Bridged tricyclic carbamoylpyridone compounds and pharmaceutical use thereof

Abstract

To provide methods for treating diseases.SOLUTION: Compounds for use in treating or preventing human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following formula (I), including stereoisomers and pharmaceutically acceptable salts thereof, where R1, R2, L, W1, W2, X, Y, and Z are as defined herein. Methods associated with the preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Reference This application claims priority to U.S. Provisional Application No. 62 / 822,703, filed March 22, 2019, and U.S. Provisional Application No. 62 / 948,697, filed December 16, 2019, both of which are incorporated by reference in their entirety for all purposes.

[0002] background Field Disclosed are compounds, compositions, and methods that can be used to treat or prevent human immunodeficiency virus (HIV) infection. In particular, novel bridged tricyclic 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 encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Drugs targeting reverse transcriptase and protease have been widely used and have shown efficacy, especially when used in combination, but toxicity and the emergence of resistant strains can limit their usefulness (Palella, et al. N. Engl. J Med. (1998) 338: 853-860; Richman, DD Nature (2001) 410: 995-1001). Therefore, new drugs that inhibit HIV replication are needed.

[0004] The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Current treatment guidelines published by the U.S. Department of Health and Human Services provide that achieving viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed February 12, 2019). Furthermore, decisions regarding the treatment of HIV-infected patients are complicated when these patients require treatment for other medical conditions (ibid., F-8). Because 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 treatments with reduced potential for drug interactions.

[0005] Furthermore, the HIV virus is known to mutate within infected subjects (Tang, et al. Drugs (2012) 72 (9) e1-e25). Due to the tendency of the HIV virus to mutate, anti-HIV drugs are required to be effective against a variety of known HIV variants (Hurt, et al. HIV / AIDS CID (2014) 58, 423-431). For certain patients, for example, those with poor or limited access to healthcare, adherence to a daily oral treatment or prophylaxis regimen can be difficult. Drugs that offer favorable pharmaceutical properties (e.g., improved efficacy, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) can be administered less frequently and provide better patient compliance. Such improvements can, in turn, optimize drug exposure and limit the emergence of drug resistance. [Prior art documents] [Non-patent literature]

[0006] [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] Tang,et al.Drugs(2012)72(9)e1-e25 [Non-patent document 4] Hurt, et al.HIV / AIDS CID(2014)58,423-431 Summary of the Invention [Means for solving the problem]

[0007] Abstract The present disclosure relates to novel compounds and pharmaceutically acceptable salts thereof with antiviral activity. In some embodiments, these compounds can be used to treat HIV infection, inhibit the activity of HIV integrase, and / or reduce HIV replication. In some embodiments, the compounds disclosed herein can be effective against certain known drug-resistant HIV mutants. In some embodiments, the compounds disclosed herein can have a reduced tendency to cause drug-drug interactions when co-administered with other drugs. In some embodiments, the compounds disclosed herein can be administered less frequently than once a day, for example, once a week, once a month, or at longer intervals.

[0008] In one embodiment, there is provided a compound having the following formula (I) or a pharmaceutically acceptable salt thereof: [ka] In formula (I), R 1 is H or C 6~10 aryl, where C 6~10 Aryl is one to four R A1 where each R is substituted as needed. A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 is alkyl; R 2 is H, C 1~6 Alkyl, or C 1~4 is haloalkyl; L is -CR 3a R 3b -, -C(O)-, -SO2-, -CH2-CH2-, or -N(R a )-and; W 1 is a bond or -CR 4a R4b - and; W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -C(O)O-, -C(O)NH-, -CR 5a R 5b -N(R 7 )-, -CR 5a R 5b -O-, -CR 5a R 5b -S(O) n -, -CR 5a R 5b -C(O)-, -CR 5a R 5b -C(O)O-, -CR 5a R 5b -OC(O)-, -CR 5a R 5b -C(O)NH- or -CR 5a R 5b -NHC(O)-; X is a bond or -CR 8a R 8b - and; Y is —C(O)NH— or Q, where Q is [ka] and; Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d - or -CR 10a =CR 10b - and; R 3a and R 3b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, or -OC 1~4alkyl; or optionally: R 3a and R 3b together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A2 where each R is substituted as needed. A2 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl; R 4a and R 4b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo; R 5a , R 5b , R 5c , and R 5d are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 alkyl; or optionally: R 5a and R 5b , or R 5c and R 5d together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A3 where each R is substituted as needed. A3 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl; or R 5a and R 5c , or R 5b and R 5dare taken together with the carbon atoms to which they are attached to form a 3- to 7-membered saturated or partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, wherein the fused ring is A3 where each R is substituted as needed. A3 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl; R 6a and R 6b each independently represents H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl; optionally: R 6a and R 6b Each of these, together with the carbon atom to which it is attached, forms a 5- to 10-membered moiety containing zero heteroatoms or one heteroatom selected from N, O, and S. A partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is a ring having 1 to 4 R A4 where each R is substituted as needed. A4 are independently halo or C 1~4 is alkyl; R 7 is H, C 1~6 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c and; R 8a and R 8b each independently represents H, hydroxyl, or -OC 1~4 Alkyl, C 1~4 Alkylene-OC 1~4 Alkyl, C 1~6 Alkyl, C 1~4 haloalkyl, cyano, or halo; or optionally: R 8a and R 8btogether with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl; or optionally: R 8a is H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkylene-OC 1~4 Alkyl, C 1~6 Alkyl, C 1~4 haloalkyl, cyano, or halo; and R 8b and R 5a , R 5b , R 5c , R 5d , and R 7 and one of, together with the atom to which each is attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is A5 where each R is substituted as needed. A5 are independently halo or C 1~4 alkyl; or R 8b and R 2 are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is A5 where each R is substituted as needed. A5 are independently halo or C 1~4 is alkyl; R 9a , R 9b , R 9c , and R 9d are each independently H, C 1~6 Alkyl, C 1~4haloalkyl, or halo; or optionally: R 9a and R 9b , or R 9c and R 9d together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A6 where each R is substituted as needed. A6 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl; or R 9a and R 9c , or R 9b and R 9d are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered saturated or partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, wherein the fused ring is A6 where each R is substituted as needed. A6 independently, halo, C 1~4 Alkyl, or C 1~4 is haloalkyl; or R 9a , R 9b , R 9c , and R 9d One of the R 4a , R 4b , R 5a , R 5b , and R 7 and one of, together with the atom to which each is attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is A6 where each R is substituted as needed. A6 are independently halo or C 1~4 is alkyl; R 10a and R 10b are independently H, halo, and C 1~4Haloalkyl, or C 1~6 alkyl; or optionally: R 10a and R 10b each together with the carbon atom to which it is attached forms a 5- to 10-membered partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, The partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring may have 1 to 4 R A7 where each R is substituted as needed. A7 are independently halo or C 1~4 is alkyl; R a are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C(O)R c , or SO2R c and; R b is H or C 1~4 is alkyl; R c is C 1~4 Alkyl or -OC 1~4 is alkyl; and Each n is 0, 1, or 2.

[0009] In one aspect, a pharmaceutical composition is provided that contains a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In another embodiment, a kit or article of manufacture is provided comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and instructions for use.

[0011] In another embodiment, there is provided 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 Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0012] In another embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating HIV infection in a human having or at risk of having HIV infection.

[0013] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0014] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0015] In another embodiment, there is provided the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HIV infection in a human having or at risk of having HIV infection.

[0016] In another embodiment, there is provided a method of using a compound of Formula I in therapy. Specifically, there is provided a method of 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 of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] In another embodiment, there is provided a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in a method of 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).

[0018] In another embodiment, a composition effective for treating or preventing HIV infection; and a method for treating or preventing HIV infection, the method comprising: A kit or article of manufacture is provided comprising packaging material containing the bell. An exemplary composition contains a compound of Formula I, or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0019] In yet another embodiment, a method of inhibiting HIV replication is provided, comprising exposing the virus to an effective amount of a compound of Formula I, or a salt thereof, under conditions such that HIV replication is inhibited.

[0020] In another embodiment, there is provided the use of a compound of formula I for inhibiting the activity of the HIV integrase enzyme.

[0021] In another embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for inhibiting the activity of the HIV integrase enzyme.

[0022] In another embodiment, there is provided the use of a compound of formula I or a salt thereof for inhibiting HIV replication.

[0023] In another embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as a research tool.

[0024] 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 of the embodiments, or may be learned by the practice of the present application. These objects and advantages will be realized and attained by the processes and compositions particularly pointed out in the specification and claims thereof. The foregoing summary is to be considered a brief, general summary of some of the embodiments disclosed herein, is provided for the benefit and convenience of the reader, and is made with the understanding that it is not intended in any way to limit the scope or equivalents of the appended claims to which they are legally entitled. DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description The following description of several embodiments is made with the understanding that this disclosure is to be considered as an exemplification of the claimed invention and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0026] definition Unless the context requires otherwise, throughout this disclosure and the claims, the term "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open, inclusive sense, i.e., "including, but not limited to."

[0027] 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 disclosed herein. Thus, the appearances of the phrase "one embodiment" or "an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0028] "Amino" refers to the -NH2 radical.

[0029] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0030] "Oxo" refers to the =O substituent.

[0031] "C u~v " or (C u~ C v ) indicates that the following group has from u to v carbon atoms. For example, "C 1~6 "Alkyl" indicates that the alkyl group contains from 1 to 6 carbon atoms.

[0032] "Alkyl" means a group consisting of carbon and hydrogen atoms, saturated, and having from 1 to 12 carbon atoms (C 1~12 alkyl), and in certain embodiments, 1 to 8 carbon atoms (C 1~8 alkyl) or 1 to 6 carbon atoms (C 1~6 alkyl), or 1 to 4 carbon atoms (C 1~4 "N" refers to a straight or branched chain hydrocarbon radical having an alkyl group (such as methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, hexyl, 3-methylhexyl, and 2-methylhexyl, and is attached to the rest of the molecule by a single bond.

[0033] "Alkylene" refers to a saturated, branched or straight-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same carbon atom or two different atoms of a parent alkane. For example, an alkylene group can have 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 atoms. Representative alkylene radicals include, but are not limited to, methylene (-CH-), 1,1-ethyl (-CH(CH)-), 1,2-ethyl (-CHCH-), 1,1-propyl (-CH(CHCH)-), 1,2-propyl (-CHCH(CH)-), 1,3-propyl (-CHCHCH-), and 1,4-butyl (-CHCHCHCHCH-).

[0034] "Aryl" or "aromatic ring" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a ring having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), 6 to 10 carbon ring atoms (i.e., C 6~10 aryl), or 5 to 10 carbon ring atoms (i.e., C 5~10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0035] "Cyano" or "carbonitrile" refers to the group --CN.

[0036] "Carbocyclic ring" refers to a non-aromatic carbocyclic ring consisting of carbon and hydrogen atoms, having from 3 to 15 carbon atoms, and in certain embodiments from 3 to 10 carbon atoms, or from 3 to 7 carbon atoms, which is saturated or partially unsaturated, and which is attached to the rest of the molecule by a single bond. Carbocyclic rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0037] "Fused" refers to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring system described herein that is bonded to an existing ring system in a compound disclosed herein through two adjacent atoms between the fused ring system and the existing ring system. For example, The bicyclic compounds illustrated below each contain a fused cyclopropane (i.e., a cyclopropane ring fused to a cyclohexane ring), a fused pyrrolidine (i.e., a pyrrolidine ring fused to a benzene ring), and a fused thiophene (i.e., a thiophene ring fused to a furan ring): [ka]

[0038] "Spiro" or "spirocyclic" refers to a carbocyclic or heterocyclic ring system described herein that is bonded to an existing ring system in a compound disclosed herein through an atom that is connected between the spiro ring system and the existing ring system. For example, the following bicyclic compounds each contain a spirocyclopropane (i.e., a cyclohexane ring and a spirocyclic cyclopropane ring), a spiro 1,3-dithiolane (i.e., a cycloheptane ring and a spirocyclic 1,3-dithiolane ring), and a spirocyclopentene (i.e., a cyclohexene ring and a spirocyclic cyclopentene ring): [ka]

[0039] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0040] "Haloalkyl" refers to an alkyl group, as defined above, that is substituted by 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, and the like.

[0041] A "heteroaromatic ring" refers to an aromatic ring having a single ring, multiple rings, or multiple fused rings and having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom). As used herein, heteroaryl contains 5 to 20 ring atoms (5- to 20-membered heteroaromatic ring), 5 to 12 ring atoms (5- to 12-membered heteroaromatic ring), 5 to 10 ring atoms (5- to 10-membered heteroaromatic ring), or 5 to 6 ring atoms (5- to 6-membered heteroaromatic ring). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.

[0042] "Heterocyclyl" or "heterocyclic ring" refers to a non-aromatic radical or ring having 3 to 15 atoms, of which 1 to 6 are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and attached to the rest of the molecule by a single bond. In certain embodiments, a "heterocyclyl" has 3 to 10 atoms, of which 1 to 4 are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or 3 to 7 atoms, of which 1 to 2 are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in a heterocyclyl can optionally be oxidized; the nitrogen atom can optionally be quaternized. As used herein, "Heterocyclyl" or "heterocyclic ring" refers to a ring that is saturated unless otherwise indicated; for example, in some embodiments, "heterocyclyl" or "heterocyclic ring" refers to a ring that is saturated or partially saturated, if specified. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0043] The embodiments disclosed herein are 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 sulfur, such as, for example, 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. In certain embodiments, radiolabeled compounds are useful to help determine or measure the efficacy of those compounds, for example, by characterizing the site or mode of action or binding affinity to a pharmacologically acceptable site of action. Certain isotopically labeled compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, for example, 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 ready means of detection.

[0044] In certain embodiments, deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may be increased or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.

[0045] 11 C. 18 F, 15 O and 13Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of Formula I can be prepared by techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, using the appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0046] The methods, compositions, kits, and articles of manufacture provided herein include compounds (e.g., compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb) or pharmaceutically acceptable salts thereof, in which one to n hydrogens bonded to a carbon atom have been replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of the compound or its pharmaceutically acceptable salt when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium. do.

[0047] The embodiments disclosed herein are also intended to encompass in vivo metabolic products of the disclosed compounds. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the administered compound, primarily due to enzymatic processes. Accordingly, the embodiments disclosed herein encompass compounds produced by a process comprising administering a compound according to embodiments disclosed herein 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 according to embodiments disclosed herein to a mammal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological sample.

[0048] "Mammals" includes humans and both domesticated animals (e.g., laboratory and domestic animals (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits)) and non-domesticated animals (e.g., wildlife, etc.).

[0049] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description encompasses instances in which the event or circumstance occurs and instances in which it does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may or may not be substituted, and that the description encompasses substituted heterocyclyl radicals and heterocyclyl radicals that have no substitution.

[0050] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substance that can be formulated with a pharmaceutically active ingredient of a pharmaceutical composition and is compatible with the other ingredients of the formulation and is suitable for use in humans or domestic animals without undue toxicity, irritation, and allergic response.

[0051] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts of compounds containing a suitable base, such as alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium, and NX4. + (where X is C 1~4 Pharmaceutically acceptable salts of the nitrogen atom of an amino group include, for example, salts derived from acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphoric acid, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, nicotinic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, phenylpropionic acid, 3- ... The pharmaceutically acceptable salts of the hydroxy groups of the compounds include organic carboxylic acids such as acetic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. + and NX4 + (where X is independently H or C 1~4The anions of the compounds may be selected from the group consisting of alkyl groups.

[0052] For use in therapy, salts of the active ingredients of the compounds disclosed herein are typically used as pharmaceuticals. The salts are physiologically acceptable. That is, these salts are salts derived from physiologically 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 an embodiment disclosed herein. All salts, whether derived from a physiologically acceptable acid or base, are within the scope of the embodiments disclosed herein.

[0053] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to an embodiment disclosed herein. Examples of metal salts prepared in this manner include 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.

[0054] Additionally, salts can be formed from the acid addition of certain organic and inorganic acids, such as HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids, to a basic center, typically an amine. Finally, it should be understood that the compositions herein contain the compounds disclosed herein in their non-ionized and zwitterionic forms.

[0055] A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein with a vehicle generally accepted in the art for the delivery of biologically active compounds to mammals (e.g., humans). Such vehicles include all pharmaceutically acceptable excipients.

[0056] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound according to embodiments disclosed herein that, when administered to a patient in need thereof, is sufficient to treat a disease state, condition, or disorder disclosed herein. Such an amount is sufficient to elicit the biological or medical response in a tissue system or patient desired by a researcher or clinician. The amount of a compound according to embodiments disclosed herein that constitutes a therapeutically effective amount will vary depending on the compound and its biological activity, the composition used for administration, the time of administration, 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 combination with or concomitantly with the compound of the embodiments disclosed herein, and factors such as the age, weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.

[0057] The terms "treat" and "treatment," as used herein, are intended to mean the administration of a compound or composition according to the present embodiments disclosed herein to reduce or eliminate one or more symptoms of HIV infection and / or to reduce the viral load in a patient. In certain embodiments, the terms "treat" and "treatment" also encompass the administration of a compound or composition according to the present embodiments disclosed herein 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 the virus from reaching detectable levels in the blood, as well as the administration of a compound or composition according to the present embodiments disclosed herein by administration to the mother before birth and to the child on the day of birth to prevent perinatal transmission of HIV from mother to newborn. The terms "treat" and "treatment" also encompass the administration of a compound or composition according to the present embodiments disclosed herein prior to an individual's exposure to the virus (also referred to as pre-exposure prophylaxis or PrEP) to prevent HIV infection from becoming established if the individual is exposed to the virus, and / or to keep the virus from establishing a persistent infection, and / or to prevent symptoms of the disease from appearing, and / or to prevent the virus from reaching detectable levels in the blood. The terms "treat" and "treatment" also encompass the administration of a compound or composition according to the present embodiments disclosed herein both before and after an individual's exposure to the virus. This includes administering a compound or composition according to the present embodiments disclosed therein.

[0058] As used herein, the terms "prevent" and "prevention" refer to the administration of a compound, composition, or pharmaceutical salt according to the present disclosure before or after a person's exposure to a virus, but before the appearance of disease symptoms and / or before the virus is detected in the blood. These terms also refer to preventing the appearance of disease symptoms and / or preventing the virus from reaching detectable levels in the blood. These terms encompass both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), as well as event-driven or "on-demand" prophylaxis. These terms also refer to the prevention of perinatal transmission of HIV from mother to newborn by administration to the mother before birth and to the child on the day of birth. These terms also refer to the prevention of HIV transmission by blood transfusion.

[0059] The term "antiviral agent," as used herein, is intended to mean an agent (compound or biological substance) that is effective to inhibit the formation and / or replication of viruses in humans, including, but not limited to, agents that interfere with either the host or viral mechanisms necessary for the formation and / or replication of viruses in humans.

[0060] The term "inhibitor of HIV replication," as used herein, is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in host cells, whether in vitro, ex vivo, or in vivo.

[0061] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus result in enantiomers, diastereomers, scalemic, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids, (D)- or (L)-. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. 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, it is intended that these compounds include both E and Z geometric isomers, as well as all tautomeric forms.

[0062] "Stereoisomer" refers to a compound composed of the same atoms connected by the same bonds but with different three-dimensional structures that are not interconvertible. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. In any of the embodiments disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

[0063] "Partially unsaturated" refers to a cyclic group that contains at least one double bond but is not aromatic. compound

[0064] As used herein, compounds that function as anti-HIV agents, such compounds optionally in combination with one or more (e.g., two, three, or four) additional therapeutic agents, are used. Pharmaceutical compositions containing the compounds, as well as methods of using such compounds and compositions, are provided. All compound embodiments described herein include any pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof.

[0065] In one embodiment, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I): R 1 is H or C 6~10 aryl, where C 6~10 Aryl is one to four R A1 where each R is substituted as needed. A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 is alkyl; R 2 is H, C 1~6 Alkyl, or C 1~4 is haloalkyl; L is -CR 3a R 3b -, -C(O)-, -SO2-, -CH2-CH2-, or -N(R a )-and; W 1 is a bond or -CR 4a R 4b - and; W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -C(O)O-, -C(O)NH-, -CR 5a R 5b -N(R 7 )-, -CR 5a R 5b -O-, -CR 5a R 5b -S(O) n -, -CR 5a R 5b -C(O)-, -CR 5a R 5b -C(O)O-, -CR 5a R 5b -OC(O)-, -CR 5a R 5b -C(O)NH- or -CR 5a R 5b -NHC(O)-; X is a bond or -CR 8a R 8b - and; Y is —C(O)NH— or Q, where Q is [ka] and; Z is -CR 9a R 9b -, -CR 9a R 9b -CR 9c R 9d - or -CR 10a =CR 10b - and; R 3a and R 3b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 alkyl; or optionally: R 3a and R 3b together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated alkyl group containing 0 to 2 heteroatoms selected from N, O, and S. form a spiro ring, wherein the spiro ring is A2 where each R is substituted as needed. A2 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl; R 4a and R 4b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo; R 5a , R 5b , R 5c , and R 5d are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 alkyl; or optionally: R 5a and R 5b , or R 5c and R 5d together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A3 where each R is substituted as needed. A3 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl; or R 5a and R 5c , or R 5b and R 5d are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered saturated or partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, wherein the fused ring is A3 where each R is substituted as needed. A3 independently, halo, C 1~4 Alkyl or C 1~4is haloalkyl; R 6a and R 6b each independently represents H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl; optionally: R 6a and R 6b are each taken together with the carbon atom to which they are attached to form a 5- to 10-membered partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is substituted with one to four R A4 where each R is substituted as needed. A4 are independently halo or C 1~4 is alkyl; R 7 is H, C 1~6 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c and; R 8a and R 8b each independently represents H, hydroxyl, or -OC 1~4 Alkyl, C 1~4 Alkylene-OC 1~4 Alkyl, C 1~6 Alkyl, C 1~4 haloalkyl, cyano, or halo; or optionally: R 8a and R 8b together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl; or optionally: R8a is H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkylene-OC 1~4 Alkyl, C 1~6 Alkyl, C 1~4 haloalkyl, cyano, or halo; and R 8b and R 5a , R 5b , R 5c , R 5d , and R 7 and one of, together with the atom to which each is attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is A5 where each R is substituted as needed. A5 are independently halo or C 1~4 alkyl; or R 8b and R 2 are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is A5 where each R is substituted as needed. A5 are independently halo or C 1~4 is alkyl; R 9a , R 9b , R 9c , and R 9d are each independently H, C 1~6 Alkyl, C1 ~4 haloalkyl, or halo; or optionally: R 9a and R 9b , or R 9c and R 9d together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A6where each R is substituted as needed. A6 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl; or R 9a and R 9c , or R 9b and R 9d are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered saturated or partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, wherein the fused ring is A6 where each R is substituted as needed. A6 independently, halo, C 1~4 Alkyl, or C 1~4 is haloalkyl; or R 9a , R 9b , R 9c , and R 9d One of the R 4a , R 4b , R 5a , R 5b , and R 7 and one of, together with the atom to which each is attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is A6 where each R is substituted as needed. A6 are independently halo or C 1~4 is alkyl; R 10a and R 10b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 alkyl; or optionally: R 10a and R 10bare each taken together with the carbon atom to which they are attached to form a 5- to 10-membered partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is substituted with one to four R A7 where each R is substituted as needed. A7 are independently halo or C 1~4 is alkyl; R a are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C(O)R c , or SO2R c and; R b is H or C 1~4 is alkyl; R c is C 1~4 Alkyl or -OC 1~4 is alkyl; and Each n is 0, 1, or 2.

[0066] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R 2 is H, C 1~4 Alkyl, or C 1~4 In some embodiments, R 2 is H or C 1~4 In some embodiments, R 2 is H. In some embodiments, R 2 is C 1~4 In some embodiments, R 2 is methyl. In some embodiments, R 2 is H or methyl. In some embodiments, R 2 is C 1~4 It is haloalkyl.

[0067] In some embodiments, R 2 is selected from the group consisting of H, -CH3, -CH2CH3, and -CH2F, or R 2 and R 8b taken together with the carbons to which they are attached form a fused 3-membered carbocyclic ring. 2 is selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , and —CH 2 F. In some embodiments, R 2 and R 8b together with the carbons to which they are attached form a three-membered fused carbocyclic ring.

[0068] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Y is -C(O)NH-. In some embodiments, Y is Q. In some embodiments, Y is [ka] is.

[0069] In some embodiments, the compound of formula I has formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, W 1 , W 2 , X, and Z are as defined in Formula I.

[0070] In some embodiments of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, R 1 is H. In some embodiments, R 1 is C 6~10 In some embodiments, R 1 is 1 to 4 R A1 where each R is optionally substituted phenyl A1 independently, halo, C 1~4 Alkyl, C 1~4Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 In some embodiments, R 1 can be one, two, three, or four R A1 In some embodiments, R 1 can be one, two, three, or four R A1 In some embodiments, R 1 can be one, two, three, or four R A1 wherein each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 In some embodiments, R 1 can be one, two, three, or four R A1 wherein each R A1 independently, halo, C 1~4 Alkyl, or C 1~4 In some embodiments, R 1 can be one, two, three, or four R A1 wherein each R A1 are independently halo or -OC 1~4 In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 halogens. 1 is phenyl substituted with 1, 2, or 3 halogens. 1 is phenyl substituted with 2 or 3 halogens. In some embodiments, R 1 is phenyl substituted with two or three halogens selected from chloro and fluoro. 1 teeth, [ka] is.

[0071] In some embodiments of compounds I or II, R 1 teeth, [ka] In some embodiments of the compounds of Formula I or II, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0072] In some embodiments of the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, L is -CR 3a R 3b - where R 3a and R 3b are independently H, C 1~4 Alkyl, C 1~6 Haloalkyl, C(O)R c , or SO2R c In some embodiments, L is -CR 3a R 3b - where R 3a and R 3b teeth Independently, H or C 1~4 In some embodiments, L is alkyl. In some embodiments, L is -CH2-. In some embodiments, L is -CH(CH3)-. In some embodiments, L is -C(O)-. In some embodiments, L is or -CH2-CH2-. In some embodiments, L is -CH2-, -CH(CH3)-, -C(O)-, or -CH2-CH2-. In some embodiments, L is -N(R a )-.

[0073] In some embodiments, the compound of formula I or II has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, W 1 , W 2 , X, and Z are as defined in Formula I.

[0074] In some embodiments, the compound of formula I or II has formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , W 1 , W 2 , X, and Z are as defined in Formula I.

[0075] In some embodiments, the compound of Formula I, II, or IV has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , W 1 , W 2 , X, and Z are as defined in Formula I.

[0076] In some embodiments, the compound of formula I or II has formula (VI): [ka] is a compound of

[0077] In some embodiments, the compound of Formula I, II, or VI has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , W 1 , W 2 , X, and Z are as defined in Formula I.

[0078] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, or VIIb, or a pharmaceutically acceptable salt thereof, W 1 is a bond. In some embodiments, W 1 Ha-CR 4a R 4b In some embodiments, W 1 Ha-CR 4a R 4b - where R 4a and R 4b is independently H or halo. In some embodiments, W 1 is -CH2-. In some embodiments, W 1 is -CF2-. In some embodiments, W 1 is -CH(F)-. In some embodiments, W 1 is a bond, —CH—, —CF—, or —CH(F)—. In some embodiments, W 1 is a bond or -CH2-.

[0079] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, or VIIb, or a pharmaceutically acceptable salt thereof, W 1 is a bond or -CR 4a R 4b - where R 4a and R 4b each independently is H, halo, or C 1~6 In any embodiment, W is alkyl. 1 is a bond or -CR 4a R 4b --, where each R 4a and R 4bis independently H, halo, or -CH3. 1 is a bond, —CH—, —CH(F)—, CF, —CH(CH)—, or —CF(CH)—.

[0080] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, or VIIb, or a pharmaceutically acceptable salt thereof, W 2 -CR 5a R 5b -, -CR 5a R 5b -CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -CR 5a R 5b -N(R 7 )-, or -CR 5a R 5b -O-, where R 5a , R 5b , R 5c , R 5d , R 6a , R 6b , and R 7 is as defined for formula I. In some embodiments, W 2 Ha-CR 5 a R 5b In some embodiments, W 2 Ha-CR 5a R 5b - where R 5a and R 5b are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 In some embodiments, W is alkyl. 2 Ha-CR 5a R 5b - where R 5aand R 5b are independently H, C 1~4 Alkyl, C 1~4 In some embodiments, W is haloalkyl, halo, or hydroxyl. 2 Ha-CR 5a R 5b - where R 5a and R 5b is independently H or halo. In some embodiments, W 2 is -CH2-. In some embodiments, W 2 is -CF2-. In some embodiments, W 2 is -CH(F)-. In some embodiments, W 2 Ha-CR 5a R 5b -CR 5c R 5d In some embodiments, W 2 Ha-CR 5a R 5b -CR 5c R 5d - where R 5a , R 5b , R 5c , and R 5d are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 In some embodiments, W is alkyl. 2 Ha-CR 5a R 5b -CR 5c R 5d - where R 5a , R 5b , R 5c , and R 5d are independently H, C 1~4 Alkyl, C 1~4 haloalkyl, halo, hydroxyl. In some embodiments, W 2 Ha-CR 5a R 5b -CR 5c R5d - where R 5a , R 5b , R 5c , and R 5d is independently H or halo. In some embodiments, W 2 is -CH2CH2-. In some embodiments, W 2 Ha-CR 5a R 5b -CR 5c R 5d - where R 5a and R 5c are independently H or halo, and R 5b and R 5d Each of these, together with the carbon atom to which it is attached, is one to three R A3 and forming a 3- to 7-membered saturated or partially unsaturated fused carbocyclic ring optionally substituted with A3 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, W is haloalkyl. 2 Ha-CR 5a R 5b -CR 5c R 5d - where R 5a and R 5c are independently H or halo, and R 5b and R 5d are taken together with the carbon atoms to which they are attached to form a 3- to 5-membered saturated fused carbocyclic ring. 2 Ha-CHR 5b -CHR 5d - where R 5b and R 5d are taken together with the carbon atoms to which they are each attached to form a 3-, 4-, or 5-membered saturated fused carbocyclic ring. 2 teeth [ka] In some embodiments, W 2 Ha-CR 6a =CR6b In some embodiments, W 2 Ha-CR 6a =CR 6b - where R 6a and R 6b are independently H, halo, and C 1~4 Haloalkyl, or C 1~4 In some embodiments, W is alkyl. 2 Ha-CR 6a =CR 6b - where R 6a and R 6b is independently H or halo. In some embodiments, W 2 is -CH=CH-. In some embodiments, W 2 Ha-CR 6a =CR 6b - where R 6a and R 6b are each taken together with the carbon atom to which they are attached to form a 5- to 10-membered partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is substituted with one to four R A4 where each R is substituted as needed. A4 are independently halo or C 1~4 In some embodiments, W is alkyl. 2 Ha-CR 6a =CR 6b - where R 6a and R 6b Each of these, together with the carbon atom to which it is attached, is one to four R A4 and forming a 5- to 10-membered partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, optionally substituted with A4 are independently halo or C 1~4 In some embodiments, W is alkyl. 2 Ha-CR6 a =CR 6b - where R 6a and R 6b Each of these, together with the carbon atom to which it is attached, is one to four R A4 and forming an optionally substituted 5- to 10-membered fused aromatic ring, wherein each R A4 are independently halo or C 1~4 In some embodiments, W is alkyl. 2 Ha-CR 6a =CR 6b - where R 6a and R 6b Each of these, together with the carbon atom to which it is attached, is one to four R A4 and R A4 are independently halo or C 1~4 In some embodiments, W is alkyl. 2 Ha-CR 6a =CR 6b - where R 6a and R 6b Each of these, together with the atom to which it is attached, is made up of 1 to 4 R A4 and forming a fused 1,2-phenylene ring optionally substituted with A4 are independently halo or C 1~4 In some embodiments, W is alkyl. 2 teeth, [ka] where p is 0, 1, 2, 3, or 4. In some embodiments, W 2 teeth, [ka] where each R A4 is independently halo. In some embodiments, W 2 teeth, [ka] where each R A4 is independently halo, and p is 0, 1, 2, or 3. In some embodiments, W 2 teeth, [ka] where each R A4 is independently halo, and p is 0, 1, or 2. In some embodiments, W 2 teeth, [ka] In some embodiments, W 2 teeth, [ka] In some embodiments, W 2 -N(R 7 In some embodiments, W 2 -N(R 7 )-, where R 7 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c In some embodiments, W 2 -N(R 7 )-, where R 7 is H, C 1~4 Alkyl, C(O)R c , or SO2R c In some embodiments, W 2 is -NH-. In some embodiments, W 2 is —N(CH)—. In some embodiments, W 2 is —N(CH(CH)—. In some embodiments, W 2 -N(C(O)R c In some embodiments, W 2is —N(C(O)CH)—. In some embodiments, W 2 HA-N(SO2R c In some embodiments, W 2 is —N(SO2CH3)—. In some embodiments, W 2 is —O—. In some embodiments, W 2 Ha-CR 5a R 5b -N(R 7 In some embodiments, W 2 is -CH2-N(R 7 In some embodiments, W 2 Ha-CR 5a R 5b In some embodiments, W 2 or —CH—O—. In some embodiments, W 2 is -CH2-, -CH2CH2-, -CH=CH-, [ka] , -NH-, -N(CH3)-, -N(CH(CH3)2)-, -N(C(O)CH3)-, -N(SO2CH3)-, -O-, or -CH2-O-.

[0081] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, or Vb, the compound has Formula (X): [ka] It has.

[0082] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, or Vb, the compound has the formula (Xa): [ka] It has.

[0083] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, or Vb, the compound has the formula (Xb): [ka] It has.

[0084] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, or Vb, the compound has Formula (XI): [ka] It has.

[0085] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, or X, the compound has Formula (XIa): [ka] It has.

[0086] In some embodiments, the compound of formula I, II, IIIa, IIIb, IV, Va, Vb, or X has formula (XIb): [ka] It has.

[0087] In some embodiments of the compound of Formula X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond or -CR 8a R 8b - where R 8a and R 8b each independently represents H, hydroxyl, or -OC 1~4 Alkyl, C 1~4 Alkylene-OC 1~4 Alkyl, C 1~6 Alkyl, C 1~4 In some embodiments, X is haloalkyl, cyano, or halo. In some embodiments, X is a bond. In some embodiments, X is -CR 8a R8b - where R 8a and R 8b each independently represents H, hydroxyl, or -OC 1~4 Alkyl, C 1~4 Alkylene-OC 1~4 Alkyl, C 1~6 Alkyl, C 1~4 In some embodiments, X is -CR 8a R 8b - where R 8a and R 8b are each independently H, C 1~6 Alkyl, C 1~4 In some embodiments, R 8a and R 8b are each independently H, —CH 3 , —CHF 2 , —CH 2 F, or halo.

[0088] In some embodiments of the compound of Formula X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b -or-CR 9a R 9b CR 9c R 9d - where R 9a , R 9b , R 9c , and R 9d are each independently H, C 1~6 Alkyl, or C 1~4 In some embodiments, Z is -CR 9a R 9b In any embodiment, Z is -CR 9a R 9b CR 9c R 9d In some embodiments, R 9a , R 9b , R 9c , and R 9d are each independently H, —CH3, —CHF2, or —CH2F.

[0089] In some embodiments of the compound of Formula XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, R 6a and R 6b each independently represents H, halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0090] In some embodiments of the compounds of formula X, Xa, or Xb, or pharmaceutically acceptable salts thereof, R 5a , R 5b , R 5c , and R 5d each independently represents H, halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0091] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond. In some embodiments, X is -CR 8a R 8b In some embodiments, X is -CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, C 1~4 In some embodiments, X is -CR 8a R 8b - where R 8a is H, fluoro, or hydroxyl, and R 8b In some embodiments, X is H or fluoro. In some embodiments, X is -CH2-. In some embodiments, X is -CF2-. In some embodiments, X is -CH(F)-. In some embodiments, X is -CH(OH)-. In some embodiments, X is -CH(CH3)-. In some embodiments, X is -CF(CH3)-. In some embodiments, X is -CH2-, -CF2-, -CH(F)-, -CH(OH)-, -CH(CH3) or -CF(CH3)-. In some embodiments, X is -CR 8a R 8b - where R 8a and R 8b together with the carbon to which they are attached form a 3-, 4-, or 5-membered saturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, X is -CR 8a R 8b - where R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro ring containing 0 heteroatoms, where the spiro ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, X is -CR 8a R 8b - where R 8a and R 8b together with the carbons to which they are attached form a spirocyclopropane ring.

[0092] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond or -CR8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro ring containing 0-2 heteroatoms selected from N, O, and S, wherein the spiro ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 It is haloalkyl.

[0093] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond or -CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbons to which they are attached form a 3- to 5-membered saturated spiroheterocyclic ring containing one or two heteroatoms selected from N, O, and S, wherein the spiro ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, X is a bond or -CR 8a R 8b - where R 8a and R 8bare independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbons to which they are attached form a 3- to 5-membered saturated spiroheterocyclic ring containing one or two heteroatoms selected from N, O, and S.

[0094] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond or -CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spirocarbocyclic ring, wherein the 3- to 5-membered saturated spirocarbocyclic ring is bound to one to four R A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, X is a bond or -CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spirocarbocyclic ring.

[0095] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond or -CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a three-membered saturated spirocarbocyclic ring, wherein the three-membered saturated spirocarbocyclic ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, X is a bond or -CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b taken together with the carbon to which they are attached form a three-membered saturated spirocarbocyclic ring.

[0096] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond, —CH—, —CF—, —CH(F)—, —CH(Cl)—, —CH(OH)—, —C(CHF)(OH)—, —C(CH)(OH)—, —CH(OCH)—, —C(CHCH)(OCH)—, —C(CHCH)(OH)—, —CH(CH)—, —CH(CHCH)—, —CF(CH)—, —CF(CHCH)—, or —CR 8a R 8b - where R 8a and R 8b together with the carbons to which they are attached form a 3-membered saturated spirocarbocyclic ring. In some embodiments, X is a bond, —CH—, —CF—, —CH(F)—, —CH(Cl)—, —CH(OH)—, —C(CHF)(OH)—, —C(CH)(OH)—, —CH(OCH)—, —C(CHCH)(OCH)—, —C(CHCH)(OH)—, —CH(CH)—, —CH(CHCH)—, —CF(CH)—, or —CF(CHCH)—.

[0097] In some embodiments, X is a bond, —CH—, —CF—, —CH(F)—, —CH(Cl)—, —CH(OH)—, —C(CHF)(OH)—, —C(CH)(OH)—, —CH(OCH)—, —C(CHCH)(OCH)—, —C(CHCH)(OH)—, —CH(CH)—, —CH(CHCH)—, —CF(CH)—, —CF(CHCH)—, —C(CHF)(H)—, or —CR 8a R 8b - where R 8a and R 8btogether with the carbons to which they are attached form a 3-membered saturated spirocarbocyclic ring. In some embodiments, X is a bond, —CH—, —CF—, —CH(F)—, —CH(Cl)—, —CH(OH)—, —C(CHF)(OH)—, —CH(OCH)—, —C(CHCH)(OCH)—, —C(CHCH)(OH)—, —CH(CH)—, —CH(CHCH)—, —CF(CH)—, —C(CHF)(H)—, or —CF(CHCH)—.

[0098] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is -CR 8a R 8b - where R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro ring containing 0-2 heteroatoms selected from N, O, and S, wherein the spiro ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 Haloalkyl(C 1-4 In some embodiments, X is -CR 8a R 8b - where R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spirocarbocyclic ring, wherein the 3- to 5-membered saturated spirocarbocyclic ring is bound to one to four R A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, X is -CR 8a R 8b - where R 8a and R8b together with the carbon to which they are attached form a 3-membered spirocarbocyclic ring. In some embodiments, X is -CR 8a R 8b - where R 8a and R 8b together with the carbons to which they are attached form a 3- to 5-membered saturated spiroheterocyclic ring containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 5-membered saturated spiroheterocyclic ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, X is -CR 8a R 8b - where R 8a and R 8b together with the carbons to which they are attached form a 3- to 5-membered saturated spiroheterocyclic ring containing one or two heteroatoms selected from N, O, and S.

[0099] In some embodiments, the compound of formula I or II has formula (VIII): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, W 1 , W 2 and Z is as defined in formula I.

[0100] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b In some embodiments, Z is -CR 9a R 9b - where R 9a and R 9bare independently H, C 1~4 Alkyl, C 1~4 In some embodiments, Z is -CR 9a R 9b - where R 9a and R 9b are independently H or C 1~4 In some embodiments, Z is -CH2-. In some embodiments, Z is -CH(CH3)-. In some embodiments, Z is -CR 9a R 9b -CR 9c R 9d In some embodiments, Z is -CR 9a R 9b -CR 9c R 9d - where R 9a , R 9b , R 9c , and R 9d are independently H, C 1~4 Alkyl, C 1~4 In some embodiments, Z is -CH2-CH2-. In some embodiments, Z is -CR 10a =CR 10b In some embodiments, Z is -CR 10a =CR 10b - where R 10a and R 10b In some embodiments, Z is -CR 10a =CR 10b - where R 10a and R 10 b are each taken together with the carbon atom to which they are attached to form a 5- to 10-membered partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is substituted with one to four R A7where each R is substituted as needed. A7 are independently halo or C 1~4 In some embodiments, Z is -CR 10a =CR 10b - where R 10a and R 10b Each of these, together with the carbon atom to which it is attached, is one to four R A7 or one heteroatom selected from N, O, and S, optionally substituted with A7 are independently halo or C 1~4 In some embodiments, Z is -CR 10a =CR 10b - where R 10a and R 10b Each of these, together with the carbon atom to which it is attached, is one to four R A7 and forming an optionally substituted 5- to 10-membered fused aromatic ring, wherein each R A7 are independently halo or C 1~4 In some embodiments, Z is -CR 10a =CR 10b - where R 10a and R 10b Each of these, together with the carbon atom to which it is attached, is one to four R A7 and R A7 are independently halo or C 1~4 In some embodiments, Z is -CR 10a =CR 10b - where R 10a and R 10b Each of these, together with the atom to which it is attached, is made up of 1 to 4 R A7 and forming a fused 1,2-phenylene ring optionally substituted with A7 are independently halo or C 1~4 In some embodiments, Z is alkyl. [ka] wherein q is 0, 1, 2, 3, or 4. In some embodiments, Z is [ka] where each R A4 is independently halo. In some embodiments, Z is [ka] where each R A4 is independently halo, and q is 0, 1, 2, or 3. In some embodiments, Z is [ka] where each R A4 is independently halo, and q is 0, 1, or 2. In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is -CH2-, -CH(CH3)-, -CH2-CH2-, [ka] is.

[0101] In some embodiments of the compound of Formula I, II, IIIa, IIIb, or VIII, or a pharmaceutically acceptable salt thereof, L is -CR 3a R 3b- and R 3a and R 3b are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 In some embodiments, R 3a and R 3b are independently H or C 1~4 In some embodiments, R 3a and R 3b is H. In some embodiments, R 3a and R 3b is C 1~4 In some embodiments, R 3a is H, and R 3b is C 1~4 In some embodiments, R 3a is H, and R 3b is methyl. In some embodiments, R 3a and R 3b together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A2 where each R is substituted as needed. A2 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 3a and R 3b together with the carbon atoms to which they are attached form a 3-, 4-, or 5-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A2 where each R is substituted as needed. A2 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 3a and R 3b is the carbon to which they are bonded. together with the atom(s) form a 3- or 4-membered saturated spiro ring containing zero heteroatoms or one heteroatom selected from N, O, and S, wherein the spiro ring is A2 where each R is substituted as needed. A2 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 3a and R 3b together with the carbon atoms to which they are attached form a three-membered saturated spiro ring containing zero heteroatoms or one heteroatom selected from N, O, and S, wherein the spiro ring is A2 where each R is substituted as needed. A2 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 3a and R 3b together with the carbon atoms to which they are attached form a spirocyclopropane ring.

[0102] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, or a pharmaceutically acceptable salt thereof, W 1 Ha-CR 4a R 4b - and R 4a and R 4b are independently H, C 1~4 Alkyl, C 1~4 In some embodiments, R 4a and R 4b is independently H or halo. In some embodiments, R 4a and R 4b is H. In some embodiments, R 4a and R 4b is halo. In some embodiments, R 4a and R 4bis fluoro. In some embodiments, R 4a is H, and R 4b is halo. In some embodiments, R 4a is H, and R 4b is fluoro.

[0103] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, W 2 Ha-CR 5a R 5b - and R 5a and R 5b are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 In some embodiments, R 5a and R 5b are independently H, C 1~4 Alkyl, C 1~4 haloalkyl, halo, or hydroxyl. In some embodiments, R 5a and R 5b is independently H or halo. In some embodiments, R 5a and R 5b is H. In any embodiment, R 5a and R 5b is halo. In some embodiments, R 5a and R 5b is fluoro. In some embodiments, R 5a is H, and R 5b is halo. In some embodiments, R 5a is H, and R 5b is fluoro. In some embodiments, R 5a and R 5btogether with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A3 where each R is substituted as needed. A3 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 5a and R 5b together with the carbon atoms to which they are attached form a 3-, 4-, or 5-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A3 where each R is substituted as needed. A3 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 5a and R 5b together with the carbon atoms to which they are attached form a 3- or 4-membered saturated spiro ring containing zero heteroatoms or one heteroatom selected from N, O, and S, wherein the spiro ring is A3 where each R is substituted as needed. A3 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 5a and R 5b together with the carbon atoms to which they are attached form a three-membered saturated spiro ring containing zero heteroatoms or one heteroatom selected from N, O, and S, wherein the spiro ring is A3 are substituted as necessary, Here each R A3 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 5a and R 5btogether with the carbon atoms to which they are attached form a spirocyclopropane ring.

[0104] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, W 2 Ha-CR 5a R 5b CR 5c R 5d - and R 5a , R 5b , R 5c , and R 5d are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 In some embodiments, R 5a , R 5b , R 5c , and R 5d are independently H, C 1~4 Alkyl, C 1~4 haloalkyl, halo, or hydroxyl. In some embodiments, R 5a , R 5b , R 5c , and R 5d is independently H or halo. In some embodiments, R 5a , R 5b , R 5c , and R 5d is H. In some embodiments, R 5a and R 5c are independently H or halo, and R 5b and R 5d Each of these, together with the carbon atom to which it is attached, is one to three R A3 and forming a 3- to 7-membered saturated or partially unsaturated fused carbocyclic ring optionally substituted with A3 independently, halo, C 1~4 Alkyl or C1~4 In some embodiments, R 5a and R 5c are independently H or halo, and R 5b and R 5d are taken together with the carbon atoms to which they are each attached to form a 3-, 4-, or 5-membered saturated fused carbocyclic ring. 5a and R 5c is H, and R 5b and R 5d are taken together with the carbon atoms to which they are each attached to form a 3-, 4-, or 5-membered saturated fused carbocyclic ring. 5a and R 5c is H, and R 5b and R 5d taken together with the carbon atoms to which each is attached form a fused cyclopropane ring.

[0105] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, W 2 Ha-CR 6a =CR 6b - and R 6a and R 6b are independently H, halo, and C 1~4 Haloalkyl, or C 1~4 In some embodiments, R 6a and R 6b is independently H or halo. In some embodiments, R 6a and R 6b is H. In some embodiments, R 6a and R 6b Each of these, together with the atom to which it is attached, is made up of 1 to 4 R A4 and forming an optionally substituted 5- to 10-membered fused aromatic ring, wherein each R A4 are independently halo or C 1~4 In some embodiments, R6a and R 6b Each of these, together with the atom to which it is attached, is made up of 1 to 4 R A4 and forming a fused 1,2-phenylene ring optionally substituted with A4 are independently halo or C 1~4 In some embodiments, R 6a and R 6b together with the atoms to which they are bonded, [ka] where p is 0, 1, 2, 3, or 4. In some embodiments, R 6a and R 6b together with the atoms to which they are bonded, [ka] where each R A4 is independently halo. In some embodiments, R 6a and R 6b together with the atoms to which they are bonded, [ka] where each R A4 is independently halo, and p is 0, 1, 2, or 3. In some embodiments, R 6a and R 6b together with the atoms to which they are bonded, [ka] where each R A4 is independently halo, and p is 0, 1, or 2. In some embodiments, R 6a and R 6b together with the atoms to which they are bonded, [ka] In some embodiments, R 6a and R 6b together with the atoms to which they are bonded, [ka] Form.

[0106] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, W 2 -N(R 7 )- and R 7 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c In some embodiments, R 7 is H, C 1~4 Alkyl, C(O)R c , or SO2R c In some embodiments, R 7 is H. In some embodiments, R 7 is C 1~4 In some embodiments, R 7 is methyl or 1-methylethyl. In some embodiments, R 7 is C(O)R c In some embodiments, R 7 is -C(O)-C 1~4 In some embodiments, R 7 is —C(O)CH. In some embodiments, R 7 is SO2R c In some embodiments, R 7 -SO2-C 1~4 In some embodiments, R 7 is -SO2CH3.

[0107] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)- and -CR 5a R 5b -O-; 5a , R 5b , R 5c , and R 5d each independently represents H, C 1~4 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 alkyl; or R 5a and R 5b , R 5c and R 5d , R 5a and R 5c , or R 5b and R 5d Each of these, together with the carbon atom to which it is attached, is one to three R A3 and forming a 3- to 7-membered saturated or partially unsaturated carbocyclic ring optionally substituted with A3 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl; R 6a and R 6b each independently represents H, halo, C 1~4 Haloalkyl, or C 1~4 alkyl; or R 6a and R 6bare each taken together with the atom to which it is attached to form (i) a 5- to 10-membered fused aromatic ring, or (ii) a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered fused aromatic ring or the 5- to 10-membered fused heteroaromatic ring is substituted with 1 to 4 R A4 where each R is substituted as needed. A4 are independently halo or C 1~4 alkyl; R 7 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c ; and R c is C 1~4 and n is 0, 1, or 2.

[0108] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)-, and -CR 5a R 5b -O-; 5a , R 5b , R 5c , and R 5d each independently represents H, C 1~4 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 alkyl; or R5a and R 5b , R 5c and R 5d , R 5a and R 5c , or R 5b and R 5d Each of these, together with the carbon atom to which it is attached, is one to three R A3 and forming an optionally substituted 3-membered carbocyclic ring with each R A3 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl; R 6a and R 6b each independently represents H, halo, C 1~4 Haloalkyl, or C 1~4 alkyl; or R 6a and R 6b are taken together with the atom to which they are attached to form (i) a fused phenyl ring, or (ii) a 5- to 6-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the fused phenyl ring or the 5- to 6-membered fused heteroaromatic ring is substituted with 1 to 4 R A4 where each R is substituted as needed. A4 are independently halo or C 1~4 alkyl; R 7 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c and Rc is C 1~4 and n is 0, 1, or 2.

[0109] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a=CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)-, and -CR 5a R 5b -O-; 5a , R 5b , R 5c , and R 5d each independently represents H, C 1~4 Alkyl, halo, hydroxyl, or -OC 1~4 alkyl; or R 5a and R 5b , R 5c and R 5d , R 5a and R 5c , or R 5b and R 5d together with the carbon atoms to which they are attached form a three-membered carbocyclic ring; R 6a and R 6b each independently is H, halo, or C 1~4 alkyl; or R 6a and R 6b are taken together with the atom to which they are attached to form (i) a fused phenyl ring, or (ii) a 5- to 6-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, wherein the fused phenyl ring or the 5- to 6-membered fused heteroaromatic ring is bonded to one or two R A4 where each R is substituted as needed. A4 are independently halo or C 1~4 alkyl; R 7 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c and;R c is C 1~4 alkyl; and n is 0 or 1.

[0110] In some embodiments, W 2 -CR5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)- and -CR 5a R 5b -O-; 5a , R 5b , R 5c , and R 5d each is independently H, —CH, halo, hydroxyl, or —OCH; or R 5a and R 5b , R 5c and R 5d , R 5a and R 5c , or R 5b and R 5d together with the carbon atoms to which they are attached form a three-membered carbocyclic ring; R 6a and R 6b each is independently H, halo, or CH; or R 6a and R 6b are taken together with the atom to which each is attached to form (i) a fused phenyl ring, or (ii) a 5-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, wherein the fused phenyl ring or the 5-membered to 6-membered fused heteroaromatic ring is bonded to one or two R A4 where each R is substituted as needed. A4 are independently halo or CH; R 7 is H, -CH3, -CH(CH3)2, -CF3, -C(O)R c , or -SO2R c and;R c is —CH 3 ; and n is 0 or 1.

[0111] In some embodiments, W 2 -CR5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)- and -CR 5a R 5b -O-; 5a , R 5b , R 5c , and R 5d each is independently H, —CH, halo, hydroxyl, or —OCH; R 6a and R 6b each independently is H, halo, or -CH; R 7 is H, -CH3, -CH(CH3)2, -CF3, -C(O)R c , or -SO2R c and;R c is —CH 3 ; and n is 0 or 1.

[0112] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is -CR 8a R 8b - and R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkylene-OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, cyano, or halo. In some embodiments, R 8a and R 8b are independently H, hydroxyl, C 1~4 alkyl, or halo. In some embodiments, R 8ais H, fluoro, or hydroxyl, and R 8b is H or fluoro. In some embodiments, R 8a and R 8b is H. In some embodiments, R 8a and R 8b is fluoro. In some embodiments, R 8a is H, and R 8b is halo. In some embodiments, R 8a is H, and R 8b is fluoro. In some embodiments, R 8a is H, and R 8b is hydroxyl. In some embodiments, R 8a is H, and R 8b is C 1~4 In some embodiments, R 8a is H, and R 8b is methyl. In some embodiments, R 8a is the halo, and R 8b is C 1~4 In some embodiments, R 8a Hafu Ruolo and R 8b is methyl. In some embodiments, R 8a and R 8b together with the carbon to which they are attached form a 3-, 4-, or 5-membered saturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A5 where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 8a and R 8b together with the carbon to which they are attached form a 3-, 4-, or 5-membered saturated spiro ring containing 0 heteroatoms, where the spiro ring is A5where each R is substituted as needed. A5 independently, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 8a and R 8b together with the carbons to which they are attached form a spirocyclopropane ring.

[0113] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b - and R 9a and R 9b are independently H, C 1~4 Alkyl, C 1~4 In some embodiments, R 9a and R 9b are independently H or C 1~4 In some embodiments, R 9a and R 9b is H. In some embodiments, R 9a and R 9b is C 1~4 In some embodiments, R 9a is H, and R 9b is C 1~4 In some embodiments, R 9a is H, and R 9b is methyl.

[0114] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b -CR 9c R 9d - and R 9a , R9b , R 9c , and R 9d are independently H, C 1~4 Alkyl, C 1~4 In some embodiments, R 9a , R 9b , R 9c , and R 9d are independently H or C 1~4 In some embodiments, R 9a , R 9b , R 9c , and R 9d is H.

[0115] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, Z is -CR 10a =CR 10b - and R 10a and R 10b are independently H, halo, and C 1~4 Haloalkyl, or C 1~4 In some embodiments, R 10a and R 10b each together with the atom to which it is attached forms a fused 5- to 10-membered aromatic or heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the aromatic or heteroaromatic ring is A7 where each R is substituted as needed. A7 are independently halo or C 1~4 In some embodiments, R 10a and R 10b Each of these, together with the atom to which it is attached, is made up of 1 to 4 R A7 and forming an optionally substituted 5- to 10-membered fused aromatic ring, wherein each R A7 are independently halo or C 1~4 In some embodiments, R 10a and R 10bEach of these, together with the atom to which it is attached, is made up of 1 to 4 R A7 and forming a fused 1,2-phenylene ring optionally substituted with A7 are independently halo or C 1~4 In some embodiments, R 10a and R 10b together with the atoms to which they are bonded, [ka] where q is 0, 1, 2, 3, or 4. In some embodiments, R 10a and R 10b together with the atoms to which they are bonded, [ka] where each R A4 is independently halo. In some embodiments, R 10a and R 10b together with the atoms to which they are bonded, [ka] where each R A4 is independently halo, and q is 0, 1, 2, or 3. In some embodiments, R 10a and R 10b together with the atoms to which they are bonded, [ka] where each R A4 is independently halo, and q is 0, 1, or 2. In some embodiments, R 10a and R 10b together with the atoms to which they are bonded, [ka] In some embodiments, R 10a and R10b together with the atoms to which they are bonded, [ka] In some embodiments, R 10a and R 10b together with the atoms to which they are bonded, [ka] Form.

[0116] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d - or -CR 10a =CR 10b - where R 9a , R 9b , R 9c , and R 9d are each independently H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo; or R 9a and R 9b , or R 9c and R 9d together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is A6 where each R is substituted as needed. A6 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl; R 10a and R 10b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 alkyl; or R10a and R 10b are each taken together with the carbon atom to which it is bonded to form (i) a 5- to 10-membered partially unsaturated fused ring containing zero heteroatoms or one heteroatom selected from N, O, and S, (ii) a 5- to 10-membered fused aromatic ring, or (iii) a 5- to 10-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered partially unsaturated fused ring, the 5- to 10-membered fused aromatic ring, or the 5- to 10-membered fused heteroaromatic ring is substituted with 1 to 4 R A7 where each R is substituted as needed. A7 are independently halo or C 1~4 It is alkyl.

[0117] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d - or -CR 10a =CR 10b - where R 9a , R 9b , R 9c , and R 9d are each independently H, CH, CHCH, CHF, or halo; or R 9a and R 9b , or R 9c and R 9d together with the carbon atoms to which they are attached form a three-membered carbocyclic ring; R 10a and R 10b are independently H, halo, or CH; or R 10a and R 10b are taken together with the carbon atoms to which they are attached to form (i) a fused phenyl ring, or (ii) a 5- to 6-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the fused phenyl ring or the fused heteroaromatic ring isA7 where each R is substituted as needed. A7 are independently halo or CH3.

[0118] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, or a pharmaceutically acceptable salt thereof, R 1 can be one, two, three, or four R A1 wherein each R A1 are independently halo or -OC 1~4 is alkyl; X is a bond or CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a three-membered saturated spirocarbocyclic ring; W 1 is a bond or -CR 4a R 4b - where R 4a and R 4b is independent , H., C. 1~6 alkyl, or halo; W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)- and -CR 5a R 5b-O-; 5a , R 5b , R 5c , and R 5d each independently represents H, C 1~4 Alkyl, halo, hydroxyl, or -OC 1~4 alkyl; R 6a and R 6b each independently is H, halo, or C 1~4 alkyl; R 7 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c and;R c is C 1~4 alkyl; and n is 0 or 1; and Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d - or -CR 10a =CR 10b - where R 9a , R 9b , R 9c , and R 9d are each independently H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo; or R 9a and R 9b , or R 9c and R 9d together with the carbon atoms to which they are attached form a three-membered carbocyclic ring; and R 10a and R 10b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0119] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, or a pharmaceutically acceptable salt thereof, R 1can be one, two, three, or four R A1 wherein each R A1 are independently halo or -OC 1~4 is alkyl; X is a bond or CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -OC 1~4 Alkyl, C 1~4 Alkyl, C 1~4 haloalkyl, or halo; W 1 is a bond or -CR 4a R 4b - where R 4a and R 4b are independently H, C 1~6 alkyl, or halo; W 2 Ha-CR 5a R 5b - where R 5a and R 5b each independently represents H, C 1~4 Alkyl, halo, hydroxyl, or -OC 1~4 is alkyl; and Z is -CR 9a R 9b - where R 9a and R 9b are each independently H, C 1~6 Alkyl, C 1~4 It is haloalkyl, or halo.

[0120] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, R a are independently H, C 1~4 Alkyl, C 1~6 Haloalkyl, C(O)R c , or SO2R c is.

[0121] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, R b is H. In some embodiments, R b is C 1~4 In some embodiments, R b is methyl.

[0122] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, R c is C 1~4 In some embodiments, R c is methyl. In some embodiments, R c -OC 1~4 It is alkyl.

[0123] A compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, X, Xa, Xb, XI, XIa, or XIb or a drug thereof In some embodiments of the biologically acceptable salt, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0124] In some embodiments, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII has Formula (IX): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is H or C 6~10 aryl, where C 6~10 Aryl is one to four R A1 where each R is substituted as needed.A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 It is alkyl.

[0125] In some embodiments, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, or IX has the formula (IXa): [ka] is a compound of

[0126] In some embodiments, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, or IX has the formula (IXb): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is H or C 6~10 aryl, where C 6~10 Aryl is one to four R A1 where each R is substituted as needed. A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 It is alkyl.

[0127] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, or Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, R 1 is H. In some embodiments, R 1 is C 6~10In some embodiments, R 1 is 1 to 4 R A1 where each R is optionally substituted phenyl A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 In some embodiments, R 1 can be one, two, three, or four R A1 In some embodiments, R 1 can be one, two, three, or four R A1 In some embodiments, R 1 can be one, two, three, or four R A1 wherein each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 In some embodiments, R 1 can be one, two, three, or four R A1 wherein each R A1 independently, halo, C 1~4 Alkyl, or C 1~4 In some embodiments, R 1 can be one, two, three, or four R A1 wherein each R A1 are independently halo or -OC 1~4 In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 halogens. 1 is phenyl substituted with 1, 2, or 3 halogens. 1 is phenyl substituted with 2 or 3 halogens. In some embodiments, R1 is phenyl substituted with two or three halogens selected from chloro and fluoro. 1 teeth, [ka] is.

[0128] In some embodiments of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, R 1 teeth, [ka] In some embodiments of the compounds of Formula I or II, R 1 teeth, [ka] is selected from the group consisting of:

[0129] In some embodiments, the compound has the formula: [ka] [ka] It has.

[0130] In some embodiments, the compound has the formula: [ka] [ka] It has.

[0131] In any embodiment, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0132] In any embodiment, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, or IXb, X, Xa, Xb, XI, XIa, or XIb is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0133] Compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb may be formed by combining rings A, B, and C as depicted below for formula I: [ka] where A represents a bridged ring to ring B, B represents a bridged ring to ring A and a fused ring to ring C, and C represents a fused ring to ring B. As noted above, these compounds may have one or more additional fused or spirocyclic rings.

[0134] Where any variable is an asymmetric group, both orientations of the group are intended to be encompassed unless otherwise specified. For example, W 2 Ga-CR 5a R 5b -N(R 7 )-, then -CR 5a R 5b -N(R 7 )- includes both orientations (i.e., ZW 1 -CR 5a R 5b -N(R 7 )-X and ZW 1 -N(R 7 )-CR 5a R 5b -X is included), and Z is [ka] If [ka] Both orientations of [ka] (both included)

[0135] Any embodiment of a compound of any one of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb above, and any particular group or substituent (e.g., R 1 , R 2 , L, W 1 , W 2, X, Y, Z, and their substituents) can be independently combined with other embodiments and / or substituents of compounds of any one of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb to form embodiments not specifically recited above. Furthermore, in certain embodiments and / or claims, the recitation of substituents may be combined with any particular R 1 , R 2 , L, W 1 , W 2 , X, Y, and Z groups are also not recited, it is understood that each individual substituent may be deleted from that particular embodiment and / or claim and the remaining recitation of that substituent is considered to be within the scope of the embodiments disclosed herein. Pharmaceutical Compositions

[0136] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0137] In some embodiments, these pharmaceutical compositions further contain one, two, three, or four additional therapeutic agents. In certain embodiments, the additional therapeutic agent(s) is an anti-HIV agent. In specific embodiments, the additional therapeutic agent(s) is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversal agent, a capsid polymerization inhibitor, an HIV bNAbs, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, the additional therapeutic agent(s) is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof. Kits and Manufactured Products

[0138] In some embodiments, the present disclosure relates to a kit comprising a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit may comprise one, two, three, or four additional therapeutic agents as previously described herein. The kit may further comprise instructions for use, for example, in inhibiting HIV integrase, for example, for treating HIV infection or AIDS, or for use as a research tool. These instructions are generally written instructions, although electronic storage media (e.g., magnetic or optical disks) containing the instructions are also acceptable.

[0139] In some embodiments, the present disclosure also relates to pharmaceutical kits comprising one or more containers containing a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof. Such container(s) may optionally be associated with a notice in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting approval by that agency for manufacture, use, or sale for human administration. Each component (if more than one component is present) may be packaged in a separate container, or several components may be combined in a single container if cross-reactivity and shelf life permit. These kits may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or subunit doses. Kits may also include multiple unit doses of the compound and instructions for use, and may be packaged in sufficient quantities for storage and use in pharmacies (eg, hospital pharmacies and compounding pharmacies).

[0140] In some embodiments, a unit dosage of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Disclosed herein is an article of manufacture that includes a compound of Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein.Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, and flexible packaging.The article of manufacture may further be sterilized and / or sealed. Treatment method

[0141] In one embodiment, there is provided a method of treating an HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having the infection, comprising administering to the human a therapeutically effective amount of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the methods further comprise administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In certain embodiments, the additional therapeutic agent(s) are anti-HIV agents. In specific embodiments, the additional therapeutic agent(s) are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAbs (broadly neutralizing HIV antibodies), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, the additional therapeutic agent(s) is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof.

[0143] In another embodiment, there is provided the use of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for treating an HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having the infection.

[0144] In another embodiment, there is provided a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for use in medical treatment.

[0145] In another embodiment, there is provided a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0146] In another embodiment, there is provided a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having HIV infection.

[0147] In another embodiment, there is provided a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human one, two, three, or four additional therapeutic agents.

[0148] In another embodiment, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, ... Pharmaceutical compositions of compounds of X, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, are provided, wherein the method further comprises administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversal agent, a capsid polymerization inhibitor, an HIV bNAbs, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, the one, two, three, or four additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, latency reversal agents, HIV capsid inhibitors, HIV bNAbs, TLR7 agonists, and combinations thereof.

[0149] In another embodiment, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIa, VIb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having HIV infection. A pharmaceutical composition of compound Ia, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is provided, wherein the method further includes administering to the human therapeutically effective amounts of tenofovir disoproxil and emtricitabine.

[0150] In another embodiment, there is provided a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human therapeutically effective amounts of tenofovir alafenamide and emtricitabine.

[0151] In another embodiment, there is provided a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil.

[0152] In another embodiment, there is provided a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.

[0153] In another embodiment, methods of using a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb in therapy are provided. Specifically, methods are provided for treating the growth of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering to the mammal a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0154] In another embodiment, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for use in a method of 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). and a composition comprising an excipient acceptable to the subject.

[0155] In one embodiment, there is provided a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for use in the prevention of HIV infection.

[0156] For example, in one embodiment, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is provided for use in pre-exposure prophylaxis (PrEP), i.e., before an individual's exposure to the HIV virus, to prevent HIV infection from becoming established when the individual is exposed to the virus, and / or to keep the virus from establishing a persistent infection and / or to prevent the appearance of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood.

[0157] In another embodiment, disclosed is the use of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating HIV infection in a human having or at risk of having HIV infection.

[0158] In another embodiment, the use of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, as a research tool is disclosed.

[0159] 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. Exemplary compositions contain a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0160] In yet another embodiment, a method of inhibiting HIV replication is disclosed comprising exposing the virus to an effective amount of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a salt thereof, under conditions such that HIV replication is inhibited.

[0161] In another embodiment, the use of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb to inhibit the activity of the HIV integrase enzyme is disclosed.

[0162] In another embodiment, the use of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a salt thereof, to inhibit HIV replication is disclosed. Administration

[0163] For administration purposes, in certain embodiments, the compounds described herein are administered as raw chemicals or formulated as pharmaceutical compositions. Pharmaceutical compositions within the scope of the embodiments disclosed herein contain a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, and a pharmaceutically acceptable excipient. The compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb is present in the composition in an amount effective to treat the specific disease or condition of interest. The activity of compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb can be determined as described in the Examples below.

[0164] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, can be administered in pure form or in a suitable pharmaceutical composition by any of the accepted methods of administering drugs to perform similar functions. Pharmaceutical compositions of the embodiments disclosed herein can be prepared by combining the compounds of the embodiments disclosed herein with suitable pharmaceutically acceptable excipients and formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, capsules, powders, granules, ointments, liquids, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, injectable, sublingual, buccal, rectal, vaginal, and intranasal. The pharmaceutical compositions of the embodiments disclosed herein are formulated so that the active ingredient contained therein is bioavailable when the composition is administered 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 a single dosage unit and a container of an aerosol form of the compound of the embodiments disclosed herein 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 event, the composition to be administered will contain a therapeutically effective amount of the compound of the embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, to treat the disease or condition of interest in accordance with the teachings of the present disclosure.

[0165] In one embodiment, the pharmaceutical composition is an oral dosage unit. In one embodiment, the pharmaceutical composition is a solid oral dosage unit. In one embodiment, the pharmaceutical composition is a tablet.

[0166] In one embodiment, the pharmaceutical composition is a parenteral dosage unit.In one embodiment, the pharmaceutical composition is a subcutaneous, intramuscular, intravenous, intradermal, intrathecal, or epidural dosage unit.In one embodiment, the pharmaceutical composition is a subcutaneous, intramuscular, or intravenous dosage unit.In one embodiment, the pharmaceutical composition is injectable.

[0167] The pharmaceutical compositions disclosed herein can be prepared by methods well known in the pharmaceutical field.For example, pharmaceutical compositions intended to be administered by injection can be prepared by combining the compounds of the embodiments disclosed herein with sterile distilled water to form a solution.Surfactants can be added to facilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that interact non-covalently with the compounds of the embodiments disclosed herein to facilitate the dissolution or homogeneous suspension of the compound in aqueous delivery systems.

[0168] The embodiment compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the particular compound used; the metabolic stability and duration of action of the compound; the patient's age, weight, general health, sex, and diet; the mode and time of administration; the rate of excretion; drug combinations; the severity of the particular disorder or condition; and the treatments the subject is receiving. Combination therapy

[0169] In certain embodiments, a method is provided for treating 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 therapeutically effective amounts of one, two, three, or four additional therapeutic agents. In one embodiment, a method is provided for treating 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 therapeutically effective amounts of one, two, three, or four additional therapeutic agents.

[0170] In one embodiment, a pharmaceutical composition is provided that contains a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0171] In certain embodiments, the present disclosure provides a method of treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents suitable for treating HIV infection.

[0172] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, 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. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents. Administration of HIV combination therapy

[0173] In certain embodiments, the compounds disclosed herein are administered with one, two, three, or four additional therapeutic agents. Co-administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally involves administering a therapeutically effective amount of the compounds disclosed herein and one, two, three, or four additional therapeutic agents. "Sequential administration" refers to the simultaneous or sequential administration of a compound disclosed herein and one, two, three, or four additional therapeutic agents such that both therapeutic agents are present in the patient's body. In the case of sequential administration, the combination may be administered in two or more doses.

[0174] Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one, two, three, or four additional therapeutic agents. For example, a compound disclosed herein may be administered within seconds, minutes, or hours of administration of one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by unit doses of one, two, three, or four additional therapeutic agents. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of time (e.g., 1-12 hours), by unit doses of one, two, three, or four additional therapeutic agents. In yet other embodiments, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed after a period of time (e.g., 1-12 hours) by a unit dose of a compound disclosed herein.

[0175] In certain embodiments, the compounds disclosed herein are combined with one, two, three, or four additional therapeutic agents in a unit dosage form for simultaneous administration to a patient, e.g., as a solid dosage form for oral administration.

[0176] In certain embodiments, kits are provided that contain a compound disclosed herein (e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb), or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, or 4) additional therapeutic agents.

[0177] In certain embodiments, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet may contain another active ingredient for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0178] In certain embodiments, such tablets are suitable for once-daily administration. HIV combination therapy

[0179] In the above embodiments, the additional therapeutic agent(s) may be other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifying agents, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy), latency reversal agents, compounds targeting the HIV capsid, capsid polymerization inhibitors, HIV bNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV The anti-HIV agent may be selected from Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, and any combination thereof.

[0180] In some embodiments, the additional therapeutic agent(s) are selected from the group consisting of HIV combination drugs, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibody and "antibody-like" therapeutic proteins, and combinations thereof. HIV combination drugs

[0181] Examples of concomitant medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine) TDF+FTC; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide, emtricitabine, and cobicistat); BIKTARVY® (bictegravir, tenofovir alafenamide, and emtricitabine); bictegravir, tenofovir disoproxil, and emtricitabine; bictegravir, tenofovir alafenamide, and lamivudine; bictegravir, tenofovir disoproxil, and lamivudine; bictegravir, abacavir, and lamivudine; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine Licitabine; Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobicistat and elvitegravir; COMBIVIR® (Zidovudine and Lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; Abacavir sulfate and Lamivudine; ABC + 3TC); KALETRA® (AL UVIA®; Lopinavir and Ritonavir; TRIUMEQ® (Dolutegravir, Abacavir and Lamivudine); JULUCA® (Dolutegravir, Rilpivirine); TRIZIVIR® (Abacavir Sulfate, Zidovudine and Lamivudine; ABC+AZT+3TC); Dolutegravir and Lamivudine; Dolutegravir and Abacavir; Cabotegravir and Lamivudine; Cabotegravir and Abacavir; Cabotegravir and Rilpivirine; Atazanavir and Cobicistat; Atazanavir Sulfate and Cobicistat; Atazanavir Sulfate and Ritonavir; Darunavir and Cobicistat; Dolutegravir and Rilpivirine; Dolutegravir and Rilpivirine dolutegravir, abacavir sulfate and lamivudine; lamivudine, nevirapine and zidovudine; raltegravir and lamivudine; doravirine, lamivudine and tenofovir disoproxil fumarate; dolutegravir + lamivudine; lamivudine + abacavir + zidovudine; lamivudine + abacavir; lamivudine + tenofovir disoproxil fumarate; lamivudine + zidovudine + nevirapine; lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine; lopinavir + ritonavir + zidovudine + lamivudine; tenofovir + lamivudine and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride. Other HIV drugs

[0182] Examples of other drugs for treating HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, prolastin, REP9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT- 107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576. HIV protease inhibitors

[0183] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911. HIV reverse transcriptase inhibitors

[0184] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and elsulfavirine (VM-1500).

[0185] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide, Fenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fosalvudine tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, rovafovir etalafenamid etalafenamide) (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461. HIV integrase inhibitors

[0186] Examples of HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK- 351, bictegravir, AVX-15567, diketoquinoline-4-one derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and cabotegravir.

[0187] Examples of HIV non-catalytic, or allosteric, integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442. HIV entry inhibitors

[0188] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, gp120 inhibitors and CXCR4 inhibitors.

[0189] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0190] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0191] Examples of CD4 binding inhibitors include ibalizumab and CDA analogs.

[0192] Examples of gp120 inhibitors include Radha-108 (receptor) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0193] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide and vMIP (vMIP). HIV maturation inhibitors

[0194] Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254 and GSK-2838232. Latent Reversal Agent

[0195] Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as Velcade), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (such as largazole analogs), APH-0812, GSK-343, and toll-like receptor modulators.

[0196] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0197] Examples of PKC activators include indolactam, prostratin, ingenol B and DAG-lactone. Capsid inhibitors

[0198] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201, AVI-301 and the AVI-CAN1-15 series. Immune-Based Therapies

[0199] Examples of immune-based therapies include toll-like receptor modulators, such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (PDL-1) modulators; IL-15 modulators; DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxychloroquine; urea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; the polymer polyethyleneimine (PEI); Gepone; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, Normferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, recombinant interleukin-15, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

[0200] Examples of TLR agonists include vesatolimod (GS-9620), lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, and RG-78. 54, and tellatolimod. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0201] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonolicib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, D These include S-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474. Alpha-4 / beta-7 antagonists

[0202] Examples of integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab. HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins

[0203] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAb®, TandAb®, Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bNAbs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and HIV These include those targeting gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, CD3 bispecific antibodies, CD16 bispecific antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, camel-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), ibalizumab, Immuglo, and MB-66.

[0204] Examples of targeting HIV in this manner include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, 10-1074, 10-1074-LS, GS-9722, DH411-2, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, N6LS, N49P6, N49P7, N49P9, N49P11, and VRC01. Examples of HIV bispecific antibodies include VRC-01-LS, PGDM1400, A32, 7B2, 10E8, 10E8VLS, 3810109, 10E8v4, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples of HIV bispecific antibodies include MGD014 and TMB-bispecific.

[0205] Examples of bNAbs delivered in vivo, e.g., AAV8-VRC07; mRNA-encoded anti-HIV antibody VRC01. Pharmacokinetic Enhancers

[0206] Examples of pharmacokinetic enhancers include cobicistat and ritonavir. Additional therapeutic agents

[0207] Examples of additional therapeutic agents include those disclosed in WO2004 / 096286 (Gilead Sciences), WO2006 / 015261 (Gilead Sciences), WO2006 / 110157 (Gilead Sciences), WO2012 / 003497 (Gilead Sciences), WO2012 / 003498 (Gilead Sciences), WO2012 / 145728 (Gilead Sciences), WO2013 / 006738 (Gilead Sciences), WO2013 / 159064 (Gilead Sciences), WO2014 / 100323 (Gilead Sciences), Sciences), US2013 / 0165489 (University of Pennsylvania), US2014 / 0221378 (Japan Tobacco), US2014 / 0221380 (Japan Tobacco), WO2009 / 062285 (Boehringer Ingelheim), WO2010 / 130034 (Boehringer Ingelheim), WO2013 / 006792 (Pharma Resources), US20140221356 (Gilead Sciences), US20100143301 (Gilead Sciences), WO2013 / 091096 (Boehringer Ingelheim), WO2018 / 145021 (Gilead Sciences), and WO2017 / 106346 (Gilead Sciences), each of which is incorporated herein by reference in its entirety. HIV vaccine

[0208] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines (e.g., pseudovirion vaccines), CombiVICHvac, LFn-p24B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-20. 10, gp41 HIV vaccine, HIV vaccine (PIKA adjuvant), Ii-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer-based vaccine, PD-201401, env(A,B,C,A / E) / gag(C) DNA vaccine, gp120(A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV vaccine (GLA-SE adjuvant), HIV p24gag pri, me-boost plasmid DNA vaccine, arenavirus vector-based immunotherapies (Vaxwave, TheraT), MVA-BN HIV vaccine regimen, UBI HIV gp120, mRNA-based prophylactic vaccines, and TBL-1203HI. HIV combination therapy

[0209] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate, TDF+FTC; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir a Alafenamide; Tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; Raltegravir; Raltegravir and lamivudine; Maraviroc; Enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine) azane; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine;Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine mesylate; Radha-108 (Receptor); Lamivudine and tenofovir disoproxil fumarate; Efavirenz, La; It is combined with one, two, three, four or more additional therapeutic agents selected from: mivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0210] Those of skill in the art will recognize that the additional therapeutic agents listed above may fall into more than one of the classes listed above, and a particular class is not intended to limit the functional groups of the compounds listed in that class.

[0211] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In additional embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four HIV bNAbs. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four HIV bNAbs and an HIV capsid inhibitor or HIV capsid polymerization inhibitor.In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four HIV bNAbs, HIV capsid inhibitors, or HIV capsid polymerization inhibitors, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase.

[0212] The compounds disclosed herein (e.g., any compound of Formula I) may be combined with one, two, three, or four additional therapeutic agents at any dosage of the compound of Formula I (e.g., 1 mg to 500 mg of the compound).

[0213] In one embodiment, a kit is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents.

[0214] In one embodiment, the additional therapeutic agent(s) of the kit are other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modifying agents, gene editing agents (CRISPR / Cas9, zincfin nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy), HIV capsid-targeting compounds, latency reversal agents, capsid polymerization inhibitors, HIV bNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV The anti-HIV agent is selected from Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, and any combination thereof.

[0215] In some embodiments, the additional therapeutic agent(s) of the kit are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibody and "antibody-like" therapeutic proteins, and combinations thereof.

[0216] In certain embodiments, the kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, the kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitor compound. In further embodiments, the kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, the kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In certain embodiments, the kits contain , a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAbs. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor or HIV capsid polymerization inhibitor. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, or HIV capsid polymerization inhibitor, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. Combined birth control (contraceptive) therapy

[0217] Therapeutic agents (contraceptives) used for birth control include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combination thereof. Gene Therapy and Cell Therapy

[0218] Gene and cell therapy approaches, including genetic modification to silence genes; genetic approaches to directly kill infected cells, or infusion of immune cells designed to replace large portions of the patient's own immune system and mount an immune response against infected cells, or activate the patient's own immune system to kill infected cells, or to find and kill infected cells; genetic approaches to modify cellular activity to further modify the endogenous immune response to infection.

[0219] An example of a dendritic cell therapy includes AGS-004.

[0220] Examples of CCR5 gene-editing drugs, such as SB-728T

[0221] Examples of CCR5 gene-editing drugs, such as Cal-1

[0222] C34-CCR5 / C34-CXCR4-expressing CD4-positive T cells

[0223] AGT-103 Converting Autologous T Cell Therapy

[0224] AAV-eCD4-Ig gene therapy gene editing agents

[0225] The genome editing system is selected from the group consisting of a CRISPR / Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonuclease system, and a meganuclease system.

[0226] Examples of HIV-targeting CRISPR / Cas9 systems include EBT-101. CAR-T cell therapy

[0227] A population of immune effector cells that have been engineered to express chimeric antigen receptors (CARs) containing HIV antigen-binding domains. HIV antigens include HIV envelope proteins or The immune effector cells include CD4+ T cells, CD8+ T cells, or a combination thereof. The immune effector cells may be T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells may be autologous or allogeneic.

[0228] Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CAR cell therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR, and C46 peptide. TCR-T cell therapy

[0229] TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells. Long-acting HIV therapy

[0230] Examples of drugs being developed as long-acting regimens include cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, MK-8591 implant, doravirine, raltegravir, and long-acting dolutegravir.

[0231] In certain embodiments, when the compounds disclosed herein are combined with one, two, three, or four 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. Route of administration

[0232] A compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof (also referred to herein as the active ingredient) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). Suitable routes can vary, for example, depending on the condition of the recipient. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

[0233] In some embodiments, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered using a syringe suitable for administering the compound. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is provided with a syringe. It is administered using an automatic injector. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof. Medication regimen

[0235] In some embodiments, a compound, e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered to a subject according to an effective dosing regimen for a desired duration, e.g., at least once daily, at least once weekly, at least once monthly, at least once every two months, at least once every three months, at least once every four months, at least once every six months, or at least once every twelve months or longer. In some embodiments, the compound is administered daily or on an intermittent schedule. In some embodiments, the compound is administered on a weekly schedule. In some embodiments, the compound is administered on a monthly schedule. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every 5 months. In some embodiments, the compound is administered every 6 months.

[0236] In some embodiments, a compound, e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered subcutaneously or intramuscularly to a subject at least once a month. In some embodiments, a compound (e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof) is administered subcutaneously or intramuscularly to a subject at least once every two months, or at least once every three months, or at least once every four months, or at least once every six months. In some embodiments, a compound (e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof) is administered subcutaneously to a subject at least once per month. In some embodiments, a compound (e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof) is administered subcutaneously to a subject at least once every two months. In some embodiments, the compound (e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof) is administered subcutaneously to a subject at least once every three months.

[0237] In some embodiments, the dosage or frequency of administration of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, will be adjusted over the course of treatment based on the judgment of the administering physician.

[0238] In some embodiments, compounds disclosed herein (e.g., Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, The compound of formula (IXa, IXb, X, Xa, Xb XI, XIa, or XIb) or a pharmaceutically acceptable salt thereof can be administered in a dosage that is effective. For example, the dosage can be from 1 mg to 1000 mg of the compound.

[0239] In some embodiments, the methods disclosed herein include event-forced administration to a subject of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0240] As used herein, the terms "event-forced" and "event-forced administration" refer to administration of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, (1) before an event (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event) that exposes the individual to HIV (or otherwise increases the individual's risk of acquiring HIV); and / or (2) during an event (or more than one recurrent event) that exposes the individual to HIV (or otherwise increases the individual's risk of acquiring HIV); and / or (3) after an event (or after the final event in a series of recurrent events) that exposes the individual to HIV (or otherwise increases the individual's risk of acquiring HIV). In some embodiments, event-forced administration occurs before the subject's exposure to HIV. In some embodiments, the event-forced administration occurs after the subject's exposure to HIV. In some embodiments, the event-forced administration occurs before the subject's exposure to HIV and after the subject's exposure to HIV.

[0241] In some embodiments, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered prior to the subject's exposure to HIV.

[0242] An example of an event-mandated dosing regimen includes administration of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to HIV exposure (e.g., first sexual activity, including intercourse, with a sexual partner known to be HIV-positive), followed by administration of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to HIV exposure (e.g., first sexual activity, including intercourse, with a sexual partner known to be HIV-positive). every 24 hours during the period of exposure (e.g., sexual activity with a sexual partner known to be HIV positive), followed by a further administration of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, after the last exposure (e.g., sexual activity with a sexual partner known to be HIV positive), and a final administration of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0243] A further example of an event-mandated dosing regimen is administration of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, within 24 hours prior to HIV exposure (e.g., sexual activity with a sexual partner known to be HIV-positive), followed by ... Daily administration during the period of sexual activity with a partner, including the last sexual intercourse, followed by a final administration (which may be an increased dose, such as a double dose) approximately 24 hours after the last exposure.

[0244] In certain embodiments, e.g., when administered as PrEP, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered daily. In certain embodiments, e.g., when administered as event-mandated PrEP, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered 1 hour to 10 days, 1 hour to 7 days, 1 hour to 5 days, 1 to 72 hours, 1 to 48 hours, 1 to 24 hours, or 12 to 12 hours before an event that increases the individual's risk of acquiring HIV (e.g., before sexual intercourse or other exposure to the HIV virus). In some embodiments, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered within 10 days, 7 days, 5 days, 72 hours, 60 hours, 48 ​​hours, 24 hours, 12 hours, 9 hours, 6 hours, 4 hours, 3 hours, 2 hours, or 1 hour before an event that increases the individual's risk of acquiring HIV (e.g., before sexual intercourse or other exposure to the HIV virus). In certain embodiments, when a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered prior to (e.g., administered prior to) an event that increases an individual's risk of acquiring HIV, it is administered daily prior to the event (e.g., sexual activity). In certain embodiments, when a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered prior to an event that increases an individual's risk of acquiring HIV, it is administered one to three times prior to the event.

[0245] In some embodiments, for example, when administered as part of an event-mandated PrEP regimen, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered during the time of HIV exposure. In certain embodiments in which a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb is administered to an exposed individual, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., as a single dose) for the duration of HIV exposure (e.g., the duration of sexual activity with a sexual partner known to be HIV positive). In some embodiments, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., for 1 to 7 days) after the last exposure to HIV (e.g., after a period of sexual activity with a sexual partner known to be HIV-positive). In some embodiments, this administration continues for 1 or 2 days after the last exposure to HIV.

[0246] Further examples of PrEP and / or PEP are described, for example, in the publication entitled "On Demand Antiretroviral Pre-exposure Prophylaxis" for HIV Infection in Men Who Have Sex With Men" (Clinical Trial # NCT01473472); Abstract of a Clinical Trial entitled "Prevention of HIV in Ile-de-France" (Clinical Trials # NCT03113123), and Molina, et al. N. Engl. J. Med. 2015, 353:2237-2246, the disclosures of each of which are incorporated herein by reference in their entirety.

[0247] In some embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) comprises administering a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, in combination with safer sex practices. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) comprises administering to a subject at risk of acquiring HIV. Examples of individuals at high risk of acquiring HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

[0248] In some embodiments, the reduction in risk of acquiring HIV is at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the reduction in risk of acquiring HIV is at least about 75%. In some embodiments, the reduction in risk of acquiring HIV is about 80%, 85%, or 90%. formulation

[0249] The preparation suitable for parenteral administration includes aqueous and non-aqueous sterile injection solution, which may contain antioxidant, buffer, bacteriostatic agent, and solute that makes the preparation isotonic with the blood of intended recipient; and aqueous and non-aqueous sterile suspension that contains suspending agent and thickening agent.In certain embodiments, this suspension is microsuspension.In certain embodiments, this suspension is nanosuspension.

[0250] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) may contain one or more excipients. The excipient should be compatible with the other ingredients of the formulation and physiologically harmless to the recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (editors Rowe, Sheskey & Quinn), 6th edition 2009.

[0251] In certain embodiments, the active ingredient (e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb XI, XIa, or XIb) is present as the free acid.

[0252] In certain embodiments, the pharmaceutical compositions disclosed herein are parenteral formulations. In certain embodiments, the formulations are administered subcutaneously to a subject in need thereof. In certain embodiments, the formulations are administered intramuscularly to a subject in need thereof.

[0253] The amount of active ingredient that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended treatment subject and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain approximately 1 to 1000 mg of active ingredient, formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material varies from about 5% to about 95% (weight:weight) of the total composition.

[0254] It should be understood that in addition to the ingredients specifically described above, the compositions of these embodiments may contain other agents conventional in the art relating to the type of composition in question; for example, those suitable for oral administration may include flavoring agents. Abbreviation

[0255] Abbreviations used herein have the following representative meanings: [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7] The following examples are offered by way of illustration and not by way of limitation. [Example]

[0256] Example 1: Preparation of (S)- and (R)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (1-1, 1-2): [ka] Synthesis of tert-butyl 3-methylene-1,5-oxazocane-5-carboxylate (1a): A solution of tert-butyl N-(3-hydroxypropyl)carbamate (1005.4 mg, 5.74 mmol) in DMF (20 mL) was stirred in an ice-salt bath while 60% sodium hydride in mineral oil (approximately 526 mg, 13.2 mmol) was added portionwise. After stirring in the cold bath for approximately 30 minutes, 3-chloro-2-(chloromethyl)prop-1-ene (0.61 mL, 5.80 mmol) was added over 15 minutes using a syringe drive. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the slow addition of ice water and diluted with water (approximately 100 mL). The product was then extracted with ethyl acetate (2 × approximately 100 mL). After washing the organic extract with water (approximately 100-150 mL × 1), the organic fractions were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 to approximately 70% ethyl acetate in hexane to give the title compound. MS (m / z) 171.74 [M+H-C4H8] + . Synthesis of tert-butyl 3-oxo-1,5-oxazocane-5-carboxylate (1b):

[0257] tert-Butyl 3-methylene-1,5-oxazocane-5-carboxylate (1a, 339 mg, 1.49 mmol) in methanol (10 mL) was stirred in a -78°C bath while ozone was bubbled through the mixture until a blue color appeared. When the blue ozone color appeared, dimethyl sulfide (5 mL) was added, and the resulting solution was stirred at room temperature for 2 hours. The solution was concentrated, and the residue was purified by column chromatography on silica gel eluting with 0-100% ethyl acetate in hexane to give the title compound. MS (m / z) 251.96 [M+Na] + . Synthesis of tert-butyl 3-((tert-butylsulfinyl)amino)-1,5-oxazocane-5-carboxylate (1c):

[0258] A solution of 1b (315 mg, 1.38 mmol), rac-2-methylpropane-2-sulfinamide (170.3 mg, 1.41 mmol), and titanium(IV) ethoxide (0.59 mL, 2.81 mmol) in THF (5.5 mL) was refluxed in a 70° C. bath for 1 h. The reaction mixture was cooled to room temperature and further cooled to approximately −50° C., after which 1 M L-Selectride in THF (5.5 mL) was added. After 30 min, the reaction mixture was allowed to warm slowly to room temperature over 2 h. The reaction mixture was cooled again to 0° C., and methanol was added until gas evolution ceased. Brine was added to the solution with vigorous stirring, the resulting mixture was filtered through Celite®, and the solid was washed with ethyl acetate. After the filtrate was extracted with ethyl acetate (three times), the combined organic fractions were washed with brine (once), combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 50-100% ethyl acetate in hexanes, followed by 0-20% methanol in ethyl acetate to give the title compound. MS (m / z) 334.94 [M+H] + . Synthesis of methyl 13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxylate (1d):

[0259] A solution of 1c (274 mg, 0.82 mmol) in dichloromethane (2 mL) was stirred at room temperature while 4 N HCl in dioxane (4 mL) was added. After 1 h, the resulting suspension was concentrated and dried overnight. To a flask containing the residue was added dimethyl 3-methoxy-4-oxo-4H-pyran-2,5-dicarboxylate (242.5 mg, 1.00 mmol) and sodium bicarbonate (278.4 mg, 3.31 mmol) in water (1 mL) and methanol (3 mL), and the resulting mixture was stirred at room temperature for 24 h and in a 40° C. bath.

[0260] The reaction mixture was cooled to room temperature, concentrated, and the residue was dissolved in aqueous DMF, filtered, and purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm) eluting with 10–60% acetonitrile (0.1% TFA) in water (0.1% TFA) for 20 min. The combined fractions were freeze-dried to give the title compound. MS (m / z) 323.16 [M+H] + . Synthesis of N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (1e):

[0261] To a solution of methyl 13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxylate (1d, 30.8 mg, 95.6 μmol) in methanol (0.5 mL) was added 1N lithium hydroxide (0.2 mL) at room temperature and stirred for 1 h. After acidifying the reaction mixture with 1N HCl (approximately 0.2 mL), the resulting solution was concentrated to dryness and coevaporated with toluene (3 times). To the residue was added (2,4-difluorophenyl)methanamine (26.1 mg, 182 μmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 62.2 mg, 163.5 μmol), and DMF (1 mL) and stirred with N,N-diisopropylethylamine (0.1 mL, 574.1 μmol) at room temperature. After 1 h, the reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (twice), saturated sodium bicarbonate solution (twice), and brine (once). After the aqueous fraction was extracted with ethyl acetate (×1), the two organic fractions were combined, dried over MgSO4, filtered, and concentrated. The residue was dissolved in DMF, filtered, and purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm) eluting with 10–60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were freeze-dried to give the title compound. MS (m / z) 434.22 [M+H] + . Synthesis of (rac), (S)- and (R)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (1,1-1,1-2):

[0262] To a solution of N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (1e, 13.7 mg, 31.6 μmol) in acetonitrile (1 mL) was added magnesium bromide (16.2 mg, 88.5 μmol) at room temperature, and the resulting mixture was stirred in a 50° C. bath. After 1 h, the reaction mixture was concentrated, and the residue was triturated with 2 N HCl (approximately 0.5 mL) and water (approximately 1.5 mL) at 0° C. After sonication, the suspension was diluted with DMF (3 mL) to give a solution, which was then filtered. The filtered solid was purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm) eluting with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were freeze-dried to give the title compound. MS (m / z) 420.23 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.31 (s, 1H), 8.40 (s, 1H), 7.40 (td, J = 8.8, 6.4 Hz, 1H), 6.93 (ddq, J = 10.8, 5.8, 2.8 Hz, 2H), 4.57 (d, J = 5.2 Hz, 2H), 4.43 - 4.26 (m, 2H), 4.07 (d,J = 33.0 Hz, 4H), 3.95 (dd, J = 14.9, 1.7 Hz, 1H), 3.75 (s, 1H), 3.13(ddd, J = 13.9, 7.5, 4.6 Hz, 1H), 2.06- 1.96 (m, 1H), 1.86 (s, 1H). 19 FNMR (376 MHz, acetonitrile-d3) δ -114.07 (p, J = 7.6 Hz), -116.55 (q, J = 8.7 Hz).

[0263] N-(2,4-Difluorobenzyl)-13-hydroxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (1, 15 mg) was separated into its individual enantiomers by preparative SFC chromatography on an AZ-H column using ethanol-TFA cosolvent to give 1-1 and 1-2. Example 2: Preparation of 13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (2): [ka] Synthesis of 13-methoxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (2a):

[0264] To a solution of methyl 13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxylate (1d, 32.7 mg, 101.5 μmol) in methanol (0.5 mL) was added 1N lithium hydroxide (0.2 mL) at room temperature and stirred for 1 hour. After acidifying the reaction mixture with 1N HCl (approximately 0.2 mL), the resulting solution was concentrated to dryness and coevaporated with toluene (3 times). To the residue was added (2,4,6-trifluorophenyl)methanamine (30.8 mg, 191.15 μmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 57.9 mg, 152.2 μmol), and DMF (1 mL) and stirred with N,N-diisopropylethylamine (0.1 mL, 574.1 μmol) at room temperature. After 1 hour, the reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (twice), saturated sodium bicarbonate solution (twice), and brine (once). After extracting the aqueous fraction with ethyl acetate (once), the two organic fractions were combined, dried over MgSO4, filtered, and concentrated. The residue was dissolved in DMF, filtered, and purified twice by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm) eluting with 10–60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were freeze-dried to give the title compound. The compound was obtained. MS (m / z) 452.23 [M+H] + . Synthesis of 13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (2):

[0265] To a solution of 13-methoxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide (2a, 9.3 mg, 20.6 μmol) in acetonitrile (1 mL) was added magnesium bromide (16.2 mg, 88.0 μmol) at room temperature, and the resulting mixture was stirred in a 50° C. bath. After 30 minutes, the reaction mixture was cooled and filtered, and the residue was dissolved in DMF (0.5 mL) and 2 N HCl (0.1 mL). After filtering the solution, the filtrate was purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm) eluting with 10–60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were freeze-dried to give the title compound. MS (m / z) 420.23 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.31 (s, 1H), 8.40 (s, 1H), 7.40 (td, J = 8.8, 6.4 Hz, 1H), 6.93 (ddq, J = 10.8, 5.8, 2.8 Hz, 2H), 4.57 (d, J = 5.2 Hz, 2H), 4.43 - 4.26 (m, 2H), 4.07 (d, J=33.0 Hz, 4H), 3.95 (dd, J = 14.9, 1.7 Hz, 1H), 3.75 (s, 1H), 3.13 (ddd, J=13.9, 7.5, 4.6 Hz, 1H), 2.06 - 1.96 (m, 1H), 1.86 (s, 1H). 19 F NMR (376 MHz, acetonitrile-d3) δ -114.07 (p, J = 7.6 Hz), -116.55 (q, J = 8.7 Hz). Example 3: Preparation of (R)- and (S)-(7R)-4,4-difluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (3-1, 3-2): [ka] Synthesis of 1-benzyl-5,5-difluoropiperidine-2-carboxylate (3b):

[0266] A solution of 1-tert-butoxycarbonyl-5,5-difluoro-piperidine-2-carboxylic acid (3a, 1.999 g, 7.54 mmol) was dissolved in methanol at 0 °C, and 2 M (trimethylsilyl)diazomethane in diethyl ether (approximately 10 mL) was added until a yellow color persisted. After 15 min, dilute acetic acid was added to the reaction mixture until the yellow color disappeared, and the mixture was concentrated. The resulting residue was purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to give 1-(tert-butyl)2-methyl 5,5-difluoropiperidine-1,2-dicarboxylate. I got the ru.

[0267] A solution of 1-(tert-butyl)2-methyl 5,5-difluoropiperidine-1,2-dicarboxylate (1.94 g, 6.93 mmol) was dissolved in dichloromethane (15 mL) and 4N HCl in dioxane (15 mL) and stirred at room temperature. After 3 hours, the solution was concentrated, and the residue was dissolved in saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate (twice). The organic extracts were washed with brine (once), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexane to give methyl 5,5-difluoropiperidine-2-carboxylate.

[0268] A solution of methyl 5,5-difluoropiperidine-2-carboxylate (962 mg, 5.37 mmol) in DMF (15 mL) was stirred at 0° C. while 60% sodium hydride in mineral oil (305 mg, 7.63 mmol) was added portionwise. After 30 minutes at 0° C., benzyl bromide (0.96 mL, 8.1 mmol) was added. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour, after which additional 60% sodium hydride in mineral oil (150 mg, 3.75 mmol) and benzyl bromide (0.5 mL, 4.20 mmol) were added at room temperature and stirred for 2.5 hours at room temperature. The reaction mixture was quenched with 2N HCl (approximately 4 mL) at 0° C. and diluted with saturated sodium bicarbonate solution (approximately 100 mL). The product was then extracted with ethyl acetate (approximately 100 mL × 2). The organic extracts were washed with water (150 mL x 1), combined, dried over MgSO, filtered, concentrated, and purified by column chromatography on silica gel eluting with 0-100% ethyl acetate in hexane to give the title compound. MS (m / z) 270.10 [M+H] + . Synthesis of 6-azido-1-benzyl-3,3-difluoroazepane (3c):

[0269] A solution of methyl 1-benzyl-5,5-difluoro-piperidine-2-carboxylate (1011 mg, 3.76 mmol) in THF (10 mL) was stirred at 0 °C while 1 M LiAlH (5 mL, 5 mmol) was added. After 30 min at 0 °C, the reaction mixture was vigorously stirred at 0 °C, quenched by the dropwise addition of water (0.19 mL), 15% NaOH (0.19 mL), and water (0.57 mL) in that order, and diluted with ethyl ether (ca. 15 mL). After vigorously stirring the resulting suspension at 0 °C for 30 min, the mixture was filtered through Celite®, and the filtrate was treated with MgSO and filtered again. The filtrate was concentrated to give (1-benzyl-5,5-difluoropiperidin-2-yl)methanol. MS (m / z) 242.10 [M+H] + .

[0270] (1-Benzyl-5,5-difluoro-2-piperidyl)methanol (606.6 mg, 2.51 mmol) was dissolved in toluene (10 mL) and thionyl chloride (3 mL, 41.1 mmol) was added. The resulting mixture was stirred at 60° C. After 1.25 h, the reaction mixture was concentrated, and the residue was dissolved in saturated sodium bicarbonate solution (approximately 20 mL) and ethyl acetate (approximately 25 mL). After separation of the two fractions, the aqueous fraction was extracted with ethyl acetate (approximately 25 mL × 1). The organic fractions were washed with brine (approximately 20 mL × 1), combined, dried over MgSO4, filtered, and concentrated to give crude 1-benzyl-2-(chloromethyl)-5,5-difluoropiperidine. MS (m / z) 260.10 [M+H] + .

[0271] The crude chloride and sodium azide (187 mg, 2.88 mmol) in DMSO (4 mL) were stirred in a 90° C. bath for 4 hours and cooled to room temperature. The reaction mixture was diluted with water (approximately 50 mL) and saturated sodium bicarbonate solution (approximately 5 mL), and the product was extracted with ethyl acetate (approximately 30 mL×3). The extracts were washed with water (approximately 50 mL×1), combined, dried (NaSO), and concentrated. The residue was dissolved in hexane and concentrated. Purification using column chromatography on silica gel eluting with 0-10% ethyl acetate in water afforded the title compound. MS (m / z) 267.06 [M+H] + . Synthesis of 12-(benzyloxy)-4,4-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (3d):

[0272] A suspension of 6-azido-1-benzyl-3,3-difluoroazepane (323 mg, 1.21 mmol) and 20% palladium hydroxide on carbon (49 mg) in methanol (10 mL) and concentrated HCl (0.5 mL) was stirred under an H atmosphere for 3 hours. The reaction mixture was filtered through Celite® and washed with methanol. The filtrate and washings were combined and completely concentrated to give crude 6,6-difluoroazepan-3-amine dihydrochloride.

[0273] Crude 6,6-difluoroazepan-3-amine dihydrochloride (119.9 mg, 0.54 mmol), methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (280.8 mg, 0.63 mmol), and sodium bicarbonate (238.7 mg, 2.84 mmol) were dissolved in methanol (5 mL) and water (1 mL), and the resulting solution was stirred in a 55° C. bath for 20 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and water. After separation of the two fractions, the aqueous fraction was extracted with ethyl acetate (1×), and the two organic fractions were washed with water (1×), combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-5% methanol in dichloromethane to give the partially purified product.

[0274] The partially purified product was dissolved in DMF, filtered, and purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm) eluting with 30–90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min, and the collected fractions were freeze-dried to give the title compound. MS (m / z) 548.14 [M+H] + . Synthesis of (R)- and (S)-(7R)-4,4-difluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (3-1.3-2)

[0275] 12-(Benzyloxy)-4,4-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (3d, 140.7 mg) was separated into its enantiomers by preparative SFC chromatography on an IA column using methanol as a cosolvent to give 47.4 mg of 3d-1 and 46.9 mg of 3d-2. The separated enantiomers were dissolved in toluene (0.5 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 30 minutes. Each reaction was concentrated, and the residue was purified using column chromatography on silica gel eluting with 0-14% methanol in dichloromethane to give the respective title compounds. MS (m / z) 458.16 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3)δ12.34 (s, 1H), 10.38 (s, 1H), 8.27 (s, 1H), 7.02 - 6.66 (m, 2H), 5.45 (s,2H),4.70 (ddt, J = 14.4, 11.6, 2.8 Hz, 1H), 4.59 (d, J = 5.8 Hz, 1H), 4.37(dd, J =13.5, 4.2 Hz, 1H), 4.04 (dd, J = 13.6, 8.2 Hz, 1H), 3.89 (ddt, J =11.8, 7.8, 3.7 Hz, 1H), 3.19 (ddd, J =31.8, 14.2, 1.9 Hz, 1H), 2.42 - 2.22 (m,1H), 2.22 - 2.06 (m, 1H), 2.06 - 1.98 (m, 1H), 1.80 - 1.62 (m, 1H). Example 4: Preparation of (R)- and (S)-(7R)-N-(2,4-difluorobenzyl)-4,4-difluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (4-1, 4-2): [ka] Synthesis of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (4a):

[0276] Crude 6,6-difluoroazepan-3-amine dihydrochloride (116.7 mg, 0.52 mmol), methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (273.2 mg, 0.64 mmol), and sodium bicarbonate (225.7 mg, 2.69 mmol) were dissolved in methanol (5 mL) and water (1 mL), and the resulting solution was stirred in a 55° C. bath for 20 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and water. After separation of the two fractions, the aqueous fraction was extracted with ethyl acetate (1×), and the two organic fractions were washed with water (1×), combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-5% methanol in dichloromethane to give the partially purified product.

[0277] The partially purified product was dissolved in DMF, filtered, and purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm) eluting with 30–90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min, and the collected fractions were freeze-dried to give the title compound. MS (m / z) 530.12 [M+H]+ . Synthesis of (R)- and (S)-(7R)-N-(2,4-difluorobenzyl)-4,4-difluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (4-1, 4-2):

[0278] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (4a, 133 4a-1 and 4a-2 were separated into their individual enantiomers by preparative SFC chromatography on an IA column using a methanol co-solvent to give 4a-1 and 4a-2. The separated enantiomers were dissolved in toluene (0.5 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 30 minutes. Each reaction was concentrated, and the residue was purified using column chromatography on silica gel eluting with 0-14% methanol in dichloromethane to give the title compound. MS (m / z) 440.19 [M+H] + . 1 H NMR (400 MHz, Setonitrile-d3) δ 12.36 (s, 1H), 10.40 (s, 1H), 8.28 (s, 1H), 7.47 -7.31(m, 1H), 6.94 (ddq, J = 11.0, 5.2, 2.8 Hz, 2H), 4.71 (tt, J = 11.7, 2.8Hz,1H), 4.57 (d, J = 6.0 Hz, 2H), 4.38 (dd, J = 13.5, 4.2 Hz, 1H), 4.06 (dd, J=13.6, 8.1 Hz, 1H), 3.90 (td, J = 8.2, 4.2 Hz, 1H), 3.20 (ddd, J = 31.8, 14.2,1.9 Hz, 1H), 2.38 - 2.22 (m, 1H), 2.19 - 2.08 (m, 1H), 2.07 - 1.98 (m, 1H), 1.80 - 1.63(m,1H). Example 5: Preparation of (R)- and (S)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxamide (5-1, 5-2): [ka] Synthesis of methyl 13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxylate (5a):

[0279] A vial was charged with azocan-3-amine (0.13 g, 1.0 mmol), sodium bicarbonate (66 mg, 0.79 mmol), methanol (3 mL), and water (0.3 mL). 3-Methoxy-4-oxo-4H-pyran-2,5-dicarboxylate dimethyl (100 mg, 0.41 mmol) was added, and the mixture was stirred at 30° C. After 2 hours, the mixture was concentrated to dryness and purified by flash column chromatography (hexane / EtOAc / MeOH) to give the title compound. MS (m / z) 321.1 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 8.07 (s, 1H), 4.43 (ddd, J = 13.6, 8.8, 4.4 Hz, 1H), 4.18 (ddt, J = 7.9, 5.3, 2.2 Hz, 1H), 4.05 (s, 3H), 3.94 (dd, J=14.4, 2.7 Hz, 1H), 3.85 (s, 3H), 3.65 (dd, J = 14.5, 2.1 Hz, 1H), 2.86 (ddd,J= 14.0, 6.2, 4.2 Hz, 1H), 2.16 (ddd, J = 15.1, 8.7, 5.4 Hz, 1H), 2.00 - 1.56(m,6H), 1.57 - 1.45 (m, 1H). Synthesis of N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxamide (5b):

[0280] 13-Methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydroxybenzoate Methyl dro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxylate (80 mg, 0.25 mmol) was dissolved in methanol (3 mL) and 1 M NaOH (0.75 mL, 0.75 mmol) was added. After 25 min, the reaction was quenched by the addition of 2 M HCl and concentrated to dryness. The residue was dissolved in DCM (2 mL) containing (2,4-difluorophenyl)methanamine (54 mg, 0.37 mmol) and triethylamine (0.10 mL, 0.75 mmol). HATU (114 mg, 0.30 mmol) was added, and the mixture was stirred at room temperature. After 15 min, the reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water (with 0.1% TFA)), and lyophilized to give the title compound. MS (m / z) 432.2 [M+H] + . Synthesis of (8R)- and (8S)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxamide (5-1, 5-2):

[0281] N-(2,4-Difluorobenzyl)-13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxamide (43 mg) was separated into its individual enantiomers by preparative SFC chromatography on an IB column using MeOH co-solvent to give 5c-1 and 5c-2. The separated enantiomers were dissolved in DMF (0.5 mL) containing lithium chloride (84 mg, 2.0 mmol) and stirred at 100 °C for 1 h. Each reaction was cooled to room temperature, diluted with aqueous TFA, purified by preparative HPLC (MeCN / water (containing 0.1% TFA)), and lyophilized to give the title compound. MS (m / z) 418.2 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.47(s, 1H),8.37 (s, 1H), 7.43 (td, J = 9.3, 8.8, 6.5 Hz, 1H), 7.10 - 6.83 (m,2H), 4.60 (d,J = 5.8 Hz, 2H), 4.48 (tt, J = 6.1, 2.5 Hz, 1H), 4.25 (ddd, J =13.6, 8.3, 2.30 - 2.17 (m, 1H), 1.94 - 1.70(m,3H), 1.62 - 1.47 (m, 4H). Example 6: Preparation of (7R,13R)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (7): [ka] Synthesis of (R)-3-(dibenzylamino)azepan-2-one (7a):

[0282] (3R)-3-aminoazepan-2-one (1.51 g, 11.8 mmol) was combined with benzaldehyde (3.61 mL, 35 mmol) and molecular sieves (4 g) in 1,2-DCE at 15° C. Sodium triacetoxyborohydride (7.49 g, 35.3 mmol) was added. After stirring for 90 minutes, the mixture was quenched with aqueous sodium bicarbonate and filtered. The organic layer was separated, dried over NaSO, filtered, concentrated, and purified by flash column chromatography (hexane / EtOAc) to give the title compound. MS (m / z) 309.4 [M+H] + . 1 H NMR (400 MHz, Roform-d) δ 7.41 (d,J = 7.2 Hz, 4H), 7.37 - 7.30 (m, 4H), 7.27 - 7.19 (m, 2H),5.64 (s, 1H), 4.09(d, J = 14.4 Hz, 2H), 3.91 (d, J = 14.4 Hz, 2H), 3.44 (d, J =10.1 Hz, 1H),3.12 (dt, J = 14.0, 6.7 Hz, 1H), 2.92 (ddd, J = 15.3, 10.8, 5.4Hz, 1H), 2.01(d, J = 11.4 Hz, 2H), 1.96 - 1.65 (m, 2H), 1.53 - 1.32 (m, 2H). Synthesis of (2R,3R)-N,N-dibenzyl-2-methylazepan-3-amine (7b):

[0283] (3R)-3-(Dibenzylamino)azepan-2-one (7a, 637 mg, 2.07 mmol) was suspended in toluene (20 mL) containing triethylamine (0.57 mL, 4.1 mmol) at 0°C. Chlorotrimethylsilane (0.29 mL, 2.3 mmol) in toluene (3 mL) was added dropwise. After 5 min, the mixture was warmed to 50°C and stirred for 3 h. The slurry was cooled to 5°C, and the precipitate was removed by filtration, rinsing with 1:1 hexane:ether. The supernatant was concentrated to dryness and placed under high vacuum overnight. The residue was dissolved in ether (30 mL), cooled to -78°C, and 1.6 M MeLi (2.84 mL) was slowly added. The reaction was allowed to warm to room temperature, and an additional 1 mL of 1.6 M MeLi was added. After 3 hours, the reaction was cooled to 5°C, quenched with aqueous ammonium chloride, and diluted with aqueous sodium bicarbonate and ethyl acetate. The organic layer was removed, dried over Na2SO4, filtered, and concentrated. The crude mixture was dissolved in DCM (50 mL) containing 5 g of 3 Å molecular sieves at 5°C. After stirring for 5 minutes, sodium triacetoxyborohydride (0.88 g, 4.1 mmol) was added, and the reaction was stirred overnight, slowly warming to room temperature. The reaction was quenched with aqueous sodium bicarbonate and filtered. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography (hexane / EtOAc) to give the title compound. MS (m / z) 309.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.48 (d,J = 7.2 Hz, 4H), 7.33 (dd, J = 8.3, 6.8 Hz, 4H), 7.24 (t, J = 7.2 Hz, 2H), 4.15(d, J = 14.3 Hz, 2H), 3.53 (d, J = 14.3 Hz, 2H), 3.19 - 3.01 (m, 1H),2.96 -2.79 (m, 1H), 2.69 (dt, J = 10.4, 6.1 Hz, 1H), 2.45 (td, J = 12.3, 3.1Hz, 1H),2.13 - 2.00 (m, 1H), 1.94 - 1.68 (m, 3H), 1.58 - 1.38 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 1.26 - 1.11 (m, 1H). Synthesis of (7R,13R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (7c):

[0284] (2R,3R)-N,N-Dibenzyl-2-methyl-azepan-3-amine (7b, 90 mg, 290 μmol) was combined with Pd / C (10 wt%, wet, E101 NE / W, 155 mg) in ethanol (20 mL) and stirred under an atmosphere of hydrogen gas for 120 h. The mixture was degassed with argon, filtered through Celite®, and 2 M HCl (2 mL) was added. The solution was concentrated to dryness to give (2R,3R)-2-methylazepan-3-amine as its hydrochloride salt. MS (m / z) 129.2 [M+H] + .

[0285] (2R,3R)-2-Methylazepan-3-amine dihydrochloride (58 mg, 0.29 mmol) was dissolved in methanol (3 mL) and water (0.5 mL) containing sodium bicarbonate (151 mg, 1.79 mmol). 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (110 mg, 0.26 mmol) was added, and the mixture was stirred at 65° C. for 4 hours. The mixture was cooled to room temperature, concentrated, dissolved in DCM, filtered, concentrated, purified by preparative HPLC (MeCN / water (with 0.1% TFA)), and lyophilized to give the title compound. MS (m / z) 508.6 [M+H] + . Synthesis of (1R,14R)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-14-methyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (7):

[0286] (7R,13R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (66 mg, 0.13 mmol) was dissolved in toluene (1 mL) containing TFA (2 mL). After 135 min, the reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water (containing 0.1% TFA)), and lyophilized to give the title compound. Chiral HPLC analysis revealed this to be a mixture of enantiomers. MS (m / z) 418.4 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.43(s, 1H), 8.43 (s, 1H), 7.44 (td, J = 9.3, 8.8, 6.5 Hz, 1H), 7.21 - 6.78 (m, 2H), 4.60 (d, J = 5.9Hz,2H), 4.44 (dt, J = 5.2, 2.2 Hz, 1H), 4.26 (ddd, J = 13.3, 8.9, 7.5 Hz, 1H), 3.86 (qd, J = 6.9, 1.7 Hz, 1H), 3.21 (ddd, J = 13.3, 7.4, 2.9 Hz, 1H), 2.13 -1.99(m, 1H), 1.89 - 1.60 (m, 1H), 1.28 (d, J = 15.2 Hz, 1H), 1.22 (d, J = 6.9 Hz,3H). Example 7: Preparation of (7S,13S)-12-hydroxy-13-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (8) [ka]

[0287] (7S,13S)-12-hydroxy-13-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (8) was reacted with (7R,13R)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (8). Pyrido[1,2-a][1,4]diazonine-10-carboxamide (7) was prepared similarly starting with (S)-3-aminoazepan-2-one and utilizing methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate instead of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate. HPLC analysis indicated a mixture of enantiomers. MS (m / z) 436.2 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.40(s, 1H), 8.43 (s, 1H), 6.98 - 6.79 (m, 2H), 4.62 (d, J = 5.5 Hz, 2H), 4.52 - 4.37 (m, 1H), 4.24 (ddd,J = 13.3, 8.9, 7.5 Hz, 1H), 3.86 (qd, J =6.9, 1.7 Hz, 1H), 3.20 (ddd, J =13.4, 7.4, 2.9 Hz, 1H), 2.06 - 2.00 (m, 1H), 1.88 - 1.66 (m, 2H), 1.34 - 1.13 (m, 4H) . Example 8: Preparation of (7R,13S)—N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (9) [ka] Synthesis of (R)-tert-butyl 3-(dibenzylamino)-2-methyleneazepane-1-carboxylate (9a):

[0288] (3R)-3-(Dibenzylamino)azepan-2-one (7a, 735 mg, 2.38 mmol) was combined with triethylamine (0.66 mL, 4.77 mmol), 4-(dimethylamino)pyridine (87 mg, 0.71 mmol), and BocO (780 mg, 3.6 mmol) in 1,2-DCE. The mixture was stirred at 35°C for 3 days. Additional 4-(dimethylamino)pyridine (291 mg, 2.38 mmol) and BocO (630 mg, 2.9 mmol) were added, and the mixture was stirred at 60°C for 4.5 hours. The mixture was cooled to 45°C, and additional BocO (1040 mg, 4.77 mmol) was added. The reaction was stirred overnight, cooled to room temperature, and quenched with aqueous ammonium chloride. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography (hexane / EtOAc) to give (R)-tert-butyl 3-(dibenzylamino)-2-oxoazepane-1-carboxylate. MS (m / z) 409.5 [M+H] + . 1 H NMR (400 MHz, chloroform) Lum-d) δ 7.37 (d,J = 7.2 Hz, 4H), 7.30 (t, J = 7.4 Hz, 4H), 7.22 (t, J = 7.2 Hz,2H), 4.12 - 4.07(m, 1H), 4.05 (d, J = 14.5 Hz, 2H), 3.87 (d, J = 14.3 Hz, 2H),3.63 - 3.47 (m,1H), 2.83 (dd, J = 15.4, 10.4 Hz, 1H), 2.03 - 1.68 (m, 3H), 1.55(d, J = 0.8Hz, 9H), 1.53 - 1.38 (m, 2H).

[0289] (3R)-tert-Butyl 3-(dibenzylamino)-2-oxoazepane-1-carboxylate (463 mg, 1.13 mmol) was placed in a round-bottom flask under argon, and a solution of dimethyltitanocene (5% in toluene / THF, 16 mL) was added. The mixture was stirred at 80 °C for 75 min, cooled to 15 °C, and quenched with aqueous sodium bicarbonate. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography (hexane / EtOAc) to give the title compound. The product was obtained. MS (m / z) 407.5 [M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 7.41 (d, J = 7.2 Hz, 4H), 7.37 - 7.29 (m, 4H), 7.27 -7.19 (m, 2H), 5.82 (d, J = 2.0 Hz, 1H), 5.17 (s, 1H), 3.97 (d, J = 14.0 Hz,2H), 3.79 (dt, J = 14.1, 4.4 Hz, 1H), 3.47(d, J = 14.0 Hz, 2H), 3.35 (dt, J =9.9, 2.4 Hz, 1H), 2.85 (s, 1H), 1.95 (q, J = 16.1, 12.0 Hz, 2H), 1.69 - 1.58 (m, 1H), 1.55 - 1.47 (m, 1H), 1.38 (s,9H),1.25 - 1.16 (m, 1H). Synthesis of (3R)-tert-butyl 3-(benzylamino)-2-methyl-azepane-1-carboxylate (9b):

[0290] (3R)-tert-Butyl 3-(dibenzylamino)-2-methylene-azepane-1-carboxylate (9a, 256 mg, 0.63 mmol) was combined with tert-butyl hydroperoxide (5-6 M in decane, 214 μL) and phenylsilane (78 μL, 0.63 mmol) in isopropanol (3 mL) under argon. Tris(dipivaloylmethanato)manganese (34 mg, 0.056 mmol) was added, and the reaction was stirred at room temperature. After 1 h, additional tris(dipivaloylmethanato)manganese (11 mg, 0.019 mmol) was added, and stirring was continued. After an additional 30 min, the reaction was concentrated and purified by flash column chromatography (hexane / EtOAc) to give the title compound as a mixture of diastereomers. MS (m / z) 319.3 [M+H] + . Synthesis of (7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (9c):

[0291] (3R)-tert-butyl 3-(benzylamino)-2-methyl-azepane-1-carboxylate (138 mg, 433 μmol) was combined with Pd / C (10 wt%, wet, E101 NE / W, 138 mg) in ethanol (10 mL) under an atmosphere of hydrogen gas and stirred vigorously overnight. The reaction was filtered through Celite® and concentrated to dryness to give crude tert-butyl (3R)-3-amino-2-methyl-azepane-1-carboxylate. MS (m / z) 229.0 [M+H] +This material was dissolved in methanol (5 mL) and water (0.5 mL) and sodium bicarbonate (146 mg, 1.73 mmol) was added, followed by methyl 3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyran-2-carboxylate (186 mg, 0.43 mmol). The mixture was stirred at 45° C. for 5 minutes, warmed to 65° C., and stirred for 40 minutes. The reaction was cooled to room temperature, concentrated to dryness, dissolved in DCM, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in toluene (4 mL) and TFA (2 mL) was added. The reaction was concentrated to dryness, dissolved in methanol (5 mL), and triethylamine (2 mL) was added. The mixture was warmed to 60° C. and stirred overnight. The reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water (with 0.1% TFA)), and lyophilized to give the title compound as a mixture of diastereomers, the major isomer being (7R,13S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 508.4 [M+H] + . Synthesis of (7R,13S)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (9):

[0292] (1R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (99 mg, 0.20 mmol) was dissolved in 4 mL of toluene and 2 mL of TFA and stirred at 30° C. After 1 h, the reaction was concentrated, purified by preparative HPLC (MeCN / water (with 0.1% TFA)), and lyophilized to give the title compound. MS (m / z) 418.3 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3)δ 10.42(s, 1H), 8.38 (s, 1H), 7.51 - 7.35 (m, 1H), 7.09 - 6.91 (m, 2H), 4.60(d, J =5.8 Hz, 2H), 4.44 (d, J = 4.4 Hz, 1H), 4.37 (dt, J = 14.3, 9.4 Hz, 1H),4.24 -4.14 (m, 1H), 2.23 - 2.05 (m, 2H), 2.04 - 1.98 (m, 1H), 1.78 - 1.62 (m,2H),1.50 (d, J = 7.4 Hz, 3H), 1.19 - 1.02 (m, 1H). Example 9: Preparation of (7S- and 7R-)-6,6-difluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10-1, 10-2): [ka] Synthesis of 12-(benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10a):

[0293] A vial was charged with methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (350 mg, 0.78 mmol), tert-butyl 3-amino-4-hydroxyazepane-1-carboxylate (180 mg, 0.78 mmol), and sodium bicarbonate (131 mg, 1.56 mmol). Methanol (3.5 mL), water (3.5 mL), and 2-methyltetrahydrofuran (2 mL) were added. The reaction mixture was stirred at room temperature overnight and partitioned between 1N HCl and ethyl acetate. The organic layer was separated and concentrated to dryness. The residue was dissolved in 1 mL of DCM and 3 mL of 4N HCl in dioxane, and the solution was stirred at room temperature for 2 hours to remove the Boc protecting group and concentrated to dryness. To the residue was added 10 mL of ethanol and DBU (0.47 mL, 3.12 mmol). The reaction mixture was heated to 120° C. in a microwave for 30 minutes. Cool to room temperature. After cooling, the reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was separated and concentrated to dryness to give the title compound. MS (m / z) 528.17 [M+H] + . Synthesis of 12-(benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10b):

[0294] To a solution of 12-(benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10a) (320 mg, 0.61 mmol) in dry DCM (15 mL) was added Dess Martin periodinane, and the mixture was stirred at room temperature for 20 minutes. DCM was added, and the organic phase was washed twice with 10% sodium thiosulfate solution, twice with 0.5 N NaOH, and with brine. The organic phase was dried and evaporated. The residue was purified by silica gel chromatography eluting with methanol in DCM to give the title compound. MS (m / z) 526.28 [M+H] + . Synthesis of 12-(benzyloxy)-6,6-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10c):

[0295] To a solution of 12-(benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10b) (200 mg, 0.38 mmol) in DCM (5 mL) cooled at −78°C under argon was added Deoxo-Fluor® (1.1 mmol, 0.42 mL, 50% in toluene) under argon. The resulting mixture was stirred at −78°C and gradually warmed to room temperature overnight. The mixture was cooled to −78°C, and Deoxo-Fluor® (0.76 mmol, 0.28 mL, 50% in toluene) was added under argon. The reaction mixture was stirred at room temperature for 1 day and diluted with DCM. The mixture was cooled in an ice / water bath and quenched by the dropwise addition of saturated aqueous sodium bicarbonate. The resulting mixture was stirred for 1 hour, and additional saturated aqueous sodium bicarbonate was added, and stirring was continued for 10 minutes until effervescence ceased. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel chromatography eluting with EtOAc / hexanes and by preparative HPLC (MeCN / water (with 0.1% TFA)) and lyophilized to give the title compound. MS (m / z) 548.25 [M+H] + . Synthesis of (7S- and 7R-)-6,6-difluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10-1, 10-2):

[0296] 12-(Benzyloxy)-6,6-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10c, 40 mg) was separated into its individual enantiomers by preparative SFC chromatography on an IA column using MeOH co-solvent to give 10c-1 and 10c-2. The separated enantiomers were dissolved in 0.5 mL of toluene and 1 mL of TFA and stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by RP-HPLC eluting with ACN / water (0.1% TFA) to give the title compound. Peak 1: MS (m / z) 458.12 [M+H] + . 1 H NMR(400 MHz, DMSO-d6) δ 10.63 (s, 1H),10.26 (t, J = 5.8 Hz, 1H), 8.48 (s, 1H),7.22 (t, J = 8.7 Hz, 2H), 5.26 - 5.17(m, 1H), 4.58 (d, J = 5.8 Hz, 2H), 4.20 (dt, J = 13.3, 8.7 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.87 (dd, J=15.5, 1.9 Hz, 1H), 3.18 (dd, J = 13.3, 6.7 Hz, 1H), 2.21 (s, 1H), 2.05 -1.83(m, 2H), 1.60 (dt, J = 34.9, 14.0 Hz, 1H). Peak 2: MS (m / z) 458.13 [M+H]+. 1 HNMR(400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.27 (t, J = 5.8 Hz, 1H), 8.48 (s,1H),7.22 (t, J = 8.7 Hz, 2H), 5.21 (d, J = 8.0 Hz, 1H), 4.58 (d, J = 5.8 Hz,2H),4.32 - 4.15 (m, 1H), 4.10 - 3.94 (m, 1H), 3.87 (dd, J = 15.5, 2.0 Hz, 1H),3.18 (dd, J= 13.4, 6.6 Hz, 1H), 2.22 (s, 1H), 1.92 (d, J = 8.1 Hz, 2H), 1.71 -1.43 (m, 1H) . Example 10: Preparation of 6,12-dihydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (11) [ka]

[0297] 12-(Benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10a) (20 mg) was dissolved in 0.3 mL of toluene and 0.6 mL of TFA and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness, and the residue was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to give the title compound. MS (m / z) 438.18 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s,1H),10.44 (t, J = 5.8 Hz, 1H), 8.28 (s, 1H), 7.28 - 7.15 (m, 2H), 4.57 (d, J =5.6Hz, 3H), 4.13 (dt, J = 13.2, 9.2 Hz, 1H), 3.91 - 3.78 (m, 2H), 3.62 (dd, J= 15.0, 1.6 Hz, 1H), 3.12(dt, J = 13.1, 4.5 Hz, 1H), 1.84 (d, J = 6.8 Hz, 2H),1.66 (d, J = 14.5 Hz, 1H),1.02 (td, J = 14.4, 13.5, 5.8 Hz, 1H). Example 11: Preparation of N-(2,4-difluorobenzyl)-6,12-dihydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (12): [ka] Synthesis of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (12a):

[0298] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (12a) was prepared similarly to compound 10a using methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate. MS (m / z) 510.23 [M+H] + . Synthesis of N-(2,4-difluorobenzyl)-6,12-dihydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (12):

[0299] The title compound was prepared using compound 12a in the same manner as compound 11. MS (m / z) 420.15 [M+H]+ . 1 HNMR(400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.43 (t, J = 5.9 Hz, 1H), 8.31 (s,1H),7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H),7.12 - 7.02 (m, 1H), 5.37 (s, 1H), 4.61 - 4.52 (m, 3H), 4.20 - 4.08 (m,1H),3.86 (td, J = 14.0, 13.0, 4.4 Hz, 2H), 3.68 - 3.59 (m, 1H), 3.17 - 3.09 (m, 1H), 1.85 (d, J = 7.4 Hz, 2H), 1.68 (d, J = 14.9 Hz, 1H), 1.04 (s, 1H). Example 12: Preparation of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (13) [ka] Synthesis of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-fluoro-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (13a):

[0300] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (12a, 47 mg, 0.092 mmol) in DCM (3 mL) cooled at −78°C under argon was added Deoxo-Fluor® (0.14 mmol, 0.05 mL, 50% in toluene) under argon. The resulting mixture was stirred at −78°C and gradually warmed to room temperature overnight. The mixture was cooled to −78°C, and Deoxo-Fluor® (0.14 mmol, 0.05 mL, 50% in toluene) was added under argon. The reaction mixture was stirred at room temperature for 2 hours and diluted with DCM. The mixture was cooled in an ice / water bath, and the reaction was quenched by dropwise addition of saturated aqueous sodium bicarbonate. The resulting mixture was stirred for 1 hour, and additional saturated aqueous sodium bicarbonate was added, and stirring was continued for 10 minutes until effervescence ceased. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to give the title compound. MS (m / z) 512.22 [M+H] + . N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyridin[1 Synthesis of [1,2-a][1,4]diazonine-10-carboxamide (13):

[0301] The title compound was prepared using 13a in a similar manner to compound 11. MS (m / z) 422.18 [M+H] + . 1 HNMR(400 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.33 (t, J = 5.9 Hz, 1H), 8.60 (s,1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (td, J = 9.6, 2.6 Hz, 1H), 7.07(td,J = 8.7, 2.5 Hz, 1H), 5.10 - 5.03 (m, 1H), 4.98 - 4.89 (m, 1H), 4.56 (d, J=6.0 Hz, 2H), 4.13 (dt, J = 13.2, 7.9 Hz, 1H), 3.90 (d, J = 15.0 Hz, 1H),3.83(dd, J = 15.1, 2.0 Hz, 1H), 3.13 (ddd, J = 13.2, 7.1, 2.9 Hz, 1H), 2.18 -2.05(m, 1H), 2.04 (s, 1H), 1.82 - 1.64 (m, 1H), 1.53 - 1.20 (m, 1H). Example 13: Preparation of (6S,7R)—N-(2,4-difluorobenzyl)-6,12-dihydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide and (6R,7S)—N-(2,4-difluorobenzyl)-6,12-dihydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (14-1, 14-2): [ka] Synthesis of benzyl 3-(((benzyloxy)carbonyl)amino)-4-hydroxyazepane-1-carboxylate (14b):

[0302] To a solution of benzyl 3-amino-4-hydroxyazepane-1-carboxylate (1.1 g, 4.16 mmol) and Na2CO3 (310 mg, 4.99 mmol) in dioxane (7 mL) and water (7 mL) was added Cbz-Cl (0.7 mL, 4.99 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 hours. Ethyl acetate was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / ethyl acetate to give the title compound. MS (m / z) 399.2 6 [M+H] + . Synthesis of (S) and (R)-benzyl 3-(((benzyloxy)carbonyl)amino)-4-oxoazepane-1-carboxylate (14c-1 and 14c-2):

[0303] To a solution of benzyl 3-(((benzyloxy)carbonyl)amino)-4-hydroxyazepane-1-carboxylate (14b) (760 mg, 1.9 mmol) in 5 mL of DCM was added Dess Martin periodinane (1.2 g, 2.8 mmol). The reaction mixture was stirred at room temperature for 30 min. DCM was added, and the organic phase was washed twice with 10% sodium thiosulfate solution, twice with 0.5 M NaOH, and with brine. The organic phase was dried and evaporated. The residue was purified by SGC eluting with EtOAc / hexane to give benzyl 3-(((benzyloxy)carbonyl)amino)-4-hydroxyazepane-1-carboxylate (14c). MS (m / z) 397.53 [M+H]+. Compound 14c was separated into its individual enantiomers by preparative SFC chromatography on an IA column using MeOH co-solvent to give 14c-1 and 14c-2. Synthesis of ((3S,4R) and (3R,4S)-4-hydroxy-4-methylazepan-3-yl)benzylcarbamate (14d-1, 14d-2):

[0304] To a flask was added methyl Grignard (1.02 mL, 3.05 mmol, [3 M in EtO]) at 0 °C. A solution of 14c-1 or 14c-2 (302 mg, 0.76 mmol) in 1 mL of THF was added slowly with stirring. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with NHCl and extracted into ethyl acetate, washed with brine, dried over MgSO, filtered, and the solvent removed under reduced pressure to give benzyl ((3S,4R)-4-hydroxy-4-methylazepan-3-yl)carbamate or benzyl ((3R,4S)-4-hydroxy-4-methylazepan-3-yl)carbamate. MS (m / z) 413.50 [M+H] + .

[0305] The residue was dissolved in absolute ethanol and sparged under an argon atmosphere. Palladium hydroxide (101 mg, 20% Pd by weight) was added, and the mixture was sparged under a hydrogen atmosphere (1 atm, balloon). The mixture was stirred vigorously over the weekend and sparged under an argon atmosphere. It was filtered through a pad of Celite®. The Celite® was washed with absolute ethanol, and the filtrate was concentrated in vacuo to give the title compound. MS (m / z) 145.16 [M+H] + . Synthesis of (6S,7R) and (6R,7S)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (14-1, 14-2):

[0306] The title compound was prepared using compounds 14d-1 and 14d-2 in the same manner as compound 12. MS (m / z) 434.15 [M+H] + . 1 HNMR(400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.46 (t, J = 6.0 Hz, 1H), 8.34 (s,1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J= 11.7, 9.4, 2.6 Hz, 1H),7.08 (td, J = 8.6, 2.7 Hz, 1H), 4.99 (s, 1H), 4.56 (d,J = 5.9 Hz, 2H), 4.30(s, 1H), 4.15 (dt, J = 13.0, 8.8 Hz, 1H), 3.85 (dd, J = 15.2, 3.0 Hz, 1H), 3.68 (dd, J = 15.2, 1.7 Hz, 1H), 3.10 (dt, J = 13.0, 4.8 Hz, 1H), 1.81 (d, J = 7.2 Hz, 2H), 1.47 (d, J = 15.4 Hz, 1H), 1.35 (s, 3H),1.23(dt, J = 14.4, 6.5 Hz, 1H). Example 14: (6R,7S)- and (6S,7R)-6-fluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]di Preparation of Azonine-10-carboxamide (15-1, 15-2): [ka] Synthesis of (7S)- and (7R)-12-(benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (15a-1, 15a-2):

[0307] 12-(Benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10b) (350 mg) was separated into its individual enantiomers by preparative SFC chromatography on an IA column using MeOH co-solvent to give 15a-1 and 15a-2. MS (m / z) 526.00 [M+H]+. Synthesis of (6S,7S)- and (6R,7R)-12-(benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamides (15b-1, 15b-2):

[0308] To a solution of 15a-1 or 15a-2 (150 mg, 0.285 mmol) in 7 mL of methanol was added NaBH4 (21.6 mg, 0.57 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min. The reaction was quenched with 1 N HCl and extracted with DCM. The organic phase was dried over MgSO4 and concentrated to dryness to give the title compound. MS (m / z) 528.26 [M+H]+. Synthesis of (6R,7S)- and (6S,7R)-6-fluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (15-1, 15-2):

[0309] The title compound was prepared using compounds 15b-1 and 15b-2 in the same manner as compound 13. 15-1: MS (m / z) 440.22 [M+H]+. 1 HNMR(400 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 7.28 - 7.15 (m, 2H), 5.12 -4.78(m, 2H), 4.65 - 4.50 (m, 2H), 4.18 - 4.06 (m, 1H), 3.89 - 3.80 (m, 2H),3.12(ddd, J = 13.2, 7.2, 2.9 Hz, 1H), 2.19 - 1.95 (m, 2H), 1.79 - 1.70 (m,1H),1.56 - 1.21 (m, 1H). 15-2:MS (m / z) 440.20 [M+H] + . 1 H NMR(400 MHz,DMSO-d6) δ 10.57 (s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H),7.28 - 7.15(m, 2H), 5.12 - 4.81 (m, 2H), 4.65 - 4.50 (m, 2H), 4.12 (dt, J = 13.3, 8.1 Hz, 1H), 3.89 (d, J=15.0 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.12 (ddd, J = 13.1, 7.0, 2.9 Hz, 1H),2.22 - 1.95 (m, 2H), 1.79 - 1.70 (m, 1H), 1.50 - 1.28 (m, 1H). Example 15: (7S)- and (7R)-N-(2,4-difluorobenzyl)-6,6-difluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-1 Preparation of 0-carboxamides (16-1, 16-2): [ka] Synthesis of (7S)- and (7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamides (16a-1, 16a-2):

[0310] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (16a) was prepared in the same manner as compound 10b using methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (16a). MS (m / z) 508.15 [M+H]+. Compound 16a was separated into its individual enantiomers by preparative SFC chromatography on an OD-H column using IPA-NH3 cosolvent to give 16a-1 and 16a-2. Synthesis of (7S)- and (7R)-N-(2,4-difluorobenzyl)-6,6-difluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (16-1, 16-2):

[0311] The title compound was prepared using 16a-1 and 16a-2, as well as compounds 10-1 and 10-2. 16-1: MS (m / z) 440.20 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.24 (t, J = 6.0 Hz, 1H), 8.50 (s,1H), 7.42 (td, J = 8.6, 6.6 Hz, 1H), 7.26 (ddd, J = 10.5, 9.4, 2.6 Hz, 1H),7.07 (td, J = 8.5, 7.6, 4.2 Hz,1H), 5.24 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H),4.27 - 4.15 (m, 1H), 4.04 (d, J = 16.5 Hz, 1H), 3.92 - 3.83 (m, 1H), 3.19 (dd, J = 13.2, 6.8 Hz, 1H), 2.22(s,1H), 1.96 (d, J = 21.8 Hz, 2H), 1.71 - 1.54 (m, 1H). 16-2:MS (m / z) 440.27 [M+H]+. 1 HNMR(400 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.24 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 7.42 (td, J = 8.7, 6.6 Hz, 1H), 7.31 - 7.20 (m, 1H), 7.07 (td, J =8.4,2.7 Hz, 1H), 5.24 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.21 (q, J = 10.2,9.7 Hz,1H), 4.04 (d, J = 15.8 Hz, 1H), 3.88 (dd, J = 15.4, 2.0 Hz, 1H), 3.18(dd, J = 13.1, 6.7 Hz, 1H), 2.22 (s, 1H), 1.97 (d, J = 22.4 Hz, 2H), 1.62 (dd, J = 35.1, 14.3 Hz, 1H). Example 16: N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (17-1a) and N-(2,4-difluorobenzyl)-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (17-1a) Preparation of 17-dopyrido[1,2-a][1,4]diazonine-10-carboxamides (17-1b, 17-2b): [ka] Synthesis of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-fluoro-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (17a-1a, 17a-2a) and 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (17a-1b, 17a-2b):

[0312] The title compound was prepared using compounds 14e-1 and 14e-2 in the same manner as compound 13a. MS (m / z) 526.16 [M+H]+. By-products (17a-1b, 17a-2b) were formed. MS (m / z) 506.13 [M+H]+. Synthesis of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (17-1a) and N-(2,4-difluorobenzyl)-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (17-1b, 17-2b):

[0313] The product mixture from the previous step (17a-1a and 17a-1b, 40 mg, approximately 0.07 mmol) or (17a-2a and 17a-2b) was dissolved in absolute ethanol (10 mL), and the solution was sparged under an argon atmosphere. Palladium hydroxide (20%, 11 mg) was added, and the mixture was sparged under a hydrogen atmosphere (1 atm, balloon). The mixture was vigorously stirred for 2 hours, sparged under an argon atmosphere, and filtered through a pad of Celite®. The Celite® was washed with absolute ethanol, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (MeCN / water (containing 0.1% TFA)) and lyophilized to give the title compound. For 17-1a: MS (m / z) 436.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s,1H), 10.33 (t, J = 6.0 Hz, 1H), 8.65 (s, 1H), 7.42 (td, J = 8.7, 6.6Hz, 1H),7.26 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.08 (td, J = 8.6, 2.7 Hz, 1H), 4.81 (d,J = 11.5 Hz, 1H), 4.63 - 4.48 (m,2H), 4.16 (q, J = 11.1 Hz, 1H), 3.92 (dd, J =15.0, 2.5 Hz, 1H), 3.80 (d, J =16.1 Hz, 1H), 3.16 (dd, J = 13.0, 7 0.8 Hz, 1H), 2.17 - 2.06 (m, 1H), 1.92 (dt, J = 13.7, 6.4 Hz, 1H), 1.73 (dt, J=19.6, 9.6 Hz, 1H), 1.49 - 1.16 (m, 4H). For 17-1b: MS (m / z) 418.28 [M+H]+. 1HNMR(400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.42 (t, J = 5.9 Hz, 1H), 8.63 (d, J =18.6Hz, 0H), 8.43 (s, 1H), 7.42 (td, J = 8.7, 6.6 Hz, 1H), 7.26 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.13 - 7.03 (m, 1H), 4.69 (s, 1H), 4.63 - 4.48(m,2H), 4.22 - 4.09 (m, 1H), 3.94 (dd, J = 14.6, 2.8 Hz, 1H), 3.71 (dd, J = 14.4,1.7 Hz, 1H), 3.14 (dd, J = 12.9, 6.7 Hz, 1H), 2.11 - 1.99 (m, 1H), 1.91 (t, J = 7.8 Hz, 2H), 1.55 (m, 1H), 1.50 (m, 1H), 0.85 (d, J = 6.9 Hz, 3H)。17-2bについ て:MS(m / z) 418.24 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.90(s,1H), 10.42 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 7.48 - 7.37 (m, 1H), 7.31 -7.21(m, 1H), 7.08 (t, J = 9.7 Hz, 1H), 4.69 (s, 1H), 4.56 (d, J = 5.1 Hz, 2H), 4.22- 4.11 (m, 1H),3.98 - 3.89 (m, 1H), 3.70 (d, J = 14.6 Hz, 1H), 3.14 (dd, J =12.9, 6.3 Hz, 1H),2.01 (m, 1H), 1.92 (m, 2H), 1.55 (m, 1H), 1.50 (m, 1H), 0.85(d, J = 6.9 Hz, 3H)。 Example 17: Preparation of 12-hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (18) [ka] Synthesis of (E)-tert-butyl 3-((tert-butylsulfinyl)imino)azepane-1-carboxylate (18a):

[0314] To a solution of tert-butyl 3-oxoazepane-1-carboxylate (0.52 g, 2.44 mmol) and 2-methylpropane-2-sulfinamide (0.35 g, 2.93 mmol) in THF (10 mL) was added titanium(IV) ethoxide (1.03 mL, 4.91 mmol) at room temperature. The resulting solution was stirred at room temperature overnight.

[0315] The reaction mixture was diluted with ethyl acetate (10 mL) and quenched with aq. NaHCO3 (approximately 5 mL). Celite® was added to the mixture, and the solid was filtered off, and the filter cake was washed with ethyl acetate (10 mL x 2). Combined washes The liquid was concentrated in vacuo. The residue was purified by CombiFlash® using EtOAc / hexane to give the title compound. MS (m / z) 317.2 [M+H] + . Synthesis of tert-butyl 3-((tert-butylsulfinyl)amino)-3-methylazepane-1-carboxylate (18b):

[0316] To tert-butyl (E)-3-((tert-butylsulfinyl)imino)azepane-1-carboxylate (0.15 g, 0.47 mmol) in DCM was added 3 M MeMgBr (0.95 mL) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight.

[0317] The reaction mixture was diluted with ethyl acetate and washed with saturated NH4Cl and brine. The mixture was dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified on a silica gel column with ethyl acetate / hexane to give the title compound. MS (m / z) 333.2 [M+H] + . Synthesis of 3-methylazepan-3-amine (18c):

[0318] At room temperature, 4 M HCl in dioxane (0.07 mL) was added to a solution of tert-butyl 3-(tert-butylsulfinylamino)-3-methyl-azepane-1-carboxylate (18b, 0.03 g, 0.1 mmol) in DCM (2 mL). After 2 h, the solvent was removed under reduced pressure, and the crude material was used directly in the next step. MS (m / z) 129.2 [M+H] + . Synthesis of 12-(benzyloxy)-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (18d):

[0319] To a mixture of 3-methylazepan-3-amine (18c, 0.013 g, 0.1 mmol) and sodium bicarbonate (45.07 mg, 0.54 mmol) in MeOH (2 mL) and water (2 mL) was added methyl 3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylate (30 mg, 0.07 mmol) at room temperature. The mixture was stirred at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified to give the title compound. MS (m / z) 526.2 [M+H] + . Synthesis of 12-hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (18):

[0320] 12-(Benzyloxy)-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (0.03 g, 0.06 mmol) was dissolved in toluene (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by HPLC to give the title compound. MS (m / z) 436.1 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 10.46 (s, 1H), 8.57(s, 1H), 6.74 - 6.62 (m, 2H), 4.69 (m, 1H), 4.47(m, 1H), 4.30 - 4.14 (m, 1H), 3.65-3.77 (m, 3H), 3.40 (m, 1H), 3.09 (m, 1H), 2.15 - 1.7 (m, 7H). Example 18: (7S)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methanopyridine Preparation of lido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (19): [ka]

[0321] (7S)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (19) was prepared similarly to 12-hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (18) using (S)-1,4-oxazepan-6-amine instead of 3-methylazepan-3-amine. 1HNMR(400 MHz, DMSO-d6) δ 10.41 (t, J = 5.8 Hz, 1H), 8.51 (s, 1H), 7.35 - 6.97 (m, 2H), 4.71 (s, 1H), 4.57 (d, J = 5.7 Hz, 2H), 4.28 (ddd, J = 13.1, 9.4, 7.3 Hz, 1H), 4.11 (d, J = 13.9 Hz, 1H), 4.07 - 3.78 (m, 6H). MS (m / z) 514.2[M+H] + . Example 19: Preparation of (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (20) [ka]

[0322] (7R)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (20) was prepared similarly to 12-hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (18), substituting (R)-1,4-oxazepan-6-amine for 3-methylazepan-3-amine. 1 HNMR(400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.51 (s, 1H), 7.22 (dd, J = 9.2, 8.0 Hz, 2H), 4.71 (d, J = 3.1 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 4.27 (ddd, J = 12.9, 9.1, 7.1 Hz, 1H), 4.16 - 3.62 (m, 6H). MS (m / z) 514.2 [M+H] + . Example 20: Preparation of N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (23) [ka] Synthesis of diethyl 1-(azepan-4-yl)-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (23a):

[0323] A reactor was charged with tert-butyl 3-aminoazepane-1-carboxylate (588 mg, 3 mmol), and NaHCO (576 mg, 7 mmol) and diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (950 mg, 3 mmol) in EtOH / water (9 mL / 6 mL) were added. The reaction mixture was heated to 50° C. overnight. The reaction was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was used in the next step without purification.

[0324] To the above residue in DCM (10 mL) was added 4N HCl solution in dioxane (3 mL). After 2 hours at room temperature, the solvent was removed under reduced pressure to give the title compound, which was used in the next step without purification. MS (m / z) 442.945 [M+H] + . Synthesis of ethyl 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxylate (23b):

[0325] EtOH (20 mL) and DBU (2.2 g, 15 mmol) were added to the residue. After heating to 110° C. in a microwave reactor for 1 hour, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound. MS (m / z) 397.113 [M+H] + . Synthesis of 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxylic acid (23c):

[0326] To the above residue (114 mg, 0.288 mmol) in MeOH (6 mL) was added 2N LiOH (1 mL) at room temperature. After 2 hours, the reaction was diluted with ethyl acetate (100 mL) and 1N HCl (20 mL). The organic layer was dried and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification. MS (m / z) 369.131 [M+H] + . Synthesis of 11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (23d):

[0327] To the above residue (57 mg, 0.155 mmol) in DCM (5 mL), (2,4-difluorophenyl)methanamine (27.4 mg, 0.17 mmol), DIPEA (60 mg, 0.46 mmol), and HATU (60.2 mg, 0.186 mmol) were added at room temperature. After 1 hour, the reaction was diluted with ethyl acetate (100 mL) and washed with brine. The organic layer was dried and concentrated under reduced pressure. The resulting residue was used in the next step. MS (m / z) 512.147 [M+H] + . Synthesis of 11-hydroxy-1,10-dioxo-N-(2,4-difluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (23):

[0328] To a solution of 11-(benzyloxy)-1,10-dioxo-N-(2,4-difluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (163 mg) in DCM (2 mL) was added TFA (1 mL). After 4 hours, the solvent was removed. The resulting residue was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to give the title compound as a TFA salt. MS (m / z) 404.154 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 10.41(t, J =5.9 Hz, 1H), 8.33 (s, 1H), 7.39 (dd, J = 8.6, 6.6 Hz, 2H), 7.22 (ddd, J= 10.7,9.3, 2.6 Hz, 1H), 7.07 - 7.01 (m, 1H), 4.99 (d, J = 11.6 Hz, 1H), 4.59- 4.46(m, 2H), 4.30 - 4.19 (m, 1H), 3.15 - 3.07 (m, 1H), 2.42 - 2.15 (m, 3H),2.07 -1.91 (m, 2H), 1.73 (d, J = 46.6 Hz, 3H). Example 21: Preparation of racemic and (R)- or (S)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24 and 24-1): [ka] Synthesis of racemic 11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24):

[0329] Racemic 11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24) was synthesized from 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxylic acid and (2,4,6-trifluorophenyl)methanamine in a manner similar to the synthesis of compound 5. MS (m / z) 422.089 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.41 (t, J = 5.9Hz,1H), 8.33 (s, 1H), 7 .39 (dd, J = 8.6, 6.6 Hz, 2H), 7.22 (ddd, J= 10.7, 9.3, 2.6 Hz, 1H), 7.07 -7.01 (m, 1H), 4.99 (d, J = 11.6 Hz, 1H), 4.59 - 4.46 (m, 2H), 4.30 - 4.19 (m,1H),3.15 - 3.07 (m, 1H), 2.42 - 2.15 (m, 2H), 2.07 - 1.91 (m, 2H), 1.73 (d, J= 46.6 Hz, 2H). Synthesis of (R)- or (S)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24-1):

[0330] (R)- or (S)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide peak 1 (24a-1) was separated from racemic 11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24a) by chiral HPLC separation (SFC chromatography on an IB 4.6 × 100 mm 5-micron column using MeOH (20) cosolvent). The isolated peak 1 was used to prepare 11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24-1). MS (m / z) 422.124 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ 10.45 (t, J = 5.8Hz,1H), 8.31 (s, 1H), 7.28 - 7.10 (m, 2H), 4.97 (d, J = 11.3 Hz, 2H), 4.61 (dd,J= 14.5, 6.1 Hz, 1H), 4.48 (dd, J = 14.6, 5.5 Hz, 1H), 4.24 (d, J = 13.0Hz,2H), 3.11 (dd, J = 13.5, 8.3 Hz, 1H), 2.37 - 2.21 (m, 2H), 2.00 (d, J =40.1Hz, 2H), 1.70 (d, J = 31.2 Hz, 2H). Example 22: Preparation of racemic and (7R)- and (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25, 25-1, 25-2): [ka] Synthesis of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25d):

[0331] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (25d) was synthesized from diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate and tert-butyl 3-aminoazepane-1-carboxylate as starting materials following a procedure similar to that for compound 24a. MS (m / z) 494.181 [M+H] + . Synthesis of racemic N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25):

[0332] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25d) (5.5 mg) in toluene (0.2 mL) was added TFA (0.2 mL) at room temperature. After 4 hours, the solvent was removed. The resulting residue was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to give the title compound as a TFA salt. MS (m / z) 404.134 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H),10.38 (t, J = 6.0 Hz, 1H), 8.47 (s,1H), 7.38 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H),7.04 (td, J = 8.6, 2.6 Hz, 1H), 4.75 (dd, J = 5.9, 2.8 Hz, 1H), 4.53 (d, J =5.9 Hz, 2H),4.12 (d, J = 13.3 Hz, 1H), 3.90 - 3.84 (m, 1H), 3.65 (dd, J =14.7, 1.9 Hz, 1H),3.07 (td, J = 6.6, 3.6 Hz, 1H), 2.02 - 1.94 (m, 1H), 1.89 -1.74 (m, 3H), 1.62(d, J = 7.6 Hz, 1H), 1.12 (d, J = 12.1Hz, 1H). Synthesis of (7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide and (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25d-1, 25d-2):

[0333] (7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25d-1) as peak 1, and (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25d-1) as peak 2. R-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (25d-2) was separated from the racemic 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (25d) by chiral HPLC separation (SFC chromatography on an IB 4.6 x 100 mm 5-micron column using MeOH (20) as cosolvent). The structure of peak 1 was confirmed by synthesis starting from (R)-azepan-3-amine. Synthesis of (7R)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25-1) and (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (25-2):

[0334] (7R)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (25-1) and (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (25-2) were synthesized from peak 1 and peak 2, respectively, following reaction conditions similar to those used to prepare compound 25. Compound 25-1: MS (m / z) 404.186 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.59(s, 1H),10.38 (t, J = 5.9 Hz, 1H), 8.47 (s, 1H), 7.38 (td, J = 8.7, 6.6 Hz,1H), 7.22(ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.04 (tdd, J = 8.6, 2.6, 1.1 Hz,1H), 4.75 (d,J = 5.4 Hz, 1H), 4.53 (d, J = 5.9 Hz, 2H), 4.17 - 4.05 (m, 1H),3.86 (d, J = 14.6 Hz, 1H), 3.65 (dd, J = 14.7, 1.9 Hz, 1H), 3.06 (ddd, J = 13.1, 6.9,3.6Hz, 1H), 1.99 (s, 1H), 1.89 - 1.74 (m, 3H), 1.62 (d, J = 8.0Hz, 1H). Compound 25-2:MS(m / z)404.165 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.61(s, 1H),10.38 (t, J = 5.9 Hz, 1H), 8.47 (s, 1H), 7.38 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.09 - 6.99 (m, 1H), 4.75 (s, 1H), 4.53 (d, J =5.9Hz, 2H), 4.12 (d, J = 13.3 Hz, 1H), 3.86 (d, J = 14.6 Hz, 1H), 3.69 - 3.60 (m,1H),3.06 (ddd, J = 13.1, 6.8, 3.6 Hz, 1H), 1.99 (s, 1H), 1.83 (d, J = 13.3 Hz,3H ), 1.67 - 1.60 (m, 1H). Example 23: Racemic 12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26), (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11 Preparation of -hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26-1) and (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26-2): [ka] Synthesis of 12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26):

[0335] 12-(Benzyloxy)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxylic acid (57 mg, 0.155 mmol) was dissolved in DCM (2 mL) containing (2,4,6-trifluorophenyl)methanamine (27 mg, 0.17 mmol) and triethylamine (60 mg, 0.464 mmol). HATU (60 mg, 0.186 mmol) was added, and the mixture was stirred at room temperature. After overnight reaction, the reaction mixture was concentrated to dryness and purified by silica gel chromatography to give compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26a). MS (m / z) 512.06 [M+H] + .

[0336] The compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26a) (7 mg, 0.014 mmol) was dissolved in toluene (1 mL), and then TFA (1 mL) was added. The resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by HPLC to give the title compound (26). MS (m / z) 422.091 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.39(t, J =5.8 Hz, 1H), 8.45 (s, 1H), 7.24 - 7.11 (m, 2H), 4.72 (dd, J = 5.9, 2.9Hz, 1H),4.54 (dd, J = 6.0, 2.4 Hz, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.88 - 3.79(m, 1H),3.64 (dd, J = 14.7, 1.9 Hz, 1H), 3.05 (dq, J = 9.5, 3.4 Hz, 1H), 2.06- 1.91 (m,1H), 1.89 - 1.74 (m, 3H), 1.61 (d, J = 7.7 Hz, 1H), 1.11 (d, J =12.7 Hz, 1H). Synthesis of (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26-2) and (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26-1):

[0337] Racemic 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (26a) was separated by chiral HPLC (IB 4.6 × 100 mm) using MeOH (20) as the cosolvent. Separation by SFC chromatography on a 5-micron column gave the compounds (7R)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26a-1) and (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26a-2).

[0338] The compound (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26a-2) (20 mg, 0.039 mmol) was dissolved in toluene (1 mL), and then TFA (1 mL) was added. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by HPLC to obtain the title compound (26-2). (MS (m / z) 422.123 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.59(s, 1H), 10.39 (d, J = 5.9 Hz, 1H), 8.45 (s, 1H), 7.18 (t, J = 8.6 Hz, 2H), 4.72(s,1H), 4.59 - 4.48 (m, 2H), 4.11 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 14.6 Hz,1H),3.69 - 3.59 (m, 1H), 3.05 (ddd, J = 11.3, 6.7, 3.6 Hz, 1H), 1.97 (m, 1H),1.87 - 1.71 (m, 3H), 1.67 - 1.55 (m, 1H), 1.10 (m, 1H).

[0339] The compound (7R)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (26a-1) (20 mg, 0.039 mmol) was dissolved in toluene (1 mL), and then TFA (1 mL) was added. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by HPLC to give the title compound (26-1). MS (m / z) 422.116 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s , 1H), 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s,1H), 7.18 (dd, J = 9.2, 8.0 Hz, 2H),4.73 (s, 1H), 4.58 - 4.49 (m, 2H), 4.11 (d,J = 13.3 Hz, 1H), 3.85 (d, J = 14.6Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.10 -3.00 (m, 1H), 1.96 (m, 1H), 1.82 (d,J = 12.2 Hz, 3H), 1.61 (d, J = 7.4 Hz, 1H), 1.18 - 1.05 (m, 1H). Example 24: Preparation of N-(2,4-difluorobenzyl)-7-hydroxy-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (27) [ka] Synthesis of 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one TFA salt (27a):

[0340] To a solution of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (55 mg, 0.02 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. After 4 hours, the solvent and excess TFA were removed to give 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one. MS (m / z) 276.676 [M+H] + . Synthesis of 7-(benzyloxy)-N-(2,4-difluorobenzyl)-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (27b):

[0341] 7-(Benzyloxy)-N-(2,4-difluorobenzyl)-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide was prepared from 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one TFA salt (45 mg, 0.163 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (70 mg, 0.163 mmol) according to a procedure similar to that for compound 25. MS (m / z) 555.034 [M+H] + . Synthesis of N-(2,4-difluorobenzyl)-7-hydroxy-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (27):

[0342] N-(2,4-difluorobenzyl)-7-hydroxy-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (27) was prepared following the same procedure as compound 26, starting from 7-(benzyloxy)-N-(2,4-difluorobenzyl)-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (11 mg). MS (m / z) 465.05 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 10.25 (t,J = 5.9 Hz, 1H), 8.61 (s, 1H), 7.42 (d, J = 7.1 Hz, 1H),7.29 (ddd, J = 12.1, 9.4, 2.8 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.14 - 7.01 (m, 3H), 5.74 (s, 2H), 5.45 (s, 1H), 4.54 (d, J = 5.8 Hz, 1H), 3.68 (s, 2H), 3.64 (d, J = 2.8 Hz, 1H) . Example 25: Preparation of (7S)—N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (28) [ka] Synthesis of (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (28a):

[0343] To a solution of 1,4-oxazepan-6-amine (18.9 mg, 0.16 mmol) in MeOH (6 mL) and water (1 mL) was added sodium bicarbonate (109.6 mg, 1.3 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (70 mg, 0.163 mmol). The reaction mixture was heated to 50° C. overnight. The reaction was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was used in the next step without purification. MS (m / z) 496.016 [M+H] + . Synthesis of (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (28):

[0344] To a solution of (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (28a) obtained from the above reaction was added toluene (1 mL) and TFA (1 mL). After 4 hours at room temperature, the solvent and excess TFA were removed under reduced pressure. The residue was dissolved in DMF and subjected to prep. HPLC purification to give the title compound. MS (m / z) 406.83 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 7.39 (td, J=8.7, 6.6 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.05 (td, J = 7.6, 6.7, 4.0 Hz,1H),5.73 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.34 - 4.23 (m, 1H), 4.10 (d, J =14.3Hz, 2H), 4.00 - 3.82 (m, 4H). Example 26: Preparation of (7R)—N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (29) [ka]

[0345] (7R)-N-(2,4-Difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (29) was synthesized from (R)-1,4-oxazepan-6-amine (18.9 mg, 0.163 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (70 mg, 0.163 mmol) according to a procedure similar to that for compound (28). MS (m / z) 406.136 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.9 Hz, 1H), 8.51 (s, 1H), 7.42 - 7.37 (m, 1H), 7.21 (dd, J=9.9, 2.5 Hz, 1H), 7.07 - 7.02 (m, 1H), 4.70 (s, 1H), 4.54 (d, J = 5.9 Hz,2H),4.30 - 4.23 (m, 1H), 4.09 (d, J = 5.8 Hz, 1H), 4.00 (d, J = 12.0 Hz, 1H), 3.89(t, J= 8.9 Hz, 3H), 3.66 (d, J = 10.0 Hz, 2H). Example 27: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (30) [ka]

[0346] N-(2,4-Difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (30) was synthesized from 1,4-diazepan-6-amine (75.1 mg, 0.652 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (140 mg, 0.326 mmol) according to a procedure similar to that for compound 28. MS (m / z) 405.183 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.70(s, 1H),10.37 (s, 1H), 8.52 (s, 1H), 7.42 - 7.34 (m, 1H), 7.22 (s, 1H), 7.05(d, J = 2.6Hz, 1H), 4.72 (s, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.16 (d, J = 12.8Hz, 2H), 3.92 (d, J = 14.8 Hz, 2H), 3.72 (d, J = 15.0 Hz, 2H), 3.15 (s, 2H). Example 28: Preparation of 5-acetyl-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (31) [ka] Synthesis of 5-acetyl-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (31):

[0347] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (30a, 26 mg, 0.053 mmol) in DCM (5 mL) was added DIPEA (27.2 mg, 0.21 mmol) and acetyl chloride (6.2 mg, 0.079 mmol) under ice-water bath cooling. After stirring for 4 h, the reaction was extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was used in the next step without purification. MS (m / z) 537.013 [M+H] + .

[0348] 5-Acetyl-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (31) was synthesized from 5-acetyl-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (31a) following debenzylation conditions similar to those used to prepare compound 30. MS (m / z) 447.159 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.36(t, J =5.9 Hz, 1H), 8.59 (d, J = 19.5 Hz, 1H), 7.39 (td, J = 8.7, 6.6 Hz, 1H),7.22(ddd, J = 10.6, 9.4, 2.7 Hz, 1H), 7.05 (ddt, J = 10.0, 7.4, 1.3 Hz, 1H),5.73 (s, 2H), 4.54 (d, J = 6.0 Hz,2H), 4.42 - 4.32 (m, 1H), 3.97 - 3.88 (m,2H), 3.78 (d, J = 15.1 Hz, 2H), 3.20 -3.15 (m, 1H), 1.86 (s, 3H). Example 29: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-5-(methylsulfonyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (32) [ka]

[0349] N-(2,4-difluorobenzyl)-12-hydroxy-5-(methylsulfonyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (32) was reacted with 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (33). Synthesized from [a][1,4,7]triazonine-10-carboxamide (26 mg, 0.053 mmol) according to the same procedure used to prepare compound 31 and using methanesulfonyl chloride (9 mg, 0.079 mmol). MS (m / z) 483.083 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ 10.36(t, J = 6.0 Hz, 1H), 8.56 (s, 1H), 7.38 (dd, J = 8.7, 6.7 Hz,1H), 7.22 (ddd, J= 10.5, 9.3, 2.6 Hz, 1H), 7.14 - 6.96 (m, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.21 (dd, J = 6.6, 3.3 Hz, 1H),3.98(s, 2H), 3.90 - 3.75 (m, 4H), 3.45 (d, J = 15.0 Hz, 1H), 3.29 (d, J = 9.2Hz,1H), 3.23 - 3.10 (m, 1H), 2.88 (s, 3H). Example 30: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (33) [ka] Synthesis of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (33):

[0350] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (24 mg, 0.049 mmol) in DMF (1.5 mL) was added DIPEA (25.1 mg, 0.194 mmol) and MeI (10.3 mg, 0.073 mmol) at room temperature. After stirring for 4 hours, the reaction was extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was used in the next step without purification. MS (m / z) 509.11 [M+H] + .

[0351] N-(2,4-difluorobenzyl)-12-hydroxy-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (33) was synthesized from 12-(benzyloxy)-N-(2,4-difluorobenzyl)-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (33a) following the same debenzylation conditions used to prepare compound 30. MS (m / z) 419.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 -8.18 (m,2H), 7.40 (td, J = 8.6, 6.6 Hz, 1H), 7.23 (td, J = 9.9, 2.6 Hz, 1H),7.05 (td, J= 8.5, 2.5 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.17 (dt, J = 13.1,8.1 Hz, 1H), 3.89 - 3.77 (m, 3H), 3.71 - 3.60 (m, 1H), 3.28 (d, J = 7.3 Hz,3H), 2.78 (s, 3H), 2.27 (s, 1H). Example 31: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-5-isopropyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (34) [ka]

[0352] N-(2,4-Difluorobenzyl)-12-hydroxy-5-isopropyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (34) was synthesized from 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazonine-10-carboxamide (24 mg, 0.049 mmol) using 2-iodopropane (12.38 mg, 0.073 mmol) according to a procedure similar to that used to prepare compound 33. MS(m / z) 447.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s,1H),10.40 - 10.30 (m, 1H), 8.58 (d, J = 17.2 Hz, 1H), 8.50 (s, 1H), 7.81 (d, J = 12.3 Hz, 1H), 7.38 (dd, J = 9.0, 6.8 Hz, 2H), 7.22 (ddd, J = 10.7, 9.3, 2.6 Hz, 2H), 7.05 (td, J = 8.5, 2.5 Hz, 2H), 4.53 (d, J = 5.7 Hz, 5H), 4.26 (s, 2H), 4.08 (s, 3H), 3.97 - 3.80 (m, 3H), 3.04 (s, 4H), 2.71 (s, 2H), 0.83 (s, 3H), 0.66 (s, 3H). Example 32: Preparation of (7R)—N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (35) [ka]

[0353] (7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (35) was synthesized from ethyl 3-(benzyloxy)-5-((3-chloro-2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (170 mg, 0.356 mmol) and (R)-azepan-3-amine (48.7 mg, 0.427 mmol) according to the same procedure used to prepare compound 28. MS (m / z) 438.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.42 (t,J = 6.0Hz, 1H), 8.47 (s, 1H), 7.37 (td, J = 8.4, 6.2 Hz, 1H), 7.27 (td, J =8.8, 1.6Hz, 1H), 4.78 - 4.70 (m, 1H), 4.57 (d, J = 5.9 Hz, 2H), 4.16 - 4.08(m, 2H),3.86 (d, J = 14.9 Hz, 1H), 3.65 (dd, J = 14.7, 1.8 Hz, 1H), 3.06 (ddd, J = 13.2, 6.9, 3.5 Hz, 1H), 1.98 (dd, J=7.5, 4.4 Hz, 1H), 1.90 - 1.70 (m, 3H), 1.62 (d, J = 7.5 Hz, 1H), 1.12 (d, J=12.7 Hz, 1H). Example 33: Preparation of N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (36) [ka] Synthesis of tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (36b):

[0354] To a solution of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (36a) (300 mg, 1.086 mmol) in THF (5 mL) was added BH3-THF solution (6 mL, 1N, 6 mmol) at room temperature. After stirring overnight, the reaction was quenched by the addition of MeOH and aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate. MS (m / z) 262.897 [M+H] + . Synthesis of 2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine (36c):

[0355] To a solution of tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (36b) (13 mg, 0.05 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. After 2 h, the solvent and excess TFA were removed. The residue was used in the next step without purification. MS (m / z) 162.952 [M+H] + . Synthesis of N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (36):

[0356] N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonine-9-carboxamide (36) was synthesized from methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (30 mg, 0.07 mmol) and 2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine according to the same procedure used to prepare compound 28. MS (m / z) 452.152 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34(t, J =5.9 Hz, 1H), 8.59 (s, 1H), 7.41 (s, 1H), 7.36 - 7.16 (m, 5H), 7.05 (tdd,J =8.5, 2.7, 1.1 Hz, 1H), 4.89 (s, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.18 (s,1H),3.74 (d, J = 2.1 Hz, 1H), 2.83 - 2.67 (m, 2H), 2.24 (s, 1H), 2.10 (s, 1H). Example 34: Preparation of (12R)- and (12S)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (37-1, 37-2): [ka]

[0357] (12R)- and (12S)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonine-9-carboxamide (37-1, 37-2) were reacted with (R)- and (S)-(2,3,4,5-tetrahydro-1H-benzo[b]azepam). 37a-1 was synthesized from tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (37a-1, 37a-2, 164 mg, 0.625 mmol for each enantiomer), which was separated from racemic tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (36b) by chiral HPLC separation (SFC chromatography on an IB 4.6 x 100 mm 5-micron column using EtOH (15%) as cosolvent) following the same procedure as used to prepare compound 28. Peak 1 (37a-1) gave 37-1. MS (m / z) 452.16 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (t,J =5.9 Hz, 1H), 8.62 (s, 1H), 7.48 - 7.21 (m, 7H), 7.13 - 7.03 (m, 1H), 4.91(dq, J= 4.9, 2.5 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.23 - 4.14 (m, 1H), 3.75 (dd, J = 14.8, 2.1 Hz, 1H), 2.79 (dtd, J = 17.3, 14.5, 9.6 Hz, 2H), 2.27 (td, J = 12.1, 11.6, 4.8 Hz, 1H), 2.15 - 2.05 (m, 1H). Peak 2 (37a-2) gave 37-2. MS (m / z) 452.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.33 (t,J = 5.9 Hz, 1H), 8.59 (s, 1H), 7.40 (d, J = 6.9 Hz, 1H), 7.36 - 7.18 (m, 5H), 7.05 (td, J = 8.4, 2.5 Hz, 1H), 4.89 (s, 1H), 4.55 (d, J = 5.9 Hz, 2H), 4.16 (d, J = 14.5 Hz, 1H), 3.86 (s, 1H), 2.81 - 2.70 (m, 2H), 2.24 (d, J = 3.5 Hz, 1H), 2.09 (d, J = 8.4 Hz, 1H). Example 35: Preparation of (12R)- and (12S)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (38-1, 38-2): [ka]

[0358] (12R)- and (12S)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamides (38-1 and 38-2) were synthesized similarly to 37-1 and 37-2, using methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate instead of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate. MS (m / z) 470.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.8 Hz, 1H), 10.25 (s, 1H), 8.57 (s, 1H), 7.36 - 7.24 (m, 4H), 7.19 (t, J = 8.6 Hz, 2H), 4.86 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H), 4.14 (d, J = 14.5 Hz, 1H), 3.71 (dd, J = 14.8, 2.0 Hz, 1H), 2.81 - 2.69 (m, 2H),2.27- 2.17 (m, 1H), 2.08 (d, J = 9.7 Hz, 1H). Example 37: Preparation of (4R,7S,8S)- and (4S,7R,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazecine-11-carboxamide (40-1, 40-2): [ka] [ka] Synthesis of 4-bromo-2-azabicyclo[4.2.1]nonan-3-one (40a):

[0359] To a solution of 2-azabicyclo[4.2.1]nonan-3-one (1 g, 7.18 mmol) in DCM (30 mL) was added PCl5 (1.496 g, 7 mmol) while cooling in an ice-water bath. After stirring at 0-5 °C for 1 h, iodine (18.2 mg, 0.7 mmol) was added, and the mixture was stirred for 5 min. A solution of bromine (1.148 g, 7 mmol) in DCM (5 mL) was added at -5 °C, and the mixture was stirred at room temperature for 1.5 h. Ice water was added. The mixture was extracted with ethyl acetate (100 mL) and water (100 mL). The residue was washed with aqueous NaSO and brine. After drying and solvent removal, the residue was crystallized from DCM and hexane to give the title compound. MS (m / z) 218.1 [M+H] + . Synthesis of 4-azido-2-azabicyclo[4.2.1]nonan-3-one (40b):

[0360] A mixture of 4-bromo-2-azabicyclo[4.2.1]nonan-3-one (40a) (330 mg, 1.513 mmol) and NaN3 (394 mg, 6 mmol) in DMF (10 mL) was heated in a microwave reactor at 120 °C overnight. The reaction mixture was extracted with ethyl acetate (100 mL) and the extract was washed with brine. The mixture was dried and the solvent was removed. The residue was purified by silica gel chromatography to give 4-azido-2-azabicyclo[4.2.1]nonan-3-one (40b). MS (m / z) 181.12 [M+H] + . rel-((1R,4S,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamic acid tert- Butyl (40c) and rel-((1R,4R,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl) carboxylate Synthesis of tert-butyl carbamate (40d):

[0361] A reactor was charged with 4-azido-2-azabicyclo[4.2.1]nonan-3-one (40b) (500 mg, 2.775 mmol), di-tert-butyl dicarbonate (1.21 g, 6 mmol), and palladium on carbon (10 wt%, wet, 296 mg) in EtOH (30 mL) under argon. The reaction mixture was placed under reduced pressure and backfilled with hydrogen gas. After vigorously stirring for 2 hours, the reaction mixture was diluted with EtOH (50 mL), filtered through Celite®, and washed with ethyl acetate. The solvent was removed, and the residue was purified by silica gel chromatography to give two diastereomeric products, peak 1 and peak 2. Peak 1, tert-butyl rel-((1R,4S,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamate (40c). MS (m / z) 255.02 [M+H] +. 1 H NMR (400 MHz, chloroform-d) δ 6.10 - 5.84 (m, 2H), 4.12 (d, J = 4.9 Hz, 1H), 3.25 (dd, J =14.6, 3.1 Hz, 1H), 3.10 (dddd, J = 14.8, 8.4, 6.9, 1.4 Hz, 1H), 2.53 (s,1H),2.36 (d, J = 6.2 Hz, 1H), 1.99 - 1.82 (m, 2H), 1.73 - 1.58 (m, 3H), 1.50(d, J = 1.9 Hz, 1H), 1.45 (s, 9H). Peak 2, rel-((1R,4R,6S)-3 ... tert-Butyl 2-azabicyclo[4.2.1]nonan-4-yl)carbamate (40d). MS (m / z) 277.2 [M+Na] + . 1 HNMR (400 MHz, chloroform-d) δ 5.89 (s,1H), 5.56 (s, 1H), 4.02 (dd, J = 6.9, 4.5 Hz,1H), 3.36 (ddd, J = 15.3, 7.6,6.0 Hz, 1H), 2.76 (dt, J = 15.4, 6.5 Hz, 1H), 2.42 - 2.31 (m, 1H), 2.17 (s,1H), 1.97 (s, 2H), 1.75 (d, J = 12.7 Hz, 2H), 1.67 - 1.55 (m, 1H), 1.45 (s, 9H),1.41(d, J = 5.7 Hz, 1H). Synthesis of rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f):

[0362] rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f) was synthesized from tert-butyl rel-((1R,4S,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamate (40c) in a similar manner to the synthesis of 2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine (36c) from tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (36a). Synthesis of (4S,7R,8R)- and (4R,7S,8S)-13-(benzyloxy)-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazecine-11-carboxamide (40g-1, 40g-2):

[0363] rel-(4R,7S,8S)-13-(benzyloxy)-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazecine-11-carboxamide (40g) was synthesized from rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f) and methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate by the same procedure as used to prepare compound 28, followed by chiral HPLC separation to give peak 1 (40g-1) and peak 2 (40g-2). MS (m / z) 538.2 [M+H] + . Synthesis of (4R,7S,8S)- and (4S,7R,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazecine-11-carboxamides (40-1 and 40-2):

[0364] (4R,7S,8S)- and (4S,7R,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazecine-11-carboxamides (40-1, 40-2) were synthesized from compounds 40h-1 and 40h-2, respectively, following the same procedure used to prepare compound 28. MS (m / z) 448.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (t,J = 5.8Hz, 1H), 8.50 (s, 1H), 7.19 (t, J = 8.6 Hz, 2H), 4.55 (dd, J = 5.9, 2.8Hz, 2H),4.51 - 4.38 (m, 1H), 4.21 (dd, J = 13.4, 7.0 Hz, 1H), 3.80 (d, J =15.1 Hz, 1H), 2.90 - 2.68 (m, 2H), 2.68 - 2.59 (m, 1H), 2.57 - 2.50 (m, 1H),2.15 - 1.99 (m, 1H) , 1.74 (d, J = 7.0 Hz, 2H), 1.49 (dd, J =14.1, 6.9 Hz, 2H), 1.16 (d, J = 14.4Hz, 1H). Example 38: Preparation of (4S,7R,8S)- and (4R,7S,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazecine-11-carboxamide (41-1 and 41-2): [ka]

[0365] (4S,7R,8S)- and (4R,7S,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazecine-11-carboxamides (41-1 and 41-2) were synthesized from tert-butyl rel-((1R,4R,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamate (40d) in a similar manner to the preparation of compounds 40-1 and 40-2. MS (m / z) 448.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (t,J = 5.8Hz, 1H), 8.48 (s, 1H), 7.19 (t, J = 8.6 Hz, 2H), 4.78 (d, J = 9.2 Hz,1H), 4.55 (t, J =5.7 Hz, 2H), 4.08 (d, J = 13.3 Hz, 1H), 3.82 (d, J = 2.5 Hz,1H), 3.05 - 2.88(m, 2H), 2.42 (s, 1H), 2.19 (d, J = 14.0 Hz, 1H), 1.63 (dd, J= 13.2, 7.2 Hz,3H), 1.40 (d, J = 11.9 Hz, 1H), 0.92 (d, J = 3.7 Hz, 1H). Example 39a: Preparation of N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazonin-7-carboxamide (42-1): [ka] Synthesis of benzyl (1-hydroxypent-4-en-2-yl)carbamate (42a):

[0366] To one round-bottom flask was added 2-aminopent-4-en-1-ol (2000 mg, 19.8 mmol), 100 mL of water, and anhydrous potassium carbonate (2.5 g, 40 mmol). To a second round-bottom flask was added 100 mL of dioxane and benzyl chloroformate (3.1 mL, 22 mmol). Each mixture was stirred to dissolve. The amine mixture was cooled in an ice bath, and the dioxane mixture was added. The reaction mixture was allowed to warm slowly to room temperature with stirring overnight. The reaction mixture was diluted with DCM and extracted twice with DCM. The organic extracts were washed with NH4Cl, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give the title compound. MS (m / z) 235.9 [M+H] + . Synthesis of benzyl (1-oxopent-4-en-2-yl)carbamate (42b):

[0367] To a round-bottom flask was added benzyl (1-hydroxypent-4-en-2-yl)carbamate (42a, 3 g, 13 mmol) and 200 mL of DCM, followed by Dess-Martin periodinane (6 g, 14.2 mmol). After stirring for 1 h, additional Dess-Martin periodinane (2 g, 4.7 mmol) was added to the reaction mixture, and stirring was continued for another 30 min. The mixture was diluted with DCM, and saturated NaHCO3 solution and 11 g of sodium thiosulfate were added. The resulting mixture was stirred for approximately 10 min and extracted twice with DCM. The organic extracts were washed with brine, water, and HCl. and NaHCO3 mixture, dried over sodium sulfate, and concentrated to give the title compound. MS (m / z) 234.0 [M+H] + . Synthesis of benzyl (1-(allylamino)pent-4-en-2-yl)carbamate (42c):

[0368] To a round-bottom flask was added benzyl (1-oxopent-4-en-2-yl)carbamate (6 g, 26 mmol) and THF (100 mL). Allylamine (2.1 mL, 28.3 mmol) and sodium triacetoxyborohydride (8.2 g, 39 mmol) were added, and the reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 (20 mL), and the mixture was extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound. MS (m / z) 275.2 [M+H] + . Synthesis of benzyl allyl(2-(((benzyloxy)carbonyl)amino)pent-4-en-1-yl)carbamate (42d):

[0369] To one round-bottom flask was added benzyl (1-(allylamino)pent-4-en-2-yl)carbamate (42c, 6.3 g, 23.1 mmol), 120 mL of water, and anhydrous potassium carbonate (2.9 g, 46.2 mmol). To a second round-bottom flask was added 120 mL of dioxane and benzyl chloroformate (3.6 mL, 25.4 mmol). Each mixture was stirred to dissolve. The amine mixture was cooled in an ice bath, and the dioxane mixture was added. The reaction mixture was allowed to warm slowly to room temperature with stirring overnight. The reaction mixture was diluted with DCM and extracted twice with DCM. The organic extracts were washed with NH4Cl, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give the title compound. MS (m / z) 409.7 [M+H] + . Synthesis of benzyl-3-(((benzyloxy)carbonyl)amino)azepane-1-carboxylate (42e-1 and 42e-2):

[0370] In a round-bottom flask, add benzyl allyl(2-(((benzyloxy)carbonyl)amino)pent-4-en-1-yl)carbamate (42d, 6.3 mg, 16 mmol), DCM (400 mL), and bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (Grubbs catalyst TM To the resulting mixture was added 42e-1 (peak 1) and 42e-2 (peak 2). MS (m / z) 381.5 [M+H]. + . Synthesis of benzyl 5-(((benzyloxy)carbonyl)amino)-3-azabicyclo[5.1.0]octane-3-carboxylate (42f-1):

[0371] To a three-neck flask was added 42e-1 (626 mg, 1.6 mmol) and DCM (3 mL). The resulting mixture was cooled to 0° C., and 1 M diethylzinc in hexanes (3.46 mL) was slowly added, followed by diiodomethane (0.5 mL, 6.6 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, and a second charge of diethylzinc and diiodomethane was added. The mixture was stirred at 0° C. for 2 hours, removed from the ice bath, and stirred for an additional 2 hours. A third charge of diethylzinc and diiodomethane was added, and the mixture was stirred overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give The title compound was obtained. MS (m / z) 395.3 [M+H] + . Synthesis of 5-(benzyloxy)-N-(2,4-difluorobenzyl)-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazonin-7-carboxamide (42h-1):

[0372] A round-bottom flask was charged with 42f-1 (200 mg, 0.5 mmol), ethanol (20 mL), and palladium on carbon (10 wt. % loading, dry basis), matrix carbon powder, wet support (216 mg, 0.2 mmol). The mixture was sparged with N and a balloon of H was attached. The reaction mixture was stirred overnight, filtered through Celite®, and concentrated. The residue was combined with methyl 3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyran-2-carboxylate (108.9 mg, 0.5 mmol), NaHCO (85 mg, 1 mmol), and MeOH (3 mL). The mixture was stirred at 70 °C for approximately 4 hours until crystallization was complete. The solid was filtered off, and the solution was concentrated. The residue was dissolved in DMF / water / TFA and purified by HPLC to give the major diastereomer of the title compound. MS (m / z) 506.2 [M+H] + . Synthesis of N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazonin-7-carboxamide (42-1):

[0373] To a vial was added 5-(benzyloxy)-N-(2,4-difluorobenzyl)-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazonin-7-carboxamide (42h-1, 63 mg, 0.12 mmol), toluene (2 mL), and TFA (1 mL). The reaction mixture was stirred until LCMS indicated complete deprotection, concentrated, diluted with DMF, and purified by HPLC to give the title compound. MS (m / z) 416.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 10.59 (s,1H), 8.55 (s, 1H), 7.41 - 7.32 (m, 1H), 6.89 - 6.78 (m, 2H), 4.67 (d, 2H), 4.64- 4.55 (m, 1H), 4.48(dd, 1H), 4.22 (dd, 1H), 3.94 - 3.83 (m, 1H), 3.75 - 3.66(m, 1H), 2.96 - 2.84(m, 1H), 1.38 - 1.07 (m, 3H), 0.49 - 0.41 (m, 1H). Example 39b: Preparation of (1aS,10R,11aS)-N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazonin-7-carboxamide (42-2): [ka]

[0374] (1aS,10R,11aS)-N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazonin-7-carboxamide (42-2) was prepared similarly to 42-1, starting with 42e-2 (peak 2) instead of 42e-1 (peak 1). MS (m / z) 416.2 [M+H] + . 1 H NMR (400 MHz , chloroform-d) δ 10.46 (s, 1H), 8.43 (s, 1H), 7.40 - 7.30 (m, 1H), 6.87 - 6.75 (m,2H), 4.64 (d, 2H), 4.56 - 4.50 (m, 1H), 4.50 - 4.40 (m, 1H), 4.18 (dd, 1H), 3.86 (dd, 1H), 3.67 (d, 1H), 2.93 - 2.80 (m,1H), 1.37 - 1.04 (m, 3H), 0.91 - 0.76 (m, 1H), 0.47 - 0.34 (m, 1H). Example 40: Preparation of 2,4,6-trifluorobenzyl (7S)-12-methoxy-1,11-dioxo-1,3,4,5,6,11-hexahydro-713-2,7-methanopyrido[2,1-c][1,4]diazonin-10-carboxylate and 2,4,6-trifluorobenzyl (7R)-12-methoxy-1,11-dioxo-1,3,4,5,6,11-hexahydro-713-2,7-methanopyrido[2,1-c][1,4]diazonin-10-carboxylate (43-1, 43-2): [ka] Synthesis of 3-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (43a):

[0375] To a solution of 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (1 g, 5.58 mmol) in DCM (25 mL) was added phosphorus pentachloride (1.16 g, 5.58 mmol) under ice-cooling. After stirring the reaction mixture for 5 hours, iodine (14.2 mg, 0.558 mmol) was added, followed by bromine (0.892 g, 5.58 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was extracted with ethyl acetate and washed with an aqueous solution of Na2S2SO3 and brine. The organic layer was dried over MgSO4, and the solvent was removed by rotary evaporation. The title compound was crystallized from a mixture of DCM / ethyl acetate. MS (m / z) 260 [M+H] + . 1 HNMR (400 MHz, DMSO-d6)δ 10.18 (s, 1H), 7.25 (td, J = 8.1, 6.3 Hz,1H), 6.99 (ddd, J = 9.4, 8.4, 1.1Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 4.65 (dd, J= 9.2, 7.3 Hz, 1H), 2.96 - 2.83(m, 1H), 2.76 - 2.59 (m, 2H), 2.47 - 2.41 (m,1H). Synthesis of 3-azido-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (43b):

[0376] To a solution of 3-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (43a, 109 mg, 0.422 mmol) in DMF (5 mL) was added sodium azide (110 mg, 1.69 mmol). After stirring at 60° C. for 4 hours, the reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over MgSO4, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column to give the title compound. MS (m / z) 221 [M+H] + . Synthesis of tert-butyl (6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (43c):

[0377] To a solution of 3-azido-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (43b, 880 mg, 4 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (1.308 g, 5.99 mmol) and 10% Pd / C (425 mg), and the mixture was then sparged under a hydrogen atmosphere (balloon pressure). After stirring the reaction for 2 hours, it was filtered through a pad of Celite® and washed with ethyl acetate, and the filtrate was concentrated on a rotary evaporator. The residue was purified on a silica gel column to give the title compound. MS (m / z) 317.1 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ9.87(s, 1H), 7.32 - 7.21 (m, 1H), 7.00 (q, J = 8.5 Hz, 2H), 6.85 (d, J = 7.9 Hz, 1H), 3.91 - 3.78 (m, 1H), 2.96 (dd, J = 14.0, 6.3 Hz, 1H), 2.45 - 2.28 (m, 1H), 2.23 - 1.98 (m, 2H), 1.32 (s, 9H). Synthesis of (S)-tert-butyl(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate and (R)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (43d-1 and 43d-2):

[0378] To a solution of tert-butyl (6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (43c, 800 mg, 2.72 mmol) in THF (30 mL) was added BH3-THF solution (1N, 13 mL) at room temperature. After stirring the reaction overnight, the reaction was quenched with MeOH (1 mL) and an aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (100 mL) and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column to give tert-butyl (6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (43d). MS (m / z) 281.2 [M+H] + .

[0379] 43d was separated into its individual enantiomers by chiral HPLC (SFC chromatography on an IB 4.6×100 mm 5 mic column using EtOH (15%) as co-solvent) to give the title compounds. Synthesis of (S)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine and (R)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine (43e-1 and 43e-2)

[0380] (S)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepi To a solution of (R)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate or (R)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (65 mg, 0.232 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. After 2 hours, the solvent and excess TFA were removed by rotary evaporation to give the title compound (43e-1 or 43e-2), which was carried on to the next step without further purification. MS (m / z) 181.2 [M+H] + . Synthesis of (S)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate and (R)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (43f-1 and 43f-2):

[0381] To a solution of (S)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine or (R)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine (43e-1 or 43e-2, 40 mg, 0.143 mmol) in MeOH / water (v / v=6 / 1, 3.5 mL) was added sodium bicarbonate (59.9 mg, 0.713 mmol) and methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (60 mg, 0.134 mmol). The reaction mixture was stirred at 60° C. overnight, extracted with ethyl acetate (100 mL), and washed with brine. The organic layer was dried over MgSO4 and the solvent was removed by rotary evaporation to give the title compound (43f-1 or 43f-2), which was carried forward without further purification. MS (m / z) 610.2 [M+H] + . (12S)-7-(benzyloxy)-1-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and (12S)-1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide, and (12R)-7-(benzyloxy)-1-fluoro Synthesis of a mixture of (12R)-1-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and (12R)-1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (a mixture of 43g-1 and 43h-1), and (a mixture of 43g-2 and 43h-2):

[0382] To a solution of crude (S)- or (R)-2-methyl 5-(2,4,6-trifluorobenzyl) 3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (43f-1 or 43f-2, 80 mg, 0.131 mmol) in MeOH (6 mL) was added an aqueous solution of LiOH (2 N, 2 mL). After stirring for 2 h, the solvent was removed and extracted with ethyl acetate (100 mL). After drying the organic layer over MgSO, the solvent was removed by rotary evaporation to give the title compounds (a mixture of 43g-1 and 43h-1, or a mixture of 43g-2 and 43h-2), which were used crude without further purification. 43g-1, 43g-2:MS (m / z) 578.2 [M+H] + 43h-1, 43h-2: MS (m / z) 501.2 [M+H] + . Synthesis of (12S)-1-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and (12R)-1-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (43-1 and 43-2):

[0383] (12S)-7-(benzyloxy)-1-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and 1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (43 g / 43 h, 1,198 mg, 0.343 mmol), or (12R)-7-(benzyloxy)-1-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (43 g / 43 h, 1,198 mg, 0.343 mmol). To a mixture of 1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and 1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (43 g / 43 h, 98 mg, 0.17 mmol) in DMF (6 mL) was added LiCl (10 equiv). After stirring at 105°C for 1.5 hours, the reaction mixture was filtered and purified by preparative HPLC (Gemini 10u C18 110A) eluting with 15-80% acetonitrile in water (0.1% TFA) over 15 minutes to give the title compound (43-1 or 43-2).

[0384] 43-1: MS (m / z) 488.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ10.34 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 7.32 (dd, J = 8.1, 6.1 Hz, 1H), 7.19(td, J = 8.3, 3.5Hz, 4H), 4.95 - 4.85 (m, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.13(d, J = 14.7 Hz,1H), 3.85 (dd, J = 14.9, 2.1 Hz, 1H), 2.88 (dd, J = 17.0, 9.7Hz, 1H), 2.71 (dd,J = 16.9, 9.2 Hz, 1H), 2.42 - 2.28 (m, 1H), 2.03 - 1.92 (m, 1H)。

[0385] 43-2:MS (m / z) 488.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6)δ10.34 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 7.33 (td, J = 8.1, 6.1 Hz, 1H), 7.19(td, J = 8.4, 4.0Hz, 3H), 4.90 (t, J = 5.8 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H),4.13 (d, J = 14.6Hz, 1H), 3.87 (d, J = 2.2 Hz, 1H), 2.88 (dd, J = 16.5, 10.1Hz, 1H), 2.71 (dd, J= 16.9, 9.2 Hz, 1H), 2.35 (q, J = 7.7, 7.0 Hz, 1H), 1.98(d, J = 8.6 Hz, 1H)。 Example 41: Preparation of (8R,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxamide and (8S,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxamide (44-1 and 44-2): [ka] Synthesis of benzyl (R,Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate and (S,Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate (44a-1 and 44a-2)

[0386] The title compound was synthesized from 2-aminopent-4-en-1-ol in a manner similar to that of 42e-1 and 42e-2, except that 42-b was reacted with but-3-en-1-amine instead of allylamine. 44a-1: MS (m / z) 395.2 [M+H] + 44b-1: MS (m / z) 395.2 [M+H] + . Synthesis of (R,Z)- and (S,Z)-1,2,3,4,7,8-hexahydroazocin-3-amine (44b-1 and 44b-2)

[0387] To a vial was added benzyl (R,Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate or (S,Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate (44a-1 or 44a-2, 500 mg, 1.3 mmol) and 4N HCl in dioxane (6.3 mL, 25 mmol). The reaction was stirred at 95° C. overnight, cooled to room temperature, and concentrated to give the title compound (44b-1 or 44b-2), which was used subsequently without further purification. MS (m / z) 127.2 [M+H] + . Synthesis of (8R,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxamide and (8S,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanopyrido[1,2-a][1,4]diazecine-11-carboxamide (44-1 and 44-2)

[0388] The title compound was synthesized from (R,Z)-1,2,3,4,7,8-hexahydroazocin-3-amine or (S,Z)-1,2,3,4,7,8-hexahydroazocin-3-amine (44b-1 or 44b-2, 18.9 mg, 0.163 mmol) and ethyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (70 mg, 0.163 mmol) according to a procedure similar to that for the preparation of compound 28.

[0389] 44-1: MS (m / z) 416.3 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 10.71-10.56 (m, 1H), 8.56 (s, 1H), 7.38 (q, 1H), 6.91-6.78 (m, 2H), 6.05(q, 1H),5.71 (q, 1H), 4.76-4.61 (m, 2H), 4.55 (ddd, 1H), 4.48-4.34 (m,1H), 4.02-3.90 (m, 1H), 3.75 (d, 1H), 3.09 - 2.97 (m, 1H), 2.73 - 2.64 (m, 1H), 2.63 - 2.52(m, 1H), 2.52 - 2.45 (m, 1H), 2.45 - 2.32 (m, 1H).

[0390] 44-2: MS (m / z) 416.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 10.66-10.51 (m, 1H), 8.52 (s, 1H), 7.38 (q, 1H), 6.84 (q, 2H), 6.05 (q, 1H), 5.71(q, 1H), 4.74-4.62 (m, 2H), 4.56 (ddd, 1H), 4.46-4.35 (m, 1H), 3.97(dd,1H), 3.75 (d, 1H), 3.08-2.99 (m, 1H), 2.71-2.63 (m, 1H), 2.63-2.54(m,1H), 2.53- 2.45 (m, 1H), 2.44 - 2.32 (m, 1H). Example 42: Preparation of (12S)-1-chloro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and (12R)-1-chloro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (45-1 and 45-2): [ka]

[0391] The title compound was prepared similarly to 43-1 and 43-2 using 6-chloro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one instead of 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one.

[0392] 45-1: MS (m / z) 504.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ10.38 (t, J = 5.8 Hz, 1H), 8.60 (s, 1H), 7.47 (dd, J = 6.7, 2.8 Hz, 1H), 7.40- 7.30 (m, 2H), 7.29 - 7.16 (m, 2H), 4.96 - 4.88 (m, 1H), 4.59 (d, J = 5.7 Hz, 2H),4.15 (dd, J =15.0, 1.9 Hz, 1H), 3.86 (dd, J = 14.7, 2.2 Hz, 1H), 3.04 (ddd, J= 17.1, 9.7,2.3 Hz, 1H), 2.86 (ddd, J = 15.8, 10.3, 5.6 Hz, 1H), 2.41 - 2.32(m, 1H), 2.06 (dd,J = 13.4, 6.9 Hz, 1H).

[0393] 45-2: MS (m / z) 504.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ10.38 (t, J = 5.8 Hz, 1H), 10.27 (s, 1H), 8.60 (s, 1H), 7.47 (dd, J = 6.7,2.7 Hz, 1H), 7.41 -7.30 (m, 2H), 7.29 - 7.16 (m, 2H), 4.96 - 4.88 (m, 1H),4.59 (d, J = 5.7 Hz,2H), 4.20 - 4.11 (m, 1H), 3.86 (dd, J = 14.7, 2.2 Hz, 1H), 3.04 (ddd, J = 17.2, 9.8, 2.3 Hz, 1H), 2.86 (dd, J = 16.8, 9.2 Hz, 1H), 2.42 - 2.33 (m, 1H), 2.04 (q, J = 13.0, 9.4 Hz, 1H). Example 43: Preparation of (12S)-4-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and (12R)-4-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (46-1 and 46-2): [ka] Synthesis of (S)- and (R)-methyl 3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (46a-1 and 46a-2):

[0394] The title compound was synthesized by the reaction of (S)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate with (R)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate. 43f-1 and 43f-2) were prepared in an analogous manner to 43f-1 and 43f-2, using 9-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one instead of 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one. Synthesis of (12S)-7-(benzyloxy)-4-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and (12R)-7-(benzyloxy)-4-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (46b-1 and 46b-2):

[0395] To a solution of methyl (S)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate or (R)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (46a-1 or 46a-2, 80 mg, 0.13 mmol) in MeOH (20 mL) was added LiOH (2 N, 4 mL) at room temperature. After heating to 50° C. and stirring for 2 hours, citric acid solution (5% in water) was added and the reaction was extracted with ethyl acetate (100 mL). Removal of the solvent gave (S)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid or (R)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid, which was carried forward without further purification. MS (m / z) 596.2 [M+H] + .

[0396] To a solution of (S)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid or (R)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid in DCM (5 mL) was added DIPEA (39 mg, 0.302 mmol) and HATU (86.1 mg, 0.227 mmol) at room temperature. After 1 hour, the reaction mixture was purified by silica gel column eluting with ethyl acetate to give the title compound (46b-1 or 46b-2). MS (m / z) 578.2 [M+H] + . Synthesis of (12S)-4-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide and (12R)-4-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (46-1 and 46-2):

[0397] To a solution of (12S)-7-(benzyloxy)-4-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide or (12R)-7-(benzyloxy)-4-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazonin-9-carboxamide (46b-1 or 46b-2, 80 mg, 0.13 mmol) in toluene (4 mL) was added TFA (1 mL) at room temperature. After stirring overnight, the solvent and excess TFA were removed by rotary evaporation, and the residue was purified by preparative HPLC to give the title compound.

[0398] 46-1: MS (m / z) 488.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ10.35 (t, J = 5.8 Hz, 1H), 8.57 (s, 1H), 7.29 (dd...

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