Bridged tricyclic carbamoyl pyridone compounds and uses thereof

Abstract

The present disclosure relates generally to compounds of Formula I. Pharmaceutical compositions comprising the compounds and methods of making the compounds are also disclosed. The compounds of the present disclosure are useful in the treatment or prevention of human immunodeficiency virus (HIV) infection. # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of April 5, 2023, an application number of 202380029590.8, and an invention title of "Bridged Tricyclic Carbamoylpyridone Compounds and Their Uses".

[0002] Cross - References

[0003] This application claims the priority of U.S. Provisional Application No. 63 / 328,061 filed on April 6, 2022 and U.S. Provisional Application No. 63 / 476,873 filed on December 22, 2022. The entire contents of these applications are incorporated herein by reference in their entirety for all purposes. Technical Field

[0004] Compounds, compositions, and methods are disclosed that can be used for the treatment or prevention of human immunodeficiency virus (HIV) infection. Specifically, novel spiro - substituted bridged tricyclic carbamoylpyridone compounds, their preparation methods, and uses as therapeutic or prophylactic agents are disclosed. Background Art

[0005] Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. The 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 have shown effectiveness, especially when used in combination, toxicity and the development of drug - resistant strains may limit their usefulness (Palella et al., N. Engl. J Med. (1998) 338:853 - 860; Richman, D. D. Nature (2001) 410:995 - 1001). Thus, new agents for inhibiting HIV replication are needed.

[0006] One 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 state 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. See http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed February 12, 2019). Additionally, when patients require treatment for other medical conditions, the decision regarding the treatment of patients infected with HIV is complex (ibid., F-8). Because the standard of care requires the use of multiple different drugs to suppress HIV and to treat other conditions the patient may be experiencing, the likelihood of drug interactions is a criterion for selecting a drug regimen. Thus, there is a need for antiretroviral therapies with a reduced likelihood of drug interactions.

[0007] Additionally, it is known that the HIV virus mutates in infected subjects (Tang et al. Drugs (2012) 72(9) e1-e25). Because of the HIV virus's propensity to mutate, there is a need for anti-HIV drugs that are effective against a range of known HIV variants (Hurt et al. HIV / AIDS CID (2014) 58, 423-431).

[0008] For some patients, such as those with difficult or limited access to healthcare, adhering to a daily oral treatment or prophylaxis regimen can be challenging. Drugs that provide favorable pharmaceutical properties (e.g., improved potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) can reduce the frequency of administration and provide better patient compliance. Such improvements can in turn optimize drug exposure and limit the emergence of drug resistance. SUMMARY OF THE INVENTION

[0009] The present disclosure relates to novel compounds having antiviral activity and pharmaceutically acceptable salts thereof. In some embodiments, these compounds can be used to treat HIV infections, inhibit the activity of HIV integrase, and / or reduce HIV replication. In some embodiments, the compounds disclosed herein can be effective against a range of known drug-resistant HIV mutants. In some embodiments, when co-administered with other drugs, the compounds disclosed herein can have a reduced propensity to cause drug-drug interactions. In some embodiments, the compounds disclosed herein can be administered at a frequency less than daily, such as once a week, once a month, once every three months, once every six months, or at longer intervals.

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

[0011]

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein:

[0014] R 1 is H, C 6-10 aryl or a 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S,

[0015] wherein the C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one, two, three, or four R A1 substituents, wherein each R A1 is independently halo, C 1-6 alkyl, C 1-4 haloalkyl,

[0016] cyano, –O–C 1-4 alkyl or C 1-4 alkyl–O–C 1-4 alkyl;

[0017] R 2 is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0018] L is –CR 3a R 3b –, –C(O)–, –SO 2 –, –CH 2 –CH 2 – or –N(R a )–;

[0019] W 1 is a bond or –CR 4a R4b –;

[0020] 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)–;

[0021] Y is –C(O)NH–,

[0022] is a three- to seven-membered spiro ring containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein the spiro ring is optionally substituted by one, two, three or four R 8 groups;

[0023] Z is –CR 9a R 9b –, –CR 9a R 9b CR 9c R 9d – or –CR 10a =CR 10b –;

[0024] R 3a and R 3b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or –O–C1-4 alkyl; or

[0025] R 3a and R 3b together with the carbon atom to which they are attached form a 3- to 7-membered spiro ring containing 0, 1 or 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by one, two or three R A2 substituents, wherein each R A2 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl;

[0026] R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo;

[0027] R 5a 、R 5b 、R 5c and R 5d are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxy, cyano, –O–C 1-4 alkyl or C 1-4 alkylene–O–C 1-4 alkyl; or

[0028] R 5a and R 5b or R 5c and R 5d together with the carbon atom to which they are attached form a 3- to 7-membered spiro ring containing 0, 1 or 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by one, two or three R A3 substituents, wherein each R A3 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl; or

[0029] R 5a and R 5c or R 5b and R 5d together with the respective carbon atoms to which they are attached form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by one to three R A3 substituents, wherein each R A3 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl;

[0030] Each R 6a and R 6bIndependently H, a halogen group, C 1-4 haloalkyl or C 1-6 alkyl; or

[0031] R 6a and R 6b together with the respective attached carbon atoms form a 5- to 10-membered partially unsaturated 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 or 2 heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally substituted by one, two, three, or four R A4 substituents, where each R A4 is independently a halogen group or C 1-4 alkyl;

[0032] R 7 is H, C 1-6 alkyl, C 1-4 haloalkyl, C(O)R c or SO 2 R c ;

[0033] Each R 8 is independently selected from the group consisting of

[0034] (i) a halogen group,

[0035] (ii) C 1-6 alkyl, which is optionally substituted by OH, C 1-6 alkoxy, C 6-10 aryl, or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, where the C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen group, CN, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, and a three- to seven-membered halogenated cycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S,

[0036] (iii) C 1-6 haloalkyl, which is optionally substituted by OH, C 1-6 alkoxy, C 6-10 aryl, or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0037] Wherein C 6-10 An aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, CN, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl and 3- to 7-membered halocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S,

[0038] (iv) CN,

[0039] (v) oxo group,

[0040] (vi) -X-R A5

[0041] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0042] wherein C 1 -C 6 alkyl or a 3- to 7-membered ring is optionally substituted with 1, 2 or 3 groups independently selected from CN, halo, C 1 -C 6 alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0043] (vii) NHR A6 ,

[0044] wherein R A6 is C 1 -C 6 alkyl;

[0045] (viii) NR A7 R A8 ,

[0046] wherein R A7 is C 1 -C 6 alkyl; and

[0047] R A8 is C 1 -C 6 alkyl,

[0048] (ix) C 6-10An aryl group, optionally substituted by 1, 2, 3 or 4 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halogen, CN, C 3-7 cycloalkyl and C 1-6 alkoxy;

[0049] wherein C 3-7 cycloalkyl is optionally substituted by 1, 2, 3 or 4 independent halogen groups,

[0050] (x) a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S,

[0051] wherein the 3- to 7-membered ring is optionally substituted by one, two or three substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, and

[0052] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0053] wherein the 5- to 10-membered heteroaryl ring is optionally substituted by one, two or three substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl,

[0054] (xii) -SO 2 R A13 ,

[0055] R A13 is C 1 -C 6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0056] wherein C 1-6 alkyl or the 3- to 7-membered ring is optionally substituted by 1, 2 or 3 groups selected from CN, halogen and C 1 -C 6 alkoxy,

[0057] (xiii) -SON(R A14 ) 2 ,

[0058] each R A14 is independently H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S;

[0059] wherein C 1-6 alkyl or a 3- to 7-membered ring is optionally substituted with one, two or three groups selected from CN, halogen and C 1 -C 6 alkoxy;

[0060] (xiv) C 2-6 alkynyl, which is optionally substituted with one, two, three or four substituents independently selected from C 1-6 alkoxy, OH, -SO 2 -(C 1-3 alkyl), or

[0061] two R 8 groups are joined to form a fused, spiro or bridged 3- to 7-membered ring containing zero, one, two or three heteroatoms selected from N, O and S;

[0062] wherein the 3- to 7-membered ring is optionally substituted with one, two or three substituents independently selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl; or

[0063] two R 8 groups on adjacent carbon atoms are joined to form a fused 6- to 10-membered aromatic ring containing zero, one, two or three heteroatoms selected from N, O and S,

[0064] wherein the fused 6- to 10-membered aromatic ring is optionally substituted with one, two or three substituents independently selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl;

[0065] R 9a 、R 9b 、R 9c and R 9d are each independently H, C 1-6 alkyl, C 1-4 haloalkyl or halogen; or

[0066] R 9a and R 9b or R 9c and R 9d together with the carbon atom to which they are attached form a 3- to 7-membered spiro ring containing zero, one or two heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted with one, two or three R A9 substituents, wherein each R A9 is independently halogen, C1-4 alkyl or C 1-4 haloalkyl; or

[0067] R 9a and R 9c or R 9b and R 9d together with the carbon atom to which each is attached form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the fused ring is optionally substituted by one, two, or three R A10 substituents, wherein each R A10 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl; or

[0068] R 9a 、R 9b 、R 9c and R 9d and one of R 4a 、R 4b 、R 5a 、R 5b and R 7 together with the atoms to which each is attached form a 3- to 7-membered fused ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the fused ring is optionally substituted by one, two, three, or four R A11 substituents, wherein each R A11 is independently halo or C 1-4 alkyl;

[0069] R 10a and R 10b are independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl; or

[0070] R 10a and R 10b together with the carbon atom to which each is attached form a 5- to 10-membered partially unsaturated 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 or 2 heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally substituted by one to four R A12 substituents, wherein each R A12 is independently halo or C 1-4 alkyl;

[0071] R a is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R c or SO 2 Rc ;

[0072] R b is H or C 1-4 alkyl;

[0073] R c is C 1-4 alkyl or C 1-4 alkoxy; and

[0074] each n is independently 0, 1, or 2.

[0075] In one embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0076] In another embodiment, a kit or article of manufacture comprising a compound of formula I or a pharmaceutically acceptable salt thereof and instructions for use.

[0077] In another embodiment, there is provided a method of treating a human infected with HIV or at risk of acquiring an HIV infection by administering to the human a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0078] In another embodiment, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, for treating an HIV infection in a human infected with HIV or at risk of acquiring an HIV infection.

[0079] In another embodiment, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an HIV infection in a human infected with HIV or at risk of acquiring an HIV infection.

[0080] In another embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0081] In another embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of an HIV infection.

[0082] Other embodiments, objects, features and advantages may be set forth in the following detailed description of the embodiments, and in part will be apparent from the description of the claimed embodiments, or may be learned by practice. These objects and advantages may be realized and obtained by the methods and compositions particularly pointed out in the specification and the claims. The foregoing summary is understood to be a brief and general overview of some of the embodiments disclosed herein, provided for the benefit and convenience of the reader, and is not intended to limit in any way the scope or equivalence legally enjoyed by the appended claims. Detailed Description

[0083] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, one skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The following description of several embodiments is provided in the understanding that the present disclosure is considered to be illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. The embodiments illustrated under any heading may be combined with the embodiments illustrated under any other heading.

[0084] I. Definitions

[0085] Unless the context requires otherwise, throughout this disclosure and the claims, the word "comprising" and variations thereof such as "comprises" and "comprising" are to be interpreted in an open, inclusive sense, i.e., as "including but not limited to".

[0086] The term "an embodiment" or "embodiments" as used throughout this specification means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment disclosed herein. Thus, the phrase "in an embodiment" or "in embodiments" that appears in various places throughout this specification is not necessarily all referring to the same embodiment. Moreover, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner.

[0087] "Amino" means -NH 2 group.

[0088] "Hydroxy" means -OH group.

[0089] As used herein, the term "C 1-n alkyl", where n is an integer, alone or in combination with another group, is intended to mean a non-cyclic, straight-chain or branched-chain alkyl containing from 1 to n carbon atoms. "C 1-6"Alkyl" includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (isopropyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, and hexyl. The abbreviations Me represents methyl; Et represents ethyl, Pr represents propyl, iPr represents 1-methylethyl, Bu represents butyl, and tBu represents 1,1-dimethylethyl.

[0090] "Alkyl" is a hydrocarbon containing primary, secondary, or tertiary atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkyl), 1 to 8 carbon atoms (i.e., C 1 -C 8 alkyl), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, CH 2 CH 3 ), 1-propyl ( n -Pr, n-butyl -propyl, -CH 2 CH 2 CH 3 ), 2-propyl ( i -Pr, iso-butyl propyl, CH(CH 3 ) 2 ), 1-butyl ( n -Bu, n-butyl -butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl ( i -Bu, iso-butyl butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl ( s -Bu, tert-butyl -butyl, CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl ( t -Bu, tert-butyl butyl, -C(CH 3 ) 3 ), 1-pentyl ( n-butyl -pentyl, CH2 CH 2 CH 2 CH 2 CH 3 )), 2-pentyl (CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (CH(CH 2 CH 3 )) 2 ), 2-methyl-2-butyl (C(CH 3 )) 2 CH 2 CH 3 ), 3-methyl-2-butyl (CH(CH 3 )CH(CH 3 )) 2 ), 3-methyl-1-butyl (CH 2 CH 2 CH(CH 3 )) 2 ), 2-methyl-1-butyl (CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 )) 3 ), 2-hexyl (CH(CH 2 ))CH 2 CH 2 CH 3 ), 3-hexyl (CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )) 3 ), 2-methyl-2-pentyl (C(CH 2 )) 2 CH 2 CH 3 ), 3-methyl-2-pentyl (CH(CH 3 ))CH(CH 3 ))CH 2 CH 3 ), 4-methyl-2-pentyl (CH(CH 3 ))CH 2 CH(CH 3 )) 2)、3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 )) 2 )、2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 )) 2 )、2,3-dimethyl-2-butyl (C(CH 3 )) 2 CH(CH 3 )) 2 )、3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 )) 3 and octyl ((CH 2 )) 7 CH 3 ). "Alkyl" also refers to a saturated, branched or straight-chain hydrocarbon group having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, the alkyl group can have 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 3 carbon atoms (i.e., C 1-3 alkyl). Typical alkyls 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(CH 3 )), 1,3-propyl (CH 2 CH 2 CH 2 ), 1,4-butyl (CH 2 CH 2 CH 2 CH 2 ), etc.

[0091] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon containing a primary, secondary or tertiary carbon atom and having at least one unsaturated site (i.e., a carbon-carbon sp 2 double bond). For example, the alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkenyl or C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2 -C 8 alkenyl or C 2-8 ) or from 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl or C 2-6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethene or vinyl (-CHCH 2 ), allyl (CH 2 CH=CH 2 ), cyclopentenyl (C 5 H 7 ), and 5 - hexenyl (CH 2 CH 2 CH 2 CH 2 CH=CH 2 ).

[0092] As used herein, the term "C 2-n alkenyl", where n is an integer, alone or in combination with another group, is intended to mean an unsaturated, acyclic straight-chain or branched-chain group containing from two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by a double bond. Examples of such groups include, but are not limited to, vinyl, 1 - propenyl, 2 - propenyl, and 1 - butenyl. Unless otherwise specified, the term "C 2-n alkenyl" should be understood to include, where possible, individual stereoisomers, including but not limited to (E) and (Z) isomers and mixtures thereof. Unless otherwise specified, when a C 2-n alkenyl group is substituted, it should be understood that the substitution occurs at any carbon atom that would bear a hydrogen atom such that the substitution will result in a chemically stable compound, such as would be recognized by one of ordinary skill in the art.

[0093] "Alkynyl" is a straight-chain or branched-chain hydrocarbon containing a primary, secondary, or tertiary carbon atom and having at least one unsaturated site (i.e., a carbon-carbon sp triple bond). For example, an alkynyl group can have from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), from 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), or from 2 to 6 carbon atoms (i.e., C 2-6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (C ＝ CH), propynyl (CH 2 C ＝ CH), etc.

[0094] As used herein, the term "C 2-n"alkynyl", where n is an integer, alone or in combination with another group, is intended to mean an unsaturated, acyclic straight-chain or branched-chain group containing from two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by a triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. Unless otherwise specified, when the C 2-n alkynyl group is substituted, it is to be understood that the substitution occurs at any carbon atom that would otherwise bear a hydrogen atom such that the substitution will result in a chemically stable compound, as recognized by those skilled in the art.

[0095] "cyano" or "nitrile" means the group -CN.

[0096] As used herein, the term "halo" or "halogen" means fluorine, chlorine, bromine, and iodine.

[0097] As used herein, the term "haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent. For example, C 1-6 haloalkyl is C 1-6 alkyl, wherein one or more hydrogen atoms have been replaced by a halo substituent. Such a range includes one halo substituent on the alkyl to complete the halogenation of the alkyl.

[0098] As used herein, the term "C 1-n haloalkyl", where n is an integer, alone or in combination with another group, is intended to mean an alkyl group having from 1 to n carbon atoms as defined above, wherein one or more hydrogen atoms are each replaced by a halo substituent. Examples of C 1-n haloalkyl include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl.

[0099] As used herein, the term "aryl" means a single aromatic ring or a bicyclic or polycyclic ring system. For example, an aryl group can have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. Aryl includes phenyl or an ortho-fused bicyclic or polycyclic group having about 9 to 14 atoms, wherein at least one ring is aromatic (e.g., an aryl fused to one or more aryl or carbocyclic rings). Such bicyclic or polycyclic rings can optionally be substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the bicyclic or polycyclic ring system. It should be understood that the point of attachment of the bicyclic or polycyclic group as defined above can be at any position of the ring, including the aryl or carbocyclic moiety of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0100] As used herein, the terms "heteroaryl", "heteroaryl ring" or "heteroaromatic ring" refer to a monocyclic aromatic or polyfused aromatic ring. The term includes monocyclic aromatic rings having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. The term also includes polyfused ring systems (e.g., ring systems containing 2 or 3 rings), wherein a heteroaryl group as defined above may be fused to one or more heteroaryl (e.g., naphthyridinyl), carbocyclic (e.g., 5,6,7,8-tetrahydroquinolinyl), or aryl (e.g., indazolyl) groups to form a polyfused ring. Such polyfused rings may optionally be substituted with one or more (e.g., 1, 2, or 3) oxo groups on the carbocyclic moiety of the fused ring. It is understood that the point of attachment of a heteroaryl polyfused ring as defined above may be at any position of the ring, including the heteroaryl, aryl, or carbocyclic moiety of the ring. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuryl, benzimidazolyl, and thianthrenyl.

[0101] As used herein, the terms "heterocyclic", "heterocycle" or "halocycloalkyl" refer to a monosaturated or partially unsaturated ring or polyfused ring. The term includes monosaturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and sulfur and nitrogen atoms may also be present in oxidized form. Such rings include, but are not limited to, azetidinyl, tetrahydrofuryl, or piperidinyl. The term also includes polyfused ring systems (e.g., ring systems containing 2 or 3 rings), wherein a heterocyclic group as defined above may be attached to two adjacent atoms (fused heterocycles) through one or more heterocycles (e.g., decahydronaphthyl), heteroaryls (e.g., 1,2,3,4-tetrahydronaphthyridinyl), carbocycles (e.g., decahydroquinolinyl), or aryls. It is understood that the point of attachment of a heterocyclic polyfused ring as defined above may be at any position of the ring, including the heterocyclic, heteroaryl, aryl, or carbocyclic moiety of the ring. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl.

[0102] As used herein, the term "ring" means a cycloalkyl or heterocyclic group. As used herein, the term ring includes, but is not limited to, spiro rings, bridged rings, and fused rings. The ring can be fully saturated or partially unsaturated.

[0103] As used herein, the terms "fused ring" and "fused" refer to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring structure as described herein that is attached to an existing ring structure in a compound disclosed herein via two adjacent atoms shared by the fused ring structure and the existing ring structure. For example, the bicyclic compounds depicted below incorporate 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:

[0104]

[0105] As used herein, the term "C 3-m cycloalkyl", where m is an integer, alone or in combination with another group, is intended to mean a cycloalkyl substituent containing from 3 to m carbon atoms and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term includes fully saturated as well as partially unsaturated rings.

[0106] It should be understood that when a variable is substituted, e.g., as described by the phrase "C 1-6 alkyl, alone or as part of a group, is optionally substituted", the phrase means that the variable C 1-6 alkyl can be substituted when alone and that the variable "C 1-6 alkyl" can also be substituted when part of a larger group. Similarly, when stated, other variables (e.g., C 2-6 alkynyl, aryl, heteroaryl, heterocycle, etc.) can also be "alone or as part of a group" substituted.

[0107] It should be understood that certain variables of formula I that connect two chemical groups can be oriented in either direction. Thus, for the X group of formula I (e.g., O, C(O), C(O)O, S, S(O), SO 2 , (C 1 -C 6 )alkylO-, (C 1 -C 6 )alkylC(O), (C 1 -C 6 )alkylC(O)O, (C 1 -C 6 )alkylS, (C 1 -C 6 )alkylS(O), and (C 1 -C 6 )alkylSO2 ) For certain X values that are asymmetric, they can be oriented in either direction. For example, relative to the groups to which it is attached, C(O)O can be oriented as C(O)O or OC(O).

[0108] The term "chiral" refers to a molecule having the property that its mirror image is non - superimposable, while the term "achiral" refers to a molecule that is superimposable on its mirror image.

[0109] The term "stereoisomer" refers to compounds having the same chemical composition but different arrangements of atoms or groups in space.

[0110] "Diastereomers" are stereoisomers that have two or more chiral centers or axes and whose molecules are not mirror images of each other. Diastereomers generally have different physical properties, such as melting point, boiling point, spectroscopic properties, and reactivity. A mixture of diastereomers can be separated by high - resolution analytical methods such as electrophoresis and chromatography.

[0111] "Enantiomers" are two stereoisomers of a compound that are non - superimposable mirror images of each other.

[0112] The term "treatment", to the extent it pertains to a disease or disorder, includes preventing the occurrence of a disease or disorder, inhibiting a disease or disorder, eliminating a disease or disorder, and / or alleviating one or more symptoms of a disease or disorder.

[0113] The term "treatment" with respect to treating a patient's disease state includes (i) inhibiting or ameliorating the patient's disease state, e.g., arresting or slowing its progression; or (ii) alleviating the patient's disease state, i.e., causing regression or cure of the disease state. In the case of HIV, treatment includes reducing the patient's HIV viral load level.

[0114] As used herein, the term "treatment" is intended to mean administering a compound or composition according to the present invention to alleviate or eliminate the symptoms of HIV infection and / or reduce the viral load of a patient. The term "treatment" also encompasses administering a compound or composition according to the present invention after an individual has been exposed to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood, to prevent the appearance of disease symptoms and / or prevent the virus from reaching a detectable level in the blood, and administering a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to infant by administering to the mother before delivery and to the infant in the first days of life.

[0115] "Protecting group" refers to a moiety of a compound that masks or modifies the properties of a functional group or the properties of the entire compound. Chemical protecting groups and strategies for protection / deprotection are well - known in the art. See, for example Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are generally used to mask the reactivity of certain functional groups to assist in the efficiency of the desired chemical reactions, such as the formation and cleavage of chemical bonds in an ordered and planned manner. The protection of functional groups in a compound alters other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties measurable by common analytical tools. Chemically protected intermediates can themselves be bioactive or inactive.

[0116] The protected compounds can also exhibit alterations in vitro and in vivo, and in some cases, optimized properties, such as passage through cell membranes and resistance to enzymatic degradation or chelation. In this role, a protected compound with an expected therapeutic effect can be referred to as a prodrug. Another function of the protecting group is to convert the parent drug into a prodrug, such that the parent drug is released upon prodrug conversion in vivo. Since the active prodrug may be absorbed more efficiently than the parent drug, the prodrug may have greater potency in vivo than the parent drug. In the case of a chemical intermediate, the protecting group is removed in vitro, and in the case of a prodrug, the protecting group is removed in vivo. For a chemical intermediate, it is not particularly important whether the resulting product after deprotection (e.g., an alcohol) is physiologically acceptable, but generally speaking, it is more desirable if these products are pharmacologically innocuous.

[0117] Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protecting group during synthetic procedures (i.e., the route or method for preparing the compounds of the present invention). In most cases, the decision regarding which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will depend on the chemistry of the reaction to be protected (e.g., acidic, basic, oxidation, reduction, or other conditions) and the expected synthetic direction. If a compound is substituted with multiple PGs, the PGs need not and generally are not the same. Typically, PGs will be used to protect functional groups such as carboxyl, hydroxyl, sulfhydryl, or amino groups, either to prevent side reactions or to otherwise enhance synthetic efficiency. The order of deprotection that yields the free deprotected group depends on the expected synthetic direction and the reaction conditions to be encountered and can occur in any order determined by one skilled in the art.

[0118] The various functional groups of the compounds of the present invention can be protected. For example, protecting groups for the -OH group (whether a hydroxyl, carboxylic acid, phosphate, or other functional group) include “ether or ester forming groups”. In the synthetic schemes described herein, ether or ester forming groups are capable of acting as chemical protecting groups. However, as will be understood by those skilled in the art, some hydroxyl and sulfhydryl protecting groups are not ether or ester forming groups and are included in amides, as described below.

[0119] Protective Groups in Organic Synthesis ,A very large number of hydroxyl protecting groups and amide-forming groups and the corresponding chemical cleavage reactions are described in Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See also Kocienski, Philip J.; P Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), the entire content of which is incorporated herein by reference. In particular, Chapter 1, Protecting Groups: An Overview, pages 1 to 20; Chapter 2, Hydroxyl Protecting Groups, pages 21 to 94; Chapter 3, Diol Protecting Groups, pages 95 to 117; Chapter 4, Carboxyl Protecting Groups, pages 118 to 154; Chapter 5, Carbonyl Protecting Groups, pages 155 to 184. For protecting groups for carboxylic acids, phosphonic acids, phosphonates, sulfonic acids and other protecting groups for acids, see Greene as described below.

[0120] As used herein, the term “protecting group” is intended to mean a protecting group that can be used during synthetic transformations, including but not limited to the examples listed in Greene, “Protective Groups in Organic Chemistry”, John Wiley & Sons, New York (1981) and its later editions.

[0121] The term “solvate” refers to a crystalline solid that contains a certain amount of solvent incorporated within the crystal structure. As used herein, the term “solvate” includes hydrates.

[0122] The term “unsolvated” refers to a crystalline solid in which no solvent molecules occupy specific crystal sites.

[0123] As used herein, the term “pharmaceutically acceptable” with respect to a substance means a substance that, within the scope of sound medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, and effective for its intended use when used in a pharmaceutical composition.

[0124] As used herein, the term "pharmaceutically acceptable salt" is intended to mean salts of the compounds according to the invention which, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, are generally water-soluble or oil-soluble or dispersible, and are effective for their intended uses. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A list of suitable salts can be found, for example, in S.M. Birge et al., J. Pharm. Sci., 1977, 66 , pp. 1-19.

[0125] As used herein, the term "pharmaceutically acceptable acid addition salt" is intended to mean those salts formed with inorganic acids and organic acids which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable, the inorganic acids including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, nitric acid, phosphoric acid, etc., and the organic acids including, but not limited to, acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfonic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.

[0126] As used herein, the term "pharmaceutically acceptable base addition salt" is intended to mean salts formed with inorganic bases that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable, which inorganic bases include, but are not limited to, ammonia or ammonium or metal cations (such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.) hydroxides, carbonates or bicarbonates. Particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, quaternary amine compounds, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, haamine, choline, betaine, ethylenediamine, glucosamine, N-methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-benzhydrylamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0127] As used herein, the term "antiviral agent" is intended to mean an agent that effectively inhibits the formation and / or replication of a virus in humans, including but not limited to agents that interfere with host or viral mechanisms necessary for the formation and / or replication of a virus in humans. The term "antiviral agent" includes, for example, HIV integrase catalytic site inhibitors selected from the group consisting of raltegravir ( Merck); elvitegravir (Gilead); soltegravir (GSK; ViiV); GSK 1265744 (GSK; ViiV) and dolutegravir; HIV nucleoside reverse transcriptase inhibitors selected from the group consisting of abacavir ( GSK); didanosine ( BMS); tenofovir ( Gilead); emtricitabine ( Gilead); lamivudine ( GSK / Shire); stavudine ( BMS); zidovudine ( GSK); alovudine (Achillion); and nelfinavir (Oncolys); HIV non-nucleoside reverse transcriptase inhibitors selected from the group consisting of nevirapine ( BI); efavirenz ( BMS); Etravirine ( J&J); Rilpivirine (TMC278, R278474; J&J); Phosphoditavirine (GSK / ViiV); and Lesinurad (Pfizer / ViiV); HIV protease inhibitors selected from the group consisting of: Atazanavir ( BMS); Darunavir ( J&J); Indinavir ( Merck); Lopinavir ( Abbott); Nelfinavir ( Pfizer); Saquinavir ( Hoffmann-LaRoche); Tipranavir ( BI); Ritonavir ( Abbott); and Fosamprenavir ( GSK / Vertex); HIV entry inhibitors selected from: Maraviroc ( Pfizer); Enfuvirtide ( Trimeris); and BMS-663068 (BMS); and HIV maturation inhibitors selected from: Bevirimat (Myriad Genetics).

[0128] As used herein, the term "antiviral agent" is intended to mean an agent that effectively inhibits the formation and / or replication of a virus in a mammal, including but not limited to an agent that interferes with a host or viral mechanism necessary for the formation and / or replication of a virus in a mammal.

[0129] As used herein, the term "HIV replication inhibitor" is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell (whether in vitro, ex vivo or in vivo).

[0130] Unless otherwise specified, the term "substituent" as used herein is intended to mean an atom, atomic group or group that can be bonded to a carbon atom, heteroatom or any other atom that can form part of a molecule or a fragment thereof, the carbon atom, heteroatom or any other atom originally being bonded to at least one hydrogen atom. Substituents contemplated in the context of a particular molecule or fragment thereof are those that result in a chemically stable compound, such as those recognized by those skilled in the art.

[0131] As used herein, the term "heteroatom" is intended to mean O, S or N.

[0132] The terms "O-C 1-n alkyl" or "C 1-n"Alkoxy", where n is an integer, alone or in combination with another group, is intended to mean an oxygen atom further bonded to an alkyl group having 1 to n carbon atoms as defined above. C 1-n Examples of alkoxy include, but are not limited to, methoxy (CH 3 O-), ethoxy (CH 3 CH 2 O-), propoxy (CH 3 CH 2 CH 2 O-), 1-methylethoxy (isopropoxy; (CH 3 ) 2 CHO) and 1,1-dimethylethoxy (tert-butoxy; (CH 3 ) 3 CO). When the C 1-n alkoxy is substituted, it is understood that the substitution is on its alkyl portion such that the substitution will result in a chemically stable compound, as recognized by those skilled in the art.

[0133] As used herein, the term "oxo group" is intended to mean an oxygen atom attached to a carbon atom as a substituent by a double bond (=O).

[0134] As used herein, the term "mammal" is intended to cover humans, as well as non-human mammals susceptible to HIV infection. Non-human mammals include, but are not limited to, domestic animals such as cattle, pigs, horses, dogs, cats, rabbits, rats, and mice, and non-domestic animals.

[0135] The embodiments disclosed herein are also intended to cover all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by having one or more atoms replaced by atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125I. In certain embodiments, these radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or mode of action or the binding affinity for a pharmacologically important site of action. Certain isotopically labeled compounds of Formula I, such as those incorporating a radioactive isotope, can be used in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly suitable for this purpose because they are readily incorporated and the means of detection are convenient.

[0136] In certain embodiments, replacement with a heavier isotope such as deuterium (i.e., 2 H) may provide certain therapeutic advantages due to higher metabolic stability. For example, the in vivo half-life may be increased or the dose requirement may be reduced. Thus, in some cases, a heavier isotope may be preferred.

[0137] Replacement with a positron-emitting isotope such as 11 C, 18 F, 15 O, and 13 N can be used for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by techniques known to those skilled in the art or by methods similar to those described in the examples set forth below, using an appropriate isotopically labeled reagent in place of the previously employed non-labeled reagent.

[0138] The methods, compositions, kits, and articles provided herein use or include a compound (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, wherein 1 to n hydrogen atoms attached to a carbon atom can be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds increase resistance to metabolism and can thus be used to increase the half-life of a compound or a pharmaceutically acceptable salt thereof when administered to a mammal. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0139] The embodiments disclosed herein also intend to cover the in vivo metabolites of the disclosed compounds. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by a process comprising administering to a mammal a compound according to the embodiments disclosed herein for a period sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound according to the embodiments disclosed herein to an animal (such as a rat, mouse, guinea pig, monkey, or human) at a detectable dose and allowing sufficient time for metabolism to occur and isolating the conversion products from urine, blood, or other biological samples.

[0140] The compounds disclosed herein or their pharmaceutically acceptable salts may contain one or more asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- according to absolute stereochemistry or as (D)- or (L)- for amino acids. This disclosure intends to include all such possible isomers as well as their racemic, non-racemic, and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or can be resolved using methods such as chromatography and fractional crystallization. Techniques for preparing / separating the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric centers, and unless otherwise specified, the compounds are intended to include the E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[0141] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl may or may not be substituted, and the description includes both substituted heterocyclyl and unsubstituted heterocyclyl.

[0142] II. Compounds

[0143] In some embodiments, the present disclosure provides a compound of formula I:

[0144]

[0145] or a pharmaceutically acceptable salt thereof, wherein:

[0146] R 1 is H, C 6-10An aryl or a 5- to 10-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S,

[0147] wherein C 6-10 The aryl or 5- to 10-membered heteroaryl is optionally substituted by one, two, three or four R A1 substituents, where each R A1 is independently a halogen, C 1-6 alkyl, C 1-4 haloalkyl, cyano, –O–C 1-4 alkyl or C 1-4 alkyl–O–C 1-4 alkyl;

[0148] R 2 is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0149] L is –CR 3a R 3b –, –C(O)–, –SO 2 –, –CH 2 –CH 2 – or –N(R a )–;

[0150] W 1 is a bond or –CR 4a R 4b –;

[0151] 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 R5b –OC(O)–, -CR 5a R 5b –C(O)NH– or –CR 5a R 5b –NHC(O)–;

[0152] Y is –C(O)NH–,

[0153] is a three- to seven-membered spiro ring containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein the spiro ring is optionally substituted by one, two, three or four R 8 groups;

[0154] Z is –CR 9a R 9b –, –CR 9a R 9b CR 9c R 9d – or –CR 10a =CR 10b –;

[0155] R 3a and R 3b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or –O–C 1-4 alkyl; or

[0156] R 3a and R 3b together with the carbon atom to which they are attached form a 3- to 7-membered spiro ring containing 0, 1 or 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by one, two or three R A2 substituents, wherein each R A2 is independently a halogen group, C 1-4 alkyl or C 1-4 haloalkyl;

[0157] R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or a halogen group;

[0158] R 5a , R 5b , R 5c and R 5d are independently H, C 1-6 alkyl, C 1-4 haloalkyl, a halogen group, a hydroxyl group, a cyano group, –O–C 1-4 alkyl or C 1-4Alkylene–O–C 1-4 alkyl; or

[0159] R 5a and R 5b or R 5c and R 5d together with the carbon atom to which they are attached form a 3- to 7-membered spiro ring containing 0, 1 or 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by one, two or three R A3 substituents, wherein each R A3 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl; or

[0160] R 5a and R 5c or R 5b and R 5d together with the respective carbon atom to which they are attached form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by one to three R A3 substituents, wherein each R A3 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl;

[0161] each R 6a and R 6b is independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl; or

[0162] R 6a and R 6b together with the respective carbon atom to which they are attached form a 5- to 10-membered partially unsaturated 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 or 2 heteroatoms selected from N, O and S, wherein the partially unsaturated fused ring, fused aromatic ring or fused heteroaromatic ring is optionally substituted by one, two, three or four R A4 substituents, wherein each R A4 is independently halo or C 1-4 alkyl;

[0163] R 7 is H, C 1-6 alkyl, C 1-4 haloalkyl, C(O)R c or SO 2 R c ;

[0164] each R 8 is independently selected from the group consisting of:

[0165] (i) Halo group,

[0166] (ii) C 1-6 alkyl group, optionally substituted by OH, C 1-6 alkoxy group, C 6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, where the C 6-10 aryl group or 5- to 10-membered heteroaryl group is optionally substituted by 1 to 4 substituents independently selected from C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group, halo group, CN, C 1 -C 3 haloalkyl group, C 3 -C 7 cycloalkyl group and a 3- to 7-membered halocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S,

[0167] (iii) C 1-6 haloalkyl group, optionally substituted by OH, C 1-6 alkoxy group, C 6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0168] where the C 6-10 aryl group or 5- to 10-membered heteroaryl group is optionally substituted by 1 to 4 substituents selected from C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group, halo group, CN, C 1 -C 3 haloalkyl group, C 3 -C 7 cycloalkyl group and a 3- to 7-membered halocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S,

[0169] (iv) CN,

[0170] (v) Oxo group,

[0171] (vi) -X-R A5

[0172] where X is O or S; and R A5 is H, C 1-6 alkyl group or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0173] where C 1 -C6 The alkyl group or a 3- to 7-membered ring is optionally substituted with 1, 2 or 3 groups independently selected from CN, halogen, C 1 -C 6 alkoxy, C 6-10 aryl, and a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0174] (vii) NHR A6 ,

[0175] wherein R A6 is C 1 -C 6 alkyl;

[0176] (viii) NR A7 R A8 ,

[0177] wherein R A7 is C 1 -C 6 alkyl;

[0178] and R A8 is C 1 -C 6 alkyl,

[0179] (ix) C 6-10 aryl, which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halogen, CN, C 3-7 cycloalkyl and C 1-6 alkoxy;

[0180] wherein C 3-7 cycloalkyl is optionally substituted with 1, 2, 3 or 4 independent halogen groups,

[0181] (x) A 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S,

[0182] wherein the 3- to 7-membered ring is optionally substituted with one, two or three substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, and

[0183] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0184] wherein the 5- to 10-membered heteroaryl ring is optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 substituted by substituents of cycloalkyl,

[0185] (xii) - SO 2 R A13 ,

[0186] R A13 is C 1 -C 6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S;

[0187] wherein the C 1-6 alkyl or 3- to 7-membered ring is optionally substituted by 1, 2 or 3 groups independently selected from CN, halo and C 1 -C 6 alkoxy groups,

[0188] (xiii) - SO(NR A14 ) 2 ,

[0189] each R A14 is independently H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S;

[0190] wherein the C 1-6 alkyl or 3- to 7-membered ring is optionally substituted by 1, 2 or 3 groups independently selected from CN, halo and C 1 -C 6 alkoxy groups,

[0191] (xiv) C 2-6 alkynyl, which is optionally substituted by one, two, three or four substituents independently selected from C 1-6 alkoxy, OH, - SO 2 -(C 1-3 alkyl), or

[0192] two R 8 groups are joined to form a fused, spiro or bridged 3- to 7-membered ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S;

[0193] wherein the 3- to 7-membered ring is optionally substituted by one, two or three substituents independently selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl; or

[0194] two R on adjacent carbon atoms8 The groups are linked to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S,

[0195] wherein the fused 6- to 10-membered aromatic ring is optionally substituted by one, two or three substituents independently selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl;

[0196] substituted;

[0197] R 9a 、R 9b 、R 9c and R 9d are each independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo; or

[0198] R 9a and R 9b or R 9c and R 9d together with the carbon atom to which they are attached form a 3- to 7-membered spiro ring containing 0, 1 or 2 heteroatoms selected from N, O and S, wherein the spiro ring is optionally substituted by one, two or three R A9 substituents, wherein each R A9 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl; or

[0199] R 9a and R 9c or R 9b and R 9d together with the respective carbon atom to which they are attached form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O and S, wherein the fused ring is optionally substituted by one, two or three R A10 substituents, wherein each R A10 is independently halo, C 1-4 alkyl or C 1-4 haloalkyl; or

[0200] R 9a 、R 9b 、R 9c and R 9d and one of R 4a 、R 4b 、R 5a 、R 5b and R 7One of them, together with the attached atom, forms a 3- to 7-membered fused ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, where the fused ring is optionally substituted by one, two, three, or four R A11 substituents, where each R A11 is independently a halogen or C 1-4 alkyl;

[0201] R 10a and R 10b are independently H, halogen, C 1-4 haloalkyl, or C 1-6 alkyl; or

[0202] R 10a and R 10b together with the attached carbon atoms form a 5- to 10-membered partially unsaturated 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 or 2 heteroatoms selected from N, O, and S, where the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally substituted by one to four R A12 substituents, where each R A12 is independently a halogen or C 1-4 alkyl;

[0203] R a is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R c or SO 2 R c ;

[0204] R b is H or C 1-4 alkyl;

[0205] R c is C 1-4 alkyl or C 1-4 alkoxy; and

[0206] each n is independently 0, 1, or 2.

[0207] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is substituted by one, two, three, or four R 8 groups; and at least one R 8 group is selected from the group consisting of:

[0208] (i) C 1-6 alkyl, which is substituted by OH, C 1-6 alkoxy, C 6-10substituted by an aryl or a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S

[0209] wherein C 6-10 the aryl or 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, CN, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl and a 3- to 7-membered halocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S

[0210] (ii) C 1-6 haloalkyl, which is substituted by OH, C 1-6 alkoxy, C 6-10 aryl or a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S

[0211] wherein C 6-10 the aryl or 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 substituents selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, CN, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl and a 3- to 7-membered halocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S

[0212] (iii) CN

[0213] (iv) oxo group

[0214] (v) -X-R A5

[0215] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S

[0216] wherein C 1 -C 6 alkyl or 3- to 7-membered ring is optionally substituted by 1, 2 or 3 groups independently selected from CN, halogen, C 1 -C 6 alkoxy, C 6-10Aryl and 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0217] (vi) NHR A6 ,

[0218] wherein R A6 is C 1 -C 6 alkyl;

[0219] (vii) NR A7 R A8 ,

[0220] wherein R A7 is C 1 -C 6 alkyl and R A8 is C 1 -C 6 alkyl;

[0221] (viii) C 6-10 aryl, which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, C 3-7 cycloalkyl and C 1-6 alkoxy; wherein C 3-7 cycloalkyl is optionally substituted by 1, 2, 3 or 4 independent halogen groups,

[0222] (ix) A 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S,

[0223] wherein the 3- to 7-membered ring is optionally substituted by one, two or three substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, and

[0224] (x) A 5- to 10-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0225] wherein the 5- to 10-membered heteroaryl ring is optionally substituted by one, two or three substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl,

[0226] (xi) -SO 2 R A13 ,

[0227] R A13 is C 1 -C 6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S;

[0228] wherein the C 1-6 alkyl or 3- to 7-membered ring is optionally substituted by 1, 2 or 3 groups independently selected from CN, halo and C 1 -C 6 alkoxy;

[0229] (xii)-SO(NR A14 ) 2 ,

[0230] each R A14 is independently H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S;

[0231] wherein the C 1-6 alkyl or 3- to 7-membered ring is optionally substituted by 1, 2 or 3 groups independently selected from CN, halo and C 1 -C 6 alkoxy;

[0232] (xiii)C 2-6 alkynyl, which is optionally substituted by one, two, three or four substituents independently selected from C 1-6 alkoxy, OH, -SO 2 -(C 1-3 alkyl), or

[0233] two R 8 groups are joined to form a fused, spiro or bridged 3- to 7-membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0234] wherein the 3- to 7-membered ring is optionally substituted by one, two or three substituents independently selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl; or

[0235] two R 8 groups on adjacent carbon atoms are joined to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0236] wherein the fused 6- to 10-membered aromatic ring is optionally substituted by one, two or three substituents independently selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C1-6 substituted by an alkoxy group and a C 3-7 substituent of a cycloalkyl group.

[0237] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a six-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S; wherein the spiro ring is optionally substituted by one, two, three, or four R 8 groups. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a six-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S; wherein the spiro ring is optionally substituted by one, two, or three R 8 groups. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a six-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S; wherein the spiro ring is optionally substituted by one or two R 8 groups.

[0238] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a six-membered spiro ring containing 1 or 2 heteroatoms selected from N and O; wherein the spiro ring is optionally substituted by one, two, three, or four R 8 groups. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a six-membered spiro ring containing 1 or 2 heteroatoms selected from N and O; wherein the spiro ring is optionally substituted by one, two, or three R 8 groups. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a six-membered spiro ring containing 1 or 2 heteroatoms selected from N and O; wherein the spiro ring is optionally substituted by one or two R 8 groups.

[0239] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a five-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S; wherein the spiro ring is optionally substituted by one, two, three, or four R 8 groups. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a five-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S; wherein the spiro ring is optionally substituted by one, two, or three R 8 groups. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is a five-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S; wherein the spiro ring is optionally substituted by one or two R 8 groups.

[0240] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a five-membered spiro ring containing 1 or 2 heteroatoms selected from N and O; wherein the spiro ring is optionally substituted with one, two, three or four R 8 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a five-membered spiro ring containing 1 or 2 heteroatoms selected from N and O; wherein the spiro ring is optionally substituted with one, two or three R 8 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a five-membered spiro ring containing 1 or 2 heteroatoms selected from N and O; wherein the spiro ring is optionally substituted with one or two R 8 groups.

[0241] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a four-membered spiro ring containing 1 or 2 heteroatoms selected from N, O and S; wherein the spiro ring is optionally substituted with one, two, three or four R 8 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a four-membered spiro ring containing 1 or 2 heteroatoms selected from N, O and S; wherein the spiro ring is optionally substituted with one, two or three R 8 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a four-membered spiro ring containing 1 or 2 heteroatoms selected from N, O and S; wherein the spiro ring is optionally substituted with one or two R 8 groups.

[0242] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a four-membered spiro ring containing 1 or 2 heteroatoms selected from N and S; wherein the spiro ring is optionally substituted with one, two, three or four R 8 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a four-membered spiro ring containing 1 or 2 heteroatoms selected from N and S, wherein the spiro ring is optionally substituted with one, two or three R 8 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is a four-membered spiro ring containing 1 or 2 heteroatoms selected from N and S; wherein the spiro ring is optionally substituted with one or two R 8 groups.

[0243] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, Selected from the group consisting of: where * indicates the attachment point to the remainder of Formula I; R d is H, C 1-4 alkyl or C 1-4 haloalkyl; and m is 0, 1, 2, 3 or 4.

[0244] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, selected from the group consisting of: where * indicates the attachment point to the remainder of Formula I; R d is H, C 1-4 alkyl or C 1-4 haloalkyl; and m is 0, 1, 2, 3 or 4.

[0245] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, selected from the group consisting of: In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, is

[0246] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, Selected from the group consisting of:

[0247] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2 or 3. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2 or 3. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2, 3 or 4. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2 or 3. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2 or 3. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2 or 3.

[0248] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula I-A:

[0249]

[0250] I-A; wherein m is 0, 1, 2 or 3.

[0251] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula I-B:

[0252]

[0253] I-B; wherein m is 0, 1, 2 or 3.

[0254] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula I-C:

[0255]

[0256] wherein R d is H, C 1-4 alkyl or C 1-4 haloalkyl; and m is 0, 1, 2 or 3.

[0257] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula I-D:

[0258]

[0259] wherein R d is H, C 1-4 alkyl or C 1-4 haloalkyl; and m is 0, 1, 2 or 3.

[0260] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula I-E:

[0261]

[0262] wherein R d is H, C 1-4 alkyl or C 1-4 haloalkyl; and m is 0, 1, 2 or 3.

[0263] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula I-F:

[0264]

[0265] wherein m is 0, 1, 2, 3 or 4.

[0266] In some embodiments of the compound of formula I, I-A, I-B, I-C, I-D, I-E or I-F or a pharmaceutically acceptable salt thereof, R 2 is H or C 1-6 alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-6 alkyl. In some embodiments, R 2 is C 1-3 alkyl. In some embodiments, R 2 is C 1-4 haloalkyl.

[0267] In some embodiments of the compound of formula I, I-A, I-B, I-C, I-D, I-E or I-F or a pharmaceutically acceptable salt thereof, Y is selected from the group consisting of: –C(O)NH–, and In some embodiments, Y is –C(O)NH–. In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is

[0268] In some embodiments of a compound of formula I, I-A, I-B, I-C, I-D, I-E or I-F or a pharmaceutically acceptable salt thereof, Y is –C(O)NH– and R 2 is H or C 1-6 alkyl.

[0269] In some embodiments of a compound of formula I or I-A or a pharmaceutically acceptable salt thereof, the compound has formula II-A:

[0270]

[0271] wherein m is 0, 1, 2 or 3.

[0272] In some embodiments of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F or II-A or a pharmaceutically acceptable salt thereof, R 1 is phenyl optionally substituted with one, two, three or four R A1 wherein each R A1 is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, cyano, –O–C 1-4 alkyl or C 1-4 alkyl–O–C 1-4 alkyl. In some embodiments, R 1 is phenyl optionally substituted with one, two, three or four R A1 wherein each R A1 is independently halo, C 1-4 alkyl, C 1-4 haloalkyl or –O–C 1-4 alkyl. In some embodiments, R 1 is phenyl substituted with one, two, three or four R A1A substituted phenyl, wherein each R A1 is independently a halogen group or –O–C 1-4 alkyl. In some embodiments, R 1 is a phenyl substituted with one, two, three or four halogens. In some embodiments, R 1 is a phenyl substituted with two or three halogens selected from chlorine and fluorine. In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is

[0273] In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is

[0274] In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is

[0275] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F or II-A or their pharmaceutically acceptable salts, R 1 is a pyridyl optionally substituted with one, two, three or four R A1 groups, wherein each R A1 is independently a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, cyano, –O–C 1-4 alkyl or C 1-4 alkyl–O–C 1-4 alkyl. In some embodiments, R 1is a pyridyl group optionally substituted by one, two, three or four R A1 , wherein each R A1 is independently a halogen group, C 1-4 alkyl, C 1-4 haloalkyl or –O–C 1-4 alkyl. In some embodiments, R 1 is a pyridyl group substituted by one, two, three or four R A1 , wherein each R A1 is independently a halogen group or –O–C 1-4 alkyl. In some embodiments, R 1 is a pyridyl group substituted by one, two, three or four halogen atoms. In some embodiments, R 1 is a pyridyl group substituted by two or three halogen atoms selected from chlorine and fluorine. In some embodiments, R 1 is

[0276] In some embodiments of the compound of formula I, I-A or II-A or a pharmaceutically acceptable salt thereof, the compound has formula II-Aa or II-Ab:

[0277]

[0278] wherein m is 0, 1, 2 or 3.

[0279] In some embodiments of the compound of formula I, I-A or II-A or a pharmaceutically acceptable salt thereof, the compound has formula II-Aa. In some embodiments of the compound of formula I, I-A or II-A or a pharmaceutically acceptable salt thereof, the compound has formula II-Ab.

[0280] In some embodiments of the compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa or II-Ab or a pharmaceutically acceptable salt thereof, L is –CR 3a R 3b –; wherein R 3a and R 3b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or –O–C 1-4 alkyl. In some embodiments, L is –CR 3a R 3b –; wherein R 3a and R 3b are independently H, C 1-6 alkyl or C 1-4 haloalkyl. In some embodiments, L is –CR 3a R 3b–; wherein R 3a and R 3b are independently H or C 1-6 alkyl. In some embodiments, L is –CR 3a R 3b –; wherein R 3a and R 3b are both H. In some embodiments, L is –C(O)–. In some embodiments, L is –SO 2 –. In some embodiments, L is –CH 2 –CH 2 –. In some embodiments, L is or –N(R a )–. In some embodiments, L is NH.

[0281] In some embodiments of the compounds of Formula I, I-A, II-A, II-Aa or II-Ab, the compound has Formula III:

[0282]

[0283] wherein m is 0, 1, 2 or 3.

[0284] In some embodiments of the compounds of Formula I, I-A, II-A, II-Aa, II-Ab or III, the compound has Formula IIIa or IIIb:

[0285]

[0286] wherein m is 0, 1, 2 or 3.

[0287] In some embodiments of the compounds of Formula I, I-A, II-A, II-Aa or III, the compound has Formula IIIa. In some embodiments of the compounds of Formula I, I-A, II-A, II-Ab or III, the compound has Formula IIIb.

[0288] In some embodiments of the compounds of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, II-Aa, II-Ab, III, IIIa or IIIb or a pharmaceutically acceptable salt thereof, W 1 is a bond or –CR 4a R 4b –; wherein R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, W 1 is a bond or –CR 4a R 4b –; wherein R4a and R 4b are independently H, C 1-6 alkyl or halo. In some embodiments, W 1 is a bond or –CR 4a R 4b –; where R 4a and R 4b are independently H, –CH 3 or halo. In some embodiments, W 1 is a bond or –CR 4a H–; where R 4a is H, C 1-6 alkyl or halo. In some embodiments, W 1 is a bond, –CH 2 – or –CH(F)–.

[0289] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, IIAa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond or –CR 4a R 4b –; where R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond or –CR 4a R 4b –; where R 4a and R 4b are independently H, C 1-6 alkyl or halo. In some embodiments, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond or –CR 4a R 4b –; where R 4a and R 4b are independently H, –CH 3 or halo. In some embodiments, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond or –CR 4a H–; where R4a is H, C 1-6 alkyl or halo. In some embodiments, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond, –CH 2 – or –CH(F)–.

[0290] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, II-Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl or C 1-4 haloalkyl. In some embodiments, Z is –CH(CH 3 )– or –CH(CH 2 F)-.

[0291] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; W 1 is a bond or –CR 4a R 4b –; wherein R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo; and Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; W 1 is a bond or –CR4a R 4b –; wherein R 4a and R 4b are each independently H, C 1-6 alkyl or halo; and Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl or C 1-4 haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; W 1 is a bond or –CR 4a R 4b –; wherein R 4a and R 4b are each independently H, –CH 3 or halo; and Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl or C 1-4 haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond or –CR 4a H–; wherein R 4a is H, C 1-6 alkyl or halo; and Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl or C 1-4 haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; W 1 is a bond, –CH 2 – or –CH(F)–; and Z is –CH(CH 3 )– or –CH(CH 2 F)-.

[0292] In some embodiments of the compounds of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, W 2 is –CR 5a R5b – or –CR 6a =CR 6b –; wherein R 5a and R 5b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxy, cyano, -O-C 1-4 alkyl or C 1-4 alkylene-O-C 1-4 alkyl; and R 6a and R 6b are independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl. In some embodiments, W 2 is –CR 5a R 5b – or –CR 6a =CR 6b –; wherein R 5a and R 5b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo or –O–C 1-4 alkyl; and R 6a and R 6b are independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl. In some embodiments, W 2 is –CR 5a R 5b – or –CR 6a =CR 6b –; wherein R 5a and R 5b are independently H, C 1-6 alkyl or halo; and R 6a and R 6b are independently H, halo or C 1-6 alkyl. In some embodiments, W 2 is –CH 2 – or -CH=CH-. In some embodiments, W 2 is –CH 2 –. In some embodiments, W 2 is -CH=CH-.

[0293] In some embodiments of the compounds of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6Alkyl; W 1 is a bond or –CR 4a R 4b –; wherein R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo; Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo; and W 2 is –CR 5a R 5b – or –CR 6a =CR 6b –; wherein R 5a and R 5b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxy, cyano, -O-C 1-4 alkyl or C 1-4 alkylene-O-C 1-4 alkyl; and R 6a and R 6b are independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl.

[0294] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; W 1 is a bond or –CR 4a R 4b –; wherein R 4a and R 4b are independently H, C 1-6 alkyl or halo; Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl or C 1-4 haloalkyl; and W 2 is –CR 5a R 5b – or –CR 6a =CR 6b –; wherein R5a and R 5b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo or –O–C 1-4 alkyl; and R 6a and R 6b are independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl.

[0295] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; W 1 is a bond or –CR 4a R 4b –; wherein R 4a and R 4b are independently H, –CH 3 or halo; Z is –CR 9a R 9b –; wherein R 9a and R 9b are each independently H, C 1-6 alkyl or C 1-4 haloalkyl; and W 2 is –CR 5a R 5b – or –CR 6a =CR 6b –; wherein R 5a and R 5b are independently H, C 1-6 alkyl or halo; and R 6a and R 6b are independently H, halo or C 1-6 alkyl.

[0296] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond or –CR 4a H–; wherein R 4a is H, C 1-6 alkyl or halo; Z is –CR 9a R 9b –; wherein R9a and R 9b each independently is H, C 1-6 alkyl or C 1-4 haloalkyl; and W 2 is –CH 2 – or -CH=CH-.

[0297] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond or –CR 4a H–; wherein R 4a is H, C 1-6 alkyl or halo; Z is –CR 9a R 9b –; wherein R 9a and R 9b each independently is H, C 1-6 alkyl or C 1-4 haloalkyl; and W 2 is –CH 2 –.

[0298] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; and W 1 is a bond or –CR 4a H–; wherein R 4a is H, C 1-6 alkyl or halo; Z is –CR 9a R 9b –; wherein R 9a and R 9b each independently is H, C 1-6 alkyl or C 1-4 haloalkyl; and W 2 is -CH=CH-.

[0299] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6Alkyl; W 1 is a bond, –CH 2 – or –CH(F)–; Z is –CH(CH 3 )– or –CH(CH 2 F)-; and W 2 is –CH 2 – or -CH=CH-.

[0300] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E or I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; W 1 is a bond, –CH 2 – or –CH(F)–; Z is –CH(CH 3 )– or –CH(CH 2 F)-; and W 2 is –CH 2 –.

[0301] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E or I-F, II-II-A, Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, Y is –C(O)NH–; R 2 is H or C 1-6 alkyl; W 1 is a bond, –CH 2 – or –CH(F)–; Z is –CH(CH 3 )– or –CH(CH 2 F)-; and W 2 is -CH=CH-.

[0302] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa or IIIb or their pharmaceutically acceptable salts, the compound has the formula IV:

[0303]

[0304] wherein m is 0, 1, 2 or 3.

[0305] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, III, IIIa or IV or their pharmaceutically acceptable salts, the compound has the formula IVa:

[0306]

[0307] where m is 0, 1, 2, or 3.

[0308] In some embodiments of a compound of Formula I, I-A, II-A, II-Ab, III, IIIb, or IV, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IVb:

[0309]

[0310] where m is 0, 1, 2, or 3.

[0311] In some embodiments of a compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, R 4a is H, C 1-6 alkyl, or C 1-4 haloalkyl.

[0312] In some embodiments of a compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, R 5a is H, a halogen, C 1-4 haloalkyl, or C 1-6 alkyl.

[0313] In some embodiments of a compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, R 4a is H, C 1-6 alkyl, or C 1-4 haloalkyl; and R 5a is H, a halogen, C 1-4 haloalkyl, or C 1-6 alkyl.

[0314] In some embodiments of a compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl, or a halogen. In some embodiments, R 9a is C 1-6 alkyl, C 1-4 haloalkyl, or a halogen. In some embodiments, R 9a is C 1-6 alkyl, or C 1-4 haloalkyl. In some embodiments, R9a is -CH 3 or -CH 2 F.

[0315] In some embodiments of the compounds of formula I, I - A, II - A, II - Aa, II - Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts, R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl or C 1-4 haloalkyl. In some embodiments, R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is -CH 3 or -CH 2 F.

[0316] In some embodiments of the compounds of formula I, I - A, I - B, I - C, I - D, I - E, I - F, II - A, II - Aa, II - Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts, each R 8 is independently:

[0317] (i) halo,

[0318] (ii) C 1-6 alkyl, optionally substituted by OH, C 1-6 alkoxy, C 6-10 aryl or 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0319] (iii) C 1-6 haloalkyl,

[0320] (iv) CN,

[0321] (v) oxo group,

[0322] (vi) -X-R A5

[0323] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0324] wherein C 1 -C 6 alkyl or the 3- to 7-membered ring is optionally substituted by 1, 2 or 3 groups independently selected from CN, halo, C 1 -C 6 alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0325] (vii) NHR A6 ,

[0326] wherein R A6 is C 1 -C 6 alkyl;

[0327] (viii) NR A7 R A8 ,

[0328] wherein R A7 is C 1 -C 6 alkyl;

[0329] and R A8 is C 1 -C 6 alkyl,

[0330] (ix) C 6-10 aryl, optionally substituted by 1, 2, 3 or 4 groups independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, C3-7 substituted by a cycloalkyl group and a C 1-6 alkoxy substituent;

[0331] wherein the C 3-7 cycloalkyl group is optionally substituted by 1, 2, 3 or 4 independent halogen groups,

[0332] (x) a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S,

[0333] wherein the 3- to 7-membered ring is optionally substituted by one, two or three substituents independently selected from a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, or

[0334] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or

[0335] wherein the 5- to 10-membered heteroaryl ring is optionally substituted by one, two or three substituents independently selected from a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, or

[0336] two R 8 groups are linked to form a fused, spiro or bridged 3- to 7-membered ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0337] wherein the 3- to 7-membered ring is optionally substituted by one, two or three substituents independently selected from a halogen group, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl; or

[0338] two R 8 groups on adjacent carbon atoms are linked to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S,

[0339] wherein the fused 6- to 10-membered aromatic ring is optionally substituted by one, two or three substituents independently selected from a halogen group, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-7 cycloalkyl.

[0340] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or pharmaceutically acceptable salts thereof, each R 8 is independently:

[0341] (i) halo;

[0342] (ii) C 1-6 alkyl, optionally substituted with OH, C 1-6 alkoxy, C 6-10 aryl or a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0343] (iii) C 1-6 haloalkyl;

[0344] (iv) CN;

[0345] (v) oxo;

[0346] (vi) -X-R A5

[0347] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0348] wherein C 1 -C 6 alkyl or the 3- to 7-membered ring is optionally substituted with 1, 2 or 3 groups independently selected from CN, halo, C 1 -C 6 alkoxy, C 6-10 aryl and a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S

[0349] (vii) NHR A6 ,

[0350] wherein R A6 is C 1 -C 6 alkyl;

[0351] (viii) NR A7 R A8 ,

[0352] wherein R A7 is C 1 -C 6 alkyl;

[0353] and RA8 is C 1 -C 6 alkyl,

[0354] (ix) C 6-10 aryl,

[0355] (x) a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S, or

[0356] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or

[0357] two R 8 groups are linked to form a fused, spiro or bridged 3- to 7-membered ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0358] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts, each R 8 is independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH 2 Ph, CH 2 OH, CH 2 OMe, NHMe, NMe 2 , OH, OMe, OCH 2 CF 3 , OCH 2 CHF 2 , OCH 2 CH 2 OMe, SMe, CHF 2 , CH 2 CF 3 , (CH 2 ) 4 Cl, CH 2 F, CH 2 CH 2 F, CH(CH 3 )F, CF 2 CH 3 , CF 3 ,

[0359] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts, each R8 Independently Cl, F, Br, oxo group, CN, methyl, ethyl, propyl, CH 2 Ph, CH 2 OH, CH 2 OMe, NHMe, NMe 2 , OH, OMe, OCH 2 CF 3 , OCH 2 CHF 2 , OCH 2 CH 2 OMe, SMe, CH 2 F, CHF 2 , CH 2 CF 3 , (CH 2 ) 4 Cl,

[0360] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts,

[0361] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0362] R 5a is H, halo group, C 1-4 haloalkyl or C 1-6 alkyl;

[0363] R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl or halo group; and

[0364] each R 8 is independently

[0365] (i) halo group,

[0366] (ii) C 1-6 alkyl, optionally substituted by OH, C 1-6 alkoxy, C 6-10 aryl or a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0367] (iii) C 1-6 haloalkyl,

[0368] (iv) CN,

[0369] (v) an oxo group,

[0370] (vi) -X-R A5

[0371] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0372] wherein the C 1 -C 6 alkyl or the 3- to 7-membered ring is optionally substituted with 1, 2 or 3 groups independently selected from CN, halo, C 1 -C 6 alkoxy, C 6-10 aryl and a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S

[0373] (vii) NHR A6 ,

[0374] wherein R A6 is C 1 -C 6 alkyl;

[0375] (viii) NR A7 R A8 ,

[0376] wherein R A7 is C 1 -C 6 alkyl;

[0377] and R A8 is C 1 -C 6 alkyl,

[0378] (ix) C 6-10 aryl,

[0379] (x) a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S, or

[0380] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or

[0381] two R 8 groups are linked to form a fused, spiro or bridged 3- to 7-membered ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0382] In some embodiments of a compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or a pharmaceutically acceptable salt thereof,

[0383] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0384] R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl;

[0385] R 9a is C 1-6 alkyl, C 1-4 haloalkyl or halo; and

[0386] each R 8 is independently

[0387] (i) halo,

[0388] (ii) C 1-6 alkyl, optionally substituted with OH, C 1-6 alkoxy, C 6-10 aryl or a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0389] (iii) C 1-6 haloalkyl,

[0390] (iv) CN,

[0391] (v) oxo,

[0392] (vi) -X-R A5

[0393] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0394] wherein C 1 -C 6 alkyl or the 3- to 7-membered ring is optionally substituted with 1, 2 or 3 groups independently selected from CN, halo, C 1 -C 6 alkoxy, C 6-10 aryl and a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S

[0395] (vii) NHR A6 ,

[0396] wherein R A6 is C 1 -C 6 alkyl;

[0397] (viii) NR A7 R A8 ,

[0398] wherein R A7 is C 1 -C 6 alkyl;

[0399] and R A8 is C 1 -C 6 alkyl,

[0400] (ix) C 6-10 aryl,

[0401] (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or

[0402] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0403] two R 8 groups are linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0404] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or their pharmaceutically acceptable salts,

[0405] R 4a is H, C 1-6 alkyl, or C 1-4 haloalkyl;

[0406] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl;

[0407] R 9a is C 1-6 alkyl, or C 1-4 haloalkyl, and

[0408] each R 8 is independently

[0409] (i) halo,

[0410] (ii) C 1-6an alkyl group, which is optionally substituted by OH, C 1-6 alkoxy, C 6-10 aryl or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0411] (iii) C 1-6 haloalkyl,

[0412] (iv) CN,

[0413] (v) an oxo group,

[0414] (vi) -X-R A5

[0415] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0416] wherein C 1 -C 6 alkyl or the 3- to 7-membered ring is optionally substituted by 1, 2 or 3 groups independently selected from CN, halogen, C 1 -C 6 alkoxy, C 6-10 aryl and a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S

[0417] (vii) NHR A6 ,

[0418] wherein R A6 is C 1 -C 6 alkyl;

[0419] (viii) NR A7 R A8 ,

[0420] wherein R A7 is C 1 -C 6 alkyl;

[0421] and R A8 is C 1 -C 6 alkyl,

[0422] (ix) C 6-10 aryl,

[0423] (x) a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S, or

[0424] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or

[0425] two R 8 groups are linked to form a fused, spiro or bridged 3- to 7-membered ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0426] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts,

[0427] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0428] R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl;

[0429] R 9a is -CH 3 or -CH 2 F.

[0430] Each R 8 is independently

[0431] (i) halo,

[0432] (ii) C 1-6 alkyl, optionally substituted by OH, C 1-6 alkoxy, C 6-10 aryl or a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0433] (iii) C 1-6 haloalkyl,

[0434] (iv) CN,

[0435] (v) oxo,

[0436] (vi) -X-R A5

[0437] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0438] wherein C 1 -C 6The alkyl group or 3- to 7-membered ring is optionally substituted with 1, 2 or 3 groups independently selected from CN, halo, C 1 -C 6 alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S

[0439] (vii)NHR A6 ,

[0440] wherein R A6 is C 1 -C 6 alkyl;

[0441] (viii)NR A7 R A8 ,

[0442] wherein R A7 is C 1 -C 6 alkyl;

[0443] and R A8 is C 1 -C 6 alkyl,

[0444] (ix)C 6-10 aryl,

[0445] (x) a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S, or

[0446] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or

[0447] two R 8 groups are linked to form a fused, spiro or bridged 3- to 7-membered ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0448] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts, each R 8 is independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH 2 Ph, CH 2 OH, CH 2 OMe, NHMe, NMe 2 , OH, OMe, OCH 2 CF 3 , OCH 2CHF 2 、OCH 2 CH 2 OMe, SMe, CH 2 F, CHF 2 、CH 2 CF 3 、(CH 2 ) 4 Cl、

[0449] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts, each R 8 is independently -Cl, -F, -Br, oxo, -CN, methyl, ethyl, propyl, -CH 2 Ph, -CH 2 CH 2 Ph, -CH(CH 3 )Ph, -CH 2 C(CH 3 ) 2 、-CH 2 OH, -CH 2 OMe, -NHMe, -NMe 2 、-OH, -OMe, -OCD 3 、-OCD3OCH 2 CF 3 、-OCH 2 CHF 2 、-OCH 2 C(CH 3 ) 2 、-OCH 2 CH 2 OMe, -SMe, -CH 2 F, -CHF 2 、-CF 3 、-CH 2 CF 3 、-(CH 2 ) 4 Cl, -SMe, -SO 2 Me, -CH 2 CH 2 F, -CH(CH 3 )F, -C(F) 2 CH 3 、-CF 3 、-OCH 2 CF 3, -C=CC(CH 3 ) 2 SO 2 CH 3 , -C=CC(CH 3 ) 2 OH,

[0450] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or pharmaceutically acceptable salts thereof, two R 8 are linked to form a fused 6-membered ring containing one O.

[0451] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or pharmaceutically acceptable salts thereof,

[0452] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0453] R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl;

[0454] R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl or halo; and

[0455] each R 8 is independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH 2 Ph, CH 2 OH, CH 2 OMe, NMe, NMe 2 , OH, OMe, OCH 2 CF 3 , OCH 2 CHF 2 , OCH 2 CH 2 OMe, SMe, CH 2 F, CHF 2 , CH 2 CF 3 , (CH 2 ) 4 Cl,

[0456] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts,

[0457] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0458] R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl;

[0459] R 9a is C 1-6 alkyl, C 1-4 haloalkyl or halo; and

[0460] each R 8 is independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH 2 Ph, CH 2 OH, CH 2 OMe, NMe, NMe 2 , OH, OMe, OCH 2 CF 3 , OCH 2 CHF 2 , OCH 2 CH 2 OMe, SMe, CH 2 F, CHF 2 , CH 2 CF 3 , (CH 2 ) 4 Cl,

[0461] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or their pharmaceutically acceptable salts,

[0462] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0463] R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl;

[0464] R 9a is C 1-6 alkyl or C 1-4 haloalkyl, and

[0465] each R 8 is independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH 2 Ph, CH 2 OH, CH 2 OMe, NMe, NMe 2 , OH, OMe, OCH 2 CF 3 , OCH 2 CHF 2 , OCH 2 CH 2 OMe, SMe, CH 2 F, CHF 2 , CH 2 CF 3 , (CH 2 ) 4 Cl,

[0466] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or pharmaceutically acceptable salts thereof,

[0467] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0468] R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl;

[0469] R 9a is C 1-6 alkyl or C 1-4 haloalkyl, and

[0470] each R 8 is independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH 2 Ph, CH 2 OH, CH 2 OMe, NMe, NMe 2 , OH, OMe, OCH 2 CF 3 , OCH 2 CHF 2 , OCH2 CH 2 OMe, SMe, CH 2 F, CHF 2 , CH 2 CF 3 , (CH 2 ) 4 Cl,

[0471] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or pharmaceutically acceptable salts thereof, m is 0, 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0472] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa or IVb or pharmaceutically acceptable salts thereof, the compound has the formula V:

[0473]

[0474] wherein R 8A and R 8B are each independently H, halo, C 1-4 alkyl or C 1-4 haloalkyl.

[0475] In some embodiments of the compounds of formula I, I-A, II-A, II-Aa, III, IIIa, IV, IVa or V or pharmaceutically acceptable salts thereof, the compound has the formula Va:

[0476]

[0477] wherein R 8A and R 8B are each independently H, halo, C 1-4 alkyl or C 1-4 haloalkyl.

[0478] In some embodiments of the compounds of formula I, I-A, II-A, II-Ab, III, IIIb, IV, IVb or V or pharmaceutically acceptable salts thereof, the compound has the formula Vb:

[0479]

[0480] wherein R 8A and R 8B are each independently H, halo, C1-4 alkyl or C 1-4 haloalkyl.

[0481] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is a halogen, C 1-4 alkyl or C 1-4 haloalkyl, and R 8B is H, a halogen, C 1-4 alkyl or C 1-4 haloalkyl. In some embodiments, R 8A is a halogen, C 1-4 alkyl or C 1-4 haloalkyl, and R 8B is H. In some embodiments, R 8A is H, a halogen, C 1-4 alkyl or C 1-4 haloalkyl, and R 8B is a halogen, C 1-4 alkyl or C 1-4 haloalkyl. In some embodiments, R 8A is H, and R 8B is a halogen, C 1-4 alkyl or C 1-4 haloalkyl.

[0482] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl.

[0483] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 5a is H, a halogen, C 1-4 haloalkyl or C 1-6 alkyl.

[0484] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl or a halogen. In some embodiments, R 9a is C 1-6 alkyl, C 1-4 haloalkyl or a halogen. In some embodiments, R 9a is C 1-6 alkyl.

[0485] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 4ais H, C 1-6 alkyl or C 1-4 haloalkyl.

[0486] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl.

[0487] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, R 9a is C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, R 9a is C 1-6 alkyl.

[0488] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is halo, C 1-4 alkyl or C 1-4 haloalkyl; R 8B is H, halo, C 1-4 alkyl or C 1-4 haloalkyl; R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl or halo.

[0489] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is halo, C 1-4 alkyl or C 1-4 haloalkyl; R 8B is H; R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is H, C 1-6 alkyl, C 1-4Halogenated alkyl or halogen group.

[0490] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is H, halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 8B is halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 4a is H, C 1-6 alkyl or C 1-4 halogenated alkyl; R 5a is H, halogen group, C 1-4 halogenated alkyl or C 1-6 alkyl; and R 9a is H, C 1-6 alkyl, C 1-4 halogenated alkyl or halogen group.

[0491] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is H; R 8B is halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 4a is H, C 1-6 alkyl or C 1-4 halogenated alkyl; R 5a is H, halogen group, C 1-4 halogenated alkyl or C 1-6 alkyl; and R 9a is H, C 1-6 alkyl, C 1-4 halogenated alkyl or halogen group.

[0492] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 8B is H, halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 4a is H, C 1-6 alkyl or C 1-4 halogenated alkyl; R 5a is H, halogen group, C 1-4 halogenated alkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl, C 1-4 halogenated alkyl or halogen group.

[0493] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is a halogen, C 1-4 alkyl or C 1-4 haloalkyl; R 8B is H; R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, a halogen, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl, C 1-4 haloalkyl or a halogen.

[0494] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is H, a halogen, C 1-4 alkyl or C 1-4 haloalkyl; R 8B is a halogen, C 1-4 alkyl or C 1-4 haloalkyl; R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, a halogen, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl, C 1-4 haloalkyl or a halogen.

[0495] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is H; R 8B is a halogen, C 1-4 alkyl or C 1-4 haloalkyl; R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, a halogen, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl, C 1-4 haloalkyl or a halogen.

[0496] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is a halogen, C 1-4 alkyl or C 1-4Halogenated alkyl; R 8B is H, a halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 4a is H, C 1-6 alkyl or C 1-4 halogenated alkyl; R 5a is H, a halogen group, C 1-4 halogenated alkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl.

[0497] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is a halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 8B is H; R 4a is H, C 1-6 alkyl or C 1-4 halogenated alkyl; R 5a is H, a halogen group, C 1-4 halogenated alkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl.

[0498] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is H, a halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 8B is a halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 4a is H, C 1-6 alkyl or C 1-4 halogenated alkyl; R 5a is H, a halogen group, C 1-4 halogenated alkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl.

[0499] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is H; R 8B is a halogen group, C 1-4 alkyl or C 1-4 halogenated alkyl; R 4a is H, C 1-6 alkyl or C 1-4 halogenated alkyl; R 5a is H, a halogen group, C 1-4haloalkyl or C 1-6 alkyl; and R 9a is C 1-6 alkyl.

[0500] In some embodiments of the compounds of formula V, Va or Vb or their pharmaceutically acceptable salts, R 8A is H; R 8B is halo, C 1-4 alkyl or C 1-4 haloalkyl; R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl; R 9a is C 1-6 alkyl; and R 1 is phenyl optionally substituted by one, two, three or four R A1 , wherein each R A1 is independently halo, C 1-4 alkyl, C 1-4 haloalkyl or –O–C 1-4 alkyl.

[0501] In some embodiments of the compounds of formula V, Va or Vb or their pharmaceutically acceptable salts, R 8A is H; R 8B is halo, C 1-4 alkyl or C 1-4 haloalkyl; R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl; R 9a is C 1-6 alkyl; and R 1 is phenyl substituted by one, two, three or four R A1 , wherein each R A1 is independently halo or –O–C 1-4 alkyl.

[0502] In some embodiments of the compounds of formula V, Va or Vb or their pharmaceutically acceptable salts, R 8A is H; R 8B is halo, C 1-4 alkyl or C 1-4 haloalkyl; R 4a is H, C 1-6 alkyl or C 1-4Halogenated alkyl; R 5a is H, halogen, C 1-4 halogenated alkyl or C 1-6 alkyl; R 9a is C 1-6 alkyl; and R 1 is phenyl substituted by one, two, three or four halogens.

[0503] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A is H; R 8B is halogen, C 1-4 alkyl or C 1-4 halogenated alkyl; R 4a is H, C 1-6 alkyl or C 1-4 halogenated alkyl; R 5a is H, halogen, C 1-4 halogenated alkyl or C 1-6 alkyl; R 9a is C 1-6 alkyl; and R 1 is phenyl substituted by two or three halogens selected from chlorine and fluorine.

[0504] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A and R 8B are each independently H, halogen, C 1-4 alkyl, C 1-4 halogenated alkyl or -X-R A5 ; where X is O, and R A5 is H, C 1-6 alkyl, C 1-6 halogenated alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S.

[0505] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof:

[0506] R 8A and R 8B are each independently H, halogen, C 1-4 alkyl, C 1-4 halogenated alkyl or -X-R A5 ; where X is O, and R A5 is H, C 1-6 alkyl, C 1-6 halogenated alkyl or a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S;

[0507] R 1is a phenyl group substituted by two or three halogens selected from chlorine and fluorine;

[0508] R 4a is H, a halogen group, C 1-6 alkyl or C 1-4 haloalkyl;

[0509] R 5a is H, a halogen group, C 1-4 haloalkyl or C 1-6 alkyl; and

[0510] R 9a is C 1-6 alkyl or C 1-4 haloalkyl.

[0511] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A and R 8B are each independently H, a halogen group, C 1-4 alkyl, C 1-4 haloalkyl or -X-R A5 ; where X is O, and R A5 is C 1-6 alkyl or C 1-6 haloalkyl.

[0512] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof:

[0513] R 8A and R 8B are each independently H, a halogen group, C 1-4 alkyl, C 1-4 haloalkyl or -X-R A5 ; where X is O, and R A5 is C 1-6 alkyl or C 1-6 haloalkyl;

[0514] R 1 is a phenyl group substituted by two or three halogens selected from chlorine and fluorine;

[0515] R 4a is H, a halogen group, C 1-6 alkyl or C 1-4 haloalkyl;

[0516] R 5a is H, a halogen group, C 1-4 haloalkyl or C 1-6 alkyl; and

[0517] R 9a is C 1-6 alkyl or C1-4 Halogenated alkyl

[0518] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof, R 8A and R 8B are each independently H, halogen, C 1-4 alkyl, C 1-4 halogenated alkyl or -X-R A5 ; wherein X is O, and R A5 is C 1-6 alkyl.

[0519] In some embodiments of the compound of formula V, Va or Vb or a pharmaceutically acceptable salt thereof:

[0520] R 8A and R 8B are each independently H, halogen, C 1-4 alkyl, C 1-4 halogenated alkyl or -X-R A5 ; wherein X is O, and R A5 is C 1-6 alkyl;

[0521] R 1 is phenyl substituted by two or three halogens selected from chlorine and fluorine;

[0522] R 4a is H, halogen, C 1-6 alkyl or C 1-4 halogenated alkyl;

[0523] R 5a is H, halogen, C 1-4 halogenated alkyl or C 1-6 alkyl; and

[0524] R 9a is C 1-6 alkyl or C 1-4 halogenated alkyl.

[0525] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0526]

[0527] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0528]

[0529] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0530]

[0531] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0532]

[0533] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0534]

[0535] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0536]

[0537] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0538]

[0539] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0540]

[0541] In some embodiments of the compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb or a pharmaceutically acceptable salt thereof, the compound is:

[0542]

[0543] In some embodiments of a compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb, or a pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of:

[0544]

[0545]

[0546]

[0547]

[0548]

[0549] In some embodiments of a compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb, or a pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of:

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559] In some embodiments of a compound of formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0560]

[0561]

[0562]

[0563]

[0564] III. Pharmaceutical Compositions

[0565] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Accordingly, the present invention also provides pharmaceutical compositions that comprise one or more of the compounds provided herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. The compounds provided herein can be the sole active ingredient or one of the active ingredients of the pharmaceutical composition. Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th ed., (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd ed. (edited by G.S. Banker and C.T. Rhodes).

[0566] In one aspect, the present invention provides pharmaceutical compositions that comprise a compound provided herein (e.g., a compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0567] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0568] The pharmaceutical composition can be administered in single or multiple doses. The pharmaceutical composition can be administered by a variety of methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0569] One mode of administration is parenteral, such as by injection. Forms in which the pharmaceutical composition described herein can be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0570] Oral administration can be another route for administering the compounds provided herein. The administration can be via, for example, capsules or enteric-coated tablets. In preparing a pharmaceutical composition comprising at least one compound provided herein or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient, such as the compound provided herein, is generally diluted with an excipient and / or encapsulated within a carrier that can be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that acts as a solvent, carrier, or medium for the active ingredient. Accordingly, the pharmaceutical composition can be in the form of tablets, pills, powders, lozenges, cachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0571] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose or any combination thereof. The pharmaceutical composition can additionally include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl benzoate and propylparaben; sweetening agents; and flavoring agents; or any combination thereof.

[0572] A pharmaceutical composition can be formulated comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof, so as to provide rapid, sustained, or delayed release of the active ingredient (such as the compounds provided herein) after administration to a subject by procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present disclosure employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of a controlled amount of the compounds provided herein. The construction and use of transdermal patches for delivering agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of the agent.

[0573] To prepare solid compositions such as tablets, the primary active ingredient can be admixed with a pharmaceutical excipient to form a solid preformulation composition that is a homogeneous mixture containing the compounds described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily subdivided into equivalent unit dosage forms such as tablets, pills, and capsules.

[0574] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form having the advantage of extended action or to protect from the acidic conditions of the stomach. For example, a tablet or pill can contain an inner dosage component and an outer dosage component, the latter in the form of an envelope over the former. The two components can be separated by an enteric layer that is resistant to disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be released therein in a delayed manner. A variety of materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0575] A pharmaceutical composition for inhalation or insufflation may comprise solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by the oral or nasal respiratory route to achieve local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. The solution, suspension or powder composition may be preferably administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0576] IV. Treatment Methods

[0577] In one embodiment, there is provided a method of treating HIV infection in a human being suffering from or at risk of acquiring an HIV (e.g., HIV-1 and / or HIV-2) infection, the method comprising administering to the human a therapeutically effective amount of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof.

[0578] In some embodiments, the method further comprises administering to a human a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In certain embodiments, one or more of the additional therapeutic agents are anti-HIV agents. In specific embodiments, one or more of the 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, gpl20 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs (broadly neutralizing HIV antibodies), TLR7 agonists, pharmacokinetic enhancers, other anti-HIV drugs, or combinations thereof. In one embodiment, the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, lenacapavir, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, lenacapavir, GS-5894, islatravir, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional therapeutic agents are lenacapavir, islatravir. In some embodiments, the additional therapeutic agent is lenacapavir. In some embodiments, the additional therapeutic agent is islatravir.

[0579] In another embodiment, provided is the use of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof for treating HIV (e.g., HIV-1 and / or HIV-2) infection in a human being suffering from or at risk of acquiring an HIV infection.

[0580] In another embodiment, provided is a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof for use in medical therapy.

[0581] In another embodiment, there is provided a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0582] In another embodiment, there is provided a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human being infected with HIV or at risk of acquiring HIV infection.

[0583] In another embodiment, there is provided a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human being infected with HIV or at risk of acquiring HIV infection, wherein the method further comprises administering to the human being one, two, three or four additional therapeutic agents.

[0584] In another embodiment, there is provided a compound of I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human being infected with or at risk of contracting HIV infection, wherein the method further comprises administering to the human being one, two, three or four additional therapeutic agents selected from the group consisting of: an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, other drugs for treating HIV or combinations thereof. In one embodiment, one, two, three or four additional therapeutic agents are selected from an HIV protease inhibitor, a non-nucleoside inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a latency reversing agent, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist and combinations thereof.

[0585] In another embodiment, there is provided a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human being infected with or at risk of contracting HIV infection, wherein the method further comprises administering to the human being a therapeutically effective amount of tenofovir disoproxil fumarate and emtricitabine.

[0586] In another embodiment, there is provided a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof for use in a method of treating HIV infection in a human being suffering from or at risk of acquiring an HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

[0587] In another embodiment, there is provided a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof for use in a method of treating HIV infection in a human being suffering from or at risk of acquiring an HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil fumarate.

[0588] In another embodiment, there is provided a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof for use in a method of treating HIV infection in a human being suffering from or at risk of acquiring an HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.

[0589] In another embodiment, a method of using a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb in therapy is provided. Specifically, a method of treating HIV virus proliferation in a mammal (e.g., a human), treating AIDS or delaying the onset of symptoms of AIDS or ARC is provided, the method comprising administering to the mammal a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0590] In another embodiment, a composition comprising a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for use in a method of treating HIV virus proliferation in a mammal (e.g., a human), treating AIDS or delaying the onset of symptoms of AIDS or ARC.

[0591] In one embodiment, a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt thereof is provided for preventing HIV infection.

[0592] For example, in one embodiment, there is provided a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, or a pharmaceutically acceptable salt thereof, for use in pre-exposure prophylaxis (PrEP), i.e., to prevent an individual from becoming infected with the HIV virus when the individual is exposed to the virus, and / or to prevent the virus from establishing a permanent infection and / or to prevent the onset of disease symptoms and / or to prevent the virus from reaching a detectable level in the blood.

[0593] In another embodiment, there is disclosed the use of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV infection in a human being suffering from or at risk of contracting HIV infection.

[0594] In another embodiment, there is disclosed the use of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, or a pharmaceutically acceptable salt thereof, as a research tool.

[0595] In another embodiment, there is disclosed an article of manufacture comprising a composition effective for the treatment of HIV infection; and packaging material including a label indicating that the composition can be used to treat an infection caused by HIV. Exemplary compositions comprise a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, or a pharmaceutically acceptable salt thereof.

[0596] In another embodiment, there is disclosed a method of inhibiting HIV replication. The method comprises exposing the virus to an effective amount of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, or a pharmaceutically acceptable salt thereof, under conditions in which HIV replication is inhibited.

[0597] In another embodiment, there is disclosed the use of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, or a pharmaceutically acceptable salt thereof, to inhibit the activity of HIV integrase.

[0598] In another embodiment, there is disclosed the use of a compound of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb, or a pharmaceutically acceptable salt thereof, to inhibit HIV replication.

[0599] V. Administration

[0600] The compounds of the present disclosure (e.g., compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb) 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), among others. It should be understood that the preferred route may vary, for example, with the condition of the recipient. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0601] The compounds of the present disclosure can be administered to an individual for a desired period or duration according to an effective dosing regimen, such as for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compounds are administered on a daily or intermittent schedule throughout the life of the individual.

[0602] The specific dosage level of the compounds of the present disclosure for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, the age, weight, general health, sex, diet, time of administration, route of administration and rate of excretion of the subject being treated, drug combination, and the severity of the particular disease. For example, the dosage may be expressed as milligrams of the compound described herein per kilogram of subject body weight (mg / kg). Dosages between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, dosages between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, dosages between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalizing based on the subject's weight is particularly useful when adjusting dosages between subjects of widely different sizes (such as when using a drug in children and adults, or when converting an effective dose in a non-human subject such as a dog to a dose suitable for a human subject).

[0603] The dosage may also be described as the total amount of the compound described herein administered per dose. The dosage of a compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof may be between about 1 mg and 4,000 mg, between about 2,000 mg to 4,000 mg, between about 1 mg to 2,000 mg, between about 1 mg to 1,000 mg, between about 10 mg to 500 mg, between about 20 mg to 500 mg, between about 50 mg to 300 mg, between about 75 mg to 200 mg, or between about 15 mg to 150 mg.

[0604] The dosage or frequency of administration of the compounds of the present disclosure may be adjusted during the course of treatment according to the judgment of the administering physician.

[0605] The compounds of the present disclosure can be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once a day. In some embodiments, the compound is administered once a week. In some embodiments, the compound is administered once a month. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every five months. In some embodiments, the compound is administered every six months. In some embodiments, the compound is administered every seven months. In some embodiments, the compound is administered every eight months. In some embodiments, the compound is administered every nine months. In some embodiments, the compound is administered every ten months. In some embodiments, the compound is administered every eleven months. In some embodiments, the compound is administered annually.

[0606] The compounds provided herein can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, the therapeutically effective amount of the compounds provided herein includes from about 0.3 mg / dose to about 30 mg / dose, or from about 30 mg / dose to about 300 mg / dose, or from about 0.3 μg / dose to about 30 mg / dose, or from about 30 μg / dose to about 300 μg / dose.

[0607] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dose of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of the compound). A therapeutically effective amount can include from about 0.1 mg / dose to about 1000 mg / dose, such as from about 50 mg / dose to about 500 mg / dose, or such as from about 100 mg / dose to about 400 mg / dose, or such as from about 150 mg / dose to about 350 mg / dose, or such as from about 200 mg / dose to about 300 mg / dose, or such as from about 0.01 mg / dose to about 1000 mg / dose, or such as from about 0.01 mg / dose to about 100 mg / dose, or such as from about 0.1 mg / dose to about 100 mg / dose, or such as from about 1 mg / dose to about 100 mg / dose, or such as from about 1 mg / dose to about 10 mg / dose, or such as from about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective amounts of the compounds of Formula I are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose or about 100 mg / dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose, 450 mg / dose, 475 mg / dose, 500 mg / dose, 525 mg / dose, 550 mg / dose, 575 mg / dose, 600 mg / dose, 625 mg / dose, 650 mg / dose, 675 mg / dose, 700 mg / dose, 725 mg / dose, 750 mg / dose, 775 mg / dose, 800 mg / dose, 825 mg / dose, 850 mg / dose, 875 mg / dose, 900 mg / dose, 925 mg / dose, 950 mg / dose, 975 mg / dose or about 1000 mg / dose per dose.

[0608] In some embodiments, the methods described herein include administering an initial daily dose of about 1 mg to 500 mg of the compounds herein to a subject and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks or once a month.

[0609] When administered orally, the total daily dose for a human subject can be between about 1 mg and 1,000 mg, between about 10 mg / day to 500 mg / day, between about 50 mg / day to 300 mg / day, between about 75 mg / day to 200 mg / day, or between about 100 mg / day to 150 mg / day. In some embodiments, the total daily dose for a human subject can be about 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, or 1,000 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, or 800 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day administered as a single dose.

[0610] In some embodiments, the total daily dose for a human subject can be about 100 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 150 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 200 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 250 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 300 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 350 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 400 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 450 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 500 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 550 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 600 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 650 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 700 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 750 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 800 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 850 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 900 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 950 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject can be about 1000 mg / day administered as a single dose.

[0611] The single dose can be administered hourly, daily, weekly, or monthly. For example, the single dose can be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. The single dose can also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. The single dose can also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, the single dose can be administered once a week. The single dose can also be administered once a month. In some embodiments, the compounds disclosed herein are administered once a day in the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice a day in the methods disclosed herein.

[0612] In some embodiments, the compounds disclosed herein are administered once every 10 days. In some embodiments, the compounds disclosed herein are administered once every 15 days. In some embodiments, the compounds disclosed herein are administered once every 20 days. In some embodiments, the compounds disclosed herein are administered once every 10 - 15 days. In some embodiments, the compounds disclosed herein are administered once every 15 - 20 days. In some embodiments, the compounds disclosed herein are administered once every 10 - 20 days. In some embodiments, the compounds disclosed herein are administered once every month. In some embodiments, the compounds disclosed herein are administered once every 2 months. In some embodiments, the compounds disclosed herein are administered once every 3 months. In some embodiments, the compounds disclosed herein are administered once every 4 months. In some embodiments, the compounds disclosed herein are administered once every 5 months. In some embodiments, the compounds disclosed herein are administered once every 6 months. In some embodiments, the compounds disclosed herein are administered once every 8 months. In some embodiments, the compounds disclosed herein are administered once every 10 months. In some embodiments, the compounds disclosed herein are administered once a year.

[0613] The dosing frequency of the compounds of the present disclosure will be determined by the needs of the individual patient and can be, for example, once a day, once a week, once every two weeks, once a month, once every two months, once every three months, once every four months, once every six months or less. The administration of the compounds continues as long as treatment of the HIV infection is required.

[0614] VI. Kits and Articles

[0615] In one aspect, the present disclosure provides a kit that contains the compounds provided herein (e.g., compounds of formula I, I - A, I - B, I - C, I - D, I - E, I - F, II - A, II - Aa, II - Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb) or pharmaceutically acceptable salts, stereoisomers, prodrugs or solvates thereof and a suitable package. In some embodiments, the kit further contains instructions for use. In some embodiments, the kit contains the compounds provided herein (e.g., compounds of formula I, I - A, I - B, I - C, I - D, I - E, I - F, II - A, II - Aa, II - Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va or Vb) or pharmaceutically acceptable salts, stereoisomers, prodrugs or solvates thereof and labels and / or instructions for use of the compounds in the treatment of the indications (including diseases or disorders) described herein.

[0616] In some embodiments, the kit further comprises one or more (e.g., one, two, three, four, one or two, one to three or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0617] In one aspect, the present disclosure provides an article of manufacture that comprises a compound or a pharmaceutically acceptable salt, isomer or mixture thereof as described herein in a suitable container. In some embodiments, the container can be a vial, bottle, ampoule, prefilled syringe or intravenous bag.

[0618] VII. Combination Therapies

[0619] In certain embodiments, there is provided a method for treating HIV infection that comprises administering to a human a therapeutically effective amount of a combination of a compound or a pharmaceutically acceptable salt thereof as disclosed herein and a therapeutically effective amount of one, two, three or four additional therapeutic agents. In one embodiment, there is provided a method for treating HIV infection that comprises administering to a human a therapeutically effective amount of a combination of a compound or a pharmaceutically acceptable salt thereof as disclosed herein and a therapeutically effective amount of one, two, three or four additional therapeutic agents.

[0620] In one embodiment, there is provided a pharmaceutical composition that comprises a combination of a compound or a pharmaceutically acceptable salt thereof as disclosed herein and one, two, three or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient.

[0621] In certain embodiments, the present disclosure provides a method for treating HIV infection that comprises administering to a subject in need thereof a therapeutically effective amount of a combination of a compound or a pharmaceutically acceptable salt thereof as disclosed herein and a therapeutically effective amount of one, two, three or four additional therapeutic agents suitable for treating HIV infection.

[0622] In certain embodiments, a compound or a pharmaceutically acceptable salt thereof as disclosed herein is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound or a pharmaceutically acceptable salt thereof as disclosed herein is combined with one, two, three or four additional therapeutic agents. In certain embodiments, a compound or a pharmaceutically acceptable salt thereof as disclosed herein is combined with two additional therapeutic agents. In other embodiments, a compound or a pharmaceutically acceptable salt thereof as disclosed herein is combined with three additional therapeutic agents. In further embodiments, a compound or a pharmaceutically acceptable salt thereof as disclosed herein is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0623] Administration of HIV Combination Therapies

[0624] In certain embodiments, the compounds disclosed herein are administered in combination with one, two, three, or four additional therapeutic agents. Co - administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally refers to simultaneous or sequential administration of the compounds disclosed herein and one, two, three, or four additional therapeutic agents such that a therapeutically effective amount of the compounds disclosed herein and one, two, three, or four additional therapeutic agents are present in the patient. When administered sequentially, the combination can be administered in two or more administrations.

[0625] Co - administration includes administering a unit dose of the compounds disclosed herein before or after administering a unit dose of one, two, three, or four additional therapeutic agents. For example, the compounds disclosed herein can be administered within seconds, minutes, or hours of administering one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of the compounds disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compounds disclosed herein within seconds or minutes. In other embodiments, a unit dose of the compounds disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents after several hours (e.g., 1 - 12 hours). In other embodiments, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compounds disclosed herein after several hours (e.g., 1 - 12 hours).

[0626] In certain embodiments, a kit is provided that contains a combination of a compound disclosed herein (e.g., a compound of formula I, I - A, I - B, I - C, I - D, I - E, I - F, II - II - A, Aa, II - Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb) or a pharmaceutically acceptable salt thereof and one or more (e.g., one, two, three, or four) additional therapeutic agents.

[0627] In a specific embodiment, the kit contains 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.

[0628] HIV combination therapy

[0629] In the above-described embodiments, one or more additional therapeutic agents can be anti-HIV agents. In some cases, the additional therapeutic agent can be an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, an HIV Tat or Rev inhibitor, an inhibitor of Tat-TAR-P-TEFb, an immunomodulator, an immunotherapeutic agent, an antibody-drug conjugate, a gene modifier, a gene editor (such as CRISPR / Cas9, zinc finger nuclease, homing nuclease, synthetic nuclease, TALEN), a cell therapy (such as chimeric antigen receptor T cells CAR-T and engineered T cell receptors TCR-T, autologous T cell therapy, engineered B cells, NK cells), a latency reversing agent, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody, and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitor, an IL-13 antagonist, a peptidylprolyl cis-trans isomerase A modulator, a protein disulfide isomerase inhibitor, a complement C5a receptor antagonist, a DNA methyltransferase inhibitor, a fatty acid synthase inhibitor, an HIV vif gene modulator, a Vif dimerization antagonist, an HIV-1 viral infectivity factor inhibitor, an HIV-1 Nef modulator, a TNFα ligand inhibitor, an HIV Nef inhibitor, an Hck tyrosine kinase modulator, a mixed lineage kinase-3 (MLK-3) inhibitor, an HIV-1 splicing inhibitor, an integrin antagonist, a nucleoprotein inhibitor, a splicing factor modulator, a COMM domain-containing protein 1 modulator, an HIV ribonuclease H inhibitor, an IFN antagonist, a defensin modulator, a CD3 antagonist, a CDK-4 inhibitor, a CDK-6 inhibitor, a CDK-9 inhibitor, a cytochrome P450 3 inhibitor, a CXCR4 modulator, a dendritic ICAM-3-grabbing non-integrin 1 inhibitor, an HIV GAG protein inhibitor, an HIV POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, an HPK1 (MAP4K1) inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase primer complex inhibitor, a G6PD and NADH oxidase inhibitor, an mTOR complex 1 inhibitor, an mTOR complex 2 inhibitor, a P-glycoprotein modulator, an RNA polymerase modulator, a TAT protein inhibitor, a prolyl endopeptidase inhibitor, a phospholipase A2 inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, an HIV vaccine, an anti-HIV peptide, and combinations thereof.

[0630] In some embodiments, one or more additional therapeutic agents 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 reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0631] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0632] In some embodiments, one or more 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, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversing agents, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligand, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0633] In some embodiments, one or more additional therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, eschavirenz, rilpivirine, and lenacapavir, and combinations thereof.

[0634] HIV Combination Drugs

[0635] Examples of combination drugs include but are not limited to (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); (Tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine and rilpivirine);

[0636] (Tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); Doravirine, tenofovir alafenamide hemifumarate, emtricitabine and cobicistat; Efavirenz, lamivudine and tenofovir disoproxil fumarate; Lamivudine and tenofovir disoproxil fumarate; Tenofovir and lamivudine; Tenofovir alafenamide and emtricitabine; Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobicistat and elvitegravir; Tenofovir analogues; (Zidovudine and lamivudine; AZT+3TC); ( (Abacavir sulfate and lamivudine; ABC+3TC); ( (Lopinavir and ritonavir); (Dolutegravir, abacavir and lamivudine); (Bictegravir + emtricitabine + tenofovir alafenamide), (Dolutegravir + lamivudine), (Abacavir Sulfate, Zidovudine and Lamivudine; ABC+AZT+3TC); 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; Raltegravir and Lamivudine; Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate; Doravirine, Lamivudine and Tenofovir Disoproxil; 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, Lopinavir, Ritonavir, Zidovudine, Lopinavir+Ritonavir+Abacavir+Lamivudine, Lamivudine, Cabotegravir+Rilpivirine, 3-BNC117+Alberavir, Erbitux (Islatravir, VM-1500) and VM-1500A, Lenacapavir+Istratravir (oral, injection) and dual-targeting HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitor.

[0637] Other HIV Drugs

[0638] Examples of other drugs for treating HIV include, but are not limited to, aspernigrin C, cefmenoxime, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimat derivatives, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, bryostatin-1, bryostatin analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, fluoro-β-D-arabinonucleic acid (FANA)-modified antisense oligonucleotides, FX-101, grazoprevir, GSK-3739937, GSK-3739937 (long-acting), HGTV-43, HPH-116, HS-10234, hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, MK-8591 (islatravir), NOV-205, OB-002H, ODE-Bn-TFV, PA-1050040 (PA-040), PC-707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-4467, thrombospondin analogs, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinoxor, IMC-M113V, IML-106, antivirin fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, nipamovir, Covimro, and ABBV-1882.

[0639] HIV Protease Inhibitors

[0640] Examples of HIV protease inhibitors include, but are not limited to, amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC-09 + ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911.

[0641] Additional examples of HIV protease inhibitors are described, for example, in U.S. Patent No. 10,294,234 and U.S. Patent Application Publication Nos. US2020030327 and US2019210978.

[0642] HIV Gag Protein Inhibitors

[0643] Examples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071.

[0644] HIV Ribonuclease H Inhibitors

[0645] Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC-727447.

[0646] HIV Nef Inhibitors

[0647] Examples of HIV Nef inhibitors include, but are not limited to, FP-1.

[0648] HIV Reverse Transcriptase Inhibitors

[0649] Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, islatravir (extended-release oral, for HIV infection), doravirine + islatravir (fixed-dose combination / oral tablet formulation, for HIV-1 infection), islatravir (long-acting injectable nanosuspension, for HIV infection), and islatravir (VM-1500).

[0650] Examples of HIV nucleosides or nucleotides of reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, half-tenofovir alafenamide fumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), half-tenofovir disoproxil fumarate, and VIDEX (didanosine, ddl), abacavir, abacavir sulfate, alovudine, aristeromycin, cinaprevir, didanosine, elvucitabine, atazanavir, fosamprenavir, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, azidothymidine, stavudine, zalcitabine, zidovudine, rovirudin-etravirine amide (GS-9131), GS-9148, MK-8504, islatravir, MK-8583, VM-2500, and KP-1461.

[0651] Additional examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286.

[0652] HIV Integrase Inhibitors

[0653] Examples of HIV integrase inhibitors include, but are not limited to, elvitegravir, elvitegravir (extended release microcapsules), curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, phenethyl caffeate, derivatives of phenethyl caffeate, tyrosine kinase inhibitors, derivatives of tyrosine kinase inhibitors, raltegravir, pegylated raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017.

[0654] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINI) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[0655] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US20200317689, US20210284642, US2014221356, and US2016016973.

[0656] HIV Viral Infectivity Factor Inhibitors

[0657] Examples of HIV viral infectivity factor inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0658] HIV Entry Inhibitors

[0659] Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0660] Examples of CCR5 inhibitors include, but are not limited to, apravir, vicriviroc, maraviroc, maraviroc (long-acting injectable nanoemulsion), cenicriviroc, lerivizumab (PRO-140), aldavertide (RAP-101), nelfinavir (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, selicriviroc, and vMIP (Haimipu).

[0661] Examples of gp41 inhibitors include, but are not limited to, albuvirtide, enfuvirtide, grazoprevir (gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biosimilar, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifuvirtide.

[0662] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs.

[0663] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicides, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0664] Examples of gp160 inhibitors include, but are not limited to, fangchinoline.

[0665] Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0666] HIV Maturation Inhibitors

[0667] Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232.

[0668] Latency Reversing Agents

[0669] Examples of latency reversing agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists such as GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as bortezomib), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580, apabetalone), ionomycin, IAP antagonists (inhibitors of apoptosis proteins such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl anilide and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins, and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (such as raglazolate analogs, APH-0812, GSK-343). Examples of PKC activators include, but are not limited to, indolactams, prostratin, ingenol B, and DAG-lactones.

[0670] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.

[0671] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944.

[0672] Histone Deacetylase (HDAC) Inhibitors

[0673] In some embodiments, an agent as described herein is administered together with an inhibitor of a histone deacetylase such as histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), remetinostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0674] Capsid Inhibitors

[0675] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, lenacapavir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University), and the compounds described in (GSK WO2019 / 087016).

[0676] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030.

[0677] Cytochrome P450 3 Inhibitors

[0678] Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553.

[0679] RNA Polymerase Modulators

[0680] Examples of RNA polymerase modulators include, but are not limited to, those described in U.S. Patent Nos. 10,065,958 and 8,008,264.

[0681] Immune Checkpoint Modulators

[0682] In various embodiments, an agent as described herein is combined with one or more blockers or inhibitors of an inhibitory immune checkpoint protein or receptor and / or with one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting an inhibitory immune checkpoint can positively regulate T cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of a stimulatory immune checkpoint can enhance the efficacy of immune checkpoint inhibitors in infectious disease treatment. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., as reviewed in Davis et al., Semin Immunol. (2017) 31:64–75; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0683] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitor 1 containing V-set domain (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-related 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9);Lymphocyte activation 3 (LAG3, CD223); Signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16-binding protein 1 (ULBP1); UL16-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); Retinoic acid early transcript 1E (RAET1E; ULBP4); Retinoic acid early transcript 1G (RAET1G; ULBP5); Retinoic acid early transcript 1L (RAET1L; ULBP6); Lymphocyte activation 3 (CD223); Killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); Killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); Killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); Killer cell lectin-like receptor C3 (KLRC3, NKG2E); Killer cell lectin-like receptor C4 (KLRC4, NKG2F); Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); Killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); Killer cell lectin-like receptor D1 (KLRD1); SLAM family member 7 (SLAMF7); and Hematopoietic progenitor kinase 1 (HPK1, MAP4K1).;

[0684] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the reagents described herein are combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell - stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; Inducible T cell co - stimulator (ICOS, CD278); Inducible T cell co - stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7 - 1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM - 1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0685] In various embodiments, an agent as described herein is combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, an agent as described herein is combined with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis et al., Semin Immunol. (2017) 31:64–75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0686] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimetic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include organic small molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, small molecule inhibitors of CD274 or PDCD1 are selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.

[0687] Examples of CTLA4 inhibitors that can be co-administered include, but are not limited to: ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and the bispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0688] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (brugatimab), PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and the bispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1) MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1) and INBRX-105 (4-1BB / PDL1).

[0689] In various embodiments, an agent as described herein is combined with an anti-TIGIT antibody (such as BMS-986207, RG-6058, and AGEN-1307).

[0690] TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

[0691] In various embodiments, an agent as described herein is combined with an agonist of one or more members of the TNF receptor superfamily (TNFRSF), such as an agonist of one or more of the following: TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI Gene ID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI Gene ID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268, NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

[0692] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (talvolizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0693] Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0694] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0695] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0696] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to: MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, an antibody or fragment thereof that co-targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0697] Bispecific and Trispecific Natural Killer (NK) Cell Engagers

[0698] In various embodiments, an agent as described herein is combined with a bispecific NK cell engager (BiKE) or a trispecific NK cell engager (TriKE) (e.g., without an Fc) or a bispecific antibody against the following: NK cell activating receptors such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more HIV-related antigens as described herein. BiKEs and TriKEs are described, for example, in Felices et al., Methods Mol Biol. (2016) 1441:333-346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell engagers (TRiKEs) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.

[0699] Indoleamine-Pyrrole-2,3-Dioxygenase (IDO1) Inhibitors

[0700] In various embodiments, an agent as described herein is combined with indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), remestemcel-L, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0701] Toll-Like Receptor (TLR) Agonists

[0702] In various embodiments, an agent as described herein is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793).Exemplary TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (vismodegib), vismodegib analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, telamod, and BDB-001.TLR8 agonists include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include resatorvid, poly ICLC. Apoxxim, IPH-33, MCT-465, MCT-475, and ND-1.1. TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0703] CDK Inhibitors or Antagonists

[0704] In some embodiments, the agents described herein are combined with an inhibitor or antagonist of CDK. In some embodiments, the CDK inhibitor or antagonist is selected from the group consisting of VS2-370.

[0705] STING Agonists, RIG-I and NOD2 Modulators

[0706] In some embodiments, the agents described herein are combined with stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic di-AMP. In some embodiments, the agents described herein are combined with an RIG-I modulator (such as RGT-100) or an NOD2 modulator (such as SB-9200 and IR-103).

[0707] LAG-3 and TIM-3 Inhibitors

[0708] In certain embodiments, the agents as described herein are combined with an anti-TIM-3 antibody (such as TSR-022, LY-3321367, MBG-453, INCAGN-2390).

[0709] In certain embodiments, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation) antibody (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

[0710] Interleukin Agonists

[0711] In certain embodiments, the agents as described herein are combined with the following: interleukin agonists (such as IL-2, IL-7, IL-15, IL-10, IL-12) agonists; examples of IL-2 agonists such as proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2 / 15; examples of IL-15 agonists such as ALT-803, NKTR-255 and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15Synthorin (pegylated Il-15), P-22339 and IL-15-PD-1 fusion protein N-809; examples of IL-7 include but are not limited to CYT-107.

[0712] Examples of additional immune-based therapies that can be combined with the agents of the present disclosure include but are not limited to interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ; FLT3 agonists such as CDX-301, GS-3583, gepon, nomiflorone, pegylated interferon α-2a, pegylated interferon α-2b and RPI-MN.

[0713] Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

[0714] Examples of PI3K inhibitors include but are not limited to idelalisib, abemaciclib, buparlisib, orotic acid CAI, copanlisib, duvelisib, gedatolisib, neratinib, panpanlisib, perifosine, idelalisib, pilaralisib, perifosine, pimasertib, regorafenib, regorafenib 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-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

[0715] α-4 / β-7 Antagonists

[0716] Examples of integrin α-4 / β-7 antagonists include but are not limited to PTG-100, TRK-170, alirocumab, etrolizumab, methyl carlogras, and vedolizumab.

[0717] HPK1 Inhibitors

[0718] Examples of HPK1 inhibitors include but are not limited to ZYF-0272 and ZYF-0057.

[0719] HIV-Targeting Antibodies

[0720] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include but are not limited to Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies), TMB-360, TMB-370, and those antibodies targeting HIV gp120 or gp41, antibody recruitment molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, clone 3 human monoclonal antibody targeting KLIC (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0721] A variety of bNAbs can be used. Examples include, but are not limited to, U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, 10,239,935, US2018371086, US2020223907, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, and PCT / US2015 / 41272, and WO2017 / 096221, including antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include those described in the following: Klein et al., Nature, 492(7427):118-22 (2012); Horwitz et al., Proc Natl Acad Sci U S A, 110(41):16538-43 (2013); Scheid et al., Science, 333:1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42(Suppl. Database issue):D1133-9 (2014); Mascola et al., Immunol Rev., 254(1):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to V1V2-glycan), 2G12 (which binds to external domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site).

[0722] Other broadly neutralizing antibodies that can be used as a second therapeutic agent in combination therapies are described, for example, in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594 and WO 2012 / 154312, WO2012 / 158948, WO 2013 / 086533, WO 2013 / 142324, WO2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, WO 2015 / 103549, WO 2015 / 117008, WO2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO2017 / 096221, WO 2017 / 133639, WO 2017 / 133640, the entire contents of which are hereby incorporated by reference herein for all purposes. Additional examples include, but are not limited to, those described in Sajadi et al., Cell. (2018) 173(7):1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1):156-64; Klein et al., Nature, 492(7427):118-22 (2012); Horwitz et al., Proc Natl Acad Sci U S A, 110(41):16538-43 (2013); Scheid et al., Science, 333:1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42 (Database issue):Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as those in 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074 and LN01 (all of which bind the MPER of gp41).

[0723] Examples of additional antibodies include, but are not limited to, Bavifermin, UB-421, BF520.1, BiIA-SG, CH01, CH59, C2F5, C4E10, C2F5 + C2G12 + C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, Cl3hmAb, GS-9722 (Ibalizumab), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (Ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (Ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8 - 5R - 100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

[0724] Examples of HIV bispecific and trispecific antibodies include, but are not limited to, MGD014, B12BiTe, BiIA - SG, TMB - bispecific, SAR - 441236, VRC - 01 / PGDM - 1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121 - VRC01.

[0725] Examples of in vivo delivered bNAbs include, but are not limited to, AAV8 - VRC07, mRNA encoding the anti - HIV antibody VRC01, and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med., 2019, 1301).

[0726] Pharmacokinetic Enhancers

[0727] Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir.

[0728] Additional Therapeutic Agents

[0729] Examples of additional therapeutic agents include, but are not limited to, the 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), and WO 2013 / 091096 (Boehringer Ingelheim).

[0730] HIV Vaccines

[0731] Examples of HIV vaccines include, but are not limited to, peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors such as Ad5, Ad26 or Ad35), simian adenoviruses (chimpanzee, gorilla, rhesus macaque, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus-based vaccines, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (such as LCMV, Pichinde), bisegmented or trisegmented arenavirus-based vaccines, trimer-based HIV-1 vaccines, measles virus-based vaccines, flavivirus vector-based vaccines, tobacco mosaic virus vector-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, and avipoxvirus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines, rhabdovirus-based vaccines such as VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines such as Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, : DOI 10.1128 / CVI.00298-16); LNP-formulated mRNA-based therapeutic vaccines; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0732] Examples of HIV vaccines include: AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664gp140 adjuvant vaccine, BG505SOSIP.GT1.1 gp140 adjuvant vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA triple vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConMSOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAX B / E (gp120), monomeric gp120 HIV-1 subtype C vaccine, MPER-656 liposomal subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multi-stage DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSPISA-51, poly-ICLC adjuvant vaccine, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, based on N123-VRC-34.01 HIV vaccines that induce antigens, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vector vaccines expressing SCaVII, 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, VIR-1111, IHV-001 and virus-like particle vaccines (such as pseudovirus particle vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIVgag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugated polypeptide vaccine, dendritic cell vaccine (such as DermaVir), gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II antigen hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol envA / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; Vaccines based on eOD-GT8 60mer, 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-1 vaccine (GLA-SE adjuvant), HIV p24gag prime-boost plasmid DNA vaccine, HIV-1iglb12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, arenavirus vector-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based prophylactic vaccine, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Research Center), TBL-1203HI, CH505 TF chTrimer, CD40.HIVRI.Env vaccine, Drep-HIV-PT-1, mRNA-1644, and mRNA-1574.

[0733] Contraceptive (Birth Control) Drug Combination Therapies

[0734] In certain embodiments, the agents described herein are combined with a birth control or contraceptive regimen. Therapeutic agents for birth control (contraceptives) that can be combined with the agents of the present disclosure include, but are not limited to, cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolic acid, levonorgestrel, linestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norethisterone, norethynodrel, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof.

[0735] In a specific embodiment, the compound or a pharmaceutically acceptable salt thereof disclosed herein is combined with one, two, three, or four 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); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); (Bictegravir + Emtricitabine + Tenofovir Alafenamide), Adefovir; Adefovir Dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir Alafenamide and Elvitegravir; Tenofovir Alafenamide + Elvitegravir (Rectal Preparation, HIV Infection); Tenofovir Disoproxil Fumarate; Tenofovir Disoproxil Fumarate; Tenofovir Alafenamide; Tenofovir Alafenamide Hemifumarate; (Dolutegravir, Abacavir and Lamivudine); Dolutegravir, Abacavir Sulfate and Lamivudine; Raltegravir; Pegylated Raltegravir; Raltegravir and Lamivudine; Lamivudine + Lopinavir + Ritonavir + Abacavir; Maraviroc; Tenofovir + Emtricitabine + 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; Pratin; Fosamprenavir; Fosamprenavir Calcium Efavirenz; Etravirine; Nelfinavir; Nelfinavir Mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir Sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir Mesylate; Aldesleukin; Zalcitabine; Telaprevir; Amprenavir; Delavirdine; Delavirdine Mesylate; Radha-108 (Receptor Alcohol); Lamivudine and Tenofovir Disoproxil Fumarate; Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate; Azidothymidine Phosphate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir Sulfate.

[0736] In some embodiments, the agents or pharmaceutical compositions disclosed herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the agents or pharmaceutical compositions disclosed herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In additional embodiments, the agents or pharmaceutical compositions disclosed herein are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the agents or pharmaceutical compositions disclosed herein are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the agents or pharmaceutical compositions disclosed herein are combined with two HIV nucleosides or nucleotides inhibitors of reverse transcriptase.

[0737] In another embodiment, the agents or pharmaceutical compositions disclosed herein are combined with a first additional therapeutic agent and a second additional therapeutic agent, the first additional therapeutic agent selected from the group consisting of dolutegravir, cabotegravir, islatravir, delavirdine, bictegravir, essexavirine, rilpivirine, and lenacapavir, and the second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0738] In some embodiments, the agents or pharmaceutical compositions disclosed herein are combined with a first additional therapeutic agent (a contraceptive agent) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol diacetate, etonogestrel, levomefolic acid, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norethisterone, norethynodrel, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof.

[0739] Gene Therapy and Cell Therapy

[0740] In certain embodiments, the agents described herein are combined with gene therapy or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modification that silences genes; gene methods that directly kill infected cells; infusion of immune cells that are designed to replace most of the patient's own immune system to enhance the immune response against infected cells, or activate the patient's own immune system to kill infected cells, or find and kill infected cells; gene methods that modify cell activity to further alter the endogenous immune response against infection. Examples of cell therapy include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPC overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapy include, but are not limited to, AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T, SB-728-HSPC. CCR5 gene inhibitors include, but are not limited to, Cal-1 and autologous CD34-positive hematopoietic progenitor cells transduced with lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy (HIV infection / HIV-associated lymphoma). In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy.

[0741] Gene Editing Agents

[0742] In certain embodiments, the agents described herein are combined with gene editors (e.g., HIV-targeted gene editors). In various embodiments, the genome editing system can be selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and meganuclease complexes. Exemplary HIV-targeted CRISPR / Cas9 systems include, but are not limited to, EBT-101.

[0743] CAR-T Cell Therapy

[0744] In some embodiments, the agents described herein can be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR) that comprises an HIV antigen-binding domain. HIV antigens include the HIV envelope protein or portions thereof, gp120 or portions thereof, the CD4-binding site on gp120, the CD4-induced binding site on gp120, the N-glycan on gp120, the V2 of gp120, the membrane-proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic. Examples of HIV CAR-Ts include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIVduoCAR-T, anti-CD4 CART cell therapy, CD4 CAR + C34-CXCR4+CCR5 ZFN T cells, dual anti-CD4 CART-T cell therapy (CD4 CAR + C34-CXCR4 T cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells engineered to express CD4 CAR and C46 peptide.

[0745] TCR T Cell Therapy

[0746] In certain embodiments, the agents described herein are combined with a population of TCR-T cells. The TCR-T cells are engineered to target an HIV-derived peptide present on the surface of virus-infected cells, such as ImmTAV.

[0747] B Cell Therapy

[0748] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells genetically modified to express a broadly neutralizing antibody, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaa x0644 (2019), May 17, 2019).

[0749] A compound as disclosed herein (e.g., any compound of formula I) can be combined with one, two, three, or four additional therapeutic agents at any dose of the compound of formula I (e.g., 1 mg to 500 mg of the compound).

[0750] In one embodiment, a kit is provided that comprises a combination of a compound or a pharmaceutically acceptable salt thereof disclosed herein and one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0751] In one embodiment, one or more of the additional therapeutic agents of the kit are 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, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy), compounds targeting the HIV capsid, latency reversing agents, HIV bNAb, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, defensin modulators, CDK-9 inhibitors, dendritic ICAM-3-grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase primer complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0752] 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 reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0753] 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, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitory compound. In further embodiments, 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 HIV nucleoside inhibitor of 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 HIV nucleosides or nucleotides inhibitors of reverse transcriptase. In a 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 capsid inhibitor. In a specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor. In a specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and an HIV capsid inhibitor. In a specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAbs. In a specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor. In a specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, and a nucleoside inhibitor of HIV reverse transcriptase.

[0754] Long-Acting HIV Treatments

[0755] Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, islatravir implant, doravirine, raltegravir, and long-acting dolutegravir.

[0756] VII. Examples

[0757] Intermediate A: (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4] diazonine-10-carboxamide:

[0758]

[0759] Step 1 : (3S,7S)-7-Methyl-2,3,4,7-Tetrahydro-1H-Azepin-3-Amine Synthesis Step 2 :

[0760] Trifluoroacetic acid (20 mL) was added to (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-azepine -1-benzyl formate (6.2 g, 15.7 mmol), and the reaction mixture was heated to 100 °C for 4 hours. The reaction mixture was concentrated and the crude product was used directly in the next step.

[0761] (3S,7S)-12-(Benzyloxy)-3-Methyl-1,11-Dioxo-N-(2,4,6-Trifluorobenzyl)-1,6, : (3S,7S)-12-(Benzyloxy)-3-Methyl-1,6,11-Trioxo-N-(2,4,6-Trifluorobenzyl)-1, (3S,7S)-12-(Benzyloxy)-3-Methyl-1,6,11-Trioxo-N-(2,4,6-Trifluorobenzyl)-1, :

[0762] Methanol (300 mL) and water (30 mL) were added to methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (6.75 g, 15.7 mmol) and (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepine -3-amine (crude reaction product from the previous step). At room temperature, NaHCO 3(13.2 g, 157 mmol) was added to the reaction mixture. The reactants were stirred overnight at room temperature and then heated to 60 °C for 5 h. The reaction mixture was concentrated, then ethyl acetate was added, and it was washed with saturated ammonium chloride solution. The organic layer was concentrated and purified by silica gel chromatography (eluted with 0%-10% MeOH / DCM) to give (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide. MS (m / z) 524.11 [M+H]+.

[0763] (3S,7S)-12-(Benzyloxy)-3-Methyl-1,6,11-Trioxo-N-(2,4,6-Trifluorobenzyl)-1, : (3S,7S)-12-(Benzyloxy)-3-Methyl-1,6,11-Trioxo-N-(2,4,6-Trifluorobenzyl)-1, (3S,7S)-12-(Benzyloxy)-3-Methyl-1,6,11-Trioxo-N-(2,4,6-Trifluorobenzyl)-1, :

[0764] Selenium dioxide (17.4 g, 157 mmol) was added to a solution of (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (the product of the previous step, 15.7 mmol) in dioxane (160 mL). Then the reactants were heated to 105 °C overnight. The reaction mixture was cooled and the solid was filtered out. The filtrate was extracted with ethyl acetate and saturated ammonium chloride solution. The organic layer was concentrated and purified by silica gel chromatography (eluted with 40%-100% ethyl acetate / hexane) to give (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide. MS (m / z) 538.095 [M+H]+.

[0765] Intermediate B: (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide:

[0766]

[0767] (3S,7R)-12-(Benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (132 mg, 0.246 mmol) was dissolved in anhydrous THF (3.0 mL), and the resulting mixture was cooled to -20 °C. A 3.0 M ethereal solution of methylmagnesium bromide (0.41 mL, 1.23 mmol) was added to the stirred and cooled mixture. After stirring for 20 minutes, the reaction was quenched with saturated NH 4 Cl. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting product was purified by silica gel chromatography (0 - 100% EtOAc / hexane). MS (m / z) 553.95 [M+H]+.

[0768] Intermediate C: (3S,7S)-12-(Benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide:

[0769]

[0770] (3S,7S)-12-(Benzyloxy)-3-Methyl-1,6,11-Trioxo-N-(2,4,6-Trifluorobenzyl)-1, : (3S,6S,7R)-12-(Benzyloxy)-6-Hydroxy-3,6-Dimethyl-1,11-Dioxo-N-(2,4,6- (3S,6S,7R)-12-(Benzyloxy)-6-Hydroxy-3,6-Dimethyl-1,11-Dioxo-N-(2,4,6- (3S,6S,7R)-12-(Benzyloxy)-6-Hydroxy-3,6-Dimethyl-1,11-Dioxo-N-(2,4,6- :

[0771] (3S,6S,7R)-12-(Benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (3.15 g, 5.69 mmol) was added to a round-bottom flask, and then Fe(acac) 3 (1.01 g, 2.85 mmol), EtOH (60 mL), PhSiH 3(2.90 mL, 22.8 mmol) and PhSH (5.69 mL, 2.85 mmol, 0.5 M solution in iPrOH). The resulting slurry was stirred at room temperature for 48 h. The reaction mixture was then concentrated in vacuo and the residue was purified by silica gel chromatography (hexane solution of 20% to 100% ethyl acetate), followed by a second purification by reverse phase chromatography (aqueous solution of 5% to 100% acetonitrile buffered with 10 mM ammonium formate, pH = 3.8). The corresponding fractions were combined, extracted with dichloromethane, and concentrated in vacuo to give (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide. MS (m / z) 556.4 [M+H]+.

[0772] (3S,7S)-12-(Benzyloxy)-3-Methyl-6-Methylene-1,11-Dioxo-N-(2,4,6-Trifluorobenz : (3S,7S)-12-(Benzyloxy)-3-Methyl-6-Methylene-1,11-Dioxo-N-(2,4,6-Trifluorobenz (Base)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Synthesis) :

[0773] To a round-bottom flask was added (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (3.20 g, 5.76 mmol), and then dichloromethane (90 mL) was added. Martin's sulfurane (8.91 g, 13.2 mmol) was added to the suspension in two portions, and the mixture was stirred at room temperature for 1 h. The resulting solution was then concentrated in vacuo and the residue was purified by reverse phase chromatography (aqueous solution of 5% to 100% acetonitrile buffered with 10 mM ammonium formate, pH = 3.8). The corresponding fractions were combined and lyophilized to give (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide. MS (m / z) 538.4 [M+H]+.

[0774] Intermediate D: (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide:

[0775]

[0776] This intermediate is prepared in a similar manner to (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate A), except that methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate is used in Step 2. MS (m / z) 520.200 [M+H]+.

[0777] Intermediate E: (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide:

[0778]

[0779] This intermediate is prepared in a similar manner to (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate B), except that (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate D) is used. MS (m / z) 536.4 [M+H]+.

[0780] Intermediate F: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide:

[0781]

[0782] (Step 1) : (3S,6S,7R)-N-(2,4-Difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo- (Synthesis of 1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide) (Synthesis) :

[0783] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (5.90 g, 11.0 mmol, 1 equiv) in methanol (500 mL) and CH 2 Cl 2 (170 mL) was added platinum(IV) oxide (0.72 g, 3.17 mmol, 0.29 equiv). The flask was degassed and backfilled with nitrogen (3x), then degassed and backfilled with hydrogen (3x). The reaction mixture was stirred at room temperature for 16 h and diluted with CH 2 Cl 2- . The reaction mixture was filtered through celite and concentrated. The residue was purified by column chromatography (0% to 10% MeOH / CH 2 Cl 2- ) and the fractions containing the product were combined and concentrated. The residue was triturated with MeOH and dried in a vacuum oven to afford (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide. MS (m / z) 448.26 [M+H]+.

[0784] (Step 2) : (3S,6S,7R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11- (Dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide) (Synthesis) :

[0785] To a suspension of (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (1.202 g, 2.69 mmol, 1 equiv) and potassium carbonate (2.225 g, 16.1 mmol, 6 equiv) in DMF (27 mL) was added benzyl bromide (0.957 mL, 8.06 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na 2 SO 4Dry, filter and concentrate. Purify the residue by column chromatography (0% to 100% EtOAc / hexane) to obtain (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide. MS (m / z) 538.11 [M+H]+.

[0786] (Step 3) : (3S,7S)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo (1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide) (Synthesis) :

[0787] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (1.258 g, 2.34 mmol, 1 eq) in toluene (15 mL) was added Martin's sulfurane (3.933 g, 5.85 mmol, 2.5 eq). The reaction mixture was heated to 40 °C for 1 h and concentrated. Purify the residue by column chromatography (0% to 100% EtOAc / hexane) to obtain (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide. MS (m / z) 520.12 [M+H]+.

[0788] Intermediate G: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide:

[0789]

[0790] To a suspension of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (0.525 g, 0.98 mmol) (Intermediate E) in toluene (10 ml) was added Martin's sulfurane (1.98 g, 2.94 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with EtOAc and washed with H 2 O and brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography to give (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide. MS (m / z) 518.23 [M+H]+.

[0791] Example 1: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclonene]-10'-carboxamide:

[0792]

[0793] (Step 1) : (3'S,5S,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'- (Dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a] [1,4]diazacyclonene]-10'-carboxamide and (3'S,5R,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-3, (3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methano (Pyrido[1,2-a][1,4]diazacyclonene]-10'-carboxamide preparation) :

[0794] To a solution of acetaldehyde oxime (666 mg, 11.3 mmol) in DMF (50 ml) at room temperature was added N-chlorosuccinimide (1.51 g, 11.3 mmol), and then the mixture was heated to 60 °C for 1 hour. After cooling to room temperature, (1S,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-13-methylene-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (Intermediate F) (1.58 g, 3.04 mmol) and triethylamine (1.539 g, 15.2 mmol) were added. After stirring the reaction mixture at room temperature overnight, by adding saturated NaHCO 3The reaction was quenched with the solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 4, filtered, concentrated and purified by silica gel column chromatography (eluting with 0% to 100% EtOAc / hexane) to give two separable isomers. MS (m / z) 577.135 [M+H]+ (major); 577.115 [M+H]+ (minor).

[0795] (Step 2) : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo (1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1, (4]diazacyclonene]-10'-carboxamide preparation) :

[0796] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (64.7 mg, 0.112 mmol) in toluene (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by reverse-phase HPLC, eluting with 10% to 90% aqueous acetonitrile to give the title compound. MS (m / z) 487.12 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.53 (s, 1H), 8.43 (s, 1H), 7.37 (td, J = 8.6, 6.3 Hz, 1H), 6.92–6.78 (m, 2H), 4.82–4.70 (m, 1H), 4.67 (t, J = 4.8 Hz, 2H), 4.18 (d, J = 2.2 Hz, 1H), 3.86 (dd, J = 14.9, 1.9 Hz, 1H), 3.72 (dd, J = 14.9, 2.7 Hz, 1H), 2.94 (d, J = 17.8 Hz, 1H), 2.53 (d, J = 17.7 Hz, 1H), 2.06 (s, 3H), 2.04–1.88 (m, 3H), 1.56 (dd, J = 14.3, 11.2 Hz, 1H), 1.32 (d, J = 6.6 Hz, 3H).

[0797] Example 2: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0798]

[0799] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (396 mg, 0.687 mmol) in toluene (5 mL) was added TFA (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC, eluting with 10% to 90% aqueous acetonitrile to give the title compound. MS (m / z) 487.103 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.53 (d, J = 5.8 Hz, 1H), 8.41 (s, 1H), 7.38 (q, J = 7.8 Hz, 1H), 6.95–6.74 (m, 2H), 4.83–4.69 (m, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.25 (s, 1H), 3.77 (dd, J = 15.2, 3.0 Hz, 1H), 3.44 (d, J = 15.2 Hz, 1H), 3.00 (d, J = 16.9 Hz, 1H), 2.83 (d, J = 16.9 Hz, 1H), 2.32–2.12 (m, 1H), 2.04 (s, 3H), 1.83 (dd, J = 15.3, 7.4 Hz, 1H), 1.75–1.58 (m, 1H), 1.42–1.33 (m, 1H), 1.30 (d, J = 6.6 Hz, 3H).

[0800] Example 3: Preparation of (3'S,5S,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0801]

[0802] (Step 1) : (3'S,5S,7'R)-12'-(Benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-tri (Fluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2- (a][1,4]diazacyclonene]-10'-carboxamide and (3'S,5R,7'R)-12'-(Benzyloxy)-3,3'-dimethyl-1', 11'-Dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2, Preparation of [7]methanobridgedpyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide :

[0803] To a solution of acetaldoxime (160 mg, 2.71 mmol) in DMF (5 mL) at room temperature was added N-chlorosuccinimide (90.5 mg, 0.68 mmol), and then the mixture was heated to 60 °C and maintained for 1 hour. After cooling to room temperature, (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate C) (119 mg, 0.221 mmol) and triethylamine (112 mg, 1.1 mmol) were added at room temperature. After stirring the reaction mixture overnight at room temperature, the reaction was quenched by adding saturated NaHCO 3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 , filtered, concentrated and purified by silica gel column chromatography (eluting with 0% to 100% EtOAc / hexane) to give two separable isomers. MS (m / z) 595.06 [M+H]+ (major); 595.09 [M+H]+ (minor).

[0804] Step 2 : (3'S,5S,7'R)-12'-Hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2, 7]methanobridgedpyrido[1,2-a][1, 4]diazacyclononene]-10'-carboxamide :

[0805] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclonene]-10'-carboxamide (72.3 mg, 0.122 mmol) in toluene (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC, eluting with 10% to 90% aqueous acetonitrile to give the title compound. MS (m / z) 505.129 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 10.51–10.41 (m, 1H), 8.40 (s, 1H), 6.70 (dd, J = 8.7, 7.5 Hz, 2H), 4.71 (ddd, J = 17.6, 11.2, 5.9 Hz, 3H), 4.13 (d, J = 2.6 Hz, 1H), 3.86 (dd, J = 14.9, 1.8 Hz, 1H), 3.70 (dd, J = 14.9, 2.7 Hz, 1H), 2.93 (d, J = 17.8 Hz, 1H), 2.52 (d, J = 17.8 Hz, 1H), 2.13–1.89 (m, 6H), 1.57 (d, J = 10.9 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H).

[0806] Example 4: Preparation of (3'S,5R,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0807]

[0808] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (10.8 mg, 0.018 mmol) in toluene (1 mL) was added TFA (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse-phase HPLC, eluting with an aqueous solution of 10% to 90% acetonitrile to give the title compound. MS (m / z) 505.142 [M+H] + 。 1HNMR (400 MHz, chloroform-d) δ 10.41 (s, 1H), 8.37 (s, 1H), 6.78–6.59 (m, 2H), 4.86–4.56 (m, 3H), 4.13 (s, 1H), 3.76 (dd, J = 15.2, 3.0 Hz, 1H), 3.43 (d, J = 15.5 Hz, 1H), 3.02 (d, J = 16.9 Hz, 1H), 2.81 (d, J = 16.9 Hz, 1H), 2.27–2.17 (m, 1H), 2.06 (s, 3H), 1.82 (dd, J = 15.3, 7.4 Hz, 1H), 1.74–1.63 (m, 1H), 1.40–1.32 (m, 1H), 1.30 (d, J = 6.6 Hz, 3H).

[0809] Example 5: Preparation of (3'S,4'S,5R,7'R)-N-(2,4-difluorobenzyl)-4'-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0810]

[0811] Step 1 : (3S,7S)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanobridgedpyrido[1,2-a][1,4]diazacyclononene-10-carboxamide Preparation of :

[0812] To a suspension of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate E) (0.525 g, 0.98 mmol) in toluene (10 ml) was added Martin's sulfurane (1.98 g, 2.94 mmol). The reaction mixture was then stirred at room temperature for 20 minutes. The reaction mixture was diluted with EtOAc and washed with H 2 O and brine. The organic layer was dried over MgSO 4 . After removal of the solvent in vacuo, the residue was purified by silica gel chromatography to afford the title compound. MS (m / z) 518.23 [M + H]+.

[0813] Step 2 : (3'S,5R,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'- dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanobridgedpyrido[1,2-a][1,4] diazacyclononene]-10'-carboxamide :

[0814] To a solution of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (0.335 g, 0.647 mmol) in DMF (2 ml) was added (1Z)-N-hydroxyacetimidoyl chloride (0.303 g, 3.24 mmol), followed by triethylamine (0.655 g, 6.47 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with H2O, 5% LiCl (aqueous solution) and brine. The organic phase was dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound. MS (m / z) 575.58 [M+H]+.

[0815] Step 3 : (3'S,4'R,5R,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-di methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanobridged pyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide :

[0816] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclonene]-10'-carboxamide (0.2 g, 0.353 mmol) in i-PrOH (3 ml) and DCM (2 ml) was added phenylsilane (0.11 g, 1.06 mmol), followed by tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (0.011 g, 0.0018 mmol). The reaction mixture was then stirred under an O 2 (g) atmosphere for 24 h. The reaction was quenched by the addition of 10% sodium thiosulfate and then extracted with EtOAc. The organic phase was washed with H 2 2O, brine and dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound. MS (m / z) 593.05 [M+H]+.

[0817] Step 4 : (3'S,4'S,5R,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanobridgedpyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide Preparation of :

[0818] To a solution of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (60 mg, 0.101 mmol) in DCM (2 mL) was added a toluene solution of deoxofluor (50%, 0.375 mL, 1.01 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and the reaction was quenched by the addition of saturated NaHCO 3 solution. The mixture was extracted with DCM, the organic separated phase was dried over MgSO 4 , filtered, concentrated and purified by silica gel column chromatography (eluting with 0%-100% hexane / EtOAc) to afford the title compound. MS (m / z) 595.04 [M+H]+.

[0819] Step 5 : (3'S,4'S,5R,7'R)-N-(2,4-difluorobenzyl)-4'-fluoro-12'-hydroxy-3,3'-dimethyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanobridgedpyrido [1,2-a][1,4]diazacyclononene]-10'-carboxamide :

[0820] To a solution of (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (11 mg, 0.0185 mmol) in toluene (1 mL) was added TFA (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse-phase HPLC, eluting with 5%-100% aqueous acetonitrile to afford the title compound. MS (m / z) 505.40 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.24 (t, J = 5.9 Hz, 1H), 8.23 (s, 1H), 7.39 (td, J = 8.6, 8.2, 6.2 Hz, 1H), 6.91–6.57 (m, 2H), 5.03 (dt, J = 46.9, 5.7 Hz, 1H), 4.93–4.78 (m, 1H), 4.76–4.52 (m, 2H), 4.26 (dd, J = 17.1, 2.7 Hz, 2H), 3.81 (d, J = 14.4 Hz, 1H), 2.84–2.65 (m, 3H), 2.14 (s, 3H), 2.03–1.82 (m, 1H), 1.48 (dd, J = 7.1, 2.3 Hz, 3H).

[0821] Example 6: Preparation of (3'S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0822]

[0823] Step 1 : ((3'S,5S,7'R)-12'-(Benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5', 11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclonon Preparation of tert-butyl (2,4-difluorobenzyl)carbamate of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclonon-10'-ylidene)carbonyl :

[0824] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (631 mg, 1.11 mmol) in toluene (20 ml) was added di-tert-butyl dicarbonate (1.45 g, 6.64 mmol) and DMAP (608 mg, 4.98 mmol). The reaction mixture was then heated to 110 °C for 4 h. After cooling the reaction mixture to room temperature, the reaction was quenched by adding saturated NaHCO 3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 , filtered, concentrated and purified by silica gel column chromatography (eluting with 30% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 676.924 [M+H]+.

[0825] Step 2 : (3'S,5S,7'R)-12'-(Benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5', 11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclonon ene]-10'-carboxylic acid preparation :

[0826] To a solution of tert-butyl ((3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carbonyl)(2,4-difluorobenzyl)carbamate (590 mg, 0.872 mmol) in MeOH (10 ml) was added 1N NaOH solution (3 ml). After 1 h at room temperature, the reaction was quenched by adding 1N HCl solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 , filtered, concentrated to give the crude title compound, which was used without purification. MS (m / z) 452.127 [M+H]+.

[0827] Step 3 : (3'S,5S,7'R)-12'-(Benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3,3'-dimethyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1, 2-a][1,4]diazacyclononene]-10'-formamide preparation :

[0828] At room temperature, (3-chloro-2,4-difluorophenyl)methanamine (30.7 mg, 0.173 mmol), HATU (98.5 mg, 0.259 mmol) and DEA (149 mg, 1.15 mmol) were added to a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxylic acid (65 mg, 0.144 mmol) in DMF (5 ml). After 1 hour at room temperature, the reaction was quenched by the addition of saturated NaHCO 3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 , filtered, concentrated and purified by silica gel column chromatography (eluting with 50% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 611.075 [M+H]+.

[0829] Step 4 : (3'S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'- dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a] [1,4]diazacyclononene]-10'-formamide preparation :

[0830] TFA (0.5 mL) was added to a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (88 mg, 0.144 mmol) in toluene (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC, eluting with 10% to 90% aqueous acetonitrile to give the title compound. MS (m / z) 521.181 [M+H]+. 11H NMR (400 MHz, chloroform-d) δ 10.59–10.49 (m, 1H), 8.39 (s, 1H), 7.32–7.27 (m, 1H), 6.96 (td, J = 8.5, 1.8 Hz, 1H), 4.72 (ddd, J = 19.4, 7.9, 4.5 Hz, 3H), 4.15 (s, 1H), 3.87 (dd, J = 14.9, 1.9 Hz, 1H), 3.71 (dd, J = 14.9, 2.7 Hz, 1H), 2.93 (d, J = 17.7 Hz, 1H), 2.59–2.49 (m, 1H), 2.15–1.92 (m, 6H), 1.56 (dd, J = 14.2, 11.2 Hz, 1H), 1.32 (d, J = 6.6 Hz, 3H).

[0831] Example 7: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-isopropyl-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0832]

[0833] (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-isopropyl-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide was prepared in a manner similar to Example 1, except that isobutyraldehyde oxime was used in Step 1. MS (m / z) 515.152 [M+H]+. 1 1H NMR (400 MHz, chloroform-d) δ 10.40 (s, 1H), 8.32 (s, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.83 (q, J = 9.7, 9.1 Hz, 2H), 4.84–4.75 (m, 1H), 4.67 (t, J = 5.4 Hz, 2H), 4.02 (s, 1H), 3.77 (dd, J = 15.2, 3.0 Hz, 1H), 3.49–3.42 (m, 1H), 3.01 (d, J = 16.8 Hz, 1H), 2.83–2.71 (m, 2H), 2.24 (d, J = 7.7 Hz, 1H), 1.86–1.81 (m, 2H), 1.70 (s, 1H), 1.31 (d, J = 6.5 Hz, 3H), 1.23 (d, J = 6.9 Hz, 6H).

[0834] Example 8: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-ethyl-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0835]

[0836] The title compound was prepared in a similar manner to Example 1, except that propionaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 501.2 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.76 (s, 1H), 8.61 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 6.88 (m, 2H), 4.74–4.53 (m, 5H), 3.76 (d, J = 14.7 Hz, 1H), 3.56 (d, J = 14.8 Hz, 1H), 2.75 (d, J = 16.7 Hz, 1H), 2.47 (d, J = 16.8 Hz, 1H), 1.97–1.50 (m, 7H), 1.45 (t, J = 12.7 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H).

[0837] Example 9: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-(2,2,2-trifluoroethyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0838]

[0839] The title compound was prepared in a similar manner to Example 3, except that 3,3,3-trifluoropropionaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 573.09 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.55 (t, J = 5.8 Hz, 1H), 8.55 (s, 1H), 6.76–6.64 (m, 2H), 4.83–4.68 (m, 2H), 4.66 (dd, J = 14.6, 5.6 Hz, 1H), 4.26 (d, J = 2.2 Hz, 1H), 3.86 (dd, J = 15.0, 1.8 Hz, 1H), 3.74 (dd, J = 15.0, 2.6 Hz, 1H), 3.47–3.17 (m, 2H), 3.11 (d, J = 18.0 Hz, 1H), 2.65 (d, J = 18.0 Hz, 1H), 2.15–1.90 (m, 3H), 1.63–1.50 (m, 1H), 1.33 (d, J = 6.6 Hz, 3H).

[0840] Example 10: Preparation of (3'S,5S,7'R)-3-(4-chlorobutyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0841]

[0842] The title compound was prepared in a similar manner to Example 3, except that 5-bromovaleraldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 581.223 [M+H]+. 1 1H NMR (400 MHz, chloroform-d) δ 10.35 (t, J = 5.7 Hz, 1H), 8.33 (s, 1H), 6.77–6.62 (m, 2H), 4.70 (td, J = 12.4, 10.4, 5.9 Hz, 3H), 4.08 (s, 1H), 3.85 (dd, J = 14.9, 1.8 Hz, 1H), 3.76–3.66 (m, 1H), 3.61 (td, J = 6.3, 2.4 Hz, 2H), 2.91 (d, J = 17.7 Hz, 1H), 2.57 (s, 1H), 2.53 (s, 1H), 2.49–2.41 (m, 2H), 1.99 (dd, J = 15.9, 9.1 Hz, 2H), 1.95–1.83 (m, 2H), 1.83–1.73 (m, 2H), 1.62–1.52 (m, 1H), 1.31 (d, J = 6.6 Hz, 3H).

[0843] Example 11: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-phenyl-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0844]

[0845] The title compound was prepared in a similar manner to Example 1, except that benzaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 549.127 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ 10.44 (t, J = 5.9 Hz, 1H), 8.48 (s, 1H), 7.68–7.56 (m, 2H), 7.52–7.39 (m, 3H), 7.37 (d, J = 6.4 Hz, 1H), 6.91–6.76 (m, 2H), 4.80 (d, J = 6.7 Hz, 1H), 4.65 (dd, J = 12.1, 5.9 Hz, 2H), 4.32 (d, J = 2.3 Hz, 1H), 3.93 (dd, J = 14.9, 1.9 Hz, 1H), 3.76 (dd, J = 14.9, 2.7 Hz, 1H), 3.38 (d, J = 17.2 Hz, 1H), 2.94 (d, J = 17.2 Hz, 1H), 2.20–1.96 (m, 3H), 1.64 (dd, J = 14.7, 11.5 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0846] Example 12: Preparation of (3'S,5S,7'R)-3-benzyl-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0847]

[0848] The title compound was prepared in a similar manner to Example 1, except that 2-phenylacetaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 563.165 [M+H]+. 11H NMR (400 MHz, chloroform-d) δ 10.45 (t, J = 5.9 Hz, 1H), 8.36 (s, 1H), 7.39 (d, J = 6.4 Hz, 1H), 7.36–7.30 (m, 2H), 7.27 (s, 1H), 7.20 (dd, J = 6.9, 1.7 Hz, 2H), 6.95–6.75 (m, 2H), 4.68 (d, J = 6.0 Hz, 3H), 4.18 (s, 1H), 3.93 (d, J = 15.1 Hz, 1H), 3.84 (dd, J = 14.9, 1.9 Hz, 1H), 3.70 (dd, J = 14.9, 2.7 Hz, 1H), 3.56 (d, J = 15.1 Hz, 1H), 2.85 (d, J = 17.6 Hz, 1H), 2.35 (d, J = 17.6 Hz, 1H), 2.11–1.89 (m, 2H), 1.80 (dd, J = 15.6, 6.4 Hz, 1H), 1.48–1.35 (m, 1H), 1.31 (d, J = 6.7 Hz, 3H).

[0849] Example 13: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-(pyridin-2-yl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0850]

[0851] The title compound was prepared in a similar manner to Example 1, except that N-hydroxypicolinimidoyl chloride was used instead of N-hydroxyacetimidoyl chloride in Step 1. MS (m / z) 550.177 [M+H]+. 11H NMR (400 MHz, chloroform-d) δ 10.50 (t, J = 5.9 Hz, 1H), 8.66 (dd, J = 4.9, 1.5 Hz, 1H), 8.43 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.96–7.83 (m, 1H), 7.55–7.43 (m, 1H), 7.39 (d, J = 7.0 Hz, 1H), 6.93–6.74 (m, 2H), 4.89–4.75 (m, 1H), 4.67 (t, J = 5.1 Hz, 1H), 4.26 (s, 1H), 3.80 (dd, J = 15.3, 3.1 Hz, 1H), 3.56 (d, J = 3.5 Hz, 2H), 2.36–2.26 (m, 3H), 1.95 (dd, J = 15.2, 7.3 Hz, 1H), 1.81 (dd, J = 15.1, 11.8 Hz, 1H), 1.52 (s, 1H), 1.34 (d, J = 6.6 Hz, 3H).

[0852] Example 14: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-(pyridin-3-yl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0853]

[0854] The title compound was prepared in a similar manner to Example 1, except that N-hydroxynicotinimidoyl chloride was used instead of N-hydroxyacetimidoyl chloride in Step 1. MS (m / z) 550.191 [M+H]+. 11H NMR (400 MHz, chloroform-d) δ 10.41 (t, J = 5.9 Hz, 1H), 8.95–8.90 (m, 1H), 8.77 (dd, J = 5.1, 1.6 Hz, 1H), 8.46 (s, 1H), 8.25 (dd, J = 8.1, 1.8 Hz, 1H), 7.63 (dd, J = 8.1, 5.1 Hz, 1H), 7.41–7.32 (m, 1H), 6.91–6.80 (m, 2H), 4.85–4.77 (m, 1H), 4.70–4.60 (m, 2H), 4.30 (s, 1H), 3.93 (dd, J = 14.9, 1.9 Hz, 1H), 3.78 (dd, J = 15.0, 2.7 Hz, 1H), 3.43 (d, J = 17.3 Hz, 1H), 2.99 (d, J = 17.3 Hz, 1H), 2.05 (s, 2H), 1.70 (d, J = 14.8 Hz, 2H), 1.36 (d, J = 6.7 Hz, 3H).

[0855] Example 15: Preparation of (3'S,5S,7'R)-3-cyclopropyl-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0856]

[0857] The title compound was prepared in a similar manner to Example 1, except that cyclopropanecarboxaldoxime was used instead of acetaldoxime in Step 1. MS (m / z) 513.16 [M+H]+. 1 1H NMR (400 MHz, chloroform-d) δ 10.43 (s, 1H), 8.35 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 6.83 (q, J = 10.0, 9.6 Hz, 2H), 4.83–4.71 (m, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.07 (s, 1H), 3.77 (d, J = 15.8 Hz, 1H), 3.42 (d, J = 15.1 Hz, 1H), 2.89 (d, J = 16.6 Hz, 1H), 2.63 (d, J = 16.6 Hz, 1H), 2.22 (dd, J = 15.0, 7.2 Hz, 2H), 1.81 (d, J = 7.7 Hz, 2H), 1.70 (d, J = 11.8 Hz, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.00 (d, J = 8.3 Hz, 2H), 0.88–0.77 (m, 2H).

[0858] Example 16: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0859]

[0860] The title compound was prepared in a similar manner to Example 1, except that 2-((tert-butyldimethylsilyl)oxy)acetaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 503.154 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ 10.63 (d, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.44–7.32 (m, 1H), 6.91–6.71 (m, 2H), 4.73 (dd, J = 14.8, 6.5 Hz, 2H), 4.65–4.49 (m, 2H), 4.37 (d, J = 13.9 Hz, 1H), 4.28 (s, 1H), 3.87–3.78 (m, 1H), 3.66 (d, J = 2.7 Hz, 1H), 3.14 (d, J = 17.9 Hz, 1H), 2.67 (d, J = 17.9 Hz, 1H), 2.12–1.96 (m, 3H), 1.78–1.65 (m, 1H), 1.32 (d, J = 6.7 Hz, 3H).

[0861] Example 17: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0862]

[0863] Step 1 : (E)-2-((tert-butyldiphenylsilyl)oxy)acetaldehyde oxime preparation :

[0864] To 2-[tert-butyl(diphenyl)silyl]oxyacetaldehyde (1 g, 3.35 mmol) in MeOH (15 ml) and H 2Hydroxylamine hydrochloride (0.28 g, 4.02 mmol) was added to a solution in O (5 ml), and then sodium bicarbonate (0.245 g, 4.02 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with H 2 O and brine. The organic phase was dried over MgSO 4 and the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography to afford the title compound. MS (m / z) 314.05 [M+H]+.

[0865] Step 2 : (3'S,5S,7'R)-12'-(Benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)- N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isox azole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-formamide and (3'S,5R,7' R)-12'-(Benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-meth yl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid ino[1,2-a][1,4]diazacyclononene]-10'-formamide preparation :

[0866] The title compound was prepared in a similar manner to Example 1, except that (E)-2-((tert-butyldiphenylsilyl)oxy)acetaldoxime was used instead of acetaldoxime. (3'S,5S,7'R)-12'-(Benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazepin]-10'-carboxamide was obtained as the major stereoisomer, and (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazepin]-10'-carboxamide was obtained as the minor stereoisomer. MS (m / z) 831.12 [M+H]+ (major); 831.13 [M+H]+ (minor).

[0867] Step 3 : (3'S,5S,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino [1,2-a][1,4]diazacyclononene]-10'-formamide preparation :

[0868] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (160 mg, 0.193 mmol) in THF (2 ml) was added TBAF (1 N) (0.578 ml, 0.578 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with NaHCO 3 (saturated) and brine. The organic phase was dried over MgSO 4 and the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography to afford the title compound. MS (m / z) 593.07 [M+H]+.

[0869] Step 4 : (3'S,5S,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino [1,2-a][1,4]diazacyclononen]-10'-carboxamide Preparation :

[0870] The title compound was prepared in a similar manner to Step 4 of Example 5, except that (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide was used instead of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 595.09 [M+H]+.

[0871] Step 5 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1, 2-a][1,4]diazacyclononen]-10'-carboxamide Preparation :

[0872] The title compound was prepared in a similar manner to Step 2 of Example 1, except that (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide was used instead of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 505.18 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ 10.49 (t, J = 6.0 Hz, 1H), 8.50 (s, 1H), 7.38 (td, J = 8.6, 6.4 Hz, 1H), 6.91–6.78 (m, 2H), 5.32 (s, 1H), 5.23 (s, 1H), 5.11 (s, 1H), 4.83–4.58 (m, 2H), 4.22 (s, 1H), 3.87 (dd, J = 15.0, 1.8 Hz, 1H), 3.74 (dd, J = 15.0, 2.6 Hz, 1H), 3.13 (dd, J = 18.0, 2.1 Hz, 1H), 2.71 (dd, J = 17.9, 2.4 Hz, 1H), 2.14–1.97 (m, 3H), 1.68–1.57 (m, 1H), 1.33 (d, J = 6.7 Hz, 3H).

[0873] Example 18: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0874]

[0875] The title compound was prepared in a similar manner to (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide in Example 17, except that (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide was used in Step 3 instead of (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 505.18 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.50 (t, J = 6.0 Hz, 1H), 8.40 (s, 1H), 7.38 (q, J = 8.1 Hz, 1H), 6.84 (q, J = 9.0 Hz, 2H), 5.25 (s, 1H), 5.13 (s, 1H), 4.79 (dt, J = 10.6, 6.7 Hz, 1H), 4.66 (d, J = 5.8 Hz, 2H), 4.23 (s, 1H), 3.79 (dd, J = 15.3, 3.1 Hz, 1H), 3.51–3.42 (m, 1H), 3.17 (d, J = 16.8 Hz, 1H), 3.02 (d, J = 17.2 Hz, 1H), 2.26 (dt, J = 14.7, 7.0 Hz, 1H), 1.88 (dd, J = 15.2, 7.4 Hz, 1H), 1.80–1.69 (m, 1H), 1.46–1.25 (m, 4H).

[0876] Example 19: Preparation of (3'S,5S,7'R)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0877]

[0878] The title compound was prepared in a manner similar to that of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide in Example 17, except that (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate C) was used instead of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate F) in Step 2. MS (m / z) 523.21 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.41 (t, J = 5.7 Hz, 1H), 8.52 (s, 1H), 6.81–6.57 (m, 2H), 5.16 (d, J = 46.5 Hz, 2H), 4.76 (dt, J = 12.0, 7.4 Hz, 2H), 4.63 (dd, J = 14.5, 5.5 Hz, 1H), 4.26 (s, 1H), 3.86 (dd, J = 15.0, 1.9 Hz, 1H), 3.73 (dd, J = 15.0, 2.7 Hz, 1H), 3.23–3.05 (m, 1H), 2.70 (dd, J = 17.8, 2.3 Hz, 1H), 2.09–1.89 (m, 3H), 1.72–1.51 (m, 1H), 1.33 (d, J = 6.7 Hz, 3H).

[0879] Example 20: Preparation of (3'S,5S,7'R)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0880]

[0881] Step 1 : (3'S,5S,7'R)-12'-(Benzyloxy)-3-formyl-3'-methyl-1',11'-dioxo-N-(2, 4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino [1,2-a][1,4]diazacyclononen]-10'-carboxamide Preparation :

[0882] At -78 °C, oxalyl chloride (0.118 ml, 1.39 mmol) was added dropwise to a mixture of DMSO (0.215 ml, 3.03 mmol) in DCM (2 ml). The mixture was stirred at -78 °C for 10 minutes, then (3'S,5S,7'R)-12'-(benzyloxy)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (370 mg, 0.606 mmol) prepared according to Example 19 in DCM (2 mL) was added dropwise. The resulting reaction mixture was stirred at -78 °C for 15 minutes. Triethylamine (0.426 ml, 3.03 mmol) was added to the reaction mixture and the cooling bath was removed. The reaction mixture was stirred at room temperature for 30 minutes. EtOAc was added to dilute the reaction mixture, then H 2 O and brine were added. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 609.09 [M+H]+.

[0883] Step 2 : (3'S,5S,7'R)-12'-(Benzyloxy)-3-(difluoromethyl)-3'-methyl-1',11'-dioxo-N- (2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyri dino[1,2-a][1,4]diazacyclononen]-10'-carboxamide Preparation :

[0884] The title compound was prepared in a similar manner to Step 4 of Example 5, except that (3'S,5S,7'R)-12'-(benzyloxy)-3-formyl-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide was used instead of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 631.13 [M+H]+.

[0885] Step 3 : (3'S,5S,7'R)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2, 4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino [1,2-a][1,4]diazacyclononen]-10'-carboxamide Preparation :

[0886] The title compound was prepared in a similar manner to Step 5 of Example 5, except that (3'S,5S,7'R)-12'-(benzyloxy)-3-(difluoromethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide was used instead of (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 541.21 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.55 (t, J = 5.9 Hz, 1H), 8.95 (s, 1H), 6.68 (t, J = 8.1 Hz, 2H), 6.57 - 6.30 (m, 1H), 4.89–4.73 (m, 3H), 4.50 (dd, J = 14.7, 4.9 Hz, 1H), 3.87 (dd, J = 15.1, 1.8 Hz, 1H), 3.78 (dd, J = 15.0, 2.5 Hz, 1H), 3.22 (d, J = 17.9 Hz, 1H), 2.66 (d, J = 17.8 Hz, 1H), 2.02 (dq, J = 20.9, 8.3, 6.4 Hz, 3H), 1.62 (dd, J = 13.9, 11.0 Hz, 1H), 1.34 (d, J = 6.6 Hz, 3H).

[0887] Example 21: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0888]

[0889] The title compound was prepared in a similar manner to Example 20, except that in Step 1, (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide was used instead of (3'S,5S,7'R)-12'-(benzyloxy)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 523.10 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.59 (t, J = 5.8 Hz, 1H), 8.85 (s, 1H), 7.36 (q, J = 8.1 Hz, 1H), 6.92–6.79 (m, 2H), 6.61–6.34 (m, 1H), 4.83–4.60 (m, 3H), 4.50 (s, 1H), 3.87 (dd, J = 15.0, 1.7 Hz, 1H), 3.77 (dd, J = 15.0, 2.5 Hz, 1H), 3.19 (d, J = 17.9 Hz, 1H), 2.71 (d, J = 17.9 Hz, 1H), 2.16–1.96 (m, 3H), 1.70–1.58 (m, 1H), 1.34 (d, J = 6.6 Hz, 3H).

[0890] Example 22: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0891]

[0892] Step 1 : (3'S,5R,7'R)-12'-(Benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)- N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]methanopyridino[1,2-a][1,4]diazacyclononen]-10'-carboxamide Preparation :

[0893] The title compound was prepared in a similar manner to Steps 1 to 2 of Example 17, except that (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate G) was used instead of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazacyclononene-10-carboxamide (Intermediate F). MS (m / z) 829.12 [M+H]+.

[0894] Step 2 : (3'S,5R,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl- 1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2- Preparation of [1,4]diazacyclononene]-10'-carboxamide :

[0895] The title compound was prepared in a similar manner to Step 3 of Example 17, except that (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclonene]-10'-carboxamide was used instead of (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclonene]-10'-carboxamide. MS (m / z) 591.13 [M+H]+.

[0896] Step 3 : (3'S,5R,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-(methoxymethyl)-3'-methyl- 1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1, 2-a][1,4]diazacyclononene]-10'-carboxamide :

[0897] At 0 °C, NaH (60% in mineral oil) (5.4 mg, 0.14 mmol) was added to a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (41 mg, 0.0694 mmol) in DMF (2 mL), and then MeI (0.004 mL, 0.0694 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with H 2 O and brine. The organic phase was dried over MgSO 4 and the solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography to afford the title compound. MS (m / z) 605.09 [M+H]+.

[0898] Step 4 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(methoxymethyl)-3'-methyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino [1,2-a][1,4]diazacyclononene]-10'-carboxamide :

[0899] A mixture of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (27 mg, 0.045 mmol) and 10% Pd / C (3.8 mg) in EtOH (2 mL) was hydrogenated at 1 atm of H 2(g) Stir at room temperature. After 2 h, the reaction mixture was filtered, concentrated and purified by reverse phase preparative HPLC (5% to 100% MeCN / H2O containing 0.1% TFA) to afford the title compound. MS (m / z) 517.19 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.37 (s, 1H), 8.39 (s, 1H), 7.39 (q, J = 8.2, 7.6 Hz, 1H), 6.84 (q, J = 8.1, 7.6 Hz, 2H), 4.80–4.59 (m, 2H), 4.25 (d, J = 12.3 Hz, 1H), 4.19 (d, J = 12.3 Hz, 1H), 4.10 (s, 1H), 3.91–3.82 (m, 1H), 3.70 (dd, J = 14.8, 2.7 Hz, 1H), 3.45 (s, 3H), 3.03 (d, J = 17.9 Hz, 1H), 2.65 (d, J = 17.9 Hz, 1H), 2.12–1.95 (m, 3H), 1.69–1.58 (m, 2H), 1.32 (d, J = 6.7 Hz, 3H).

[0900] Example 23: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazecin]-10'-carboxamide:

[0901]

[0902] Step 1: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazecin]-10'-carboxamide and (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazecin]-10'-carboxamide:

[0903] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (43 mg, 0.075 mmol) in THF (10 ml) at -78 °C was added a 1 M solution of LiHMDS in THF (0.373 ml). After 30 minutes, a solution of MeI in THF (12.7 mg in 2 ml) was added at -78 °C, and then the temperature was raised to -20 °C. After 2 hours, the reaction was quenched by adding saturated NH 4 Cl solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 , filtered, concentrated and purified by silica gel column chromatography (eluting with 0% to 5% MeOH / EtOAc) to give the title compound. MS (m / z) 591.138 [M+H]+, and MS (m / z) 593.189 [M+H]+.

[0904] Step 2 : (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-di oxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a] [1,4]diazacyclononene]-10'-carboxamide :

[0905] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (14 mg, 0.024 mmol) in toluene (1 mL) was added TFA (0.3 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC, eluting with 10% to 90% aqueous acetonitrile to give the title compound. MS (m / z) 501.282 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 10.53 (s, 1H), 8.29 (s, 1H), 7.45–7.33 (m, 1H), 6.84 (q, J = 9.6, 9.0 Hz, 2H), 4.65 (t, J = 5.5 Hz, 3H), 4.10 (s, 1H), 3.76 (dd, J = 15.3, 3.1 Hz, 1H), 3.59–3.49 (m, 1H), 2.76 (d, J = 7.1 Hz, 1H), 2.31–2.20 (m, 1H), 2.08 (s, 3H), 1.99 (dd, J = 15.6, 7.9 Hz, 1H), 1.58 (dd, J = 15.6, 11.6 Hz, 1H), 1.47–1.35 (m, 1H), 1.31 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 7.1 Hz, 3H).

[0906] Example 24: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0907]

[0908] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (14 mg, 0.024 mmol) in toluene (1 mL) was added TFA (0.3 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC, eluting with an aqueous solution of 10% to 90% acetonitrile to give the title compound. MS (m / z) 503.265 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 10.91 (s, 1H), 8.33 (s, 1H), 7.32 (d, J = 6.8 Hz, 1H), 6.92–6.77 (m, 2H), 4.89 (s, 1H), 4.80 (s, 1H), 4.72 (d, J = 7.1 Hz, 1H), 4.62 (td, J = 13.3, 11.4, 5.8 Hz, 2H), 3.70–3.51 (m, 2H), 2.10 (d, J = 7.1 Hz, 4H), 1.66 (s, 3H), 1.30 (d, J = 6.6 Hz, 3H).

[0909] Example 25: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0910]

[0911] Step 1 : (3'S,5S,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4, 11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1, 2-a][1,4]diazacyclononene]-10'-carboxamide :

[0912] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (9 mg, 0.0152 mmol) prepared according to Example 23 in DCM (3 ml) at room temperature was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (dess-Martin periodinane) (10 mg, 0.023 mmol). The reaction was quenched by adding saturated NaHCO 3 and Na 2 SO 3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 filtered, concentrated and purified by silica gel column chromatography (eluting with 50% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 590.906 [M+H]+.

[0913] Step 2 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a] [1,4]diazacyclononene]-10'-carboxamide :

[0914] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (8.97 mg, 0.0152 mmol) in toluene (1 mL) was added TFA (0.3 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC, eluting with 10% to 90% aqueous acetonitrile to give the title compound. MS (m / z) 500.995 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.42 (s, 1H), 8.37 (s, 1H), 7.38 (q, J = 8.1 Hz, 1H), 6.84 (q, J = 9.1, 8.6 Hz, 2H), 4.81 (s, 1H), 4.65 (d, J = 5.8 Hz, 1H), 4.13–3.99 (m, 2H), 3.74 (dd, J = 15.3, 2.8 Hz, 1H), 2.19 (s, 3H), 2.12 (d, J = 15.4 Hz, 1H), 1.94–1.85 (m, 3H), 1.66–1.59 (m, 1H), 1.38 (d, J = 6.7 Hz, 3H).

[0915] Example 26: Preparation of (3'S,4S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0916]

[0917] (3'S,4S,5S,7'R)-N-(2,4-Difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazocine]-10'-carboxamide was prepared in a similar manner to Example 23, except that in Step 2, (3'S,4S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazocine]-10'-carboxamide was used instead of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazocine]-10'-carboxamide. MS (m / z) 501.193 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ 10.47 (s, 1H), 8.40 (s, 1H), 7.47–7.34 (m, 1H), 6.93–6.75 (m, 2H), 4.69 (dt, J = 14.6, 6.8 Hz, 3H), 4.18 (s, 1H), 3.85 (dd, J = 14.9, 1.9 Hz, 1H), 3.76–3.61 (m, 1H), 3.18 (d, J = 7.3 Hz, 1H), 2.12–1.87 (m, 6H), 1.32 (d, J = 6.7 Hz, 3H), 1.23 (dd, J = 14.5, 11.1 Hz, 1H), 0.82 (d, J = 7.3 Hz, 3H).

[0918] Example 27: Preparation of (3'S,4S,5R,7'R)-N-(2,4-difluorobenzyl)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (Peak 1) and (3'S,4R,5R,7'R)-N-(2,4-difluorobenzyl)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (Peak 2):

[0919]

[0920] Step 1 : (3'S,5S,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'-dimethyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1, [1,4]diazacyclononene]-10'-carboxamide :

[0921] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazacyclononene]-10'-carboxamide (82 mg, 0.138 mmol) prepared according to Example 26 in DCM (4 ml) at 0 °C was added bis(2-methoxyethyl)aminosulfur trifluoride (153 mg, 0.692 mmol). After 30 minutes, the reaction was quenched by adding saturated NaHCO 3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 , filtered, concentrated and purified by silica gel column chromatography (eluting with 0% to 100% EtOAc / hexane) to give the title compounds as a mixture of stereoisomers. MS (m / z) 595.046

[0922] Step 2 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'- dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a] Preparation of [[1,4]diazacyclononene]-10'-carboxamide :

[0923] To a solution of a mixture of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (25.1 mg, 0.0422 mmol) in toluene (2 mL) was added TFA (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was separated and purified by reverse-phase preparative HPLC, eluting with 10% to 90% aqueous acetonitrile to give the title compound.

[0924] Peak 1: MS (m / z) 505.173 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.33 (d, J = 5.9 Hz, 1H), 8.61 (d, J = 6.2 Hz, 1H), 7.44–7.33 (m, 1H), 6.83 (q, J = 7.9 Hz, 2H), 5.03 (d, J = 53.7 Hz, 1H), 4.84 (d, J = 10.5 Hz, 1H), 4.75–4.54 (m, 3H), 3.81 (dd, J = 4.2, 2.3 Hz, 2H), 2.18 (d, J = 3.3 Hz, 3H), 2.09–1.98 (m, 3H), 1.54 (dd, J = 15.8, 6.2 Hz, 1H), 1.33 (d, J = 6.7 Hz, 3H).

[0925] Peak 2: MS (m / z) 505.154 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.50 (d, J = 5.9 Hz, 1H), 8.33 (s, 1H), 7.38 (q, J = 8.4, 8.0 Hz, 1H), 6.92–6.78 (m, 2H), 5.34 (d, J = 53.8 Hz, 1H), 4.85–4.59 (m, 3H), 3.93 (dd, J = 14.9, 1.8 Hz, 1H), 3.87 (s, 1H), 3.75 (d, J = 14.7 Hz, 1H), 2.21 (d, J = 2.5 Hz, 3H), 2.19–2.15 (m, 1H), 2.12 (d, J = 7.0 Hz, 1H), 2.06–1.99 (m, 1H), 1.53–1.44 (m, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0926] Example 28: Preparation of (3'S,4S,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0927]

[0928] The title compound was prepared in a similar manner to Example 24, except that (3'S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide prepared according to Example 26 was used instead of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 503.299 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 11.60 (s, 1H), 9.95–9.84 (m, 1H), 8.33 (s, 1H), 7.40 (q, J = 8.3, 7.8 Hz, 1H), 6.86 (dt, J = 10.2, 6.9 Hz, 2H), 5.16 (s, 1H), 4.86 (td, J = 14.8, 7.2 Hz, 2H), 4.40 (dd, J = 14.9, 3.9 Hz, 1H), 3.98–3.84 (m, 2H), 3.66 (dd, J = 14.6, 2.7 Hz, 1H), 2.29 (dd, J = 16.4, 6.3 Hz, 1H), 2.10 (s, 3H), 2.08–1.94 (m, 2H), 1.31 (d, J = 6.6 Hz, 3H), 0.93 (q, J = 7.5 Hz, 1H).

[0929] Example 29: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0930]

[0931] The title compound was prepared in a similar manner to Example 25, except that (3'S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide prepared according to Example 26 was used instead of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 500.97 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.13 (s, 1H), 7.42–7.33 (m, 1H), 6.84 (q, J = 9.4, 8.7 Hz, 2H), 4.81 (dd, J = 11.3, 6.1 Hz, 1H), 4.73 (dd, J = 15.4, 6.2 Hz, 1H), 4.55 (dd, J = 15.4, 5.4 Hz, 1H), 4.22 (s, 1H), 3.95–3.78 (m, 2H), 2.18 (s, 3H), 2.14–2.05 (m, 2H), 1.63 (t, J = 5.1 Hz, 2H), 1.37 (d, J = 6.6 Hz, 3H).

[0932] Example 30: Preparation of (3'S,4R,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0933]

[0934] Step 1 : (3'S,4S,5R,7'R)-12'-(Benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl -1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridine [1,2-a][1,4]diazacyclononene]-10'-carboxamide (Peak 1) and (3'S,4R,5R,7'R)-12'-(benzyloxy)- N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7' H-spiro[isoxazole-5,6'-[2,7]methanopyridine[1,2-a][1,4]diazacyclononene]-10'-carboxamide (Peak 2) Preparation :

[0935] At room temperature, sodium borohydride (2.4 mg, 0.064 mmol) was added to a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (25 mg, 0.0423 mmol) in DCM (3 ml). After completion, the reaction was quenched by adding saturated NaHCO 3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4 , filtered, concentrated and purified by silica gel column chromatography (eluting with 20% to 100% EtOAc / hexane) to give the title compound in the form of peak 1 and peak 2. MS (m / z) 593.101 [M+H]+.

[0936] Step 2 : (3'S,4R,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1', 11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridine[1, 2-a][1,4]diazacyclononene]-10'-carboxamide Preparation :

[0937] The title compound was prepared in a similar manner to Example 24, except that (3'S,4R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (peak 2 from step 1) was used instead of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 503.231 [M+H] + .1 1H NMR (400 MHz, chloroform-d) δ 10.16 (s, 1H), 8.89 (s, 1H), 7.47–7.32 (m, 1H), 6.90–6.76 (m, 2H), 4.91–4.82 (m, 1H), 4.81 (s, 1H), 4.71 (d, J = 10.4 Hz, 1H), 4.40 (d, J = 17.4 Hz, 1H), 3.95–3.87 (m, 1H), 3.79 (d, J = 14.6 Hz, 1H), 3.70–3.61 (m, 1H), 2.11 (d, J = 5.1 Hz, 3H), 2.01 (s, 1H), 1.70 (s, 1H), 1.64–1.56 (m, 1H), 1.45 (d, J = 11.8 Hz, 1H), 1.31 (dd, J = 6.7, 2.3 Hz, 3H).

[0938] Example 31: Preparation of (3'S,4S,5R,7'R)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide:

[0939]

[0940] Step 1 : (3'S,4S,5R,7'R)-12'-(Benzyloxy)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo- N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridine [1,2-a][1,4]diazacyclononene]-10'-carboxamide Preparation :

[0941] At -40 °C and under air, a 1 N solution of LiHMDS in THF (1.2 ml, 1.2 mmol) was added to a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (204 mg, 0.343 mmol), prepared according to Example 3, in THF (10 ml). After 30 minutes, a solution of MeI in THF (73 mg, 0.515 mmol) was added at -40 °C, and then the temperature was raised to -20 °C over 2 hours. The reaction was quenched by adding saturated NH 4 Cl solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO 4It was dried, filtered, concentrated and purified by silica gel column chromatography (eluting with 10% to 80% EtOAc / hexane) to obtain the title compound. MS (m / z) 611.058 [M+H]+.

[0942] Step 2 : (3'S,4S,5R,7'R)-4,12'-Dihydroxy-3,3'-d...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is:

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is:

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is:

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is:

6. The compound according to claim 1, wherein the compound is:

7. The compound according to claim 1, wherein the compound is:

8. The compound according to claim 1, wherein the compound is:

9. The compound according to claim 1, wherein the compound is:

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 9, and a pharmaceutically acceptable excipient.

11. The pharmaceutical composition according to claim 10, which further comprises one, two, three or four additional therapeutic agents.

12. The pharmaceutical composition according to claim 11, wherein one or more of the additional therapeutic agents are anti - HIV agents.

13. The pharmaceutical composition according to any one of claims 10 - 12, wherein the pharmaceutical composition is for oral or parenteral administration.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 9 or the pharmaceutical composition according to any one of claims 10 - 13, for use in a method of treating HIV infection in a human being infected with HIV or at risk of becoming infected with HIV, the method comprising administering to the human a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 9 or the pharmaceutical composition according to any one of claims 10 - 13.

15. The compound or pharmaceutical composition for use according to claim 14, wherein the method further comprises administering to the human a therapeutically effective amount of one, two, three or four additional therapeutic agents.

16. The compound or pharmaceutical composition for use according to claim 15, wherein one or more of the additional therapeutic agents are anti - HIV agents.

17. The compound or pharmaceutical composition for use according to any one of claims 14 - 16, wherein the administration is oral, intravenous, subcutaneous or intramuscular.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 9 or the pharmaceutical composition according to any one of claims 10 - 13, for use in medical therapy.

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