 g, 4.06 mmol) in THF (20 mL) was stirred in an ice bath, at which time 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 re-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% to 40% EOAc / hexane) to give 56-E (1.59 g, 81.3%). LCMS-ESI + (m / z):[M+H] + calculated for C 28 H 39 NO4Si:481.7;found:482.337.

[0424] Process 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. Diisopropyl azodicarboxylate, 95% (1.46 mL, 7.42 mmol) was added. The mixture was then warmed to room temperature and stirred for 20 h. The reaction mixture was then concentrated, and the residue was dissolved in ether, cooled in an ice bath, and stirred for 1.5 h. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica column chromatography (10% to 30% EtOAc / hexane) to give the protected amino compound (1.86 g, 92.8%).

[0425] 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 off, and the filtrate was concentrated to dryness under reduced pressure.

[0426] Process 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 NaHCO (347 mg, 4.12 mmol) in water (15 mL) and EtOH (15 mL) was stirred for 20 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, and the combined organic layers were dried (NaSO) and concentrated. The residue (1.5 g) was dissolved in CHCl (5 mL), and 4 N HCl in dioxane (18.6 mL) was added. After 1.5 h, the mixture was concentrated to dryness, co-evaporated with toluene, and dried in vacuo.

[0427] The crude residue (1.38 g) and DBU (1.4 ml, 9.38 mmol) in toluene (25 ml) were stirred at 110° C. After 35 min, the mixture was concentrated and the residue was purified by silica column chromatography (5% to 15% MeOH / EtOAc) to give 56-G (450 mg, 72.3%). LCMS-ESI + (m / z):[M+H] + calculated for C 39 H 42 N2O6Si:662.85;found:663.766.

[0428] Process 7 A mixture of 56-G (890 mg, 1.34 mmol) in MeOH (14 mL) and THF (14 mL) was stirred at room temperature, at which time 1 M KOH (7.09 mL) was added. After 30 min, the reaction mixture was neutralized with 1 N HCl, extracted with EtOAc (twice), and the combined organic extracts were dried (NaSO) and concentrated.

[0429] A suspension of this 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, at which time 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 min, the mixture was diluted with water and extracted with EtOAc (3 times), the combined organic phases were dried (Na2SO4), concentrated, and the residue was purified by silica column chromatography (50% to 75% EtOAc / hexanes) to give 56-H (919 mg, 88.23%). LCMS-ESI + (m / z):[M+H] + calculated for C 44 H 42F3N3O5Si:777.9;found:778.409.

[0430] Process 8 A solution of 56-H (915 mg, 1.18 mmol) in THF (5 mL) was stirred in an ice bath, at which time 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 reduced pressure, and the residue was diluted with EtOAc, washed with water, dried (NaSO), concentrated, and the residue was purified by silica column chromatography (50% to 75% EtOAc / hexanes, then 5% MeOH / EtOAc). The resulting material (248 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL) and cooled to −78° C., at which time diethylaminosulfur trifluoride (0.07 mL, 0.55 mmol) was added dropwise, and the reaction was warmed to room temperature and stirred for 1 hour. The reaction was cooled in an ice bath and quenched with saturated NaHCO, the two phases were separated, and the separated aqueous fraction was extracted with CHCl. ​​The two organic fractions were combined, dried (NaSO) 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] + calculated for C 28 H 23 F4N3O4: 541.49; found: 542.320) and 56-I (30 mg) (LCMS-ESI + (m / z):[M+H] + calculated for C 28 H 22 F3N3O4: 521.49; found: 522.05).

[0431] Process 9 Compound 56-J (75 mg, 139 mmol) was dissolved in TFA (1 mL) and stirred at room temperature for 10 min. The solution was concentrated, and the residue was purified by reverse-phase HPLC (Gemini, 15% to 43% ACN / HO + 0.1% TFA) to give compound 56. 1 H-NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.80 (s, 1H), 7.17 (t, J = 8.6 Hz, 2H), 5.45 - 5.18 (m, 1H), 4.70 - 4.39 (m, 3H), 4.23 (d, J = 11.5 Hz, 1H), 4.11 - 3.85 (m, 2H), 2.85 (dd, J = 4.2, 2.0 Hz, 1H), 2.34 - 2.13 (m, 1H), 1.81 (s, 1H), 1.55 - 1.33 (m, 2H). 19 F-NMR (376 MHz, DMSO-d6) δ -74.20 (m), -106.95 - -116.45 (m), -190.65 - -194.54 (m).

[0432] 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

[0433] [ka]

[0434] [ka]

[0435] Process 1 A solution of 57-A (1.45 g, 5.34 mmol) in dichloromethane (30 mL) was cooled in an ice bath, at which time Dess Martin periodinane (4.53 g, 10.69 mmol) was added portionwise, and the reaction was stirred at room temperature for 18 h. The reaction was quenched by the addition of water, the precipitate was filtered off, and a saturated solution of NaSO was added. The mixture was stirred until the solution turned basic, then saturated NaHCO was added, and the aqueous layer was extracted with CHCl. ​​The combined organic fractions were dried (NaSO) and concentrated. The residue was purified by silica column chromatography (30% to 50% EtOAc / hexanes) to give 57-B (1.13 g, 78.2%). LCMS-ESI + (m / z):[M+H] + calculated for C 13 H 19 NO5:269.29;found:269.722.

[0436] Process 2 A solution of 57-B (0.5 g, 1.86 mmol) in dichloromethane (10 mL) was cooled to −78 °C, at which time diethylaminosulfur trifluoride (0.52 mL, 3.91 mmol) was added dropwise, and the reaction was warmed to room temperature and stirred for 18 h. The reaction was cooled in an ice bath and quenched with saturated NaHCO. The two phases were separated, and the separated aqueous fraction was extracted with CHCl. ​​The two organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by silica column chromatography (20% to 50% EtOAc / hexanes) to give 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).

[0437] Process 3 A solution of 57-C (935 mg, 3.21 mmol) in THF (10 mL) was stirred in an ice bath, at which time 2.0 M LiBH4 in THF (3.22 mL) was added, and the resulting mixture was stirred at room temperature for 18 h. 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% to 40% EtOAc / hexane) to give 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).

[0438] Process 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. Diisopropyl azodicarboxylate, 95% (1.22 mL, 6.19 mmol) was added. The mixture was then warmed to room temperature and stirred for 20 hours. The reaction mixture was then concentrated, and the residue was dissolved in ether, cooled in an ice bath, and stirred for 1.5 hours. After filtering off the solid, the filtrate was concentrated. The residue was purified by silica column chromatography (40% to 60% EtOAc / hexane) to give the phthalimide adduct (1.07 g, 99.7%). LCMS-ESI + (m / z):[M+H] + calculated for C 20 H 22 F2N2O4:392.4;found:393.204.

[0439] A solution of the 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 ether (10 mL) was added. The mixture was stirred for 30 minutes. The formed solid was filtered off, and the filtrate was concentrated to dryness under reduced pressure to give crude 57-E.

[0440] Process 5 A mixture of crude 57-E (709 mg, 2.7 mmol), compound 38-F (Example 38) (936 mg, 2.7 mmol), and NaHCO (454 mg, 5.41 mmol) in water (15 mL) and EtOH (15 mL) was stirred for 20 h. The reaction mixture was concentrated under reduced pressure, 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 SO ) and concentrated. The residue (1.5 g) was dissolved in CHCl (7 mL), and 4 N HCl in dioxane (26.9 mL) was added. After 1.5 h, the mixture was concentrated to dryness, co-evaporated with toluene, and dried in vacuo. The crude residue (1.3 g) and DBU (2 mL, 13.4 mmol) in toluene (25 mL) were stirred at 110 °C. After 35 min, the mixture was concentrated and the residue was purified by silica column chromatography (5% to 15% MeOH / EtOAc) to give 57-F (426 mg, 36.17%). + (m / z):[M+H] + calculated for C 23 H 22 F2N2O5:444.43;found:445.280.

[0441] Process 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, at which time 1 M KOH (5.06 mL) was added. After 30 min, the reaction mixture was neutralized with 1 N HCl, extracted with EtOAc (twice), and the combined organic extracts were dried (NaSO) and concentrated to give crude 57-G.

[0442] Process 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, at which time N,N-diisopropylethylamine (DIPEA) (0.59 mL, 3.4 mmol) was added. After 1 h, the mixture was diluted with water and extracted with EtOAc (3 times). The combined organic phases were dried (NaSO) and concentrated to give 57-H. LCMS-ESI + (m / z):[M+H] + calculated for C 28 H 22 F5N3O4:559.48;found:560.24.

[0443] Process 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 / HO + 0.1% TFA) to give compound 57 (85 mg, 67.5%). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 16 F5N3O4:469.36;found:470.229. 1H-NMR (400 MHz, DMSO-d6) δ 10.41 (t, J = 5.6 Hz, 1H), 8.20 (s, 1H), 7.12 (t, J = 8.7 Hz, 2H), 4.79 (s, 1H), 4.48 (m, 3H), 4.10 (m, 2H), 3.02 (d, J = 5.7 Hz, 1H), 2.33 (m, 1H), 2.22 - 1.97 (m, 2H), 1.85 (d, J = 11.0 Hz, 1H), 1.21 (s, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -69.88 , -71.77 , -74.09 , -88.33 (dd, J = 222.6, 23.8 Hz), -109.15 - -109.60 (m), -110.04 , -112.44 (t, J = 7.6 Hz).

[0444] 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

[0445] [ka]

[0446] Process 1 A suspension of 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, at which time N,N-diisopropylethylamine (DIPEA) (0.38 mL, 0.28 mmol) was added. After 1 h, the mixture was diluted with water and extracted with EtOAc (3 times), and the combined organic phases were dried (NaSO) and concentrated to give 58-A. LCMS-ESI +(m / z):[M+H] + calculated for C 28 H 22 ClF4N3O4:575.94;found:576.394.

[0447] Process 2 Compound 58-A (166 mg) was dissolved in TFA (2 mL) and stirred at room temperature for 10 minutes. The solution was concentrated. The residue was purified by reverse-phase HPLC (Gemini, 15% to 70% ACN / HO + 0.1% TFA) to give compound 57 (60 mg, 42.8%). LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 16 ClF4N3O4:485.82;found:486.135. 1 H-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 (376 MHz, DMSO-d6) δ -87.63 , -88.23 , -108.67 , -109.27 , -116.42 (t, J = 7.0 Hz), -118.48 (d, J = 7.8 Hz).

[0448] 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

[0449] [ka]

[0450] [ka]

[0451] Process 1 A solution of 57-B (1.9 g, 7.06 mmol) in methanol (35 mL) was stirred at 0 °C, at which time sodium borohydride (667 mg, 17.64 mmol) was added portionwise, and the resulting mixture was stirred at room temperature for 30 min. 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 extracted again with EtOAc, and the combined organic layers were dried (NaSO) and concentrated. The residue was purified by silica column chromatography (30% to 60% EtOAc / hexanes) 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 (96mg): 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).

[0452] Process 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 h, the mixture was diluted with water, extracted with EtOAc (twice), and the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by silica column chromatography (10%-20% EtOAc / hexanes) to give 59-C. LCMS-ESI + (m / z):[M+H] + calculated for C 29 H 39 NO5Si:509.71;found:510.793.

[0453] Process 3 A solution of 59-C (1.23 g, 2.41 mmol) in THF (13 mL) was stirred in an ice bath, at which time 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 h. The reaction mixture was then diluted with ethyl acetate, 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% to 40% EtOAc / hexane) to give 59-D. LCMS-ESI + (m / z):[M+H] + calculated for C 28 H 39 NO4Si:481.7;found:482.741.

[0454] Process 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 warmed to room temperature and stirred for 20 hours. The reaction mixture was then concentrated, and the residue was dissolved in ether, cooled in an ice bath, and stirred for 1.5 hours. The solid was then filtered off, and the filtrate was concentrated. The residue was purified by silica column chromatography (10% to 30% EtOAc / hexane) to give the phthalimide adduct. LCMS-ESI + (m / z):[M+H] + calculated for C 36 H 42 N2O5Si:610.81;found:611.935.

[0455] 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 ether (10 mL) was added and the mixture was stirred for 30 minutes. The solid formed was filtered off, and the filtrate was concentrated to dryness under reduced pressure to give 59-E. LCMS-ESI + (m / z):[M+H] + calculated for C 28 H 40 N2O3Si:480.71;found:481.356.

[0456] Process 5 A mixture of crude 59-E (770 mg, 1.60 mmol), compound 38-F (Example 38) (555 mg, 1.60 mmol), and NaHCO (269 mg, 3.20 mmol) in water (12 mL) and EtOH (12 mL) was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The aqueous layer was extracted again with EtOAc, and the combined organic layers were dried (NaSO) and concentrated.

[0457] The residue (1.29 g) was dissolved in CH2Cl2 (4 mL) and 4N HCl in dioxane (15.6 mL) was added. After 1.5 h, the mixture was concentrated to dryness, coevaporated with toluene, and dried in vacuo. LCMS-ESI + (m / z):[M+H] + calculated for C 41 H 48 N2O7Si:708.91;found:709.782.

[0458] The crude residue (1.09 mg) and DBU (1.17 ml, 7.8 mmol) in toluene (20 ml) were stirred at 110° C. After 35 min, the mixture was concentrated and the residue was purified by silica column chromatography (5% to 15% MeOH / EtOAc) to give 59-F. LCMS-ESI + (m / z):[M+H] + calculated for C 39 H 42 N2O6Si:662.85;found:663.677.

[0459] Process 6 A mixture of 59-F (680 mg, 1.03 mmol) in MeOH (10 mL) and THF (10 mL) was stirred at room temperature, at which time 1 M KOH (5.42 mL) was added. After 30 min, the reaction mixture was neutralized with 1 N HCl, extracted with EtOAc (2×), and the combined organic extracts were dried (NaSO) and concentrated. LCMS-ESI + (m / z):[M+H]+ calculated for C 37 H 38 N2O6Si:634.79;found:635.466.

[0460] 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, at which time N,N-diisopropylethylamine (DIPEA) (1.34 mL, 7.68 mmol) was added. After 2 h, the mixture was diluted with water, extracted with EtOAc (3 times), and the combined organic phases were dried (NaSO), concentrated, and the residue was purified by silica column chromatography (50% to 75% EtOAc / hexanes) to give 59-G. LCMS-ESI + (m / z):[M+H] + calculated for C 44 H 42 F3N3O5Si:777.9;found:778.566.

[0461] Process 7 A solution of 59-G (648 mg, 0.83 mmol) in THF (10 mL) was stirred in an ice bath, at which time 1.0 M tetrabutylammonium fluoride in THF (0.83 mL) was added dropwise, and 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 reduced pressure, and the residue was diluted with EtOAc, washed with water, dried (NaSO), concentrated, and the residue was 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., at which time diethylaminosulfur trifluoride (0.09 mL, 0.65 mmol) was added dropwise, and the reaction was warmed to room temperature and stirred for 2.5 hours. The reaction was cooled in an ice bath, quenched with saturated NaHCO, the two phases were separated, and the separated aqueous fraction was extracted with CHCl. ​​The two organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by silica column chromatography (1% MeOH / EtOAc) to give 59-H. LCMS-ESI + (m / z):[M+H] + calculated for C 28 H 23 F4N3O4:541.49;found:542.320.

[0462] Process 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 off, and the precipitated product was washed with water and dried under reduced pressure to give compound 59. LCMS-ESI + (m / z):[M+H] + calculated for C 21 H 17 F4N3O4:451.37, found:452.226. 1H-NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.34 (s, 1H), 7.18 (t, J = 8.6 Hz, 2H), 5.15 - 4.88 (m, 1H), 4.73 (d, J = 3.3 Hz, 1H), 4.49 (m, 3H), 4.04 (t, J = 12.4 Hz, 1H), 3.65 (dd, J = 12.4, 3.7 Hz, 1H), 2.95 - 2.76 (m, 1H), 2.26 - 2.03 (m, 1H), 1.96 - 1.64 (m, 3H). 19 F-NMR (376 MHz, DMSO-d6) δ -73.93 , -74.74 (d, J = 28.8 Hz), -109.31 (m), -112.51 (m), -165.65 (m).

[0463] 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

[0464] [ka]

[0465] Process 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 h. 4 M HCl (in dioxane, 55 mL, 221 mmol) was added, and the solution was heated at 50 °C for 2 h. 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 CHCl (4 times). The combined CHCl extracts were dried over NaSO and concentrated to give 60-A. LCMS-ESI + (m / z):[M+H] + calculated for C 16 H 19 N2O5:319.13;found:319.20.

[0466] Process 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. The volatiles were removed in vacuo, and the resulting aqueous layer was acidified with 1 N HCl. The resulting white solid was filtered, washed with water, and dried in vacuo to give 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] + calculated for C 15 H 17 N2O5:305.11;found:305.15.

[0467] Process 3 To a solution of 60-B (0.10 g, 0.33 mmol) in CHCl (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 judged complete by LC / MS. The reaction mixture was diluted with CHCl and washed with 1 N HCl. The aqueous layer was back-extracted with CHCl, and the combined organic layers were dried over NaSO and concentrated in vacuo. The crude material was dissolved in hot DMF and precipitated upon cooling. Filtration afforded 60-C. LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 22 Cl2N3O4:462.10;found:462.14.

[0468] Process 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 at 45 °C for 2.5 h and then cooled to room temperature. The slurry was diluted with CHCl and washed with 1 N HCl and brine. The aqueous layer was back-extracted with CHCl (twice), and the combined organic layers were dried over NaSO and concentrated in vacuo. The crude solid was triturated with methanol and filtered to give 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] + calculated for C 21 H 20 Cl2N3O4:448.08;found:448.18.

[0469] 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

[0470] [ka]

[0471] [ka]

[0472] 61 was prepared analogously to Example 60, using tert-butyl (1S,3S,4R)-3-(aminomethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (prepared in Example 55) instead of 41-E and (3-chloro-2,4-difluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. 1H-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] + calculated for C 21 H 19 ClF2N3O4:450.10;found:450.15.

[0473] 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

[0474] [ka]

[0475] 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] + calculated for C 22 H 20 F4N3O5:482.13;found:482.145.

[0476] 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

[0477] [ka]

[0478] 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] + calculated for C 21 H 20 ClFN3O5:448.10;found:448.143.

[0479] 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

[0480] [ka]

[0481] Compound 64 was prepared in a similar manner to compound 42, using (2,4,5-trifluorophenyl)methanamine in place 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] + calculated for C 21 H 19 F3N3O5:450.12;found:450.119.

[0482] 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

[0483] [ka]

[0484] 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] + calculated for C 21 H 19 ClF2N3O5:466.09;found:466.107.

[0485] 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

[0486] [ka]

[0487] Compound 66 was prepared in a similar manner 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]+ calculated for C 21 H 20 F2N3O4:416.13;found:416.415.

[0488] 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

[0489] [ka]

[0490] Compound 67 was prepared in a similar manner to compound 60, using (4-fluoro-2-(trifluoromethyl)phenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. 1 H-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] + calculated for C 22 H 20 F4N3O4:466.13;found:466.297.

[0491] 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

[0492] [ka]

[0493] Compound 68 was prepared in a similar manner to compound 60, using (2-chloro-4-fluorophenyl)methanamine in place of (2,3-dichlorophenyl)methanamine. 1 H-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] + calculated for C 21 H 20 ClFN3O4:432.10;found:432.214.

[0494] 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

[0495] [ka]

[0496] Compound 69 was prepared in a similar manner to compound 60, using (3-chloro-2,4-difluorophenyl)methanamine in place of (2,3-dichlorophenyl)methanamine. 1 H-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] + calculated for C 21 H 19 ClF2N3O4:450.10;found:450.27.

[0497] 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

[0498] [ka]

[0499] Compound 70 was prepared in a similar manner to compound 60, using (2-fluoro-3-methylphenyl)methanamine in place 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] + calculated for C 22 H 23 FN3O4:412.16;found:412.26.

[0500] 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

[0501] [ka]

[0502] Compound 71 was prepared in a similar manner to compound 60, using (3,6-dichloro-2-fluorophenyl)methanamine in place 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] +calculated for C 21 H 19 Cl2FN3O4:466.07;found:466.257.

[0503] 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

[0504] [ka]

[0505] Compound 72 was prepared in a similar manner to compound 60, using (3-chlorophenyl)methanamine in place of (2,3-dichlorophenyl)methanamine. 1 H-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] + calculated for C 21 H 21 ClN3O4:414.11;found:414.21.

[0506] 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

[0507] [ka]

[0508] Compound 73 was prepared in a similar manner to compound 60, using (3-chloro-2,6-difluorophenyl)methanamine in place of (2,3-dichlorophenyl)methanamine. 1 H-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] + calculated for C 21 H 19 ClF2N3O4:450.10;found:450.16.

[0509] 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

[0510] [ka]

[0511] Compound 74 was prepared in a similar manner to compound 60, using (2-fluoro-3-(trifluoromethyl)phenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. 1 H-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] + calculated for C 22 H 20 F4N3O4:466.13;found:466.142.

[0512] 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

[0513] [ka]

[0514] Compound 75 was prepared in a similar manner to compound 60, using (3-chloro-4-fluorophenyl)methanamine in place 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] + calculated for C 21 H 20 ClFN3O4:432.10;found:432.159.

[0515] 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

[0516] [ka]

[0517] Compound 76 was prepared in a similar manner to compound 60, using (3,5-difluoropyridin-2-yl)methanamine instead of (2,3-dichlorophenyl)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] + calculated for C 20 H 19 F2N4O4:417.13;found:417.189.

[0518] 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

[0519] [ka]

[0520] Process 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 h. The reaction mixture was concentrated to a low volume, redissolved in EtOAc (50 mL), washed with saturated NaHCO (twice), saturated NH Cl, and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel using hexane-EtOAc to give 77-B as a white solid. LCMS-ESI + (m / z):[M+H] + found:538.

[0521] Process 2 A 50 mL round-bottom flask was charged with 77-B (0.20 g, 0.37 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 flash chromatography using EtOAc-20% MeOH in EtOAc as the eluent to give compound 77. 1 H-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). 19 F-NMR (376 MHz, chloroform-d) δ -109.65 - -111.29 (m), -111.76 - -113.09 (m). LCMS-ESI + (m / z):[M+H] + found:448.

[0522] 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

[0523] [ka]

[0524] [ka]

[0525] Process 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 h. The reaction mixture was concentrated to a low volume, redissolved in EtOAc (50 mL), washed with saturated NaHCO (twice), saturated NH Cl, and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel using hexane-EtOAc to give 78-B as a white solid. LCMS-ESI + (m / z):[M+H] + ;found:478.

[0526] Process 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 1 N hydrochloric acid (4 mL) was added. Additional water (approximately 5 mL) was added, and the solid was filtered, washed with water, and dried to give compound 78. 1 H-NMR (400 MHz, chloroform-d) δ 12.30 (s, 1H), 10.59 (d, J = 8.3 Hz, 1H), 8.21 (s, 1H), 6.60 (t, J = 8.4 Hz, 2H), 5.59 (t, J = 7.4 Hz, 1H), 5.37 (dd, J = 9.4, 4.1 Hz, 1H), 5.31 - 5.09 (m, 1H), 4.64 (t, J = 3.0 Hz, 1H), 4.20 (dd, J = 12.9, 4.1 Hz, 2H), 3.96 (dd, J = 12.8, 9.4 Hz, 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.

[0527] 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

[0528] [ka]

[0529] Process 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 h. The reaction mixture was concentrated to a low volume, redissolved in EtOAc (50 mL), washed with saturated NaHCO (twice), saturated NH Cl, and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel using hexane-EtOAc to give 79-B as a white solid. LCMS-ESI + (m / z):[M+H] + ;found:524.

[0530] Process 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 flash chromatography using EtOAc-20% MeOH in EtOAc as the eluent to give compound 79. 1 H-NMR (400 MHz, chloroform-d) δ 11.70 (s, 1H), 10.65–10.18 (m, 1H), 8.27 (s, 1H), 7.26 (m, 1H), 6.90 (td, J = 9.7, 6.4 Hz, 1H), 4.89 (s, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.09 (dd, J = 11.4, 2.6 Hz, 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.

[0531] 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

[0532] [ka]

[0533] Process 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 h. The reaction mixture was concentrated to a low volume, redissolved in EtOAc (50 mL), washed with saturated NaHCO (twice), saturated NH Cl, and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel using hexane-EtOAc to give 80-B as a white solid. LCMS-ESI + (m / z):[M+H] + ;found:541.

[0534] Process 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 flash chromatography 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). 19 F-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.

[0535] 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

[0536] [ka]

[0537] [ka]

[0538] Process 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 NaHCO (5 mL) was added dropwise to quench the reaction. The reaction mixture was then diluted with EtOAc (100 mL), washed with sat. NaHCO, brine, and dried over NaSO. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 81-B. LCMS-ESI + (m / z):[M+H] + found:274.

[0539] Process 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 (3.2 mL, 6.4 mmol) in THF was slowly added. The reaction mixture was then warmed and stirred at room temperature for 3 h. The reaction mixture was then diluted with EtOAc (100 mL) and slowly treated with water (H evolution). After separation of the two phases, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over NaSO. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 81-C. LCMS-ESI + (m / z):[M+H] + found:246.

[0540] Process 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 with stirring. Diisopropyl azodicarboxylate (DIAD) (1.0 mL, 5.1 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 the eluent to give 81-D. LCMS-ESI + (m / z):[M+H] + found:375.

[0541] Process 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. with stirring for 3 h. After filtering to remove the solid, the filtrate was concentrated to give 81-E. LCMS-ESI + (m / z):[M+H] + found:245.

[0542] Process 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 (twice). The aqueous fraction was extracted with EtOAc (once), and the organic fractions were combined, dried (NaSO), and concentrated. The crude 81-G was used in the next step without further purification. LCMS-ESI + (m / z):[M+H] + found:573.

[0543] Process 6 A 100 mL round-bottom flask was charged with 81-G (1.1 g, 1.9 mmol) in 4 N HCl / dioxane (11 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 1.0 g of the intermediate was obtained. This intermediate and DBU (1.3 g, 8.8 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110° C. with stirring for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 81-H. LCMS-ESI + (m / z):[M+H] + found:413.

[0544] Process 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). 1 N KOH (4 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was acidified by adding 1 N HCl (4 mL). After concentration, the residue was coevaporated with toluene (3 times). 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 h. The mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO (2 times), saturated NH Cl (2 times), and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 81-I. LCMS-ESI + (m / z):[M+H] + found:542.

[0545] Process 8 A 50 mL round-bottom flask was charged with 81-I (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 give compound 81. 1 H-NMR (400 MHz, chloroform-d) δ 10.29 (s, 1H), 8.31 (s, 1H), 6.65 (dd, J = 8.7, 7.5 Hz, 2H), 5.05 - 4.75 (m, 2H), 4.65 (d, J = 5.6 Hz, 2H), 4.11 (d, J = 12.2 Hz, 1H), 3.83 (t, J = 12.3 Hz, 1H), 3.56 (dd, J = 12.3, 3.3 Hz, 1H), 2.77 (s, 1H), 2.25 - 1.97 (m, 2H), 1.95 (d, J = 11.0 Hz, 2H), 1.77 (d, J = 11.2 Hz, 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.

[0546] 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

[0547] [ka]

[0548] [ka]

[0549] Process 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 h. The mixture was cooled back to 0 °C. Saturated NaHCO (5 mL) was added dropwise to quench the reaction. The reaction mixture was then diluted with EtOAc (100 mL), washed with sat. NaHCO, brine, and dried over NaSO. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 82-B. LCMS-ESI + (m / z):[M+H] + found:274.

[0550] Process 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 (1.6 mL, 3.2 mmol) in THF was slowly added. The reaction mixture was then warmed and stirred at room temperature for 3 h. The reaction mixture was then diluted with EtOAc (100 mL), and water was slowly added (H evolution). After separation of the two phases, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over NaSO. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 82-C. LCMS-ESI + (m / z):[M+H] + found:246.

[0551] Process 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. with 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 the eluent to give 82-D. LCMS-ESI + (m / z):[M+H] + found:375.

[0552] Process 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. with stirring for 3 h. After filtering to remove the solid, the filtrate was concentrated to give 82-E. LCMS-ESI + (m / z):[M+H] + found:245.

[0553] Process 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 (twice). The aqueous fraction was extracted with EtOAc, and the organic fractions were combined, dried (NaSO), and concentrated. The crude 82-G was used in the next step without further purification. LCMS-ESI + (m / z):[M+H] + found:573.

[0554] Process 6 A 100 mL round-bottom flask was charged with 82-G (0.49 g, 0.86 mmol) in 4 N HCl / dioxane (5 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 0.4 g of the intermediate was obtained. This intermediate and DBU (0.6 g, 4.0 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110° C. with stirring for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 82-H. LCMS-ESI + (m / z):[M+H] + found:413.

[0555] Process 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). 1 N KOH (1.5 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was acidified by adding 1 N HCl (1.5 mL). After concentration, the residue was coevaporated with toluene (3 times). 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 h. The mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO (twice), saturated NH Cl (twice), and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 82-I. LCMS-ESI + (m / z):[M+H] + found:542.

[0556] Process 8 A 50 mL round-bottom flask was charged with 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 give 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.

[0557] 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

[0558] [ka]

[0559] [ka]

[0560] Process 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.

[0561] Process 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 NaHCO (5 mL) was added dropwise to quench the reaction. The reaction mixture was then diluted with EtOAc (100 mL), washed with sat. NaHCO, brine, and dried over NaSO. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 83-C. LCMS-ESI + (m / z):[M+H] + found:292.

[0562] Process 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 (1.6 mL, 3.2 mmol) in THF was slowly added. The reaction mixture was then warmed and stirred at room temperature for 3 h. The reaction mixture was then diluted with EtOAc (100 mL), and water was slowly added (H evolution). After separation of the two phases, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over NaSO. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 83-D. LCMS-ESI + (m / z):[M+H] + found:264.

[0563] Process 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. with 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 the eluent to give 83-E. LCMS-ESI + (m / z):[M+H] + found:393.

[0564] Process 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. with stirring for 3 h. After filtering to remove the solid, the filtrate was concentrated to give 83-F. LCMS-ESI + (m / z):[M+H] + found:263.

[0565] Process 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 (NaSO), and concentrated. The crude 83-H was used in the next step without further purification. LCMS-ESI + (m / z):[M+H] + found:591.

[0566] Process 7 A 100 mL round-bottom flask was charged with 83-H (0.4 g, 0.68 mmol) in 4 N HCl / dioxane (3.8 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 0.35 g of the intermediate was obtained. This intermediate and DBU (0.51 g, 3.3 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110° C. with stirring for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 83-I. LCMS-ESI + (m / z):[M+H] + found:431.

[0567] Process 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). 1 N KOH (1.4 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was acidified by adding 1 N HCl (1.4 mL). After concentration, the residue was coevaporated with toluene (3 times). 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 h. The mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO (twice), saturated NH Cl (twice), and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 83-J. LCMS-ESI + (m / z):[M+H] + found:560.

[0568] Process 9 A 50 mL rbf was charged with 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 give 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). 19F-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.

[0569] 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

[0570] [ka]

[0571] [ka]

[0572] Process 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 eluents to give 84-B. LCMS-ESI + (m / z):[M+H] + found:270.

[0573] Process 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 h. The mixture was cooled back to 0 °C. Saturated NaHCO (5 mL) was added dropwise to quench the reaction. The reaction mixture was stirred at room temperature for an additional 15 min and filtered through Celite. The filter cake was washed with DCM (twice). The combined filtrate was concentrated in vacuo, and the residue was purified by flash chromatography using hexane-EtOAc as eluent to give 84-C. LCMS-ESI + (m / z):[M+H] + found:268.

[0574] Process 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 give 84-D. LCMS-ESI + (m / z):[M+H] + found:270.

[0575] Process 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 (13.2 mL, 26.4 mmol) in THF was slowly added. The reaction mixture was then warmed and stirred at room temperature for 3 h. The reaction mixture was then diluted with EtOAc (100 mL), and water was slowly added (H evolution). After separation of the two phases, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over NaSO. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 84-E. LCMS-ESI + (m / z):[M+H]+ found:242.

[0576] Process 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. with 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 the eluent to give 84-F. LCMS-ESI + (m / z):[M+H] + found:371.

[0577] Process 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. with stirring for 3 h. After filtering to remove the solid, the filtrate was concentrated to give 84-G. LCMS-ESI + (m / z):[M+H] + found:241.

[0578] Process 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 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 (2 times). The aqueous fraction was extracted with EtOAc, and the organic fractions were combined, dried (NaSO), and concentrated. The crude 84-I was used in the next step without further purification. LCMS-ESI + (m / z):[M+H] + found:583.

[0579] Process 8 A 100 mL rbf was charged with 84-I (0.84 g, 1.4 mmol) in 4 N HCl / dioxane (8.2 mL). The reaction mixture was then stirred at room temperature for 1 hour. After concentration, 0.74 g of the intermediate was obtained. This intermediate and DBU (1.1 g, 7.2 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110° C. with stirring for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 84-J. LCMS-ESI + (m / z):[M+H] + found:409.

[0580] Process 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 h. The reaction mixture was acidified by adding 1N HCl (3.0 mL). After concentration, the residue was coevaporated with toluene (3 times). The crude acid, 2,4,6-trifluorobenzylamine (0.32 g, 1.96 mmol), N,N-diisopropylethylamine (DIPEA) (0.63 g, 4.9 mmol), and HATU (0.74 g, 1.9 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO (twice), saturated NH Cl (twice), and dried over Na SO . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give 84-K. LCMS-ESI + (m / z):[M+H] + found:538.

[0581] 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 give 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.

[0582] 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

[0583] [ka]

[0584] Process 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, at which time N-iodosuccinimide (885 mg, 3.934 mmol) was added. After 2 h, additional N-iodosuccinimide (88 mg, 0.391 mmol) was added, and the resulting mixture was stirred at room temperature for 1.5 h. The dark brown reaction mixture was diluted with EtOAc and washed with a mixture of 10% aq. NaSO and aq. NaHCO solutions (approximately 1:4 mixture), followed by water (containing some brine). After extracting the aqueous fraction with EtOAc, the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to give 85-B. 1 H-NMR (400 MHz, CDCl3) δ 7.51 - 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 = 5.3 Hz, 1H), 3.54 - 3.44 (m, 1H), 3.27 (t, J = 4.5 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.30 (dddd, J = 14.8, 13.1, 7.2, 5.8 Hz, 1H), 2.14 (dddd, J = 14.8, 13.0, 6.1, 2.1Hz, 1H), 1.97 (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] + calculated for C 18 H 25 INO3:430.1;found:430.0.

[0585] Process 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 h, 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 (NaSO), and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 85-C. 1 H-NMR (400 MHz, CDCl3) δ 7.57 - 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 = 6.7 Hz, 1H), 3.83 (d, J = 5.1 Hz, 1H), 3.48 (t, J = 4.6 Hz, 1H), 3.19 - 3.04 (m, 1H), 2.58 (p, J = 4.0 Hz, 1H), 2.30 (dddd, J = 14.7, 13.1, 7.0, 4.5 Hz, 1H), 1.98 (d, J = 11.2 Hz, 1H), 1.64 (tdd, J = 13.3, 6.2, 2.6 Hz, 1H), 1.49 - 1.33 (m, 3H), 1.37 (d, J = 6.7 Hz, 3H), 1.32 - 1.26 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS-ESI + (m / z):[M+H] + calculated for C 18 H 26 NO3:304.2;found:304.1.

[0586] Process 3 A mixture of 85-C (725 mg, 2.39 mmol) and 20% Pd(OH) / C (351 mg) in EtOH (25 mL) and 4 N HCl in dioxane (0.9 mL) was stirred under an H atmosphere. After 2 h, the reaction mixture was filtered and the filtrate was concentrated. LCMS-ESI + (m / z):[M+H] + calculated for C 10 H 18 NO3: 200.13; found: 200.1. After coevaporating the residue with toluene (twice), the residue and Boc2O (720 mg, 3.299 mmol) in THF (15 mL) were stirred at room temperature, at which time N,N-diisopropylethylamine (DIPEA) (1.2 mL, 6.889 mmol) was added. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc (twice). After washing the organic extract with water, the combined extracts were dried (Na2SO4) and concentrated. The residue was purified by flash using hexane-EtOAc as eluent to give 85-D, which appears to be a mixture of rotamers. 1 H-NMR (400 MHz, CDCl3) 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] + calculated for C 15 H 26 NO5:300.2;found:299.7.

[0587] Process 4 To a solution of 85-D (568 mg, 1.897 mmol) and pyridine (0.25 mL, 3.091 mmol) in THF (5 mL) was added phenyl chlorothionoformate (0.3 mL, 2.169 mmol) at 0 °C. This resulted in the rapid formation of insoluble material. After approximately 30 min at 0 °C, additional pyridine (0.3 mL, 3.709 mmol) and phenyl chlorothionoformate (0.3 mL, 2.169 mmol) were added. After 1.5 h at 0 °C and 1 h 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 approximately 0.1 N HCl, saturated aqueous NaHCO 3 , and brine. After extracting the aqueous fraction 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 give 85-E. 1 H-NMR (400 MHz, CDCl3) δ 7.47 - 7.37 (m, 2H), 7.30 (t, J = 6.9 Hz, 1H), 7.11 (dd, J = 8.0, 4.0 Hz, 2H), 5.54 (dt, J = 9.0, 4.9 Hz, 1H), 4.50 (dt, J = 9.8, 5.3 Hz, 1H), 4.35 (dd, J = 21.4, 5.0 Hz, 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, 7.1 Hz, 3H). LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 30 NO6S:436.2;found:435.8.

[0588] Process 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 h, the reaction mixture was concentrated, and the residue was dissolved in EtOAc and then washed with water and brine. After extracting the aqueous fraction with EtOAc, the combined organic fractions were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography using EtOAc / hexane as the eluent to give 85-F, which appears to be a mixture of rotamers. 1 H-NMR (400 MHz, CDCl3) 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): [M-C4H8+H] + calculated for C 11 H 18 NO4:228.1;found:227.9.

[0589] Process 6 85-F (420 mg) was purified again, and the purified 85-F in THF (3 mL) was stirred at 0 °C, at which time 2.0 M LiBH4 in THF (1.5 mL) was added. After 5 min, the mixture was stirred at room temperature for 17 h, and additional 2.0 M LiBH4 in THF (1.5 mL) was added at room temperature. After 23 h at room temperature, additional 2.0 M LiBH4 in THF (3 mL) was added, and the resulting mixture was stirred for approximately 72 h. After slow addition of water and further dilution with water, the reaction mixture was stirred at 0 °C, and the product was extracted with EtOAc (twice). The extracts were washed with water, combined, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to give 85-G.1 H-NMR (400 MHz, CDCl3) 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): [M-C4H8+H] + calculated for C9H 16 NO3:186.1;found:186.0.

[0590] Process 7 A solution of 85-G (198 mg, 0.820 mmol), phthalimide (200 mg, 1.359 mmol), and PPh3 (488 mg, 1.861 mmol) in THF (10 mL) was stirred in a 0 °C bath, at which time DIAD (0.36 mL, 1.828 mmol) was added. After 30 min at 0 °C, the mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography using hexane-EtOAc as eluents to give 85-H, which appears to be a mixture of rotamers. 1 H-NMR (400 MHz, CDCl3) 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] + calculated for C21 H 27 N2O4:371.2;found:370.8.

[0591] Process 8 To a solution of 85-H (270 mg, 0.729 mmol) in EtOH (12 mL) was added hydrazine hydrate (0.145 mL, 3.083 mmol) at room temperature, and the resulting solution was stirred at 70 °C. After 1.5 h, the mixture was cooled to 0 °C and diluted with ether (30 mL), then stirred at 0 °C for 1 h. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CHCl and filtered to remove some insoluble material. The filtrate was concentrated. The residue was combined with 85-I (257 mg, 0.742 mmol) and NaHCO (131 mg, 1.559 mmol) in water (3 mL) and EtOH (3 mL) and stirred at room temperature. After 1 h, the mixture was diluted with water and extracted with EtOAc (twice). After washing the extracts with water, the organic extracts were combined, dried (NaSO), and concentrated. To a solution of the residue in CHCl (2 mL) was added 4 N HCl in dioxane (6 mL). After 1.5 h 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 h, additional DBU (0.3 mL, 2.006 mmol) was added, and the mixture was stirred at 100° C. for an additional 1 h. After concentrating the mixture, the residue was purified by flash chromatography using EtOAc-20% MeOH / EtOAc as the eluent to provide 85-J. 1H-NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.71 - 7.62 (m, 2H), 7.36 - 7.29 (m, 2H), 7.29 - 7.23 (m, 1H), 5.44 (d, J = 9.8 Hz, 1H), 5.10 (d, J = 9.8 Hz, 1H), 4.44 - 4.28 (m, 3H), 4.23 (t, J = 13.0 Hz, 1H), 3.99 (ddt, J = 10.2, 6.3, 3.6 Hz, 2H), 2.44 - 2.36 (m, 1H), 2.29 (dt, J = 11.6, 5.3 Hz, 1H), 1.84 (dt, J = 10.8, 5.3 Hz, 2H), 1.77 - 1.61 (m, 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 = 7.1Hz, 3H). LCMS-ESI + (m / z):[M+H] + calculated for C 24 H 27 N2O5:423.2;found:423.3.

[0592] Process 9 A mixture of 85-J (214 mg, 0.507 mmol) in THF (4 mL) and MeOH (4 mL) was stirred at room temperature, at which time 1 N KOH (1.1 mL) was added. After 30 min, the reaction mixture was concentrated to approximately 1 mL, acidified with 1 N HCl (approximately 1.2 mL), and diluted with brine, then extracted with CHCl (20 mL × 2). The combined extracts were dried (NaSO) and concentrated to give the crude acid. LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 23 N2O5:395.2;found:395.3.

[0593] 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 CHCl (6 mL) was stirred at room temperature, at which time N,N-diisopropylethylamine (DIPEA) (0.62 mL, 3.559 mmol) was added. After 30 min, the reaction mixture was concentrated, and the residue was dissolved in EtOAc and washed with saturated aqueous NHCl (twice), saturated aqueous NaHCO (twice), and brine. After extracting the aqueous fraction with EtOAc, the two organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by flash elution using EtOAc-20% MeOH / EA as the eluent to afford 85-K. 1 H-NMR (400 MHz, CDCl3) δ 10.40 (t, J = 5.7 Hz, 1H), 8.42 (s, 1H), 7.68 - 7.54 (m, 2H), 7.33 (ddd, J = 7.7, 6.3, 1.5 Hz, 2H), 7.30 - 7.26 (m, 1H), 6.74 - 6.60 (m, 2H), 5.37 (d, J = 10.0 Hz, 1H), 5.17 (d, J = 10.0 Hz, 1H), 4.76 - 4.57 (m, 2H), 4.46 (dd, J = 6.0, 4.3 Hz, 1H), 4.34 (t, J = 12.4 Hz, 1H), 4.07 (dd, J = 12.4, 3.6 Hz, 1H), 3.91 (dt, J = 12.4, 3.9 Hz, 1H), 2.52 - 2.44 (m, 1H), 2.32 (dd, J = 11.8, 6.2 Hz, 1H), 1.92 (dt, J = 10.7, 5.4 Hz, 1H), 1.83 - 1.70 (m, 3H), 1.67 (d, J = 11.7 Hz, 1H), 1.52 (dddt, J = 25.5, 17.0, 11.8, 5.3 Hz, 2H). 19F-NMR (376 MHz, CDCl3) 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] + calculated for C 29 H 27 F3N3O4:538.2;found:538.3.

[0594] Step 10 85-K (187 mg, 0.348 mmol) was dissolved in trifluoroacetic acid (3 mL) at room temperature and stirred at room temperature. After 1 h, the solution was concentrated, and the residue was dissolved in CHCl. ​​After washing the solution with 0.1 N HCl, the aqueous fraction was extracted with CHCl (twice). The organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by flash chromatography using CHCl—20% MeOH in CHCl as the eluent to give 150 mg (96%) of compound 85. Compound 85 was further purified by recrystallization from methanol (10 mL) to give compound 85. 1 H-NMR (400 MHz, CDCl3) δ 12.09 (s, 1H), 10.39 (t, J = 5.7 Hz, 1H), 8.36 (s, 1H), 6.74 - 6.48 (m, 2H), 4.64 (d, J = 5.7 Hz, 2H), 4.59 (dd, J = 6.1, 4.4 Hz, 1H), 4.36 - 4.18 (m, 2H), 4.12 (dt, J = 12.4, 4.1 Hz, 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). 19F-NMR (376 MHz, CDCl3) 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] + calculated for C 22 H 21 F3N3O4:448.2;found:448.3.

[0595] 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

[0596] [ka]

[0597] [ka]

[0598] Process 1 A solution of 86-A (10.160 g, 39.48 mmol) in DMSO (52 mL) and water (6.5 mL) was stirred at room temperature, at which time N-iodosuccinimide (8.888 g, 39.50 mmol) was added. After 30 min, the dark brown reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO, 10% aqueous NaSO, and brine. After extracting the aqueous fraction with EtOAc, the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 86-B as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.33 - 7.19 (m, 5H), 4.25 - 4.12 (m, 1H), 3.79 (q, J = 1.6 Hz, 1H), 3.72 (q, J = 6.5 Hz, 1H), 3.51 (s, 1H), 3.47 (s, 3H), 3.31 (dd, J = 3.9, 1.6 Hz, 1H), 2.76 - 2.69 (m, 1H), 2.13 (ddd, J = 14.3, 7.8, 1.7 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.91 (dtd, J = 14.1, 4.0, 1.5 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H). LCMS-ESI + (m / z):[M+H] + calculated for C 16 H 21 INO3:402.1;found:402.0.

[0599] Process 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 min, 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 (NaSO), and concentrated. The residue was purified twice by flash chromatography using hexane-EtOAc as the eluent to give 86-C. 1H-NMR (400 MHz, CDCl3) δ 7.39 - 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 = 3.4 Hz, 1H), 3.27 (d, J = 6.4 Hz, 1H), 2.65 - 2.51 (m, 1H), 1.92 (ddd, J = 13.6, 6.8, 2.4 Hz, 1H), 1.69 - 1.50 (m, 2H), 1.47 (d, J = 10.1 Hz, 1H), 1.41 (d, J = 6.6 Hz, 3H), 1.21 - 1.07 (m, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 16 H 22 NO3:276.2;found:276.1.

[0600] Process 3 A mixture of 86-C (4.187 g, 15.21 mmol) and 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 h, the reaction mixture was filtered and the filtrate was concentrated. The residue was co-evaporated with toluene and then used in the next step. LCMS-ESI + (m / z):[M+H] + calculated for C8H 14 NO3:172.1;found:172.1.

[0601] After coevaporating the residue with toluene, the residue and BocO (5.712 g, 26.17 mmol) in THF (45 mL) were stirred at room temperature, at which time N,N-diisopropylethylamine (DIPEA) (8 mL, 45.93 mmol) was added. After 30 min, the reaction mixture was diluted with water and extracted with EtOAc (twice). After washing the organic extracts with water, the combined extracts were dried (NaSO) and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluents to give 86-D. 1 The 1 H NMR spectrum suggests a mixture of rotamers. 1 H-NMR (400 MHz, CDCl3) 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] + calculated for C 13 H 22 NO5:272.2;found:271.6.

[0602] Process 4 A solution of 86-D (1659 mg, 6.115 mmol) in CHCl (35 mL) was stirred in a 0 °C bath, at which time Dess-Martin periodinane (5.183 g, 12.22 mmol) was added portionwise. After 5 min, the mixture was stirred at room temperature. After 2 h, the reaction mixture was cooled in an ice bath, quenched with water, and filtered. The filtrate was washed with saturated NaHCO, dried (NaSO), and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to give 86-E. 1 1 H NMR suggests two rotamers. 1 H-NMR (400 MHz, CDCl3) δ 4.43 (d, J = 3.8 Hz, 0.5H), 4.39 (s, 1H), 4.26 (s, 0.5H), 3.75 (s, 3H), 3.10 (s, 1H), 2.24 (d, J = 4.5 Hz, 0.5H), 2.19 (d, J = 4.4 Hz, 0.5H), 2.12 (d, J = 4.4 Hz, 0.5H), 2.07 (d, J = 4.2 Hz, 0.5H), 2.01 (dd, J = 4.5, 2.2 Hz, 0.5H), 1.98 (dt, J = 4.3, 1.9 Hz, 0.5H), 1.80 (s, 0.5H), 1.77 (s, 0.5H), 1.46 (s, 4.5H), 1.40 (d, J = 2.8 Hz, 4.5H). LCMS-ESI + (m / z): [M-C4H8+H] + calculated for C9H 12 NO5:214.1;found:213.8.

[0603] Process 5 A solution of 86-E (528 mg, 1.961 mmol) in THF (12 mL) was stirred at 0 °C, at which time a solution of 0.5 M Tebbe 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 h. The reaction mixture was stirred in a 0 °C bath, at which time the reaction was carefully quenched by adding saturated aqueous NaHCO. After diluting the mixture with CHCl and stirring at room temperature for 15 min, the resulting mixture was filtered through a Celite pad, and the filter cake was washed with CHCl. ​​After separation of the two fractions in the filtrate, the aqueous fraction was extracted with CHCl, and the organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluents to give 86-F. 1 1 H NMR suggests two rotamers. 1 H-NMR (400 MHz, CDCl3) δ 5.13 (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 = 3.7 Hz, 0.4H), 4.24 (d, J = 3.7 Hz, 0.6H), 3.71 (s, 3H), 2.84 (s, 1H), 2.14 (m, 2H), 1.75 (s, 0.6H), 1.74 - 1.70 (s, 0.4H), 1.55 (m, 1H), 1.45 (s, 3.6H), 1.37 (s, 5.4H). LCMS-ESI + (m / z):[M+H] + calculated for C 14 H 22 NO4:268.2;found:267.6.

[0604] Process 6 A mixture of 86-F (333 mg, 1.246 mmol) and 20% Pd(OH) / C (53 mg) in EtOH (5 mL) was stirred under an H atmosphere. After 30 min, the mixture was filtered and the filtrate was concentrated to give 86-G. 1 1 H NMR suggests two rotamers. 1 H-NMR (400 MHz, CDCl3) 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] + calculated for C 14 H 24 NO4:270.2;found:269.7.

[0605] Process 7 A solution of 86-G (336 mg, 1.482 mmol) in THF (5 mL) was stirred at 0 °C, at which time 2.0 M LiBH4 in THF (1.5 mL) was added. After 5 min, the mixture was stirred at room temperature. After 2 h, additional 2.0 M LiBH4 in THF (1.5 mL) was added. After 21 h at room temperature, additional 2.0 M LiBH4 in THF (3 mL) was added. After 3 h at room temperature, the solution was heated at 35 °C for 18 h. The reaction mixture was cooled to 0 °C and carefully quenched with water. After extracting the mixture with EtOAc (twice), the two organic fractions were washed with water, combined, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography using hexanes-EtOAc to give 86-H. 1H-NMR (400 MHz, CDCl3) δ 4.95 - 4.09 (br, 1H), 4.05 (s, 1H), 3.82 (dd, J = 11.5, 7.7 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.66 (d, J = 11.5 Hz, 1H), 2.45 (d, J = 4.1 Hz, 1H), 2.03 (dqdd, J = 11.4, 7.0, 4.5, 2.6 Hz, 1H), 1.77 - 1.57 (m, 2H), 1.48 (dd, J = 10.1, 1.8 Hz, 1H), 1.45 (s, 9H), 1.00 (d, J = 6.9 Hz, 3H), 0.93 (ddd, J = 13.2, 4.7, 2.6 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 13 H 24 NO3:242.2;found:241.7.

[0606] Process 8 A solution of 86-H (218 mg, 0.903 mmol), phthalimide (218 mg, 1.482 mmol), and PPh3 (535 mg, 2.040 mmol) in THF (10 mL) was stirred in a 0 °C bath, at which time DIAD (0.40 mL, 2.032 mmol) was added. After 10 min at 0 °C, the mixture was stirred at room temperature for 19 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography using hexane-EtOAc as eluents to give 86-I. 1 1 H NMR suggests two rotamers. 1H-NMR (400 MHz, CDCl3) 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] + calculated for C 21 H 27 N2O4:371.2;found:370.8.

[0607] Process 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 h, the mixture was cooled to 0 °C and diluted with ether (25 mL), then stirred at 0 °C for 1 h. 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 give the crude amine. LCMS-ESI + (m / z):[M+H] + calculated for C 13 H 25 N2O2:241.2;found:240.9.

[0608] After coevaporating the crude amine with toluene, a mixture of the crude amine, 85-I (300 mg, 0.866 mmol), and NaHCO (150 mg, 1.845 mmol) in water (3 mL) and EtOH (3 mL) was stirred at room temperature. After 2 h, the mixture was diluted with water and extracted with EtOAc (twice). After washing the extracts with water, the organic extracts were combined, dried (Na SO ), and concentrated. To a solution of the residue in CHCl (2 mL) was added 4 N HCl in dioxane (6 mL). After 1.5 h at room temperature, the solution was concentrated and coevaporated with toluene. A mixture of the residue and DBU (0.65 mL, 4.347 mmol) in toluene (6 mL) was stirred at 100 °C. After 1 h, additional DBU (0.65 mL, 4.347 mmol) was added, and the mixture was stirred at 100 °C. After 1 h, additional DBU (0.65 mL, 4.347 mmol) was added, and the mixture was stirred at 100 °C for an additional 2.5 h. The mixture was diluted with CHCl and washed with 3 mL of 1 N HCl in water. The organic fraction was dried (NaSO) and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH / EtOAc as eluent to give 86-J. 1H-NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.70 - 7.62 (m, 2H), 7.37 - 7.27 (m, 3H), 5.48 (d, J = 9.9 Hz, 1H), 5.16 (d, J = 9.9 Hz, 1H), 4.53 (s, 1H), 4.38 (m, 2H), 4.11 (m, 1H), 3.97 (dd, J = 12.2, 3.0 Hz, 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] + calculated for C 24 H 27 N2O5:423.2;found:423.2.

[0609] 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, at which time 1N KOH (0.4 mL) was added. After 30 min, the reaction mixture was diluted with water and washed with CHCl. ​​After acidifying the aqueous fraction with 1N HCl (0.45 mL), the product was extracted with CHCl (twice). The combined extracts were dried (NaSO) and concentrated to give the crude acid. LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 23 N2O5:395.2;found:395.2.

[0610] 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 CHCl (3 mL) was stirred at room temperature, at which time N,N-diisopropylethylamine (DIPEA) (0.25 mL, 1.435 mmol) was added. After 30 min, the reaction mixture was concentrated, and the residue was dissolved in EtOAc and washed with saturated aqueous NHCl (twice), saturated aqueous NaHCO (twice), and brine. After extracting the aqueous fraction with EtOAc, the two organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH / EtOAc as the eluent to provide 86-K. 1 H-NMR (400 MHz, CDCl3) δ 10.40 (t, J = 5.7 Hz, 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 = 10.0 Hz, 1H), 5.18 (d, J = 10.0 Hz, 1H), 4.73 - 4.58 (m, 2H), 4.53 (s, 1H), 4.22 - 4.11 (m, 1H), 4.03 (dd, J = 12.4, 3.1 Hz, 1H), 3.81 (dt, J = 12.3, 3.1 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.29 (dddd, J = 11.4, 7.1, 4.7, 2.4 Hz, 1H), 1.94 (ddd, J = 13.5, 11.2, 4.6 Hz, 1H), 1.88 - 1.67 (m, 2H), 1.06 (d, J = 7.0 Hz, 3H), 1.03-1.09 (m, 1H). 19 F-NMR (376 MHz, CDCl3) 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] + calculated for C 29 H 27 F3N3O4:538.2;found:538.1.

[0611] Step 11 86-K (61 mg, 0.113 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at room temperature. After 1 h, the solution was concentrated, and the residue was dissolved in CHCl. ​​After washing the solution with 0.1 N HCl, the aqueous fraction was extracted with CHCl (twice). The organic fractions were combined, dried (NaSO), and concentrated. The residue was purified by flash chromatography using CHCl—20% MeOH in CHCl as the eluent to give compound 86. 1 H-NMR (400 MHz, CDCl3) δ 12.02 (s, 1H), 10.40 (t, J = 5.7 Hz, 1H), 8.35 (s, 1H), 6.63 (t, J = 8.1 Hz, 2H), 4.62 (d, J = 5.7 Hz, 2H), 4.59 (s, 1H), 4.22 (dd, J = 12.2, 3.5 Hz, 1H), 4.13 (t, J = 11.9 Hz, 1H), 4.05 (dt, J = 12.0, 3.1 Hz, 1H), 2.77 - 2.70 (m, 1H), 2.31 m, 1H), 2.09 - 1.93 (m, 1H), 1.93 - 1.81 (m, 2H), 1.10 (ddd, J = 13.9, 5.0, 2.1 Hz, 1H), 1.02 (d, J = 6.9 Hz, 3H). 19 F-NMR (376 MHz, CDCl3) 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] + calculated for C 22 H 21 F3N3O4:448.2;found:448.3.

[0612] Example 87 Preparation of cis-5-aminotetrahydro-2H-pyran-3-ol

[0613] [ka]

[0614] Process 1 A solution of benzyl (5-oxotetrahydro-2H-pyran-3-yl)carbamate (740 mg, 3.0 mmol) and cerium(III) chloride pentahydrate (1.12 g, 3.0 mmol) in 20 mL of methanol was cooled to 0 °C, and then sodium borohydride (120 mg, 3.2 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 45 min and then quenched by the slow addition of 1 mL of acetone, followed by stirring at room temperature for 3 h. The reaction mixture was partitioned between water and dichloromethane, and the aqueous phase was extracted with dichloromethane followed by 2-butanol. The combined organic phases were dried over magnesium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (0% to 100% EtOAc / hexanes) to give the desired 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.

[0615] Process 2 To a solution of cis-((3R,5S)-5-hydroxytetrahydro-2H-pyran-3-yl)benzylcarbamate (290 mg, 1.16 mmol) in 5 mL of 1:1 DCM:EtOH was added 10 wt % Pd / C (255 mg). The mixture was stirred under balloon pressure hydrogen for 18 h, and the palladium was removed by filtration through Celite, rinsing with ethanol. The filtrate was concentrated to give cis-5-aminotetrahydro-2H-pyran-3-ol, which was carried on crude.

[0616] 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

[0617] [ka]

[0618] Compound 88 was prepared in a similar manner to compound 15, using (3-chloro-2-fluorophenyl)methanamine in place of (4-fluorophenyl)methanamine. 1 H-NMR (400 MHz, chloroform-d) δ 10.43 (br s, 1H), 8.34 (br s, 1H), 7.32 - 7.24 (m, 2H), 7.02 (t, J = 7.9 Hz, 1H), 5.36 (d, J = 9.4 Hz, 1H), 5.30 (s, 2H), 4.70 (d, J = 6.0 Hz, 3H), 4.24 (d, J = 12.0 Hz, 1H), 4.00 (dd, J = 12.7, 9.5 Hz, 1H), 2.18 - 1.96 (m, 4H), 1.96 - 1.83 (m, 1H), 1.60 (dt, J = 12.4, 3.1 Hz, 1H). LCMS-ESI +(m / z):[M+H] + calculated for C 21 H 19 ClFN3O5: 448.11; found: 448.2 was prepared.

[0619] 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

[0620] [ka]

[0621] Compound 89 was prepared in a similar manner to compound 15, using (2,5-difluorophenyl)methanamine in place of (4-fluorophenyl)methanamine. 1 H-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] + calculated for C 21 H 19 F2N3O5:432.14;found:432.2.

[0622] 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

[0623] [ka]

[0624] Compound 90 was prepared in a similar manner to compound 41, using (3-chloro-2-fluorophenyl)methanamine in place 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] + calculated for C 21 H 19 ClFN3O4:432.11;found:432.2.

[0625] 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

[0626] [ka]

[0627] Compound 91 was prepared in a similar manner to compound 41, using (2,3,4-trifluorophenyl)methanamine in place of (2,4,6-trifluorophenyl)methanamine. 1 H-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] + calculated for C 21 H 18 F3N3O4:434.13;found:434.2.

[0628] 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

[0629] [ka]

[0630] Compound 92 was prepared in a similar manner to compound 41, using (4-chloro-2-fluorophenyl)methanamine in place of (2,4,6-trifluorophenyl)methanamine. 1H-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] + calculated for C 21 H 19 ClFN3O4:432.11;found:432.2.

[0631] 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

[0632] [ka]

[0633] Process 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. To this was added 5 mL of degassed DMF. The sealed vessel was heated at 110 °C for 18 h, diluted with ethyl acetate, and diluted with 9:1 NHOH:NHCl. (aq) twice with 5% LiCl (aq)The organic layer was washed sequentially with HCl (2× and brine). The organic layer was then dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (100% hexanes) to give 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).

[0634] Process 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 for 18 hours until all solvent was lost. The residue was redissolved in 3 mL of THF, cooled to 0° C., and added with HCl. (aq) A 6M solution of NaOH was carefully added and the mixture was returned to reflux for 30 minutes. The reaction mixture was cooled again to 0°C and 4M NaOH was added. (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% to 10% MeOH / DCM) to give (2-chloro-4,6-difluorophenyl)methanamine. 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).

[0635] 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 complete disappearance of 93-A and formation of 93-B were observed by LCMS. 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 / HO + 0.1% TFA) to give compound 93. 1 H-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] + calculated for C 21 H 18 ClF2N3O4:450.10;found:450.2.

[0636] 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

[0637] [ka]

[0638] Compound 94 was prepared in a similar manner to compound 41, using phenylmethanamine in place of (2,4,6-trifluorophenyl)methanamine. 1 H-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] + calculated for C 21 H 21 N3O4:380.16;found:380.2.

[0639] 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

[0640] [ka]

[0641] Process 1 To a 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 at 0 °C was added dropwise a solution of diisopropyl azodicarboxylate (0.35 mL, 1.8 mmol) in 1 mL of THF. The reaction mixture was warmed to room temperature, stirred for 90 minutes, concentrated onto silica, and purified by flash chromatography (0% to 25% EtOAc / hexanes) to give 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] + calculated for C 19 H 23 N2O4:343.2;found:342.8.

[0642] Process 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 eluent to give chiral 95-A (first-eluting peak) and 95-B (second-eluting peak) in enantiomerically enriched form. For 95-A: 144 mg, 98% ee (absolute stereochemistry unknown). For 95-B: 242 mg, 49% ee (absolute stereochemistry unknown).

[0643] 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

[0644] [ka]

[0645] Process 1 To a solution of intermediate 95-A (141 mg, 0.41 mmol, 98% ee, absolute stereochemistry unknown) in 9 mL of ethanol was added hydrazine hydrate (0.5 mL, 10.3 mmol) and stirred at 70 °C for 18 h to give 96-A of unknown absolute stereochemistry. The solids were removed by filtration, and the filtrate was concentrated and carried on crude.

[0646] Process 2 A mixture of crude 96-A (estimated 0.41 mmol), 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 that, the reaction mixture was diluted with water and extracted three times with 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, and 4 mL of 4 N HCl in dioxane was added and stirred at room temperature for 90 minutes. The mixture was concentrated to dryness and coevaporated 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 onto silica gel and purified by flash chromatography (0% to 10% MeOH / DCM) to give 96-C. LCMS-ESI + (m / z):[M+H] + calculated for C 22 H 22 N2O5:395.16;found:395.2.

[0647] Process 3 A mixture of 96-C (112 mg, 0.28 mmol), 1 M aqueous potassium hydroxide (1 mL), 4 mL of methanol, and 4 mL of THF was stirred at room temperature for 3 h, at which point the mixture was diluted with dichloromethane, acidified by the addition of 1 M hydrochloric acid, and the organic phase was extracted with dichloromethane. The combined organics were dried, filtered, and concentrated from toluene. After drying under reduced pressure, 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 h to give 96-D, which was carried forward crude.

[0648] Process 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. 1 mL of DMF was then added, and the reaction mixture was concentrated to approximately 1 mL, filtered, and purified by preparative HPLC (ACN / water + 0.1% TFA) to give compound 96 (absolute stereochemistry unknown). 1 H-NMR (400 MHz, DMSO-d6) δ 10.45 - 10.35 (m, 1H), 8.39 (s, 1H), 7.23 - 7.09 (m, 2H), 4.67 (dd, J = 12.6, 4.8 Hz, 2H), 4.53 (d, J = 5.5 Hz, 2H), 4.20 (dd, J = 11.9, 3.8 Hz, 1H), 4.05 - 3.95 (m, 1H), 2.96 - 2.88 (m, 1H), 2.16 (d, J = 7.0 Hz, 1H), 1.97 (d, J = 7.0 Hz, 1H), 1.68 - 1.60 (m, 1H), 1.53 - 1.45 (m, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 20 H 16F3N3O4:420.12;found:420.2.

[0649] 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

[0650] [ka]

[0651] Compound 97 (49% ee, absolute stereochemistry unknown) was prepared in a manner similar to compound 96, using intermediate 95-B (49% ee, absolute stereochemistry unknown) in place of the opposite enantiomer of intermediate 95-A. 1 H-NMR (400 MHz, DMSO-d6) δ 10.39 (t, J = 5.7 Hz, 1H), 8.42 (s, 1H), 7.25 - 7.13 (m, 2H), 4.73 - 4.66 (m, 2H), 4.54 (d, J = 5.7 Hz, 2H), 4.20 (dd, J = 12.3, 3.9 Hz, 1H), 4.01 (t, J = 12.4 Hz, 1H), 2.93 (dd, J = 6.7, 3.4 Hz, 1H), 2.19 - 2.14 (m, 1H), 1.97 (d, J = 8.3 Hz, 1H), 1.65 (dd, J = 10.4, 7.9 Hz, 1H), 1.49 (dd, J = 10.5, 7.7 Hz, 1H). LCMS-ESI + (m / z):[M+H] + calculated for C 20 H 16 F3N3O4:420.12;found:420.2.

[0652] 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

[0653] [ka]

[0654] Process 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 h, quenched with saturated aqueous NaSO / NaHCO (7:1) (160 mL), and vigorously stirred 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 using 0% to 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] + calculated for C 13 H 19 NO5:269.13;found:270.78.

[0655] Process 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 at room temperature overnight, the reaction mixture was cooled back to 0 °C. Saturated NaHCO (10 mL) was added slowly. The mixture was extracted twice with DCM and dried over NaSO. After concentration, the residue was purified by flash chromatography with 0% to 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] + calculated for C 13 H 19 F2NO4:291.13;found:291.55.

[0656] Process 3 98-C (476 mg, 1.634 mmol) in THF (20 mL) was stirred at 0 °C, at which time 2.0 M LiBH4 in THF (2.4 mL, 4.8 mmol) was added. The mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with ice and diluted with EtOAc and saturated NH4Cl (some H2 evolution). 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 directly in the next step. LCMS-ESI + (m / z):[M+H] + calculated for C 12 H 19F2NO3:263.13;found:164.10.

[0657] Process 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, at which time DIAD (0.642 mL, 3.26 mmol) was added. After the addition, the mixture was stirred at 0 °C for 30 min and...

Claims

1. Formula (I): 【Chemical 1】 or a stereoisomer or a pharmaceutically acceptable salt thereof, In formula (I): X is —O— or —NZ 3 -or-CHZ 3 - and; W is -CHZ 2 - and; 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 and together form -L-, 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 -, or -C(R a ) 2 C (R a ) 2 C (R a ) 2 C (R a ) 2 -, where Z 1 and Z 2 , or Z 1 and Z 3 at least one of which taken together form -L-; Z 4 is a bond, -CH 2 - or -CH 2 CH 2 - and; Y 1 and Y 2 are each independently hydrogen, C 1~3 Alkyl or C 1~3 haloalkyl; R 1 is phenyl substituted with 1 to 3 halogens; and Each R a are independently hydrogen, halo, hydroxyl or C 1~4 is alkyl, A compound or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. Formula (II-A) below: 【Chemistry 2】 2. The compound of claim 1 having the formula:

3. Formula (II-B) below: 【Chemistry 3】 2. The compound of claim 1 having the formula:

4. Formula (II-C) below: 【Chemistry 4】 2. The compound of claim 1 having the formula:

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

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

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

8. Each R a The compound according to any one of claims 1 to 7, wherein is hydrogen.

9. 1 R a is methyl, and the remaining R a The compound of any one of claims 1 to 7, wherein each of is hydrogen.

10. At least one R a is a halogen, and the remaining R a The compound of any one of claims 1 to 7, wherein each of is hydrogen.

11. Two R's a is a halogen, and the remaining R a The compound of any one of claims 1 to 7, wherein each of is hydrogen.

12. 1 R a is a halogen, and the remaining R a The compound of any one of claims 1 to 7, wherein each of is hydrogen.

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

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

15. The compound of any one of claims 1-2 or 5-12, wherein X is -NH-.

16. X is -CHZ 3 - and Z 1 and Z 3 and together form -L-.

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

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

19. Z 4 is a bond or -CH 2 20. The compound of claim 1, wherein:

20. Z 4 Ha-CH 2 20. The compound of claim 1, wherein:

21. Z 4 The compound of any one of claims 1 or 5 to 18, wherein is a bond.

22. Y 1 and Y 2 The compound of any one of claims 1 or 5-21, wherein each is independently hydrogen, methyl, or trifluoromethyl.

23. R 1 The compound according to any one of claims 1 to 22, wherein is substituted with one halogen.

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

25. R 1 The compound according to any one of claims 1 to 22, wherein is substituted with two halogens.

26. 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.

27. R 1 is 2,4-difluorophenyl.

28. R 1 The compound according to any one of claims 1 to 22, wherein is substituted with three halogens.

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

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

31. [Chemical 5] 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 2. The compound of claim 1 selected from:

32. 【Catalog 17】 【Chemistry 18】 2. The compound of claim 1 selected from:

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

34. 34. The pharmaceutical composition of claim 33, further comprising one or more additional therapeutic agents.

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

36. 36. The pharmaceutical composition of claim 35, wherein the one or more additional therapeutic agents are selected from the group consisting of 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.

37. 34. A method of treating HIV infection in a human having or at risk of having HIV infection by administering to said human a therapeutically effective amount of a compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33.

38. 38. The method of claim 37, further comprising administering to the human a therapeutically effective amount of one or more additional therapeutic agents.

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

40. 40. The method of claim 39, wherein the one or more additional therapeutic agents are selected from the group consisting of 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.

41. Use of a compound according to any one of claims 1 to 32, or a pharmaceutical composition according to claim 33, for the treatment of HIV infection in a human having or at risk of having HIV infection.

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

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

44. 44. The use of claim 43, wherein the one or more additional therapeutic agents are selected from the group consisting of 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.

45. 33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

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

47. Formula (I): 【Chemistry 19】 or a stereoisomer or a pharmaceutically acceptable salt thereof, In formula (I): X is —O— or —NZ 3 -or-CHZ 3 - and; W is —O— or —NZ 2 -or-CHZ 2 - and; 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 and together form -L-, 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 -または-C(R a ) 2 NR a SO 2 C(R a ) 2 - and; 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 - and; Y 1 and Y 2 are each independently hydrogen, C 1~3 Alkyl or C 1~3 haloalkyl, or Y 1 and Y 2 and 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, wherein the carbocyclic ring or heterocyclic ring is selected from the group consisting of one or more R a and optionally substituted with; R 1 is optionally substituted aryl or optionally substituted heteroaryl; and Each R a are independently hydrogen, halo, hydroxyl or C 1~4 alkyl or two R a groups, together with the carbon atom to which they are attached, form C=O, and (i) Z 1 and Z 2 , or Z 1 and Z 3 and together form -L-; or (ii) Y 1 and Y 2 and 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, A compound or a stereoisomer or a pharmaceutically acceptable salt thereof.

48. W is -CHZ 2 The compound of claim 47, wherein

49. Z 1 and Z 2 , or Z 1 and Z 3 and taken together form -L-.

50. The following formula (II-A), (II-B), or (II-C): 【Chemistry 20】 【Chemical 21】 and ここでLは、-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 The compound of claim 49, wherein

51. Y 1 and Y 2 and 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.

52. The compounds of the following formula (III-A), (III-B), (III-C) or (III-D): [Chemical 22] 【Chemical formula 23】 and Here, Z 1 and Z 3 are each independently hydrogen or C 1~3 52. The compound of claim 51, which is alkyl.

53. The compounds of the following formula (III-E), (III-F), (III-G) or (III-H): 【Chemistry 24】 and Here, Z 1 and Z 3 are each independently hydrogen or C 1~3 52. The compound of claim 51, which is alkyl.

54. (i) Z 1 and Z 2 , or Z 1 and Z 3 and (ii) Y 1 and Y 2 and 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.

55. The following formula (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG) or (IV-AH): 【Chemistry 25】 【Chemical 26】 【Chemical 27】 and ここでLは、-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 The compound of claim 54, wherein

56. The compounds of the following formula (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) or (IV-BH): 【Chemical 28】 【Chemical 29】 and ここでLは、-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 The compound of claim 54, wherein

57. 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 The compound according to any one of claims 47 to 50 or 54 to 56, wherein

58. L is -C(R a ) 2 The compound of claim 57, wherein

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

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

61. Each R a The compound of any one of claims 47 to 50 or 54 to 60, wherein is hydrogen.

62. 1 R a is methyl, and the remaining R a 61. The compound of any one of claims 47-50 or 54-60, wherein each of is hydrogen.

63. At least one R a is a halogen, and the remaining R a 61. The compound of any one of claims 47-50 or 54-60, wherein each of is hydrogen.

64. Two R's a is a halogen, and the remaining R a 61. The compound of any one of claims 47-50 or 54-60, wherein each of is hydrogen.

65. 1 R a is a halogen, and the remaining R a 61. The compound of any one of claims 47-50 or 54-60, wherein each of is hydrogen.

66. 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 The compound according to any one of claims 47 to 50 or 54 to 56, wherein

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

68. Each R a 68. The compound of claim 66 or 67, wherein is hydrogen.

69. 1 R a is methyl, and the remaining R a 68. The compound of claim 66 or 67, wherein each of is hydrogen.

70. At least one R a is a halogen, and the remaining R a 68. The compound of claim 66 or 67, wherein each of is hydrogen.

71. Two R's a is a halogen, and the remaining R a 68. The compound of claim 66 or 67, wherein each of is hydrogen.

72. 1 R a is a halogen, and the remaining R a 68. The compound of claim 66 or 67, wherein each of is hydrogen.

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

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

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

76. 73. The compound of any one of claims 47 to 72, wherein X is -NH-.

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

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

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

80. Z 4 Ha-CH 2 79. The compound of any one of claims 47 to 49, 51, 54 or 57 to 78, wherein

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

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

83. R 1 The compound of any one of claims 47 to 82, wherein is phenyl.

84. R 1 The compound of any one of claims 47 to 82, wherein is pyridinyl.

85. R 1 is substituted with at least one halogen.

86. R 1 The compound according to any one of claims 47 to 84, wherein is substituted with one halogen.

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

88. R 1 The compound according to any one of claims 47 to 84, wherein is substituted with two halogens.

89. 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.

90. R 1 is 2,4-difluorophenyl.

91. R 1 The compound according to any one of claims 47 to 84, wherein is substituted with three halogens.

92. R 1 is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

93. R 1 is 2,4,6-trifluorophenyl.

94. R 1 86. The compound of claim 85, wherein is 3-trifluoromethyl-4-fluorophenyl or 2-cyclopropoxy-4-fluorophenyl.

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

96. 96. The pharmaceutical composition of claim 95, further comprising one or more additional therapeutic agents.

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

98. 98. The pharmaceutical composition of claim 97, wherein the one or more additional therapeutic agents are selected from the group consisting of 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.

99. 95. A method of treating HIV infection in a human having or at risk of having HIV infection by administering to said human a therapeutically effective amount of a compound according to any one of claims 47 to 94, or a pharmaceutical composition according to claim 95.

100. 100. The method of claim 99, further comprising administering to the human a therapeutically effective amount of one or more additional therapeutic agents.

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

102. The method of claim 101, wherein the one or more additional therapeutic agents are selected from the group consisting of 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 for treating HIV, and combinations thereof.

103. 96. Use of a compound according to any one of claims 47 to 94, or a pharmaceutical composition according to claim 95, for the treatment of HIV infection in a human having or at risk of having HIV infection.

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

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

106. The use of claim 105, wherein the one or more additional therapeutic agents are selected from the group consisting of 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 for treating HIV, and combinations thereof.

107. 95. A compound according to any one of claims 47 to 94, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

108. 95. A compound according to any one of claims 47 to 94, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of HIV infection.

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