Bridged tricyclic carbamoyl pyridinone compounds and uses thereof

Abstract

The present disclosure relates generally to compounds of Formula I. Also disclosed are pharmaceutical compositions comprising the compounds and methods of making the compounds. The compounds of the present disclosure are useful for treating or preventing human immunodeficiency virus (HIV) infection.

Description

[0001] Cross-references

[0002] This application claims priority to U.S. Provisional Application No. 63 / 328,061, filed April 6, 2022, and U.S. Provisional Application No. 63 / 476,873, filed December 22, 2022. The entire contents of these applications are incorporated herein by reference for all purposes. Technical Field

[0003] Compounds, compositions, and methods for treating or preventing human immunodeficiency virus (HIV) infection are disclosed. Specifically, novel spirocyclic-substituted bridged tricyclic carbamoylpyridinone compounds, their preparation methods, and their use as therapeutic or preventative agents are disclosed. Background Technology

[0004] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. HIV 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, DDNature (2001) 410:995-1001). Therefore, new agents to inhibit HIV replication are needed.

[0005] One goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Current treatment guidelines issued by the U.S. Department of Health and Human Services specify that achieving viral suppression requires the use of combination therapy, i.e., several drugs in at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at: http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed February 12, 2019). Additionally, decisions about treating HIV-infected patients are complicated when the patient requires treatment for other medical conditions (Id., F-8). Because the standard of care requires the use of multiple different drugs to suppress HIV, and to treat other conditions that the patient can be experiencing, the potential for drug interactions is a criterion for selecting a drug regimen. Thus, there is a need for antiretroviral therapy with a reduced potential for drug interactions.

[0006] Additionally, it is known that the HIV virus mutates in infected subjects (Tang et al. Drugs (2012) 72(9) el-e25). Because of the propensity of the HIV virus 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).

[0007] For certain patients, such as those with difficulty or limitations in obtaining healthcare, adherence to a daily oral treatment or prophylaxis regimen can be challenging. Drugs that provide advantageous pharmaceutical properties (e.g., improved potency, long-lasting 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

[0008] The present disclosure relates to novel compounds having antiviral activity and pharmaceutically acceptable salts thereof. In some embodiments, the compounds are useful for treating HIV infection, inhibiting the activity of HIV integrase, and / or reducing HIV replication. In some embodiments, the compounds disclosed herein are effective against a range of known drug resistant HIV mutants. In some embodiments, the compounds disclosed herein can have a reduced propensity to cause drug-drug interactions when co-administered with other drugs. In some embodiments, the compounds disclosed herein can be administered less frequently than daily, e.g., once a week, once a month, once every three months, once every six months, or longer intervals.

[0009] In one embodiment, the present disclosure provides a compound of Formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] R 1 is H, C 6-10 alkyl, aryl, or 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S,

[0013] wherein C 6-10 alkyl, aryl, or 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, A1 substituted with one, two, three, or four R A1 independently halo, C 1-6 alkyl, C 1-4 haloalkyl, cyano, -O-C 1-4 alkyl, or C 1-4 alkyl–O–C 1-4 alkyl;

[0014] R 2 is H, C 1-6 alkyl, or C 1-4 haloalkyl;

[0015] L is -CR 3a R 3b -, -C(O)-, -SO2-, -CH2-CH2-, or -N(R a )-;

[0016] W 1 is a bond or -CR 4a R 4b -;

[0017] W 2 is -CR 5a R 5b -, -CR 5a R5b 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)–;

[0018] Y is -C(O)NH–,

[0019] is a three- to seven-membered spiro ring containing one, two, or three heteroatoms selected from N, O, and S; wherein the spiro ring is optionally substituted with one, two, three, or four R 8 groups;

[0020] Z is -CR 9a R 9b –, -CR 9a R 9b CR 9c R 9d –, or -CR 10a =CR 10b –;

[0021] R 3a and R 3b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, or -O–C 1-4 alkyl; or

[0022] R 3a and R 3btogether with the carbon atom to which they are attached form a 3- to 7-membered spirocycle containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally substituted with one, two, or three R A2 substituents, wherein each R A2 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl;

[0023] R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, or halo;

[0024] R 5a , R 5b , R 5c , and R 5d are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxyl, cyano, -O-C 1-4 alkyl, or C 1-4 alkylene-O-C 1-4 alkyl; or

[0025] 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 spirocycle containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally substituted with one, two, or three R A3 substituents, wherein each R A3 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl; or

[0026] R 5a and R 5c or R 5b and R 5d together with the carbon atom to which they are attached form a 3- to 7-membered fused ring containing 0 or 1 heteroatoms selected from N, O, and S, wherein the fused ring is optionally substituted with one to three R A3 substituents, wherein each R A3 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl;

[0027] each R 6a and R 6b is independently H, halo, C 1-4 haloalkyl, or C 1-6 alkyl; or

[0028] R 6a and R 6b together with the carbon atom to which each is attached form a 5- to 10-membered partially unsaturated fused ring, 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, the fused aromatic ring, or the fused heteroaromatic ring is optionally substituted with one, two, three, or four R A4 , wherein each R A4 is independently halo or C 1-4 alkyl;

[0029] R 7 is H, C 1-6 alkyl, C 1-4 haloalkyl, C(O)R c , or SO2R c ;

[0030] each R 8 is independently selected from the group consisting of:

[0031] (i) halo,

[0032] (ii) C 1-6 alkyl optionally substituted with 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,

[0033] wherein C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and three- to seven-membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S,

[0034] (iii) C 1-6 haloalkyl optionally substituted with 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,

[0035] wherein C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and three- to seven-membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S,

[0036] (iv) CN,

[0037] (v) oxo,

[0038] (vi) -X-R A5

[0039] 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;

[0040] wherein C1-C6alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups independently selected from CN, halo, C1-C6alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0041] (vii) NHR A6 ,

[0042] wherein R A6 is C1-C6alkyl;

[0043] (viii) NR A7 R A8 ,

[0044] wherein R A7 is C1-C6alkyl; and

[0045] R A8 is C1-C6alkyl,

[0046] (ix) C 6-10 aryl optionally substituted with 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;

[0047] wherein C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 independent halo groups,

[0048] (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S,

[0049] wherein 3- to 7-membered ring is optionally substituted with 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

[0050] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0051] wherein the 5- to 10-membered heteroaryl ring is optionally substituted with 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,

[0052] (xii) -SO2R A13 ,

[0053] R A13 is C1-C6 alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0054] wherein the C 1-6 alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy,

[0055] (xiii) -SON(R A14 )2,

[0056] 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;

[0057] wherein the C 1-6 alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy,

[0058] (xiv) C 2-6 alkynyl, which is optionally substituted with one, two, three, or four substituents independently selected from C 1-6 alkoxy, OH, -SO2-(C 1-3 alkyl), or

[0059] 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;

[0060] wherein the 3- to 7-membered ring is optionally substituted with one, two, or three substituents independently selected from halo, OH,

[0061] C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-7 cycloalkyl; or

[0062] two R groups on adjacent carbon atoms are joined to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S, 8 one, two, or three R

[0063] wherein the fused 6- to 10-membered aromatic ring is optionally substituted with 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;

[0064] ring together with the carbon atom to which they are attached form a 3- to 7-membered spirocycle containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally substituted with one, two, or three R

[0065] R 9a , R 9b , R 9c , and R 9d are each independently H, C 1-6 alkyl, C 1-4 haloalkyl, or halo; 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 fused ring containing 0 or 1 heteroatoms selected from N, O, and S, wherein the fused ring is optionally substituted with one, two, or three R A9 , wherein each R A9 is independently halo, C 1-4 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 they are attached form a 3- to 7-membered fused ring containing 0 or 1 heteroatoms selected from N, O, and S, wherein the fused ring is optionally substituted with one, two, or three R A10 , wherein each R A10 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl; or

[0068] one of R 9a , R 9b , R 9c , and R 9d and R 4a , R 4b , R 5a , R 5b , and R 7one, two, three, or four R A11 substituted, 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, 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, the fused aromatic ring, or the fused heteroaromatic ring is optionally substituted with one to four R A12 substituted, 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 SO2R c ;

[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, 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 is provided.

[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 is provided.

[0077] In another embodiment, a method of treating an HIV infection in a human having or at risk of having an HIV infection is provided 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, 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 having or at risk of having an HIV infection is provided.

[0079] In another embodiment, 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 the manufacture of a medicament for treating an HIV infection in a human having or at risk of having an HIV infection is provided.

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

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

[0082] Other embodiments, objectives, features, and advantages will be set forth in the detailed description of the embodiments, and will be apparent from the description thereof, or can be learned by practice of the embodiments. These objectives and advantages will be realized and attained by the method and compositions particularly pointed out in the specification and claims hereof. The preceding summary is intended to be a summary and is not intended to limit the scope of the appended claims or the scope or the equivalents thereof. DETAILED DESCRIPTION

[0083] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments disclosed herein. However, one skilled in the art will understand that the embodiments disclosed herein can be practiced without these details. In other instances, well-known structures have not been described in detail in order to avoid obscuring the understanding of this description. The following description is presented for the purpose of illustrating certain embodiments disclosed herein and is not intended to limit the scope of the claims appended hereto. The headings used herein are for the convenience of the reader and are not intended to limit the scope of the claims appended hereto. Embodiments illustrated under any heading can be combined with embodiments illustrated under any other heading.

[0084] I. Definitions

[0085] Unless the context otherwise requires, throughout this disclosure and the claims, the word “comprising” and its variations such as “including” and “containing” shall be interpreted in an open, inclusive sense, that is, as “including but not limited to”.

[0086] Throughout this specification, the phrase "an embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment disclosed herein. Therefore, the phrases "in an embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner.

[0087] "Amino" refers to the -NH2 group.

[0088] "Hydroxy group" refers to the -OH group.

[0089] As used in this article, the term "C" 1-n "alkyl", where n is an integer, alone or in combination with another group, is intended to refer to a non-cyclic, straight-chain or branched alkyl group containing 1 to n carbon atoms. 1-6 Alkyl groups include, but are 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 represent methyl; Et represent ethyl; Pr represent 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., C1-C2). 20 Alkyl groups, 1 to 10 carbon atoms (i.e., C1-C1) 10 Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, CH2CH3), 1-propyl ( n -Pr, n-propyl, -CH2CH2CH3), 2-propyl ( i -Pr, isopropyl, CH(CH3)2), 1-butyl ( n -Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl ( i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl ( s -Bu, tert-butyl, CH(CH3)CH2CH3), 2-methyl-2-propyl ( t -Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, CH2CH2CH2CH2CH3), 2-pentyl (CH(CH3)CH2CH2CH3), 3-pentyl (CH(CH2CH3)2), 2-methyl-2-butyl (C(CH3)2CH2CH3), 3-methyl-2-butyl (CH(CH3)CH(CH3)2), 3-methyl-1-butyl (CH2CH2CH(CH3)2), 2-methyl-1-butyl (CH2CH(CH3)CH2CH3), 1-hexyl (CH2CH2CH2CH2CH2CH3), 2-hexyl (CH(CH3)CH2CH2CH2CH3), 3-hexyl (CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (C(CH3)2CH2CH2CH3) 2-methyl-2-pentyl (CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl ((CH2)7CH3). "Alkyl" also refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent groups at its center derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C2C2CH2CH3). 1-10 Alkyl groups or 1 to 6 carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-6 Alkyl groups or 1 to 3 carbon atoms (i.e., C464, C56, C6 ... 1-3 Alkyl groups. Typical alkyl groups include, but are not limited to, methylene (CH2), 1,1-ethyl (CH(CH3)), 1,2-ethyl (CH2CH2), 1,1-propyl (CH(CH2CH3)), 1,2-propyl (CH2CH(CH3)), 1,3-propyl (CH2CH2CH2), 1,4-butyl (CH2CH2CH2CH2), etc.

[0091] As used herein, the term "alkenyl" refers to a substance containing a primary, secondary, or tertiary carbon atom and having at least one unsaturated site (i.e., carbon-carbon sp). 2 Alkenyl groups are straight-chain or branched hydrocarbons with double bonds. For example, the alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C2). 20Alkenyl or C 2-20 Alkenyl), 2 to 8 carbon atoms (i.e., C2-C8alkenyl or C 2-8 Alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6alkenyl or C 2-6 Alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CHCH2), allyl (CH2CH=CH2), cyclopentenyl (C5H7), and 5-hexenyl (CH2CH2CH2CH2CH=CH2).

[0092] As used herein, the term “C 2-n Alkenyl”, where n is an integer, alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight-chain or branched-chain radical containing 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, ethenyl, 1 -propenyl, 2-propenyl, and 1 -butenyl. Unless otherwise specified, the term “C 2-n Alkenyl” is to be understood as including individual stereoisomers, where possible, 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 is to be understood as substituted on any carbon atom that it would bear a hydrogen atom, such that the substitution would result in a chemically stable compound, as recognized by one of skill in the art.

[0093] “Alkynyl” is a straight-chain or branched hydrocarbon containing a primary carbon atom, a secondary carbon atom, or a tertiary carbon atom and having at least one unsaturation (i.e., a carbon-carbon sp triply bonded). For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), or 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (CºCH), propynyl (CH2CºCH), and the like.

[0094] As used herein, the term “C 2-n Alkynyl”, where n is an integer, alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight-chain or branched-chain radical containing 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 a C 2-n Alkynyl group is substituted, it is to be understood as substituted on any carbon atom that it would bear a hydrogen atom, such that the substitution would result in a chemically stable compound, as recognized by one of skill in the art.

[0095] “Cyano” or “nitrile” refers to the group -CN.

[0096] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

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

[0098] As used herein, the term "C 1-n haloalkyl," wherein n is an integer, alone or in combination with another group, is intended to mean an alkyl group as defined above having 1 to n carbon atoms, wherein one or more hydrogen atoms are each replaced with a halo substituent. C 1-n Examples of 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" refers to a single aromatic ring or a bicyclic or polycyclic ring. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl or a peri-fused bicyclic or polycyclic group having about 9 to 14 atoms, wherein at least one ring is aromatic (e.g., aryl fused to one or more aryl or carbocyclic rings). Such bicyclic or polycyclic rings can be optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the bicyclic or polycyclic ring. It will be appreciated that the point of attachment of a bicyclic or polycyclic group as defined above can be at any position of the ring, including the aryl or carbocyclic portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthryl, and the like.

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

[0101] As used herein, the term "heterocyclyl," "heterocycle," or "halocycloalkyl" refers to a mono saturated or partially unsaturated ring or polyfused ring. The term includes a monosaturated or partially unsaturated ring (e.g., 3, 4, 5, 6, or 7 membered ring) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring can be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms can also be present in oxidized forms. Such rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, or piperidinyl. The term also includes polyfused ring systems (e.g., ring systems comprising 2 or 3 rings) in which a heterocyclyl group, as defined above, can be linked to two adjacent atoms (fused heterocycle) through one or more heterocyclic (e.g., decahydronaphthalenyl), heteroaryl (e.g., 1,2,3,4-tetrahydronaphthridinyl), carbocyclic (e.g., decahydroquinolinyl), or aryl. It will be appreciated that the point of attachment of the heterocyclic polyfused ring, as defined above, can be at any position of the ring, including the heterocyclic, heteroaryl, aryl, or carbocyclic portion of the ring. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, benzodihydropyranyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl.

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

[0103] As used herein, the terms "fused ring," "fused" refer to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring structure described herein that is attached to an existing ring structure in the compounds disclosed herein via two adjacent atoms that the fused ring structure and the existing ring structure share. 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 radical, 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 rings that are fully saturated as well as partially unsaturated rings.

[0106] It should be understood that when a variable is substituted, for example, as described by the phrase "C 1-6 Alkyl, alone or as part of a radical, is optionally substituted" means that the variable C 1-6 Alkyl can be substituted when alone, and the variable "C 1-6 Alkyl" can also be substituted when part of a larger radical. Similarly, when stated, other variables (e.g., C 2-6 Alkynyl, aryl, heteroaryl, heterocycle, etc.) can also be "alone or as part of a radical" 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), SO2, (C1-C6)alkylO-, (C1-C6)alkylC(O), (C1-C6)alkylC(O)O, (C1-C6)alkylS, (C1-C6)alkylS(O), and (C1-C6)alkylSO2), certain X values that are not symmetrical can be oriented in either direction. For example, C(O)O can be oriented as C(O)O or OC(O) with respect to the groups to which it is connected.

[0108] The term "chiral" refers to a molecule that has the property of non- superimposability of its mirror image partners, while the term "achiral" refers to a molecule that is superimposable with its mirror image partner.

[0109] The term "stereoisomers" refers to compounds which have identical chemical constitution, but different spatial arrangement of atoms.

[0110] "Diastereomers" refers to stereoisomers that have two or more chiral centers or axes and whose molecules are not mirror images of each other. Diastereomers usually have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography.

[0111] "Enantiomers" refers to two stereoisomers of a compound that are mirror images of each other and are not superimposable.

[0112] The term "treatment" includes preventing or eliminating the disease or condition, and / or alleviating one or more of the symptoms of the disease or condition, to the extent that it relates to a disease or condition.

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

[0114] The term "treatment" as used herein is intended to mean the administration of a compound or composition according to the present application to alleviate or eliminate the symptoms of HIV infection and / or to reduce the viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the present application after exposure to the virus but before the appearance of symptoms of the disease and / or before the virus is detected in the blood, to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood, as well as the administration of a compound or composition according to the present application to prevent perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the child within the first days of life.

[0115] "Protecting group" refers to a moiety of a compound that masks or alters 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, e.g. Protective Groups in Organic Chemistry , Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to facilitate the efficiency of desired chemical reactions, such as the formation and cleavage of chemical bonds in an orderly and planned fashion. The protection of a functional group of a compound changes other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. The intermediates of chemical protection can themselves be biologically active or inactive.

[0116] Protected compounds can also exhibit alterations, in some cases, optimized properties in vitro and in vivo, such as passage through cell membranes and resistance to enzymatic degradation or sequestration. In this role, a protected compound with an intended therapeutic effect can be referred to as a prodrug. Another function of a protecting group is to convert a parent drug into a prodrug, which releases the parent drug upon conversion of the prodrug in vivo. Because active prodrugs can be absorbed more efficiently than the parent drug, prodrugs can have greater potency in vivo than the parent drug. In the case of chemical intermediates, the protecting group is removed in vitro, and in the case of prodrugs, the protecting group is removed in vivo. It is not particularly important whether the resulting product after deprotection (e.g., an alcohol) is physiologically acceptable, but generally it is preferable if the product is not pharmacologically detrimental.

[0117] Protecting groups are available, generally known, and used, and are optionally used to prevent side reactions with the protecting group during the synthetic procedure, i.e., the route or method by which the compounds of the invention are prepared. In most cases, the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group, “PG,” will depend on the chemical nature of the reaction to be protected (e.g., acidic, basic, oxidative, reductive, or other conditions) and the intended direction of synthesis. If a compound is substituted with multiple PGs, the PGs need not, and generally are not, identical. Typically, the PG will be used to protect a functional group such as a carboxyl, hydroxyl, thio, or amino group, to prevent side reactions or otherwise facilitate synthetic efficiency. The sequence of deprotection to yield the free deprotection group depends on the intended direction of synthesis and the reaction conditions to be encountered, and can occur in any order determined by the skilled artisan.

[0118] Various functional groups of the compounds of the invention can be protected. For example, protecting groups for -OH groups, whether hydroxyl, carboxylic acid, phosphoric acid, or other functional groups, include “ether or ester forming groups.” In the synthetic schemes described herein, ether or ester forming groups are capable of functioning as chemical protecting groups. However, as understood by one of skill in the art, some hydroxyl and thio protecting groups are not ether or ester forming groups, and include 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.; Protecting Groups (Georg Thieme Verlag, Stuttgart, 1995, ISBN 3-13- 019301-2). rotecting Groups(Georg Thieme Verlag Stuttgart, New York, 1994), the entire contents of which are hereby incorporated by reference. In particular, Chapter 1, Protecting Groups: An Overview, pages 1-20; Chapter 2, Hydroxyl Protecting Groups, pages 21-94; Chapter 3, Diol Protecting Groups, pages 95-117; Chapter 4, Carboxyl Protecting Groups, pages 118-154; Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acids, phosphonic acids, phosphonate esters, sulfonic acids and other protecting groups for acids, see Greene, infra.

[0120] As used herein, the term "protecting group" is intended to mean protecting groups 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 more recent editions thereof.

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

[0122] The term "non-solvate" refers to a crystalline solid in which no solvent molecules occupy specific crystal sites.

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

[0124] As used herein, the term "pharmaceutically acceptable salt" is intended to mean a salt of a compound according to the application which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for its intended use in the pharmaceutical composition. The term includes pharmaceutically acceptable acid addition salts and base addition salts. Lists of suitable salts are found in, e.g., S. M. Birge et al., J. Pharm. Sci., 1977, 66:1-19. 66 As used herein, the term "pharmaceutically acceptable salt" is intended to mean a salt of a compound according to the application which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for its intended use in the pharmaceutical composition. The term includes pharmaceutically acceptable acid addition salts and base addition salts. Lists of suitable salts are found in, e.g., S. M. Birge et al., J. Pharm. Sci., 1977, 66:1-19.

[0125] As used herein, the term "pharmaceutically acceptable acid addition salt" is intended to mean those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acids, nitric acid, phosphoric acid and the like, and organic acids such as 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, hemisulfic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenic 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 and the like.

[0126] As used herein, the term "pharmaceutically acceptable base addition salt" is intended to mean those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases, including but not limited to, ammonium hydroxide, or an alkali, alkaline earth metal or aluminum, zinc, copper, manganese, aluminum hydroxides, carbonates or bicarbonates such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum hydroxides, carbonates or bicarbonates. Particularly preferred are the ammonium, potassium, sodium, calcium 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 for example methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, glycamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compound, tetraethylammonium compound, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, polyamine resins and the like. 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 effective to inhibit the formation and / or replication of a virus in a human, including but not limited to agents that interfere with host or viral mechanisms necessary for the formation and / or replication of a virus in a human. The term "antiviral agent" includes, for example, HIV integrase catalytic site inhibitors selected from the group consisting of raltegravir (Isentress®), elvitegravir (Vicriviroc), and dolutegravir (Tivicor®). Merck); Avira (Gilead); Soltegravir (GSK; ViiV); GSK 1265744 (GSK; ViiV) and Dulutevir; HIV nucleoside reverse transcriptase inhibitors selected from the group consisting of: Abacavir ( GSK); Didanoxin ( BMS); Tenofovir ( Gilead); Enqutabin Gilead); Lamivudine GSK / Shire); Stavudine ( BMS); Zidovudine ( GSK; Avtabin (Achillion); Fentenavir (Oncolys); HIV non-nucleoside reverse transcriptase inhibitors, selected from the group consisting of the following: Nevirapine ( BI); According to the law, Weilen ( BMS); Itravirine ( J&J); Rilpivirine (TMC278, R278474; J&J); Folicidiline (GSK / ViiV); and Lesvirine (Pfizer / ViiV); HIV protease inhibitors selected from the group consisting of: Atazanavir ( BMS); Derlinavir ( J&J); Indinavir ( Merck); Lopinavir Abbott); Nefinavir Pfizer); Saquinavir ( Hoffmann-LaRoche); Tiranavir BI); ritonavir ( Abbott); and fossavir ( GSK / Vertex); HIV entry inhibitors, selected from: Maravero ( Pfizer); Enfvir peptide ( Trimeris; and BMS-663068 (BMS); and HIV maturation inhibitors, selected from 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 viruses in mammals, including but not limited to agents that interfere with the host or viral mechanisms necessary for the formation and / or replication of viruses in mammals.

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

[0130] Unless otherwise indicated, the term "substituent" as used herein is intended to mean an atom, an atom group, or a group that can be bonded to a carbon atom, a heteroatom, or any other atom that is otherwise bonded to at least one hydrogen atom that forms part of a molecule or a fragment thereof. 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 one of skill 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 from 1 to n carbon atoms as defined above. Examples of C 1-n alkoxy groups include, but are not limited to, methoxy (CH3O-), ethoxy (CH3CH2O-), propoxy (CH3CH2CH2O-), 1-methylethoxy (isopropoxy; (CH3)2CHO), and 1,1-dimethylethoxy (tert-butoxy; (CH3)3CO). When C 1-n alkoxy is substituted, it is understood to be substituted on its alkyl portion such that the substitution will result in a chemically stable compound, such as recognized by one of skill in the art.

[0133] As used herein, the term "oxo" is intended to mean an oxygen atom attached to a carbon atom through a double bond (=0) as a substituent.

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

[0135] The embodiments disclosed herein are also intended to encompass all pharmaceutically acceptable compounds of Formula I that are isotopically-labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. In some embodiments, these radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or pattern of action or the binding affinity to a pharmacologically important site of action. Certain isotope-labeled compounds of formula I, such as those doped with a radioisotope, can be used for drug and / or substrate tissue distribution studies. Radioisotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) They are particularly suitable for this purpose because they are easy to incorporate and convenient to detect.

[0136] In some implementations, heavier isotopes such as deuterium (i.e., 2 H) substitution may offer certain therapeutic advantages due to its greater metabolic stability. For example, it may increase the half-life in vivo or reduce the dosage requirement. Therefore, in some cases, heavier isotopes may be preferred.

[0137] Using positron emission isotopes such as 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds disclosed herein can generally be prepared using techniques known to those skilled in the art, or by methods similar to those described in the examples listed below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

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

[0139] The embodiments disclosed herein are also intended to encompass in vivo metabolic products of the disclosed compounds. Such products can result, for example, from oxidative, reductive, hydrolytic, amidation, esterification, and / or other metabolic processes, often depending on the enzyme

[0140] The compounds disclosed herein, or their pharmaceutically acceptable salts, can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms in addition to the racemic mixtures. The present disclosure is intended to include all such possible isomers, as well as, their racemic, scalemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can, for example, be prepared using chiral synths or chiral reagents, or resolved using, for example, chromatographic and fractional crystallization techniques. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor (e.g., an ester of a carboxylic acid), or resolution of the racemic mixture (or the racemic mixture of the salt or derivative) by, for example, high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds, other geometric isomers are intended, unless otherwise stated. Likewise, when the compounds described herein contain other geometrically asymmetric centers, such as the aspartate moiety, all geometric isomeric forms of the compounds are intended, unless otherwise stated.

[0141] “Optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, “optionally substituted heterocyclyl” means that the heterocyclyl group can or can not be substituted and that the description includes substituted heterocyclyl and non-substituted 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 6-10 1-4 alkyl, aryl, or 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S,

[0147] wherein C 6-10 is H, C A1 1-4 alkyl, aryl, or 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, A1 is independently halo, C 1-6 1-4 alkyl, C 1-4 haloalkyl, cyano,

[0148] wherein C 1-4 1-4 alkyl, or C 1-4 1-4 alkyl–O–C 1-4 1-4 alkyl;

[0149] R 2 is H, C 1-6 1-4 alkyl, or C 1-4 haloalkyl;

[0150] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CH2–CH2–, or –N(R a )–;

[0151] W 1 is a bond or –CR 4a R 4b –;

[0152] W 2 is –CR 5a R 5b –, –CR 5a R 5b CR 5c R5d -, -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)-;

[0153] Y is -C(O)NH-,

[0154] is a three to seven membered spiro ring containing one, two, or three heteroatoms selected from N, O, and S; wherein the spiro ring is optionally substituted with one, two, three, or four R 8 groups;

[0155] Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d -, or -CR 10a =CR 10b -;

[0156] R 3a and R 3b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, or -O-C 1-4 alkyl; or

[0157] R 3a and R 3btogether with the carbon atom to which they are attached form a 3- to 7-membered spirocycle containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally substituted with one, two, or three R A2 substituted, wherein each R A2 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl;

[0158] R 4a and R 4b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, or halo;

[0159] R 5a , R 5b , R 5c , and R 5d are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxyl, cyano, -O-C 1-4 alkyl, or C 1-4 alkylene-O-C 1-4 alkyl; or

[0160] 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 spirocycle containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally substituted with one, two, or three R A3 substituted, wherein each R A3 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl; or

[0161] R 5a and R 5c or R 5b and R 5d together with the carbon atom to which they are attached form a 3- to 7-membered fused ring containing 0 or 1 heteroatoms selected from N, O, and S, wherein the fused ring is optionally substituted with one to three R A3 substituted, wherein each R A3 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl;

[0162] each R 6a and R 6b are independently H, halo, C 1-4 haloalkyl, or C 1-6 alkyl; or

[0163] R 6a and R 6b together with the carbon atom to which each is attached form a 5- to 10-membered partially unsaturated fused ring, 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, the fused aromatic ring or the fused heteroaromatic ring is optionally substituted with one, two, three or four R A4 , wherein each R A4 is independently halo or C 1-4 alkyl;

[0164] R 7 is H, C 1-6 alkyl, C 1-4 haloalkyl, C(O)R c or SO2R c ;

[0165] each R 8 is independently selected from the group consisting of:

[0166] (i) halo,

[0167] (ii) C 1-6 alkyl optionally substituted with 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,

[0168] wherein C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl and three- to seven-membered halocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S,

[0169] (iii) C 1-6 haloalkyl optionally substituted with 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,

[0170] wherein C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl and three- to seven-membered halocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S,

[0171] (iv) CN,

[0172] (v) oxo,

[0173] (vi) -X-R A5

[0174] 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;

[0175] wherein C1-C6alkyl or 3- to 7-membered ring is optionally substituted with 1, 2 or 3 groups independently selected from CN, halo, C1-C6alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0176] (vii) NHR A6 ,

[0177] wherein R A6 is C1-C6alkyl;

[0178] (viii) NR A7 R A8 ,

[0179] wherein R A7 is C1-C6alkyl;

[0180] and R A8 is C1-C6alkyl,

[0181] (ix) C 6-10 aryl optionally substituted with 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;

[0182] wherein C 3-7 cycloalkyl is optionally substituted with 1, 2, 3 or 4 independent halo groups,

[0183] (x) a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms independently selected from N, O and S, wherein the 3- to 7-membered ring is optionally substituted with 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

[0184] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0185] wherein the 5- to 10-membered heteroaryl ring is optionally substituted with 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,

[0186] (xii) -SO2R A13 ,

[0187] R A13 is C1-C6 alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S;

[0188] wherein the C 1-6 alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy,

[0189] (xiii) -SO(NR A14 )2,

[0190] 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;

[0191] wherein the C 1-6 alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy,

[0192] (xiv) C 2-6 alkynyl optionally substituted with one, two, three, or four substituents independently selected from C 1-6 alkoxy, OH, -SO2-(C 1-3 alkyl), or

[0193] 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;

[0194] wherein the 3- to 7-membered ring is optionally substituted with one, two, or three substituents independently selected from halo, OH,

[0195] C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-7 cycloalkyl; or

[0196] two R groups on adjacent carbon atoms are joined to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S, 8 ring, a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S,

[0197] wherein the fused 6- to 10-membered aromatic ring is optionally substituted with 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;

[0198] ring, a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S,

[0199] R 9a , R 9b , R 9c , and R 9d are each independently H, C 1-6 alkyl, C 1-4 haloalkyl, or halo; or

[0200] 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 with one, two, or three R A9 , wherein each R A9 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl; or

[0201] R 9a and R 9c or R 9b and R 9d together with the carbon atom to which they are attached form a 3- to 7-membered fused ring containing 0 or 1 heteroatoms selected from N, O, and S, wherein the fused ring is optionally substituted with one, two, or three R A10 , wherein each R A10 is independently halo, C 1-4 alkyl, or C 1-4 haloalkyl; or

[0202] one of R 9a , R 9b , R 9c , and R 9d and R 4a , R 4b , R 5a , R 5b , and R 7One of them, together with the atoms to which they are attached, forms 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 bounded by one, two, three, or four R atoms. A11 Replace, where each R A11 Independently a halogenated or C 1-4 alkyl;

[0203] R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0204] R 10a and R 10b Together with their respective attached carbon atoms, they form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally surrounded by one to four R atoms. A12 Replace, where each R A12 Independently a halogenated or C 1-4 alkyl;

[0205] R a Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R c or SO2R c ;

[0206] R b For H or C 1-4 alkyl;

[0207] R c C 1-4 Alkyl or C 1-4 alkoxy groups; and

[0208] Each n is independently 0, 1, or 2.

[0209] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, By one, two, three or four R 8 Group substitution; and at least one R 8 The group is selected from the group consisting of the following:

[0210] (i)C 1-6 Alkyl groups, which are reacted with OH and C 1-6 Alkoxy, C 6-10aryl or 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0211] wherein C 6-10 aryl or 5- to 10-membered heteroaryl optionally substituted with 1 to 4 substituents selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, halo, CN, C1-C3haloalkyl, C3-C7cycloalkyl, and three- to seven-membered halocycloalkyl comprising 1, 2, or 3 heteroatoms selected from N, O, and S,

[0212] (ii) C 1-6 haloalkyl substituted with OH, C 1-6 alkoxy, C 6-10 aryl or 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0213] wherein C 6-10 aryl or 5- to 10-membered heteroaryl optionally substituted with 1 to 4 substituents selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, halo, CN, C1-C3haloalkyl, C3-C7cycloalkyl, and three- to seven-membered halocycloalkyl comprising 1, 2, or 3 heteroatoms selected from N, O, and S,

[0214] (iii) CN,

[0215] (iv) oxo,

[0216] (v) -X-R A5

[0217] wherein X is O or S; and R A5 is H, C 1-6 alkyl or a 3- to 7-membered ring comprising 0, 1, or 2 heteroatoms selected from N, O, and S;

[0218] wherein C1-C6alkyl or a 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups independently selected from CN, halo, C1-C6alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0219] (vi) NHR A6 ,

[0220] wherein R A6 is C1-C6alkyl;

[0221] (vii) NR A7 R A8 ,

[0222] wherein R A7C1-C6alkyl and R A8 is C1-C6alkyl;

[0223] (viii) C 6-10 aryl optionally substituted with 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 with 1, 2, 3, or 4 independent halo groups,

[0224] (ix) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S,

[0225] wherein the 3- to 7-membered ring is optionally substituted with 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

[0226] (x) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0227] wherein the 5- to 10-membered heteroaryl ring is optionally substituted with 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,

[0228] (xi) -SO2R A13 ,

[0229] R A13 is C1-C6alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0230] wherein C 1-6 alkyl or the 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6alkoxy,

[0231] (xii) -SO(NR A14 )2,

[0232] 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;

[0233] wherein C1-6 alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6alkoxy,

[0234] (xiii) C 2-6 alkynyl, which is optionally substituted with one, two, three, or four substituents independently selected from C 1-6 alkoxy, OH, -SO2-(C 1-3 alkyl), or

[0235] two R 8 groups join 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;

[0236] wherein the 3- to 7-membered ring is optionally substituted with 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

[0237] two R 8 groups on adjacent carbon atoms join to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S,

[0238] wherein the fused 6- to 10-membered aromatic ring is optionally substituted with 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.

[0239] 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 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 six-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 six-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.

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

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

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

[0243] In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, It is a four-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, three, or four R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a four-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, or three R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a four-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one or two R atoms. 8 Group substitution.

[0244] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof It is a four-membered spirocycle containing one or two heteroatoms selected from N and S; wherein the spirocycle is optionally bounded by one, two, three or four R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, A quaternary spirocycle containing one or two heteroatoms selected from N and S, wherein the spirocycle is optionally bounded by one, two or three R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a four-membered spirocycle containing one or two heteroatoms selected from N and S; wherein the spirocycle is optionally bounded by one or two R atoms. 8 Group substitution.

[0245] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof Choose from the following groups: Where * indicates The attachment point with residual I; R d For H, C 1-4 Alkyl or C 1-4 Haloalkyl; and m is 0, 1, 2, 3 or 4.

[0246] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof Choose from the following groups: Where * indicates The attachment point with residual I; R d For H, C 1-4 Alkyl or C 1-4 Haloalkyl; and m is 0, 1, 2, 3 or 4.

[0247] In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is

[0248] In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0249] In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2, or 3. In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2, or 3. In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is wherein m is 0, 1, 2, or 3. In some embodiments of a 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.

[0250] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has Formula I-A:

[0251]

[0252] wherein m is 0, 1, 2, or 3.

[0253] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has Formula I-B:

[0254]

[0255] wherein m is 0, 1, 2, or 3.

[0256] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has Formula I-C:

[0257]

[0258] wherein R d is H, C 1-4 alkyl, or C 1-4 haloalkyl; and m is 0, 1, 2, or 3.

[0259] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has Formula I-D:

[0260]

[0261] wherein R d is H, C 1-4 alkyl, or C 1-4 haloalkyl; and m is 0, 1, 2, or 3.

[0262] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has Formula I-E:

[0263]

[0264] wherein R d is H, C 1-4 alkyl, or C 1-4 haloalkyl; and m is 0, 1, 2, or 3.

[0265] In some embodiments of a compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound is of Formula I-F:

[0266]

[0267] wherein m is 0, 1, 2, 3, or 4.

[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, 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.

[0269] 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 selected from the group consisting of: -C(O)NH-, 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

[0270] 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 -C(O)NH- and R 2 is H or C 1-6 alkyl.

[0271] In some embodiments of the compound of Formula I or I-A, or a pharmaceutically acceptable salt thereof, the compound is of Formula II-A:

[0272]

[0273] wherein m is 0, 1, 2, or 3.

[0274] In some embodiments of the 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 A1 , wherein each R A1 is independently halo or -O-C 1-4 alkyl. In some embodiments, R 1 is phenyl substituted with one, two, three, or four halogens. In some embodiments, R 1 is 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

[0275] 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

[0276] In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is

[0277] In some embodiments of the 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 pyridyl 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 pyridyl 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 pyridyl substituted with one, two, three, or four R A1 , wherein each R A1 is independently halo or -O-C 1-4 alkyl. In some embodiments, R 1 is pyridyl substituted with one, two, three, or four halogen. In some embodiments, R 1pyridinyl substituted with two or three halogens selected from chlorine and fluorine. In some embodiments, R 1 is

[0278] In some embodiments of the compound of Formula I, I-A, or II-A, or a pharmaceutically acceptable salt thereof, the compound is of Formula II-Aa or II-Ab:

[0279]

[0280] wherein m is 0, 1, 2, or 3.

[0281] In some embodiments of the compound of Formula I, I-A, or II-A, or a pharmaceutically acceptable salt thereof, the compound is of 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 is of Formula II-Ab.

[0282] 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 -SO2-. In some embodiments, L is -CH2-CH2-. In some embodiments, L is -N(R a )-. In some embodiments, L is NH.

[0283] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, or II-Ab, the compound is of Formula III:

[0284]

[0285] wherein m is 0, 1, 2, or 3.

[0286] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, or III, the compound is of Formula IIIa or IIIb:

[0287]

[0288] wherein m is 0, 1, 2, or 3.

[0289] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, or III, the compound is of Formula IIIa. In some embodiments of the compound of Formula I, I-A, II-A, II-Ab, or III, the compound is of Formula IIIb.

[0290] In some embodiments of the compound 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 R 4a 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 -; wherein R 4a and R 4b are independently H, -CH3, or halo. In some embodiments, W 1 is a bond or -CR 4a H-; wherein R 4a is H, C 1-6 alkyl, or halo. In some embodiments, W 1 is a bond, -CH2-, or -CH(F)-.

[0291] In some embodiments of the compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II, II-A, IIAa, II-Ab, III, Ilia, or IIIb, or a pharmaceutically acceptable salt thereof, 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 ; wherein R 4a and R 4b 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; and W 1 is a bond or -CR 4a R 4b ; wherein R 4a and R 4b are each 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 ; wherein R 4a and R 4b are each independently H, -CH3, 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-; wherein R 4a 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, -CH2-, or -CH(F)-.

[0292] In some embodiments of the compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, II-Aa, II-Ab, III, Ilia, or IIIb, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b ; wherein R 9a and R 9b are each independently H, C 1-6 alkyl, C1-4 Halogenated alkyl or halogenated. In some embodiments, Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Halogenated alkyl group. In some embodiments, Z is –CH(CH3)– or –CH(CH2F)-.

[0293] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl, C 1-4 Haloalkyl or halogroup; and Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl, C 1-4 Haloalkyl or halogenated. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl or haloyl; and Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently H, –CH3, or a halogroup; and Z is –CR. 9a R9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; and W 1 For key or –CR 4a H–; where R 4a For H, C 1-6 Alkyl or haloyl; and Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For a bond, –CH2– or –CH(F)–; and Z is –CH(CH3)– or –CH(CH2F)-.

[0294] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, W 2 For –CR 5a R 5b –or–CR 6a =CR 6b –; where R 5a and R 5b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; and R 6a and R 6b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl group. In some embodiments, W 2 For –CR 5a R 5b –or–CR 6a =CR 6b –; where R 5a and R 5b Independently for H and C 1-6 Alkyl, C 1-4haloalkyl, halo, or -O-C 1-4 alkyl; and R 6a and R 6b are each 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 each independently H, C 1-6 alkyl, or halo; and R 6a and R 6b are each independently H, halo, or C 1-6 alkyl. In some embodiments, W 2 is -CH2- or -CH=CH-. In some embodiments, W 2 is -CH2-. In some embodiments, W 2 is -CH=CH-.

[0295] In some embodiments of the compound 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 a pharmaceutically acceptable salt thereof, 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, 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 each independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxyl, cyano, -O-C 1-4 alkyl, or C 1-4alkylene-O-C 1-4 alkyl; and R 6a and R 6b are independently H, halo, C 1-4 haloalkyl, or C 1-6 alkyl.

[0296] In some embodiments of the compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, Ilia, or IIIb, or a pharmaceutically acceptable salt thereof, 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 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.

[0297] In some embodiments of the compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, Ilia, or IIIb, or a pharmaceutically acceptable salt thereof, 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, -CH3, 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.

[0298] In some embodiments of the compound 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 a pharmaceutically acceptable salt thereof, 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 are each independently H, C 1-6 alkyl or C 1-4 haloalkyl; and W 2 is -CH2- or -CH=CH-.

[0299] In some embodiments of the compound 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 a pharmaceutically acceptable salt thereof, 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 are each independently H, C 1-6 alkyl or C 1-4 haloalkyl; and W 2is -CH2-.

[0300] In some embodiments of the compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, Ilia, or IIIb, or a pharmaceutically acceptable salt thereof, 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 are each independently H, C 1-6 alkyl or C 1-4 haloalkyl; and W 2 is -CH=CH-.

[0301] In some embodiments of the compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, Ilia, or IIIb, or a pharmaceutically acceptable salt thereof, Y is -C(O)NH-; R 2 is H or C 1-6 alkyl; W 1 is a bond, -CH2- or -CH(F)-; Z is -CH(CH3)- or -CH(CH2F)-; and W 2 is -CH2- or -CH=CH-.

[0302] In some embodiments of the compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, Ilia, or IIIb, or a pharmaceutically acceptable salt thereof, Y is -C(O)NH-; R 2 is H or C 1-6 alkyl; W 1 is a bond, -CH2- or -CH(F)-; Z is -CH(CH3)- or -CH(CH2F)-; and W 2 is -CH2-.

[0303] In some embodiments of the compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, Aa, II-Ab, III, Ilia, or IIIb, or a pharmaceutically acceptable salt thereof, Y is -C(O)NH-; R 2 is H or C 1-6 alkyl; W 1is -CH=CH-. 2 is -CH=CH-.

[0304] In some embodiments of the 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

[0305]

[0306] wherein m is 0, 1, 2, or 3.

[0307] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, III, IIIa, or IV, or a pharmaceutically acceptable salt thereof, the compound is of Formula IVa:

[0308]

[0309] wherein m is 0, 1, 2, or 3.

[0310] In some embodiments of the compound of Formula I, I-A, II-A, II-Ab, III, IIIb, or IV, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula IVb:

[0311]

[0312] wherein m is 0, 1, 2, or 3.

[0313] In some embodiments of the 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.

[0314] In some embodiments of the 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, halo, C 1-4 haloalkyl, or C 1-6 alkyl.

[0315] In some embodiments of the 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, C1-6 alkyl or C 1-4 haloalkyl; and R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl.

[0316] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, 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 or C 1-4 haloalkyl. In some embodiments, R 9a is -CH3or -CH2F.

[0317] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, 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 C1-4 Halogenated alkyl groups. In some embodiments, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a It is -CH3 or -CH2F.

[0318] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently:

[0319] (i) Halogen group,

[0320] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0321] (iii)C 1-6 Halogenated alkyl groups,

[0322] (iv)CN,

[0323] (v) Oxide group,

[0324] (vi)-XR A5

[0325] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0326] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0327] (vii)NHR A6 ,

[0328] Where R A6 It is a C1-C6 alkyl group;

[0329] (viii)NR A7 RA8 ,

[0330] wherein R A7 is C1-C6 alkyl;

[0331] and R A8 is C1-C6 alkyl,

[0332] (ix) C 6-10 aryl optionally substituted with 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;

[0333] wherein C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, or 4 independent halo groups,

[0334] (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S,

[0335] wherein the 3- to 7-membered ring is optionally substituted with 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, or

[0336] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0337] wherein the 5- to 10-membered heteroaryl ring is optionally substituted with 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, or

[0338] 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.

[0339] wherein the 3- to 7-membered ring is optionally substituted with one, two, or three substituents independently selected from halo, OH,

[0340] C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 3-7 cycloalkyl; or

[0341] two R groups on adjacent carbon atoms are joined to form a fused 6- to 10- membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S, 8 ring, a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S,

[0342] wherein the fused 6- to 10-membered aromatic ring is optionally substituted with 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.

[0343] 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, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8 is independently:

[0344] (i) halo,

[0345] (ii) C 1-6 alkyl optionally substituted with 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,

[0346] (iii) C 1-6 haloalkyl,

[0347] (iv) CN,

[0348] (v) oxo,

[0349] (vi) -X-R A5

[0350] 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;

[0351] wherein C1-C6 alkyl or the 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups independently selected from CN, halo, C1-C6 alkoxy,

[0352] C 6-10 aryl, and 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S

[0353] (vii) NHR A6 ,

[0354] wherein R A6C1-C6alkyl;

[0355] (viii) NR A7 R A8 ,

[0356] wherein R A7 is C1-C6alkyl;

[0357] and R A8 is C1-C6alkyl,

[0358] (ix) C 6-10 aryl,

[0359] (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S,

[0360] or

[0361] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0362] 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.

[0363] 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, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8 is independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CHF2, CH2CF3, (CH2)4Cl, CH2F, CH2CH2F, CH(CH3)F, CF2CH3, CF3,

[0364] 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, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl,

[0365] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof,

[0366] R 4a 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; 1-4 haloalkyl;

[0367] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl;

[0368] R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl, or halo; and

[0369] each R 8 is independently

[0370] (i) halo,

[0371] (ii) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0372] (iii) C 1-6 haloalkyl,

[0373] (iv) CN,

[0374] (v) oxo,

[0375] (vi) -X-R A5

[0376] 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;

[0377] wherein C1-C6alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups independently selected from CN, halo, C1-C6alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S

[0378] (vii) NHR A6 ,

[0379] wherein R A6 is C1-C6alkyl;

[0380] (viii) NR A7 R A8 ,

[0381] wherein R A7 is C1-C6alkyl;

[0382] and R A8 is C1-C6alkyl,

[0383] (ix) C 6-10 aryl,

[0384] (x) 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S,

[0385] or

[0386] (xi) 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0387] 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.

[0388] In some embodiments of the 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,

[0389] R 4a is H, C 1-6 alkyl, or C 1-4 haloalkyl;

[0390] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl;

[0391] R 9a is C 1-6 alkyl, C 1-4 haloalkyl, or halo; and

[0392] each R 8 is independently

[0393] (i) halo,

[0394] (ii) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0395] (iii) C 1-6 haloalkyl,

[0396] (iv) CN,

[0397] (v) oxo,

[0398] (vi) -X-R A5

[0399] 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;

[0400] wherein C1-C6 alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups independently selected from CN, halo, C1-C6 alkoxy, C 6-10 aryl, and 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S

[0401] (vii) NHR A6 ,

[0402] wherein R A6 is C1-C6 alkyl;

[0403] (viii) NR A7 R A8 ,

[0404] wherein R A7 is C1-C6 alkyl;

[0405] and R A8 is C1-C6 alkyl,

[0406] (ix) C 6-10 aryl,

[0407] (x) 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S,

[0408] or

[0409] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0410] two R 8 groups join 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.

[0411] In some embodiments of the 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,

[0412] R 4a is H, C 1-6 alkyl, or C 1-4 haloalkyl;

[0413] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl;

[0414] R 9a is C 1-6 alkyl, or C 1-4 haloalkyl, and

[0415] each R 8 is independently

[0416] (i) halo,

[0417] (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,

[0418] (iii) C 1-6 haloalkyl,

[0419] (iv) CN,

[0420] (v) oxo,

[0421] (vi) -X-R A5

[0422] 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;

[0423] wherein C1-C6alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups independently selected from CN, halo, C1-C6alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S

[0424] (vii) NHR A6 ,

[0425] wherein R A6 is C1-C6alkyl;

[0426] (viii) NR A7 R A8 ,

[0427] wherein R A7 is C1-C6alkyl;

[0428] and R A8 is C1-C6alkyl,

[0429] (ix) C 6-10 aryl,

[0430] (x) 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S,

[0431] or

[0432] (xi) 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0433] 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.

[0434] In some embodiments of the 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,

[0435] R 4a is H, C 1-6 alkyl, or C 1-4 haloalkyl;

[0436] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl;

[0437] R 9a is -CH3or -CH2F.

[0438] each R 8independently

[0439] (i) halo,

[0440] (ii) C 1-6 alkyl optionally substituted with OH, C 1-6 alkoxy, C 6-10 aryl or 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S,

[0441] (iii) C 1-6 haloalkyl,

[0442] (iv) CN,

[0443] (v) oxo,

[0444] (vi) -X-R A5

[0445] 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;

[0446] wherein C1-C6 alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups independently selected from CN, halo, C1-C6 alkoxy, C 6-10 aryl and 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S

[0447] (vii) NHR A6 ,

[0448] wherein R A6 is C1-C6 alkyl;

[0449] (viii) NR A7 R A8 ,

[0450] wherein R A7 is C1-C6 alkyl;

[0451] and R A8 is C1-C6 alkyl,

[0452] (ix) C 6-10 aryl,

[0453] (x) 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S,

[0454] or

[0455] (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0456] two R 8 groups join 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.

[0457] 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, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8 is independently -Cl, -F, -Br, oxo, -CN, methyl, ethyl, propyl, -CH2Ph, -CH2CH2Ph, -CH(CH3)Ph, -CH2C(CH3)2, -CH2OH, -CH2OMe, -NHMe, -NMe2, -OH, -OMe, -OCD3, -OCD3OCH2CF3, -OCH2CHF2, -OCH2C(CH3)2, -OCH2CH2OMe, -SMe, -CH2F, -CHF2, -CF3, -CH2CF3, -(CH2)4Cl, -SMe, -SO2Me, -CH2CH2F, -CH(CH3)F, -C(F)2CH3, -CF3, -OCH2CF3, -C=CC(CH3)2SO2CH3, -C=CC(CH3)2OH,

[0458] 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, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8 is independently -Cl, -F, -Br, oxo, -CN, methyl, ethyl, propyl, -CH2Ph, -CH2CH2Ph, -CH(CH3)Ph, -CH2C(CH3)2, -CH2OH, -CH2OMe, -NHMe, -NMe2, -OH, -OMe, -OCD3, -OCD3OCH2CF3, -OCH2CHF2, -OCH2C(CH3)2, -OCH2CH2OMe, -SMe, -CH2F, -CHF2, -CF3, -CH2CF3, -(CH2)4Cl, -SMe, -SO2Me, -CH2CH2F, -CH(CH3)F, -C(F)2CH3, -CF3, -OCH2CF3, -C=CC(CH3)2SO2CH3, -C=CC(CH3)2OH,

[0459] 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, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, two R 8connection forms a fused 6-membered ring containing one O.

[0460] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof,

[0461] R 4a is H, C 1-6 alkyl, or C 1-4 haloalkyl;

[0462] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl;

[0463] R 9a is H, C 1-6 alkyl, C 1-4 haloalkyl, or halo; and

[0464] each R 8 is independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl,

[0465] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof,

[0466] R 4a is H, C 1-6 alkyl, or C 1-4 haloalkyl;

[0467] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl;

[0468] R 9a is C 1-6 alkyl, C 1-4 haloalkyl, or halo; and

[0469] each R 8independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl,

[0470] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof,

[0471] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0472] R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl;

[0473] R 9a is C 1-6 alkyl or C 1-4 haloalkyl, and

[0474] each R 8 independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl,

[0475] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof,

[0476] R 4a is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0477] R 5a is H, halo, C 1-4 haloalkyl or C 1-6 alkyl;

[0478] R 9a is C 1-6 alkyl or C 1-4 haloalkyl, and

[0479] each R 8 independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl,

[0480] 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, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, or a pharmaceutically acceptable salt 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.

[0481] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, the compound is of Formula V:

[0482]

[0483] wherein R 8A and R 8B each independently H, halo, C 1-4 alkyl, or C 1-4 haloalkyl.

[0484] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, III, Ilia, IV, IVa, or V, or a pharmaceutically acceptable salt thereof, the compound is of Formula Va:

[0485]

[0486] wherein R 8A and R 8B each independently H, halo, C 1-4 alkyl, or C 1-4 haloalkyl.

[0487] In some embodiments of the compound of Formula I, I-A, II-A, II-Ab, III, Illb, IV, IVb, or V, or a pharmaceutically acceptable salt thereof, the compound is of Formula Vb:

[0488]

[0489] wherein R 8A and R8B Each is independently H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0490] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, and R 8B H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups. In some embodiments, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, and R 8B For H. In some implementations, R 8A H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, and R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups. In some embodiments, R 8A For H, and R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0491] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups.

[0492] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl.

[0493] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 9a C 1-6 alkyl.

[0494] 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.

[0495] 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 alkyl, or C 1-6 haloalkyl.

[0496] 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, or C 1-4 haloalkyl, or halo. In some embodiments, R 9a is C 1-6 alkyl, or C 1-4 haloalkyl, or halo. In some embodiments, 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 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 alkyl, or C 1-6 haloalkyl; and R 9a is H, C 1-6 alkyl, or C 1-4 haloalkyl, or halo.

[0498] 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 alkyl, or C 1-6 haloalkyl; and R9a H, halo, C 1-6 alkyl, C 1-4 haloalkyl or halo.

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

[0500] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A H; R 8B halo, C 1-4 alkyl or C 1-4 haloalkyl; R 4a H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a H, halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a H, C 1-6 alkyl, C 1-4 haloalkyl or halo.

[0501] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A halo, C 1-4 alkyl or C 1-4 haloalkyl; R 8B H, halo, C 1-4 alkyl or C 1-4 haloalkyl; R 4a H, C 1-6 alkyl or C 1-4 haloalkyl; R 5a H, halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a C 1-6 alkyl, C1-4 haloalkyl or halo.

[0502] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A 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 C 1-6 alkyl, C 1-4 haloalkyl or halo.

[0503] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A halo, C 1-4 alkyl or C 1-4 haloalkyl; 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; and R 9a is C 1-6 alkyl, C 1-4 haloalkyl or halo.

[0504] 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 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 C 1-6 alkyl, C 1-4 haloalkyl or halo.

[0505] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R8A halo, C 1-4 alkyl or C 1-4 haloalkyl; R 8B halo, C 1-4 alkyl or C 1-4 haloalkyl; R 4a halo, C 1-6 alkyl or C 1-4 haloalkyl; R 5a halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a C 1-6 alkyl.

[0506] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A halo, C 1-4 alkyl or C 1-4 haloalkyl; R 8B halo, C 4a alkyl or C 1-6 haloalkyl; R 1-4 halo, C 5a alkyl or C 1-4 haloalkyl or C 1-6 alkyl; and R 9a C 1-6 alkyl.

[0507] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A halo, C 1-4 alkyl or C 1-4 haloalkyl; R 8B halo, C 1-4 alkyl or C 1-4 haloalkyl; R 4a halo, C 1-6 alkyl or C 1-4 haloalkyl; R 5a halo, C 1-4 haloalkyl or C 1-6 alkyl; and R 9a C 1-6 alkyl.

[0508] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A halo, C 8B alkyl or C 1-4 haloalkyl; R 1-4 halo, C 4a alkyl or C 1-6 haloalkyl; R1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 alkyl.

[0509] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; R 9a C 1-6 Alkyl; and R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 alkyl.

[0510] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; R 9a C 1-6 Alkyl; and R 1 For being one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently a halogenated group or –O–C 1-4 alkyl.

[0511] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4haloalkyl; 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 with one, two, three or four halogen.

[0512] 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 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 with two or three halogen selected from chlorine and fluorine.

[0513] 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, halo, C 1-4 alkyl, C 1-4 haloalkyl or -X-R A5 ; wherein X is O, and R A5 is H, C 1-6 alkyl, C 1-6 haloalkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S.

[0514] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof:

[0515] R 8A and R 8B are each independently H, halo, C 1-4 alkyl, C 1-4 haloalkyl or -X-R A5 ; wherein X is O, and R A5 is H, C 1-6 alkyl, C 1-6 haloalkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S.

[0516] R 1 is phenyl substituted with two or three halogens selected from chlorine and fluorine;

[0517] R 4a is H, halo, C 1-6 alkyl, or C 1-4 haloalkyl;

[0518] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl; and

[0519] R 9a is C 1-6 alkyl, or C 1-4 haloalkyl.

[0520] 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, halo, C 1-4 alkyl, C 1-4 haloalkyl, or -X-R A5 ; wherein X is O, and R A5 is C 1-6 alkyl, or C 1-6 haloalkyl.

[0521] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof:

[0522] R 8A and R 8B are each independently H, halo, C 1-4 alkyl, C 1-4 haloalkyl, or -X-R A5 ; wherein X is O, and R A5 is C 1-6 alkyl, or C 1-6 haloalkyl;

[0523] R 1 is phenyl substituted with two or three halogens selected from chlorine and fluorine;

[0524] R 4a is H, halo, C 1-6 alkyl, or C 1-4 haloalkyl;

[0525] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl; and

[0526] R 9a is C 1-6 alkyl or C 1-4 haloalkyl.

[0527] 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, halo, C 1-4 alkyl, C 1-4 haloalkyl, or -X-R A5 ; wherein X is O, and R A5 is C 1-6 alkyl.

[0528] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof:

[0529] R 8A and R 8B are each independently H, halo, C 1-4 alkyl, C 1-4 haloalkyl, or -X-R A5 ; wherein X is O, and R A5 is C 1-6 alkyl;

[0530] R 1 is phenyl substituted with two or three halogen selected from chloro and fluoro;

[0531] R 4a is H, halo, C 1-6 alkyl, or C 1-4 haloalkyl;

[0532] R 5a is H, halo, C 1-4 haloalkyl, or C 1-6 alkyl; and

[0533] R 9a is C 1-6 alkyl, or C 1-4 haloalkyl.

[0534] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0535]

[0536] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0537]

[0538] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0539]

[0540] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0541]

[0542] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0543]

[0544] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0545]

[0546] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0547]

[0548] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0549]

[0550] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0551]

[0552] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of:

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of:

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570] In some embodiments of the compound of Formula I, I-A, II-A, II-Aa, II-Ab, III, Ilia, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is:

[0571]

[0572]

[0573]

[0574]

[0575] III. Pharmaceutical Compositions

[0576] The compounds provided herein are typically administered in the form of pharmaceutical compositions. Thus, also provided herein are pharmaceutical compositions comprising one or more compounds provided herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. The compounds provided herein can be the only 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 solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the art of pharmacy. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker and C. T. Rhodes, Eds.).

[0577] In one aspect, provided herein are pharmaceutical compositions comprising 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, Ilia, 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.

[0578] 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 compositions further comprise 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.

[0579] The pharmaceutical compositions can be administered in single or multiple doses. The pharmaceutical compositions can be administered by various methods including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical compositions can be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0580] One mode of administration is parenteral, e.g., by injection. Forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil as customarily is employed, and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0581] Oral administration can be another route for administering the compounds provided herein. Administration can be via, for example, a capsule or enteric-coated tablet. In making the pharmaceutical compositions that include at least one of the compounds provided herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, the active ingredient is typically diluted by an excipient and / or enclosed in a form that can be in the form of a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it can be in the form of a solid, semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, 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.

[0582] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combination thereof. The pharmaceutical compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents; or any combination thereof.

[0583] Pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, can be formulated so as to provide rapid, sustained, or delayed release of the active ingredient (such as a compound provided herein) after administration to a subject by employing procedures known in the art. Controlled release pharmaceutical delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymeric agents or a drug-polymer matrix formulation. 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 transdermal delivery devices (“patches”). Such transdermal patches can be used to provide continuous or discontinuous infusion of a compound provided herein in controlled amounts. The construction and use of transdermal patches for the delivery of agents is well known. See, e.g., U.S. Patents 5,023,252; 4,992,445; and 5,001,139. Such patches can be constructed to deliver drugs continuously or on a pulsed basis, or on demand.

[0584] To prepare solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a compound described herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient can be dispersed essentially evenly throughout the composition so that the composition can be subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0585] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form with prolonged action or to protect the active ingredient from the acidic conditions of the stomach. For example, a tablet or pill can comprise an inner dosage component and an outer dosage component. The outer component can be in the form of an envelope which encases the inner component. The two components can be adjoined by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetrimonium, and cellulose acetate.

[0586] Pharmaceutical compositions for inhalation or insufflation can include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions can be nebulized using an inert gas from a suitable device to administer the composition in a pharmaceutically acceptable solvent. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered preferably orally or nasally from devices that deliver the formulation in an appropriate manner.

[0587] IV. Methods of Treatment

[0588] In one embodiment, a method of treating an HIV infection in a human having or at risk of having an HIV (e.g., HIV-1 and / or HIV-2) infection is provided, 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 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.

[0589] In some embodiments, the method further comprises administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In certain embodiments, the one or more additional therapeutic agents is an anti-HIV agent. In specific embodiments, the one or more additional therapeutic agents is an HIV protease inhibitor, an HIV reverse transcriptase non-nucleoside or non-nucleotide inhibitor, an HIV reverse transcriptase nucleoside or nucleotide inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb (broadly neutralizing HIV antibody), a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, GS-5894, islatravir, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional therapeutic agents is lenacapavir, islatravir. In some embodiments, the additional therapeutic agent is lenacapavir. In some embodiments, the additional therapeutic agent is islatravir.

[0590] In another embodiment, there is provided a 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 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 treatment of an HIV infection in a human having, or at risk of having, an HIV (e.g., HIV-1 and / or HIV-2) infection.

[0591] 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 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 medicine.

[0592] 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, Ilia, 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in treating an HIV infection.

[0593] 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, Ilia, 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having, or at risk of having, an HIV infection.

[0594] 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, Ilia, 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having, or at risk of having, an HIV infection, wherein the method further comprises administering to the human one, two, three, or four additional therapeutic agents.

[0595] 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 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 a method of treating an HIV infection in a human having, or at risk of having, the HIV infection, wherein the method further comprises administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, the one, two, three, or four additional therapeutic agents are selected from an HIV protease inhibitor, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, a latency reversing agent, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist, and a combination thereof.

[0596] 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 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 a method of treating an HIV infection in a human having, or at risk of having, the HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

[0597] 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, Ilia, 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having, or at risk of having, the HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

[0598] 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, Ilia, 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having, or at risk of having, the HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.

[0599] 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, Ilia, 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having, or at risk of having, the HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.

[0600] 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, Ilia, Illb, IV, IVa, IVb, V, Va, or Vb in therapy is provided. In particular, a method of treating HIV viral proliferation, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human) 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, Ilia, Illb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0601] 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, Ilia, Illb, 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 viral proliferation, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human).

[0602] 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, Ilia, Illb, 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, Ilia, Illb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in preventing HIV infection.

[0603] For example, 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, Ilia, Illb, 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, Ilia, Illb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for pre-exposure prophylaxis (pREP), i.e., to prevent an individual exposed to the HIV virus from becoming infected with HIV and / or to stop the virus from establishing a permanent infection and / or to prevent the appearance of symptoms of disease and / or to prevent the virus from reaching detectable levels in the blood prior to the individual being exposed to the virus.

[0604] In another embodiment, 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, Ilia, Illb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an HIV infection in a human having or at risk of having an HIV infection is disclosed.

[0605] In another embodiment, 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, Ilia, Illb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, as a research tool is disclosed.

[0606] In another embodiment, an article of manufacture containing a composition effective to treat an HIV infection; and packaging material comprising a label that indicates the composition can be used to treat an infection caused by HIV is disclosed. Exemplary compositions include a compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-A, II-Aa, II-Ab, III, Ilia, Illb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof.

[0607] In another embodiment, a method of inhibiting HIV replication is disclosed. The method includes exposing a 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, Ilia, Illb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, under conditions in which HIV replication is inhibited.

[0608] In another embodiment, 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, to inhibit the activity of HIV integrase is disclosed.

[0609] In another embodiment, 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, to inhibit HIV replication is disclosed.

[0610] V. Administration

[0611] 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, Ilia, IIIb, IV, IVa, IVb, V, Va, or Vb) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be appreciated that the preferred route can vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0612] The compounds of the present disclosure can be administered to an individual for a period of time or duration required, according to an effective dosing regimen, such as 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 more. In some embodiments, the compounds are administered on a daily or intermittent schedule for the lifetime of the individual.

[0613] The specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion of the subject being treated, drug combinations, and the severity of the particular disease undergoing treatment. For example, dosages can be expressed in mg / kg of subject body weight of the compounds described herein. Dosages between about 0.1 mg / kg and 150 mg / kg can be appropriate. In some embodiments, dosages between about 0.1 mg / kg and 100 mg / kg can be appropriate. In other embodiments, dosages between 0.5 mg / kg and 60 mg / kg can be appropriate. Normalization to subject body weight is particularly useful in adjusting dosages between subjects that differ greatly in size, such as when using a drug in children and adults, or when converting an effective dosage of a non-human subject, such as a dog, to a dosage suitable for a human subject.

[0614] Doses can also be described as the total amount of a compound described herein administered per dose. A dose 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 can be between about 1 mg and 4,000 mg, between about 2,000 mg and 4,000 mg, between about 1 mg and 2,000 mg, between about 1 mg and 1,000 mg, between about 10 mg and 500 mg, between about 20 mg and 500 mg, between about 50 mg and 300 mg, between about 75 mg and 200 mg, or between about 15 mg and 150 mg.

[0615] The dose or frequency of administration of a compound of the present disclosure can be adjusted during the course of treatment according to the judgment of the administering physician.

[0616] 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 every year.

[0617] The compounds provided herein can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a 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, a therapeutically effective amount of a compound 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 mg / dose to about 30 mg / dose, or from about 30 mg / dose to about 300 mg / dose.

[0618] The compounds of the present disclosure can be combined with one or more additional therapeutic agents in 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 about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose, or such as about 0.01 mg / dose to about 1000 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 10 mg / dose, or such as 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.

[0619] In some embodiments, the methods described herein comprise administering to the subject an initial daily dose of about 1 mg to 500 mg of a compound herein, 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.

[0620] When administered orally, the total daily dose to 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 to 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 1000 mg / day administered in a single dose. In some embodiments, the total daily dose to 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 in a single dose. In some embodiments, the total daily dose to a human subject can be about 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day administered in a single dose.

[0621] In some embodiments, the total daily dose for a human subject can be about 100 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 150 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 200 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 250 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 300 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 350 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 400 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 450 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 550 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 600 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 650 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 700 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 750 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 800 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 850 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 900 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 950 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 1000 mg / day administered in a single dose.

[0622] A single dose can be administered every hour, every day, every week, or every month. For example, a 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. A 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. A single dose can also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once a week. A single dose can also be administered once a month. In some embodiments, a compound disclosed herein is administered once a day in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice a day in a method disclosed herein.

[0623] In some embodiments, a compound disclosed herein is administered once every 10 days. In some embodiments, a compound disclosed herein is administered once every 15 days. In some embodiments, a compound disclosed herein is administered once every 20 days. In some embodiments, a compound disclosed herein is administered once every 10-15 days. In some embodiments, a compound disclosed herein is administered once every 15-20 days. In some embodiments, a compound disclosed herein is administered once every 10-20 days. In some embodiments, a compound disclosed herein is administered once every month. In some embodiments, a compound disclosed herein is administered once every 2 months. In some embodiments, a compound disclosed herein is administered once every 3 months. In some embodiments, a compound disclosed herein is administered once every 4 months. In some embodiments, a compound disclosed herein is administered once every 5 months. In some embodiments, a compound disclosed herein is administered once every 6 months. In some embodiments, a compound disclosed herein is administered once every 8 months. In some embodiments, a compound disclosed herein is administered once every 10 months. In some embodiments, a compound disclosed herein is administered once every year.

[0624] The frequency of administration of the compounds of the present disclosure will be determined by the needs of the individual patient and can be, for example, once per day, once per week, once every two weeks, once per month, once every two months, once every three months, once every four months, once every six months, or less. Administration of the compounds continues for as long as the HIV infection is being treated.

[0625] VI. Kits and Articles of Manufacture

[0626] In one aspect, provided herein is a kit comprising 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, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises 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, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for use of the compound in the treatment of an indication described herein, including a disease or condition.

[0627] 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.

[0628] In one aspect, provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, in a suitable container. In some embodiments, the container can be a vial, jar, ampule, pre-filled syringe, or intravenous bag.

[0629] VII. Combination Therapies

[0630] In certain embodiments, a method for treating an HIV infection is provided, the method comprising administering to a human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In one embodiment, a method for treating an HIV infection is provided, the method comprising administering to a human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

[0631] In one embodiment, a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient is provided.

[0632] In certain embodiments, the present disclosure provides a method for treating an HIV infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents suitable for treating an HIV infection.

[0633] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents 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.

[0634] Administration of HIV Combination Therapy

[0635] In certain embodiments, a compound disclosed herein is administered with one, two, three, or four additional therapeutic agents. Co-administration of a compound disclosed herein with one, two, three, or four additional therapeutic agents generally means that a therapeutically effective amount of both the compound disclosed herein and the one, two, three, or four additional therapeutic agents are present in the patient’s body at the same time. When administered sequentially, the combination can be administered in two or more administrations.

[0636] Co-administration includes administration of a unit dose of a compound disclosed herein prior to or following administration of a unit dose of one, two, three, or four additional therapeutic agents. For example, a compound disclosed herein can be administered within seconds, minutes, or hours of administration of one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one, two, three, or four additional therapeutic agents. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed within seconds or minutes by administration of a unit dose of a compound disclosed herein. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one, two, three, or four additional therapeutic agents after a number of 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 administration of a unit dose of a compound disclosed herein after a number of hours (e.g., 1-12 hours).

[0637] In certain embodiments, a kit is provided comprising 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, in combination with one or more (e.g., one, two, three, or four) additional therapeutic agents.

[0638] In a particular 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 or an HIV capsid polymerization inhibitor.

[0639] HIV combination therapy

[0640] In the above embodiments, the one or more additional therapeutic agents can be an anti-HIV agent. 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 modifying agent, a gene editor such as CRISPR / Cas9, a zinc finger nuclease, a homing nuclease, a synthetic nuclease, a TALEN, a cellular therapy such as chimeric antigen receptor T cell CAR-T and engineered T cell receptor TCR-T, an autologous T cell therapy, an engineered B cell, an NK cell, a latency reversing agent, an immune-based therapy, a phosphoinositide 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody and “antibody-like” therapeutic protein, an HIV p17 matrix protein inhibitor, an IL-13 antagonist, a peptidyl prolyl 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 TNF alpha 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 nonintegrin 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 initiation 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.

[0641] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and “antibody-like” therapeutic proteins, and combinations thereof.

[0642] 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.

[0643] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, HIV reverse transcriptase non-nucleoside or non-nucleotide inhibitors, HIV reverse transcriptase nucleoside or nucleotide inhibitors, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversing agents, HIV bNAb, 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 that target HIV antigens, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0644] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, isosaflyn, rilpivirine, and lenacapavir, and combinations thereof.

[0645] HIV Combination Drugs

[0646] Examples of combination drugs include, but are not limited to (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); (Tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobistat; 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, cobistat, and elvitegravir; tenofovir analogs; (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 cobistat; atazanavir sulfate and cobistat; atazanavir sulfate and ritonavir; darunavir and cobistat; 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 fumarate; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotegravir + rilpivirine, 3-BNC117 + ibalizumab, edurant (icierisvir, VM-1500), and VM-1500A, lenacapavir + islatravir (oral, injectable), and dual-targeted HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0647] Other HIV Drugs

[0648] Examples of other drugs used to treat HIV include, but are not limited to, aspernigrin C, acemannan, ala- bocevir, BanLec, deferitrone, 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 derivative, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, bryostatins-1, bryostatins analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, fluoro-beta-D-arabinonucleic acid (FANA) modified antisense oligonucleotide, FX-101, griffithsin, 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, coagulostatin analog, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antivirin fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, nipamovir, Covimro, and ABBV-1882.

[0649] HIV Protease Inhibitors

[0650] 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.

[0651] 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.

[0652] HIV Gag Protein Inhibitors

[0653] Examples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071.

[0654] HIV Ribonuclease H Inhibitors

[0655] Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC-727447.

[0656] HIV Nef Inhibitors

[0657] Examples of HIV Nef inhibitors include, but are not limited to, FP-1.

[0658] HIV Reverse Transcriptase Inhibitors

[0659] Examples of HIV non-nucleoside or non-nucleotide inhibitors of 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, HIV infection), doravirine + islatravir (fixed-dose combination / oral tablet formulation, HIV-1 infection), islatravir (long-acting injectable nano-suspension, HIV infection), and islatravir (VM-1500).

[0660] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octoxoethyl (AGX-1009), tenofovir disoproxil hemifumarate, and VIDEX (didanosine, ddl), abacavir, abacavir sulfate, alovudine, alitretinoin, censavudine, didanosine, elvucitabine, fomivirsen, phosphonoformic ester, CMX-157, dapivirine, doravirine, edoxudine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphonoformic ester, stavudine, zalcitabine, zidovudine, rofavir, GS-9131, GS-9148, MK-8504, islatravir, MK-8583, VM-2500, and KP-1461.

[0661] Additional examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286.

[0662] HIV Integrase Inhibitors

[0663] Examples of HIV integrase inhibitors include, but are not limited to, Elvitegravir, Elvitegravir (extended release microcapsules), Curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurothioglycerol, a derivative of aurothioglycerol, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrosine kinase inhibitor, a derivative of a tyrosine kinase inhibitor, quercetin, a derivative of quercetin, Raltegravir, PEGylated Raltegravir, Doravirine, JTK-351, Biktarvy, AVX-15567, Cabotegravir (long-acting injectable), diketohydroquinoline-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, stilbene disulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017.

[0664] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINI) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[0665] 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.

[0666] HIV Viral Infectivity Factor Inhibitors

[0667] 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.

[0668] HIV Entry Inhibitors

[0669] 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.

[0670] Examples of CCR5 inhibitors include, but are not limited to, aplaviroc, vicriviroc, maraviroc, maraviroc (long-acting injectable nanoemulsion), cenicriviroc, lerolimomab (PRO-140), adatansvir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, selatrevir, and vMIP (Haimipu).

[0671] Examples of gp41 inhibitors include, but are not limited to, ibalizumab, enfuvirtide, griffithsin (gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biobetters, enfuvirtide biosimilars, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifuvirtide.

[0672] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs.

[0673] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicide, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicine, fostemsavir aminoditol, IQP-0831, VVX-004, and BMS-663068.

[0674] Examples of gp160 inhibitors include, but are not limited to, fuzixanthine.

[0675] Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0676] HIV Maturation Inhibitors

[0677] Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232.

[0678] Latency Reversing Agents

[0679] 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 Velcade), 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, aniline, 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 lagerstatin, APH-0812, GSK-343). Examples of PKC activators include, but are not limited to, indolactam, prostratin, largazole, and DAG-lactones.

[0680] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.

[0681] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944.

[0682] Histone Deacetylase (HDAC) Inhibitors

[0683] In some embodiments, an agent as described herein is administered with an inhibitor of histone deacetylases, e.g., 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), resminostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0684] Capsid Inhibitors

[0685] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid disruption 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).

[0686] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030.

[0687] Cytochrome P450 3 Inhibitors

[0688] Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553.

[0689] RNA Polymerase Modulators

[0690] 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.

[0691] Immune Checkpoint Modulators

[0692] In various embodiments, an agent as described herein is combined with one or more blocking agents or inhibitors of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulating agents, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibition of inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape of infected cells. Activation or stimulation of stimulatory immune checkpoints can enhance the effect of immune checkpoint inhibitors in infectious treatments. In various embodiments, the immune checkpoint protein or receptor modulates T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, the immune checkpoint protein or receptor modulates NK cell responses (e.g., reviewed in Davis et al., Semin Immunol. (2017) 31:64-75; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0693] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), 2 with transmembrane and immunoglobulin domains (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitor 1 with V-set domains (VTCN1, B7H4); V-set immunomodulator receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator 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 gene 3 (LAG3, CD223); Signaling lymphocyte 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 gene 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).

[0694] In various embodiments, the agents described herein are combined with one or more blocking agents 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 gene 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 agents as 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 stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; Inducible T cell costimulator (ICOS, CD278); Inducible T cell costimulator 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.

[0695] In various embodiments, the agents as described herein are combined with one or more blocking agents 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 Cl (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents as described herein are 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.

[0696] In some embodiments, the one or more immune checkpoint inhibitors include a protein (e.g., an antibody or fragment thereof or an antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors include a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is 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.

[0697] 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 multispecific 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).

[0698] 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, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (bulevirtide), PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (domvanalimab), 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 multispecific 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).

[0699] In various embodiments, an agent as described herein is combined with an anti-TIGIT antibody, such as BMS-986207, RG-6058, and AGEN-1307.

[0700] Agonists or Activators of Members of the TNF Receptor Superfamily (TNFRSF)

[0701] In various embodiments, an agent as described herein is combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, such as an agonist of one or more of 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).

[0702] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0703] 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.

[0704] In some embodiments, an anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0705] 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.

[0706] 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.

[0707] Bispecific and Trispecific Natural Killer (NK) Cell Engagers

[0708] 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 Fc) or a bispecific antibody (e.g., with Fc) against an NK cell activating receptor, 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 receptors FcyR (which mediate antibody-dependent cellular 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 can or can not have an Fc. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKEs and TriKEs are described, e.g., 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.

[0709] Indoleamine-Pyrrole-2,3-Dioxygenase (IDO1) Inhibitors

[0710] 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 vaccine, PF-06840003, pyranonique derivative (SN-35837), rilmazafone, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0711] Toll-Like Receptor (TLR) Agonists

[0712] 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).Example TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (vesatolimod), vesatolimod 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), and 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, tiramode 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 resiquimod, polyICLC, Apoxxim, IPH-33, MCT-465, MCT-475, and ND-1.1. TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0713] CDK Inhibitors or Antagonists

[0714] 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.

[0715] STING Agonists, RIG-I and NOD2 Modulators

[0716] In some embodiments, the agents described herein are combined with a 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 a RIG-I modulator (such as RGT-100) or a NOD2 modulator (such as SB-9200 and IR-103).

[0717] LAG-3 and TIM-3 Inhibitors

[0718] 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).

[0719] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with an anti-LAG-3 (lymphocyte activation) antibody (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

[0720] Interleukin Agonists

[0721] In certain embodiments, the agents as described herein are combined with an interleukin agonist (such as IL-2, IL-7, IL-15, IL-10, IL-12) agonist; 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), belatacept, 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-15 Synthorin (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.

[0722] Examples of additional immune-based therapies that can be combined with the agents of the present disclosure include, but are not limited to, interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma; FLT3 agonists such as CDX-301, GS-3583, gepon, nomifensine, peginterferon alfa-2a, peginterferon alfa-2b, and RPI-MN.

[0723] Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

[0724] Examples of PI3K inhibitors include, but are not limited to, idelalisib, alpelisib, buparlisib, CAI, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, idelalisib, pilaralisib, plafibrocal mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-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.

[0725] Alpha-4 / Beta-7 Antagonists

[0726] Examples of integrin α-4 / β-7 antagonists include, but are not limited to, PTG-100, TRK-170, aliruzumab, ectolizumab, methylcarograss, and vedolzumab.

[0727] HPK1 Inhibitors

[0728] Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.

[0729] HIV Targeting Antibodies

[0730] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include, but are not limited to, those mentioned above. Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360, TMB-370, and HIV-targeting antibodies Antibodies targeting gp120 or gp41, HIV-targeting antibody recruitment molecules, 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, recombinant human mAb (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, clone 3 human monoclonal antibodies targeting KLIC (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0731] Various 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 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):D1133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to 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 CD4 binding site).

[0732] Other broadly neutralizing antibodies that can be used as second therapeutic agents in combination therapy are described in, e.g., U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, and WO 2012 / 154312, WO 2012 / 158948, WO 2013 / 086533, WO 2013 / 142324, WO 2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, WO 2015 / 103549, WO 2015 / 117008, WO 2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO 2017 / 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): D1133-9 (2014); Mascola et al., Immunol Rev., 254(l): 225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074, and LN01 (all of which bind to the MPER of gp41).

[0733] Examples of additional antibodies include, but are not limited to, bavituximab, 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, Cl3 hmAb, GS-9722 (ebivirumab), 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, DRVI A7, 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, 35022, ACS202, VRC34, and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LNOl.

[0734] 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.

[0735] Examples of bNAbs delivered in vivo include, but are not limited to, AAV8-VRC07, mRNA encoding anti-HIV antibody VRC01, and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med., 2019, 1301).

[0736] Pharmacokinetic Enhancers

[0737] Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir.

[0738] Additional Therapeutic Agents

[0739] Examples of additional therapeutic agents include, but are not limited to, 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), US2013 / 0165489 (University of Pennsylvania), US2014 / 0221378 (Japan Tobacco), US2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US20140221356 (Gilead Sciences), US20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim).

[0740] HIV Vaccines

[0741] 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, adenoviral vector vaccines (adenoviral vectors such as Ad5, Ad26, or Ad35), simian adenoviruses (chimpanzee, gorilla, rhesus macaque, i.e. rhAd), adeno-associated viral 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), bisection or trisection-based arenavirus 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), NYVAC of orthopoxvirus origin, and ALVAC (Avianpox virus) strain of fowlpox virus origin); fowlpox virus-based vaccines, rhabdovirus-based vaccines such as VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines such as Simian

[0742] Examples of HIV vaccines include: AAVLP-HIV vaccine, AE-298p, Anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1 gp140 adjuvanted vaccine, ChAdOxl.tHIVconsvl vaccine, CMV-MVA triple vaccine, ChAdOxl.HTI, Chimigen HIV vaccine, ConMSOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAX B / E (gpl20), monomeric gpl20 HIV-1C subtype vaccine, MPER-656 liposomal subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multistage 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 / VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[delta]V2.TV1 + MF-59, rVSVIN HIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, N123-VRC-34.01 HIV vaccines inducing 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, HIV gag / 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, multistage 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 env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer-based vaccine, PD-201401, env(A,B,C,A / E) / gag(C) DNA vaccine, gp120(A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24 gag prime-boost plasmid DNA vaccine, HIV-1 iglb12 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.

[0743] Contraceptive (Birth Control) Combination Therapy

[0744] In certain embodiments, the agents described herein are combined with a birth control or contraceptive regimen. Therapeutic agents for birth control drugs (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, norethindrone, etonogestrel, levomefomin, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norethisterone, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof.

[0745] In one particular embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, 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; (Etravirine, 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 etravirine); (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; combivir; emtricitabine; tenofovir; tenofovir alafenamide and elvitegravir; tenofovir alafenamide + elvitegravir (rectal formulation, HIV infection); tenofovir disoproxil; 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 combivir; atazanavir and combivir; darunavir and combivir; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; platin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptor alcohol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0746] In some embodiments, the agents disclosed herein, or pharmaceutical compositions thereof, 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 disclosed herein, or pharmaceutical compositions thereof, are combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibiting compound. In further embodiments, the agents disclosed herein, or pharmaceutical compositions thereof, are combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the agents disclosed herein, or pharmaceutical compositions thereof, are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the agents disclosed herein, or pharmaceutical compositions thereof, are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0747] In another embodiment, the agents disclosed herein, or pharmaceutical compositions thereof, are combined with a first additional therapeutic agent selected from the group consisting of dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsicavir, rilpivirine, and lenacapavir, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0748] In some embodiments, the agents disclosed herein, or pharmaceutical compositions thereof, are combined with a first additional therapeutic agent (a contraceptive agent) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etogestrel, levomefomin, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norethisterone, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof.

[0749] Gene Therapy and Cell Therapy

[0750] In certain embodiments, the agents described herein are combined with a gene therapy or cell therapy regimen. Gene therapy and cell therapy include, but are not limited to, gene modification to silence genes; gene methods to directly kill infected cells; infusion of immune cells designed to replace a large portion of a patient’s own immune system to enhance the immune response to infected cells, or to activate a patient’s own immune system to kill infected cells, or to find and kill infected cells; gene methods to modify cellular activity to further alter the endogenous immune response to 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 therapy. 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 lentiviral vector CCR5 shRNA / TRIM5a / TAR decoy transduced autologous CD34-positive hematopoietic progenitor cells (HIV infection / HIV-associated lymphoma). In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multi-specific 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.

[0751] Gene Editors

[0752] In certain embodiments, the agents described herein are combined with a gene editor (e.g., an HIV-targeting gene editor). In various embodiments, the genome editing system can be selected from the group consisting of a CRISPR / Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonuclease complex, and a meganuclease complex. Exemplary HIV-targeting CRISPR / Cas9 systems include, but are not limited to, EBT-101.

[0753] CAR-T Cell Therapy

[0754] 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), wherein the CAR comprises an HIV antigen binding domain. HIV antigens include HIV envelope protein or portions thereof, gpl20 or portions thereof, CD4 binding site on gpl20, CD4 induced binding site on gpl20, N-glycan on gpl20, V2 of gpl20, 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, switchable CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-CD4 CART cell therapy, CD4 CAR + C34-CXCR4 + CCR5 ZFN T cells, dual anti-CD4 CAR 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 genetically engineered to express CD4 CAR and C46 peptide.

[0755] TCR T Cell Therapy

[0756] In certain embodiments, the agents described herein are combined with a population of TCR-T cells. TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus infected cells, for example ImmTAV.

[0757] B Cell Therapy

[0758] In certain embodiments, the antibodies or antigen binding fragments described herein are combined with a population of B cells genetically modified to express broadly neutralizing antibodies, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaax0644 (2019), May 17, 2019).

[0759] A compound as disclosed herein (e.g., any compound of Formula I) can be combined with one, two, three, or four additional therapeutic agents in any dosage of the compound of Formula I (e.g., 1 mg to 500 mg of the compound).

[0760] In one embodiment, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two or one to three) additional therapeutic agents.

[0761] In one embodiment, the one or more additional therapeutic agents of the kit is an anti-HIV agent selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modifying agents, gene editors such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, cell therapies such as chimeric antigen receptor T cells CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapies, compounds targeting the HIV capsid, latency reversing agents, HIV bNAb, immune-based therapies, phosphoinositide 3-kinases (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 nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapies, HIV vaccines, and combinations thereof.

[0762] In some embodiments, the one or more additional therapeutic agents of the kit are selected from the group consisting of combination drugs for HIV, other drugs for the treatment of 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.

[0763] In one 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 one 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 a HIV protease inhibiting 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 nucleoside or nucleotide inhibitors of reverse transcriptase. In one 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 a HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, a nucleoside inhibitor of HIV reverse transcriptase, and a HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAb. In one specific embodiment, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAb, and a HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAb, a HIV capsid inhibitor, and a nucleoside inhibitor of HIV reverse transcriptase.

[0764] HIV Long-Acting Therapy

[0765] Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotevir, rilpivirine, any integrase LA, VM-1500LAI, maraviro (LAI), tenofovir implant, isratrovir implant, doravirine, retegvir, and long-acting durutvir.

[0766] VII. Examples

[0767] 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-bridged methylenepyrido[1,2-a][1,4]diazonine-10-carboxamide

[0768]

[0769] Step 1 : Synthesis of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-3-amine Step 2 :

[0770] Add 20 mL of trifluoroacetic acid to (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-aza The reaction mixture was heated to 100°C and held for 4 hours in benzyl 1-carboxylate (6.2 g, 15.7 mmol). The reaction mixture was concentrated and the crude product was used directly in the next step.

[0771] Synthesis 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]diazocin-10-carboxamide : Step 3 Synthesis of (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]diazocin-10-carboxamide :

[0772] 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-aza -3-amine (crude reaction product from previous step). NaHCO3(13.2 g, 157 mmol) was added to the reaction mixture at room temperature. The reaction was stirred at room temperature overnight, then heated to 60 °C for 5 h. The reaction mixture was concentrated, then ethyl acetate was added and washed with saturated ammonium chloride solution. The organic layer was concentrated and purified by silica gel chromatography eluting 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]diazocin-10- carboxamide. MS (m / z) 524.11 [M+H]+.

[0773] Step 1 : Synthesis of (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]diazocin-10-carboxamide Step 2 :

[0774] 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]diazocin-10-carboxamide (product of previous step, 15.7 mmol) in dioxane (160 mL). The reaction was then heated to 105 °C overnight. The reaction mixture was cooled and the solids were filtered off. The filtrate was extracted using ethyl acetate and saturated ammonium chloride solution. The organic layer was concentrated and purified by silica gel chromatography eluting with 40-100% ethyl acetate / hexanes 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]diazocin-10-carboxamide. MS (m / z) 538.095 [M+H]+.

[0775] 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]diazocin-10- carboxamide:

[0776]

[0777] (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide (132 mg, 0.246 mmol) was dissolved in anhydrous THF (3.0 mL) and the resulting mixture was cooled to -20 °C. To this stirring, cooled mixture was added methylmagnesium bromide, 3.0 M in ether (0.41 mL, 1.23 mmol). After stirring for 20 min, the reaction was quenched with saturated NH4Cl. 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 / hexanes). MS (m / z) 553.95 [M+H]+.

[0778] Intermediate C: (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide:

[0779]

[0780] Synthesis of (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide : ​ ​ ​ :

[0781] To a round bottom flask was added (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6- dimethyl-l,l l-dioxo-N-(2,4,6-trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (3.15 g, 5.69 mmol) followed by Fe(acac)3(1.01 g, 2.85 mmol), EtOH (60 mL), PhSiH3(2.90 mL, 22.8 mmol), and PhSH (5.69 mL, 2.85 mmol, 0.5 M 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 (20% to 100% ethyl acetate in hexanes) followed by a second purification by reverse phase chromatography (5% to 100% acetonitrile in water with 10 mM ammonium formate buffer, pH = 3.8). The corresponding fractions were combined, extracted with dichloromethane, and concentrated in vacuo to yield (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide. MS (m / z) 556.4 [M+H]+.

[0782] ​ : ​ Synthesis 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]diazocin-10- formamide Synthesis 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]diazocin-10- formamide :

[0783] To a round bottom flask was added (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6- dimethyl-l,l l-dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (3.20 g, 5.76 mmol) followed by dichloromethane (90 mL). To this suspension was added Lawesson's Reagent in two portions (8.91 g, 13.2 mmol) and the mixture was stirred at room temperature for 1 hour. The resulting solution was then concentrated in vacuo and the residue purified by reverse phase chromatography (5% to 100% acetonitrile in water with 10 mM ammonium formate buffer, pH = 3.8). The corresponding fractions were combined and lyophilized to yield (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide. MS (m / z) 538.4 [M+H]+.

[0784] Intermediate D: (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-l,6,l l- trioxo-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0785]

[0786] This intermediate was prepared in a similar manner as (3S,7R)-12-(benzyloxy)-3- methyl-l,6,l l-trioxo-N-(2,4,6-trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (Intermediate A) except that methyl 3- (benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate was used in Step 2. MS (m / z) 520.200 [M+H]+.

[0787] Intermediate E: (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6- dimethyl-l,l l-dioxo-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide:

[0788]

[0789] This intermediate was prepared in a similar manner to (3S,6S,7R)-12-(benzyloxy)-6- hydroxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6-trifluorobenzyl)-l,6,7, l l-tetrahydro-3H- 2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (Intermediate B), except (3S,7R)- 12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-l,6,l l-trioxo-l,6,7, l l-tetrahydro-3H- 2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (Intermediate D) was used. MS (m / z) 536.4 [M+H]+.

[0790] Intermediate F: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6- methylene-l, l l-dioxo-l,4,5,6,7, l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide:

[0791]

[0792] Step 1 Synthesis 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]diazocin-10- formamide Step 2 Synthesis 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]diazocin-10-carboxamide

[0793] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6- dimethyl-l, l l-dioxo-l,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide (5.90 g, 11.0 mmol, 1 equiv) in methanol (500 mL) and CH2Cl2(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 hours and diluted with CH2Cl2(500 mL). The reaction mixture was filtered through celite and concentrated. The crude material was purified by column chromatography (0% to 10% MeOH / CH2Cl2). 2- 2- ​​​The residue was triturated with MeOH and dried in a vacuum oven to give (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-l, l l-dioxo- 1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide. MS (m / z) 448.26 [M+H]+.

[0794] Step 3 : Synthesis 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]diazocin-10-carboxamide Step 1 Preparation 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]diazocin]-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]methanopyrido[1,2-a][1,4]diazocin]-10'-carboxamide :

[0795] To a suspension of (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6- dimethyl-l, l l-dioxo- 1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-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 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (0% to 100% EtOAc / hexanes) to give (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-l, l l-dioxo- 1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide. MS (m / z) 538.11 [M+H]+.

[0796] Step 2 : 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]diazocin]-10'-carboxamide Step 1 Preparation 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]diazocin]-10'-carboxamide and (3'S, 5R, 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]diazocin]-10'-carboxamide :

[0797] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6- dimethyl-l, 11-dioxo- 1,4,5,6,7, 11-hexahydro-3H-2,7-methano pyrido[ 1,2-a] [ 1,4] diazacyclononedece-10-carboxamide (1.258 g, 2.34 mmol, 1 equiv) in toluene (15 mL) was added Martin's sulfane (3.933 g, 5.85 mmol, 2.5 equiv). The reaction mixture was heated to 40 °C for 1 h and concentrated. The residue was purified by column chromatography (0% to 100% EtOAc / hexanes) to give (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-l, 11-dioxo- 1,4,5,6,7, 11-hexahydro-3H-2,7-methano pyrido[ 1,2-a] [ 1,4] diazacyclononedece-10- carboxamide. MS (m / z) 520.12 [M+H]+.

[0798] 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-methano pyrido[ 1,2-a] [ 1,4] diazacyclononedece-10- carboxamide:

[0799]

[0800] To a suspension of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6- dimethyl-l, 11-dioxo- 1,4,5,6,7, 11-hexahydro-3H-2,7-methano pyrido[ 1,2-a] [ 1,4] diazacyclononedece-10-carboxamide (0.525 g, 0.98 mmol) (Intermediate E) in toluene (10 ml) was added Martin's sulfane (1.98 g, 2.94 mmol). The reaction was stirred at room temperature for 20 min. The reaction was diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4, 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-l, 11-dioxo- 1,4,5,6,7, 11-hexahydro-3H-2,7-methano pyrido[ 1,2-a] [ 1,4] diazacyclononedece-10- carboxamide. MS (m / z) 518.23 [M+H]+.

[0801] Example 1: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'- dimethyl-1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]bridgemethylpyrrolo[1,2-a][1,4]diazocin]-10'-formamide:

[0802]

[0803] ​ : ​ ​ ​ ​ ​ :

[0804] To a solution of acetaldoxime (666 mg, 11.3 mmol) in DMF (50 ml) was added N- chlorosuccinimide (1.51 g, 11.3 mmol) at room temperature and then heated to 60 °C for 1 h. 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 at room temperature. After stirring the reaction mixture at room temperature overnight, the reaction was quenched by the addition of saturated NaHC03solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated and purified by silica gel 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).

[0805] ​ : ​ ​ ​ :

[0806] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'- dimethyl-1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyrido[1,2-a][1,4]diazocin]-10'-formamide (64.7 mg, 0.1 12 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% acetonitrile in water to give the title compound. MS (m / z) 487.12 [M+H] + . 1 H 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).

[0807] Example 2: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'- dimethyl-1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyrido[1,2-a][1,4]diazocin]-10'-formamide:

[0808]

[0809] 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]fused pyrrolo[1,2-a][1,4]diazocin]-10'-formamide (396 mg, 0.687 mmol) prepared according to Example 1 in toluene (5 mL) was added TFA (1 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% acetonitrile in water 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).

[0810] 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]fused pyrrolo[1,2- a][1,4]diazocin]-10'-formamide:

[0811]

[0812] ​ : ​ ​ ​ 11'-Dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrrolo[1,2-a][1,4]diazocin]-10'-formamide Preparation 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide :

[0813] To a solution of acetaldoxime (160 mg, 2.71 mmol) in DMF (5 ml) was added N- chlorosuccinimide (90.5 mg, 0.68 mmol) at room temperature, then heated to 60 °C for 1 h. 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-bridged methylenepyrido[1,2- a][1,4]diazocin-10-carboxamide (Intermediate C) (119 mg, 0.221 mmol) and triethylamine (112 mg, 1.1 mmol) were added at room temperature. After the reaction mixture was stirred at room temperature overnight, the reaction was quenched by the addition of saturated NaHC03solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated and purified by silica gel chromatography (eluted with 0% to 100% EtOAc / hexanes) to give two separable isomers. MS (m / z) 595.06 [M+H]+(major); 595.09 [M+H]+(minor).

[0814] Step 2 : Preparation 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide Step 1 Preparation 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide :

[0815] 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]bridged methylenepyrido[1,2-a][1,4]diazocin]-10'-carboxamide (72.3 mg, 0.122 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 eluted with 10% to 90% acetonitrile in water to give the title compound. MS (m / z) 505.129 [M+H] + . 1H 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).

[0816] Example 4: Preparation of (3'S,5R,7'R)-12'-hydroxy-3,3'-dimethyl-l',ll'- dioxo-N-(2,4,6-trifluorobenzyl)-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide:

[0817]

[0818] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-3,3'-dimethyl-l',ll'-dioxo-N-(2,4,6- trifluorobenzyl)-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide (10.8 mg, 0.018 mmol) prepared according to Example 3 in toluene (1 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% acetonitrile in water to give the title compound. MS (m / z) 505.142 [M+H] + . 1H NMR (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).

[0819] 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]fused pyrrolo[1,2-a][1,4]diazocin]-10'-formamide:

[0820]

[0821] Step 2 : Preparation 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide Step 3 Preparation 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide :

[0822] 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-fused pyrrolo[1,2-a][1,4]diazocin-10- carboxamide (Intermediate E) (0.525 g, 0.98 mmol) in toluene (10 ml) was added Lawesson's reagent (1.98 g, 2.94 mmol). The reaction was then stirred at room temperature for 20 minutes. The reaction was diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography to give the title compound. MS (m / z) 518.23 [M+H]+.

[0823] Step 4 : Preparation 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide Step 5 Preparation 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide :

[0824] To a solution of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6- methylene-1,1 1 -dioxo-1,6,7,1 1 -tetrahydro-3H-2,7-bridged methylenopyrido[1,2- a][1,4]diazocin-10-carboxamide (0.335 g, 0.647 mmol) in DMF (2 ml) was added (1 Z)-N-hydroxyacetimidoyl chloride (0.303 g, 3.24 mmol) followed by triethylamine (0.655 g, 6.47 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with H2O, 5% LiCI (aq) and brine. The organic phase was dried over MgS04. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography to give the title compound. MS (m / z) 575.58 [M+H]+.

[0825] Step 1 : ((3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5', ​ ​ :

[0826] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'- dimethyl-1 ',1 1 '-dioxo-1 ',1 1 '-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7] bridged methylenopyrido[1,2-a][1,4]diazocin]-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 was then stirred under an atmosphere of 02(g) for 24 hours. The reaction was quenched by the addition of 10% sodium thiosulfate and then extracted with EtOAc. The organic phase was washed with H2O, brine and dried over MgS04. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography to give the title compound. MS (m / z) 593.05 [M+H]+.

[0827] ​ : ​ ​ ​ :

[0828] To a solution of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'- hydroxy-3,3'-dimethyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused pyrrolo[l,2-a][l,4]diazocin]-10'-formamide (60 mg, 0.101 mmol) in DCM (2 mL) at 0 °C was added deoxofluor in toluene (50%, 0.375 mL, 1.01 mmol). The reaction mixture was stirred at 0 °C for 15 min and quenched by the addition of saturated NaHC03solution. The mixture was extracted with DCM, the organic separated and dried over MgS04, filtered, concentrated and purified by silica gel chromatography (eluting with 0-100% hexanes / EtOAc) to give the title compound. MS (m / z) 595.04 [M+H]+.

[0829] ​ : ​ ​ ​ :

[0830] To a solution of (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'- dimethyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused pyrrolo[l,2- a][l,4]diazocin]-10'-formamide (11 mg, 0.0185 mmol) in toluene (1 mL) was added TFA (1 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 5-100% acetonitrile in water to give 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).

[0831] Example 6: Preparation of (3'S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'- hydroxy-3,3'-dimethyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide:

[0832]

[0833] ​ : ​ 11 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrrolo[1,2- a][1,4]diazonin]-10'-carbonyl)(2,4-difluorobenzyl)carbamic acid tert-butyl ester Preparation 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]methanopyrrolo[1,2-a][1,4]diazonin]- 10'-carboxylic acid :

[0834] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'- dimethyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide (631 mg, 1.11 mmol) prepared according to Example 1 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 to room temperature, the reaction was quenched by the addition of a saturated NaHC03solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated and purified by silica gel column chromatography (eluting with 30% to 100% EtOAc / hexanes) to give the title compound. MS (m / z) 676.924 [M+H]+.

[0835] 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]methanopyrrolo[1,2-a][1,4]diazonin]-10'-carboxylic acid Preparation 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]methano pyrrolo[1,2-a][1,4]diazonin]-10'-carboxamide Step 3 :

[0836] 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]bridged methylenepyrido[1,2-a][1,4]diazocin]-10'-carbonyl)(2,4- difluorobenzyl)carbamic acid tert-butyl ester (590 mg, 0.872 mmol) in MeOH (10 ml) was added 1 N NaOH solution (3 ml) at room temperature. After 1 hour at room temperature, the reaction was quenched by the addition of 1 N HC1 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated to give the crude title compound which was used without purification. MS (m / z) 452.127 [M+H]+.

[0837] (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]methanopyrrolo[1,2- a][1,4]diazonin]-10'-carboxamide : 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]methanopyrrolo[1,2-a][1,4] diazonin]-10'-carboxamide Step 1 :

[0838] 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]bridged methylenepyrido[1,2-a][1,4]diazocin]-10'-carboxylic acid (65 mg, 0.144 mmol) in DMF (5 ml) was added (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) at room temperature. After 1 hour at room temperature, the reaction was quenched by the addition of saturated NaHC03solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated and purified by silica gel chromatography eluting with 50% to 100% EtOAc / hexanes to give the title compound. MS (m / z) 611.075 [M+H]+.

[0839] Preparation of (E)-2-((tert-butyldiphenylsilyl)oxy)acetaldoxime : 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[isoxazole- 5,6'-[2,7]methanopyrrolo[1,2-a][1,4]diazonin]-10'-carboxamide 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]methanopyrrolo[1,2- a][1,4]diazonin]-10'-carboxamide Step 3 :

[0840] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)- 3,3'-dimethyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide (88 mg, 0.144 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% acetonitrile in water to give the title compound. MS (m / z) 521.181 [M+H]+. 1 H 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).

[0841] Example 7: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3- isopropyl-3'-methyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide:

[0842]

[0843] (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-isopropyl-3'-methyl-l',ll'- dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyrido[ 1,2-a][ 1,4]diazocin]- 10 '-formamide was prepared in a similar manner as Example 1, except isobutyraldoxime was used in Step 1. MS (m / z) 515.152 [M+H]+. 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).

[0844] 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]fused pyrrolo[1,2-a][1,4]diazocin]-10'-formamide:

[0845]

[0846] The title compound was prepared in a similar manner as Example 1, except that propionaldoxime was used instead of acetaldoxime 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).

[0847] 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]fused pyrrolo[1,2-a][1,4]diazocin]-10'-formamide:

[0848]

[0849] The title compound was prepared in a similar manner to Example 3, except that 3,3,3-trifluoropropanal oxime was used instead of acetaldoxime 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).

[0850] 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]bridgemethylenopyrano[1,2-a][1,4]diazocin]-10'- carboxamide:

[0851]

[0852] The title compound was prepared in a similar manner to Example 3, except that 5- bromopentanal oxime was used instead of acetaldoxime in Step 1. MS (m / z) 581.223 [M+H]+. 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).

[0853] 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]fused pyrindo[1,2-a][1,4]diazanamantane]-10'-formamide:

[0854]

[0855] The title compound was prepared in a similar manner as Example 1, except using benzaldehyde oxime instead of acetaldehyde oxime in Step 1. MS (m / z) 549.127 [M+H]+. 1 H 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).

[0856] Example 12: Preparation of (3'S,5S,7'R)-3-benzyl-N-(2,4-difluorobenzyl)-12'- hydroxy-3'-methyl-1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused pyrrolo[1,2-a][1,4]diazocin]-10'-formamide:

[0857]

[0858] The title compound is prepared in a similar manner as Example 1, except that 2- phenylacetaldoxime is used instead of acetaldoxime in Step 1. MS (m / z) 563.165 [M+H]+. 1 H 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).

[0859] Example 13: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'- methyl-1 ',1 1 '-dioxo-3-(pyridin-2-yl)-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused pyrrolo[1,2-a][1,4]diazocin]-10'-formamide:

[0860]

[0861] The title compound is prepared in a similar manner as Example 1, except N- hydroxypicolinimidoyl chloride is used instead of N-hydroxyacetimidoyl chloride in Step 1. MS (m / z) 550.177 [M+H]+. 1 H 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).

[0862] 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]bridgemethylenopyrrolo[1,2-a][1,4]diazocin]-10'-formamide:

[0863]

[0864] The title compound is prepared in a similar manner as Example 1, except N- hydroxynicotinimidoyl chloride is used instead of N-hydroxyacetimidoyl chloride in Step 1. MS (m / z) 550.191 [M+H]+. 1H 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).

[0865] Example 15: Preparation of (3'S,5S,7'R)-3-cyclopropyl-N-(2,4-difluorobenzyl)-12'- hydroxy-3'-methyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused pyrrolo[l,2-a][l,4]diazocin]-10'-formamide:

[0866]

[0867] The title compound was prepared in a similar manner as Example 1, except that cyclopropylcarboxaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 513.16 [M+H]+. 1 H 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).

[0868] Example 16: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3- (hydroxymethyl)-3'-methyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H- spiro[isoxazole-5,6'-[2,7]bridgemethylpyrrolo[l,2-a][l,4]diazocin]-10'-formamide:

[0869]

[0870] The title compound is prepared in a similar manner as Example 1, except that 2- ((tert-butyldimethylsilyl)oxy)acetaldoxime is used instead of acetaldoxime 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).

[0871] Example 17: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'- hydroxy-3'-methyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]bridgemethylpyrrolo[l,2-a][l,4]diazocin]-10'-formamide:

[0872]

[0873] (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]methanopyrrolo[1,2- a][1,4]diazonin]-10'-carboxamide : Step 4 :

[0874] To a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetaldehyde (1 g, 3.35 mmol) in MeOH (15 ml) and H2O (5 ml) was added hydroxylamine hydrochloride (0.28 g, 4.02 mmol) followed by sodium bicarbonate (0.245 g, 4.02 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4and the solvent was removed in vacuo. The residue was purified by silica gel chromatography to give the title compound. MS (m / z) 314.05 [M+H]+.

[0875] ​ : ​ ​ ​ ​ ​ ​ :

[0876] 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]bridgedmethylenepyrido[1,2-a][1,4]diazocin]-10'-formamide 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]bridgedmethylenepyrido[1,2-a][1,4]diazocin]-10'-formamide was obtained as the minor stereoisomer. MS (m / z) 831.12 [M+H]+(major); 831.13 [M+H]+(minor).

[0877] ​ : ​ ​ ​ :

[0878] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)- N-(2,4-difluorobenzyl)-3'-methyl-1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H- spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazocin]-10'-formamide (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 h. The reaction mixture was diluted with EtOAc and washed with NaHC03(sat.) and brine. The organic phase was dried over MgS04, the solvent was removed in vacuo. The residue was purified by silica gel chromatography to give the title compound. MS (m / z) 593.07 [M+H]+.

[0879] ​ : (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,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide 1 ',11 '-dioxo-1 ',4',5',11 '-tetrahydro-3'H,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide Preparation of (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,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide :

[0880] 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 ',1 1 '- dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2- a][1,4]diazocin]-10'-formamide was used instead of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4- difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H- spiro[isoxazole-5,6'-[2,7]methanopyridino[1,2-a][1,4]diazocin]-10'-formamide. MS (m / z) 595.09 [M+H]+.

[0881] Step 5 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1', 1 ',11 '-dioxo-1 ',4',5',11 '-tetrahydro-3'H,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide Step 1 :

[0882] The title compound is prepared in a similar manner as Step 2 of Example 1, except (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]bridgedmethylenepyrido[1,2-a][1,4]diazocin]-10'-formamide is 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]bridgedmethylenepyrido[1,2-a][1,4]diazocin]-10'-formamide. 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).

[0883] 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]bridgedmethylenepyrido[1,2-a][1,4]diazocin]-10'-formamide:

[0884]

[0885] The title compound is prepared in a manner similar to (3'S,5S,7'R)-N-(2,4- difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-l',ll'-dioxo-l',4',5',ll'- tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyridino[1,2- a][1,4]diazocin]-10'-formamide in Example 17, except using (3'S,5R,7'R)-12'- (benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'- methyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide instead of (3'S,5S,7'R)-12'- (benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'- methyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide in Step 3. 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).

[0886] 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]bridged methylenepyrido[1,2-a][1,4]diazocin]-10'- carboxamide:

[0887]

[0888] 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]bridged methylenepyrido[1,2- a][1,4]diazocin]-10'-carboxamide in Example 17, except (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-bridged methylenepyrido[1,2-a][1,4]diazocin-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-bridged methylenepyrido[1,2-a][1,4]diazocin-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).

[0889] Example 20: Preparation of (3'S,5S,7'R)-3-(difluoromethyl)-12'-hydroxy-3'- methyl-1 ',1 1 '-dioxo-N-(2,4,6-trifluorobenzyl)-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H- spiro[isoxazole-5,6'-[2,7]bridgemethylpyrindolo[1,2-a][1,4]diazocin]-10'-formamide:

[0890]

[0891] (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4- difluorobenzyl)-3'-methyl-1 ',11 '-dioxo-1 ',11 '-dihydro-3'H,4'H,7'H-spiro[isoxazole-5,6'- pyrido[1,2-a][1,4]diazacyclononaphan]-10'-carboxamide : Preparation of (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,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide Step 2 (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl-1', :

[0892] To a mixture of DMSO (0.215 ml, 3.03 mmol) in DCM (2 ml) at -78 °C was added dropwise oxalyl chloride (0.118 ml, 1.39 mmol). The mixture was stirred at -78 °C for 10 minutes, then dropwise added (3'S,5S,7'R)-12'-(benzyloxy)-3-(hydroxymethyl)-3'-methyl-1 ',1 1 '- dioxo-N-(2,4,6-trifluorobenzyl)-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]bridgemethylpyrindolo[1,2-a][1,4]diazocin]-10'-formamide (370 mg, 0.606 mmol) prepared according to Example 19 in DCM (2 mL). The resulting reaction mixture was stirred at -78 °C for 15 minutes. To the reaction mixture was added triethylamine (0.426 ml, 3.03 mmol) and the cooling bath removed. The reaction mixture was stirred at room temperature for 30 minutes. EtOAc was added to dilute the reaction mixture, then H2O and brine were added. The organic phase was dried over MgS04and the solvent removed in vacuo. The resulting residue was purified by silica gel chromatography to give the title compound. MS (m / z) 609.09 [M+H]+.

[0893] 1 ',11 '-dioxo-1 ',4',5',11 '-tetrahydro-3'H,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide : 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,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide Preparation of (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,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide :

[0894] The title compound is prepared in a similar manner as Example 5, Step 4, except (3'S,5S,7'R)-12'-(benzyloxy)-3-formyl-3'-methyl-l',ll'-dioxo-N-(2,4,6- trifluorobenzyl)-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]bridged methylenepyridino[ 1,2-a] [ 1,4]diazocin]- 10'-formamide is used instead of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'- dimethyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]bridged methylenepyridino[ 1,2-a] [ 1,4]diazocin]- 10'-formamide. MS (m / z) 631.13 [M+H]+.

[0895] Step 1 : (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4- difluorobenzyl)-3'-methyl-1 ',11 '-dioxo-1 ',11 '-dihydro-3'H,4'H,7'H-spiro[isoxazole-5,6'- pyrido[1,2-a][1,4]diazacyclononaphan]-10'-carboxamide Preparation of (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,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide Step 2 :

[0896] The title compound was prepared in a similar manner to Step 5 of Example 5, except (3'S,5S,7'R)-12'-(benzyloxy)-3-(difluoromethyl)-3'-methyl-l',ll'-dioxo-N-(2,4,6- trifluorobenzyl)-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide 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]fused methylenepyridino[ 1,2-a] [ 1,4]diazocin]- 10 '-formamide. 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).

[0897] 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]fused methylenepyridino[ 1,2-a] [ 1,4]diazocin]- 10 '-formamide:

[0898]

[0899] The title compound was prepared in a similar manner to Example 20, 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]fused methylenepyrido[1,2- a][1,4]diazocin]-10'-formamide was used in Step 1 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]fused methylenepyrido[1,2-a][1,4]diazocin]-10'-formamide. 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).

[0900] 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]fused methylenepyrido[1,2-a][1,4]diazocin]-10'-formamide:

[0901]

[0902] (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl-1', : 1 ',11 '-dioxo-1 ',4',5',11 '-tetrahydro-3'H,4'H,7'H-spiro[isoxazole-5,6'-pyrido[1,2- a][1,4]diazacyclononaphan]-10'-carboxamide ​ ​ :

[0903] 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-bridged methylenopyrano[1,2- a][1,4]diazacyclononadecane-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-bridged methylenopyrano[1,2-a][1,4]diazacyclononadecane-10-carboxamide (Intermediate F). MS (m / z) 829.12 [M+H]+.

[0904] ​ : ​ ​ 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide :

[0905] 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]bridged methylenopyrano[1,2-a][1,4]diazacyclononadecane]-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 ',4',5',11 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]bridged methylenopyrano[1,2-a][1,4]diazacyclononadecane]-10'-carboxamide. MS (m / z) 591.13 [M+H]+.

[0906] Step 3 : (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(methoxymethyl)-3'-methyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide Step 4 :

[0907] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'- methyl-1 ',1 1 '-dioxo-1 ',1 1 '-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazocin]-10'-formamide (41 mg, 0.0694 mmol) in DMF (2 ml) was added NaH (60% in mineral oil) (5.4 mg, 0.14 mmol) at 0 °C, then Mel (0.004 ml, 0.0694 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgS04and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to give the title compound. MS (m / z) 605.09 [M+H]+.

[0908] (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]methanopyrrolo[1,2-a][1,4]diazocin]-10'- formamide : 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]methanopyrrolo[1,2-a][1,4]diazocin]-10'- formamide Step 1 :

[0909] A mixture of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3- (methoxymethyl)-3'-methyl-l',ll'-dioxo-l',ll'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide (27 mg, 0.045 mmol) and 10% Pd / C (3.8 mg) in EtOH (2 mL) was stirred at room temperature under 1 atm of H2(g). After 2 h, the reaction mixture was filtered, concentrated and purified by reverse phase preparative HPLC (5% to 100% MeCN / water with 0.1% TFA) to give 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).

[0910] Example 23: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4- trimethyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused

[0911]

[0912] Step 1 : Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'- dimethyl-1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]bridged methylenopyrano[1,2-a][1,4]diazocin]-10'-formamide and (3'S,5S,7'R)- 12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1 ',1 1 '-dioxo-1 ',4',5', 1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenopyrano[1,2- a][1,4]diazocin]-10'-formamide:

[0913] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl- 1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenopyrano[1,2-a][1,4]diazocin]-10'-formamide prepared according to Example 1 (43 mg, 0.075 mmol) in THF (10 ml) was added LiHMDS 1 M in THF (0.373 ml) at -78°C. After 30 min, a solution of Mel in THF (12.7 mg in 2 ml) was added at -78°C then the temperature was allowed to warm to -20°C. After 2 h, the reaction was quenched by the addition of a saturated NH4CI solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated and purified by silica gel chromatography (elution with 0% to 5% MeOH / EtOAc) to give the title compounds. MS (m / z) 591.138 [M+H]+and MS (m / z) 593.189 [M+H]+.

[0914] (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]methanopyrrolo[1,2-a][1,4]diazocin]-10'- formamide : 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]methanopyrrolo[1,2- a][1,4]diazocin]-10'-formamide 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]methanopyrrolo[1,2-a][1,4]diazocin]-10'- formamide :

[0915] 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]fused methylenepyrido[1,2-a][1,4]diazocin]-10'-formamide (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% acetonitrile in water to give the title compound. MS (m / z) 501.282 [M+H] + . 1 H 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).

[0916] 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]fused methylenepyrido[1,2-a][1,4]diazocin]-10'-formamide:

[0917]

[0918] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4- hydroxy-3,3'-dimethyl-l',l l'-dioxo-l',4',5',l l'-tetrahydro-3'H,4H,7'H-spiro[isoxazole- 5,6'-[2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide (14 mg, 0.024 mmol) prepared according to Example 23 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% acetonitrile in water to give the title compound. MS (m / z) 503.265 [M+H] + . 1 H 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).

[0919] Example 25: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'- dimethyl-l',4,l l'-trioxo-l',4',5',l l'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused

[0920]

[0921] 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]methanopyrrolo[1,2-a][1,4]diazocin]-10'- formamide ​ ​ :

[0922] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4- hydroxy-3,3'-dimethyl-l',ll'-dioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H- spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[l,2-a][l,4]diazocin]- 10'-formamide prepared according to Example 23 (9 mg, 0.0152 mmol) in DCM (3 ml) at room temperature was added l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3-(lH)-one (Dess-Martin periodinane) (10 mg, 0.023 mmol). The reaction was quenched by the addition of saturated NaHC03and Na2S03solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated and purified by silica gel column chromatography eluting with 50% to 100% EtOAc in hexanes to give the title compound. MS (m / z) 590.906 [M+H]+.

[0923] ​ : ​ ​ ​ :

[0924] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'- dimethyl-l',4,ll'-trioxo-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]bridged methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide (8.97 mg, 0.0152 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% acetonitrile in water 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).

[0925] Example 26: Preparation of (3'S,4S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy- 3,3',4-trimethyl-l',l l'-dioxo-l',4',5',l l'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide:

[0926]

[0927] (3'S,4S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-l',l l'- dioxo-l',4',5',l l'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide was prepared in a similar manner as Example 23, except that (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-l',l l'- dioxo-l',4',5',l l'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide was used in place of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-l',l l'-dioxo-l',4',5',l l'- tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused methylenepyrido[l,2-a][l,4]diazocin]-10'- formamide in Step 2. 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).

[0928] 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]fused methylenepyrido[1,2-a][1,4]diazocin]-10'- formamide (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]fused methylenepyrido[1,2-a][1,4]diazocin]-10'- formamide (Peak 2):

[0929]

[0930] ​ : ​ ​ ​ :

[0931] 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]fused methylenepyrido[1,2-a][1,4]diazocin]-10'- formamide (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 min, the reaction was quenched by the addition of saturated NaHC03solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated and purified by silica gel chromatography eluting with 0% to 100% EtOAc / hexanes to give the title compound as a mixture of stereoisomers. MS (m / z) 595.046

[0932] ​ : ​ ​ Preparation of (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]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide :

[0933] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'- dimethyl-1 ',1 1 '-dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7] bridged methylenopyrido[1,2-a][1,4]diazocin]-10'-formamide (25.1 mg, 0.0422 mmol) in toluene (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was separated and purified by reverse phase preparative HPLC eluting with 10% to 90% acetonitrile in water to give the title compound.

[0934] 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).

[0935] 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).

[0936] Example 28: Preparation of (3'S,4S,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'- dihydroxy-3,3'-dimethyl-l',l l'-dioxo-l',4',5',l l'-tetrahydro-3'H,4H,7'H- spiro[isoxazole-5,6'-[2,7]methanopyrrolo[1,2-a][1,4]diazocin]-10'-formamide:

[0937]

[0938] The title compound is prepared in a similar manner as Example 24, except that (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl- 1',1 l'-dioxo-1',4',5',1 l'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrrolo[1,2-a][1,4]diazocin]-10'-formamide prepared according to Example 26 is used instead of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl- 1',1 l'-dioxo-1',4',5',1 l'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrrolo[1,2-a][1,4]diazocin]-10'-formamide. 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).

[0939] 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]fused methylenepyrido[1,2-a][1,4]diazocin]-10'-formamide:

[0940]

[0941] The title compound is prepared in a similar manner as Example 25, except (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]fused methylenepyrido[1,2- a][1,4]diazocin]-10'-formamide prepared according to Example 26 is 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]fused methylenepyrido[1,2- a][1,4]diazocin]-10'-formamide. MS (m / z) 500.97 [M+H] + . 1 HNMR (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).

[0942] 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]fused

[0943]

[0944] 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]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide (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]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide (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]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide Step 2 (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]fused methylenepyridino[1, 2-a][1,4]diazocin]-10'-formamide Step 1 :

[0945] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'- dimethyl-1 ',4,1 1 '-trioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'- [2,7]fused pyrrolo[1,2-a][1,4]diazocin]-10'-formamide (25 mg, 0.0423 mmol) prepared according to example 29 in DCM (3 ml) at room temperature was added sodium borohydride (2.4 mg, 0.064 mmol). Upon completion, the reaction was quenched by the addition of a saturated NaHC03solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgS04, filtered, concentrated and purified by silica gel column chromatography eluting with 20% to 100% EtOAc in hexanes to give the title compound as peak 1 and peak 2 forms. MS (m / z) 593.101 [M+H]+.

[0946] (3'S,4S,5R,7'R)-12'-(benzyloxy)-4-fluoro-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]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide : (3'S,4S,5R,7'R)-12'-(benzyloxy)-4-fluoro-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]fused methylenepyridino[1,2-a][1,4]diazocin]-10'-formamide Step 2 (3'S,4S,5R,7'R)-4-fluoro-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]fused :

[0947] 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 ',1 1 '- dioxo-1 ',4',5',1 1 '-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused pyrrolo[1,2- a][1,4]diazocin]-10'-formamide (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 ',1 1 '-dioxo-1 ',4',5', 1 1 '- tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]fused pyrrolo[1,2-a][1,4]diazocin]-10'- formamide. MS (m / z) 503.231 [M+H] + . 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).

[0948] 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]bridgemethylenopyrido[1,2-a][1,4]diazanam]-10'-formamide:

[0949]

[0950] ​ : ​ ​ ​ :

[0951] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-l',ll'-dioxo-N-(2,4,6- trifluorobenzyl)-l',4',5',ll'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7] bridged methylenepyrido[l,2-a][l,4]diazocin]-10'-formamide prepared according to Example 3 (204 mg, 0.343 mmol) in THF (10 mL) was added LiHMDS in THF (1.2 mL, 1.2 mmol) of a 1 N solution at -40 °C under air. After 30 min, Mel in THF (73 mg, 0.515 mmol) was added at -40 °C and then allowed to warm to -20 °C over 2 h. The reaction was quenched by the addition of saturated NH4Cl solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated and pu...

Claims

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

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

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

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

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

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

7. The compound of claim 1, wherein the compound is:

8. The compound of claim 1, wherein the compound is:

9. The compound of claim 1, wherein the compound is:

10. The compound of claim 1, wherein the compound is:

11. The compound of claim 1, wherein the compound is:

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12, further comprising one, two, three or four additional therapeutic agents.

14. The pharmaceutical composition of claim 13, wherein one or more additional therapeutic agents are anti-HIV agents.

15. The pharmaceutical composition of any one of claims 12-14, wherein the pharmaceutical composition is for oral or parenteral administration.

16. Use of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 12-15, in the preparation of a medicament for treating HIV infection in a person who has or is at risk of HIV infection.

17. The use according to claim 16, wherein the medicament further comprises, or is used in combination with, one, two, three or four additional therapeutic agents in a therapeutically effective amount.

18. The use according to claim 17, wherein one or more of the additional therapeutic agents are anti-HIV agents.

19. The use according to any one of claims 16-18, wherein the drug is formulated for oral, intravenous, subcutaneous or intramuscular administration.

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