Bridged tricyclic carbamoyl pyridone compounds and pharmaceutical uses thereof

Abstract

Compounds for the treatment or prevention of human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following formula (I): including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2, L, W1, W2, X, Y and Z are as defined herein. Also disclosed are methods associated with the preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds. # imgabs0 #

Description

[0001] This application is a divisional application of an invention patent application with an application date of March 20, 2020, application number 202080034051.X, and invention name “Bridged tricyclic aminoformyl pyridone compounds and their pharmaceutical uses”.

[0002] Cross-references

[0003] This application claims priority to U.S. Provisional Application No. 62 / 822,703, filed on March 22, 2019, and U.S. Provisional Application No. 62 / 948,697, filed on December 16, 2019, both of which are incorporated herein in their entirety for all purposes. Background Art

[0004] field

[0005] Disclosed are compounds, compositions and methods useful for treating or preventing human immunodeficiency virus (HIV) infection. Specifically, disclosed are novel bridged tricyclic carbamoyl pyridone compounds, methods for their preparation and use as therapeutic or prophylactic agents.

[0006] Description of Related Technology

[0007] Human immunodeficiency virus infection and related diseases are major public health issues worldwide. Human immunodeficiency virus encodes three enzymes required for viral replication: reverse transcriptase, protease and integrase. Although drugs targeting reverse transcriptase and protease are widely used and show effectiveness, especially when used in combination, toxicity and the development of drug-resistant strains may limit their effectiveness (Palella, et al. N. Engl. J Med. (1998) 338: 853–860; Richman, DDNature (2001) 410: 995–1001). Therefore, new agents that inhibit HIV replication are needed.

[0008] The goal of antiretroviral therapy is to achieve viral suppression in patients infected with HIV. Current treatment guidelines issued by the U.S. Department of Health and Human Services stipulate 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 from http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed on February 12, 2019). In addition, decisions about the treatment of HIV-infected patients are complex when patients require treatment for other medical conditions (Id. at F-8). Since the standard of care requires the use of multiple different drugs to suppress HIV and other diseases that patients may be experiencing, the possibility of drug interactions is a criterion for selecting a drug treatment regimen. Therefore, antiretroviral therapies with reduced potential for drug interactions are needed.

[0009] In addition, HIV is known to mutate in infected individuals (Tang, et al. Drugs (2012) 72 (9) e1-e25). Since HIV has a tendency to mutate, anti-HIV drugs are required to be effective against a range of known HIV variants (Hurt, et al. HIV / AIDS CID (2014) 58, 423-431).

[0010] For some patients, for example, those with limited or limited access to healthcare, adherence to a daily oral therapeutic or preventive regimen may be challenging. Drugs that provide favorable pharmaceutical properties (e.g., improved efficacy, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) are suitable for less frequent administration and provide better patient compliance. Such improvements, in turn, can optimize drug exposure and limit the emergence of drug resistance. Summary of the invention

[0011] The present disclosure relates to novel compounds with antiviral activity and pharmaceutically acceptable salts thereof. In some embodiments, the 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 are effective against a series of known drug-resistant HIV mutants. In some embodiments, when co-administered with other drugs, the compounds disclosed herein may have a reduced tendency to cause drug-drug interactions. In some embodiments, the compounds disclosed herein can be administered at a frequency lower than once daily, for example, once a week, once a month, or at longer intervals.

[0012] In one embodiment, a compound having the following formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0013]

[0014] in

[0015] R 1 H or C 6-10 Aryl, where C 6-10 The aryl group is optionally substituted with 1 to 4 R A1 Substitute, where each R A1 are independently halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkyl-OC 1-4 alkyl;

[0016] R 2 H, C 1-6 Alkyl or C 1-4 Haloalkyl;

[0017] L is -CR 3a R 3b -、-C(O)-、-SO 2 -、-CH 2 -CH 2 -or-N(R a )-;

[0018] W 1 Key or -CR 4a R 4b -;

[0019] W 2 For-CR 5a R 5b -、-CR 5a R 5b CR 5c R 5d -、-CR6a =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)-;

[0020] X is a bond or -CR 8a R 8b -;

[0021] Y is -C(O)NH- or Q, wherein Q is

[0022] Z is -CR 9a R 9b -、-CR 9a R 9b CR 9c R 9d -or-CR 10a =CR 10b -;

[0023] R 3a and R 3b Independently H, C 1-6 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Alkyl; or optionally:

[0024] R 3a and R 3b Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A2 Substitute, where each R A2 are independently halogen, C1-4 Alkyl or C 1-4 Haloalkyl;

[0025] R 4a and R 4b Independently H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogen;

[0026] R 5a , R 5b , R 5c and R 5d Independently H, C 1-6 Alkyl, C 1-4 Haloalkyl, halogen, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; or optionally:

[0027] R 5a and R 5b or R 5c and R 5d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or

[0028] R 5a and R 5c or R 5b and R 5d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0029] Each R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 Alkyl; optionally:

[0030] R 6a and R 6bTogether with the carbon atoms to which they are attached, they form a 5- to 10-membered partially saturated fused ring containing 0 or 1 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 1 to 2 heteroatoms selected from N, O and S, wherein the partially saturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by 1 to 4 R A4 Substitute, where each R A4 are independently halogen or C 1-4 alkyl;

[0031] R 7 H, C 1-6 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO 2 R c ;

[0032] R 8a and R 8b Each independently represents H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 haloalkyl, cyano or halogen; or optionally:

[0033] R 8a and R 8b Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or optionally:

[0034] R 8a H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 haloalkyl, cyano or halogen; and

[0035] R 8b With R 5a , R 5b , R 5c , R 5d and R 7One of them and the atoms to which they are each attached together form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally fused with 1 to 4 R A5 Substitute, where each R A5 are independently halogen or C 1-4 Alkyl; or

[0036] R 8b and R 2 Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen or C 1-4 alkyl;

[0037] R 9a , R 9b , R 9c and R 9d Each independently is H, C 1-6 Alkyl, C 1-4 haloalkyl or halogen; or optionally:

[0038] R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A6 Substitute, where each R A6 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or

[0039] R 9a and R 9c or R 9b and R 9d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 3 R A6 Substitute, where each R A6 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or

[0040] R 9a , R 9b , R 9c and R 9d One and R 4a, R 4b , R 5a , R 5b and R 7 One of them and the atoms to which they are each attached together form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally fused with 1 to 4 R A6 Substitute, where each R A6 are independently halogen or C 1-4 alkyl;

[0041] R 10a and R 10b are independently H, halogen, C 1-4 Haloalkyl, or C 1-6 Alkyl; or optionally:

[0042] R 10a and R 10b Together with the carbon atoms to which they are attached, they form a 5- to 10-membered partially saturated fused ring containing 0 or 1 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 1 to 2 heteroatoms selected from N, O and S, wherein the partially saturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by 1 to 4 R A7 Substitute, where each R A7 are independently halogen or C 1-4 alkyl;

[0043] R a Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R c or SO 2 R c ;

[0044] R b H or C 1-4 alkyl;

[0045] R c C 1-4 Alkyl or -OC 1-4 Alkyl; and

[0046] Each n is 0, 1 or 2.

[0047] In one aspect, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0048] In another embodiment, a kit or article of manufacture comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and instructions for use.

[0049] In another embodiment, a method of treating HIV infection in a human suffering from or at risk of HIV infection is provided, wherein the method is performed 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.

[0050] In another embodiment, there is provided a 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 person suffering from HIV infection or having HIV infection.

[0051] In another embodiment, 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 is provided.

[0052] In another embodiment, 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 treating HIV infection is provided.

[0053] In another embodiment, there is provided the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV infection in a human suffering from or at risk of HIV infection.

[0054] In another embodiment, a method of using a compound of formula I in therapy is provided. Specifically, a method of treating HIV viral proliferation, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human) is provided, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient to the mammal.

[0055] In another embodiment, a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in a method of treating HIV viral proliferation, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

[0056] In another embodiment, a kit or article of manufacture is provided, comprising a composition effective for treating or preventing HIV infection; a packaging material comprising a label indicating that the composition can be used to treat or prevent HIV infection. An exemplary composition comprises a compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0057] In 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 that inhibit HIV replication.

[0058] In another embodiment, there is provided a use of a compound of Formula I for inhibiting HIV integrase activity.

[0059] In another embodiment, there is provided a use of a compound of Formula I or a pharmaceutically acceptable salt thereof for inhibiting HIV integrase activity.

[0060] In another embodiment, there is provided a use of a compound of Formula I or a salt thereof for inhibiting HIV replication.

[0061] In another embodiment, there is provided use of a compound of Formula I or a pharmaceutically acceptable salt thereof as a research tool.

[0062] Other embodiments, objects, features and advantages may be shown in the subsequent detailed description of the embodiments, and may be apparent from the present specification in part, or may be learned by practice. These objects and advantages may be achieved and obtained by the methods and compositions specifically pointed out in the present specification and the claims thereof. The above summary of the invention is made with the understanding that the above summary of the invention should be regarded as a brief description and general overview of some embodiments disclosed herein, and the summary of the invention is provided for the benefit and convenience of the reader and is not intended to limit in any way the scope or equivalent scope legally enjoyed by the claims attached to the present invention. DETAILED DESCRIPTION

[0063] In the following description, some specific details are shown to provide a thorough understanding of the various embodiments disclosed herein. However, it will be appreciated by those skilled in the art that the embodiments disclosed herein can be practiced without these details. The following description of several embodiments is carried out with the understanding that the application will be regarded as an example of the claimed subject matter, and is not intended to limit the attached claims to the specific embodiments described. The titles provided in the full text of this application are only for convenience and should not be interpreted as limiting the claims in any way. The scheme illustrated by example under any title can be combined with the embodiment illustrated by example under any other title.

[0064] definition

[0065] Unless the context requires otherwise, throughout this application and claims, the word "comprise" and variations such as "include" and "comprising" should be interpreted in an open and inclusive sense to mean "including but not limited to".

[0066] References throughout this specification to "one embodiment" or "an embodiment" mean that the specific features, structures, or characteristics described in connection with that embodiment are included in at least one embodiment of the present application. Thus, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0067] "Amino" refers to -NH 2 Group.

[0068] "Hydroxy" refers to an -OH group.

[0069] "Oxo" refers to a =0 substituent.

[0070] Prefixes such as "C u-v " or (C u -C v ) indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms.

[0071] "Alkyl" refers to a straight or branched chain hydrocarbon group consisting of carbon and hydrogen atoms, which is saturated and has 1 to 12 carbon atoms (C 1-12 alkyl), 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 Alkyl) which is attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1 dimethylethyl (tert-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, etc.

[0072] "Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene radical may have 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1,1-ethyl (-CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1-propyl (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH3 )-), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -)wait.

[0073] "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, an aryl group has 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 anthracenyl.

[0074] "Cyano" or "nitrile" refers to a -CN group.

[0075] "Carbocycle" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having from 3 to 15 carbon atoms, in certain embodiments from 3 to 10 carbon atoms or from 3 to 7 carbon atoms, being saturated or partially unsaturated, and being attached to the rest of the molecule by a single bond. Carbocycles include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0076] "Fused" refers to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring structure as described herein, which is connected to an existing ring structure in a compound disclosed herein through two adjacent atoms shared by the fused ring structure and the existing ring structure. For example, the bicyclic compound described below comprises 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), respectively:

[0077]

[0078] "Spiro" or "spirocyclic" refers to a carbocyclic or heterocyclic structure as described herein, which is connected to an existing ring structure in a compound disclosed herein through a single atom shared by the spirocyclic structure and the existing ring structure. For example, the following bicyclic compound contains a spirocyclopropane (i.e., a cyclopropane ring that forms a spirocyclic ring with a cyclohexane ring), a spirocyclo-1,3-dithiolane (i.e., a 1,3-dithiolane that forms a spirocyclic ring with a cycloheptane ring), and a spirocyclopentene (i.e., a cyclopentene ring that forms a spirocyclic ring with a cyclohexene ring), respectively:

[0079]

[0080] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[0081] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0082] "Heteroaromatic ring" refers to an aromatic group having one or more ring heteroatoms (e.g., 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom) independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 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 include pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl and pyrazolyl.

[0083] "Heterocyclyl" or "heterocycle" refers to a non-aromatic group or ring having 3 to 15 atoms, of which 1 to 6 atoms are heteroatoms selected from nitrogen, oxygen and sulfur and are connected to the rest of the molecule by a single bond. In certain embodiments, "heterocyclyl" has 3 to 10 atoms, of which 1 to 4 atoms are heteroatoms selected from nitrogen, oxygen and sulfur; or 3 to 7 atoms, of which 1 to 2 atoms are heteroatoms selected from nitrogen, oxygen and sulfur. The nitrogen, carbon or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized. As used herein, unless otherwise indicated, "heterocyclyl" or "heterocycle" refers to a saturated ring, for example, in some embodiments, "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated ring when specified. Examples of such heterocyclyl groups 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.

[0084] 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 can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, such as 2 H. 3H. 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, these radiolabeled compounds can be used to help determine or measure the effectiveness of a compound, for example, by characterizing the site or mode of action, or binding affinity for a pharmacologically important 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, those containing 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 suitable for this purpose because they are easy to incorporate and can be easily detected.

[0085] In certain embodiments, heavier isotopes such as deuterium are used. 2 H, substitution may offer certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life may be increased or dosage requirements may be reduced. Therefore, in some circumstances, heavier isotopes may be preferred.

[0086] Using positron emitting isotopes (such as 11 C, 18 F, 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine 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 described below, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously used.

[0087] The methods, compositions, kits and articles provided herein use or include a compound (e.g., 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, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, wherein n is the number of hydrogen atoms in the molecule. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds increase resistance to metabolism and therefore can be used to increase the half-life of a compound or a pharmaceutically acceptable salt thereof 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 in a manner known in the art, for example by using a starting material in which one or more hydrogen atoms have been replaced by deuterium.

[0088] The embodiments disclosed herein are also intended to cover the in vivo metabolites of the disclosed compounds. Such products can be produced by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, for example, mainly by enzymatic processes. Therefore, the embodiments disclosed herein include compounds produced by methods including: administering a compound according to the embodiments disclosed herein to a mammal for a period of time sufficient to produce its metabolites. Such products are generally identified as follows: a detectable dose of a radiolabeled compound according to the embodiments disclosed herein is administered to an animal, such as a rat, mouse, guinea pig, monkey or human, allowing enough time for metabolism to occur, and separating the conversion products from urine, blood or other biological samples.

[0089] "Mammal" includes humans and domestic animals, such as laboratory animals and household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals, such as wild animals, and the like.

[0090] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted heterocyclyl" means that the heterocyclyl may or may not be substituted, and that the description includes substituted heterocyclyls and unsubstituted heterocyclyls.

[0091] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier or other pharmacologically inactive substance which is formulated in combination with the pharmaceutically active ingredient of the pharmaceutical composition, is compatible with the other components of the formulation, is suitable for use in humans or livestock and is not overly toxic, irritating, causes allergic reactions, etc.

[0092] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from appropriate bases, such as alkali metals (eg, sodium), alkaline earth metals (eg, magnesium), ammonium and NX 4 + (Where X is C 1-4 The pharmaceutically acceptable salts of the nitrogen atom or the amino group include, for example, salts of organic carboxylic acids, such as 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, caproic 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, 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-naphthalenesulfonic acid; inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and aminosulfonic acid. Pharmaceutically acceptable salts of hydroxy compounds include anions of the compounds with suitable cations such as Na + and NX 4 + (wherein X is independently selected from H or C 1-4 alkyl) combinations.

[0093] For therapeutic use, salts of the active ingredients of the compounds disclosed herein are generally pharmaceutically acceptable, i.e., they will be salts derived from physiologically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be used, for example, to prepare or purify a compound of Formula I or another compound of the embodiments disclosed herein. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the embodiments disclosed herein.

[0094] The metal salt is typically prepared by reacting a metal hydroxide with a compound according to the embodiments disclosed herein. Examples of metal salts prepared in this manner are Li + 、Na + and K +A less soluble metal salt can be precipitated from a solution of a more soluble salt by adding an appropriate metal compound.

[0095] In addition, salts can be made from certain organic and inorganic acids (e.g., HCl, HBr, H 2 SO 4 , H 3 PO 4 ) or an organic sulfonic acid to a basic center (usually an amine). Finally, it should be understood that the compositions herein comprise the compounds disclosed herein in unionized form as well as in zwitterionic form.

[0096] "Pharmaceutical composition" refers to a preparation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for delivering biologically active compounds to mammals (eg, humans). Such medium includes all pharmaceutically acceptable excipients.

[0097] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound according to the embodiments disclosed herein, which is sufficient to achieve effective treatment of the disease state, condition or disorder disclosed herein when it is administered to a patient in need. Such an amount will be sufficient to cause the biological or medical response of the tissue system or patient sought by the researcher or clinician. The amount of the compound according to the embodiments disclosed herein that constitutes a therapeutically effective amount will vary according to factors such as the following: the compound and its biological activity, the composition for administration, the time of administration, the route of administration, the discharge rate of the compound, the duration of treatment, the type of disease state or disorder treated and its severity, the drugs used in combination or concurrently with the compounds of the embodiments disclosed herein, and the age, weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined by those of ordinary skill in the art based on their own knowledge, the prior art and this application.

[0098] As used herein, the terms "treating" and "treatment" are intended to refer to the use of a compound or composition according to an embodiment disclosed herein to reduce or eliminate one or more symptoms of HIV infection and / or reduce viral load in a patient. In certain embodiments, the terms "treating" and "treatment" also include applying a compound or composition according to the present embodiment disclosed herein after an individual is exposed to the virus but before symptoms of the disease appear and / or before the virus is detected in the blood, to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching a detectable level in the blood, and to apply a compound or composition according to the present embodiment disclosed herein to prevent perinatal HIV from being transmitted from mother to baby (by applying to the mother before delivery and to the child within the first few days after birth). The terms "treating" and "treatment" also include applying a compound or composition according to the present embodiment disclosed herein (also referred to as pre-exposure prophylaxis or PrEP) before an individual is exposed to the virus, to prevent HIV infection (if the individual is exposed to the virus) and / or to prevent the virus from forming a permanent infection and / or to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching a detectable level in the blood. The terms "treating" and "treatment" also include administering a compound or composition according to the present embodiments disclosed herein before and after an individual is exposed to a virus.

[0099] As used herein, the terms "preventing" and "prevention" refer to the administration of a compound, composition or pharmaceutical salt according to the present application before or after a human is exposed to a virus but before symptoms of the disease appear and / or before the virus is detected in the blood. The term also refers to preventing the appearance of symptoms of the disease and / or preventing the virus from reaching detectable levels in the blood. The term includes pre-exposure prophylaxis (PrEP) as well as post-exposure prophylaxis (PEP) and event-driven or "on-demand" prevention. The term also relates to the prevention of perinatal transmission of HIV from mother to baby by administration to the mother before delivery and to the baby within the first few days after birth. The term also refers to the prevention of HIV transmission through blood transfusions.

[0100] As used herein, the term "antiviral agent" is intended to mean an agent (compound or organism) that effectively inhibits virus formation and / or replication in the human body, including but not limited to agents that interfere with host or viral mechanisms necessary for virus formation and / or replication in the human body.

[0101] As used herein, the term "HIV replication inhibitor" is intended to mean an agent that is capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo, or in vivo.

[0102] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus giving enantiomers, diastereomers, and other stereoisomeric forms, which may be defined according to absolute stereochemistry as (R)- or (S)- or, such as (D)- or (L)- of amino acids. The present application is intended to include all of these possible isomers, as well as their racemic, asymmetric, 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 preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, unless otherwise indicated, it is intended that the compound includes E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0103] "Stereoisomers" refers to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present application encompasses various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other. In any embodiment disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

[0104] "Partially unsaturated" refers to a cyclic group that contains at least one double bond but is not aromatic.

[0105] Compound

[0106] Provided herein are compounds useful as anti-HIV agents, pharmaceutical compositions comprising such compounds in combination with one or more (e.g., two, three or four) additional therapeutic agents, and methods of using such compounds and compositions. All compound embodiments described herein include any pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

[0107] In one embodiment, a compound of the following formula (I) is provided:

[0108]

[0109] or a pharmaceutically acceptable salt thereof, wherein

[0110] R 1 H or C 6-10 Aryl, where C 6-10 The aryl group is optionally substituted by 1 to 4 R A1, where each R A1 are independently halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkyl-OC 1-4 alkyl;

[0111] R 2 For H, C 1-6 Alkyl or C 1-4 Haloalkyl;

[0112] L is -CR 3a R 3b -,-C(O)-,-SO 2 -,-CH 2 -CH 2 -or-N(R a )-;

[0113] W 1 Key or -CR 4a R 4b -;

[0114] W 2 For-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)-;

[0115] X is a bond or -CR 8a R 8b -;

[0116] Y is -C(O)NH- or Q, wherein Q is

[0117] Z is -CR 9a R 9b -、-CR 9a R 9b -CR 9c R 9d -or-CR 10a =CR 10b -;

[0118] R 3a and R 3b Independently H, C 1-6 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Alkyl; or optionally:

[0119] R 3a and R 3b Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A2 Substitute, where each R A2 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0120] R 4a and R 4b Independently H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogen;

[0121] R 5a , R 5b , R 5c and R 5d Independently H, C 1-6 Alkyl, C 1-4 Haloalkyl, halogen, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; or optionally:

[0122] R 5a and R 5b or R 5c and R 5dTogether with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or

[0123] R 5a and R 5c or R 5b and R 5d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0124] Each R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 Alkyl; optionally:

[0125] R 6a and R 6b Together with the carbon atoms to which they are attached, they form a 5- to 10-membered partially saturated fused ring containing 0 or 1 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 1 to 2 heteroatoms selected from N, O and S, wherein the partially saturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by 1 to 4 R A4 Substitute, where each R A4 are independently halogen or C 1-4 alkyl;

[0126] R 7 H, C 1-6 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO 2 R c ;

[0127] R 8a and R 8b Each independently represents H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4haloalkyl, cyano or halogen; or optionally:

[0128] R 8a and R 8b Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or optionally:

[0129] R 8a H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 haloalkyl, cyano or halogen; and

[0130] R 8b With R 5a , R 5b , R 5c , R 5d and R 7 One of them and the atoms to which they are each attached together form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally fused with 1 to 4 R A5 Substitute, where each R A5 are independently halogen or C 1-4 Alkyl; or

[0131] R 8b and R 2 Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen or C 1-4 alkyl;

[0132] R 9a , R 9b , R 9c and R 9d Each independently is H, C 1-6 Alkyl, C 1-4 haloalkyl or halogen; or optionally:

[0133] R 9a and R 9b or R 9c and R9d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A6 Substitute, where each R A6 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or

[0134] R 9a and R 9c or R 9b and R 9d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 3 R A6 , where each R A6 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or

[0135] R 9a , R 9b , R 9c and R 9d One and R 4a , R 4b , R 5a , R 5b and R 7 One of them and the atoms to which they are each attached together form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally fused with 1 to 4 R A6 Substitute, where each R A6 are independently halogen or C 1-4 alkyl;

[0136] R 10a and R 10b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 Alkyl; or optionally:

[0137] R 10a and R 10b Together with the carbon atoms to which they are attached, they form a 5- to 10-membered partially saturated fused ring containing 0 or 1 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 1 to 2 heteroatoms selected from N, O and S, wherein the partially saturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by 1 to 4 R A7 Substitute, where each R A7 are independently halogen or C1-4 alkyl;

[0138] R a Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R c or SO 2 R c ;

[0139] R b H or C 1-4 alkyl;

[0140] R c C 1-4 Alkyl or -OC 1-4 Alkyl; and

[0141] Each n is 0, 1 or 2.

[0142] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 2 H, C 1-4 Alkane or C 1-4 In some embodiments, R 2 H or C 1-4 In some embodiments, R 2 is H. In some embodiments, R 2 C 1-4 In some embodiments, R 2 In some embodiments, R 2 is H or methyl. In some embodiments, R 2 C 1-4 Halogenated alkyl.

[0143] In some embodiments, R 2 Selected from H, -CH 3 、-CH 2 CH 3 and -CH 2 F or R 2 and R 8b and the carbon to which they are attached together form a 3-membered fused carbocyclic ring. 2 Selected from H, -CH 3 、-CH 2 CH 3 and -CH 2 F. In some embodiments, R 2 and R 8b Together with the carbon atoms to which they are attached, they form a 3-membered fused carbocyclic ring.

[0144] 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

[0145] In some embodiments, the compound of formula I is a compound of formula (II):

[0146]

[0147] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, W 1 , W 2 , X and Z are as defined in Formula I.

[0148] 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 C 6-10 In some embodiments, R 1 is optionally replaced by 1 to 4 R A1 Substituted phenyl, where each R A1 are independently halogen, 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 For 1, 2, 3 or 4 R A1 In some embodiments, R 1 For 1, 2, 3 or 4 R A1 In some embodiments, R 1 For 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 In some embodiments, R 1 For 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, R 1 For 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen or -OC1-4 In some embodiments, R 1 is phenyl substituted by 1, 2, 3 or 4 halogens. 1 is phenyl substituted by 1, 2 or 3 halogens. 1 is phenyl substituted by 2 or 3 halogens. 1 is phenyl substituted by 2 or 3 halogens selected from chlorine and fluorine. 1 for

[0149]

[0150] In some embodiments of the compound of Formula I or II, R 1 Selected from In some embodiments of the compound of Formula I or II, R 1 Selected from In some embodiments, R 1 Selected from

[0151] 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 Independently H, C 1-4 Alkyl, C 1-6 Haloalkyl, C(O)R c or SO 2 R c In some embodiments, L is -CR 3a R 3b -, where R 3a and R 3b are independently H or C 1-4 In some embodiments, L is -CH 2 In some embodiments, L is -CH(CH 3 )-. In some embodiments, L is -C(O)-. In some embodiments, L is either -CH 2 -CH 2 -. In some embodiments, L is -CH 2 -、-CH(CH 3 )-, -C(O)- or -CH 2 -CH 2 -. In some embodiments, L is -N(Ra )-.

[0152] In some embodiments, the compound of Formula I or II is a compound of the formula:

[0153]

[0154] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, W 1 , W 2 , X and Z are as defined in Formula I.

[0155] In some embodiments, the compound of Formula I or II is a compound of Formula (IV):

[0156]

[0157] or a pharmaceutically acceptable salt thereof, wherein R 1 , W 1 , W 2 , X and Z are as defined in Formula I.

[0158] In some embodiments, the compound of Formula I, II or IV is a compound of the formula:

[0159]

[0160] or a pharmaceutically acceptable salt thereof, wherein R 1 , W 1 , W 2 , X and Z are as defined in Formula I.

[0161] In some embodiments, the compound of Formula I or II is a compound of Formula (VI):

[0162]

[0163]

[0164] In some embodiments, the compound of Formula I, II or VI is a compound of the formula:

[0165]

[0166] or a pharmaceutically acceptable salt thereof, wherein R 1 , W 1 , W 2 , X and Z are as defined in Formula I.

[0167] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa or VIIb, or a pharmaceutically acceptable salt thereof, W 1In some embodiments, W 1 For-CR 4a R 4b -. In some embodiments, W 1 For-CR 4a R 4b -, where R 4a and R 4b is independently H or halogen. In some embodiments, W 1 -CH 2 -. In some embodiments, W 1 For-CF 2 -. In some embodiments, W 1 In some embodiments, W 1 For the bond, -CH 2 -, -CF 2 - or -CH(F)-. In some embodiments, W 1 is a bond or -CH 2 -.

[0168] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa or VIIb, or a pharmaceutically acceptable salt thereof, W 1 Key or -CR 4a R 4b -, where each R 4a and R 4b are independently H, halogen or C 1-6 In some embodiments, W 1 Key or -CR 4a R 4b -, where each R 4a and R 4b are independently H, halogen or -CH 3 In some embodiments, W 1 For the bond, -CH 2 -、-CH(F)-、CF 2 、-CH(CH 3 )-or-CF(CH 3 )-.

[0169] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa or VIIb, or a pharmaceutically acceptable salt thereof, W 2 For-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 As defined in Formula I. In some embodiments, W 2 For-CR 5a R 5b -. In some embodiments, W 2 For-CR 5a R 5b -, where R 5a and R 5b Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 In some embodiments, W 2 For-CR 5a R 5b -, where R 5a and R 5b Independently H, C 1-4 Alkyl, C 1-4 In some embodiments, W 2 For-CR 5a R 5b -, where R 5a and R 5b is independently H or halogen. In some embodiments, W 2 -CH 2 -. In some embodiments, W 2 For-CF 2 -. In some embodiments, W 2 is -CH(F)-. In some embodiments, W 2 For-CR 5a R 5b -CR 5c R 5d -. In some embodiments, W 2 For-CR 5a R 5b -CR5c R 5d -, where R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 In some embodiments, W 2 For-CR 5a R 5b -CR 5c R 5d -, where R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, C 1-4 In some embodiments, W 2 For-CR 5a R 5b -CR 5c R 5d -, where R 5a , R 5b , R 5c and R 5d is independently H or halogen. In some embodiments, W 2 -CH 2 CH 2 -. In some embodiments, W 2 For-CR 5a R 5b -CR 5c R 5d -, where R 5a and R 5c are independently H or halogen, and R 5b and R 5d Together with the carbon atoms to which they are attached, they form a A3 A substituted 3- to 7-membered saturated or partially saturated fused carbocyclic ring, wherein each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, W 2 For-CR 5a R 5b -CR 5c R 5d -, where R 5a and R 5care independently H or halogen, and R 5b and R 5d Together with the carbon atoms to which they are attached, they form a 3- to 5-membered saturated fused carbocyclic ring. 2 -CHR 5b -CHR 5d -, where R 5b and R 5d Together with the carbon atoms to which they are attached, they form a 3-, 4- or 5-membered saturated fused carbocyclic ring. 2 for In some embodiments, W 2 For-CR 6a =CR 6b -. In some embodiments, W 2 For-CR 6a =CR 6b -, where R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-4 In some embodiments, W 2 For-CR 6a =CR 6b -, where R 6a and R 6b is independently H or halogen. In some embodiments, W 2 is -CH=CH-. In some embodiments, W 2 For-CR 6a =CR 6b -, where R 6a and R 6b Together with the carbon atoms to which they are attached, they form a 5- to 10-membered partially saturated fused ring containing 0 or 1 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 1 to 2 heteroatoms selected from N, O and S, wherein the partially saturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by 1 to 4 R A4 Substitute, where each R A4 are independently halogen or C 1-4 In some embodiments, W 2 For-CR 6a =CR 6b -, where R 6a and R 6b Together with the carbon atoms to which they are attached, they form a A4 A substituted 5- to 10-membered partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein each R A4are independently halogen or C 1-4 In some embodiments, W 2 For-CR 6a =CR 6b -, where R 6a and R 6b Together with the carbon atoms to which they are attached, they form a A4 A substituted 5- to 10-membered fused aromatic ring wherein each R A4 are independently halogen or C 1-4 In some embodiments, W 2 For-CR 6a =CR 6b -, where R 6a and R 6b Together with the carbon atoms to which they are attached, they form a A4 A substituted 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein each R A4 are independently halogen or C 1-4 In some embodiments, W 2 For-CR 6a =CR 6b -, where R 6a and R 6b Together with the atoms to which they are attached, they form a A4 A substituted fused 1,2-phenylene ring, wherein each R A4 are independently halogen or C 1-4 In some embodiments, W 2 for wherein p is 0, 1, 2, 3 or 4. In some embodiments, W 2 for Each R A4 is independently halogen. In some embodiments, W 2 for Each R A4 is independently halogen, and p is 0, 1, 2 or 3. In some embodiments, W 2 for Each R A4 is independently halogen and p is 0, 1 or 2. In some embodiments, W 2 for In some embodiments, W 2 for In some embodiments, W 2 -N(R 7 )-. In some embodiments, W 2 -N(R7 )-, where R 7 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO 2 R c In some embodiments, W 2 -N(R 7 )-, where R 7 H, C 1-4 Alkyl, C(O)R c or SO 2 R c In some embodiments, W 2 In some embodiments, W 2 -N(CH 3 )-. In some embodiments, W 2 -N(CH(CH 3 ) 2 )-. In some embodiments, W 2 -N(C(O)R c )-. In some embodiments, W 2 -N(C(O)CH 3 )-. In some embodiments, W 2 for -N(SO 2 R c )-. In some embodiments, W 2 for -N(SO 2 CH 3 )-. In some embodiments, W 2 In some embodiments, W 2 For-CR 5a R 5b -N(R 7 )-. In some embodiments, W 2 -CH 2 -N(R 7 )-. In some embodiments, W 2 is-CR 5a R 5b -O-. In some embodiments, W 2 Or -CH 2 -O-. In some embodiments, W 2 -CH 2 -、-CH 2 CH 2 -、-CH=CH-、 -NH-, -N(CH 3 )-、-N(CH(CH3 ) 2 )-、-N(C(O)CH 3 )-、-N(SO 2 CH 3 )-, -O- or -CH 2 -O-.

[0170] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va or Vb, the compound has Formula (X):

[0171]

[0172]

[0173] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va or Vb, the compound has Formula (Xa):

[0174]

[0175] In some embodiments of compounds of Formula I, II, IIIa, IIIb, IV, Va or Vb, the compound has Formula (Xb):

[0176]

[0177] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va or Vb, the compound has Formula (XI):

[0178]

[0179] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb or X, the compound has Formula (XIa):

[0180]

[0181] In some embodiments, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb or X has Formula (XIb):

[0182]

[0183] In some embodiments, 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, -OC 1-4Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 In some embodiments, X is a bond. In some embodiments, X is -CR 8a R 8b -; where R 8a and R 8b Each independently represents H, hydroxyl, -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 Each independently is H, C 1-6 Alkyl, C 1-4 In some embodiments, R 8a and R 8b Each independently represents H, -CH 3 , -CHF 2 、-CH 2 F or halogen.

[0184] In some embodiments, for a 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 Each independently is H, C 1-6 Alkyl or C 1-4 In some embodiments, Z is -CR 9a R 9b -. In some embodiments, Z is -CR 9a R 9b CR 9c R 9d -. In some embodiments, R 9a , R 9b , R 9c and R 9d Each independently represents H, -CH 3 , -CHF 2or -CH 2 F.

[0185] In some embodiments of the compound of Formula XI, XIa or XIb, or a pharmaceutically acceptable salt thereof, each R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 alkyl.

[0186] In some embodiments of the compound of Formula X, Xa or Xb, or a pharmaceutically acceptable salt thereof, each R 5a , R 5b , R 5c and R 5d are independently H, halogen, C 1-4 Haloalkyl or C 1-6 alkyl.

[0187] 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, fluorine or hydroxyl, and R 8b In some embodiments, X is -CH 2 -. In some embodiments, X is -CF 2 -. In some embodiments, X is -CH(F)-. In some embodiments, X is -CH(OH)-. In some embodiments, X is -CH(CH 3 In some embodiments, X is -CF(CH 3 In some embodiments, X is -CH 2 -、-CF 2 -, -CH(F)-, -CH(OH)-, -CH(CH 3 ) or -CF(CH 3 In some embodiments, X is -CR 8a R 8b -, where R 8a and R8b and the carbon to which they are attached form a 3-, 4- or 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spirocyclic ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b and the carbon to which they are attached together form a 3- to 5-membered saturated spirocyclic ring containing 0 heteroatoms, wherein the spirocyclic ring is optionally replaced by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, 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 they form a spirocyclopropane ring.

[0188] In some embodiments of the 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 halogen, or wherein R 8a and R 8b and the carbon to which they are attached together form a 3- to 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spirocyclic ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0189] In some embodiments of the 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 R8a and R 8b are independently H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 haloalkyl or halogen, or wherein R 8a and R 8b and the carbon to which they are attached form a 3- to 5-membered saturated spiro heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, 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 halogen, or wherein R 8a and R 8b Together with the carbon to which they are attached, they form a 3- to 5-membered saturated spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S.

[0190] In some embodiments of the 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 halogen, or wherein R 8a and R 8b and the carbon to which they are attached together form a 3-5 membered saturated spiro carbocyclic ring, wherein the 3-5 membered saturated spiro carbocyclic ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, 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, C1-4 haloalkyl or halogen, or wherein R 8a and R 8b Together with the carbon atoms to which they are attached, they form a 3-5 membered saturated spiro carbon ring.

[0191] In some embodiments of the 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 halogen, or wherein R 8a and R 8b and the carbon to which they are attached together form a 3-membered saturated spiro carbocyclic ring, wherein the 3-membered saturated spiro carbocyclic ring is optionally substituted by 1 to 4 R A5 , where each R A5 are independently halogen, 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 halogen, or wherein R 8a and R 8b Together with the carbon atoms to which they are attached, they form a 3-membered saturated spiro carbocyclic ring.

[0192] In some embodiments of the 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 2 -、-CF 2 -, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH 2 F)(OH)-、-C(CH 3 )(OH)-、-CH(OCH 3 )-、-C(CH 2 CH 3 )(OCH 3 )-、-C(CH 2 CH 3)(OH)-、-CH(CH 3 )-、-CH(CH 2 CH 3 )-、-CF(CH 3 )-、-CF(CH 2 CH 3 )-or-CR 8a R 8b -, where R 8a and R 8b and the carbon to which they are attached together form a 3-membered saturated spiro carbocyclic ring. In some embodiments, X is a bond, -CH 2 -、-CF 2 -, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH 2 F)(OH)-、-C(CH 3 )(OH)-、-CH(OCH 3 )-、-C(CH 2 CH 3 )(OCH 3 )-、-C(CH 2 CH 3 )(OH)-、-CH(CH 3 )-、-CH(CH 2 CH 3 )-、-CF(CH 3 )-or-CF(CH 2 CH 3 )-.

[0193] In some embodiments, X is a bond, -CH 2 -、-CF 2 -, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH 2 F)(OH)-、-C(CH 3 )(OH)-、-CH(OCH 3 )-、-C(CH 2 CH 3 )(OCH 3 )-、-C(CH 2 CH 3 )(OH)-、-CH(CH 3 )-、-CH(CH 2 CH 3 )-、-CF(CH 3 )-、-CF(CH 2 CH 3 )-、-C(CH 2 F)(H)-or-CR 8a R8b -, where R 8a and R 8b and the carbon to which they are attached together form a 3-membered saturated spiro carbocyclic ring. In some embodiments, X is a bond, -CH 2 -、-CF 2 -, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH 2 F)(OH)-、-C(CH 3 )(OH)-、-CH(OCH 3 )-、-C(CH 2 CH 3 )(OCH 3 )-、-C(CH 2 CH 3 )(OH)-、-CH(CH 3 )-、-CH(CH 2 CH 3 )-、-CF(CH 3 )-、-C(CH 2 F)(H)- or -CF(CH 2 CH 3 )-.

[0194] In some embodiments of the 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 and the carbon to which they are attached together form a 3- to 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spirocyclic ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b and the carbon to which they are attached together form a 3-5 membered saturated spiro carbocyclic ring, wherein the 3-5 membered saturated spiro carbocyclic ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, X is -CR 8a R 8b-, where R 8a and R 8b and the carbon to which they are attached together form a 3-membered spirocarbocyclic ring. In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b and the carbon to which they are attached together form a 3- to 5-membered saturated spiro heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, wherein the 3- to 5-membered saturated spiro heterocyclic ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, 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, they form a 3- to 5-membered saturated spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S.

[0195] In some embodiments, the compound of Formula I or II is a compound of Formula (VIII):

[0196]

[0197] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, W 1 , W 2 and Z are as defined in Formula I.

[0198] In some embodiments of the compound of Formula III, 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 9b 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 -CH 2 In some embodiments, Z is -CH(CH 3In 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 Independently H, C 1-4 Alkyl, C 1-4 In some embodiments, Z is -CH 2 -CH 2 -. 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 10b Together with the carbon atoms to which they are attached, they form a 5- to 10-membered partially saturated fused ring containing 0 or 1 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 1 to 2 heteroatoms selected from N, O and S, wherein the partially saturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by 1 to 4 R A7 Substitute, where each R A7 are independently halogen or C 1-4 In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b Together with the carbon atoms to which they are attached, they form a A7 A substituted 5- to 10-membered partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein each R A7 are independently halogen or C 1-4 In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b Together with the carbon atoms to which they are attached, they form a A7A substituted 5- to 10-membered fused aromatic ring wherein each R A7 are independently halogen or C 1-4 In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b Together with the carbon atoms to which they are attached, they form optionally 1 to 4R A7 a substituted 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein each R A7 are independently halogen or C 1-4 In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b and the atoms to which they are attached together form a group optionally represented by 1 to 4 R A7 A substituted fused 1,2-phenylene ring, wherein each R A7 are independently halogen or C 1-4 In some embodiments, Z is wherein q is 0, 1, 2, 3 or 4. In some embodiments, Z is Each R A4 In some embodiments, Z is Each R A4 is independently halogen and q is 0, 1, 2 or 3. In some embodiments, Z is Each R A4 is independently halogen and q is 0, 1 or 2. In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is -CH 2 -、-CH(CH 3 )-、-CH 2 -CH 2 -、

[0199] 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 Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4In some embodiments, R 3a and R 3b independently H or C 1-4 In some embodiments, R 3a and R 3b is H. In some embodiments, R 3a and R 3b C 1-4 In some embodiments, R 3a For H and R 3b C 1-4 In some embodiments, R 3a H and R 3b In some embodiments, R 3a and R 3b Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A2 Substitute, where each R A2 are independently halogen, 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, they form a 3-, 4- or 5-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A2 Substitute, where each R A2 are independently halogen, 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, they form a 3- or 4-membered saturated spirocyclic ring containing 0 or 1 heteroatom selected from N, O and S, wherein the spirocyclic ring is optionally substituted by 1 to 3 R A2 Substitute, where each R A2 are independently halogen, 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, they form a 3-membered saturated spiro ring containing 0 or 1 heteroatom selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A2 Substitute, where each R A2 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, R 3a and R3b Together with the carbon atoms to which they are attached they form a spirocyclopropane ring.

[0200] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb or VIII, or a pharmaceutically acceptable salt thereof, W 1 For-CR 4a R 4b - and R 4a and R 4b Independently H, C 1-4 Alkyl, C 1-4 In some embodiments, R 4a and R 4b is independently H or halogen. In some embodiments, R 4a and R 4b is H. In some embodiments, R 4a and R 4b In some embodiments, R 4a and R 4b In some embodiments, R 4a H and R 4b In some embodiments, R 4a H and R 4b For fluorine.

[0201] 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 For-CR 5a R 5b - and R 5a and R 5b Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 In some embodiments, R 5a and R 5b Independently H, C 1-4 Alkyl, C 1-4 In some embodiments, R 5a and R 5b is independently H or halogen. In some embodiments, R 5a and R 5b is H. In some embodiments, R 5a and R5b In some embodiments, R 5a and R 5b In some embodiments, R 5a H and R 5b In some embodiments, R 5a H and R 5b In some embodiments, R 5a and R 5b Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, 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, they form a 3-, 4- or 5-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, 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, they form a 3- or 4-membered saturated spirocyclic ring containing 0 or 1 heteroatom selected from N, O and S, wherein the spirocyclic ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, 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, they form a 3-membered saturated spiro ring containing 0 or 1 heteroatom selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, 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 they form a spirocyclopropane ring.

[0202] 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 For-CR 5a R 5b CR 5c R 5d - and R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, 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 Independently H, C 1-4 Alkyl, C 1-4 In some embodiments, R 5a , R 5b , R 5c and R 5d is independently H or halogen. 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 halogen and R 5b and R 5d Together with the carbon atoms to which they are attached, they form a A3 A substituted 3- to 7-membered saturated or partially saturated fused carbocyclic ring, wherein each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, R 5a and R 5c are independently H or halogen and R 5b and R 5d Together with the carbon atoms to which they are attached, they form a 3-, 4- or 5-membered saturated fused carbocyclic ring. 5a and R 5c H and R 5b and R 5dTogether with the carbon atoms to which they are attached, they form a 3-, 4- or 5-membered saturated fused carbocyclic ring. 5a and R 5c H and R 5b and R 5d Together with the carbon atoms to which they are attached, they form a fused cyclopropane ring.

[0203] 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 For-CR 6a =CR 6b - and R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-4 In some embodiments, R 6a and R 6b is independently H or halogen. In some embodiments, R 6a and R 6b is H. In some embodiments, R 6a and R 6b and the atoms to which they are attached together form a group optionally represented by 1 to 4 R A4 A substituted 5- to 10-membered fused aromatic ring wherein each R A4 are independently halogen or C 1-4 In some embodiments, R 6a and R 6b and the atoms to which they are attached together form a group optionally represented by 1 to 4 R A4 A substituted fused 1,2-phenylene ring, wherein each R A4 are independently halogen or C 1-4 In some embodiments, R 6a and R 6b Together with the atoms to which they are attached, they form wherein p is 0, 1, 2, 3 or 4. In some embodiments, R 6a and R 6b Together with the atoms to which they are attached, they form Each R A4 In some embodiments, R 6a and R 6b Together with the atoms to which they are attached, they form Each R A4 is independently halogen and p is 0, 1, 2 or 3. In some embodiments, R6a and R 6b Together with the atoms to which they are attached, they form Each R A4 is independently halogen and p is 0, 1 or 2. In some embodiments, R 6a and R 6b Together with the atoms to which they are attached, they form In some embodiments, R 6a and R 6b Together with the atoms to which they are attached, they form

[0204] 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 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO 2 R c In some embodiments, R 7 H, C 1-4 Alkyl, C(O)R c or SO 2 R c In some embodiments, R 7 is H. In some embodiments, R 7 C 1-4 In some embodiments, R 7 is methyl or 1-methylethyl. In some embodiments, R 7 C(O)R c In some embodiments, R 7 -C(O)-C 1-4 In some embodiments, R 7 -C(O)CH 3 In some embodiments, R 7 For SO 2 R c In some embodiments, R 7 For-SO 2 -C 1-4 In some embodiments, R 7 For-SO 2 CH 3 .

[0205] 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 Selected from -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-; where each R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, 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 Together with the carbon atoms to which they are attached, they form a A3 A substituted 3- to 7-membered saturated or partially saturated carbocyclic ring, wherein each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; each R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-4 Alkyl; or R 6a and R 6b Together with the atoms to which they are attached, they form (i) a 5- to 10-membered fused aromatic ring or (ii) a 5- to 10-membered fused heteroaromatic ring comprising 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 optionally substituted by 1 to 4 R A4 Substitute, where each R A4are independently halogen or C 1-4 Alkyl; R 7 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO 2 R c ; R c C 1-4 alkyl; and n is 0, 1 or 2.

[0206] 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 Selected from -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-; where each R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, 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 Together with the carbon atoms to which they are attached, they form a A3 A substituted 3-membered carbocyclic ring, wherein each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; each R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C1-4 Alkyl; or R 6a and R 6b Together with the atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-6 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the fused benzene ring or the 5-6 membered fused heteroaromatic ring is optionally substituted by 1 to 4 R A4 Substitute, where each R A4 are independently halogen or C 1-4 Alkyl; R 7 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO 2 R c ; Rc is C 1-4 alkyl; and n is 0, 1 or 2.

[0207] 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 Selected from -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-; where each R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, halogen, 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, they form a 3-membered carbocyclic ring; each R 6a and R 6b are independently H, halogen or C 1-4Alkyl; or R 6a and R 6b Together with the atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-6 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, wherein the fused benzene ring or the 5-6 membered fused heteroaromatic ring is optionally substituted by 1 to 2 R A4 Substitute, where each R A4 are independently halogen or C 1-4 Alkyl; R 7 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO 2 R c ; R c C 1-4 alkyl; and n is 0 or 1.

[0208] In some embodiments, W 2 Selected from -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-; where each R 5a , R 5b , R 5c and R 5d are independently H, -CH 3 , halogen, hydroxyl or -OCH 3 ; 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, they form a 3-membered carbocyclic ring; each R 6a and R 6b are independently H, halogen or CH 3 ; or R 6a and R 6bTogether with the atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, wherein the fused benzene ring or the 5-6-membered fused heteroaromatic ring is optionally replaced by 1 or 2 R A4 Substitute, where each R A4 are independently halogen or CH 3 ; R 7 H, -CH 3 、-CH(CH 3 ) 2 , -CF 3 、-C(O)R c or -SO 2 R c ; R c -CH 3 ; and n is 0 or 1.

[0209] In some embodiments, W 2 Selected from -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-; where each R 5a , R 5b , R 5c and R 5d are independently H, -CH 3 , halogen, hydroxyl or -OCH 3 ; Each R 6a and R 6b are independently H, halogen or -CH 3 ; R 7 H, -CH 3 、-CH(CH 3 ) 2 , -CF 3 、-C(O)R c or -SO 2 R c ; R c -CH 3 ; and n is 0 or 1.

[0210] In some embodiments of the 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 In some embodiments, R 8a and R 8b are independently H, hydroxyl, C 1-4 In some embodiments, R 8a is H, fluorine or hydroxyl and R 8b is H or fluorine. In some embodiments, R 8a and R 8b is H. In some embodiments, R 8a and R 8b In some embodiments, R 8a H and R 8b In some embodiments, R 8a H and R 8b In some embodiments, R 8a H and R 8b In some embodiments, R 8a H and R 8b C 1-4 In some embodiments, R 8a H and R 8b In some embodiments, R 8a is a halogen and R 8b C 1-4 In some embodiments, R 8a is fluorine and R 8b In some embodiments, R 8a and R 8b and the carbon to which they are attached form a 3-, 4- or 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spirocyclic ring is optionally substituted by 1 to 4 R A5 substituted, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, R 8a and R8b and the carbon to which they are attached together form a 3-, 4- or 5-membered saturated spirocyclic ring containing 0 heteroatoms, wherein the spirocyclic ring is optionally substituted by 1 to 4 R A5 , where each R A5 are independently halogen, 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 they form a spirocyclopropane ring.

[0211] In some embodiments of the 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 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 C 1-4 In some embodiments, R 9a For H and R 9b C 1-4 In some embodiments, R 9a For H and R 9b It is methyl.

[0212] In some embodiments of the 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 , R 9b , R 9c and R 9d Independently H, C 1-4 Alkyl, C 1-4 In some embodiments, R 9a , R 9b , R9c and R 9d are independently H or C 1-4 In some embodiments, R 9a , R 9b , R 9c and R 9d For H.

[0213] In some embodiments of the 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, halogen, C 1-4 Haloalkyl or C 1-4 In some embodiments, R 10a and R 10b and the atoms to which they are each attached together form a 5- to 10-membered fused aromatic ring or a heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the aromatic ring or heteroaromatic ring is optionally substituted by 1 to 4 R A7 Substitute, where each R A7 are independently halogen or C 1-4 In some embodiments, R 10a and R 10b and the atoms to which they are attached together form a group optionally represented by 1 to 4 R A7 A substituted 5- to 10-membered fused aromatic ring wherein each R A7 are independently halogen or C 1-4 In some embodiments, R 10a and R 10b and the atoms to which they are attached together form a group optionally represented by 1 to 4 R A7 A substituted fused 1,2-phenylene ring, wherein each R A7 are independently halogen or C 1-4 In some embodiments, R 10a and R 10b Together with the atoms to which they are attached, they form wherein q is 0, 1, 2, 3 or 4. In some embodiments, R 10a and R 10b Together with the atoms to which they are attached, they form Each R A4 In some embodiments, R 10a and R 10b Together with the atoms to which they are attached, they form Each R A4 is independently halogen and q is 0, 1, 2 or 3. In some embodiments, R 10a and R 10b Together with the atoms to which they are attached, they form Each R A4 is independently halogen and q is 0, 1 or 2. In some embodiments, R 10a and R 10b Together with the atoms to which they are attached, they form In some embodiments, R 10a and R 10b Together with the atoms to which they are attached, they form In some embodiments, R 10a and R 10b Together with the atoms to which they are attached, they form

[0214] In some embodiments of the 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 Each independently is H, C 1-6 Alkyl, C 1-4 haloalkyl or halogen; or R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A6 Substitute, where each R A6 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 10a and R 10b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 Alkyl; or R 10a and R10b Together with the carbon atoms to which they are attached, they form (i) a 5-10 membered partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, (ii) a 5-10 membered fused aromatic ring or (iii) a 5-10 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the 5-10 membered partially saturated fused ring, the 5-10 membered fused aromatic ring or the 5-10 membered fused heteroaromatic ring is optionally substituted by 1 to 4 R A7 Substitute, where each R A7 are independently halogen or C 1-4 alkyl.

[0215] In some embodiments of the 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 Each independently is H, CH 3 , CH 2 CH 3 , CHF 2 or halogen; or R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form a 3-membered carbocyclic ring; R 10a and R 10b are independently H, halogen or CH 3 ; or R 10a and R 10b Together with the carbon atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-6 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the fused benzene ring or the fused heteroaromatic ring is optionally substituted by 1 to 2 R A7 Substitute, where each R A7 are independently halogen or CH 3 .

[0216] 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, wherein

[0217] R1 For 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen or -OC 1-4 alkyl;

[0218] X is a key 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 halogen, or R 8a and R 8b Together with the carbon to which they are attached, they form a 3-membered saturated spirocarbocyclic ring;

[0219] W 1 Key or -CR 4a R 4b -; where R 4a and R 4b Independently H, C 1-6 Alkyl or halogen;

[0220] W 2 Selected from -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-; where each R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, halogen, hydroxyl or -OC 1-4 Alkyl; each R 6a and R 6b are independently H, halogen or C 1-4 Alkyl; R 7 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO 2 R c ; Rc C 1-4 alkyl; and n is 0 or 1; and

[0221] 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 Each independently is H, C 1-6 Alkyl, C 1-4 haloalkyl or halogen; or R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form a 3-membered carbocyclic ring; and R 10a and R 10b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 alkyl.

[0222] In some embodiments of the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb or VIII, or a pharmaceutically acceptable salt thereof,

[0223] R 1 For 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen or -OC 1-4 alkyl;

[0224] X is a key 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 halogen;

[0225] W 1 Key or -CR 4a R 4b -; where R 4a and R 4b Independently H, C 1-6 Alkyl or halogen;

[0226] W 2 For-CR5a R 5b -; where each R 5a and R 5b Independently H, C 1-4 Alkyl, halogen, hydroxyl or -OC 1-4 Alkyl; and

[0227] Z is -CR 9a R 9b -; where R 9a and R 9b Each independently is H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogen.

[0228] 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 Independently H, C 1-4 Alkyl, C 1-6 Haloalkyl, C(O)R c or SO 2 R c .

[0229] 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 C 1-4 In some embodiments, R b It is methyl.

[0230] 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 C 1-4 In some embodiments, R c In some embodiments, R c For-OC 1-4 alkyl.

[0231] In some embodiments of 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 pharmaceutically acceptable salt thereof, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0232] In some embodiments, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb or VIII is a compound of Formula (IX):

[0233]

[0234] or a pharmaceutically acceptable salt thereof, wherein R 1 H or C 6-10 Aryl, where C 6-10 The aryl group is optionally substituted with 1 to 4 R A1 Substitute, where each R A1 are independently halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkyl-OC 1-4 alkyl.

[0235] [1] In some embodiments, the compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII or IX is a compound of formula (IXa):

[0236]

[0237] In some embodiments, the compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII or IX is a compound of Formula (IXb):

[0238]

[0239] or a pharmaceutically acceptable salt thereof, wherein R 1 H or C 6-10 Aryl, where C 6-10 The aryl group is optionally substituted with 1 to 4 R A1 Substitute, where each R A1 are independently halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkyl-OC 1-4 alkyl.

[0240] 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 C 6-10 In some embodiments, R 1 is optionally replaced by 1 to 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen, 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 For 1, 2, 3 or 4 R A1 In some embodiments, R 1 is substituted by 1, 2, 3 or 4 R A1 phenyl, where each R A1 are independently halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 In some embodiments, R 1 For 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen, C 1-4 Alkyl or C 1-4 In some embodiments, R 1 For 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen or -OC 1-4 In some embodiments, R 1 is phenyl substituted with 1, 2, 3 or 4 halogens. 1 is phenyl substituted by 1, 2 or 3 halogens. 1 is phenyl substituted by 2 or 3 halogens. 1 is phenyl substituted by 2 or 3 halogens selected from chlorine and fluorine. 1 for

[0241]

[0242] In some embodiments of 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, R 1 Selected from In some embodiments of the compound of Formula I or II, R 1 Selected from

[0243] In some embodiments, the compound has the formula:

[0244]

[0245]

[0246] In some embodiments, the compound has the formula:

[0247]

[0248]

[0249] 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 is selected from:

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, 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 selected from:

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] or a pharmaceutically acceptable salt thereof.

[0274] 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 described with reference to the following description of Rings A, B and C as depicted in Figure I:

[0275]

[0276] wherein A represents a bridged ring relative to ring B, B represents a bridged ring relative to ring A and a fused ring relative to ring C, and C represents a fused ring relative to ring B. As described above, the compound may have one or more additional fused rings or spiro rings.

[0277] When any variable is an asymmetric group, both orientations of the group are contemplated unless otherwise specified.2 For-CR 5a R 5b -N(R 7 )-, including -CR 5a R 5b -N(R 7 )-two orientations (i.e., including ZW 1 -CR 5a R 5b -N(R 7 )-X and ZW 1 -N(R 7 )-CR 5a R 5b -X both), when Z is When, including Two orientations (i.e., including and Both).

[0278] It is to be understood that the embodiments of compounds of any of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa or XIb listed above, as well as any specific group or substituent (e.g., R) shown herein in compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa or XIb, are not limited to the following: 1 , R 2 , L, W 1 , W 2 , X, Y, Z and substituents thereof) can be independently combined with other embodiments and / or substituents of compounds of any 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 listed above. In addition, if any particular R is not specified in a specific embodiment and / or claim, 1 , R 2 , L, W 1 , W 2 , X, Y, and Z groups list a list of substituents, it should be understood that each individual substituent may be deleted from the specific embodiments and / or claims and the remaining list of substituents will be considered to be within the scope of the embodiments disclosed herein.

[0279] Pharmaceutical composition

[0280] In another embodiment, a pharmaceutical composition is provided 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.

[0281] In some embodiments, the pharmaceutical composition further comprises 1, 2, 3 or 4 additional therapeutic agents. In certain embodiments, the additional one or more therapeutic agents are anti-HIV agents. In specific embodiments, the additional one or more therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonylamino)-1-(2,2,2)-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

[0282] Kits and Products

[0283] In some embodiments, the present application 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 1, 2, 3 or 4 additional therapeutic agents as described above. The kit may also comprise instructions for use, such as for inhibiting HIV integrase, such as for treating HIV infection or AIDS, or for use as a research tool. The instructions for use are usually written instructions, but electronic storage media (e.g., disks or optical disks) containing instructions are also acceptable. A notice (in a form prescribed by a government agency that manages the manufacture, use or sale of drugs) is optionally associated with one or more containers, which reflects that the manufacture, use or sale for human administration has been approved by the agency. Each component (if there are multiple components) can be packaged in a separate container, or some components can be combined in one container where cross-reactivity and shelf life allow. The kit can be in unit dosage form, bulk packaging (e.g., multi-dose packaging) or sub-unit dosage form. The kit can also include multiple unit doses of the compound and instructions for use, and is packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0284] In some embodiments, disclosed herein are articles comprising a unit dose 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, in a package suitable for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampoules, bottles, jars, flexible packaging, etc. The article may be further sterilized and / or sealed.

[0285] Treatment

[0286] In one embodiment, a method of treating a human having or at risk of HIV infection (e.g., HIV-1 and / or HIV-2) is provided, 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 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.

[0287] In some embodiments, the method further comprises administering to the human a therapeutically effective amount of 1, 2, 3 or 4 additional therapeutic agents. In certain embodiments, one or more additional therapeutic agents are anti-HIV agents. In specific embodiments, one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV 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 or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonylamino)-1-(2,2,2)-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

[0288] 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 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 treating HIV infection in a human having HIV (e.g., HIV-1 and / or HIV-2) infection or at risk of HIV infection.

[0289] 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 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 medical therapy.

[0290] 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 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 treating HIV infection.

[0291] 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 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 a method of treating HIV infection in a human having or at risk of HIV infection.

[0292] 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 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 a method of treating HIV infection in a human having or at risk of HIV infection, wherein the method further comprises administering to the human 1, 2, 3 or 4 additional therapeutic agents.

[0293] 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, IX, IXa, IXb, X, Xa, Xb, XI, XIa or XIb, or a pharmaceutically acceptable salt thereof, is provided. A composition for use in a method of treating HIV infection in a person suffering from HIV infection or at risk of HIV infection, wherein the method further comprises administering to the person 1, 2, 3 or 4 additional therapeutic agents selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, the 1, 2, 3 or 4 additional therapeutic agents are selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, latency reversal agents, HIV capsid inhibitors, HIV bNAbs, TLR7 agonists, and combinations thereof.

[0294] 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 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 a method of treating HIV infection in a human having or at risk of HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil and emtricitabine.

[0295] 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 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 a method of treating HIV infection in a human having or at risk of HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of alafenamide and emtricitabine.

[0296] 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 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 a method of treating HIV infection in a human having or at risk of HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil.

[0297] 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 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 a method of treating HIV infection in a human having or at risk of HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.

[0298] In another embodiment, a method 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 is provided. Specifically, a method of treating HIV virus replication, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human) is provided, the method 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.

[0299] In another embodiment, a 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 is provided for use in a method of treating HIV viral replication, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

[0300] 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 preventing HIV infection.

[0301] 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 is exposed to HIV virus to prevent the occurrence of HIV infection (how the individual is exposed to the virus) and / or to prevent the virus from establishing a permanent infection and / or to prevent the appearance of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood.

[0302] In another embodiment, disclosed is the use of a compound of 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 preparation of a medicament for treating HIV infection in a human having or at risk of HIV infection.

[0303] 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, as a research tool.

[0304] In another embodiment, an article of manufacture is disclosed, comprising a composition effective for treating HIV infection; and packaging material comprising a label indicating that the composition can be used to treat HIV infection. Exemplary compositions comprise 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.

[0305] In another embodiment, a method of inhibiting HIV replication is disclosed. The method comprises exposing the virus to an effective amount of a compound of Formula I, 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 that inhibit HIV replication.

[0306] 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 for inhibiting HIV integrase activity.

[0307] 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 salt thereof for inhibiting HIV replication.

[0308] Application

[0309] For the purpose of administration, in certain embodiments, the compounds described herein are administered in the form of raw chemicals or formulated into pharmaceutical compositions. The pharmaceutical compositions within the scope of the embodiments disclosed herein include compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa or XIb and pharmaceutically acceptable excipients. The compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa or XIb are present in the composition in an amount effective to treat a specific target disease or condition. The activity of the 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.

[0310] The compound of the embodiment disclosed herein or its pharmaceutically acceptable salt is administered in pure form or in the form of a suitable pharmaceutical composition, and can be carried out by any acceptable mode of administration used for medicaments providing similar efficacies. The pharmaceutical composition of the embodiment disclosed herein can be prepared by combining the compound of the embodiment disclosed herein with a suitable pharmaceutically acceptable excipient, and can be formulated into solid, semisolid, liquid or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Typical administration routes of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhaled, parenteral, injection, sublingual, oral, rectal, vaginal and intranasal. The pharmaceutical composition of the embodiment disclosed herein is formulated to allow the active ingredients contained therein to be bioavailable after the composition is administered to the patient. The composition applied to an individual or patient is in the form of one or more dosage units, wherein, for example, a tablet can be a single dosage unit, and a container containing a compound of the embodiment disclosed herein in the form of an aerosol can accommodate multiple dosage units. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the composition to be administered comprises a therapeutically effective amount of a compound of the embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, for treating the intended disease or condition in accordance with the teachings of the present disclosure.

[0311] 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.

[0312] 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.

[0313] The pharmaceutical compositions disclosed herein can be prepared by methods well known in the pharmaceutical field. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining the compound of the embodiments disclosed herein with sterile distilled water to form a solution. Surfactants can be added to promote the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compounds of the embodiments disclosed herein to promote the dissolution or uniform suspension of the compound in an aqueous delivery system.

[0314] The compounds of the embodiments 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 specific compound used; the metabolic stability and duration of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; drug combinations; the severity of the particular disease or condition; and the subject being treated.

[0315] Combination therapy

[0316] In certain embodiments, a method for treating HIV infection in a human suffering from or at risk of HIV infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of 1, 2, 3, or 4 additional therapeutic agents. In one embodiment, a method for treating HIV infection in a human suffering from or at risk of HIV infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of 1, 1, 3, or 4 additional therapeutic agents.

[0317] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with 1, 2, 3 or 4 additional therapeutic agents and a pharmaceutically acceptable carrier, diluent or excipient.

[0318] In certain embodiments, the present application provides a method for treating 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 a therapeutically effective amount of 1, 2, 3 or 4 additional therapeutic agents suitable for treating HIV infection.

[0319] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 1, 2, 3, 4 or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 2 additional therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 3 additional therapeutic agents. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 4 additional therapeutic agents. The 1, 2, 3, 4 or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0320] Administration of HIV combination therapy

[0321] In certain embodiments, the compounds disclosed herein are administered with 1, 2, 3, or 4 additional therapeutic agents. Co-administration of compounds disclosed herein with 1, 2, 3, or 4 additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and the 1, 2, 3, or 4 additional therapeutic agents, such that a therapeutically effective amount of the compounds disclosed herein and the 1, 2, 3, or 4 additional therapeutic agents are present in the patient. When administered sequentially, the combination may be administered in the form of two or more administrations.

[0322] Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of 1, 2, 3 or 4 additional therapeutic agents. For example, the compounds disclosed herein can be administered within a few seconds, minutes or hours of administering 1, 2, 3 or 4 additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is first administered, and then a unit dose of 1, 2, 3 or 4 additional therapeutic agents is administered within a few seconds or minutes. Alternatively, a unit dose of 1, 2, 3 or 4 additional therapeutic agents is first administered, and then a unit dose of a compound disclosed herein is administered within a few seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein is first administered, and then a unit dose of 1, 2, 3 or 4 additional therapeutic agents is administered after a few hours (e.g., 1-12 hours). In other embodiments, a unit dose of 1, 2, 3 or 4 additional therapeutic agents is first administered, and then a unit dose of a compound disclosed herein is administered after a few hours (e.g., 1-12 hours).

[0323] In certain embodiments, a compound disclosed herein is combined with 1, 2, 3, or 4 additional therapeutic agents in a single dosage form for simultaneous administration to a patient, for example, as a solid dosage form for oral administration.

[0324] In certain embodiments, kits are provided that include 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.

[0325] In certain 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 is formulated into a tablet, which may optionally contain one or more other compounds for treating HIV. In certain embodiments, the tablet may contain another active ingredient for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers and combinations thereof.

[0326] In certain embodiments, such tablets are suitable for once-daily administration.

[0327] HIV combination therapy

[0328] In the above embodiments, the additional one or more therapeutic agents can be anti-HIV agents selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy), latency reversal agents, compounds targeting 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 infection factor inhibitors, TAT protein inhibitors, HIV 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-3grabbing nonintegrin 1inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, 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, HIV vaccines and combinations thereof.

[0329] In some embodiments, the additional therapeutic agent(s) is selected from 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 antibodies, and "antibody-like" therapeutic proteins and combinations thereof.

[0330] HIV combination drugs

[0331] Examples of combination drugs include: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (nofovir alafenamide and emtricitabine); (nofovir alafenamide, emtricitabine, and rilpivirine); (nofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); (darunavir, norfovir alafenamide, emtricitabine, and cobicistat); (bictegravir, alafenamide, and emtricitabine); bictegravir, tenofovir disoproxil and emtricitabine; bictegravir, 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; alafenamide and emtricitabine; alafenamide hemifumarate and emtricitabine; alafenamide hemifumarate, emtricitabine and rilpivirine; alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; (zidovudine and lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); ( lopinavir and ritonavir); (dolutegravir, abacavir, and lamivudine); (dolutegravir, ripilvirine); (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 hydrochloride; dolutegravir, abacavir sulfate and lamivudine; lamivudine, nevirapine and zidovudine; raltegr avir) and lamivudine; doravirine, lamivudine and tenofovir disoproxil fumarate; 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.

[0332] Other HIV medicines

[0333] Examples of other drugs used to treat HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenfarin, naltrexone, Prolastin, REP 9, 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, M K-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, S B-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

[0334] HIV protease inhibitors

[0335] Examples of HIV protease inhibitors include amprenavir, atazanavir, brenavir, 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.

[0336] HIV reverse transcriptase inhibitors

[0337] Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse chlorosis include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and elsulfavirine (VM-1500).

[0338] Examples of nucleoside or nucleotide inhibitors of HIV reverse chlorosis include adefovir, adefovir disoproxil, azvudine, emtricitabine, tenofovir, alafenamide, alafenamide fumarate, alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (didanosine, DDL), abacavir, abacavir sulfate, alovudine, aritivabine, censavudine, didanosine, eficitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine ester, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461.

[0339] HIV integrase inhibitors

[0340] Examples of HIV integrase inhibitors include elvitegravir, curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, a derivative of aurintricarboxylic acid, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrphostin, an inhibitor of a tyrphostin, quercetin, a derivative of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, Wei, AVX-15567, diketoquinoline-4-1 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.

[0341] Examples of HIV non-catalytic site (or allosteric) integrase inhibitors include CX-05045, CX-05168, and CX-14442.

[0342] HIV entry inhibitors

[0343] Examples of HIV entry (fusion) inhibitors include Cineviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

[0344] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cineviroc, 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).

[0345] 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.

[0346] Examples of CD4 attachment inhibitors include ibatumomab and CADA analogs.

[0347] Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicines, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0348] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0349] HIV maturation inhibitors

[0350] Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, and GSK-2838232.

[0351] Latency reversal agents

[0352] Examples of latency reversing 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, aniline 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.

[0353] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0354] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone.

[0355] Capsid inhibitors

[0356] 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 AVI-CAN1-15 series.

[0357] Immune-based therapies

[0358] Examples of immunotherapy-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); interleukins (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; morphine Mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI); gepon; 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.

[0359] Examples of TLR agonists include vesatolimod (GS-9620), lefitolimod, tilsotolimod, lintamod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, and tiramod.

[0360] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0361] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439 , CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1 117, 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.

[0362] Alpha-4 / beta-7 antagonists

[0363] Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, Abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0364] HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins

[0365] [2] Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bNAbs (broadly neutralizing HIV antibodies), BMS-936559, TMB-360 and those targeting HIV gp120 or gp41, antibody recruitment 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), ibatumomab, Immuglo and MB-66.

[0366] Examples of those that target HIV in this manner include bavirimab, 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, VRC01 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 antibodies.

[0367] Examples of bNAbs delivered in vivo, such as AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01.

[0368] Pharmacokinetic enhancers

[0369] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0370] Additional therapeutic agents

[0371] Examples of additional therapeutic agents include compounds disclosed in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), WO 2013 / 091096 (Boehringer Ingelheim), WO 2018 / 145021 (Gilead Sciences), and WO 2017 / 106346 (Gilead Sciences), each of which is incorporated herein by reference in its entirety.

[0372] HIV vaccine

[0373] 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 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 envA / B / C vaccine, Pennvax-G, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSPISA-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, Ad-4 (Ad4-env evolutionary branch 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 such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV vaccine, HIV vaccine (PIKA adjuvant), II-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-clade Env vaccine, MVA vaccine, Pennvax-GP, pp71-defective 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, variant gp120 peptide vaccine, rAd5gag-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; based on eOD-GT8 60mer 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 (with GLA-SE adjuvant), HIV p24gag pri, me-boost plasmid DNA vaccine, arenavirus-based immunotherapy (Vaxwave, TheraT), MVA-BN HIV vaccine regimen, UBI HIV gp120, mRNA-based preventive vaccine, and TBL-1203HI.

[0374] HIV combination therapy

[0375] In specific embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 1, 2, 3, or 4 additional therapeutic agents selected from: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (nofovir alafenamide and emtricitabine); (nofovir alafenamide, emtricitabine, and rilpivirine); (Alafenamide, Emtricitabine, Cobicistat and Elvitegravir); Adefovir; Adefovir disoproxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Alafenamide; Alafenamide hemifumarate; (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); (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 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 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0376] Those skilled in the art will appreciate that the additional therapeutic agents listed above may include more than one of the classes listed above. The specific classes are not intended to limit the functionality of those compounds listed in those classes.

[0377] In a specific embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In a specific embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitory compound. In another embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase and a pharmacokinetic enhancer. In certain embodiments, the compound disclosed herein or its pharmaceutically acceptable salt is combined with at least one nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor and a pharmacokinetic enhancer. In another embodiment, the compound disclosed herein or its pharmaceutically acceptable salt is combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase. In specific embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, or HIV capsid polymerization inhibitors. In specific embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 1, 2, 3, or 4 HIV bNAbs. In specific embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 1, 2, 3, or 4 HIV bNAbs and HIV capsid inhibitors or HIV capsid polymerization inhibitors. In specific embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 1, 2, 3, or 4 HIV bNAbs, HIV capsid inhibitors, or HIV capsid polymerization inhibitors, and nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

[0378] The compounds disclosed herein (eg, any compound of Formula I) can be combined with 1, 2, 3, or 4 additional therapeutic agents at any dose of the compound of Formula I (eg, from 1 mg to 500 mg of compound).

[0379] In one embodiment, a kit is provided comprising 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.

[0380] In one embodiment, one or more additional therapeutic agents of the kit are anti-HIV agents selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (e.g., chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy), compounds targeting HIV capsid, latency reversal agents, capsid polymerization inhibitors, HIV bNAbs, immunotherapies, 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 infection factor inhibitors, TAT protein inhibitors, HIV 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 regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3grabbing nonintegrin 1inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, 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, HIV vaccines and combinations thereof.

[0381] In some embodiments, one or more additional therapeutic agents of the kit are selected from 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 antibodies, and "antibody-like" therapeutic proteins and combinations thereof.

[0382] In a specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In a specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitory compound. In another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase and a pharmacokinetic enhancer. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor and a pharmacokinetic enhancer. In another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and two nucleoside or nucleotide inhibitors of HIV reverse transcriptase. In specific embodiments, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. In specific embodiments, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and 1, 2, 3, or 4 HIV bNAbs. In specific embodiments, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, 1, 2, 3, or 4 HIV bNAbs, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. In specific embodiments, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, 1, 2, 3, or 4 HIV bNAbs, an HIV capsid inhibitor or an HIV capsid polymerization inhibitor, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase.

[0383] Birth control (contraceptive) combination therapy

[0384] Therapeutic agents used for birth control (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, norethindrone, etonogestrel, Levomefolate, levonorgestrel, ethinyl estradiol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, noregestromin, norethisterone, norethisterone, norgestimate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combination thereof.

[0385] Gene therapy and cell therapy

[0386] Gene therapy and cell therapy include genetic modification to silence genes; genetic approaches to directly kill infected cells; immune cell infusions that are designed to replace much of the patient's own immune system to boost the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches that alter cell activity to further alter the endogenous immune response to infection.

[0387] Examples of dendritic cell therapies include AGS-004.

[0388] Examples of CCR5 gene editing drugs, such as SB-728T

[0389] Examples of CCR5 gene inhibitors, such as Cal-1

[0390] CD4-positive T cells expressing C34-CCR5 / C34-CXCR4

[0391] AGT-103-transfected autologous T cell therapy

[0392] AAV-eCD4-Ig gene therapy

[0393] Gene Editor

[0394] The genome editing system is selected from: CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system and meganuclease system.

[0395] Examples of CRISPR / Cas9 systems targeting HIV include EBT-101.

[0396] CAR-T cell therapy

[0397] A group of immune effector cells, which are engineered to express chimeric antigen receptors (CARs), wherein CARs include HIV antigen binding domains. HIV antigens include HIV envelope proteins or a portion thereof, gp120 or a portion thereof, CD4 binding sites on gp120, CD4 induction binding sites on gp120, N polysaccharides on gp120, V2 of gp120, and proximal regions on gp41. Immune effector cells are T cells or NK cells. In some embodiments, T cells are CD4+T cells, CD8+T cells, or a combination thereof. Cells can be autologous or allogeneic.

[0398] Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CART cell therapy, and autologous hematopoietic stem cells genetically modified to express CD4 CAR and C46 peptide.

[0399] TCR-T cell therapy

[0400] TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells.

[0401] Long-acting HIV therapy

[0402] Examples of drugs being developed as long-acting regimens include cabotegravir, rilpivirine, any integrase LA, VM-1500LAI, maraviroc (LAI), tenofovir implant, MK-8591 implant, doravirine, raltegravir, and long-acting dolutegravir.

[0403] In some embodiments, when the compounds disclosed herein are combined with 1, 2, 3 or 4 additional therapeutic agents as described above, the components of the composition can be administered in a simultaneous or sequential manner. When administered sequentially, the combination can be administered in two or more administrations.

[0404] Route of administration

[0405] Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa or XIb compounds or pharmaceutically acceptable salts thereof (also referred to as active ingredients) can be administered by any route suitable for 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) etc. It should be understood that suitable routes can vary with, for example, the condition of the recipient. In certain embodiments, the compounds disclosed herein can be administered parenterally. In certain embodiments, the compounds disclosed herein can be administered intravenously, subcutaneously or intramuscularly. In some cases, the compounds disclosed herein are orally bioavailable and can be administered orally.

[0406] 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 its pharmaceutically acceptable salt is administered with a syringe suitable for administering the compound. In certain embodiments, the syringe is disposable. In certain embodiments, the syringe is reusable. In certain embodiments, the syringe is pre-filled with Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa or XIb or its pharmaceutically acceptable salt.

[0407] 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 with an automatic injection device comprising a syringe. In certain embodiments, the syringe is disposable. In certain embodiments, the syringe is reusable. In certain 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.

[0408] Dosage regimen

[0409] In some embodiments, a compound, such as 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 an individual according to an effective dosing regimen for a desired period of time or a desired duration, such as at least about once a day, at least about once a week, at least about once a month, at least about once every 2 months, at least about once every 3 months, at least about once every 4 months, at least about once every 6 months, or at least about once every 12 months or longer. In some embodiments, the compound is administered in a daily or intermittent regimen. In some embodiments, the compound is administered in a weekly regimen. In some embodiments, the compound is administered in a monthly regimen. In some embodiments, the compound is administered once every two months. In some embodiments, the compound is administered once every three months. In some embodiments, the compound is administered once every four months. In some embodiments, the compound is administered once every five months. In some embodiments, the compound is administered once every six months.

[0410] 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 or intramuscularly to an individual at least about once a month. 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 or intramuscularly to an individual at least about once every 2 months, at least about once every 3 months, at least about once every 4 months, or at least about once every 6 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 an individual at least about once a month. 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 an individual at least about once every 2 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 an individual at least about once every 3 months.

[0411] In some embodiments, the dose 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, is adjusted during the course of treatment at the discretion of the administering physician.

[0412] In some embodiments, the 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 is administered in an effective dose. For example, the compound dose may be 1 mg to 1000 mg / kg.

[0413] In some embodiments, the methods disclosed herein comprise event-driven 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, to a subject.

[0414] As used herein, the terms "driven by an event" and "event-driven 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, at the following times: (1) before an event that would expose an individual to HIV (or otherwise increase the risk of an individual contracting HIV) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event); and / or (2) during an event (or multiple recurring events) that would expose an individual to HIV (or otherwise increase the risk of an individual contracting HIV); and / or (3) after an event (or after the last event in a series of recurring events) that would expose an individual to HIV (or otherwise increase the risk of an individual contracting HIV). In some embodiments, event-driven administration is performed before an individual is exposed to HIV. In some embodiments, event-driven administration is performed after an individual is exposed to HIV. In some embodiments, event-driven administration is performed before the individual is exposed to HIV and after the individual is exposed to HIV.

[0415] 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 exposure of the individual to HIV.

[0416] In some embodiments, the drug 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 the subject prior to exposure to HIV.

[0417] An example of an event-driven dosing regimen includes 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, within 24 to 2 hours prior to HIV exposure (e.g., first sexual intercourse, including sexual 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, every 24 hours during the exposure (e.g., sexual intercourse with a sexual partner known to be HIV positive). , XIa or XIb, or a pharmaceutically acceptable salt thereof, 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 intercourse 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.

[0418] An example of an event-driven dosing regimen includes 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, within 24 hours prior to HIV exposure (e.g., with a sexual partner known to be HIV positive), then 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, every 24 hours during exposure (e.g., sexual intercourse with a sexual partner known to be HIV positive, including the last sexual intercourse), then administering a final administration (which may be an increased dose, such as a double dose) about 24 hours after the last exposure.

[0419] In certain embodiments, for example, when administered as PrEP, 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 once daily. In certain embodiments, for example, when administered as event-driven PrEP, 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 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 risk of HIV infection in an individual (e.g., before sexual activity or other exposure to HIV virus). In certain 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 risk of HIV infection in an individual (e.g., before sexual intercourse or other behavior exposed to HIV virus). In some embodiments, when 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 before an event that increases the risk of HIV infection in an individual, it is administered once a day before the event (e.g., sexual intercourse). In some 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 the risk of an individual contracting HIV, the administration is 1 to 3 times prior to the event (e.g., sexual activity).

[0420] In some embodiments, for example, when administered as part of a 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 HIV exposure. In some 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 is administered prior to exposure, 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 once daily (as a single dose) during HIV exposure (e.g., during 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 once daily (e.g., for 1 to 7 days) after the final HIV exposure (e.g., after a period of sexual intercourse with a sexual partner known to be HIV positive). In some embodiments, administration continues for 1 or 2 days after the final HIV exposure.

[0421] Other examples of PrEP and / or PEP can be found in, for example, the clinical trial abstracts entitled “On Demand Antiretroviral Pre-exposure Prophylaxis for HIV Infection in Men Who Have Sex With Men” (Clinical Trial No. NCT01473472); -de-France" (clinical trial number 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.

[0422] In some embodiments, the method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) includes 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 and a combination of safer sex. In certain embodiments, the method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) includes administering to an individual at risk of infection with HIV. Examples of individuals with a high risk of infection with HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

[0423] In some embodiments, the risk of contracting HIV is reduced by at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the risk of contracting HIV is reduced by at least about 75%. In some embodiments, the risk of contracting HIV is reduced by about 80%, 85%, or 90%.

[0424] formula

[0425] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. In certain embodiments, the suspension is a microsuspension. In certain embodiments, the suspension is a nanosuspension.

[0426] In some embodiments, one or more excipients will be included in formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration). The excipient should be compatible with the other ingredients of the formulation and physiologically harmless to its 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 (ed. Rowe, Sheskey & Quinn), 2009 6th edition.

[0427] 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 in the free acid form.

[0428] In certain embodiments, the pharmaceutical compositions disclosed herein are parenteral formulations. In certain embodiments, the formulations are administered subcutaneously to an individual in need thereof. In certain embodiments, the formulations are administered intramuscularly to an individual in need thereof.

[0429] The amount of active ingredients that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended treatment target and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to a human can contain about 1 to 1000 mg of an active substance, formulated with a suitable and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material accounts for about 5% to about 95% (weight: weight) of the total composition.

[0430] It should be understood that in addition to the ingredients particularly mentioned above, the compositions of the embodiments may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.

[0431] abbreviation

[0432] The abbreviations used in this article have the following meanings:

[0433] ACN Acetonitrile

[0434] aq. Aqueous solution

[0435] AXI Anion Exchange Isocratic

[0436] AZ-H Amylose tris(3-chloro-4-methylphenylcarbamate)

[0437] AZT azidothymidine or zidovudine

[0438] atm atmosphere

[0439] Bn Benzyl

[0440] bNAbs broadly neutralizing HIV antibodies

[0441] Boc or BOC tert-butoxycarbonyl

[0442] Boc 2 O Di-tert-butyl dicarbonate

[0443] Cbz benzyloxycarbonyl

[0444] CbzCl or Cbz-Cl Benzyl chloroformate

[0445] Cp Cyclopentadienyl

[0446] CC 50 50% cytotoxic concentration

[0447] CCM cell culture medium

[0448] Cp 2 TiMe 2Dimethyl titanocene or bis(cyclopentadienyl) dimethyl titanium or

[0449] Petasis Reagents

[0450] DBU 1,8-Azabicyclo[5.4.0]undec-7-ene

[0451] DCE Dichloroethane

[0452] DCM Dichloromethane

[0453] dd double doublet

[0454] ddd double double peak

[0455] dddd double double double peak

[0456] ddq double quadruple peak

[0457] DDT Double Triple Peak

[0458] DIPEA N,N-Diisopropylethylamine

[0459] DMF Dimethylformamide

[0460] DMP Desmartin Periodinane

[0461] DMSO Dimethyl sulfoxide

[0462] dpm Divalerylmethoxyketoic acid or 2,2,6,6-tetramethyl-3,5-heptanedione

[0463] dq double quartet

[0464] dt double triplet

[0465] dtd double triple double peak

[0466] EC 50 Half maximum effective concentration

[0467] Et Ethyl

[0468] Et 2 O Ether

[0469] Et 3 N-Triethylamine

[0470] EtOAc Ethyl acetate

[0471] EtOH

[0472] FBS Fetal bovine serum (culture medium)

[0473] Gen

[0474] Grubbs Gen 1 First generation Grubbs catalyst TM

[0475] h hour

[0476] HATU 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl

[0477] Urea hexafluorophosphate

[0478] HPLC High Pressure Liquid Chromatography

[0479] HS human serum

[0480] Hz Hertz

[0481] IA Amylose tris(3,5-dimethylphenylcarbamate)

[0482] IB Cellulose tris(3,5-dimethylphenylcarbamate)

[0483] IPA Isopropyl Alcohol

[0484] LA long-acting

[0485] LCMS or LC-MS Liquid chromatography-mass spectrometry

[0486] m multiplet

[0487] M Moore

[0488] Me Methyl

[0489] MeCN Acetonitrile

[0490] MeI Methyl iodide

[0491] MeLi Methyl lithium

[0492] MeMgBr Methylmagnesium bromide

[0493] MeOH Methanol

[0494] Me 2 S-Dimethyl Sulfide

[0495] Me 3 SiCNH 2 (Trimethylsilyl)diazomethane

[0496] MHz Megahertz

[0497] min.

[0498] mmol millimole

[0499] μM micromolar

[0500] μmol micromole

[0501] mL milliliters

[0502] Mn(dpm) 3 Tris(divalerylketoacetic acid)manganese

[0503] MS

[0504] MT-4 or MT4 Metallothionein 4 Human T Cell Line

[0505] m / z mass-to-charge ratio

[0506] N Normal

[0507] NMR Nuclear Magnetic Resonance

[0508] OAc acetate

[0509] OD-H Cellulose tris(3,5-dimethylphenylcarbamate)

[0510] p Quintet

[0511] PA Modulated Protein

[0512] Ph Phenyl

[0513] PhCHO Benzaldehyde

[0514] PhS 3 Phenylsilane

[0515] ppm parts per million

[0516] prep. Preparation

[0517] q quartet

[0518] qd quadruple double peak

[0519] rac racemic

[0520] rel relative (stereochemistry or configuration)

[0521] RLuc Renilla luciferase or Renilla-luciferin 2-monooxygenase

[0522] RP Invert

[0523] RPMI Roswell Park Memorial Institute (culture medium)

[0524] RT or RT Room temperature

[0525] s Single peak

[0526] SFC Supercritical Fluid Chromatography

[0527] SGC Solvation Gas Chromatography

[0528] STAB Sodium triacetoxyborohydride

[0529] t Triplet

[0530] td triple double peak

[0531] tdd triple double peak

[0532] TFA Trifluoroacetic acid

[0533] THF Tetrahydrofuran

[0534] Ti(OEt) 4 Titanium(IV) ethoxide

[0535] TMS Trimethylsilyl

[0536] TLR toll-like receptor

[0537] tt triple triplet

[0538] UV

[0539] wt weight

[0540] The following examples are offered by way of illustration and not by way of limitation.

[0541] Example

[0542] 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-methanpyrido[1,2-d][1,4,7]oxadiazacyclodecene-11-carboxamide (1-1, 1-2):

[0543]

[0544] Synthesis of tert-butyl 3-methylene-1,5-oxacyclooctane-5-carboxylate (1a):

[0545] 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 (~526 mg, 13.2 mmol) in mineral oil was added in portions. After stirring in the cold bath for about 30 minutes, 3-chloro-2-(chloromethyl)prop-1-ene (0.61 mL, 5.80 mmol) was added by pushing a syringe over 15 minutes. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by slowly adding ice water, diluted with water (about 100 mL), and then the product was extracted with ethyl acetate (2×about 100 mL). After the organic extract was washed with water (about 100-150 mL×1), the organic portion was combined and MgSO 4 Dry, filter and concentrate. The residue is purified by silica gel column chromatography eluting with 0-about 70% ethyl acetate in hexane to give the title compound. MS (m / z) 171.74 [M+HC 4 H 8 ] + .

[0546] Synthesis of tert-butyl 3-oxo-1,5-oxacyclooctane-5-carboxylate (1b):

[0547] A solution of tert-butyl 3-methylene-1,5-oxacyclooctane-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 a 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 silica gel column chromatography eluted with a hexane solution of 0-100% ethyl acetate to give the title compound. MS (m / z) 251.96 [M+Na] + .

[0548] Synthesis of tert-butyl 3-((tert-butylsulfinyl)amino)-1,5-oxaoctane-5-carboxylate (1c):

[0549] A solution of 1b (315 mg, 1.38 mmol), racemic-2-methylpropane-2-sulfenamide (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 hour. The reaction mixture was cooled to room temperature and further cooled to about -50 °C before adding a 1 M solution of lithium tri-sec-butylborohydride (L-Selectride) in THF (5.5 mL). After 30 minutes, the reaction mixture was slowly warmed to room temperature over 2 hours. The reaction mixture was cooled to 0 °C again and methanol was added until no gas evolved. Brine was added to the solution under vigorous stirring and the resulting mixture was stirred for 2 hours. The solid was filtered and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (×3), and the combined organic fractions were washed with brine (×1), combined, and washed with MgSO 4 Dry, filter and concentrate. The residue is purified by silica gel column chromatography (eluting sequentially with 50-100% ethyl acetate in hexanes and 0-20% methanol in ethyl acetate) to give the title compound. MS (m / z) 334.94 [M+H] + .

[0550] Synthesis of 13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanpyrido[1,2-d] [1,4,7]Oxadiazacyclodecene-11-carboxylic acid methyl ester (1d):

[0551] A solution of 1c (274 mg, 0.82 mmol) in dichloromethane (2 mL) was stirred at room temperature while 4N HCl in dioxane (4 mL) was added. After 1 hour, the resulting suspension was concentrated and dried overnight. A solution of 3-methoxy-4-oxo-4H-pyran-2,5-dicarboxylic acid dimethyl ester (242.5 mg, 1.00 mmol) and sodium bicarbonate (278.4 mg, 3.31 mmol) in water (1 mL) and methanol (3 mL) was added to the flask containing the residue, and the resulting mixture was stirred at room temperature for 24 hours and in a 40°C bath.

[0552] 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) (eluted with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes). The combined fractions were freeze-dried to give the title compound. MS (m / z) 323.16 [M+H] + .

[0553] Synthesis of N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8- Methylpyrido[1,2-d][1,4,7]oxadiazacyclodecene-11-carboxamide (1e):

[0554] To a solution of methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazacyclodecene-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 hour at room temperature. After the reaction mixture was acidified with 1N HCl (~0.2 mL), the resulting solution was concentrated to dryness and co-evaporated with toluene (×3). To the previous 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 at room temperature for N,N-diisopropylethylamine (0.1 mL, 574.1 μmol). After 1 hour, the reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (×2), saturated sodium bicarbonate solution (×2) and brine (×1). The aqueous portion was extracted with ethyl acetate (×1), and the two organic portions were combined and washed with MgSO 4 Dry, filter and concentrate. The residue was dissolved in DMF, filtered and purified by preparative HPLC (column, Gemini 10μC18 110A, AXI / ; 250×21.2 mm) (eluted with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes). The combined fractions were freeze-dried to give the title compound. MS (m / z) 434.22 [M+H] + .

[0555] 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-methanpyrido[1,2-d][1,4,7]oxadiazacyclodecene-11-carboxamide (1,1- 2)：

[0556] To a solution of N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-carboxypyrido[1,2-d][1,4,7]oxadiazacyclodecene-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 hour, the reaction mixture was concentrated and the residue was triturated with 2N HCl (~0.5 mL) and water (~1.5 mL) at 0°C. After sonication, the suspension was diluted with DMF (3 mL) to a solution and then filtered. The filtered solution was purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm) (eluted with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes). The combined fractions were freeze-dried to give the title compound. MS (m / z) 420.23 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d 3 )δ10.31(s,1H),8.40(s,1H),7.40(td,J=8.8,6.4Hz,1H),6.93(ddq,J=10.8,5.8,2.8Hz,2H),4.57(d,J=5.2Hz,2H),4.43-4.26(m,2H) ,4.07(d,J=33.0Hz,4H),3.95(dd,J=14.9,1.7Hz,1H),3.75(s,1H),3.13(ddd,J=13.9,7.5,4.6Hz,1H),2.06-1.96(m,1H),1.86(s,1H). 19 F NMR (376 MHz, acetonitrile-d 3 )δ-114.07(p,J=7.6Hz),-116.55(q,J=8.7Hz).

[0557] 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]oxadiazacyclodecene-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.

[0558] 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]oxadiazacyclodecene-11-carboxamide (2):

[0559]

[0560] Synthesis of 13-methoxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2, 8-Methylpyrido[1,2-d][1,4,7]oxadiazacyclodecene-11-carboxamide (2a):

[0561] To a solution of 13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazacyclodecene-11-carboxylic acid methyl ester (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 at room temperature. After the reaction mixture was acidified with 1N HCl (~0.2 mL), the resulting solution was concentrated to dryness and co-evaporated with toluene (×3). To the previous residue were 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 at room temperature for N,N-diisopropylethylamine (0.1 mL, 574.1 μmol). After 1 hour, the reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (×2), saturated sodium bicarbonate solution (×2) and brine (×1). After the aqueous portion was extracted with ethyl acetate (×1), the two organic portions were combined and precipitated with MgSO 4 Dry, filter and concentrate. The residue was dissolved in DMF, filtered and purified twice by preparative HPLC (column, Gemini 10μC18 110A, AXI / ; 250×21.2 mm) (eluted with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes). The combined fractions were freeze-dried to give the title compound. MS (m / z) 452.23 [M+H] + .

[0562] Synthesis of 13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8- Methylpyrido[1,2-d][1,4,7]oxadiazacyclodecene-11-carboxamide (2):

[0563] 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]oxadiazacyclodecene-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 bath at 50° C. After 30 minutes, the reaction mixture was cooled and concentrated, and the residue was dissolved in DMF (0.5 mL) and 2N 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) (eluted with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes). The combined fractions were freeze-dried to give the title compound. MS (m / z) 420.23 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d 3 )δ10.31(s,1H),8.40(s,1H),7.40(td,J=8.8,6.4Hz,1H),6.93(ddq,J=10.8,5.8,2.8Hz,2H),4.57(d,J=5.2Hz,2H),4.43-4.26(m,2H) ,4.07(d,J=33.0Hz,4H),3.95(dd,J=14.9,1.7Hz,1H),3.75(s,1H),3.13(ddd,J=13.9,7.5,4.6Hz,1H),2.06-1.96(m,1H),1.86(s,1H). 19 F NMR (376 MHz, acetonitrile-d 3 )δ-114.07(p,J=7.6Hz),-116.55(q,J=8.7Hz).

[0564] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (3-1, 3-2):

[0565]

[0566] Synthesis of 1-benzyl-5,5-difluoropiperidine-2-carboxylate (3b):

[0567] 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 2M (trimethylsilyl)diazomethane in diethyl ether (~10 mL) was added until the yellow color persisted. After 15 minutes, 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 silica gel column chromatography (eluted with 0-30% ethyl acetate in hexanes) to give 1-(tert-butyl) 2-methyl 5,5-difluoropiperidine-1,2-dicarboxylate.

[0568] 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 h, the solution was concentrated, the residue was dissolved in saturated sodium bicarbonate solution and the product was extracted with ethyl acetate (×2). The organic extract was washed with brine (×1) and MgSO 4 Dry, filter and concentrate.The residue was purified by silica gel column chromatography (eluting with 0-100% ethyl acetate in hexanes) to give methyl 5,5-difluoropiperidine-2-carboxylate.

[0569] A solution of methyl 5,5-difluoropiperidine-2-carboxylate (962 mg, 5.37 mmol) in DMF (15 mL) was stirred at 0°C while adding 60% sodium hydride (305 mg, 7.63 mmol) in mineral oil in portions. 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, then 60% sodium hydride (150 mg, 3.75 mmol) and benzyl bromide (0.5 mL, 4.20 mmol) in mineral oil were added at room temperature and stirred at room temperature for 2.5 hours. The reaction mixture was quenched with 2N HCl (~4 mL) at 0°C, diluted with saturated sodium bicarbonate solution (~100 mL), and then the product was extracted with ethyl acetate (~100 mL×2). The organic extracts were washed with water (150 mL×1), combined, and precipitated with MgSO 4 Dry, filter, concentrate, and purify by silica gel column chromatography (eluting with 0-100% ethyl acetate in hexanes) to give the title compound. MS (m / z) 270.10 [M+H] + .

[0570] Synthesis of 6-azido-1-benzyl-3,3-difluoroazepane (3c):

[0571] A solution of 1-benzyl-5,5-difluoro-piperidine-2-carboxylic acid methyl ester (1011 mg, 3.76 mmol) in THF (10 mL) was stirred at 0 °C while adding 1 M LiAlH 4 (5 mL, 5 mmol). After 30 minutes at 0°C, the reaction mixture was vigorously stirred at 0°C and quenched by sequentially adding water (0.19 mL), 15% NaOH (0.19 mL) and water (0.57 mL), and diluted with ether (~15 mL). After the resulting suspension was vigorously stirred at 0°C for 30 minutes, the mixture was Filter and wash the filtrate with MgSO 4 Treat and filter again. Concentrate the filtrate to obtain (1-benzyl-5,5-difluoropiperidin-2-yl)methanol. MS (m / z) 242.10 [M+H] + .

[0572] (1-Benzyl-5,5-difluoro-2-piperidinyl)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 hours, the reaction mixture was concentrated and the residue was dissolved in saturated sodium bicarbonate solution (~20 mL) and ethyl acetate (~25 mL). After separation of the two parts, the aqueous part was extracted with ethyl acetate (~25 mL x 1). The organic part was washed with brine (~20 mL x 1), combined, and precipitated with MgSO 4 Drying, filtration and concentration gave unpurified 1-benzyl-2-(chloromethyl)-5,5-difluoropiperidine. MS (m / z) 260.10 [M+H] + .

[0573] The unpurified chloride and sodium azide (187 mg, 2.88 mmol) in DMSO (4 mL) were stirred in a 90°C bath for 4 hours and then cooled at room temperature. The reaction mixture was diluted with water (~50 mL) and saturated sodium bicarbonate solution (~5 mL), and the product was extracted with ethyl acetate (~30 mL x 3). The extracts were washed with water (~50 mL x 1), combined, and dried (Na 2 SO 4 ) and concentrated. The residue was purified using silica gel column chromatography eluting with 0-10% ethyl acetate in hexanes to give the title compound. MS (m / z) 267.06 [M+H] + .

[0574] 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]diazacyclononatetraene-10-carboxamide (3d):

[0575] A suspension of 6-azido-1-benzyl-3,3-difluoro-azepane (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 in H 2 The reaction mixture was stirred for 3 hours under a 4% CO atmosphere. The mixture was filtered and washed with methanol. The filtrate and washings were combined and concentrated completely to give unpurified 6,6-difluoroazepan-3-amine dihydrochloride.

[0576] Unpurified 6,6-difluoroazepan-3-amine dihydrochloride (119.9 mg, 0.54 mmol), 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylic acid methyl ester (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, and MgSO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (eluting with 0-5% methanol in dichloromethane) to give a partially purified product.

[0577] The partially purified product was dissolved in DMF, filtered, and purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm) (eluted with 30-90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes), and the collected fractions were freeze-dried to give the title compound. MS (m / z) 548.14 [M+H] + .

[0578] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (3-1, 3-2)

[0579] 12-(Benzyloxy)-4,4-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (3d, 140.7 mg) was separated into its individual enantiomers by preparative SFC chromatography (using methanol co-solvent on IA column) 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. The reactions were each concentrated and the residue was purified using silica gel column chromatography (eluted 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-d 3 )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=14.4,11.6,2.8Hz,1H),4.59(d,J=5.8Hz,1H),4.37(dd,J=13.5,4.2Hz,1H),4.04( dd,J=13.6,8.2Hz,1H),3.89(ddt,J=11.8,7.8,3.7Hz,1H),3.19(ddd,J=31.8,14.2,1 .9Hz,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).

[0580] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (4-1, 4-2):

[0581]

[0582] 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]diazacyclononatetraene-10-carboxamide (4a):

[0583] Unpurified 6,6-difluoroazepan-3-amine dihydrochloride (116.7 mg, 0.52 mmol), 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylic acid methyl ester (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 portion was extracted with ethyl acetate (×1), and the two organic portions were washed with water (x1), combined, and MgSO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (eluting with 0-5% methanol in dichloromethane) to give a partially purified product.

[0584] The partially purified product was dissolved in DMF, filtered, and purified by preparative HPLC (column, Gemini 10μ C18110A, AXI / ; 250×21.2 mm) (eluted with 30-90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes), and the collected fractions were freeze-dried to give the title compound. MS (m / z) 530.12 [M+H] + .

[0585] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (4-1,4- 2)：

[0586] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methylpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (4a, 133 mg) was separated into its individual enantiomers by preparative SFC chromatography (using methanol co-solvent on an IA column) 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. The reactions were each concentrated and the residue was purified using silica gel column chromatography (eluted with 0-14% methanol in dichloromethane) to give the title compound. MS (m / z) 440.19 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d 3)δ12.36(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 .8Hz,2H),4.71(tt,J=11.7,2.8Hz,1H),4.57(d,J=6.0Hz,2H),4.38(dd,J=13.5,4.2Hz, 1H), 4.06 (dd, J=13.6, 8.1Hz, 1H), 3.90 (td, J=8.2, 4.2Hz, 1H), 3.20 (ddd, J=31.8, 14.2, 1.9Hz,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).

[0587] 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-methanpyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (5-1, 5-2):

[0588]

[0589] Synthesis of 13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a] [1,4] Methyl diazacyclodecene-11-carboxylate (5a):

[0590] Azocan-3-amine (0.13 g, 1.0 mmol), sodium bicarbonate (66 mg, 0.79 mmol), methanol (3 mL) and water (0.3 mL) were placed in a vial. Dimethyl 3-methoxy-4-oxo-4H-pyran-2,5-dicarboxylate (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] + . 1H 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).

[0591] Synthesis of N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8- Methylpyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (5b):

[0592] 13-Methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methylpyrido[1,2-a][1,4]diazacyclodecene-11-carboxylic acid methyl ester (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 minutes, 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)methylamine (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 minutes, the reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water, containing 0.1% TFA) and lyophilized to obtain the title compound. MS (m / z) 432.2 [M+H] + .

[0593] 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-methanpyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (5-1, 5-2):

[0594] N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methylpyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (43 mg) was separated into its individual enantiomers by preparative SFC chromatography (using MeOH co-solvent on an IB column) 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 hour. The reactions were each 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 ,8.3,5.2Hz,1H),3.91(dd,J=14.5,2.8Hz,1H),3.80(dd,J=14.5,2.1Hz,1H),3.03(d dd,J=13.8,6.0,4.8Hz,1H),2.30-2.17(m,1H),1.94-1.70(m,3H),1.62-1.47(m,4H).

[0595] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (7):

[0596]

[0597] Synthesis of (R)-3-(dibenzylamino)azepan-2-one (7a):

[0598] (3R)-3-aminoazacycloheptan-2-one (1.51 g, 11.8 mmol) was mixed 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 and washed with Na 2 SO 4Dry, filter, concentrate, and purify by flash column chromatography (hexane / EtOAc) to give the title compound. MS (m / z) 309.4 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ7.41 (d, J = 7.2Hz, 4H), 7.37-7.30 (m, 4H), 7.27-7.19 (m,2H),5.64(s,1H),4.09(d,J=14.4Hz,2H),3.91(d,J=14.4Hz,2H),3.44 (d,J=10.1Hz,1H),3.12(dt,J=14.0,6.7Hz,1H),2.92(ddd,J=15.3,10.8, 5.4Hz, 1H), 2.01 (d, J = 11.4Hz, 2H), 1.96-1.65 (m, 2H), 1.53-1.32 (m, 2H).

[0599] Synthesis of (2R,3R)-N,N-dibenzyl-2-methylazepan-3-amine (7b):

[0600] (3R)-3-(Dibenzylamino)azepan-2-one (7a, 637 mg, 2.07 mmol) was suspended in toluene (20 mL) and triethylamine (0.57 mL, 4.1 mmol) at 0 °C. Trimethylsilyl chloride (0.29 mL, 2.3 mmol) in toluene (3 mL) was added dropwise. After 5 minutes, the mixture was warmed to 50 °C and stirred for 3 hours. The slurry was cooled to 5 °C, filtered to remove the precipitate, and rinsed 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 1.6 M MeLi (1 mL) 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 and washed with Na 2 SO 4 Dry, filter and concentrate. The unpurified mixture was dissolved in 5 g of After stirring for 5 minutes, sodium triacetoxyborohydride (0.88 g, 4.1 mmol) was added and the reaction was stirred overnight and slowly warmed to room temperature. The reaction was quenched with aqueous sodium bicarbonate and filtered. The organic layer was separated and washed with Na 2 SO 4 Dry, filter, concentrate, and purify by flash column chromatography (hexane / EtOAc) to give the title compound. MS (m / z) 309.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ7.48 (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=10.4,6.1Hz,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=6.9Hz,3H),1.26-1.11(m,1H).

[0601] 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]diazacyclononatetraene-10-carboxamide (7c):

[0602] (2R,3R)-N,N-dibenzyl-2-methylazepan-3-amine (7b, 90 mg, 290 μmol) was mixed with Pd / C (10 wt%, wet, E101 NE / W, 155 mg) in ethanol (20 mL) and stirred under a hydrogen atmosphere for 120 h. The mixture was degassed with argon and heated to 40 °C. Filter, and add 2M HCl (2 mL). Concentrate the solution to dryness to obtain the hydrochloride salt of (2R,3R)-2-methylazepan-3-amine. MS (m / z) 129.2 [M+H] +.

[0603] (2R, 3R)-2-methylazepan-3-amine dihydrochloride (58 mg, 0.29 mmol) was dissolved in methanol (3 mL) and water (0.5 mL) together with sodium bicarbonate (151 mg, 1.79 mmol). 3-(Benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester (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, containing 0.1% TFA) and lyophilized to give the title compound. MS (m / z) 508.6 [M+H] +.

[0604] Synthesis of (1R,14R)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-14-methyl-5,8-dioxo-2,9-difluorophenyl Azatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (7):

[0605] (7R,13R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (66 mg, 0.13 mmol) was dissolved in toluene (1 mL) and TFA (2 mL). After 135 minutes, the reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water with 0.1% TFA) and lyophilized to give the title compound. Chiral HPLC analysis indicated it was 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 = 5.9 Hz, 2H), 4.44 (dt, J = 5.2, 2.2 Hz, 1H), 4.26 (ddd, J = 13 .3,8.9,7.5Hz,1H),3.86(qd,J=6.9,1.7Hz,1H),3.21(ddd,J=13.3,7.4,2.9Hz,1H), 2.13-1.99(m,1H),1.89-1.60(m,1H),1.28(d,J=15.2Hz,1H),1.22(d,J=6.9Hz,3H).

[0606] 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]diazacyclononatetraene-10-carboxamide (8):

[0607]

[0608] (7S,13S)-12-hydroxy-13-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (7) was prepared in a similar manner to (7R,13R)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide 1-Hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (8), starting from (S)-3-aminoazepan-2-one and using 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylic acid methyl ester instead of 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester. HPLC analysis indicated a mixture of enantiomers. MS (m / z) 436.2 [M+H] + . 1 H NMR (400MHz, acetonitrile-d3) δ10.40(s,1H),8.43(s,1H),6.98-6.79(m,2H),4.62(d,J=5.5Hz,2H),4.52-4.37(m,1H),4.24(ddd,J=13.3,8.9, 7.5Hz, 1H), 3.86 (qd, J=6.9, 1.7Hz, 1H), 3.20 (ddd, J=13.4, 7.4, 2.9Hz, 1H), 2.06-2.00 (m, 1H), 1.88-1.66 (m, 2H), 1.34-1.13 (m, 4H).

[0609] 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]diazacyclononatetraene-10-carboxamide (9):

[0610]

[0611] Synthesis of (R)-tert-butyl 3-(dibenzylamino)-2-methyleneazepane-1-carboxylate (9a):

[0612] (3R)-3-(Dibenzylamino)azepan-2-one (7a, 735 mg, 2.38 mmol) was mixed with triethylamine (0.66 mL, 4.77 mmol), 4-(dimethylamino)pyridine (87 mg, 0.71 mmol) and Boc 2O (780 mg, 3.6 mmol). The mixture was stirred at 35°C for 3 days. 4-(Dimethylamino)pyridine (291 mg, 2.38 mmol) and Boc 2 O (630 mg, 2.9 mmol), and the mixture was stirred at 60 °C for 4.5 hours. The mixture was cooled to 45 °C and more Boc 2 O (1040 mg, 4.77 mmol). The reaction was stirred overnight, cooled to room temperature and quenched with aqueous ammonium chloride. The organic layer was separated and washed with Na 2 SO 4 Dry, filter, concentrate, and purify by flash column chromatography (hexanes / EtOAc) to give (R)-tert-butyl 3-(dibenzylamino)-2-oxazepane-1-carboxylate. MS (m / z) 409.5 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ7.37(d,J=7.2Hz,4H),7.30(t,J=7.4Hz,4H),7.22(t,J=7.2Hz,2H),4.12-4.07(m,1H),4.05(d,J=14.5Hz,2H),3 .87(d,J=14.3Hz,2H),3.63-3.47(m,1H),2.83(dd,J=15.4,10.4Hz,1H),2.03-1.68(m,3H),1.55(d,J=0.8Hz,9H),1.53-1.38(m,2H).

[0613] Under argon, (3R)-3-(dibenzylamino)-2-oxo-azepane-1-carboxylic acid tert-butyl ester (463 mg, 1.13 mmol) was placed in a round-bottom flask, and dimethyl titanocene (5% toluene solution / THF, 16 mL) was added. The mixture was stirred at 80°C for 75 minutes, cooled to 15°C, and quenched with aqueous sodium bicarbonate. The organic layer was separated and washed with Na 2 SO 4 Dry, filter, concentrate, and purify by flash column chromatography (hexane / EtOAc) to give the title compound. MS (m / z) 407.5 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ7.41 (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=14.0Hz,2H),3.35(dt,J=9.9,2.4Hz,1H),2.85(s,1H),1.95(q,J=16.1 ,12.0Hz,2H),1.69-1.58(m,1H),1.55-1.47(m,1H),1.38(s,9H),1.25-1.16(m,1H).

[0614] Synthesis of (3R)-3-(Benzylamino)-2-methyl-azepane-1-carboxylic acid tert-butyl ester (9b):

[0615] Under argon, (3R)-3-(dibenzylamino)-2-methylene-azepane-1-carboxylic acid tert-butyl ester (9a, 256 mg, 0.63 mmol) was mixed with tert-butyl hydroperoxide (5-6 M decane solution, 214 μl) and phenylsilane (78 μl, 0.63 mmol) in isopropanol (3 mL). Tris(di-pivaloylmethane)manganese (34 mg, 0.056 mmol) was added and the reaction was stirred at room temperature. After 1 hour, tris(di-pivaloylmethane)manganese (11 mg, 0.019 mmol) was added and stirring was continued. After another 30 minutes, 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] + .

[0616] 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]diazacyclononatetraene-10-carboxamide (9c):

[0617] (3R)-3-(Benzylamino)-2-methyl-azepane-1-carboxylic acid tert-butyl ester (138 mg, 433 μmol) was mixed with Pd / C (10 wt%, wet, E101 NE / W, 138 mg) in ethanol (10 mL) under hydrogen atmosphere and stirred vigorously overnight. Filtration and concentration to dryness gave unpurified (3R)-3-amino-2-methyl-azepane-1-carboxylic acid tert-butyl ester. MS (m / z) 229.0 [M+H] +. The material was dissolved in methanol (5 mL) and water (0.5 mL), sodium bicarbonate (146 mg, 1.73 mmol) was added, followed by 3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyran-2-carboxylic acid methyl ester (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, and washed with Na 2 SO 4 Dry, filter and concentrate. 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 heated to 60 ° C and stirred overnight. The reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water, 0.1% TFA) and lyophilized to give the title compound, which is a mixture of diastereomers, the main 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-methyl-bridged pyrido [1,2-a] [1,4] diazacyclononatetraene-10-carboxamide. MS (m / z) 508.4 [M+H] + .

[0618] 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]diazacyclononatetraene-10-carboxamide (9):

[0619] [3] (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 hour, 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] + . 1H 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).

[0620] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (10-1, 10-2):

[0621]

[0622] Synthesis of 12-(Benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexa Hydrogen-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (10a):

[0623] A vial was charged with 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylic acid methyl ester (350 mg, 0.78 mmol), 3-amino-4-hydroxyazepane-1-carboxylic acid tert-butyl ester (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 distributed 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. 10 mL of ethanol and DBU (0.47 mL, 3.12 mmol) were added to the residue. The reaction mixture was heated to 120 °C in a microwave for 30 minutes. After cooling to room temperature, 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] + .

[0624] 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]diazacyclononatetraene-10-carboxamide (10b):

[0625] 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]diazacyclononatetraene-10-carboxamide (10a) (320 mg, 0.61 mmol) in anhydrous 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 0.5N NaOH and 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] + .

[0626] 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]diazacyclononatetraene-10-carboxamide (10c):

[0627] [4] 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-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (10b) (200 mg, 0.38 mmol) in DCM (5 mL) under argon and cooled at -78°C was added Deoxo- (1.1 mmol, 0.42 mL, 50% in toluene). The resulting mixture was stirred at -78°C and allowed to gradually warm to room temperature overnight. The mixture was cooled at -78°C and Deoxo- (0.76mmol, 0.28mL, 50% in toluene). 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 dropwise addition of saturated aqueous sodium bicarbonate solution. The resulting mixture was stirred for 1 hour, more saturated aqueous sodium bicarbonate solution was added, and stirring was continued for 10 minutes until bubbling ceased. The organic layer was separated and washed with Na 2 SO 4 Dry and filter. Concentrate the filtrate to dryness. The residue is purified by silica gel chromatography (eluting with EtOAc / hexane), purified by preparative HPLC (MeCN / water, containing 0.1% TFA), and freeze-dried to give the title compound. MS (m / z) 548.25 [M+H] + .

[0628] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (10-1,10- 2)：

[0629] 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]diazacyclononatetraene-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 toluene and 1 mL 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 (400MHz, DMSO-d6) δ10.63 (s, 1H), 10.26 (t, J = 5.8Hz, 1H), 8.48 (s, 1H), 7. 22(t,J=8.7Hz,2H),5.26-5.17(m,1H),4.58(d,J=5.8Hz,2H),4.20(dt,J=13. 3,8.7Hz,1H),4.07-3.97(m,1H),3.87(dd,J=15.5,1.9Hz,1H),3.18(dd,J=13 .3, 6.7Hz, 1H), 2.21 (s, 1H), 2.05-1.83 (m, 2H), 1.60 (dt, J = 34.9, 14.0Hz, 1H). Peak 2: MS (m / z) 458.13 [M+H]+. 1 HNMR (400MHz, DMSO-d6) δ10.63(s,1H),10.27(t,J=5.8Hz,1H),8.48(s,1H),7.22(t,J=8.7Hz,2H),5.21(d,J=8.0Hz,1H),4.58(d,J=5.8Hz,2H),4.3 2-4.15(m,1H),4.10-3.94(m,1H),3.87(dd,J=15.5,2.0Hz,1H),3.18(dd, J=13.4,6.6Hz,1H),2.22(s,1H),1.92(d,J=8.1Hz,2H),1.71-1.43(m,1H).

[0630] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (11):

[0631]

[0632] 12-(Benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (10a) (20 mg) was dissolved in 0.3 mL toluene and 0.6 mL TFA and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the residue was purified by RP-HPLC (eluted with ACN / water (0.1% TFA)) to provide the title compound. MS (m / z) 438.18 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),10.44(t,J=5.8Hz,1H),8.28(s,1H),7 .28-7.15(m,2H),4.57(d,J=5.6Hz,3H),4.13(dt,J=13.2,9.2Hz,1H),3.91-3 .78(m,2H),3.62(dd,J=15.0,1.6Hz,1H),3.12(dt,J=13.1,4.5Hz,1H),1.84 (d, J=6.8Hz, 2H), 1.66 (d, J=14.5Hz, 1H), 1.02 (td, J=14.4, 13.5, 5.8Hz, 1H).

[0633] Example 11: Preparation of N-(2,4-difluorobenzyl)-6,12-dihydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (12):

[0634]

[0635] Synthesis of 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexa Hydrogen-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (12a):

[0636] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (12a) was prepared in a manner similar to compound 10a using 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester. MS (m / z) 510.23 [M+H] + .

[0637] Synthesis of N-(2,4-difluorobenzyl)-6,12-dihydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2, 7-Methylpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (12):

[0638] The title compound was prepared using compound 12a in a manner similar to compound 11. MS (m / z) 420.15 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ10.77(s,1H),10.43(t,J=5.9Hz,1H),8.31(s,1H),7.41(td, J=8.7,6.6Hz,1H),7.25(ddd,J=10.6,9.3,2.6Hz,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=14.0,13.0,4.4Hz,2H),3.68-3.59 (m,1H),3.17-3.09(m,1H),1.85(d,J=7.4Hz,2H),1.68(d,J=14.9Hz,1H),1.04(s,1H).

[0639] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (13):

[0640]

[0641] Synthesis of 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-fluoro-1,11-dioxo-1,4,5,6,7,11-hexa Hydrogen-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (13a):

[0642] 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-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (12a, 47 mg, 0.092 mmol) in DCM (3 mL) under argon and cooled at -78°C was added Deoxo- (0.14 mmol, 0.05 mL, 50% toluene solution). The resulting mixture was stirred at -78 °C and allowed to gradually warm to room temperature overnight. The mixture was cooled at -78 °C and Deoxo- (0.14mmol, 0.05mL, 50% toluene solution). 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 quenched by dropwise addition of saturated aqueous sodium bicarbonate solution. The resulting mixture was stirred for 1 hour and more saturated aqueous sodium bicarbonate solution was added, and stirring was continued for 10 minutes until bubbling stopped. The organic layer was separated and washed with Na 2 SO 4 Dry and filter. Concentrate the filtrate to dryness to obtain the title compound. MS (m / z) 512.22 [M+H] + .

[0643] Synthesis 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]diazacyclononatetraene-10-carboxamide (13):

[0644] The title compound was prepared using 13a in a manner similar to compound 11. MS (m / z) 422.18 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),10.33(t,J=5.9Hz,1H),8.60(s,1H),7.41(td,J=8.7,6.6Hz,1H) ,7.25(td,J=9.6,2.6Hz,1H),7.07(td,J=8.7,2.5Hz,1H),5.10-5.03(m,1H),4.98-4.89(m,1H),4.56( d,J=6.0Hz,2H),4.13(dt,J=13.2,7.9Hz,1H),3.90(d,J=15.0Hz,1H),3.83(dd,J=15.1,2.0Hz,1H),3. 13(ddd,J=13.2,7.1,2.9Hz,1H),2.18-2.05(m,1H),2.04(s,1H),1.82-1.64(m,1H),1.53-1.20(m,1H).

[0645] 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-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-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-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (14-1, 14-2):

[0646]

[0647]

[0648] Synthesis of benzyl 3-(((benzyloxy)carbonyl)amino)-4-hydroxyazepane-1-carboxylate (14b):

[0649] At 0 °C, 3-amino-4-hydroxyazepane-1-carboxylic acid benzyl ester (1.1 g, 4.16 mmol) and Na 2 CO 3 To a solution of (310 mg, 4.99 mmol) in dioxane (7 mL) and water (7 mL) was added Cbz-Cl (0.7 mL, 4.99 mmol). 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) 399.26 [M+H] + .

[0650] Synthesis of (S) and (R)-3-(((Benzyloxy)carbonyl)amino)-4-oxazepane-1-carboxylic acid benzyl ester (14c-1 and 14c-2):

[0651] To a solution of 3-(((benzyloxy)carbonyl)amino)-4-hydroxyazepane-1-carboxylic acid benzyl ester (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 minutes. DCM was added and the organic phase was washed twice with 10% sodium thiosulfate solution and twice with 0.5 M NaOH and brine. The organic phase was dried and evaporated. The residue was purified by SGC eluting with EtOAc / hexane to give 3-((((benzyloxy)carbonyl)amino)-4-hydroxyazepane-1-carboxylic acid benzyl ester (14c). MS (m / z) 397.53 [M+H]+. Compound 14c was separated into individual enantiomers by preparative SFC chromatography (using MeOH co-solvent on IA column) to give 14c-1 and 14c-2.

[0652] Synthesis of ((3S,4R)- and (3R,4S)-4-hydroxy-4-methylazepan-3-yl)carbamic acid benzyl ester (14d- 1，14d-2)：

[0653] At 0°C, methyl Grignard reagent (1.02 mL, 3.05 mmol, [3M Et 2 O solution]). A solution of 14c-1 or 14c-2 (302 mg, 0.76 mmol) in 1 mL THF was slowly added while stirring. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was heated with NH 4 Cl was quenched and extracted into ethyl acetate, washed with brine, and MgSO 4Dry, filter, and remove the solvent in vacuo to obtain 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] + .

[0654] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (14-1, 14-2)：

[0655] The title compound was prepared using compounds 14d-1 and 14d-2 in a manner similar to compound 12. MS (m / z) 434.15 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),10.46(t,J=6.0Hz,1H),8.34(s,1H),7.41(td,J=8.7,6.6Hz,1H),7. 25(ddd,J=11.7,9.4,2.6Hz,1H),7.08(td,J=8.6,2.7Hz,1H),4.99(s,1H),4.56(d,J=5.9Hz,2H),4.30(s, 1H), 4.15 (dt, J=13.0, 8.8Hz, 1H), 3.85 (dd, J=15.2, 3.0Hz, 1H), 3.68 (dd, J=15.2, 1.7Hz, 1H), 3.10 (dt, J= 13.0, 4.8Hz, 1H), 1.81 (d, J = 7.2Hz, 2H), 1.47 (d, J = 15.4Hz, 1H), 1.35 (s, 3H), 1.23 (dt, J = 14.4, 6.5Hz, 1H).

[0656] Example 14: Preparation 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (15-1, 15-2):

[0657]

[0658] 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]diazacyclononatetraene-10-carboxamide (15a-1,15a-2):

[0659] 12-(Benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (10b) (350 mg) was separated into its individual enantiomers by preparative SFC chromatography (using MeOH co-solvent on IA column) to give 15a-1 and 15a-2. MS (m / z) 526.00 [M+H]+.

[0660] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (15b-1, 15b-2):

[0661] To a solution of 15a-1 or 15a-2 (150 mg, 0.285 mmol) in 7 mL of methanol was added NaBH 4 (21.6 mg, 0.57 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was quenched with 1N HCl and extracted with DCM. The organic phase was washed with MgSO 4 Dry and concentrate to dryness to give the title compound. MS (m / z) 528.26 [M+H] +.

[0662] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (15-1, 15-2)：

[0663] The title compound was prepared using compounds 15b-1 and 15b-2 in a manner similar to compound 13. 15-1: MS (m / z) 440.22 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),10.35(t,J=5.8Hz,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=13.2,7.2,2.9Hz,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] + . 1H NMR (400MHz, DMSO-d6) δ10.57 (s, 1H), 10.35 (t, J = 5.8Hz, 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 ,8.1Hz,1H),3.89(d,J=15.0Hz,1H),3.86-3.77(m,1H),3.12(ddd,J=13.1 ,7.0,2.9Hz,1H),2.22-1.95(m,2H),1.79-1.70(m,1H),1.50-1.28(m,1H).

[0664] Example 15: Preparation 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (16-1, 16-2):

[0665]

[0666] 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]diazacyclononatetraene-10-carboxamide (16a-1, 16a-2):

[0667] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methylpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (16a) was prepared using 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester (16a) in a manner similar to compound 10b. MS (m / z) 508.15 [M+H]+. Compound 16a was purified by preparative SFC chromatography (using IPA-NH 3 co-solvent) into their individual enantiomers to afford 16a-1 and 16a-2.

[0668] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (16-1,16- 2)：

[0669] The title compound was prepared using 16a-1 and 16a-2 in a manner similar to compounds 10-1 and 10-2. 16-1: MS (m / z) 440.20 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.64(s,1H),10.24(t,J=6.0Hz,1H),8.50(s,1H),7.42(td,J=8 .6,6.6Hz,1H),7.26(ddd,J=10.5,9.4,2.6Hz,1H),7.07(td,J=8.5,7.6,4.2Hz,1H),5.24 (s,1H),4.56(d,J=5.8Hz,2H),4.27-4.15(m,1H),4.04(d,J=16.5Hz,1H),3.92-3.83(m,1 H), 3.19 (dd, J = 13.2, 6.8Hz, 1H), 2.22 (s, 1H), 1.96 (d, J = 21.8Hz, 2H), 1.71-1.54 (m, 1H). 16-2: MS(m / z)440.27[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),10.24(t,J=5.9Hz,1H),8.50(s,1H),7.42(td,J=8.7, 6.6Hz,1H),7.31-7.20(m,1H),7.07(td,J=8.4,2.7Hz,1H),5.24(s,1H),4.56(d,J=5.9Hz,2 H),4.21(q,J=10.2,9.7Hz,1H),4.04(d,J=15.8Hz,1H),3.88(dd,J=15.4,2.0Hz,1H),3.18( dd,J=13.1,6.7Hz,1H),2.22(s,1H),1.97(d,J=22.4Hz,2H),1.62(dd,J=35.1,14.3Hz,1H).

[0670] Example 16: Preparation of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-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-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (17-1b, 17-2b):

[0671]

[0672] 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]diazacyclononatetraene-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- Methylpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (17a-1b, 17a-2b):

[0673] The title compound was prepared in a similar manner to compound 13a using compounds 14e-1 and 14e-2. MS (m / z) 526.16 [M+H] +. Byproducts (17a-1b, 17a-2b) were produced. MS (m / z) 506.13 [M+H] +.

[0674] 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]diazacyclononatetraene-10-carboxamide (17-1a) and N-(2,4-dihydro- fluorobenzyl)-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a] [1,4]Diazacyclononatetraene-10-carboxamide (17-1b, 17-2b):

[0675] The product from the previous step (17a-1a and 17a-1b, 40 mg, ~0.07 mmol) or a mixture of (17a-2a and 17a-2b) was dissolved in anhydrous ethanol (10 mL) and the solution was bubbled under an argon atmosphere. Palladium hydroxide (20%, 11 mg) was added and the mixture was bubbled under a hydrogen atmosphere (1 atm, balloon). The mixture was vigorously stirred for 2 hours, bubbled under an argon atmosphere, and filtered by Pad filtration. The pad was washed with anhydrous 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 (400MHz, DMSO-d6) δ10.82(s,1H),10.33(t,J=6.0Hz,1H),8.65(s,1H),7.42(td,J=8.7,6.6Hz,1H), 7.26(ddd,J=10.6,9.3,2.6Hz,1H),7.08(td,J=8.6,2.7Hz,1H),4.81(d,J=11.5Hz,1H),4.63-4.48(m,2 H),4.16(q,J=11.1Hz,1H),3.92(dd,J=15.0,2.5Hz,1H),3.80(d,J=16.1Hz,1H),3.16(dd,J=13.0,7.8H z,1H),2.17-2.06(m,1H),1.92(dt,J=13.7,6.4Hz,1H),1.73(dt,J=19.6,9.6Hz,1H),1.49-1.16(m,4H). For 17-1b: MS(m / z)418.28[M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.42(t,J=5.9Hz,1H),8.63(d,J=18.6Hz,0H),8.43(s,1H),7.4 2(td,J=8.7,6.6Hz,1H),7.26(ddd,J=10.6,9.3,2.6Hz,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=14.6,2.8Hz,1H),3.71(dd,J=14.4,1.7Hz,1H),3.14(dd,J=12.9 ,6.7Hz,1H),2.11-1.99(m,1H),1.91(t,J=7.8Hz,2H),1.55(m,1H),1.50(m,1H),0.85(d,J=6.9Hz,3H). For 17-2b:MS(m / z)418.24[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 10.42 (t, J = 6.0Hz, 1H), 8.43 (s, 1H), 7.48-7.3 7(m,1H),7.31-7.21(m,1H),7.08(t,J=9.7Hz,1H),4.69(s,1H),4.56(d,J=5.1Hz,2H ),4.22-4.11(m,1H),3.98-3.89(m,1H),3.70(d,J=14.6Hz,1H),3.14(dd,J=12.9,6. 3Hz,1H),2.01(m,1H),1.92(m,2H),1.55(m,1H),1.50(m,1H),0.85(d,J=6.9Hz,3H).

[0676] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (18):

[0677]

[0678] Synthesis of tert-butyl (E)-3-((tert-butylsulfinyl)imino)azepane-1-carboxylate (18a):

[0679] To a solution of tert-butyl 3-oxazepane-1-carboxylate (0.52 g, 2.44 mmol) and 2-methylpropane-2-sulfenamide (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.

[0680] The reaction mixture was diluted with ethyl acetate (10 mL) and washed with NaHCO 3 The mixture was quenched with aqueous solution (~5 mL). The solid was filtered off and the filter cake was washed with ethyl acetate (10 mL x 2). The combined washings were concentrated in vacuo. The residue was purified by Purify using EtOAc / hexane to give the title compound. MS (m / z) 317.2 [M+H] +

[0681] Synthesis of tert-butyl 3-((tert-butylsulfinyl)amino)-3-methylazepane-1-carboxylate (18b):

[0682] To (E)-tert-butyl 3-((tert-butylsulfinyl)imino)azepane-1-carboxylate (0.15 g, 0.47 mmol) in DCM was added 3M MeMgBr (0.95 mL) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred at room temperature overnight.

[0683] [5] The reaction mixture was diluted with ethyl acetate and saturated with NH 4 The mixture was washed with MgSO 4 Dry and remove the solvent in vacuo. The residue is purified by silica gel column with ethyl acetate / hexane to give the title compound. MS (m / z) 333.2 [M+H] +

[0684] Synthesis of 3-methylazepan-3-amine (18c):

[0685] 4M HCl (0.07 mL) in dioxane was added to tert-butyl 3-(tert-butylsulfinylamino)-3-methyl-azepane-1-carboxylate (18b, 0.03 g, 0.1 mmol) in DCM (2 mL) at room temperature. After 2 hours, the solvent was removed in vacuo and the unpurified material was used directly in the next step. MS (m / z) 129.2 [M+H] +

[0686] Synthesis of 12-(Benzyloxy)-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexa Hydrogen-3H-2,7-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (18d):

[0687] 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 3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylic acid methyl ester (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, washed with water and brine, and washed with MgSO 4 Dry. Remove the solvent under vacuum and purify the residue to obtain the title compound. MS (m / z) 526.2 [M+H] +

[0688] 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]diazacyclononatetraene-10-carboxamide (18):

[0689] 12-(Benzyloxy)-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylpyrido[1,2-a][1,4]diazacyclononatetraene-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 in vacuo and the residue was purified by HPLC to give the title compound. MS (m / z) 436.1 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.46 (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)

[0690] Example 18: Preparation of (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methanpyrido[1,2-d][1,4,7]oxadiazacyclononatetraene-10-carboxamide (19):

[0691]

[0692] (7S)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-carboxypyrido[1,2-d][1,4,7]oxadiazacyclononatetraene-10-carboxamide (19) was prepared in a similar manner to 12-hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (18) using (S)-1,4-oxaazepan-6-amine instead of 3-methylazepan-3-amine. 1H NMR(400MHz,DMSO-d6)δ10.41(t,J=5.8Hz,1H),8.51(s,1H),7.35-6.97(m,2H),4.71(s,1H),4.5 7(d,J=5.7Hz,2H), 4.28(ddd,J=13.1,9.4,7.3Hz,1H), 4.11(d,J=13.9Hz,1H), 4.07-3.78(m,6H). MS(m / z)514.2[M+H] +

[0693] 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]diazacyclononatetraene-10-carboxamide (20):

[0694]

[0695] (7R)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-carboxypyrido[1,2-d][1,4,7]oxadiazacyclononatetraene-10-carboxamide (20) was prepared in a manner similar to 12-hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (18) using (R)-1,4-oxaazepan-6-amine instead of 3-methylazepan-3-amine. 1H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.51(s,1H),7.22(dd,J=9.2,8.0Hz,2H),4.71(d,J =3.1Hz, 1H), 4.57 (d, J = 5.7Hz, 2H), 4.27 (ddd, J = 12.9, 9.1, 7.1Hz, 1H), 4.16-3.62 (m, 6H). MS(m / z)514.2[M+H] +

[0696] Example 20: Preparation of N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (23):

[0697]

[0698] Synthesis of diethyl 1-(azepan-4-yl)-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (23a)：

[0699] The reactor was charged with tert-butyl 3-aminoazepane-1-carboxylate (588 mg, 3 mmol) and NaHCO in EtOH / water (9 mL / 6 mL) was added. 3 (576 mg, 7 mmol) and diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (950 mg, 3 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 in vacuo. The residue was used in the next step without purification.

[0700] To the above residue in DCM (10 mL) was added 4N HCl in dioxane (3 mL). After 2 hours at room temperature, the solvent was removed in vacuo to give the title compound, which was used in the next step without purification. MS (m / z) 442.945 [M+H] + .

[0701] Synthesis of 11-(Benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethylpyrido[1,2-a] [1,4]Diazacyclooctatetraene-9-carboxylic acid ethyl ester (23b):

[0702] EtOH (20 mL) and DBU (2.2 g, 15 mmol) were added to the above residue. After heating to 110 ° C for 1 hour under a microwave reactor, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated in vacuo. The resulting residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 397.113 [M+H] + .

[0703] Synthesis of 11-(Benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethylpyrido[1,2-a] [1,4]Diazacyclooctatetraene-9-carboxylic acid (23c):

[0704] 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 in vacuo. The resulting residue was used in the next step without purification. MS (m / z) 369.131 [M+H] + .

[0705] Synthesis of 11-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethyl Bridged pyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (23d):

[0706] To the above residue (57 mg, 0.155 mmol) in DCM (5 mL) was added (2,4-difluorophenyl)methanamine (27.4 mg, 0.17 mmol), DIPEA (60 mg, 0.46 mmol) and HATU (60.2 mg, 0.186 mmol) 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 in vacuo. The resulting residue was used in the next step. MS (m / z) 512.147 [M+H] + .

[0707] Synthesis of 11-hydroxy-1,10-dioxo-N-(2,4-difluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethylpyrrolidone Imido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (23):

[0708] [6] To a solution of 11-(benzyloxy)-1,10-dioxo-N-(2,4-difluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-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] + . 1H NMR (400MHz, DMSO-d6) δ10.41(t,J=5.9Hz,1H),8.33(s,1H),7.39(dd,J=8.6,6.6Hz,2H),7.22(ddd,J=10.7,9.3,2.6Hz,1H),7.07-7.01(m,1H) ,4.99(d,J=11.6Hz,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=46.6Hz,3H).

[0709] 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-ethoxypyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (24 and 24-1):

[0710]

[0711] Synthesis of racemic 11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro- 2,6-Ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (24):

[0712] Racemic 11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (24) was synthesized from 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxylic acid and (2,4,6-trifluorophenyl)methanamine in a manner similar to compound 5. MS (m / z) 422.089 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.41(t,J=5.9Hz,1H),8.33(s,1H),7.39(dd,J=8.6,6.6Hz,2H),7.22(ddd,J=10.7,9.3,2.6Hz,1H),7.07-7.01(m,1H) ,4.99(d,J=11.6Hz,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=46.6Hz,2H).

[0713] Synthesis of (R)- or (S)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexa Hydrogen-2,6-ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (24-1):

[0714] (R)- or (S)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-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-ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (24a) by chiral HPLC separation (SFC chromatography on an IB 4.6×100 mm 5mic 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-ethylpyrido[1,2-a][1,4]diazacyclooctatetraene-9-carboxamide (24-1). MS (m / z) 422.124 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.45(t,J=5.8Hz,1H),8.31(s,1H),7.28-7.10(m,2H),4.97(d,J=11.3Hz,2H),4.61(dd,J=14.5,6.1Hz,1H),4.48(dd ,J=14.6,5.5Hz,1H),4.24(d,J=13.0Hz,2H),3.11(dd,J=13.5,8.3Hz,1H),2.37-2.21(m,2H),2.00(d,J=40.1Hz,2H),1.70(d,J=31.2Hz,2H).

[0715] 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-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (25,25-1,25-2):

[0716]

[0717] Synthesis of 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2, 7-Methoxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (25d):

[0718] 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]diazacyclononatetraene-10-carboxamide (25d) was synthesized from 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate and diethyl tert-butyl 3-aminoazepane-1-carboxylate as starting materials according to a method similar to compound 24a. MS (m / z) 494.181 [M+H] + .

[0719] 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]diazacyclononatetraene-10-carboxamide (25):

[0720] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-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 (400MHz, DMSO-d6) δ10.61(s,1H),10.38(t,J=6.0Hz,1H),8.47(s,1H),7.38(td,J=8.7,6.6Hz,1H ),7.22(ddd,J=10.6,9.3,2.6Hz,1H),7.04(td,J=8.6,2.6Hz,1H),4.75(dd,J=5.9,2.8Hz,1H),4.53( d,J=5.9Hz,2H),4.12(d,J=13.3Hz,1H),3.90-3.84(m,1H),3.65(dd,J=14.7,1.9Hz,1H),3.07(td,J= 6.6, 3.6Hz, 1H), 2.02-1.94 (m, 1H), 1.89-1.74 (m, 3H), 1.62 (d, J = 7.6Hz, 1H), 1.12 (d, J = 12.1Hz, 1H).

[0721] 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]diazacyclononatetraene-10-carboxamide and (7S)-12-(benzyloxy)-N-(2, 4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a][1,4]diazepine Cyclononatetraene-10-carboxamide (25d-1, 25d-2):

[0722] (7R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (25d) was isolated as peak 1 by chiral HPLC separation (SFC chromatography on an IB 4.6×100 mm 5 mic column using MeOH (20) as cosolvent). ,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (25d-1) and (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (25d-2) as peak 2. The structure of peak 1 was confirmed by the synthesis starting from (R)-azepan-3-amine.

[0723] Synthesis of (7R)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2, 7-Methoxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (25-1) and (7S)-N-(2,4-difluorobenzyl)- 1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a][1,4]diazepine Cyclononatetraene-10-carboxamide (25-2):

[0724] According to the reaction conditions similar to those used to prepare compound 25, (7R)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-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-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (25-2) were prepared from peak 1 and peak 2, respectively. Compound 25-1: MS (m / z) 404.186 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.59(s,1H),10.38(t,J=5.9Hz,1H),8.47(s,1H),7.38(td,J=8.7,6.6 Hz,1H),7.22(ddd,J=10.6,9.3,2.6Hz,1H),7.04(tdd,J=8.6,2.6,1.1Hz,1H),4.75(d,J=5.4Hz , 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, 3.6 Hz, 1H), 1.99 (s, 1H), 1.89-1.74 (m, 3H), 1.62 (d, J = 8.0 Hz, 1H). Compound 25-2: MS (m / z) 404.165 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),10.38(t,J=5.9Hz,1H),8.47(s,1H),7.38(td,J=8 .7,6.6Hz,1H),7.22(ddd,J=10.5,9.3,2.6Hz,1H),7.09-6.99(m,1H),4.75(s,1H),4.53 (d,J=5.9Hz,2H),4.12(d,J=13.3Hz,1H),3.86(d,J=14.6Hz,1H),3.69-3.60(m,1H),3.0 6(ddd,J=13.1,6.8,3.6Hz,1H),1.99(s,1H),1.83(d,J=13.3Hz,3H),1.67-1.60(m,1H).

[0725] Example 23: Preparation of racemic 12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (26), (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide 11-Hexahydro-3H-2,7-methanpyrido[1,2-a][1,4]diazacyclononatetraene-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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (26-2):

[0726]

[0727] Synthesis of 12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7- Methylpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (26):

[0728] 12-(Benzyloxy)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxylic acid (57 mg, 0.155 mmol) was dissolved in DCM (2 mL) with (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 reacting overnight, 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (26a) MS (m / z) 512.06 [M+H] + .

[0729] Compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylpyrido[1,2-a][1,4]diazacyclononatetraene-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 at room temperature overnight. The solvent was removed in vacuo, and the residue was purified by HPLC to obtain the title compound (26). MS (m / z) 422.091 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.39(t,J=5.8Hz,1H),8.45(s,1H),7.24-7.11(m,2H), 4.72(dd,J=5.9,2.9Hz,1H), 4.54(dd,J=6.0,2.4Hz,2H), 4.11(d,J=13.3Hz,1H), 3.88-3.79(m,1H),3.64(dd,J=14.7,1.9Hz,1H),3.05(dq,J=9.5,3.4Hz,1H),2.0 6-1.91(m,1H),1.89-1.74(m,3H),1.61(d,J=7.7Hz,1H),1.11(d,J=12.7Hz,1H).

[0730] 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]diazacyclononatetraene-10-carboxamide (26-2) and (7R)-12-hydroxy-1,11- N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a][1,4]diazo Heterocyclic nonatetraene-10-carboxamide (26-1):

[0731] 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]diazacyclononatetraene-10-carboxamide (26a) was separated by chiral HPLC separation (SFC chromatography on an IB 4.6×100 mm 5mic column using MeOH (20) as cosolvent) to afford 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]diazacyclononatetraene-10-carboxamide -1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a][1,4]diazacyclononatetraene-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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (26a-2).

[0732] Compound (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-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 in vacuo and the residue was purified by HPLC to give the title compound (26-2). (MS (m / z) 422.123 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),10.39(d,J=5.9Hz,1H),8.45(s,1H),7.18(t,J=8.6Hz,2H),4.72(s,1H),4.59-4.48(m,2H),4.11(d,J=13.2Hz ,1H),3.85(d,J=14.6Hz,1H),3.69-3.59(m,1H),3.05(ddd,J=11.3,6.7,3 .6Hz,1H),1.97(m,1H),1.87-1.71(m,3H),1.67-1.55(m,1H),1.10(m,1H).

[0733] Compound (7R)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4]diazacyclononatetraene-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 in vacuo, and the residue was purified by HPLC to obtain the title compound (26-1). MS (m / z) 422.116 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.58(s,1H),10.39(t,J=5.8Hz,1H),8.45(s,1H),7 .18(dd,J=9.2,8.0Hz,2H),4.73(s,1H),4.58-4.49(m,2H),4.11(d,J=13.3H z,1H),3.85(d,J=14.6Hz,1H),3.65(d,J=14.2Hz,1H),3.10-3.00(m,1H),1. 96(m,1H),1.82(d,J=12.2Hz,3H),1.61(d,J=7.4Hz,1H),1.18-1.05(m,1H).

[0734] 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]diazacyclononatetraene-9-carboxamide (27):

[0735]

[0736] Synthesis of 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one TFA salt (27a):

[0737] To a solution of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-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]azepine-2-one. MS (m / z) 276.676 [M+H] + .

[0738] Synthesis of 7-(Benzyloxy)-N-(2,4-difluorobenzyl)-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5, 12-Methoxybenzo[e]pyrido[1,2-a][1,4]diazacyclononatetraene-9-carboxamide (27b):

[0739] 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]diazacyclononatetraene-9-carboxamide was synthesized from 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one TFA salt (45 mg, 0.163 mmol) and 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester (70 mg, 0.163 mmol) according to a method similar to compound 25. MS (m / z) 555.034 [M+H] + .

[0740] Synthesis of N-(2,4-difluorobenzyl)-7-hydroxy-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methoxy Cross-linked benzo[e]pyrido[1,2-a][1,4]diazacyclononatetraene-9-carboxamide (27):

[0741] 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]diazacyclononatetraene-9-carboxamide (27) was prepared by the same method 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]diazacyclononatetraene-9-carboxamide (11 mg). MS (m / z) 465.05 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.25(t,J=5.9Hz,1H),8.61(s,1H),7.42(d,J=7.1Hz,1H),7.29(ddd,J=12.1,9.4,2.8Hz,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=5.8Hz,1H),3.68(s,2H),3.64(d,J=2.8Hz,1H).

[0742] Example 25: Preparation of (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanpyrido[1,2-d][1,4,7]oxadiazacyclononatetraene-10-carboxamide (28):

[0743]

[0744] 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]oxadiazacyclononatetraene-10-carboxamide (28a):

[0745] To a solution of 1,4-oxazepine-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 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester (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 in vacuo. The residue was used in the next step without purification. MS (m / z) 496.016 [M+H] + .

[0746] Synthesis of (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7- Methylpyrido[1,2-d][1,4,7]oxadiazacyclononatetraene-10-carboxamide (28):

[0747] To a solution of (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-carboxypyrido[1,2-d][1,4,7]oxadiazacyclononatetraene-10-carboxamide (28a) 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 in vacuo. The residue was dissolved in DMF and purified by preparative HPLC to give the title compound. MS (m / z) 406.83 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.36(t,J=5.9Hz,1H),8.50(s,1H),7.39(td,J=8.7,6.6Hz,1H),7.27-7.20(m,1H),7.05(td,J =7.6,6.7,4.0Hz,1H),5.73(s,2H),4.54(d,J=5.9Hz,2H),4.34-4.23(m,1H),4.10(d,J=14.3Hz,2H),4.00-3.82(m,4H).

[0748] 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]oxadiazacyclononatetraene-10-carboxamide (29):

[0749]

[0750] (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]oxadiazacyclononatetraene-10-carboxamide (29) was synthesized from (R)-1,4-oxazepan-6-amine (18.9 mg, 0.163 mmol) and 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester (70 mg, 0.163 mmol) in a similar manner to compound (28). MS (m / z) 406.136 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.36(t,J=5.9Hz,1H),8.51(s,1H),7.42-7.37(m,1H),7.21(dd,J=9.9,2.5Hz,1H),7.07-7.02(m,1H),4.70(s,1 H), 4.54 (d, J = 5.9Hz, 2H), 4.30-4.23 (m, 1H), 4.09 (d, J = 5.8Hz, 1H), 4.00 (d, J = 12.0Hz, 1H), 3.89 (t, J = 8.9Hz, 3H), 3.66 (d, J = 10.0Hz, 2H).

[0751] Example 27: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanpyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (30):

[0752]

[0753] 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]triazacyclononatetraene-10-carboxamide (30) was synthesized from 1,4-diazepan-6-amine (75.1 mg, 0.652 mmol) and 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester (140 mg, 0.326 mmol) according to a method similar to compound 28. MS (m / z) 405.183 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.70(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 = 5.7Hz, 2H), 4.16 (d, J = 12.8Hz, 2H), 3.92 (d, J = 14.8Hz, 2H), 3.72 (d, J = 15.0Hz, 2H), 3.15 (s, 2H).

[0754] 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-methanpyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (31):

[0755]

[0756] Synthesis of 5-acetyl-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexa Hydrogen-3H-2,7-methanopyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (31):

[0757] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methylpyrido[1,2-a][1,4,7]triazacyclononatetraene-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 cooling. After stirring for 4 hours, the reaction was extracted with ethyl acetate (100 mL). The organic layer was concentrated in vacuo. The residue was used in the next step without purification. MS (m / z) 537.013 [M+H] + .

[0758] 5-Acetyl-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (31a) was synthesized from 5-acetyl-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (31a) according to debenzylation conditions similar to those for preparing compound 30. MS (m / z) 447.159 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.36(t,J=5.9Hz,1H),8.59(d,J=19.5Hz,1H),7.39(td,J=8.7,6.6Hz,1H),7.22(ddd,J=10.6,9.4,2.7Hz,1H),7.05(ddt,J=1 0.0,7.4,1.3Hz,1H),5.73(s,2H),4.54(d,J=6.0Hz,2H),4.42-4.32(m,1H) ,3.97-3.88(m,2H),3.78(d,J=15.1Hz,2H),3.20-3.15(m,1H),1.86(s,3H).

[0759] 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]triazacyclononatetraene-10-carboxamide (32):

[0760]

[0761] N-(2,4-difluorobenzyl)-12-hydroxy-5-(methylsulfonyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (32) was synthesized from 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (26 mg, 0.053 mmol) using methanesulfonyl chloride (9 mg, 0.079 mmol) in the same manner as compound 31. MS (m / z) 483.083 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.36(t,J=6.0Hz,1H),8.56(s,1H),7.38(dd,J=8.7 ,6.7Hz,1H),7.22(ddd,J=10.5,9.3,2.6Hz,1H),7.14-6.96(m,1H),4.54(d, J=5.9Hz,2H),4.21(dd,J=6.6,3.3Hz,1H),3.98(s,2H),3.90-3.75(m,4H),3 .45(d,J=15.0Hz,1H),3.29(d,J=9.2Hz,1H),3.23-3.10(m,1H),2.88(s,3H).

[0762] 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-methanpyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (33):

[0763]

[0764] Synthesis of 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexa Hydrogen-3H-2,7-methanopyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (33):

[0765] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methylpyrido[1,2-a][1,4,7]triazacyclononatetraene-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 in vacuo. The residue was used in the next step without purification. MS (m / z) 509.11 [M+H] + .

[0766] N-(2,4-difluorobenzyl)-12-hydroxy-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4,7]triazacyclononatetraene-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-carboxypyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (33a) under the same debenzylation conditions as those for compound 30. MS (m / z) 419.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.60–8.18(m,2H),7.40(td,J=8.6,6.6Hz,1H),7.23(td,J=9.9,2.6Hz,1H),7.05(td,J=8.5,2.5Hz,1H),4.54 (d,J=5.9Hz,2H),4.17(dt,J=13.1,8.1Hz,1H),3.89–3.77(m,3H),3.71–3.60(m,1H),3.28(d,J=7.3Hz,3H),2.78(s,3H),2.27(s,1H).

[0767] 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-methanpyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (34):

[0768]

[0769] N-(2,4-difluorobenzyl)-12-hydroxy-5-isopropyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-carboxypyrido[1,2-a][1,4,7]triazacyclononatetraene-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-carboxypyrido[1,2-a][1,4,7]triazacyclononatetraene-10-carboxamide (24 mg, 0.049 mmol) using 2-iodopropane (12.38 mg, 0.073 mmol). MS (m / z) 447.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 10.40-10.30 (m, 1H), 8.58 (d, J = 17.2Hz, 1H), 8.50(s,1H),7.81(d,J=12.3Hz,1H),7.38(dd,J=9.0,6.8Hz,2H),7.22(ddd,J=10.7 ,9.3,2.6Hz,2H),7.05(td,J=8.5,2.5Hz,2H),4.53(d,J=5.7Hz,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).

[0770] 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-methanpyrido[1,2-a][1,4]diazacyclononatetraene-10-carboxamide (35):

[0771]

[0772] According to the same method as compound 28, (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]diazacyclononatetraene-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). MS (m / z) 438.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.42(t,J=6.0Hz,1H),8.47(s,1H),7.37(td,J=8.4,6.2Hz,1H),7 .27(td,J=8.8,1.6Hz,1H),4.78-4.70(m,1H),4.57(d,J=5.9Hz,2H),4.16-4.08(m,2H),3. 86(d,J=14.9Hz,1H),3.65(dd,J=14.7,1.8Hz,1H),3.06(ddd,J=13.2,6.9,3.5Hz,1H),1.9 8(dd,J=7.5,4.4Hz,1H),1.90-1.70(m,3H),1.62(d,J=7.5Hz,1H),1.12(d,J=12.7Hz,1H).

[0773] 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]diazacyclononatetraene-9-carboxamide (36):

[0774]

[0775] Synthesis of tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate (36b):

[0776] To a solution of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate (36a) (300 mg, 1.086 mmol) in THF (5 mL) was added BH 3 -THF solution (6mL, 1N, 6mmol). After stirring overnight, MeOH and sodium bicarbonate aqueous solution were added to quench the reaction. The resulting mixture was extracted with ethyl acetate (100mL). The organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography to give tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate. MS (m / z) 262.897 [M+H] + .

[0777] Synthesis of 2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-amine (36c):

[0778] To a solution of tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate (36b) (13 mg, 0.05 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. After 2 hours, the solvent and excess TFA were removed. The residue was used in the next step without purification. MS (m / z) 162.952 [M+H] + .

[0779] Synthesis of N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methoxybenzene [e]pyrido[1,2-a][1,4]diazacyclononatetraene-9-carboxamide (36):

[0780] 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]diazacyclononatetraene-9-carboxamide (36) was synthesized from 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester (30 mg, 0.07 mmol) and 2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-amine in the same manner as compound 28. MS (m / z) 452.152 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.34(t,J=5.9Hz,1H),8.59(s,1H),7.41(s,1H),7.36-7.16(m,5H),7.05(tdd,J=8.5,2.7,1.1Hz ,1H),4.89(s,1H),4.55(d,J=6.0Hz,2H),4.18(s,1H),3.74(d,J=2.1Hz,1H),2.83-2.67(m,2H),2.24(s,1H),2.10(s,1H).

[0781] 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]diazacyclononatetraene-9-carboxamide (37-1, 37-2):

[0782]

[0783] According to the same method as compound 28, (12R) and (12S)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methylbenzyl)-1,2 ... The (R) and (S)-tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamates were separated from racemic (2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate (36b) by chiral HPLC separation (SFC chromatography on IB 4.6×100mm 5mic column using EtOH (15%) as co-solvent). Peak 1 (37a-1) gave 37-1. MS (m / z) 452.16 [M+H] + . 1H 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) δ10.33(t,J=5.9Hz,1H),8.59(s,1H),7.40(d,J=6.9Hz,1H),7.36-7.18(m,5H),7.05(td,J=8.4,2.5Hz,1H),4. 89 (s, 1H), 4.55 (d, J = 5.9Hz, 2H), 4.16 (d, J = 14.5Hz, 1H), 3.86 (s, 1H), 2.81-2.70 (m, 2H), 2.24 (d, J = 3.5Hz, 1H), 2.09 (d, J = 8.4Hz, 1H).

[0784] 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]diazacyclononatetraene-9-carboxamide (38-1, 38-2):

[0785]

[0786] Analogously to 37-1 and 37-2, 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylic acid methyl ester was used instead of 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid methyl ester to synthesize (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]diazacyclononatetraene-9-carboxamide (38-1 and 38-2). MS (m / z) 470.1 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ10.36(t,J=5.8Hz,1H),10.25(s,1H),8.57(s,1H),7.36-7.24(m,4H),7.19(t,J=8.6Hz,2H),4.86(s,1H),4.5 6(d,J=5.8Hz,2H),4.14(d,J=14.5Hz,1H),3.71(dd,J=14.8,2.0Hz,1H),2.81-2.69(m,2H),2.27-2.17(m,1H),2.08(d,J=9.7Hz,1H).

[0787] 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-dimethoxypyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (40-1, 40-2):

[0788]

[0789]

[0790] Synthesis of 4-bromo-2-azabicyclo[4.2.1]nonan-3-one (40a):

[0791] To a solution of 2-azabicyclo[4.2.1]nonan-3-one (1 g, 7.18 mmol) in DCM (30 mL) was added PCl under ice-water cooling. 5 (1.496 g, 7 mmol). After stirring at 0-5°C for 1 hour, iodine (18.2 mg, 0.7 mmol) was added and the mixture was stirred for 5 minutes. 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 hours. Ice water was added and stirring was continued for 30 minutes. The mixture was extracted with ethyl acetate (100 mL) and Na 2 S 2 O 3 The product was washed with water and brine. After drying and removal of the solvent, the residue was crystallized from DCM and hexane to give the title compound. MS (m / z) 218.1 [M+H] + .

[0792] Synthesis of 4-azido-2-azabicyclo[4.2.1]nonan-3-one (40b):

[0793] 4-Bromo-2-azabicyclo[4.2.1]nonan-3-one (40a) (330 mg, 1.513 mmol) and NaN 3A mixture of (394 mg, 6 mmol) in 10 mL DMF was heated in a microwave reactor at 120°C overnight. The reaction mixture was extracted with ethyl acetate (100 mL), the extract was washed with brine and 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] + .

[0794] Synthesis of rel-tert-butyl ((1R,4S,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamate (40c) and rel-tert-butyl ((1R,4R,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamate (40d):

[0795] Under argon, the 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). The reaction mixture was placed under vacuum and backfilled with hydrogen. After vigorous stirring for two hours, the reaction mixture was diluted with EtOH (50 mL) and the mixture was stirred for 2 hours. Filter and wash with ethyl acetate. Remove the solvent and purify the residue by silica gel chromatography to obtain two diastereomers of the product, peak 1 and peak 2. Peak 1, rel-tert-butyl ((1R, 4S, 6S)-3-oxo-2-azabicyclo [4.2.1] non-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-tert-butyl (1R, 4R, 6S)-3-oxo-2-azabicyclo[4.2.1]non-4-yl)carbamate (40d). MS (m / z) 277.2 [M+Na] + . 1H NMR (400MHz, chloroform-d) δ5.89(s,1H),5.56(s,1H),4.02(dd,J=6.9,4.5Hz,1H),3.36(ddd,J=15.3,7.6,6.0Hz,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=12.7Hz,2H),1.67-1.55(m,1H),1.45(s,9H),1.41(d,J=5.7Hz,1H).

[0796] Synthesis of rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f):

[0797] rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f) was synthesized from rel-tert-butyl((1R,4S,6R)-3-oxo-2-azabicyclo[4.2.1]nonan-4-amine (40f) in a manner analogous to the synthesis of 2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate (36a) from tert-butyl(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate (36a).

[0798] 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-dimethylpyrido[1,2-a][1,4]diazacyclodecene-11-yl) Formamide (40g-1, 40g-2):

[0799] By the same method as for preparing compound 28, 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-dimethylpyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (40g) was synthesized from rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f) and 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylic acid methyl ester, and then separated by chiral HPLC to obtain peak 1 (40g-1) and peak 2 (40g-2). MS (m / z) 538.2 [M+H] + .

[0800] 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-dimethylpyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (40-1 and 40-2):

[0801] By the same method as compound 28, (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]diazacyclodecene-11-carboxamide (40-1, 40-2) were synthesized from compounds 40h-1 and 40h-2, respectively. MS (m / z) 448.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.37(t,J=5.8Hz,1H),8.50(s,1H),7.19(t,J=8.6Hz,2H), 4.55(dd,J=5.9,2.8Hz,2H),4.51-4.38(m,1H),4.21(dd,J=13.4,7.0Hz,1H),3.80(d ,J=15.1Hz,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 = 7.0Hz, 2H), 1.49 (dd, J = 14.1, 6.9Hz, 2H), 1.16 (d, J = 14.4Hz, 1H).

[0802] 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-dimethoxypyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (41-1 and 41-2):

[0803]

[0804]

[0805] In a manner similar to the preparation of compounds 40-1 and 40-2, (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]diazacyclodecene-11-carboxamide (41-1 and 41-2) were synthesized from rel-tert-butyl((1R,4R,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamate (40d). MS (m / z) 448.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.38(t,J=5.8Hz,1H),8.48(s,1H),7.19(t,J=8.6H z,2H),4.78(d,J=9.2Hz,1H),4.55(t,J=5.7Hz,2H),4.08(d,J=13.3Hz,1H),3 .82(d,J=2.5Hz,1H),3.05-2.88(m,2H),2.42(s,1H),2.19(d,J=14.0Hz,1H) ,1.63(dd,J=13.2,7.2Hz,3H), 1.40(d,J=11.9Hz,1H), 0.92(d,J=3.7Hz,1H).

[0806] Example 39a: Preparation of N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropyl[f]pyrido[1,2-a][1,4]diazacyclononatetraene-7-carboxamide (42-1):

[0807]

[0808] Synthesis of benzyl (1-hydroxypent-4-en-2-yl)carbamate (42a):

[0809] 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 slowly warm to room temperature while stirring overnight. The reaction mixture was diluted with DCM and extracted twice with DCM. The organic extract was washed with NH 4 The residue was washed with Cl, 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] + .

[0810] Synthesis of benzyl (1-oxopent-4-en-2-yl)carbamate (42b):

[0811] 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 hour, more Dess-Martin periodinane (2 g, 4.7 mmol) was added to the reaction mixture and stirring was continued for another 30 minutes. The mixture was diluted with DCM and saturated NaHCO 3The resulting mixture was stirred for about 10 minutes and extracted twice with DCM. The organic extracts were washed with brine, water and NaHCO 3 The mixture was washed with 1% ethanol, dried over sodium sulfate and concentrated to give the title compound. MS (m / z) 234.0 [M+H] + .

[0812] Synthesis of benzyl (1-(allylamino)pent-4-en-2-yl)carbamate (42c):

[0813] 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 heated to 40 °C with saturated NaHCO 3 The mixture was quenched with aqueous solution (20 mL) and 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] + .

[0814] Synthesis of benzyl allyl (2-(((benzyloxy)carbonyl)amino)pent-4-en-1-yl)carbamate (42d):

[0815] 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 slowly warm to room temperature while stirring overnight. The reaction mixture was diluted with DCM and extracted twice with DCM. The organic extract was washed with NH 4 The residue was washed with Cl, 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] + .

[0816] Synthesis of benzyl-3-(((benzyloxy)carbonyl)amino)azepane-1-carboxylate (42e-1 and 42e-2):

[0817] To a round bottom flask was added benzyl allyl (2-(((benzyloxy)carbonyl)amino)pent-4-en-1-yl)carbamate (42d, 6.3 mg, 16 mmol), DCM (400 mL) and bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride (Grubbs Catalyst TMThe mixture was heated at reflux overnight and concentrated. The residue was dissolved in DCM and purified by silica gel chromatography. The enantiomeric mixture was separated by Preparative SFC chromatography on an OJ-H column using MeOH co-solvent separated the individual enantiomers to give 42e-1 (peak 1) and 42e-2 (peak 2). MS (m / z) 381.5 [M+H]+.

[0818] Synthesis of benzyl 5-(((benzyloxy)carbonyl)amino)-3-azabicyclo[5.1.0]octane-3-carboxylate (42f-1):

[0819] 42e-1 (626 mg, 1.6 mmol) and DCM (3 mL) were added to a three-necked flask. The resulting mixture was cooled to 0 ° C, 1M diethylzinc in hexane (3.46 mL) was slowly added, and then diiodomethane (0.5 mL, 6.6 mmol) was slowly added. The reaction mixture was stirred at 0 ° C for 10 minutes, and diethylzinc and diiodomethane were loaded for the second time. The mixture was stirred at 0 ° C for 2 hours, removed from the ice bath and stirred for another 2 hours. Diethylzinc and diiodomethane were added for the third time 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. MS (m / z) 395.3 [M + H] + .

[0820] Synthesis of 5-(Benzyloxy)-N-(2,4-difluorobenzyl)-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro- 3,10-Methoxycyclopropyl[f]pyrido[1,2-a][1,4]diazacyclononatetraene-7-carboxamide (42h-1):

[0821] A round-bottom flask was charged with 42f-1 (200 mg, 0.5 mmol), ethanol (20 mL), palladium on carbon (10 wt% loading on a dry basis), matrix carbon powder, and wet support (216 mg, 0.2 mmol). The mixture was heated with N 2 Bubble and add H 2 The reaction mixture was stirred overnight and The residue was mixed with 3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyran-2-carboxylate (108.9 mg, 0.5 mmol), NaHCO 3 (85 mg, 1 mmol) and MeOH (3 mL) were mixed. The mixture was stirred at 70 ° C for about 4 hours until the cyclization 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 obtain the major diastereomer of the title compound. MS (m / z) 506.2 [M+H] + .

[0822] Synthesis of N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3, 10-Methoxycyclopropyl[f]pyrido[1,2-a][1,4]diazacyclononatetraene-7-carboxamide (42-1):

[0823] 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-carboxycyclopropyl[f]pyrido[1,2-a][1,4]diazacyclononatetraene-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).

[0824] 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-methanocyclopropyl[f]pyrido[1,2-a][1,4]diazacyclononatetraene-7-carboxamide (42-2):

[0825]

[0826] In a manner similar to 42-1, starting with 42e-2 (peak 2) instead of 42e-1 (peak 1), (1aS, 10R, 11aS)-N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropyl[f]pyrido[1,2-a][1,4]diazacyclononatetraene-7-carboxamide (42-2) was prepared. MS (m / z) 416.2 [M+H] + . 1HNMR (400 MHz, CHLOROFORM-d) δ10.46 (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).

[0827] Example 40: Preparation of (7S)-2,4,6-trifluorobenzyl 12-methoxy-1,11-dioxo-1,3,4,5,6,11-hexahydro-713-2,7-methanpyrido[2,1-c][1,4]diazacyclononatetraene-10-carboxylate and (7R)-2,4,6-trifluorobenzyl 12-methoxy-1,11-dioxo-1,3,4,5,6,11-hexahydro-713-2,7-methanpyrido[2,1-c][1,4]diazacyclononatetraene-10-carboxylate (43-1, 43-2):

[0828]

[0829] Synthesis of 3-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (43a) :

[0830] Under ice bath, phosphorus pentachloride (1.16 g, 5.58 mmol) was added to a solution of 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (1 g, 5.58 mmol) in DCM (25 mL). After the reaction mixture was stirred 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 Na 2 S 2 SO 3 The organic layer was washed with MgSO 4 Dry and remove the solvent by rotary evaporator. The title compound is crystallized from a DCM / ethyl acetate mixture. MS (m / z) 260 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.18(s,1H),7.25(td,J=8.1,6.3Hz,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, 7.3Hz, 1H), 2.96–2.83 (m, 1H), 2.76–2.59 (m, 2H), 2.47–2.41 (m, 1H).

[0831] Synthesis of 3-azido-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (43b) :

[0832] To a solution of 3-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-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 washed with MgSO 4 Dry and remove the solvent by rotary evaporator. Purify the residue by silica gel column to obtain the title compound. MS (m / z) 221 [M+H] + .

[0833] Synthesis of (6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamic acid Tert-Butyl Ester (43c) :

[0834] To a solution of 3-azido-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (43b, 880 mg, 4 mmol) in THF (30 mL) was added di-tert-butyl dicarboxylate (1.308 g, 5.99 mmol) and 10% Pd / C (425 mg), and then the mixture was bubbled under a hydrogen atmosphere (balloon pressure). The reaction was stirred for 2 h and then precipitated by The pad was filtered and washed with ethyl acetate, and the filtrate was concentrated in a rotary evaporator. The residue was purified by silica gel column to give the title compound. MS (m / z) 317.1 [M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.87(s,1H),7.32–7.21(m,1H),7.00(q,J=8.5Hz,2H),6.85(d,J=7.9Hz,1H),3.91–3.7 8(m,1H),2.96(dd,J=14.0,6.3Hz,1H),2.45–2.28(m,1H),2.23–1.98(m,2H),1.32(s,9H).

[0835] Synthesis of tert-butyl (S)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate Acid esters and (R)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate (43d-1 and43d-2) :

[0836] To a solution of tert-butyl (6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate (43c, 800 mg, 2.72 mmol) in THF (30 mL) was added BH 3 -THF solution (1N, 13 mL). After the reaction was stirred overnight, the reaction was quenched with MeOH (1 mL) and aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (100 mL) and washed with brine. The organic layer was washed with MgSO 4 Dry and concentrate in vacuo. The residue is purified by silica gel column to give tert-butyl (6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) carbamate (43d). MS (m / z) 281.2 [M+H] + .

[0837] [7] 43d was separated into its individual enantiomers by chiral HPLC (SFC chromatography on an IB 4.6×100 mm 5mic column using EtOH (15%) as cosolvent) to afford the title compound.

[0838] Synthesis of (S)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-amine and (R)-6-fluoro- 2,3,4,5-Tetrahydro-1H-benzo[b]azepine-3-amine (43e-1 and 43e-2)

[0839] To a solution of (S)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)carbamate or (R)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-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 evaporator to give the title compound (43e-1 or 43e-2), which was used in the next step without further purification. MS (m / z) 181.2 [M+H] + .

[0840] Synthesis of (S)-3-(Benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3- (R)-3-(benzyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid methyl ester and (R)-3-(benzyl)- Oxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-oxo-5-((2,4,6-trihydro- (43f-1 and 43f-2):

[0841] To (S)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-amine or (R)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-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 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylic acid methyl ester (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 washed with MgSO 4 Drying and removal of the solvent by rotary evaporation afforded the title compound (43f-1 or 43f-2), which was used in the next step without further purification. MS (m / z) 610.2 [M+H] + .

[0842] Synthesis of (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]diazacyclononatetraene-9-carboxamide and (12S)-1- Fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methoxybenzo [e]pyrido[1,2-a][1,4]diazacyclononatetraene-9-carboxamide and (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]diazacyclononatetraene-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]diazacyclononanetetrakis A mixture of olefin-9-carboxamides (a mixture of 43g-1 and 43h-1) and (a mixture of 43g-2 and 43h-2):

[0843] To a solution of the crude product (S)- or (R)-2-methyl 5-(2,4,6-trifluorobenzyl) 3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (43f-1 or 43f-2, 80 mg, 0.131 mmol) in methanol (6 mL) was added aqueous LiOH (2N, 2 mL). After the reaction was stirred for 2 hours, the solvent was removed and extracted with ethyl acetate (100 mL). The organic layer was purified by MgSO 4 After drying, the solvent was removed by rotary evaporation to give the title compound (a mixture of 43g-1 and 43h-1 or a mixture of 43g-2 and 43h-2), which was used as a crude product 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] + .

[0844] Synthesis of (12S)-1-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro- 12H-5,12-Methoxybenzo[e]pyrido[1,2-a][1,4]diazacyclononatetraene-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]pyridine [1,2-a][1,4]diazacyclononatetraene-9-carboxamide (43-1 and 43-2):

[0845] To a mixture of (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]diazacyclononatetraene-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]diazacyclononatetraene-9-carboxamide (43 g-1 / 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]diazacyclononatetraene-9-carboxamide (43 g-1 / 43 h-1, 198 mg, 0.343 mmol) To a solution of a mixture of 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]diazacyclononatetraene-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]diazacyclononatetraene-9-carboxamide (43 g-2 / 43h-2, 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).

[0846] 43-1: MS (m / z) 488.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.34(t,J=5.8Hz,1H),8.58(s,1H),7.32(dd,J=8.1,6.1Hz,1H),7.19(td,J=8.3,3.5Hz,4H),4.95–4.85(m,1H),4.56(d,J=5.7Hz,2H),4.13( d,J=14.7Hz,1H),3.85(dd,J=14.9,2.1Hz,1H),2.88(dd,J=17.0,9.7Hz,1H),2.71(dd,J=16.9,9.2Hz,1H),2.42–2.28(m,1H),2.03–1.92(m,1H).

[0847] 43-2: MS (m / z) 488.1 [M+H] + . 1H NMR (400 MHz, DMSO-d 6 )δ10.34(t,J=5.8Hz,1H),8.58(s,1H),7.33(td,J=8.1,6.1Hz,1H),7.19( td,J=8.4,4.0Hz,3H),4.90(t,J=5.8Hz,1H),4.56(d,J=5.7Hz,2H),4.13(d ,J=14.6Hz,1H),3.87(d,J=2.2Hz,1H),2.88(dd,J=16.5,10.1Hz,1H),2.71 (dd, J=16.9, 9.2Hz, 1H), 2.35 (q, J=7.7, 7.0Hz, 1H), 1.98 (d, J=8.6Hz, 1H).

[0848] Example 41: Preparation of (8R,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanpyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide and (8S,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanpyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide (44-1 and 44-2):

[0849]

[0850] Synthesis of benzyl (R, Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazoctatetraene-1(2H)- Formate and (S,Z)-3-(((Benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazoctatetraene-1(2H)-carboxylate (44a-1 and 44a-2)

[0851] The title compound was synthesized from 2-aminopent-4-en-1-ol in a manner similar to 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] + .

[0852] Synthesis of (R,Z) and (S,Z)-1,2,3,4,7,8-hexahydroazoctatetraen-3-amine (44b-1 and 44b-2)

[0853] To a vial was added benzyl (R,Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazoctate-1(2H)-carboxylate or (S,Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazoctate-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 in the next step without further purification. MS (m / z) 127.2 [M+H] + .

[0854] Synthesis of (8R,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2, 8-methoxypyrido[1,2-a][1,4]diazacyclodecene-11-carboxamide and (8S,Z)-N-(2,4-difluorobenzyl)-13- Hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanpyrido[1,2-a][1,4]diazacyclodecene- 11-Formamide (44-1 and 44-2)

[0855] The title compound was synthesized from (R,Z)-1,2,3,4,7,8-hexahydroazacyclooctatetraen-3-amine or (S,Z)-1,2,3,4,7,8-hexahydroazacyclooctatetraen-3-amine (44b-1 or 44b-2, 18.9 mg, 0.163 mmol) and 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylic acid ethyl ester (70 mg, 0.163 mmol).

[0856] 44-1: MS (m / z) 416.3 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.71–10.56(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).

[0857] 44-2: MS (m / z) 416.2 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.66–10.51(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).

[0858] 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]diazacyclononatetraene-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]diazacyclononatetraene-9-carboxamide (45-1 and 45-2):

[0859]

[0860] The title compound was prepared in a similar manner to 43-1 and 43-2, substituting 6-chloro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one for 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one.

[0861] 45-1: MS (m / z) 504.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.38(t,J=5.8Hz,1H),8.60(s,1H),7.47(dd,J=6.7,2.8Hz,1H),7.40–7.30(m, 2H),7.29–7.16(m,2H),4.96–4.88(m,1H),4.59(d,J=5.7Hz,2H),4.15(dd,J=15.0 ,1.9Hz,1H),3.86(dd,J=14.7,2.2Hz,1H),3.04(ddd,J=17.1,9.7,2.3Hz,1H),2.8 6(ddd,J=15.8,10.3,5.6Hz,1H),2.41–2.32(m,1H),2.06(dd,J=13.4,6.9Hz,1H).

[0862] 45-2: MS (m / z) 504.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.38(t,J=5.8Hz,1H),10.27(s,1H),8.60(s,1H),7.47(dd,J=6.7,2.7Hz,1H) ,7.41–7.30(m,2H),7.29–7.16(m,2H),4.96–4.88(m,1H),4.59(d,J=5.7Hz,2H), 4.20–4.11(m,1H),3.86(dd,J=14.7,2.2Hz,1H),3.04(ddd,J=17.2,9.8,2.3Hz,1 H), 2.86 (dd, J=16.8, 9.2Hz, 1H), 2.42–2.33 (m, 1H), 2.04 (q, J=13.0, 9.4Hz, 1H).

[0863] 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]diazacyclononatetraene-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]diazacyclononatetraene-9-carboxamide (46-1 and 46-2):

[0864]

[0865] Synthesis of (S)- and (R)-3-(Benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepane 4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid methyl ester (46a-1 and 46a-2):

[0866] 9-Fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one was substituted for 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one to give (S)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-oxo-5-((2,4,6-trifluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-oxo-5-((2,4,6-trifluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one)-1-(9-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-oxo-5-((2,4,6-tri ... Prepared in a similar manner to (43f-1 and 43f-2) methyl (R)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate and methyl (R)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate.

[0867] 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]diazacyclononatetraene-9-carboxamide and (12R)-7- (Benzyloxy)-4-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methoxybenzene [e]pyrido[1,2-a][1,4]diazacyclononatetraene-9-carboxamide (46b-1 and 46b-2) :

[0868] To a solution of (S)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid methyl ester or (R)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-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 (2N, 4 mL) at room temperature. After heating to 50°C and stirring for 2 hours, citric acid solution (5% aqueous solution) 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]azepine-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]azepine-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid, which was used in the next step without purification. MS (m / z) 596.2 [M+H] + .

[0869] To a solution of (S)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepine-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]azepine-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 initiation with ethyl acetate to give the title compound (46b-1 or 46b-2). MS (m / z) 578.2 [M+H] + .

[0870] Synthesis of (12S)-4-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro- 12H-5,12-Methoxybenzo[e]pyrido[1,2-a][1,4]diazacyclononatetraene-9-carboxamide and (12R)-4-fluoro- ...

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 H or C 6-10 Aryl, where C 6-10 The aryl group is optionally substituted with 1 to 4 R A1 Substitute, where each R A1 are independently halogen, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkyl-OC 1-4 alkyl; R 2 H, C 1-6 Alkyl or C 1-4 Haloalkyl; L is -CR 3a R 3b -, -C(O)-, -SO2-, -CH2-CH2- or -N(R a )-; W 1 Key or -CR 4a R 4b -; W 2 is -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 -; Y is -C(O)NH- or Q, wherein Q is Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d - or -CR 10a =CR 10b -; R 3a and R 3b 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, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A2 Substitute, where each R A2 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 4a and R 4b Independently H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogen; R 5a , R 5b , R 5c and R 5d Independently H, C 1-6 Alkyl, C 1-4 Haloalkyl, halogen, 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, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or R 5a and R 5c or R 5b and R 5d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 3 R A3 Substitute, where each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; Each R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 Alkyl; optionally: R 6a and R 6b Together with the carbon atoms to which they are attached, they form a 5- to 10-membered partially saturated fused ring containing 0 or 1 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 1 to 2 heteroatoms selected from N, O and S, wherein the partially saturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by 1 to 4 R A4 Substitute, where each R A4 are independently halogen or C 1-4 alkyl; R 7 H, C 1-6 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO2R c ; R 8a and R 8b Each independently represents H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 haloalkyl, cyano or halogen; or optionally: R 8a and R 8b Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or optionally: R 8a H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 haloalkyl, cyano or halogen; and R 8b With R 5a , R 5b , R 5c , R 5d and R 7 One of them and the atoms to which they are each attached together form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally fused with 1 to 4 R A5 Substitute, where each R A5 are independently halogen or C 1-4 Alkyl; or R 8b and R 2 Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen or C 1-4 alkyl; R 9a , R 9b , R 9c and R 9d Each independently is H, C 1-6 Alkyl, C 1-4 haloalkyl or halogen; or optionally: R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated spiro ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A6 Substitute, where each R A6 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or R 9a and R 9c or R 9b and R 9d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by 1 to 3 R A6 Substitute, where each R A6 are independently halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or R 9a , R 9b , R 9c and R 9d One and R 4a , R 4b , R 5a , R 5b and R 7 One of them and the atoms to which they are each attached together form a 3- to 7-membered saturated or partially saturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is optionally fused with 1 to 4 R A6 Substitute, where each R A6 are independently halogen or C 1-4 alkyl; R 10a and R 10b are independently H, halogen, C 1-4 Haloalkyl, or C 1-6 Alkyl; or optionally: R 10a and R 10b Together with the carbon atoms to which they are attached, they form a 5- to 10-membered partially saturated fused ring containing 0 or 1 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 1 to 2 heteroatoms selected from N, O and S, wherein the partially saturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by 1 to 4 R A7 Substitute, where each R A7 are independently halogen or C 1-4 alkyl; R a Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R c or SO2R c ; R b H or C 1-4 alkyl; R c C 1-4 Alkyl or -OC 1-4 Alkyl; and Each n is 0, 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, -CH3, -CH2CH3 and -CH2F or R 2 and R 8b Together with the carbon to which they are attached they form a 3-membered fused carbocyclic ring.

3. The compound according to claim 0 or 0 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, -CH3, -CH2CH3 and -CH2F.

4. The compound according to claim 0 or 0 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 8b Together with the carbon to which they are attached they form a 3-membered fused carbocyclic ring.

5. The compound according to claim 0 or a pharmaceutically acceptable salt thereof, wherein R 2 H or C 1-4 alkyl.

6. The compound according to claim 0 or 0 or a pharmaceutically acceptable salt thereof, wherein R 2 It is H or methyl.

7. The compound according to any one of claims 0 to 0, or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)NH-.

8. The compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, which has formula (II):

9. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 1 to 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkyl-OC 1-4 alkyl.

10. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted by 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 alkyl.

11. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 For 1, 2, 3 or 4 R A1 Substituted phenyl, wherein each R A1 are independently halogen or -OC 1-4 alkyl.

12. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 13. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 14. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 15. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted by 1, 2, 3 or 4 halogens.

16. A compound according to any one of claims 0-0 and 0 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted by 2 or 3 halogens selected from chlorine and fluorine.

17. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 18. A compound according to any one of claims 0 to 0 or a pharmaceutically acceptable salt thereof, wherein R 1 for 19. The compound according to any one of claims 0 to 0, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -CH(CH3)-, -C(O)-, or -CH2-CH2-.

20. The compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, which has the following formula:

21. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, which has formula (IV):

22. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, which has the following formula:

23. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, which has formula (VI):

24. A compound according to any one of claims 0-0 and 0, or a pharmaceutically acceptable salt thereof, having the following formula:

25. A compound according to any one of claims 0 to 24 or a pharmaceutically acceptable salt thereof, wherein W 1 Key or -CR 4a R 4b -; where R 4a and R 4b Independently H, C 1-6 Alkyl or halogen.

26. A compound according to any one of claims 0 to 25 or a pharmaceutically acceptable salt thereof, wherein W 1 Key or -CR 4a R 4b -; where R 4a and R 4b are independently H, -CH3 or halogen.

27. A compound according to any one of claims 0 to 26 or a pharmaceutically acceptable salt thereof, wherein W 1 is a bond, -CH2-, -CF2-, -CH(F)-, -CH(CH3)- or -CF(CH3)-.

28. A compound according to any one of claims 0-25 and 0 or a pharmaceutically acceptable salt thereof, wherein W 1 is a bond, -CH2-, -CF2- or -CH(F)-.

29. A compound according to any one of claims 1 to 0 or a pharmaceutically acceptable salt thereof, wherein W 2 Selected from -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-; where Each R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, 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 Together with the carbon atoms to which they are attached, they form a A3 A substituted 3- to 7-membered saturated or partially saturated carbocyclic ring, wherein each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; Each R 6a和 R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-4 Alkyl; or R 6a and R 6b Together with the atoms to which they are attached, they form (i) a 5- to 10-membered fused aromatic ring or (ii) a 5- to 10-membered fused heteroaromatic ring comprising 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 optionally substituted by 1 to 4 R A4 Substitute, where each R A4 are independently halogen or C 1-4 alkyl; R 7 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO2R c ; R c C 1-4 alkyl; and n is 0, 1 or 2.

30. A compound according to any one of claims 1 to 0 or a pharmaceutically acceptable salt thereof, wherein W 2 Selected from -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-; where Each R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, 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 Together with the carbon atoms to which they are attached, they form a A3 A substituted 3-membered carbocyclic ring, wherein each R A3 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; Each R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-4 Alkyl; or R 6a and R 6b Together with the atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-6 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the fused benzene ring or the 5-6 membered fused heteroaromatic ring is optionally substituted by 1 to 4 R A4 Substitute, where each R A4 are independently halogen or C 1-4 alkyl; R 7 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO2R c ; R c C 1-4 alkyl; and n is 0, 1 or 2.

31. A compound according to any one of claims 1 to 0 or a pharmaceutically acceptable salt thereof, wherein W 2 Selected from -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-; where Each R 5a , R 5b , R 5c and R 5d Independently H, C 1-4 Alkyl, halogen, 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, they form a 3-membered carbocyclic ring; Each R 6a and R 6b are independently H, halogen or C 1-4 Alkyl; or R 6a and R 6b Together with the atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-6 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, wherein the fused benzene ring or the 5-6 membered fused heteroaromatic ring is optionally substituted by 1 to 2 R A4 Substitute, where each R A4 are independently halogen or C 1-4 alkyl; R 7 H, C 1-4 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO2R c ; R c C 1-4 alkyl; and n is 0 or 1.

32. A compound according to any one of claims 1 to 0 or a pharmaceutically acceptable salt thereof, wherein W 2 Selected from -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-; where Each R 5a , R 5b , R 5c and R 5d are independently H, -CH3, halogen, hydroxyl or -OCH3; 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, they form a 3-membered carbocyclic ring; Each R 6a and R 6b are independently H, halogen or CH3; or R 6a and R 6b Together with the atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, wherein the fused benzene ring or the 5-membered fused heteroaromatic ring is optionally substituted by 1 to 2 R A4 Substitute, where each R A4 are independently halogen or CH3; R 7 H, -CH3, -CH(CH3)2, -CF3, -C(O)R c or-SO2R c ; R c is -CH3; and n is 0 or 1.

33. A compound according to any one of claims 1 to 0 or a pharmaceutically acceptable salt thereof, wherein W 2 Selected from -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-; where Each R 5a , R 5b , R 5c and R 5d are independently H, -CH3, halogen, hydroxyl or -OCH3; Each R 6a and R 6b are independently H, halogen or -CH3; R 7 H, -CH3, -CH(CH3)2, -CF3, -C(O)R c or-SO2R c ; R c is -CH3; and n is 0 or 1.

34. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein W 2 -CH2-, -CH2CH2-, -CH=CH-, -NH-, -N(CH3)-, -N(CH(CH3)2)-, -N(C(O)CH3)-, -N(SO2CH3)-, -O- or -CH2-O-.

35. A compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-, -CF2-, -CH(F)-, -CH(OH)-, -CH(CH3)-, -CH(CH2F)-, or -CF(CH3)-.

36. A compound according to any one of claims 0-0, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-, -CF2-, -CH(F)-, -CH(OH)-, -CH(CH3) or -CF(CH3)-.

37. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein 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 halogen; or R 8a and R 8b Together with the carbon to which they are attached, they form a 3- to 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spirocyclic ring is optionally substituted by 1 to 4 R A5 substituted, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

38. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein 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 halogen; or R 8a and R 8b Together with the carbon to which they are attached, they form a 3-5 membered saturated spiro carbocyclic ring, wherein the 3-5 membered saturated spiro carbocyclic ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

39. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein 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 halogen, or R 8a and R 8b Together with the carbon to which they are attached they form a 3-membered saturated spiro carbocyclic ring.

40. A compound according to any one of claims 24 to 28, or a pharmaceutically acceptable salt thereof, wherein X is a bond, -CH2-, -CF2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH2F)(H)-, -C(CH2F)(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -C(CH2CH3)(OCH3)-, -C(CH2CH3)(OH)-, -CH(CH3)-, -CH(CH2CH3)-, -CF(CH3)-, -CF(CH2CH3)-, or -CR 8a R 8b -, where R 8a and R 8b Together with the carbon to which they are attached they form a spirocyclopropane ring.

41. A compound according to any one of claims 0 to 40, or a pharmaceutically acceptable salt thereof, wherein X is a bond, -CH2-, -CF2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH2F)(H)-, -C(CH2F)(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -C(CH2CH3)(OCH3)-, -C(CH2CH3)(OH)-, -CH(CH3)-, -CH(CH2CH3)-, -CF(CH3)-, or -CF(CH2CH3)-.

42. A compound according to any one of claims 24 to 28, or a pharmaceutically acceptable salt thereof, wherein X is a bond, -CH2-, -CF2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH2F)(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -C(CH2CH3)(OCH3)-, -C(CH2CH3)(OH)-, -CH(CH3)-, -CH(CH2CH3)-, -CF(CH3)-, -CF(CH2CH3)-, or -CR 8a R 8b -, where R 8a and R 8b Together with the carbon to which they are attached they form a spirocyclopropane ring.

43. A compound according to any one of claims 24 to 28, or a pharmaceutically acceptable salt thereof, wherein X is a bond, -CH2-, -CF2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH2F)(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -C(CH2CH3)(OCH3)-, -C(CH2CH3)(OH)-, -CH(CH3)-, -CH(CH2CH3)-, -CF(CH3)-, or -CF(CH2CH3)-.

44. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein X is -CR 8a R 8b -, where R 8a and R 8b Together with the carbon to which they are attached, they form a 3- to 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spirocyclic ring is optionally substituted by 1 to 4 R A5 Substitute, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

45. A compound according to any one of claims 0-0 and 0 or a pharmaceutically acceptable salt thereof, wherein X is -CR 8a R 8b -, where R 8a and R 8b Together with the carbon to which they are attached, they form a 3-5 membered saturated spiro carbocyclic ring, wherein the 3-5 membered saturated spiro carbocyclic ring is optionally substituted by 1 to 4 R A5 substituted, where each R A5 are independently halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

46. ​​A compound according to any one of claims 0-0, 0 and 0, or a pharmaceutically acceptable salt thereof, wherein X is -CR 8a R 8b -, where R 8a and R 8b Together with the carbon to which they are attached they form a 3-membered spirocarbocycle.

47. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, which has formula (VIII):

48. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein Z is -CR 9a R 9b -、-CR 9a R 9b CR 9c R 9d -or-CR 10a =CR 10b -;in R 9a , R 9b , R 9c and R 9d Each independently is H, C 1-6 Alkyl, C 1-4 haloalkyl or halogen; or R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form a 3- to 7-membered saturated or partially saturated ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by 1 to 3 R A6 substituted, where each R A6 are independently halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 10a and R 10b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 Alkyl; or R 10a and R 10b Together with the carbon atoms to which they are attached, they form (i) a 5-10 membered partially saturated fused ring containing 0 or 1 heteroatom selected from N, O and S, (ii) a 5-10 membered fused aromatic ring or (iii) a 5-10 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the 5-10 membered partially saturated fused ring, the 5-10 membered fused aromatic ring or the 5-10 membered fused heteroaromatic ring is optionally substituted by 1 to 4 R A7 Substitute, where each R A7 are independently halogen or C 1-4 alkyl.

49. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein 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 Each independently is H, C 1-6 Alkyl, C 1-4 haloalkyl or halogen; or R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form a 3-membered saturated spirocarbocyclic ring; R 10a and R 10b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 Alkyl; or R 10a and R 10b Together with the carbon atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-6 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the fused benzene ring or the fused heteroaromatic ring is optionally substituted by 1 to 2 R A7 Substitute, where each R A7 are independently halogen or C 1-4 alkyl.

50. The compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein Z is -CR 9a R 9b -、-CR 9a R 9b CR 9c R 9d -or-CR 10a =CR 10b -;in R 9a , R 9b , R 9c and R 9d each independently is H, CH3, CH2CH3, CHF2 or halogen; or R 9a and R 9b or R 9c and R 9d Together with the carbon atom to which they are attached, they form a 3-membered carbocyclic ring; R 10a and R 10b are independently H, halogen or CH3; or R 10a and R 10b Together with the carbon atoms to which they are attached, they form (i) a fused benzene ring or (ii) a 5-6 membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the fused benzene ring or the fused heteroaromatic ring is optionally substituted by 1 to 2 R A7 Substitute, where each R A7 are independently halogen or CH3.

51. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein Z is -CH2-, -CH(CH3)-, -CH2-CH2-, 52. A compound according to any one of claims 0-0, wherein the compound has formula (IX): or a pharmaceutically acceptable salt thereof.

53. A compound according to any one of claims 0-0, wherein the compound has formula (IXa): or a pharmaceutically acceptable salt thereof.

54. A compound according to any one of claims 0-0, wherein the compound has formula (IXb): or a pharmaceutically acceptable salt thereof.

55. The compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (X):

56. A compound according to any one of claims 0-0 and 0, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Xa):

57. A compound according to any one of claims 0-0 and 0, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Xb):

58. A compound according to any one of claims 0-0, wherein X is a bond or -CR 8a R 8b -; where R 8a and R 8b Each independently represents H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano or halogen.

59. The compound of any one of claims 0-0, wherein X is a bond.

60. The compound according to any one of claims 0-0, wherein X is -CR 8a R 8b -; where R 8a and R 8b Each independently represents H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano or halogen.

61. A compound according to any one of claims 0-0 and 0, wherein X is -CR 8a R 8b -; where R 8a and R 8b Each independently is H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogen.

62. according to the compound described in any one of claim 0-0, 0 and 0, wherein R 8a and R 8b Each is independently H, -CH3, -CHF2, -CH2F or halogen.

63. A compound according to any one of claims 0-0, wherein 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 Each independently is H, C 1-6 Alkyl or C 1-4 Halogenated alkyl.

64. A compound according to any one of claims 0-0, wherein Z is -CR 9a R 9b -.

65. A compound according to any one of claims 0-0, wherein Z is -CR 9a R 9b CR 9c R 9d -.

66. A compound according to any one of claims 0-0, wherein R 9a , R 9b , R 9c and R 9d Each is independently H, -CH3, -CHF2 or -CH2F.

67. According to the compound described in any one of claims 0-0, wherein each R 5a , R 5b , R 5c and R 5d are independently H, halogen, C 1-4 Haloalkyl or C 1-6 alkyl.

68. A compound according to any one of claims 0-0 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (XI):

69. A compound according to any one of claims 0-0 and 0, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (XIa):

70. The compound according to any one of claims 0-0 and 0, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (XIb):

71. A compound according to any one of claims 0-0, wherein X is a bond or -CR 8a R 8b -; where R 8a and R 8b Each independently represents H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano or halogen.

72. A compound according to any one of claims 0-0, wherein X is a bond.

73. A compound according to any one of claims 0-0, wherein X is -CR 8a R 8b -; where R 8a and R 8b Each independently represents H, hydroxyl, -OC 1-4 Alkyl, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-6 Alkyl, C 1-4 Haloalkyl, cyano or halogen.

74. A compound according to any one of claims 0-0 and 0, wherein X is -CR 8a R 8b -; where R 8a and R 8b Each independently is H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogen.

75. according to the compound described in any one of claim 0-0, 0 and 0, wherein R 8a and R 8b Each is independently H, -CH3, -CHF2, -CH2F or halogen.

76. A compound according to any one of claims 0-0, wherein 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 Each independently is H, C 1-6 Alkyl or C 1-4 Halogenated alkyl.

77. A compound according to any one of claims 0-0, wherein Z is -CR 9a R 9b -.

78. A compound according to any one of claims 0-0, wherein Z is -CR 9a R 9b CR 9c R 9d -.

79. according to the compound described in any one of claims 0-0, wherein R 9a , R 9b , R 9c and R 9d Each is independently H, -CH3, -CHF2 or -CH2F.

80. According to the compound described in any one of claims 0-0, wherein each R 6a and R 6b are independently H, halogen, C 1-4 Haloalkyl or C 1-6 alkyl.

81. A compound having the formula: or a pharmaceutically acceptable salt thereof.

82. A compound having the formula: or a pharmaceutically acceptable salt thereof.

83. A compound selected from: or a pharmaceutically acceptable salt thereof.

84. A compound selected from: or a pharmaceutically acceptable salt thereof.

85. A compound selected from: or a pharmaceutically acceptable salt thereof.

86. A compound selected from: or a pharmaceutically acceptable salt thereof.

87. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

88. The pharmaceutical composition of claim 87, further comprising 1, 2, 3 or 4 additional therapeutic agents.

89. The pharmaceutical composition of claim 88, wherein the one or more additional therapeutic agents are anti-HIV agents.

90. The pharmaceutical composition of claim 87 or 88, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

91. The pharmaceutical composition of any one of claims 87-90, wherein the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonylamino)-1-(2,2,2)-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide or a pharmaceutically acceptable salt thereof.

92. A pharmaceutical composition according to any one of claims 87-91, wherein the pharmaceutical composition is for oral or parenteral administration.

93. A kit comprising a compound of any one of claims 1-86 or a pharmaceutically acceptable salt thereof and instructions for use.

94. The kit of claim 93, further comprising 1, 2, 3 or 4 additional therapeutic agents.

95. The kit of claim 93 or 94, wherein the one or more additional therapeutic agents are anti-HIV agents.

96. A kit according to any one of claims 93-95, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

97. The kit of any one of claims 93-96, wherein the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonylamino)-1-(2,2,2)-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide or a pharmaceutically acceptable salt thereof.

98. A method of treating HIV infection in a human suffering from or at risk of HIV infection, comprising administering to the human a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as described in any one of claims 1-86, or a pharmaceutical composition as described in any one of claims 87-92.

99. The method of claim 98, further comprising administering to the human a therapeutically effective amount of 1, 2, 3 or 4 additional therapeutic agents.

100. The method of claim 99, wherein the one or more additional therapeutic agents are anti-HIV agents.

101. The method of claim 99 or 100, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

102. The method of any one of claims 99-101, wherein the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonylamino)-1-(2,2,2)-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

103. The method of any one of claims 98-102, wherein the administration is oral, intravenous, subcutaneous or intramuscular.

104. Use of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-86 or a pharmaceutical composition as described in any one of claims 87-92 for treating HIV infection in a person suffering from or at risk of HIV infection.

105. A compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 86 or a pharmaceutical composition as described in any one of claims 87 to 92 for use in medical therapy.

106. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 86 or a pharmaceutical composition according to any one of claims 87 to 92 for use in treating HIV infection.

107. Use of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-86 or a pharmaceutical composition as described in any one of claims 87-92 in the preparation of a medicament for treating HIV infection in a person suffering from or at risk of HIV infection.

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