Bridged tricyclic carbamoylpyridone compounds and uses thereof

Abstract

To provide bridged tricyclic carbamoylpyridone compounds and uses thereof.SOLUTION: The present disclosure relates generally to compounds of Formula I. There are also disclosed pharmaceutical compositions comprising the compounds and methods of making the compounds. The compounds of the disclosure are useful in treating or preventing human immunodeficiency virus (HIV) infection. The present disclosure is directed to novel compounds having antiviral activity and pharmaceutically acceptable salts thereof. In some embodiments, the compounds may be used to treat HIV infections, to inhibit the activity of HIV integrase and / or to reduce HIV replication.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 328,061, filed April 6, 2022, and U.S. Provisional Patent Application No. 63 / 476,873, filed December 22, 2022, the entire contents of which are incorporated herein in their entirety for all purposes.

[0002] Disclosed are compounds, compositions, and methods that can be used to treat or prevent human immunodeficiency virus (HIV) infection. In particular, novel spirocyclic-substituted bridged tricyclic carbamoylpyridone compounds, and methods for their preparation and use as therapeutic or prophylactic agents, are disclosed. [Background technology]

[0003] Human immunodeficiency virus infection and related diseases are major public health problems worldwide. Human immunodeficiency virus encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown utility, especially when used in combination, toxicity and the development of resistant strains can limit their effectiveness (Palella, et al. N. Engl. J Med. (1998) 338:853-860; Richman, DD Nature (2001) 410:995-1001). Therefore, new drugs that inhibit HIV replication are needed.

[0004] The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Current treatment guidelines published by the United States Department of Health and Human Services suggest that achieving viral suppression requires the use of combination therapy, i.e., the use of several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed February 12, 2019). In addition, treatment decisions for HIV-infected patients are complicated when patients require treatment for other medical conditions (ibid. F-8). Because standard treatment requires the use of multiple different drugs to suppress HIV and treat other conditions a patient may experience, the potential for drug interactions is a criterion for selecting a drug regimen. Therefore, there is a need for antiretroviral therapy with a reduced potential for drug interactions.

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

[0006] [Non-Patent Document 1] Palella, et al. N. Engl. J Med. (1998) 338:853-860 [Non-patent document 2] Richman, DDNature (2001) 410:995-1001 [Non-patent document 3] 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.http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. [Non-patent document 4] Tang,et al.Drugs(2012)72(9)e1-e25 [Non-patent document 5] Hurt, et al.HIV / AIDS CID(2014)58,423-431 Summary of the Invention

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

[0008] In one embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, C 6~10 aryl or a 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; C 6~10 The aryl or 5- to 10-membered heteroaryl may be one, two, three, or four R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 is alkyl, R 2 is H, C 1~6 Alkyl, or C 1~4 is haloalkyl, L is -CR 3a R 3b -, -C(O)-, -SO2-, -CH2-CH2-, or -N(R a )- and W1 is a bond or -CR 4a R 4b - and W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =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)-, Y is -C(O)NH-, [ka] and [ka] is a 3- to 7-membered spiro ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, and the spiro ring is 8 optionally substituted with a group, Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d- or -CR 10a =CR 10b - and R 3a and R 3b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl or -OC 1~4 alkyl, or R 3a and R 3b together with the carbon atoms 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, and the spiro ring is A2 and each R A2 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl, R 4a and R 4b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, R 5a , R 5b , R 5c , and R 5d are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 alkyl, or R 5a and R 5b or R 5c and R 5d together with the carbon atoms to which they are attached form a 3- to 7-membered spiro ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the spiro ring is A3 and each R A3 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl, or R 5a and R5c or R 5b and R 5d are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, and the fused ring is bonded to 1 to 3 R A3 and each R A3 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl, Each R 6a and R 6b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 alkyl, or R 6a and R 6b are taken together with the carbon atoms to which they are bonded to form a 5- to 10-membered partially unsaturated fused ring containing 0 or 1 heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, and S, and the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is selected from 1, 2, 3, or 4 R A4 and each R A4 are independently halo or C 1~4 is alkyl, R 7 is H, C 1~6 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c and Each R 8 is, independently, (i) halo, (ii) C optionally substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; C 6~10aryl or 5-10 membered heteroaryl 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 3-7 membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; (iii) C optionally substituted with OH 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; C 6~10 aryl or 5-10 membered heteroaryl optionally substituted with 1-4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and 3-7 membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; (iv) CN, (v) oxo, (vi)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C 6~10 optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vii) NHR A6 And, In the formula, R A6 is C1-C6 alkyl, (viii)NR A7 R A8 And, In the formula, RA7 is a C1-C6 alkyl, R A8 is C1-C6 alkyl, (ix) C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, CN, C 3~7 Cycloalkyl, and C 1~6 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkoxy; 6~10 aryl, C 3~7 cycloalkyl optionally substituted with 1, 2, 3, or 4 independent halo groups; (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; 3-7 membered rings are halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2 or 3 substituents independently selected from cycloalkyl; (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; The 5- to 10-membered heteroaryl ring is preferably a halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2 or 3 substituents independently selected from cycloalkyl; (xii)-SO2R A13 And, R A13 is a C1-C6 alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S; C 1~6 the alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy; (xiii)-SON(R A14 )2, Each R A14 are 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; C 1~6 the alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy; (xiv)C 1~6 Alkoxy, OH, -SO2-(C 1~3 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, 2~6 alkynyl, or The Two R's 8 the groups are linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; 3-7 membered rings include halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; Two R on adjacent carbon atoms 8 the groups are linked to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; Fused 6- to 10-membered aromatic rings include halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; R 9a , R 9b , R 9c , and R 9d are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo; or R 9a and R9b or R 9c and R 9d together with the carbon atoms 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, and the spiro ring is A9 and each R A9 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl, or R 9a and R 9c or R 9b and R 9d are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, and the fused ring is preferably bonded to one, two, or three R A10 and each R A10 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl, or R 9a , R 9b , R 9c , and R 9d One of the following, as well as R 4a , R 4b , R 5a , R 5b , and R 7 and one of R, taken together with the atom to which each is attached, forms a 3- to 7-membered fused ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the fused ring is A11 and each R A11 are independently halo or C 1~4 is alkyl, R 10a and R 10b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 alkyl, or R 10a and R 10bare taken together with the carbon atoms to which they are bonded to form a 5- to 10-membered partially unsaturated fused ring containing 0 or 1 heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, and S, and the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is A12 and each R A12 are independently halo or C 1~4 is alkyl, R a are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C(O)R c , or SO2R c and R b is H or C 1~4 is alkyl, R c is C 1~4 Alkyl or C 1~4 is alkyloxy, Each n is independently 0, 1, or 2.

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

[0010] 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.

[0011] In another embodiment, there is provided a method of treating an HIV infection in a human having or at risk of having such infection by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof.

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

[0013] In another embodiment, there is provided the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having such infection.

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

[0015] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0016] Other embodiments, objects, features, and advantages may be set forth in the following detailed description of the embodiments, and in part may be obvious from the description of the claimed embodiments, or may be learned by the practice thereof. These objects and advantages may be realized and attained by the processes and compositions particularly pointed out in the detailed description and claims. The foregoing summary is to be considered a brief and general overview of some of the embodiments disclosed herein, and is provided for the benefit and convenience of the reader, with the understanding that it is not intended in any way to limit the scope of the appended claims to which they are legally entitled or the scope of equivalents thereof. DETAILED DESCRIPTION OF THE INVENTION

[0017] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The following description of several embodiments is made with the understanding that the disclosure should be considered as an illustration of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0018] I. Definition Unless otherwise required by context, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises," i.e., " "Comprising" is to be interpreted in an open and inclusive sense, i.e. "including but not limited to."

[0019] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment disclosed herein. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0020] "Amino" refers to the -NH2 radical.

[0021] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0022] As used herein, the term "C 1~n"Alkyl," alone or in combination with another radical, is intended to mean an acyclic, straight-chain or branched-chain alkyl radical containing 1 to n carbon atoms. 1~6 "Alkyl" includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1 methylethyl (isopropyl), 1 methylpropyl (sec-butyl), 2 methylpropyl (iso-butyl), 1,1 dimethylethyl (tertbutyl), pentyl, and hexyl. The abbreviation Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, iPr represents a 1-methylethyl group, Bu represents a butyl group, and tBu represents a 1,1-dimethylethyl group.

[0023] An "alkyl" is a hydrocarbon containing normal, secondary, or tertiary atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1 to C2). 20 alkyl), 1 to 10 carbon atoms (i.e., C1 10The alkyl group may have 1 to 8 carbon atoms (i.e., C alkyl), or 1 to 6 carbon atoms (i.e., C alkyl). Examples of suitable alkyl groups include methyl (Me, -CH), ethyl (Et, CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCHCH), 2-propyl (i-Pr, i-propyl, CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, CH(CH)CHCH), 2-methyl-2-propyl (t-Bu, t-butyl, -CHCH(CH)), 2-methyl-3-propyl (t-Bu, t-butyl, -CHCH(CH)), 2-methyl-4-propyl (t-Bu, t-butyl, -CHCH(CH)), 2-methyl-5-propyl (t-Bu, t-butyl, -CHCH(CH)), 2-methyl-6 ... 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 (CH2CH2CH2CH2CH2 CH3), 2-hexyl (CH(CH3)CH2CH2CH2CH3), 3-hexyl (CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (C(CH3)2CH2CH2CH3), 3-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 radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkyl group can be one to ten carbon atoms (i.e., C1- 10alkyl), or 1 to 6 carbon atoms (i.e., C alkyl), or 1 to 3 carbon atoms (i.e., C alkyl). Typical alkyl radicals include, but are not limited to, methylene (CH), 1,1-ethyl (CH(CH)), 1,2-ethyl (CHCH), 1,1-propyl (CH(CHCH)), 1,2-propyl (CHCH(CH)), 1,3-propyl (CHCHCH), 1,4-butyl (CHCHCHCHCH), and the like.

[0024] As used herein, the term "alkenyl" refers to an alkyl group containing normal, secondary, or tertiary carbon atoms and at least one site of unsaturation, i.e., carbon-carbon, sp 2 It refers to a straight or branched chain hydrocarbon having a double bond. For example, an alkenyl group is an alkyl group having 2 to 20 carbon atoms (i.e., C2 to C6). 20 Alkenyl or C2~ 20 alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl or C2-8), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl or C2-6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (CH=CH2), allyl (CH2CH=CH2), cyclopentenyl (C5H7), and 5-hexenyl (CH2CH2CH2CH2CH=CH2).

[0025] As used herein, "C 2~n The term "alkenyl" (where n is an integer), alone or in combination with another radical, is intended to mean an unsaturated acyclic straight or branched chain radical containing 2 to n carbon atoms, at least two of which are joined together by a double bond. Examples of such radicals include, but are not limited to, ethenyl (vinyl), 1 propenyl, 2 propenyl, and 1 butenyl. Unless otherwise specified, "C 2~n The term "alkenyl" is understood to encompass the individual stereoisomers, where possible, including, but not limited to, the (E) and (Z) isomers, and mixtures thereof.2~n If an alkenyl group is substituted, it is understood that, unless otherwise specified, it is substituted on any carbon atom that would otherwise carry a hydrogen atom, and it is understood that the substitution results in a chemically stable compound as recognized by one of ordinary skill in the art.

[0026] "Alkynyl" refers to a straight or branched chain hydrocarbon containing normal, secondary, or tertiary carbon atoms and having at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. For example, an alkynyl group can be any group having 2 to 20 carbon atoms (i.e., C2 to C6). 20 The alkynyl group may have 2 to 8 carbon atoms (i.e., C2-8 alkyne), or 2 to 6 carbon atoms (i.e., C2-6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenyl (C=CH), propargyl (CHC=CH), and the like.

[0027] As used herein, "C 2~n The term "alkynyl" (where n is an integer), alone or in combination with another radical, is intended to mean an unsaturated acyclic straight or branched chain radical containing 2 to n carbon atoms, at least two of which are joined to each other by a triple bond. Examples of such radicals include, but are not limited to, ethynyl, 1 propynyl, 2 propynyl, and 1 butynyl. 2~n If an alkynyl group is substituted, it is understood that, unless otherwise specified, it is substituted on any carbon atom that would otherwise carry a hydrogen atom, and it is understood that the substitution results in a chemically stable compound as recognized by one of ordinary skill in the art.

[0028] "Cyano" or "carbonitrile" refers to the group --CN.

[0029] The term "halo" or "halogen," as used herein, refers to fluoro, chloro, bromo, or iodo.

[0030] The term "haloalkyl," as used herein, refers to an alkyl, as defined herein, in which one or more hydrogen atoms are each replaced by a halo substituent. For example, a C1-6 haloalkyl is a C1-6 alkyl in which one or more of the hydrogen atoms are replaced with a halo substituent. Such a range includes one halo substituent on the alkyl group to complete the halogenation of the alkyl group.

[0031] As used herein, "C 1~n The term "haloalkyl" (wherein n is an integer), alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms, as defined above, in which one or more hydrogen atoms are respectively replaced by halo substituents. 1~n Examples of haloalkyl include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl.

[0032] As used herein, the term "aryl" refers to a single aromatic ring, or a bicyclic or polycyclic ring. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical or an ortho-fused bicyclic or polycyclic radical having about 9 to 14 atoms, in which at least one ring is aromatic (e.g., an aryl ring fused to one or more aryl or carbocyclic rings). Such bicyclic or polycyclic rings may 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 is understood that the point of attachment of the bicyclic or polycyclic radical defined above can be at any position on 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, anthracenyl, and the like.

[0033] The terms "heteroaryl," "heteroaryl ring," or "heteroaromatic ring," as used herein, refer to a single aromatic ring or multiple condensed rings. The term includes aromatic monocyclic rings of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The sulfur and nitrogen atoms may be present in oxidized form, provided the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. The term also includes multiple condensed rings (e.g., ring systems containing two or three rings), in which a heteroaryl group, as defined above, can be fused to one or more heteroaryls (e.g., naphthyridinyl), carbocycles (e.g., 5,6,7,8-tetrahydroquinolyl), or aryls (e.g., indazolyl) to form multiple condensed rings. The multiple fused rings may optionally be substituted with one or more (e.g., 1, 2, or 3) oxo groups on the carbocyclic portion of the fused ring. It is understood that the point of attachment of the heteroaryl multiple fused rings defined above can be at any position on the ring, including the heteroaryl, aryl, or carbocyclic portions of the ring. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, and thianaphthenyl.

[0034] As used herein, "heterocyclyl," "heterocycle," or "halocycloalkyl" refers to a single saturated or partially unsaturated ring or multiple condensed rings. This term includes saturated or partially unsaturated monocyclic rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Such rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, or piperidinyl. The term also includes multiple condensed ring systems (e.g., ring systems containing two or three rings), in which a heterocyclic group (as defined above) can be attached to two adjacent atoms (fused heterocycles) with one or more heterocyclic (e.g., decahydronaphthyridinyl), heteroaryl (e.g., 1,2,3,4-tetrahydronaphthyridinyl), carbocyclic (e.g., decahydroquinolyl), or aryl groups. It is understood that the point of attachment of multiple condensed rings of the heterocyclic rings defined above can be at any position on the ring, including the heterocyclyl, heteroaryl, aryl, or carbocyclic portions 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-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl.

[0035] 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, and fused rings. The ring may be fully saturated or partially unsaturated.

[0036] As used herein, the term "fused ring" refers to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring structure described herein that is connected to an existing ring structure in a compound disclosed herein through two adjacent atoms shared by the fused ring structure and the existing ring structure. For example, the bicyclic compounds shown below each 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 thiene ring fused to a furan ring). [ka]

[0037] As used herein, "C 3~m The term "cycloalkyl" (where m is an integer), alone or in combination with another radical, means a cycloalkyl substituent containing 3 to m carbon atoms, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. This term includes fully saturated rings as well as partially unsaturated rings.

[0038] When a variable is substituted, for example, as expressed by the phrase "Ci_6 alkyl, alone or as part of a group, is optionally substituted," this phrase should be understood to mean that the variable Ci_6 alkyl can be substituted when alone, and also that the variable "Ci_6 alkyl" can be substituted when part of a larger group. Similarly, when so stated, other variables (e.g., C2-C6 alkynyl, aryl, heteroaryl, heterocycle, etc.) can also be substituted "alone or as part of a group."

[0039] It should be understood that certain variables in Formula I that connect two chemical groups can be oriented in either direction. Thus, for X groups in Formula I (e.g., O, C(O), C(O)O, S, S(O), SO, (C-C)alkylO-, (C-C)alkylC(O), (C-C)alkylC(O)O, (C-C)alkylS, (C-C)alkylS(O), and (C-C)alkylSO), certain values ​​of X that are not symmetric can be oriented in either direction. For example, C(O)O can be oriented as either C(O)O or OC(O) relative to the connecting group.

[0040] The term "chiral" refers to molecules that possess the property of non-superimposability of their mirror image partners, while the term "achiral" refers to molecules that possess the property of non-superimposability of their mirror image partners. Refers to a molecule that can be superimposed on a partner.

[0041] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0042] "Diastereomer" refers to a stereoisomer with two or more centers or axes of chirality and whose molecules are not mirror images of one another. Diastereomers typically have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0043] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0044] The term "treatment" or "treating," with respect to a disease or condition, includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and / or alleviating one or more symptoms of the disease or condition.

[0045] The term "treating," in reference to treating a disease state in a patient, includes (i) inhibiting or ameliorating the disease state in the patient, e.g., preventing or slowing its onset, or (ii) palliating the disease state in the patient, i.e., causing regression or cure of the disease state. In the case of HIV, treating includes reducing the level of HIV viral load in the patient.

[0046] As used herein, the term "treatment" is intended to mean administering a compound or composition according to the invention to reduce or eliminate the symptoms of HIV infection and / or to reduce the viral load in a patient. The term "treatment" also encompasses administering a compound or composition according to the invention after an individual has been exposed to the virus but before symptoms of the disease appear and / or before the virus is detectable in the blood, to prevent the onset of disease symptoms and / or the virus from reaching detectable levels in the blood, and administering a compound or composition according to the invention to a mother before birth and to her child within the first few days of life, to prevent perinatal transmission of HIV from mother to infant.

[0047] A "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to aid in the efficiency of desired chemical reactions, for example, to create and break chemical bonds in an orderly and planned manner. Protection of a compound's functional group alters 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. Chemically protected intermediates may themselves be biologically active or inactive.

[0048] Protected compounds may also exhibit altered, and 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, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of protecting groups is to convert parent drugs into prodrugs, whereby the parent drug is released upon in vivo conversion of the prodrug. Because active prodrugs may be absorbed more effectively than the parent drug, prodrugs may have greater in vivo efficacy than the parent drug. Protecting groups are removed in vitro in the case of chemical intermediates, or in vivo in the case of prodrugs. In the case of chemical intermediates, it is not particularly important that the product obtained after deprotection, such as an alcohol, is physiologically acceptable, although it is generally more desirable if the product is pharmacologically harmless.

[0049] Protecting groups are available, commonly known, and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e., routes or methods, for preparing compounds of the present invention. In most cases, the decisions regarding which groups to protect, when to protect, and the nature of the chemical protecting group "PG" depend on the chemical nature of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive, or other conditions) and the intended direction of synthesis. When a compound is substituted with multiple PGs, the PGs do not need to be, and generally are not, the same. Generally, PGs are used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups, thus preventing side reactions or otherwise facilitating synthetic efficiency. The order of deprotection to obtain free deprotected groups depends on the intended direction of synthesis and the reaction conditions encountered, and can occur in any order as determined by one of ordinary skill in the art.

[0050] Various functional groups in the compounds of the present invention can be protected. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functional groups) include "ether- or ester-forming groups." Ether- or ester-forming groups can function as chemical protecting groups in the synthetic schemes described herein. However, as will be appreciated by those skilled in the art, some hydroxyl- and thio-protecting groups are not ether- or ester-forming groups, and are included with amides, discussed below.

[0051] A large number of hydroxyl-protecting and amide-forming groups, as well as the corresponding chemical cleavage reactions, are described in Protective Groups in Organic Synthesis, 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, New York, 1994), which is incorporated herein by reference in its entirety. 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, and Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and other protecting groups for acids, see Greene, infra.

[0052] As used herein, the term "protecting group" is intended to mean protecting groups that may be used during synthetic transformations, including, but not limited to, examples listed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981) and more recent editions thereof.

[0053] The term "solvate" refers to a crystalline solid that contains an amount of solvent incorporated into its crystal structure. As used herein, the term "solvate" includes hydrates.

[0054] The term "non-solvate" refers to a crystalline solid in which the solvent molecules do not occupy specific crystallographic sites.

[0055] As used herein, the term "pharmaceutically acceptable" with respect to a substance means, within the scope of sound medical judgment, a substance that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio and is effective for its intended use when employed in pharmaceutical compositions.

[0056] As used herein, the term "pharmaceutically acceptable salt" is intended to mean a salt of a compound according to the invention 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 reaction, etc., commensurate with a reasonable benefit / risk ratio, and generally water- or oil-soluble or dispersible and effective for its intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Lists of suitable salts can be found, for example, in S. M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19.

[0057] As used herein, the term "pharmaceutically acceptable acid addition salts" refers to those salts of inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable, as well 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, glycerophosphate, hemisulfonic acid, hexaacetic acid, hydroxybenzoic ... "Salts" are intended to mean salts formed with organic acids, including, but not limited to, carboxylic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like.

[0058] As used herein, the term "pharmaceutically acceptable base addition salts" is intended to mean salts formed with inorganic bases, including, but not limited to, hydroxides, carbonates, or bicarbonates of ammonia or ammonium, or metal cations such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, which retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. Particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, Examples of suitable non-toxic bases include, but are not limited to, salts of caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0059] As used herein, the term "antiviral agent" is intended to mean an agent that is effective in inhibiting the formation and / or replication of a virus in humans, including, but not limited to, an agent that interferes with either the host or viral mechanisms necessary for the formation and / or replication of a virus in humans.The term "antiviral agent" includes, for example, HIV integrase catalytic site inhibitors selected from the group consisting of raltegravir (ISENTRESS®, Merck), elvitegravir (Gilead), soltegravir (GSK, ViiV), GSK1265744 (GSK, ViiV) and dolutegravir, abacavir (ZIAGEN®, GSK), didanosine (VIDEX®, BMS), tenofovir (VIREAD®, Gilead), emtricitabine (EMTRIVA®), tetanus (Tetanus, Gilead ... ), Gilead), lamivudine (EPIVIR®, GSK / Shire), stavudine (ZERIT®, BMS), zidovudine (RETROVIR®, GSK), elvucitabine (Achillion), and festinavir (Oncolys), an HIV nucleoside reverse transcriptase inhibitor selected from the group consisting of nevirapine (VIRAMUNE®, BI), efavirenz (SUSTIVA®, BMS), etravirine (INTELENCE®, J&J), rilpivirine (TMC HIV non-nucleoside reverse transcriptase inhibitors selected from the group consisting of atazanavir (REYATAZ®, BMS), darunavir (PREZISTA®, J&J), indinavir (CRIXIVAN®, Merck), lopinavir (KELETRA®, Abbott), nelfinavir (VIRACEPT®, Pfizer), saquinavir (INVIRASE®), fluconazole (Fenavir®, Pfizer ... ), Hoffmann-LaRoche), tipranavir (APTIVUS®, BI), ritonavir (NORVIR®, Abbott), and fosamprenavir (LEXIVA®, GSK / Vertex); an HIV entry inhibitor selected from the group consisting of maraviroc (SELZENTRY®, Pfizer), enfuvirtide (FUZEON®, Trimeris), and BMS-663068 (BMS); and Bevirimat (Myriad. and HIV maturation inhibitors selected from the Genetics Group.

[0060] 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 mammal, including, but not limited to, an agent that interferes with either host or viral mechanisms necessary for the formation and / or replication of a virus in a mammal.

[0061] 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 host cells, whether in vitro, ex vivo or in vivo.

[0062] As used herein, the term "substituent," unless otherwise specified, is intended to mean an atom, radical, or group that may be bonded to a carbon atom, heteroatom, or any other atom that may form a part of a molecule or fragment thereof, and that is otherwise bonded to at least one hydrogen atom. Substituents contemplated in the context of a particular molecule or fragment thereof are those that result in chemically stable compounds, as recognized by one of ordinary skill in the art.

[0063] As used herein, the term "heteroatom" is intended to mean O, S, or N.

[0064] The terms "OC" and "OCD" are used interchangeably herein. 1~n Alkyl" or "C 1~n "Alkoxy", alone or in combination with other radicals, is intended to mean an oxygen atom further bonded to an alkyl group having 1 to n carbon atoms, as defined above, where n is an integer. 1~n Examples of alkoxy include, but are not limited to, methoxy (CHO-), ethoxy (CHCHO-), propoxy (CHCHCHO-), 1-methylethoxy (iso-propoxy, (CH)CHO), and 1,1-dimethylethoxy (tert-butoxy, (CH)CO).1~n It is understood that when an alkoxy is substituted, it is substituted on the alkyl portion thereof such that the substitution results in a chemically stable compound as recognized by one of ordinary skill in the art.

[0065] As used herein, the term "oxo" is intended to mean an oxygen atom attached to a carbon atom as a substituent by a double bond (=O).

[0066] As used herein, the term "mammal" is intended to include humans as well as non-human mammals susceptible to HIV infection, including, but not limited to, domestic animals such as cows, pigs, horses, dogs, cats, rabbits, rats, and mice, and non-domestic animals.

[0067] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125In certain embodiments, these radiolabeled compounds are useful for determining or measuring the efficacy of compounds, for example, by characterizing the site or mode of action or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of Formula I, for example, those incorporating a radioisotope, are useful in drug research and / or substrate tissue distribution studies. The radioisotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose because of their ease of incorporation and facile means of detection.

[0068] In certain embodiments, deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced required dosage. Thus, in some situations, heavier isotopes may be preferred.

[0069] Substitution with positron-emitting isotopes, e.g. 11 C. 18 F, 15 O, and 13 N may be useful in positron emission topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the compounds disclosed herein can be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples below, using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0070] The methods, compositions, kits, and articles of manufacture provided herein employ or include a compound (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by a deuterium atom, or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds are useful for increasing the half-life of a compound or its pharmaceutically acceptable salt when administered to a mammal because they have increased resistance to metabolism. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends See Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0071] The embodiments disclosed herein are also meant to encompass in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to embodiments disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound according to embodiments disclosed herein to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0072] The compounds disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to encompass 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 be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0073] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may be substituted or unsubstituted, and that the description includes both substituted and unsubstituted heterocyclyl radicals.

[0074] II. Compounds In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, C 6~10 aryl or a 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; C 6~10 The aryl or 5- to 10-membered heteroaryl may be one, two, three, or four R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 is alkyl, R 2 is H, C 1~6 Alkyl or C 1~4 is haloalkyl, L is -CR 3a R 3b -, -C(O)-, -SO2-, -CH2-CH2-, or -N(R a )- and W 1 But bond or -CR 4a R 4b - and W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -C(O)O-, -C(O)NH-, -CR 5a R 5b -N(R 7 )-, -CR 5a R 5b -O-, -CR 5a R 5b -S(O) n -, -CR 5a R 5b -C(O)-, -CR5a 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)-, Y is -C(O)NH-, [ka] and [ka] is a 3- to 7-membered spiro ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, and the spiro ring is 8 optionally substituted with a group, Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d - or -CR 10a =CR 10b - and R 3a and R 3b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl or -OC 1~4 alkyl, or R 3a and R 3b together with the carbon atoms 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, and the spiro ring is A2 and each R A2 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl, R 4a and R 4b are independently H, C 1~6Alkyl, C 1~4 haloalkyl or halo, R 5a , R 5b , R 5c , and R 5d are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 alkyl, or R 5a and R 5b or R 5c and R 5d together with the carbon atoms to which they are attached form a 3- to 7-membered spiro ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the spiro ring is A3 and each R A3 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl, or R 5a and R 5c or R 5b and R 5d are taken together with the carbon atoms to which they are attached to form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, and the fused ring is bonded to 1 to 3 R A3 and each R A3 independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl, Each R 6a and R 6b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 alkyl, or R 6a and R 6bare taken together with the carbon atoms to which they are bonded to form a 5- to 10-membered partially unsaturated fused ring containing 0 or 1 heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, and S, and the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is selected from 1, 2, 3, or 4 R A4 and each R A4 are independently halo or C 1~4 is alkyl, R 7 is H, C 1~6 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c and Each R 8 is, independently, (i) halo, (ii) C optionally substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; C 6~10 aryl or 5-10 membered heteroaryl 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 3-7 membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; (iii) C optionally substituted with OH 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; C 6~10aryl or 5-10 membered heteroaryl optionally substituted with 1-4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and 3-7 membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; (iv) CN, (v) oxo, (vi)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C 6~10 optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vii) NHR A6 And, In the formula, R A6 is C1-C6 alkyl, (viii)NR A7 R A8 And, In the formula, R A7 is a C1-C6 alkyl, R A8 is C1-C6 alkyl, (ix) C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, CN, C 3~7 Cycloalkyl, and C 1~6 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkoxy; 6~10 aryl, C 3~7 cycloalkyl optionally substituted with 1, 2, 3, or 4 independent halo groups; (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; 3-7 membered rings are halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2 or 3 substituents independently selected from cycloalkyl; (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; The 5- to 10-membered heteroaryl ring is preferably a halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2 or 3 substituents independently selected from cycloalkyl; (xii)-SO2R A13 And, R A13 is a C1-C6 alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S; C 1~6 the alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy; (xiii)-SO(NR A14 )2, Each R A14 are 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; C 1~6 the alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy; (xiv)C 1~6 Alkoxy, OH, -SO2-(C 1~3 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, 2~6alkynyl, or The Two R's 8 the groups are linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; 3-7 membered rings include halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; Two R on adjacent carbon atoms 8 the groups are linked to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; Fused 6- to 10-membered aromatic rings include halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; R 9a , R 9b , R 9c , and R 9d are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo; or R 9a and R 9b or R 9c and R 9d together with the carbon atoms to which they are attached form a 3- to 7-membered spiro ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the spiro ring is A9 and each R A9 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl, or R 9a and R 9c or R 9b and R 9dare taken together with the carbon atoms to which they are attached to form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, and the fused ring is preferably formed from 1, 2, or 3 R A10 and each R A10 independently, halo, C 1~4 Alkyl or C 1~4 haloalkyl, or R 9a , R 9b , R 9c , and R 9d One of the following, as well as R 4a , R 4b , R 5a , R 5b , and R 7 and one of R, taken together with the atom to which each is attached, forms a 3- to 7-membered fused ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the fused ring is A11 and each R A11 are independently halo or C 1~4 is alkyl, R 10a and R 10b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 alkyl, or R 10a and R 10b are taken together with the carbon atoms to which they are bonded to form a 5- to 10-membered partially unsaturated fused ring containing 0 or 1 heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, and S, and the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is A12 and each R A12 are independently halo or C 1~4 is alkyl, R a are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C(O)R c, or SO2R c and R b is H or C 1~4 is alkyl, R c is C 1~4 Alkyl or C 1~4 alkyloxy, Each n is independently 0, 1, or 2.

[0075] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is 1, 2, 3, or 4 R 8 group and at least one R 8 The base is (i) C substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; C 6~10 aryl or 5-10 membered heteroaryl 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 3-7 membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; (ii) C substituted with OH 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 aryl or a 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; C 6~10aryl or 5-10 membered heteroaryl optionally substituted with 1-4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and 3-7 membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; (iii) CN, (iv) oxo, (v)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C 6~10 optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vi) NHR A6 And, In the formula, R A6 is C1-C6 alkyl, (vii)NR A7 R A8 And, In the formula, R A7 is a C1-C6 alkyl, and R A8 is C1-C6 alkyl, (viii)C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, CN, C 3~7 Cycloalkyl, and C 1~6 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkoxy; 6~10 Aryl, C 3~7 cycloalkyl optionally substituted with 1, 2, 3, or 4 independent halo groups; (ix) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; 3-7 membered rings are halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2 or 3 substituents independently selected from cycloalkyl; (x) a 5-10 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; The 5- to 10-membered heteroaryl ring is preferably a halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2 or 3 substituents independently selected from cycloalkyl; (xi)-SO2R A13 And, R A13 is a C1-C6 alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S; C 1~6 the alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy; (xii)-SO(NR A14 )2, Each R A14 are 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; C 1~6 the alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy; (xiii)C 1~6 Alkoxy, OH, -SO2-(C 1~3 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, 2~6alkynyl, or The Two R's 8 the groups are linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; 3-7 membered rings include halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; Two R on adjacent carbon atoms 8 the groups are linked to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; Fused 6- to 10-membered aromatic rings include halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 Optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl.

[0076] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 6-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S, and the spiro ring may contain 1, 2, 3, or 4 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 6-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S, and the spiro ring may contain 1, 2, or 3 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 6-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring is 8 The group is optionally substituted.

[0077] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 6-membered spiro ring containing 1 or 2 heteroatoms selected from N and O, and the spiro ring may contain 1, 2, 3, or 4 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 6-membered spiro ring containing 1 or 2 heteroatoms selected from N and O, and the spiro ring may contain 1, 2, or 3 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 6-membered spiro ring containing one or two heteroatoms selected from N and O, and the spiro ring is 8 The group is optionally substituted.

[0078] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 5-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S, and the spiro ring may contain 1, 2, 3, or 4 R8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 5-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S, and the spiro ring may contain 1, 2, or 3 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 5-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring is 8 is optionally substituted with a group.

[0079] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 5-membered spiro ring containing 1 or 2 heteroatoms selected from N and O, and the spiro ring may contain 1, 2, 3, or 4 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 5-membered spiro ring containing 1 or 2 heteroatoms selected from N and O, and the spiro ring may contain 1, 2, or 3 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 5-membered spiro ring containing one or two heteroatoms selected from N and O, and the spiro ring is 8 is optionally substituted with a group.

[0080] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 4-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S, and the spiro ring may be selected from 1, 2, 3, or 4 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 4-membered spiro ring containing 1 or 2 heteroatoms selected from N, O, and S, and the spiro ring may contain 1, 2, or 3 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 4-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring is 8 is optionally substituted with a group.

[0081] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 4-membered spiro ring containing 1 or 2 heteroatoms selected from N and S, and the spiro ring may contain 1, 2, 3, or 4 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 4-membered spiro ring containing 1 or 2 heteroatoms selected from N and S, and the spiro ring may be substituted with 1, 2 or 3 R 8 In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] is a 4-membered spiro ring containing one or two heteroatoms selected from N and S, and the spiro ring is 8 The group is optionally substituted.

[0082] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein: * teeth, [ka] indicates the point of attachment of R to the remainder of formula I; d is H, C 1~4 Alkyl or C 1~4 haloalkyl, and m is 0, 1, 2, 3, or 4.

[0083] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein: * teeth, [ka] indicates the point of attachment of R to the remainder of formula I; d is H, C 1~4 Alkyl or C 1~4 haloalkyl, and m is 0, 1, 2, 3, or 4.

[0084] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0085] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is selected from the group consisting of:

[0086] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein m is 0, 1, 2, or 3. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein m is 0, 1, 2, or 3. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein m is 0, 1, 2, 3, or 4. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein m is 0, 1, 2, or 3. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein m is 0, 1, 2, or 3. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] wherein m is 0, 1, 2 or 3.

[0087] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has the formula IA: [ka] In the formula, m is 0, 1, 2, or 3.

[0088] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has the formula IB: [ka] In the formula, m is 0, 1, 2, or 3.

[0089] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has the formula IC: [ka] In the formula, R d is H, C 1~4 Alkyl or C 1~4 haloalkyl, and m is 0, 1, 2, or 3.

[0090] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has the formula ID: [ka] In the formula, R d is H, C 1~4 Alkyl or C 1~4 haloalkyl, and m is 0, 1, 2, or 3.

[0091] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has the formula IE: [ka] In the formula, R d is H, C 1~4 Alkyl or C 1~4haloalkyl, and m is 0, 1, 2, or 3.

[0092] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound has the formula IF: [ka] In the formula, m is 0, 1, 2, 3, or 4.

[0093] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, or IF, or a pharmaceutically acceptable salt thereof, R 2 is H or C 1~6 In some embodiments, R 2 is H. In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is C 1~3 In some embodiments, R 2 is C 1~4 It is haloalkyl.

[0094] In some embodiments of the compound of formula I, IA, IB, IC, ID, IE, or IF, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH—, [ka] In some embodiments, Y is selected from the group consisting of: [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] is.

[0095] In some embodiments of the compound of Formula I, IA, IB, IC, ID, IE, or IF, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 It is alkyl.

[0096] In some embodiments of Formula I or IA, or a pharmaceutically acceptable salt thereof, the compound has the formula II-A: [ka] In the formula, m is 0, 1, 2, or 3.

[0097] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, or II-A, or a pharmaceutically acceptable salt thereof, R 1 is 1, 2, 3, or 4 R A1 and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC1~4 In some embodiments, R 1 is 1, 2, 3, or 4 R A1 and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 In some embodiments, R 1 is 1, 2, 3, or 4 R A1 and each R A1 are independently halo or -OC 1~4 In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 halogens. 1 is phenyl substituted with two or three halogens selected from chloro and fluoro. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0098] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0099] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0100] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, or II-A, or a pharmaceutically acceptable salt thereof, R 1 is 1, 2, 3, or 4 R A1 wherein each R is A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 In some embodiments, R 1 is 1, 2, 3, or 4 R A1 wherein each R is A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 In some embodiments, R 1 is 1, 2, 3, or 4 R A1 and each R is a pyridyl substituted with A1 are independently halo or -OC 1~4 In some embodiments, R 1 is pyridyl substituted with 1, 2, 3, or 4 halogens. 1 is pyridyl substituted with two or three halogens selected from chloro and fluoro. In some embodiments, R 1 teeth, [ka] is.

[0101] In some embodiments of the compound of Formula I, IA, or II-A, or a pharmaceutically acceptable salt thereof, the compound has the formula II-Aa or II-Ab: [ka] In the formula, m is 0, 1, 2, or 3.

[0102] In some embodiments of the compound of Formula I, IA, or II-A, or a pharmaceutically acceptable salt thereof, the compound has the formula II-Aa: In some embodiments of the compound of Formula I, IA, or II-A, or a pharmaceutically acceptable salt thereof, the compound has the formula II-Ab:

[0103] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, 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 -OC 1~4 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 In some embodiments, L is -CR 3a R 3b -, wherein R 3a and R 3b are independently H or C 1~6 In some embodiments, L is -CR 3a R 3b -, wherein R 3a and R 3bare both H. In some embodiments, L is —C(O)—. In some embodiments, R is —SO—. In some embodiments, L is —CH—CH—. In some embodiments, L is —N(R a )-. In some embodiments, L is NH.

[0104] In some embodiments of the compound of Formula I, IA, II-A, II-Aa, or II-Ab, the compound has Formula III: [ka] In the formula, m is 0, 1, 2, or 3.

[0105] In some embodiments of Formula I, IA, II-A, II-Aa, II-Ab, or III, the compound has Formula IIIa or IIIb: [ka] In the formula, m is 0, 1, 2, or 3.

[0106] In some embodiments of Formula I, IA, II-A, II-Aa, or III, the compound has Formula IIIa. In some embodiments of Formula I, IA, II-A, II-Ab, or III, the compound has Formula IIIb.

[0107] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, 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 In some embodiments, W is a haloalkyl or halo. 1 is a bond or -CR4a R 4b -, wherein R 4a and R 4b are independently H, C 1~6 In some embodiments, W is alkyl, or halo. 1 is a bond or -CR 4a R 4b -, wherein R 4a and R 4b is independently H, —CH, or halo. In some embodiments, W 1 is a bond or -CR 4a H-, where R 4a is H, C 1~6 In some embodiments, W is alkyl, or halo. 1 is a bond, —CH2, or —CH(F)—.

[0108] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, IIAa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond or -CR 4a R 4b -, wherein R 4a and R 4b are independently H, C 1~6 Alkyl, C 1~4 In some embodiments, Y is —C(O)NH— and 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 In some embodiments, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond or -CR 4a R4b -, wherein R 4a and R 4b is independently H, —CH, or halo. In some embodiments, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond or -CR 4a H-, where R 4a is H, C 1~6 In some embodiments, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond, —CH— or —CH(F)—.

[0109] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, II-Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl, C 1~4 In some embodiments, Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl, or C 1~4 In some embodiments, Z is —CH(CH 3 )— or —CH(CH 2 F)—.

[0110] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond or -CR4a R 4b -, wherein R 4a and R 4b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl, C 1~4 In some embodiments, Y is —C(O)NH— and 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, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl, or C 1~4 In some embodiments, Y is —C(O)NH— and 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, and Z is —CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl, or C 1~4 In some embodiments, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond or -CR 4a H-, where R4a is H, C 1~6 alkyl or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl or C 1~4 In some embodiments, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond, —CH— or —CH(F)—, and Z is —CH(CH— or —CH(CHF)—.

[0111] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, W 2 -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, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 alkyl, and R 6a and R 6b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 In some embodiments, W is alkyl. 2 -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 -OC 1~4 alkyl, and R 6a and R6b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 In some embodiments, W is alkyl. 2 -CR 5a R 5b -or-CR 6a =CR 6b -, wherein R 5a and R 5b are independently H, C 1~6 alkyl or halo, R 6a and R 6b are independently H, halo, or C 1~6 In some embodiments, W is alkyl. 2 is —CH— or —CH═CH—. In some embodiments, W 2 is -CH-. In some embodiments, W 2 is -CH=CH-.

[0112] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 But bond or -CR 4a R 4b -, wherein R 4a and R 4b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, W 2 -CR 5a R 5b -or-CR 6a =CR 6b -, wherein R 5a and R5b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 alkyl, and R 6a and R 6b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0113] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 But bond or -CR 4a R 4b -, wherein R 4a and R 4b are independently H, C 1~6 alkyl or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl or C 1~4 haloalkyl, W 2 -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 -OC 1~4 alkyl, and R 6a and R 6b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0114] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 But bond or -CR 4a R 4b -, wherein R 4a and R 4b are independently H, —CH3, or halo, and Z is —CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl or C 1~4 haloalkyl, W 2 -CR 5a R 5b -or-CR 6a =CR 6b -, wherein R 5a and R 5b are independently H, C 1~6 alkyl or halo, R 6a and R 6b are independently H, halo, or C 1~6 It is alkyl.

[0115] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond or -CR 4a H-, where R 4a is H, C 1~6 alkyl or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl or C1~4 haloalkyl, W 2 is -CH2- or -CH=CH-.

[0116] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond or -CR 4a H-, where R 4a is H, C 1~6 alkyl or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl or C 1~4 haloalkyl, W 2 is -CH2-.

[0117] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and R 2 is H or C 1~6 alkyl, W 1 is a bond or -CR 4a H-, where R 4a is H, C 1~6 alkyl or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are independently H, C 1~6 Alkyl or C 1~4 haloalkyl, W 2 is -CH=CH-.

[0118] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and 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)-, W 2 is -CH2- or -CH=CH-.

[0119] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, or IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and 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)-, W 2 is -CH2-.

[0120] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, or IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is —C(O)NH— and 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)-, W 2 is -CH=CH-.

[0121] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, the compound has Formula IV: [ka] In the formula, m is 0, 1, 2, or 3.

[0122] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, III, IIIa, or IV, or a pharmaceutically acceptable salt thereof, the compound has the formula IVa: [ka] In the formula, m is 0, 1, 2, or 3.

[0123] In some embodiments of a compound of Formula I, IA, II-A, II-Ab, III, IIIb, or IV, or a pharmaceutically acceptable salt thereof, the compound has the formula IVb: [ka] In the formula, m is 0, 1, 2, or 3.

[0124] In some embodiments of a compound of Formula I, IA, 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 It is haloalkyl.

[0125] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0126] In some embodiments of a compound of Formula I, IA, 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 H, halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0127] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, R 9a is H, C 1~6 Alkyl, C 1~4 haloalkyl, or 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 In some embodiments, R 9a is -CH3 or -CH2F.

[0128] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a 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, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 Alkyl, C 1~4haloalkyl, or halo. In some embodiments, R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 Alkyl or C 1~4 In some embodiments, R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is -CH3 or -CH2F.

[0129] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8 is, independently, (i) halo, (ii) C optionally substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (iii)C 1~6 haloalkyl, (iv) CN, (v) oxo, (vi)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C6~10 optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vii) NHR A6 And, In the formula, R A6 is C1-C6 alkyl, (viii)NR A7 R A8 And, In the formula, R A7 is a C1-C6 alkyl, R A8 is C1-C6 alkyl, (ix) C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, CN, C 3~7 Cycloalkyl, and C 1~6 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkoxy; 6~10 aryl, C 3~7 cycloalkyl optionally substituted with 1, 2, 3, or 4 independent halo groups; (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; 3-7 membered rings are halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; or (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or The 5- to 10-membered heteroaryl ring is preferably a halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; The Two R's 8 the groups are linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; 3-7 membered rings include halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; Two R on adjacent carbon atoms 8 the groups are linked to form a fused 6- to 10-membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; Fused 6- to 10-membered aromatic rings include halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 Optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkyl.

[0130] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8 is, independently, (i) halo, (ii) C optionally substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (iii)C 1~6 haloalkyl, (iv) CN, (v) oxo, (vi)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C 6~10 optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vii) NHR A6 And, In the formula, R A6 is C1-C6 alkyl, (viii)NR A7 R A8 And, In the formula, R A7 is a C1-C6 alkyl, R A8 is C1-C6 alkyl, (ix) C 6~10 aryl, (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; or (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; or The Two R's 8 The groups may be linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0131] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CHOMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CHF2, CH2CF3, (CH2)4Cl, CH2F, CH2CH2F, CH(CH3)F, CF2CH3, CF3, [ka] is.

[0132] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8 are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CHOMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] is.

[0133] In some embodiments of a compound of Formula I, IA, 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 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, Each R 8is, independently, (i) halo, (ii) C optionally substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (iii)C 1~6 haloalkyl, (iv) CN, (v) oxo, (vi)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C 6~10 optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vii) NHR A6 And, In the formula, R A6 is C1-C6 alkyl, (viii)NR A7 R A8 And, In the formula, R A7 is a C1-C6 alkyl, R A8 is C1-C6 alkyl, (ix) C 6~10 aryl, (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; or (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; or The Two R's 8The groups may be linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0134] In some embodiments of a compound of Formula I, IA, 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 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is C 1~6 Alkyl, C 1~4 haloalkyl or halo, Each R 8 is, independently, (i) halo, (ii) C optionally substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (iii)C 1~6 haloalkyl, (iv) CN, (v) oxo, (vi)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C 6~10optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vii) NHR A6 And, In the formula, R A6 is C1-C6 alkyl, (viii)NR A7 R A8 And, In the formula, R A7 is a C1-C6 alkyl, R A8 is C1-C6 alkyl, (ix) C 6~10 aryl, (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; or (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; or The Two R's 8 The groups may be linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0135] In some embodiments of a compound of Formula I, IA, 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 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is C 1~6 Alkyl or C 1~4 is haloalkyl, Each R 8 is, independently, (i) halo, (ii) C optionally substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (iii)C 1~6 haloalkyl, (iv) CN, (v) oxo, (vi)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C 6~10 optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vii) NHR A6 And, In the formula, R A6 is C1-C6 alkyl, (viii)NR A7 R A8 And, In the formula, R A7 is a C1-C6 alkyl, R A8 is C1-C6 alkyl, (ix) C 6~10 aryl, (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; or (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; or The Two R's 8The groups may be linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0136] In some embodiments of a compound of Formula I, IA, 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 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is -CH3 or -CH2F. Each R 8 is, independently, (i) halo, (ii) C optionally substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 aryl or 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (iii)C 1~6 haloalkyl, (iv) CN, (v) oxo, (vi)-XR A5 And, 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; C1-C6 alkyl or 3-7 membered ring is CN, halo, C1-C6 alkoxy, C 6~10 optionally substituted with 1, 2, or 3 groups independently selected from aryl and 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (vii) NHRA6 And, In the formula, R A6 is C1-C6 alkyl, (viii)NR A7 R A8 And, In the formula, R A7 is a C1-C6 alkyl, R A8 is C1-C6 alkyl, (ix) C 6~10 aryl, (x) a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S; or (xi) a 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; or The Two R's 8 The groups may be linked to form a fused, spiro, or bridged 3- to 7-membered ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0137] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8 are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CHOMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] is.

[0138] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, each R 8are 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, [ka] is.

[0139] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, two R 8 are linked to form a fused six-membered ring containing one O.

[0140] In some embodiments of a compound of Formula I, IA, 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 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, Each R 8are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CHOMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] is.

[0141] In some embodiments of a compound of Formula I, IA, 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 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is C 1~6 Alkyl, C 1~4 haloalkyl or halo, Each R 8 are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CHOMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] is.

[0142] In some embodiments of a compound of Formula I, IA, 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 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is C 1~6 Alkyl or C 1~4 is haloalkyl, Each R 8 are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CHOMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] is.

[0143] In some embodiments of a compound of Formula I, IA, 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 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is C 1~6 Alkyl or C 1~4 is haloalkyl, Each R 8 are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CHOMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] is.

[0144] In some embodiments of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, 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.

[0145] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or a pharmaceutically acceptable salt thereof, the compound has Formula V: [ka] In the formula, R 8A and R 8B are independently H, halo, and C 1~4 Alkyl or C 1~4 It is haloalkyl.

[0146] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, III, IIIa, IV, IVa, or V, or a pharmaceutically acceptable salt thereof, the compound has the formula Va: [ka] In the formula, R 8A and R 8B are independently H, halo, and C 1~4 Alkyl or C 1~4 It is haloalkyl.

[0147] In some embodiments of a compound of Formula I, IA, II-A, II-Ab, III, IIIb, IV, IVb, or V, or a pharmaceutically acceptable salt thereof, the compound has the formula Vb: [ka] In the formula, R 8A and R 8B are independently H, halo, and C 1~4 Alkyl or C 1~4 It is haloalkyl.

[0148] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8B H, halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 8A Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8B is H. In some embodiments, R 8A H, halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 8A is H and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 It is haloalkyl.

[0149] 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 It is haloalkyl.

[0150] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0151] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 9a is H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 9a is C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 9a is C 1~6 It is alkyl.

[0152] 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 It is haloalkyl.

[0153] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0154] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 9a is H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 9a is C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 9a is C 1~6 It is alkyl.

[0155] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8B H, halo, C 1~4 Alkyl or C 1~4haloalkyl, and R 4a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is H, C 1~6 Alkyl, C 1~4 It is haloalkyl or halo.

[0156] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8B is H and R 4a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is H, C 1~6 Alkyl, C 1~4 It is haloalkyl or halo.

[0157] In some embodiments 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, and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is H, C 1~6 Alkyl, C 1~4 It is haloalkyl or halo.

[0158] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A is H and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is H, C 1~6 Alkyl, C 1~4 It is haloalkyl or halo.

[0159] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8B H, halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 Alkyl, C 1~4 It is haloalkyl or halo.

[0160] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8B is H and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C1~6 alkyl, and R 9a is C 1~6 Alkyl, C 1~4 It is haloalkyl or halo.

[0161] In some embodiments 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, and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 Alkyl, C 1~4 It is haloalkyl or halo.

[0162] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A is H and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 Alkyl, C 1~4 It is haloalkyl or halo.

[0163] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8BH, halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 It is alkyl.

[0164] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 8B is H and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 It is alkyl.

[0165] In some embodiments 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, and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 It is alkyl.

[0166] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A is H and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 It is alkyl.

[0167] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A is H and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 alkyl, and R 1 is 1, 2, 3, or 4 R A1 and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 It is alkyl.

[0168] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A is H and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl, or C 1~4haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 alkyl, and R 1 is 1, 2, 3, or 4 R A1 and each R A1 are independently halo or -OC 1~4 It is alkyl.

[0169] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A is H and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 alkyl, and R 1 is phenyl optionally substituted with 1, 2, 3, or 4 halogens.

[0170] In some embodiments of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A is H and R 8B Ha, Halo, C 1~4 Alkyl or C 1~4 haloalkyl, and R 4a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 alkyl, and R 9a is C 1~6 alkyl, and R 1is phenyl optionally substituted with two or three halogens selected from chloro and fluoro.

[0171] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A and R 8B are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 where 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.

[0172] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A and R 8B are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 where 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; R 1 is phenyl substituted with two or three halogens selected from chloro and fluoro; R 4a is R 4a H, halo, C 1~6 Alkyl or C 1~4 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is C 1~6 Alkyl or C 1~4 It is haloalkyl.

[0173] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A and R 8B are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 where X is O and R A5 is C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0174] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A and R 8B are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 where X is O and R A5 is C 1~6 Alkyl or C 1~6 is haloalkyl, R 1 is phenyl substituted with two or three halogens selected from chloro and fluoro; R 4a is R 4a H, halo, C 1~6 Alkyl, or C 1~4 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is C 1~6 Alkyl or C 1~4 It is haloalkyl.

[0175] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A and R 8B are independently H, halo, and C 1~4Alkyl, C 1~4 Haloalkyl or -XR A5 where X is O and R A5 is C 1~6 It is alkyl.

[0176] In some embodiments of the compound of Formula V, Va, or Vb, or a pharmaceutically acceptable salt thereof, R 8A and R 8B are independently H, halo, and C 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 where X is O and R A5 is C 1~6 is alkyl, R 1 is phenyl substituted with two or three halogens selected from chloro and fluoro; R 4a is R 4a H, halo, C 1~6 Alkyl or C 1~4 is haloalkyl, R 5a H, halo, C 1~4 Haloalkyl, or C 1~6 is alkyl, R 9a is C 1~6 Alkyl or C 1~4 It is haloalkyl.

[0177] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0178] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0179] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0180] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0181] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0182] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0183] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0184] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0185] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0186] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0187] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0188] In some embodiments of a compound of Formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the compound is [ka] [ka] [ka] [ka] is.

[0189] III. Pharmaceutical Compositions The compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, pharmaceutical compositions comprising one or more of the compounds provided herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients are also provided herein. The compounds provided herein may be the only active ingredient or may be one of the active ingredients of the pharmaceutical composition. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0190] In one aspect, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0191] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., 1; 2; 3; 4; 1 or 2; 1 to 3; or 1 to 4) 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., 1; 2; 3; 4; 1 or 2; 1 to 3; or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0192] The pharmaceutical compositions may be administered in either a single dose or multiple doses. The pharmaceutical compositions may be administered by a variety of methods, including, for example, rectal, oral, intranasal, and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0193] One mode of administration is parenterally, for example, by injection. Forms into which the pharmaceutical compositions described in the present disclosure can be incorporated for administration by injection include, for example, aqueous or oily suspensions, or emulsions including sesame oil, corn oil, cottonseed oil, or peanut oil, or elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0194] Oral administration may be another route for administering the compounds provided herein. Administration may be, for example, via capsules or enteric-coated tablets. When preparing pharmaceutical compositions containing at least one compound provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as a compound provided herein) is typically diluted with an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile-packaged powders.

[0195] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. The pharmaceutical composition can further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents, or any combination thereof.

[0196] Pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, can be formulated to provide rapid, sustained, or delayed release of the active ingredient (such as the compounds provided herein) after administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and solution-based systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are provided in U.S. Patent Nos. 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 the compounds provided herein in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0197] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient may be dispersed evenly throughout the composition, so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0198] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter in the form of an envelope over the former. The two components can be separated by an enteric layer that resists disintegration in the stomach and allows 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, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0199] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may 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 in pharmaceutically acceptable solvents may be atomized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0200] IV. Treatment method In one embodiment, there is provided a method of treating an HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having such infection, comprising administering to the human a therapeutically effective amount of a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof.

[0201] 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 additional therapeutic agent is an anti-HIV agent. In certain embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent infection reactivator, 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 additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, or a pharmaceutically acceptable salt thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, GS-5894, islatravir, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional therapeutic agent is lenacapavir or islatravir. In some embodiments, the additional therapeutic agent is lenacapavir. In some embodiments, the additional therapeutic agent is islatravir.

[0202] In another embodiment, there is provided a use of a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for treating HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having such infection.

[0203] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0204] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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 Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0205] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, 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 for treating HIV infection in a human having or at risk of having the infection.

[0206] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having the infection, wherein the method further comprises administering one, two, three, or four additional therapeutic agents to the human.

[0207] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having the infection, said method comprising the step of administering to said human a 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 latent infection reactivator, a capsid polymerization inhibitor, an HIV The method further comprises administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of a 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 reactivator, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist, and a combination thereof.

[0208] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, 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 for treating HIV infection in a human having or at risk of having the infection, the method further comprising administering therapeutically effective amounts of tenofovir disoproxil and emtricitabine to the human.

[0209] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having, having, or at risk of having the infection, the method further comprising administering therapeutically effective amounts of tenofovir alafenamide and emtricitabine to the human.

[0210] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having the infection, wherein the method further comprises administering a therapeutically effective amount of tenofovir disoproxil to the human.

[0211] In another embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having the infection, wherein the method further comprises administering a therapeutically effective amount of tenofovir alafenamide to the human.

[0212] In another embodiment, methods of use in therapy of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are provided. In particular, methods of treating HIV viral growth, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human) are provided, comprising administering to the mammal a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0213] In another embodiment, there is provided a composition comprising a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in a method of treating HIV viral growth, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

[0214] In one embodiment, there is provided a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in the prevention of HIV infection.

[0215] For example, in one embodiment, a compound of Formula I, IA, IB, IC, ID, IE, IF, 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, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in pre-exposure prophylaxis (PrEP), i.e., before an individual is exposed to the HIV virus, to prevent establishment of HIV infection when the individual is exposed to the virus and / or to prevent the virus from establishing a persistent infection and / or to prevent symptoms of the disease from appearing and / or to prevent the virus from reaching detectable levels in the blood.

[0216] In another embodiment, disclosed is the use of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating HIV infection in a human having or at risk of having the infection.

[0217] In another embodiment, the use of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, as a research tool is disclosed.

[0218] In another embodiment, an article of manufacture comprising a composition effective for treating HIV infection, and packaging material comprising a label indicating that the composition can be used to treat infection by HIV, is disclosed. Exemplary compositions comprise a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof.

[0219] In yet another embodiment, a method of inhibiting HIV replication is disclosed, the method comprising exposing an effective amount of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, to the virus under conditions that inhibit HIV replication.

[0220] In another embodiment, the use of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIaIIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for inhibiting the activity of HIV integrase enzyme is disclosed. In another embodiment, the use of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for inhibiting the replication of HIV is disclosed.

[0221] V. Administration Compounds of the present disclosure (e.g., compounds of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, 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 understood that the preferred route may vary depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0222] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen for any desired period or duration, 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 duration of the individual's life.

[0223] The specific dose level of a compound of the present disclosure for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject receiving therapy. For example, dosages may be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing by subject body weight is particularly useful when adjusting dosages between subjects of widely different sizes, such as occurs when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0224] The dosage may also be described as the total amount of a compound described herein administered per administration. The dosage of a compound of Formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg, about 1 to 2,000 mg, about 1 to 1,000 mg, about 10 to 500 mg, about 20 to 500 mg, about 50 to 300 mg, about 75 to 200 mg, or about 15 to 150 mg.

[0225] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0226] 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 daily. In some embodiments, the compound is administered once weekly. In some embodiments, the compound is administered once monthly. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every five months. In some embodiments, the compound is administered every six months. In some embodiments, the compound is administered every seven months. In some embodiments, the compound is administered every eight months. In some embodiments, the compound is administered every nine months. In some embodiments, the compound is administered every ten months. In some embodiments, the compound is administered every eleven months. In some embodiments, the compound is administered annually.

[0227] The compounds provided herein can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound can include about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, e.g., about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of a compound provided herein can include about 0.3 mg to about 30 mg per dose, or about 30 mg to about 300 mg per dose, or about 0.3 μg to about 30 mg per dose, or about 30 μg to about 300 μg per dose.

[0228] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., 1 mg to 1000 mg of compound). Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose, or from about 0.01 mg per dose to about 1000 mg per dose, or from about 0.01 mg per dose to about 100 mg per dose, or from about 0.1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 10 mg per dose, or from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of a compound of formula I are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of compounds of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0229] In some embodiments, the methods described herein include administering to a subject an initial daily dose of about 1-500 mg of a compound of formula (I) described herein, and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, daily, twice weekly, weekly, every two weeks, every three weeks, or monthly.

[0230] When administered orally, the total daily dosage for a human subject may be about 1 mg to 1,000 mg, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day. In some embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg / day administered in a single dose.

[0231] In some embodiments, the total daily dosage for a human subject may be about 100 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 450 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 750 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 950 mg / day administered in a single dose.In some embodiments, the total daily dosage for a human subject may be about 1000 mg / day administered in a single dose.

[0232] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once per week. A single dose can also be administered once per month. In some embodiments, a compound disclosed herein is administered once daily in the methods disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in the methods disclosed herein.

[0233] 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, the compounds disclosed herein are administered once every 10 months. In some embodiments, the compounds disclosed herein are administered once every year.

[0234] 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 daily, once weekly, once every two weeks, once a month, once every two months, once every three months, once every four months, once every six months, or less. Administration of the compounds will continue for as long as needed to treat HIV infection.

[0235] VI. Kits and Manufactured Products In one aspect, provided herein are kits that include a compound provided herein (e.g., a compound of Formula I, IA, IB, IC, ID, IE, IF, 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 includes instructions for use. In some embodiments, the kit includes a compound provided herein (e.g., a compound of Formula I, IA, IB, IC, ID, IE, IF, 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 treating an indication, including a disease or condition described herein.

[0236] In some embodiments, the kit further comprises one or more (e.g., 1; 2; 3; 4; 1 or 2; 1 to 3; or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0237] In one aspect, provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, in a suitable container, hi some embodiments, the container may be a vial, jar, ampoule, pre-filled syringe, or infusion bag.

[0238] VII. Combination Therapy In certain embodiments, methods are provided for treating HIV infection, comprising administering to a human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents. In one embodiment, methods are provided for treating HIV infection, comprising administering to a human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with therapeutically effective amounts of one, two, three, or four additional therapeutic agents.

[0239] In one embodiment, a pharmaceutical composition is provided 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.

[0240] In certain embodiments, the present disclosure provides a method for treating an HIV infection, 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 therapeutically effective amounts of one, two, three, or four additional therapeutic agents suitable for treating an HIV infection.

[0241] 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 can be selected from different classes of therapeutic agents.

[0242] Administration of HIV combination therapy 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 refers to simultaneous or sequential administration of a compound disclosed herein with one, two, three, or four additional therapeutic agents such that therapeutically effective amounts of both the compound disclosed herein and the one, two, three, or four additional therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in two or more administrations.

[0243] Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of unit doses of one, two, three, or four additional therapeutic agents. For example, a compound disclosed herein may be administered within seconds, minutes, or hours of administration of one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by unit doses of one, two, three, or four additional therapeutic agents. Alternatively, unit doses of one, two, three, or four additional therapeutic agents are administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by unit doses of one, two, three, or four additional therapeutic agents. In still other embodiments, unit doses of one, two, three, or four additional therapeutic agents are administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein.

[0244] In certain embodiments, kits are provided that include a compound disclosed herein (e.g., of Formula I, IA, IB, IC, ID, IE, IF, 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., 1, 2, 3, or 4) additional therapeutic agents.

[0245] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor.

[0246] HIV combination therapy In the above embodiments, the additional therapeutic agent or agents may be anti-HIV agents. In some examples, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV 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 inhibitors, inhibitors of Tat-TAR-P-TEFb, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells, etc.), latent infection reactivators, immune system therapeutics, phosphatidylinositol 3-kinase (PI3K) inhibitors, 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, fatty acid synthase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF α ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV The inhibitor may be a 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 priming 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, and an anti-HIV peptide, and combinations thereof.

[0247] In some embodiments, the additional therapeutic agent or agents are selected from HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0248] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, 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 reactivators, capsid inhibitors, immune system therapeutics, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0249] In some embodiments, the additional therapeutic agent or agents are selected from 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 capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latent infection reactivators, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, HIV antigen-targeting chimeric T cell receptors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0250] In some embodiments, the additional therapeutic agent or additional therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0251] HIV combination drugs Examples of combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCO VY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine Mivudine; Tenofovir alafenamide and emtricitabine; Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; Tenofovir analogs; COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); KALETR A® (ALUVIA®, lopinavir and ritonavir), TRIUMEQ® (dolutegravir, abacavir, and lamivudine); BIKTARVY® (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO® (dolutegravir + lamivudine), TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir;Darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + These include, but are not limited to, 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 + albuvirtide, elpida (elsulfavirine, VM-1500), and VM-1500A, lenacapavir + islatravir (oral, injectable), and dual-targeted HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors;

[0252] Other HIV drugs Examples of other drugs for treating HIV include, but are not limited to, aspernigrin C, acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-Dicameoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, Bevirimat derivatives, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, bryostatin-1, bryostatin analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, fluoro-beta-D-arabinose nucleic acid (FANA)-modified antisense oligonucleotides oligonucleotides, 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, thrombospondin 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, antiviral fc conjugates (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, Nipamobil, Covimro, and ABBV-1882.

[0253] HIV protease inhibitors 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 plus ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911.

[0254] Additional examples of HIV protease inhibitors are described, for example, in U.S. Pat. No. 10,294,234, and U.S. Patent Application Publication No. 2020 / 030327, and U.S. Patent Application Publication No. 2019 / 210978.

[0255] HIV Gag protein inhibitors Examples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071.

[0256] HIV ribonuclease H inhibitors Examples of HIV RNase H inhibitors include, but are not limited to, NSC-727447.

[0257] HIV Nef inhibitors Examples of HIV Nef inhibitors include, but are not limited to, FP-1.

[0258] HIV reverse transcriptase inhibitors 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, elsulfavirine (extended-release oral, HIV infection), doravirine plus islatravir (fixed-dose combination / oral tablet formulation, HIV-1 infection), elsulfavirine (long-acting injectable nanosuspension, HIV infection), and elsulfarabine (VM-1500).

[0259] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir disoproxil hemifumarate, VIDEX® and VIDEXEC® (didanosine, ddl), abacavir , abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, ethidovudine lavirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, islatravir, MK-8583, VM-2500, and KP-1461.

[0260] Additional examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, those described in U.S. Patent Application Publication Nos. 2007 / 049754, 2016 / 250215, 2016 / 237062, 2016 / 251347, 2002 / 119443, 2013 / 065856, 2013 / 090473, 2014 / 221356, and WO 04096286.

[0261] HIV integrase inhibitors Examples of HIV integrase inhibitors include elvitegravir, elvitegravir (sustained-release microcapsules), curcumin, curcumin derivatives, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, pegylated raltegravir, dolutegravir, JTK-351, bictegravir, These include, but are not limited to, AVX-15567, cabotegravir (long-acting injectable solution), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017.

[0262] HIV non-catalytic site or allosteric integrase inhibitors or allosteric, integrase inhibitor, NCINI) is an example of CX-050 45, CX-05168, and CX-14442.

[0263] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. 2020 / 0317689, 2021 / 0284642, 2014 / 221356, and 2016 / 016973.

[0264] HIV viral infectivity factor inhibitors Examples of HIV viral infectivity inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0265] HIV entry inhibitors Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0266] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, maraviroc (long-acting injectable nanoemulsion), cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc, and vMIP (Hai mipu).

[0267] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, and gp41 inhibitors. These include rififiscin (gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biobetter, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifuvirtide. Not limited.

[0268] Examples of CD4 binding inhibitors include, but are not limited to, ibalizumab and CDA analogs.

[0269] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicides, Radha-108 (receptor) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemasavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0270] Examples of gp160 inhibitors include, but are not limited to, fangchinoline.

[0271] Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0272] HIV maturation inhibitors Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232.

[0273] Latent infection reactivator Examples of latent infection reactivators include toll-like receptors (TLRs) ) agonists (including TLR7 agonists, e.g., GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors, e.g., Velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BET-bromodomain 4, BRD4 inhibitors (e.g., ZL-0580, apabetalone), ionomycin, IAP antagonists (inhibitors of apoptotic proteins such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (IL-15, IL-15 fusion proteins, and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, and GSK-343. Examples of PKC activators include, but are not limited to, indolactam, prostratin, ingenol B, and DAG-lactone.

[0274] Additional examples of TLR7 agonists include, but are not limited to, those described in US Patent Application Publication No. 2010 / 143301.

[0275] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. 2017 / 071944.

[0276] Histone deacetylase (HDAC) inhibitors In some embodiments, the agents described herein are further combined with an inhibitor of histone deacetylase, 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, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0277] Capsid inhibitors Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, lenacavir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitor (HIV-1 infection, Shandong University), and compounds described in (GSK WO 2019 / 087016).

[0278] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication No. 2018 / 051005 and U.S. Patent Application Publication No. 2016 / 108030.

[0279] Cytochrome P450 3 inhibitors Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in US Pat. No. 7,939,553.

[0280] RNA polymerase modulators Examples of RNA polymerase modulators include, but are not limited to, those described in US Pat. No. 10,065,958 and US Pat. No. 8,008,264.

[0281] Immune Checkpoint Modulators In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can effectively regulate T cell or NK cell activation and prevent immune leakage of infected cells. Activation or stimulation of stimulatory immune checkpoints can enhance the effects of immune checkpoint inhibitors in infection treatments. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., as reviewed in Davis et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0282] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane domain and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T-cell activation inhibitory factor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule 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 (BT) LA); 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 4 (TIMD4; TIM4); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Lymphocyte activation 3 (LAG3, CD223); Signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLA MF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16-binding protein 1 (ULBP1); UL16-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, one Ig domain, and a long cytoplasmic tail Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (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).

[0283] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 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-associated immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell 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, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, 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 costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule 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.

[0284] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating 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.

[0285] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprise 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 comprises BPI-002.

[0286] Examples of CTLA4 inhibitors that can be co-administered include 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, and 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).

[0287] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include 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, and BI-75409. 1, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (budidalimab), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostallimab), 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).Not limited to these.

[0288] In various embodiments, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058, and AGEN-1307.

[0289] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In various embodiments, the agents described herein are agonists of one or more TNF receptor superfamily (TNFRSF) members, such as 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 (C D27, 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), T NFRSF10D (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 (N In combination with one or more agonists of GFR, 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).

[0290] Examples of anti-TNFRSF4 (OX40) antibodies that may be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tabolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO 2016179517, WO 2017096179, WO 2017096182, WO 2017096281, and WO 2018089628.

[0291] Examples of anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0292] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0293] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0294] 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 International Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. 2017 / 096179 and 2018 / 089628.

[0295] Bispecific and trispecific natural killer (NK) cell engagement Ja In various embodiments, the agents described herein bind to NK cell activating receptors, e.g., 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 FcγR (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 the like. and a bi-specific NK cell engager against CD137 (41BB) The anti-CD16 binding bispecific molecule may be combined with a CD16-binding NK cell engager (BiKE) or trispecific NK cell engager (TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that may be co-administered target CD16 and one or more HIV-associated antigens, as described herein. BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell inducers (TRiKEs) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3TriKE.

[0296] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In various embodiments, the agents described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0297] Toll-like receptor (TLR) agonists In some embodiments, an agent described herein is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Exemplary TLR7 agonists that may be co-administered include 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 those disclosed in U.S. Patent Application Publication Nos. 20100143301 (Gilead Sciences), 20110098248 (Gilead Sciences), and U.S. Patent Application Publication Nos. 20100143301 (Gilead Sciences), 20110098248 (Gilead Sciences), and 20110098248 (Gilead Sciences). Sciences), and No. 20090047249 (Gilead Sciences), 20140045849 (Janssen), 20140073642 (Janssen), WO 2014 / 056953 (Janssen), 2014 / 076221 (Janssen), 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), 20080306050 (Array Biopharma), 20100029585 (Ventirx Pharma), 20110092485 (Ventirx Pharma), No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Pharma), 20140088085 (Ventirx Pharma), 20140275167 (Novira Therapeutics), and 20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, telluritolimod, and BDB-001. Examples of TLR8 agonists include 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 U.S. Patent Application Publication No. 20140045849 (Janssen) and U.S. Patent Application Publication No. 20140073642 (J Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Examples of compounds include, but are not limited to, compounds disclosed in U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics).TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, ritenimod, 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 lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0298] CDK inhibitors or antagonists In some embodiments, an agent described herein is combined with an inhibitor or antagonist of a CDK, hi some embodiments, the inhibitor or antagonist of a CDK is selected from the group consisting of VS2-370.

[0299] STING agonists, RIG-I and NOD2 modulators In some embodiments, an agent described herein is 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, an agent described herein is combined with a RIG-I modulator such as RGT-100, or a NOD2 modulator such as SB-9200 and IR-103.

[0300] LAG-3 and TIM-3 inhibitors In certain embodiments, the agents described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, or INCAGN-2390.

[0301] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with an anti-LAG-3 (lymphocyte activating) antibody, such as leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, or INCAGN2385.

[0302] Interleukin agonists In certain embodiments, the agents described herein are interleukin agonists, such as IL-2, IL-7, IL-15, IL-10, and IL-12 agonists; examples of IL-2 agonists include Proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214), modified variants of IL-2 (e.g., THOR-707), bempegaldesleukin, AIC-284, and ALKS-4230. Examples of IL-15 agonists include, but are not limited to, IL-15, CUI-101, Neo-2 / 15; ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 symbolin (PEGylated IL-15), P-22339, and IL-15-PD-1 fusion protein N-809; and examples of IL-7 include, but are not limited to, CYT-107.

[0303] Examples of additional immune system therapeutics 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, Gapion, Nucleoferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and RPI-MN.

[0304] Phosphatidylinositol 3-kinase (PI3K) inhibitors Examples of PI3K inhibitors include idelalisib, alpelisib, bupallisib, CAI orotate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonoliside, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and DS-742. 3, 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.

[0305] Alpha-4 / beta-7 antagonists Examples of integrin alpha-4 / beta-7 antagonists include, but are not limited to, PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0306] HPK1 inhibitors Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.

[0307] HIV targeting antibody Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies), TMB-360, TMB-370, and HIV These include, but are not limited to, antibodies targeting gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, KLIC-targeting clone 3 human monoclonal antibody (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0308] Various bNAbs can be used, including, for example, those described in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, and 10,239,935, U.S. Patent Application Publication Nos. 2018 / 371086, 2020 / 223907, WO 2014 / 063059, 2012 / 158948, and 2015 / 117008, and International Application Nos. PCT / US2015 / 41272 and WO 2017 / 096221. Examples of antibodies include, but are not limited to, 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 Klein et al., Nature, 492(7427):118-22(2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41):16538-43(2013); Scheid et al., Science, 333:1633-1637(2011); Scheid et al., Nature, 458:636-640(2009); Eroshkin et al., Nucleic Acids Res., 42(Database Issue):Dl 133-9(2014); Mascola et al., Immunol Rev., 254(l):225-44(2013), for example, 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to the V1V2-glycan), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site).

[0309] Additional broadly neutralizing antibodies that can be used as second therapeutic agents in combination therapy are described in, for example, U.S. Pat. Nos. 8,673,307, 9,493,549, and 9,783,594, and WO 2012 / 154312, 2012 / 158948, 2013 / 086533, 2013 / 142324, 2014 / 063059, 2014 / 089152, and WO 2015 / 048 Nos. 462, 2015 / 103549, 2015 / 117008, 2016 / 014484, 2016 / 154003, 2016 / 196975, 2016 / 149710, 2017 / 096221, 2017 / 133639, and 2017 / 133640, which are incorporated by reference in their entireties for all purposes. Further examples include, but are not limited to, 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 USA,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): D1 133-9 (2014), Mascola et al., Immunol Rev., 254(1): 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).

[0310] Examples of additional antibodies include 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, Cl3hmAb, GS-9722 (elipovimab), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, and 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, DR VIA7,VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC 29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E, and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34, and VRC34.Examples of suitable fluoropolymers include, but are not limited to, 01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

[0311] 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.

[0312] Examples of in vivo delivered bNAbs include, but are not limited to, AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and genetically engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301).

[0313] Pharmacokinetic enhancers Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir.

[0314] Additional therapeutic agents Examples of additional therapeutic agents include those 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), U.S. Patent Application Publication No. 2013 / 0165489 (University of

[0023] Examples of compounds disclosed in U.S. Patent Publication Nos. 2014 / 0221378 (Japan Tobacco), 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), 2010 / 130034 (Boehringer Ingelheim), 2013 / 006792 (Pharma Resources), U.S. Patent Application Publication Nos. 20140221356 (Gilead Sciences), 20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim).

[0315] HIV vaccine Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors such as Ad5, Ad26, or Ad35), simian adenovirus vaccines (chimpanzee, gorilla, rhesus macaque, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus-based vaccines, and Enterovirus-based vaccines, gorilla adenovirus vaccines, lentivirus-vectored vaccines, arenavirus vaccines (e.g., LCMV, Pichinde), two-segmented or three-segmented arenavirus-based vaccines, trimerized HIV-1 vaccines, measles virus-based vaccines, flavivirus-vectored vaccines, tobacco mosaic virus-vectored vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, avipox, etc.) ALVAC (Canarypox virus) strains derived from variola viruses; fowlpox virus-based vaccines, rhabdovirus-based vaccines, such as VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines, such as , Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128 / CVI.00298-16); LNP-formulated mRNA-based therapeutic vaccines; LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0316] Examples of 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, ChAdOx1.tHIV consv1 vaccine, CMV-MVA triple vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAX B / E (gp120), monomeric gp120 HIV-1 subtype C vaccine, MPER-656 liposomal subunit vaccine, Remune, ITV-1, and Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-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, and N123-VRC-34.01 (including epitope-based HIV vaccines), 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 Virus-like particle vaccines such as 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 pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccines, conjugate polypeptide vaccines, dendritic cell vaccines (e.g., DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, -rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI, and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980, eOD-GT8 60mer 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 immunostimulatory), HIV p24gag basal-enhanced 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 regimens include mRNA-based prophylactic vaccines, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Center), TBL-1203HI, CH505 TF chTrimer, CD40.HIVRI.Env vaccine, Drep-HIV-PT-1, mRNA-1644, and mRNA-1574.

[0317] Combined birth control (contraceptive) therapy In certain embodiments, the agents described herein are combined with birth control or contraceptive regimens. Therapeutic agents used for birth control (contraception) that can be combined with the agents of the present disclosure include, but are not limited to, cyproterone acetate, desostril, ethinyl estradiol, ethynodiol, etonogestrill, levomycin, levonorgestrel, linepolistin, misoprostrol, nomedistrol acetate, norelgestromin, norethindrone, noregestrol, norelgestromin, norethoxyfene, sedisterone acetate, and any combination thereof.

[0318] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate, TDF+FTC; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY® (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir Tenofovir; Tenofovir alafenamide and elvitegravir; Tenofovir alafenamide + elvitegravir (rectal formulation, HIV infection), Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); Dolutegravir, abacavir sulfate, and lamivudine; Raltegravir; Pegylated raltegravir; Raltegravir and lamivudine; Lamivudine + lopinavir + ritonavir + abacavir; Malategravir Viroc; tenofovir + emtricitabine + maraviroc, enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat;Atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium; efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevira in combination with one, two, three, or four additional therapeutic agents selected from: benzodiazepine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazides; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0319] In some embodiments, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In an additional embodiment, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a drug disclosed herein, or a pharmaceutical composition thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0320] In another embodiment, a drug disclosed herein or a pharmaceutical composition thereof is combined with a first additional therapeutic agent selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0321] In some embodiments, the agents disclosed herein, or pharmaceutical compositions thereof, are combined with a first additional therapeutic agent (a contraceptive) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestreno, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, norethynodrel, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof.

[0322] Gene Therapy and Cell Therapy In certain embodiments, the agents described herein are combined with gene or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches to modify cell activity to further alter endogenous immune responsiveness 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 and SB-728-HSPC. CCR5 gene inhibitors include, but are not limited to, Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy transduced autologous CD34-positive hematopoietic progenitor cells (HIV infection / HIV-associated lymphoma). In some embodiments, C34-CCR5 / C34-CXCR4-expressing CD4-positive T cells are co-administered with one or more multispecific antigen binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy.

[0323] Gene Editor In certain embodiments, the agents described herein are combined with a gene editor, such as 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 targets for the CRISPR / Cas9 system include, but are not limited to, EBT-101.

[0324] CAR-T cell therapy In some embodiments, the agents described herein are immune effector cells engineered to express a chimeric antigen receptor (CAR). The CAR can be co-administered with a population of HIV antigens, wherein the CAR comprises an HIV antigen-binding domain. The HIV antigens include an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-induced binding site on gp120, an N-glycan on gp120, V2 of gp120, and a membrane proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic. Examples of HIV CAR-Ts include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-CD4 CART cell therapy, and CD4 CAR+C34-CXCR4+CCR5 ZFN. These include 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, for HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR, and C46 peptide.

[0325] TCR-T cell therapy In certain embodiments, the agents described herein are combined with a population of TCR-T cells that are genetically engineered to target an HIV-derived peptide, e.g., ImmTAV, present on the surface of virally infected cells.

[0326] B cell therapy In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells engineered to express broadly neutralizing antibodies, such as 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019).

[0327] A compound disclosed herein (e.g., any compound of Formula I) may be combined with one, two, three, or four additional therapeutic agents in any dosage relative to the compound of Formula I (e.g., 1 mg to 500 mg of compound).

[0328] In one embodiment, a kit is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1; 2; 3; 1 or 2; or 1 to 3) additional therapeutic agents.

[0329] In one embodiment, the additional therapeutic agent or agents in the kit are 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, immunomodulatory agents, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapies (such as chimeric antigen receptor T cells, T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapies, etc.), compounds targeting the HIV capsid, latency reactivators, capsid polymerization inhibitors, HIV bNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV 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, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIVThe anti-HIV agent is selected from a POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, an HIV vaccine, and a combination thereof.

[0330] In some embodiments, the additional therapeutic agent or agents in the kit are selected from HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0331] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitor compound. In an additional embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the 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 certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside inhibitor of reverse transcriptase and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and one, two, three, or four HIV bNAbs. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor.In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, and an HIV nucleoside inhibitor of reverse transcriptase.

[0332] HIV long-acting therapy Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, islatravir implant, doravirine, raltegravir, and long-acting dolutegravir. VII. Working Examples Intermediate A: (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0333] Step 1: Synthesis of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepin-3-amine: Trifluoroacetic acid (20 mL) was added to benzyl (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (6.2 g, 15.7 mmol) and the reaction was heated to 100° C. for 4 hours. The reaction mixture was concentrated and the crude material was used directly in the next step.

[0334] Step 2: 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]diazonin-10-carboxamide: 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-azepin-3-amine (crude reaction product from previous step). At room temperature, NaHCO (13.2 g, 157 mmol) was added to the reaction mixture. The reaction was stirred at room temperature overnight and then heated to 60° C. for 5 hours. The reaction mixture was concentrated, followed by the addition of ethyl acetate and washing with saturated ammonium chloride solution. The organic layer was concentrated and purified by silica 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]diazonin-10-carboxamide. MS (m / z) 524.11 [M+H]+.

[0335] 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]diazonin-10-carboxamide: Selenium dioxide (17.4 g, 157 mmol) was added to (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]diazonin-10-carboxamide (product from the 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 solid was filtered off. The filtrate was extracted with ethyl acetate and saturated ammonium chloride solution. The organic layer was concentrated and purified by silica 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]diazonin-10-carboxamide. MS (m / z) 538.095 [M+H]+. 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]diazonin-10-carboxamide: [ka]

[0336] (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]diazonin-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 stirred, cold mixture was added a 3.0 M ethereal solution of methylmagnesium bromide (0.41 mL, 1.23 mmol). After stirring for 20 min, the reaction was quenched with saturated NH4Cl. The reaction was extracted with EtOAc, and 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]+. Synthesis of Intermediate C: (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0337] 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]diazonin-10-carboxamide: A round-bottom flask was charged with (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]diazonin-10-carboxamide (3.15 g, 5.69 mmol), followed by Fe(acac) (1.01 g, 2.85 mmol), EtOH (60 mL), PhSiH (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 (20–100% ethyl acetate in hexanes) and then a second time by reverse-phase chromatography (5%–100% acetonitrile in water buffered with 10 mM ammonium formate, pH 3.8). The corresponding fractions were combined, extracted with dichloromethane, and concentrated in vacuo to give (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 556.4 [M+H]+.

[0338] Step 2: Synthesis of (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: A round-bottom flask was charged with (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]diazonin-10-carboxamide (3.20 g, 5.76 mmol) followed by dichloromethane (90 mL). To this suspension was added martinsulfurane (8.91 g, 13.2 mmol) in two portions, and the mixture was stirred at room temperature for 1 h. The resulting solution was then concentrated in vacuo, and the residue was purified by reverse-phase chromatography (5–100% acetonitrile in water buffered with 10 mM ammonium formate, pH 3.8). The corresponding fractions were combined and lyophilized to give (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide, MS (m / z) 538.4 [M+H]. Intermediate D: (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0339] This intermediate was prepared similarly to (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate A), except that methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate was used in the second step. MS (m / z) 520.200 [M+H]. Intermediate E: (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0340] This intermediate was prepared similarly to (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate B), except that (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate D) was used. MS (m / z) 536.4 [M+H]. Intermediate F: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0341] Step 1: (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]diazonin-10-carboxamide: To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (5.90 g, 11.0 mmol, 1 equiv.) in methanol (500 mL) and CHCl (170 mL) was added platinum(IV) oxide (0.72 g, 3.17 mmol, 0.29 equiv.). The flask was evacuated and refilled with nitrogen (three times), then evacuated and refilled with hydrogen gas (three times). The reaction mixture was stirred at room temperature for 16 hours and diluted with CHCl. ​​The reaction mixture was filtered through Celite and concentrated. The residue was purified by column chromatography (0-10% MeOH / CHCl), and the product-containing fractions were pooled and concentrated. 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-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 448.26 [M+H].

[0342] 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]diazonin-10-carboxamide: To a suspension of (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-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 rt for 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0–100% EtOAc / hexanes) to give (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]diazonin-10-carboxamide, MS (m / z) 538.11 [M+H].

[0343] 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]diazonin-10-carboxamide: To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (1.258 g, 2.34 mmol, 1 equiv.) in toluene (15 mL) was added martensulfurane (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 (0–100% EtOAc / hexanes) to give (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]diazonin-10-carboxamide. MS (m / z) 520.12 [M+H]+. Intermediate G: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0344] To a suspension of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (0.525 g, 0.98 mmol) (Intermediate E) in toluene (10 mL) was added martensulfurane (1.98 g, 2.94 mmol). The reaction was 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, filtered, and concentrated. The residue was purified by silica gel column chromatography to give (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 518.23 [M+H]+. Example 1: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0345] Step 1: (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide and Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of acetaldehyde oxime (666 mg, 11.3 mmol) in DMF (50 mL), N-chlorosuccinimide (1.51 g, 11.3 mmol) was added at room temperature, followed by heating to 60° C. for 1 hour. After cooling to room temperature, (1S,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-13-methylene-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (Intermediate F) (1.58 g, 3.04 mmol) and triethylamine (1.539 g, 15.2 mmol) were added at room temperature. The reaction mixture was stirred at room temperature overnight, and then quenched by adding saturated NaHCO solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel chromatography column (eluted with 0–100% EtOAc / hexanes) to give two separate isomers: MS (m / z) 577.135 [M+H] (major), 577.115 [M+H] (minor).

[0346] 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]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (64.7 mg, 0.112 mmol) in toluene (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to give the title compound. MS (m / z) 487.12 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.53(s,1H),8.43(s,1H),7.37(td,J=8.6,6.3Hz,1H),6.92-6. 78(m,2H),4.82-4.70(m,1H),4.67(t,J=4.8Hz,2H),4.18(d,J=2.2Hz,1H),3.86(dd,J=14 .9,1.9Hz,1H),3.72(dd,J=14.9,2.7Hz,1H),2.94(d,J=17.8Hz,1H),2.53(d,J=17.7Hz,1 H),2.06(s,3H),2.04-1.88(m,3H),1.56(dd,J=14.3,11.2Hz,1H),1.32(d,J=6.6Hz,3H). Example 2: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0347] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (396 mg, 0.687 mmol), prepared according to Example 1, in toluene (5 mL) was added TFA (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to give the title compound. MS (m / z) 487.103 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.53(d,J=5.8Hz,1H),8.41(s,1H),7.38(q,J=7.8Hz,1H),6.95-6.74 (m,2H),4.83-4.69(m,1H),4.65(d,J=5.6Hz,2H),4.25(s,1H),3.77(dd,J=15.2,3.0Hz,1H),3. 44(d,J=15.2Hz,1H),3.00(d,J=16.9Hz,1H),2.83(d,J=16.9Hz,1H),2.32-2.12(m,1H),2.04(s ,3H),1.83(dd,J=15.3,7.4Hz,1H),1.75-1.58(m,1H),1.42-1.33(m,1H),1.30(d,J=6.6Hz,3H). Example 3: Preparation of (3'S,5S,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0348] Step 1: (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]diazonin]-10'-carboxamide and Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of acetaldehyde oxime (160 mg, 2.71 mmol) in DMF (5 mL), N-chlorosuccinimide (90.5 mg, 0.68 mmol) was added at room temperature, followed by heating to 60° C. for 1 hour. After cooling to room temperature, (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate C) (119 mg, 0.221 mmol) and triethylamine (112 mg, 1.1 mmol) were added at room temperature. The reaction mixture was stirred at room temperature overnight, and then quenched by adding saturated NaHCO solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel chromatography column (eluted with 0–100% EtOAc / hexanes) to give two separate isomers: MS (m / z) 595.06 [M+H] (major), 595.09 [M+H] (minor).

[0349] Step 2: Preparation of (3'S,5S,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-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 eluting with 10-90% acetonitrile in water to give the title compound. MS (m / z) 505.129 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.51-10.41(m,1H),8.40(s,1H),6.70(dd,J=8.7,7.5 Hz,2H),4.71(ddd,J=17.6,11.2,5.9Hz,3H),4.13(d,J=2.6Hz,1H),3.86(dd,J= 14.9,1.8Hz,1H),3.70(dd,J=14.9,2.7Hz,1H),2.93(d,J=17.8Hz,1H),2.52(d, J=17.8Hz,1H),2.13-1.89(m,6H),1.57(d,J=10.9Hz,1H),1.31(d,J=6.6Hz,3H). Example 4: Preparation of (3'S,5R,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0350] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (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 overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to give the title compound. MS (m / z) 505.142 [M+H] + . 1 H 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=16.9Hz,1H),2.81(d,J=16.9Hz,1H),2.27-2.17(m,1H),2.06(s,3H),1.82(dd ,J=15.3,7.4Hz,1H),1.74-1.63(m,1H),1.40-1.32(m,1H),1.30(d,J=6.6Hz,3H). Example 5: Preparation of (3'S,4'S,5R,7'R)-N-(2,4-difluorobenzyl)-4'-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0351] Step 1: Preparation of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: To a suspension of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate E) (0.525 g, 0.98 mmol) in toluene (10 mL) was added martensulfurane (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 removing the solvent in vacuo, the residue was purified by silica gel chromatography to give the title compound. MS (m / z) 518.23 [M+H]+.

[0352] Step 2: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (0.335 g, 0.647 mmol) in DMF (2 mL) was added (1Z)-N-hydroxyacetimidoyl chloride (0.303 g, 3.24 mmol), followed by triethylamine (0.655 g, 6.47 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with HO, 5% LiCl (aq), and brine. The organic phase was dried over MgSO. After the solvent was removed in vacuo, the residue was purified by silica gel chromatography to give the title compound. MS(m / z) 575.58 [M+H]+.

[0353] Step 3: Preparation of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-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 O2 (g) for 24 h. The reaction was quenched by adding 10% sodium thiosulfate and then extracted with EtOAc. The organic phase was washed with H2O, brine, and dried over MgSO4. After removing the solvent in vacuo, the residue was purified by silica gel chromatography to give the title compound. MS (m / z) 593.05 [M+H]+.

[0354] Step 4: Preparation of (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (60 mg, 0.101 mmol) in DCM (2 mL) was added a solution of dexofluorin in toluene (50%, 0.375 mL, 1.01 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes, and the reaction was quenched by the addition of saturated NaHCO solution. The mixture was extracted with DCM, and the organic phase was separated, dried over MgSO, 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].

[0355] Step 5: Preparation of (3'S,4'S,5R,7'R)-N-(2,4-difluorobenzyl)-4'-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (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(400MHz,chloroform-d)δ10.24(t,J=5.9Hz,1H),8.23(s,1H),7.39(td,J=8.6, 8.2,6.2Hz,1H),6.91-6.57(m,2H),5.03(dt,J=46.9,5.7Hz,1H),4.93-4.78(m ,1H),4.76-4.52(m,2H),4.26(dd,J=17.1,2.7Hz,2H),3.81(d,J=14.4Hz,1H), 2.84-2.65(m,3H),2.14(s,3H),2.03-1.82(m,1H),1.48(dd,J=7.1,2.3Hz,3H). Example 6: Preparation of (3'S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0356] Step 1: Preparation of tert-butyl ((3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carbonyl)(2,4-difluorobenzyl)carbamate: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (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 hours. After cooling to room temperature, the reaction was quenched by adding saturated NaHCO solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel column chromatography (eluting with 30-100% EtOAc / hexanes) to give the title compound. MS (m / z) 676.924 [M+H].

[0357] Step 2: 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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxylic acid: To a solution of tert-butyl ((3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carbonyl)(2,4-difluorobenzyl)carbamate (590 mg, 0.872 mmol) in MeOH (10 mL) was added 1N NaOH solution (3 mL) at room temperature. After 1 hour at room temperature, the reaction was quenched by adding 1N HCl solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO4, filtered, and concentrated to give the crude title compound, which was used without purification. MS(m / z) 452.127[M+H] +.

[0358] Step 3: 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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-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 h at room temperature, the reaction was quenched by adding saturated NaHCO solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel chromatography column (eluted with 50-100% EtOAc / hexanes) to give the title compound. MS (m / z) 611.075 [M+H].

[0359] Step 4: Preparation of (3'S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (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 10-90% 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=14.9,1.9Hz,1H),3.71(dd,J=14.9,2.7Hz,1H),2.93(d,J=17.7Hz,1H),2.59-2. 49(m,1H),2.15-1.92(m,6H),1.56(dd,J=14.2,11.2Hz,1H),1.32(d,J=6.6Hz,3H). Example 7: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-isopropyl-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0360] (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-isopropyl-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was prepared in a manner similar to that described in Example 1, except that isobutyraldehyde oxime was used in step 1. MS (m / z) 515.152 [M+H] + . 1 H 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 Hz) ,3.0Hz,1H),3.49-3.42(m,1H),3.01(d,J=16.8Hz,1H),2.83-2.71(m,2H),2.24(d,J=7 .7Hz,1H),1.86-1.81(m,2H),1.70(s,1H),1.31(d,J=6.5Hz,3H),1.23(d,J=6.9Hz,6H). Example 8: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-ethyl-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0361] The title compound was prepared in a similar manner to Example 1, except that propanal oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 501.2 [M+H]+. 1H NMR(400MHz,chloroform-d)δ10.76(s,1H),8.61(s,1H),7.38(t,J=8.0Hz,1H),6.88(m,2H),4.74-4.53(m,5H),3.76(d,J=14.7Hz,1H),3. 56(d,J=14.8Hz,1H),2.75(d,J=16.7Hz,1H),2.47(d,J=16.8Hz,1H),1.97-1.50(m,7H),1.45(t,J=12.7Hz,1H),1.31(d,J=6.6Hz,3H). Example 9: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-(2,2,2-trifluoroethyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0362] The title compound was prepared in a manner similar to Example 3, except that 3,3,3-trifluoropropanal oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 573.09 [M+H]. 1H NMR (400 MHz, chloroform-d) δ 10.55 (t, J = 5.8 Hz, 1H), 8.55 (s, 1H), 6.76-6.64 (m, 2H), 4.83-4.68 (m, 2H), 4.66 (dd, J = 14.6, 5.6 Hz, 1H), 4.26 (d, J = 2.2 Hz, 1H), 3.86 (dd, J = 15.0 ,1.8Hz,1H),3.74(dd,J=15.0,2.6Hz,1H),3.47-3.17(m,2H),3.11(d,J=18.0Hz,1H) ,2.65(d,J=18.0Hz,1H),2.15-1.90(m,3H),1.63-1.50(m,1H),1.33(d,J=6.6Hz,3H). Example 10: Preparation of (3'S,5S,7'R)-3-(4-chlorobutyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0363] The title compound was prepared in a manner similar to Example 3, except that 5-bromopentanal oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 581.223 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.35(t,J=5.7Hz,1H),8.33(s,1H),6.77-6.62(m,2H),4.70(td,J=12. 4,10.4,5.9Hz,3H),4.08(s,1H),3.85(dd,J=14.9,1.8Hz,1H),3.76-3.66(m,1H),3.61(td,J=6. 3,2.4Hz,2H),2.91(d,J=17.7Hz,1H),2.57(s,1H),2.53(s,1H),2.49-2.41(m,2H),1.99(dd,J=1 5.9,9.1Hz,2H),1.95-1.83(m,2H),1.83-1.73(m,2H),1.62-1.52(m,1H),1.31(d,J=6.6Hz,3H). 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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0364] The title compound was prepared in a manner similar to Example 1, except that benzaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 549.127 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.44(t,J=5.9Hz,1H),8.48(s,1H),7.68-7.56(m,2H),7.52-7.39(m,3H) ,7.37(d,J=6.4Hz,1H),6.91-6.76(m,2H),4.80(d,J=6.7Hz,1H),4.65(dd,J=12.1,5.9Hz,2H),4.3 2(d,J=2.3Hz,1H),3.93(dd,J=14.9,1.9Hz,1H),3.76(dd,J=14.9,2.7Hz,1H),3.38(d,J=17.2Hz,1 H),2.94(d,J=17.2Hz,1H),2.20-1.96(m,3H),1.64(dd,J=14.7,11.5Hz,1H),1.35(d,J=6.6Hz,3H). Example 12: Preparation of (3'S,5S,7'R)-3-benzyl-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0365] The title compound was prepared in a manner similar to Example 1, except that 2-phenylacetaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 563.165 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.45(t,J=5.9Hz,1H),8.36(s,1H),7.39(d,J=6.4Hz,1H),7.36-7.30(m,2H),7.27(s ,1H),7.20(dd,J=6.9,1.7Hz,2H),6.95-6.75(m,2H),4.68(d,J=6.0Hz,3H),4.18(s,1H),3.93(d,J=15.1Hz,1H) ,3.84(dd,J=14.9,1.9Hz,1H),3.70(dd,J=14.9,2.7Hz,1H),3.56(d,J=15.1Hz,1H),2.85(d,J=17.6Hz,1H),2. 35(d,J=17.6Hz,1H),2.11-1.89(m,2H),1.80(dd,J=15.6,6.4Hz,1H),1.48-1.35(m,1H),1.31(d,J=6.7Hz,3H). Example 13: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-(pyridin-2-yl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0366] The title compound was prepared in a manner similar to Example 1, except that N-hydroxypicolinimidoyl chloride was used instead of N-hydroxyacetimidoyl chloride in step 1. MS (m / z) 550.177 [M+H] + . 1H 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=5.1Hz,1H),4.26(s,1H),3.80(dd,J=15.3,3.1Hz,1H),3.56(d,J=3.5Hz,2H),2.36-2.26 (m,3H),1.95(dd,J=15.2,7.3Hz,1H),1.81(dd,J=15.1,11.8Hz,1H),1.52(s,1H),1.34(d,J=6.6Hz,3H). 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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0367] The title compound was prepared in a manner similar to Example 1, except that N-hydroxynicotinimidoyl chloride was used instead of N-hydroxyacetimidoyl chloride in step 1. MS (m / z) 550.191 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.41(t,J=5.9Hz,1H),8.95-8.90(m,1H),8.77(dd,J=5.1,1.6Hz,1H),8.46(s, 1H),8.25(dd,J=8.1,1.8Hz,1H),7.63(dd,J=8.1,5.1Hz,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=14.9,1.9Hz,1H),3.78(dd,J=15.0,2.7Hz,1H),3 .43(d,J=17.3Hz,1H),2.99(d,J=17.3Hz,1H),2.05(s,2H),1.70(d,J=14.8Hz,2H),1.36(d,J=6.7Hz,3H). Example 15: Preparation of (3'S,5S,7'R)-3-cyclopropyl-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0368] The title compound was prepared in a manner similar to Example 1, except that cyclopropanecarbaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 513.16 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 10.43 (s, 1H), 8.35 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 6.83 (q, J = 10.0, 9.6 Hz, 2H), 4.83-4.71 (m, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.07 (s, 1H), 3.77 (d, J = 15.8 Hz, 1H), 3.42 (d, J = 15. 1Hz,1H),2.89(d,J=16.6Hz,1H),2.63(d,J=16.6Hz,1H),2.22(dd,J=15.0,7.2Hz,2H),1.81(d,J=7 .7Hz,2H),1.70(d,J=11.8Hz,1H),1.30(d,J=6.4Hz,3H),1.00(d,J=8.3Hz,2H),0.88-0.77(m,2H). Example 16: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0369] The title compound was prepared in a manner similar to that of Example 1, except that 2-((tert-butyldimethylsilyl)oxy)acetaldehyde oxime was used instead of acetaldehyde oxime in Step 1. MS (m / z) 503.154 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.63(d,J=6.0Hz,1H),8.62(s,1H),7.44-7.32(m,1H),6. 91-6.71(m,2H),4.73(dd,J=14.8,6.5Hz,2H),4.65-4.49(m,2H),4.37(d,J=13.9Hz, 1H),4.28(s,1H),3.87-3.78(m,1H),3.66(d,J=2.7Hz,1H),3.14(d,J=17.9Hz,1H), 2.67(d,J=17.9Hz,1H),2.12-1.96(m,3H),1.78-1.65(m,1H),1.32(d,J=6.7Hz,3H). Example 17: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0370] Step 1: Preparation of (E)-2-((tert-butyldiphenylsilyl)oxy)acetaldehyde oxime: To a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetaldehyde (1 g, 3.35 mmol) in MeOH (15 mL) and HO (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. It was diluted with EtOAc and washed with HO and brine. The organic phase was dried over MgSO and the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography to give the title compound. MS (m / z) 314.05 [M+H].

[0371] 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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide and Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared in a manner similar to Example 1, except that (E)-2-((tert-butyldiphenylsilyl)oxy)acetaldehyde oxime was used instead of acetaldehyde oxime. (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was obtained as the major stereoisomer. (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was obtained as the minor stereoisomer. MS (m / z) 831.12 [M+H] (major), 831.13 [M+H] (minor).

[0372] Step 3: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (160 mg, 0.193 mmol) in THF (2 mL) was added TBAF (1N) (0.578 mL, 0.578 mmol). The reaction mixture was stirred at room temperature for 1 h. It was diluted with EtOAc and washed with NaHCO3 (sat.) and brine. The organic phase was dried over MgSO4, and the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography to give the title compound: MS (m / z) 593.07 [M+H]+.

[0373] Step 4: 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,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared by the procedure described above using (3'S,5S, 4'R, 5R, 7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,5S, Prepared in a similar manner as in step 4 of Example 5, except using 7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 595.09 [M+H]+.

[0374] Step 5: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared by the procedure 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]diazonin]-10'-carboxamide instead of (3'S,5S,7'R)-1 Prepared in a similar manner as in Step 2 of Example 1, except using 2'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 505.18 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ 10.49 (t, J = 6.0 Hz, 1H), 8.50 (s, 1H), 7.38 (td, J = 8.6, 6.4 Hz, 1H), 6.91-6.78 (m, 2H), 5.32 (s, 1H), 5.23 (s, 1H), 5.11 (s, 1H), 4.83-4.58 (m, 2H), 4.22 (s, 1H) ,3.87(dd,J=15.0,1.8Hz,1H),3.74(dd,J=15.0,2.6Hz,1H),3.13(dd,J=18.0,2.1Hz,1H), 2.71(dd,J=17.9,2.4Hz,1H),2.14-1.97(m,3H),1.68-1.57(m,1H),1.33(d,J=6.7Hz,3H). Example 18: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0375] The title compound was prepared in Step 3 by the reaction of (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide with (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. Prepared in the same manner as (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide in Example 17, except that 3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS (m / z) 505.18 [M+H]+. 1H NMR (400MHz, 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=15.3,3.1Hz,1H),3.51-3.42(m,1H),3.17(d,J=16.8Hz,1H),3.02(d,J=17.2Hz,1H) ,2.26(dt,J=14.7,7.0Hz,1H),1.88(dd,J=15.2,7.4Hz,1H),1.80-1.69(m,1H),1.46-1.25(m,4H). Example 19: Preparation of (3'S,5S,7'R)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0376] The title compound was prepared in Step 2 by substituting (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate F) with (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate F). Prepared similarly to (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide in Example 17, except for using H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate C). MS (m / z) 523.21 [M+H]+. 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=15.0,1.9Hz,1H),3.73(dd,J=15.0,2.7Hz,1H),3.23-3.05(m,1H),2.7 0(dd,J=17.8,2.3Hz,1H),2.09-1.89(m,3H),1.72-1.51(m,1H),1.33(d,J=6.7Hz,3H). Example 20: Preparation of (3'S,5S,7'R)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0377] Step 1: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-3-formyl-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a mixture of DMSO (0.215 mL, 3.03 mmol) in DCM (2 mL) at −78° C., oxalyl chloride (0.118 mL, 1.39 mmol) was added dropwise. The mixture was stirred at −78° C. for 10 minutes, and then (3′S,5S,7′R)-12′-(benzyloxy)-3-(hydroxymethyl)-3′-methyl-1′,11′-dioxo-N-(2,4,6-trifluorobenzyl)-1′,4′,5′,11′-tetrahydro-3′H,4H,7′H-spiro[isoxazole-5,6′-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10′-carboxamide (370 mg, 0.606 mmol) prepared according to Example 19 in DCM (2 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 15 minutes. Triethylamine (0.426 mL, 3.03 mmol) was added to the reaction mixture, and the cold bath was removed. The reaction mixture was stirred at room temperature for 30 minutes. EtOAc was added to dilute the reaction mixture, followed by the addition of H2O and brine. The organic phase was dried over MgSO4, and the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography to give the title compound. MS (m / z) 609.09 [M+H]+.

[0378] Step 2: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-3-(difluoromethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared by the procedure described above using (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S, Prepared as in step 4 of Example 5, except using 5S,7'R)-12'-(benzyloxy)-3-formyl-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 631.13 [M+H]+.

[0379] Step 3: Preparation of (3'S,5S,7'R)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared by the procedure described above using (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,5S,7' Prepared in a manner similar to step 5 of Example 5, except using R)-12'-(benzyloxy)-3-(difluoromethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 541.21 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.55 (t, J = 5.9 Hz, 1H), 8.95 (s, 1H), 6.68 (t, J = 8.1 Hz, 2H), 6.57-6.30 (m, 1H), 4.89-4.73 (m, 3H), 4.50 (dd, J = 14.7, 4.9 Hz, 1H), 3.87 (dd, J = 15.1, 1.8 Hz,1H),3.78(dd,J=15.0,2.5Hz,1H),3.22(d,J=17.9Hz,1H),2.66(d,J=17.8Hz,1H),2 .02(dq,J=20.9,8.3,6.4Hz,3H),1.62(dd,J=13.9,11.0Hz,1H),1.34(d,J=6.6Hz,3H). Example 21: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0380] The title compound was prepared in step 1 by the addition of (3'S,5S,7'R)-12'-(benzyloxy)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3' Prepared in a similar manner as in Example 20 except using (S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 523.10 [M+H]+. 1H NMR (400MHz, chloroform-d) δ10.59(t,J=5.8Hz,1H),8.85(s,1H),7.36(q,J=8.1Hz, 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=15.0,1.7Hz,1H),3.77(dd,J=15.0,2.5Hz,1H),3.19(d,J=17.9Hz,1H),2.7 1(d,J=17.9Hz,1H),2.16-1.96(m,3H),1.70-1.58(m,1H),1.34(d,J=6.6Hz,3H). Example 22: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0381] Step 1: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared in a similar manner to steps 1-2 of Example 17, except that (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]diazonin-10-carboxamide (Intermediate G) was used instead of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate F). MS(m / z) 829.12 [M+H]+.

[0382] Step 2: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared by the procedure of (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,5 Prepared in a similar manner to step 3 of Example 17, except using R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 591.13 [M+H]+.

[0383] Step 3: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (41 mg, 0.0694 mmol) in DMF (2 mL) was added NaH (60% in mineral oil) (5.4 mg, 0.14 mmol) followed by MeI (0.004 mL, 0.0694 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with HO and brine. The organic phase was dried over MgSO and the solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography to give the title compound: MS (m / z) 605.09 [M+H]+.

[0384] Step 4: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: A mixture of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (27 mg, 0.045 mmol) and 10% Pd / C (3.8 mg) in EtOH (2 mL) was stirred at room temperature under 1 atmosphere of H2(g). After 2 h, the reaction mixture was filtered, concentrated, and purified by reverse-phase preparative HPLC (5-100% MeCN / water with 0.1% TFA) to give the title compound. MS (m / z) 517.19 [M+H]+. 1H NMR (400MHz, chloroform-d) δ 10.37 (s, 1H), 8.39 (s, 1H), 7.39 (q, J = 8.2, 7.6Hz, 1H), 6.84 (q, J = 8.1, 7.6Hz, 2H), 4.80-4.59 (m, 2H), 4.25 (d, J = 12.3Hz, 1H), 4.19 (d, J = 12.3Hz, 1H), 4.10 (s,1H),3.91-3.82(m,1H),3.70(dd,J=14.8,2.7Hz,1H),3.45(s,3H),3.03(d,J=17.9Hz, 1H), 2.65(d,J=17.9Hz,1H),2.12-1.95(m,3H),1.69-1.58(m,2H),1.32(d,J=6.7Hz,3H). Example 23: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0385] Step 1: (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide and ( Preparation of 3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide:

[0386] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (43 mg, 0.075 mmol) prepared according to Example 1 in THF (10 mL) was added a 1 M solution of LiHMDS in THF (0.373 mL) at -78°C. After 30 minutes, a solution of MeI in THF (12.7 mg in 2 mL) was added at -78°C, followed by warming to -20°C. After 2 h, the reaction was quenched by adding saturated NH4Cl solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography column (eluted with 0-5% MeOH / EtOAc) to give the title compound. MS (m / z) 591.138 [M+H]+, and MS (m / z) 593.189 [M+H]+.

[0387] Step 2: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: 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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (14 mg, 0.024 mmol) in toluene (1 mL) was added TFA (0.3 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% 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=7.1Hz,1H),2.31-2.20(m,1H),2.08(s,3H),1.99(dd,J=15.6,7.9Hz,1H),1.5 8(dd,J=15.6,11.6Hz,1H),1.47-1.35(m,1H),1.31(d,J=6.6Hz,3H),1.21(d,J=7.1Hz,3H). Example 24: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0388] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (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 overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to give the title compound. MS (m / z) 503.265 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.91(s,1H),8.33(s,1H),7.32(d,J=6.8Hz,1H),6.92-6.77(m,2H),4.89(s,1H),4.80(s,1H),4.72(d ,J=7.1Hz,1H),4.62(td,J=13.3,11.4,5.8Hz,2H),3.70-3.51(m,2H),2.10(d,J=7.1Hz,4H),1.66(s,3H),1.30(d,J=6.6Hz,3H). Example 25: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0389] Step 1: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (9 mg, 0.0152 mmol) prepared according to Example 23 in DCM (3 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane) (10 mg, 0.023 mmol) at room temperature. The reaction was quenched by adding saturated NaHCO3 and Na2SO3 solutions. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 50-100% EtOAc / hexane) to give the title compound. MS (m / z) 590.906 [M+H]+.

[0390] Step 2: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (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 10-90% acetonitrile in water to give the title compound. MS (m / z) 500.995 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ10.42(s,1H),8.37(s,1H),7.38(q,J=8.1Hz,1H),6.84(q,J=9.1,8.6Hz,2H),4.81(s,1H),4.65(d,J=5.8Hz,1H),4.1 3-3.99(m,2H),3.74(dd,J=15.3,2.8Hz,1H),2.19(s,3H),2.12(d,J=15 .4Hz,1H),1.94-1.85(m,3H),1.66-1.59(m,1H),1.38(d,J=6.7Hz,3H). Example 26: Preparation of (3'S,4S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0391] In step 2, (3'S,4S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was reacted with (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H, Prepared in a manner similar to Example 23, except that (3'S,4S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was used instead of 4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 501.193 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.47(s,1H),8.40(s,1H),7.47-7.34(m,1H),6.9 3-6.75(m,2H),4.69(dt,J=14.6,6.8Hz,3H),4.18(s,1H),3.85(dd,J=14.9 ,1.9Hz,1H),3.76-3.61(m,1H),3.18(d,J=7.3Hz,1H),2.12-1.87(m,6H),1 .32(d,J=6.7Hz,3H),1.23(dd,J=14.5,11.1Hz,1H),0.82(d,J=7.3Hz,3H). Example 27: (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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (Peak 1) and preparation of (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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (peak 2): [ka]

[0392] Step 1: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (82 mg, 0.138 mmol) prepared according to Example 26 in DCM (4 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (153 mg, 0.692 mmol) at 0° C. After 30 min, the reaction was quenched by adding saturated NaHCO solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel chromatography column (eluted with 0-100% EtOAc / hexanes) to give the title compound as a mixture of stereoisomers. MS (m / z) 595.046

[0393] Step 2: Preparation of (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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (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 isolated and purified by reverse-phase preparative HPLC eluting with 10-90% acetonitrile in water to give the title compound. Peak 1: MS (m / z) 505.173 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.33(d,J=5.9Hz,1H),8.61(d,J=6.2Hz,1H),7.44-7.33(m,1H),6.83(q,J=7.9Hz,2H),5.03(d,J=53.7Hz,1H),4.84(d,J=10). 5Hz,1H),4.75-4.54(m,3H),3.81(dd,J=4.2,2.3Hz,2H),2.18(d,J=3.3Hz, 3H),2.09-1.98(m,3H),1.54(dd,J=15.8,6.2Hz,1H),1.33(d,J=6.7Hz,3H).

[0394] Peak 2: MS (m / z) 505.154 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.50(d,J=5.9Hz,1H),8.33(s,1H),7.38(q,J=8.4,8.0Hz,1 H),6.92-6.78(m,2H),5.34(d,J=53.8Hz,1H),4.85-4.59(m,3H),3.93(dd,J=14.9,1. 8Hz,1H),3.87(s,1H),3.75(d,J=14.7Hz,1H),2.21(d,J=2.5Hz,3H),2.19-2.15(m,1H ),2.12(d,J=7.0Hz,1H),2.06-1.99(m,1H),1.53-1.44(m,1H),1.35(d,J=6.6Hz,3H). Example 28: Preparation of (3'S,4S,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0395] The title compound was prepared according to Example 26, substituting (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. Prepared in a manner similar to Example 24, except using (S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 503.299 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ11.60(s,1H),9.95-9.84(m,1H),8.33(s,1H),7.40(q,J=8.3,7. 8Hz,1H),6.86(dt,J=10.2,6.9Hz,2H),5.16(s,1H),4.86(td,J=14.8,7.2Hz,2H),4.40(d d,J=14.9,3.9Hz,1H),3.98-3.84(m,2H),3.66(dd,J=14.6,2.7Hz,1H),2.29(dd,J=16.4, 6.3Hz,1H),2.10(s,3H),2.08-1.94(m,2H),1.31(d,J=6.6Hz,3H),0.93(q,J=7.5Hz,1H). Example 29: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0396] The title compound was prepared according to Example 26, substituting (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. Prepared in a manner similar to Example 25, except using (S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 500.97 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ10.46(s,1H),8.13(s,1H),7.42-7.33(m,1H),6.84(q,J=9.4,8.7Hz,2H),4.81(dd,J=11.3,6.1Hz,1H),4.73(dd,J=15.4,6. 2Hz,1H),4.55(dd,J=15.4,5.4Hz,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=5.1Hz,2H),1.37(d,J=6.6Hz,3H). Example 30: Preparation of (3'S,4R,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0397] 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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (Peak 1) Preparation of (3'S,4R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (peak 2): To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (25 mg, 0.0423 mmol) prepared according to Example 29 in DCM (3 mL) was added sodium borohydride (2.4 mg, 0.064 mmol) at room temperature. After completion, the reaction was quenched by adding saturated NaHCO solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel column chromatography (eluting with 20-100% EtOAc / hexanes) to give the title compounds as peak 1 and peak 2. MS (m / z) 593.101 [M+H].

[0398] Step 2: Preparation of (3'S,4R,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared by the procedure described above using (3'S,4R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,4R,5R,7'R) Prepared in a manner similar to Example 24, except using -12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (peak 2 from step 1). MS (m / z) 503.231 [M+H] + . 1 H 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=14.6Hz,1H),3.70-3.61(m,1H),2.11(d,J=5.1Hz,3H),2.01(s,1 H),1.70(s,1H),1.64-1.56(m,1H),1.45(d,J=11.8Hz,1H),1.31(dd,J=6.7,2.3Hz,3H). Example 31: Preparation of (3'S,4S,5R,7'R)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0399] Step 1: Preparation of (3'S,4S,5R,7'R)-12'-(benzyloxy)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (204 mg, 0.343 mmol) prepared according to Example 3 in THF (10 mL) was added a 1N solution of LiHMDS in THF (1.2 mL, 1.2 mmol) under air at -40°C. After 30 minutes, a solution of MeI in THF (73 mg, 0.515 mmol) was added at -40°C, followed by warming to -20°C over 2 hours. The reaction was quenched by adding saturated NH4Cl solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluted with 10-80% EtOAc / hexane) to give the title compound. MS (m / z) 611.058 [M+H]+.

[0400] Step 2: Preparation of (3'S,4S,5R,7'R)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,4S,5R,7'R)-12'-(benzyloxy)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (75 mg, 0.123 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 isolated and purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to give the title compound. MS (m / z) 521.234 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ 11.60 (s, 1H), 10.11-9.97 (m, 1H), 8.40 (s, 1H), 6.69 (t, J = 8.1 Hz, 2H), 5.32 (s, 1H), 5.23 (s, 1H), 5.01 (dd, J = 14.5, 8.1 Hz, 1H), 4.89-4.77 (m, 1H), 4.37 (dd, J = 14.6, 3.0). 8Hz,1H),3.94(s,1H),3.93-3.84(m,1H),3.65(dd,J=14.8,2.7Hz,1H),2.30(dd,J=16.4,6.3Hz ,1H),2.19(s,3H),2.06(d,J=8.2Hz,1H),1.64(dd,J=16.5,11.2Hz,1H),1.31(d,J=6.6Hz,3H). Example 32: Preparation of (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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0401] Step 1: Preparation of (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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluoro-6-methylbenzyl)-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]diazonin]-10'-carboxamide (35 mg, 0.059 mmol) prepared according to Example 3 and N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (22.5 mg, 0.072 mmol) in THF (10 mL) was added a 1 M solution of LiHMDS in THF (0.15 mL) at -78°C. After 30 minutes, the reaction was allowed to warm to room temperature. The reaction was then quenched by the addition of saturated NH4Cl solution. The mixture was extracted with EtOAc, and the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluted with 0-80% EtOAc / hexane) to give the title compound. MS (m / z) 613.029 [M+H]+.

[0402] Step 2: Preparation of (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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (99 mg, 0.162 mmol) in toluene (3 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 10-90% acetonitrile in water to give the title compound. MS (m / z) 523.181 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.49(d,J=5.9Hz,1H),8.44(s,1H),6.70(t,J=8.1Hz,2H) ,5.38(d,J=53.9Hz,1H),4.83-4.70(m,2H),4.63(dd,J=14.6,5.6Hz,1H),3.98(s,1 H),3.92(dd,J=15.0,1.8Hz,1H),3.80-3.72(m,1H),2.18(d,J=2.3Hz,3H),2.16-2. 06(m,2H),2.06-1.94(m,1H),1.45(dd,J=15.2,11.7Hz,1H),1.34(d,J=6.7Hz,3H). Example 33: Preparation of (3'S,4R,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]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0403] The title compound was prepared according to Example 31, substituting (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. Prepared in a manner similar to Example 27, except using 4S,5R,7'R)-12'-(benzyloxy)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 523.135 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ10.30(s,1H),8.61(d,J=6.2Hz,1H),6.76-6.63(m,2H),5.04(d,J=53.7Hz,1H),4.88-4.78(m,1H),4.78-4.70(m,1H) ),4.63(q,J=9.0,7.3Hz,2H),3.80(dd,J=4.6,2.3Hz,2H),2.18(d,J=3.3Hz,3H),2.13-1.92(m,3H),1.58-1.49(m,1H),1.33(d,J=6.8Hz,3H). Example 34: Preparation of (3'S,4S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0404] The title compound was prepared according to Example 6, substituting (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]diazonin]-10'-carboxamide (3'S, Prepared in a manner similar to Example 23, except using 5S,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 535.208 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 10.48 (s, 1H), 8.36 (s, 1H), 7.34-7.30 (m, 1H), 6.96 (t, J = 8.6 Hz, 1H), 4.75-4.67 (m, 2H), 4.16 (s, 1H), 3.86 (d, J = 15.0 Hz, 1H), 3.71 (d, J = 2.7H) z,1H),3.17(d,J=7.4Hz,1H),2.09(d,J=8.4Hz,1H),2.01(d,J=1.0Hz,3H),1.98(d, J=7.2Hz,3H),1.32(d,J=6.6Hz,3H),1.25(d,J=12.3Hz,1H),0.82(d,J=7.3Hz,3H). Example 35: Preparation of (3'S,4S,5R,7'R)-N-(3-chloro-2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0405] The title compound was prepared according to Example 34, substituting (3'S,4 Prepared in a manner similar to Example 24, except using (S,5R,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 537.085 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.00(s,1H),8.34(s,1H),7.30-7.25(m,1H),6.97(t ,J=8.2Hz,1H),5.18(s,1H),4.85(dd,J=14.6,7.4Hz,2H),4.47-4.36(m,1H),3 .96(s,1H),3.94-3.87(m,1H),3.67(d,J=14.5Hz,1H),2.29(dd,J=16.2,5.8Hz ,1H),2.14(s,3H),2.03(s,2H),1.64(d,J=15.0Hz,1H),1.32(d,J=6.6Hz,3H). Example 36: Preparation of (3'S,5S,7'R)-12'-hydroxy-3-methoxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide [ka]

[0406] Step 1: (3'S,5S,7'R)-12'-(benzyloxy)-3-bromo-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluo...

Claims

1. Compound of formula (I-A): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, R1 is a 5-10 membered heteroaryl compound containing 1, 2, 3, or 4 heteroatoms independently selected from H, C6-10 aryls, or N, O, and S. The C6-10 aryl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 R A1, each R A1 independently being halo, C1-6 alkyl, C1-4 haloalkyl, cyano, -O-C1-4 alkyl, or C1-4 alkyl-O-C1-4 alkyl. R2 is H, C1-6 alkyl, or C1-4 haloalkyl. L is -CR 3a R 3b-, -C(O)-, -SO 2-, -CH 2-CH 2-, or -N(Ra)-, W1 is a bond or -CR 4a R 4b-, W 2 is -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -C(O)O-, -C(O)NH-, -CR 5a R 5b -N(R 7 )-, -CR 5a R 5b -O-, -CR 5a R 5b -S(O) n -, -CR 5a R 5b -C(O)-, -CR 5a R 5b -C(O)O-, -CR 5a R 5b -OC(O)-, -CR 5a R 5b -C(O)NH- or -CR 5a R 5b -NHC(O)-, Y is -C(O)NH-, 【Chemistry 2】 And, Z is -CR 9a R 9b-, -CR 9a R 9b CR 9c R 9d-, or -CR 10a = CR 10b-, R3a and R3b are independently H, C1-6 alkyl, C1-4 haloalkyl, or -O-C1-4 alkyl, or R3a and R3b, together with the carbon atoms to which they are bonded, 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 1, 2, or 3 R A2, each R A2 independently being a halo, C1-4 alkyl, or C1-4 haloalkyl. R 4a and R 4b are independently H, C1-6 alkyl, C1-4 haloalkyl, or halo. R 5a, R 5b, R 5c, and R 5d are independently H, C1-6 alkyl, C1-4 haloalkyl, halo, hydroxyl, cyano, -O-C1-4 alkyl, or C1-4 alkylene-O-C1-4 alkyl, or R 5a and R 5b or R 5c and R 5d, together with the carbon atoms to which they are bonded, 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 1, 2, or 3 R A3, each R A3 independently being a halo, C 1-4 alkyl, or C 1-4 haloalkyl, or R 5a and R 5c or R 5b and R 5d, together with the carbon atoms to which they are bonded, form a 3- to 7-membered condensed ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the condensed ring is optionally substituted with 1 to 3 R A3, each R A3 independently being a halo, C 1-4 alkyl, or C 1-4 haloalkyl. Each R 6a and R 6b is independently H, halo, C1-4 haloalkyl, or C1-6 alkyl, R 6a and R 6b, together with the carbon atoms to which they are bonded, form a 5-10 member partially unsaturated condensed ring or a 5-10 member condensed aromatic ring containing 0 or 1 heteroatom selected from N, O, and S, or a 5-10 member condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the partially unsaturated condensed ring, condensed aromatic ring, or condensed heteroaromatic ring is optionally substituted with 1, 2, 3, or 4 R A4, each R A4 independently being a halo or C 1-4 alkyl group. R7 is H, C1-6 alkyl, C1-4 haloalkyl, C(O)Rc, or SO2Rc. m is 0, 1, 2, or 3. Each R8 independently produces Cl, F, Br, oxo, methyl, ethyl, CH₂Ph, CH₂OH, CH₂OMe, NHMe, NMe₂, OH, OMe, OCH₂CF₃, OCH₂CHF₂, SMe, CH₂F, CHF₂, CH₂CF₃, CH₂CH₂F, CH(CH₃)F, CF₂CH₃, CF₃, 【Transformation 3】 And, R9a, R9b, R9c, and R9d are each independently H, C1-6 alkyl, C1-4 haloalkyl, or halo, R9a and R9b or R9c and R9d, together with the carbon atoms to which they are bonded, 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 1, 2, or 3 R A9, each R A9 independently being a halo, C1-4 alkyl, or C1-4 haloalkyl, or R9a and R9c or R9b and R9d, together with the carbon atoms to which they are bonded, form a 3- to 7-membered condensed ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the condensed ring is optionally substituted with 1, 2, or 3 R A10, each R A10 independently being a halo, C1-4 alkyl, or C1-4 haloalkyl, or One of R9a, R9b, R9c, and R9d, and one of R4a, R4b, R5a, R5b, and R7, together with the atom to which they are bonded, form a 3- to 7-membered condensed ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the condensed ring is optionally substituted with 1, 2, 3, or 4 R A11, each R A11 independently being a halo or C1-4 alkyl. R 10a and R 10b are independently H, halo, C 1-4 haloalkyl, or C 1-6 alkyl, or R10a and R10b, together with the carbon atoms to which they are bonded, form a 5-10 member partially unsaturated condensed ring or a 5-10 member condensed aromatic ring containing 0 or 1 heteroatom selected from N, O, and S, or a 5-10 member condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the partially unsaturated condensed ring, condensed aromatic ring, or condensed heteroaromatic ring is optionally substituted with 1 to 4 R A12, each R A12 independently being a halo or C1-4 alkyl. Ra is independently H, C1-6 alkyl, C1-6 haloalkyl, C(O)Rc, or SO2Rc. R b is H or C 1-4 alkyl, R c is a C1-4 alkyl or C1-4 alkyloxy, Each n is independently 0, 1, or 2. However, the aforementioned compound or its pharmaceutically acceptable salts: 【Chemistry 4】 【Transformation 5】 A compound that is neither a compound having the structure of the above, nor a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is H and / or Y is -C(O)NH-.

3. The compound has formula II-A, 【Transformation 6】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or 3.

4. (a) R1 is a phenyl which is optionally substituted with 1, 2, 3, or 4 R A1, each R A1 independently being halo, C1-4 alkyl, C1-4 haloalkyl, cyano, -O-C1-4 alkyl, or -C1-4 alkyl-O-C1-4 alkyl; or (b) R1 is a phenyl molecule optionally substituted with 1, 2, 3, or 4 R A1s, each R A1 independently being a halo, C1-4 alkyl, C1-4 haloalkyl, or -O-C1-4 alkyl; or (c) R1 is a phenyl molecule substituted with 1, 2, 3, or 4 R A1s, each R A1 independently being a halo or -O-C1-4 alkyl group; or (d) R1 is a phenyl substituted with 1, 2, 3, or 4 halogens; or (e) R1 is a phenyl compound substituted with two or three halogens selected from chloro and fluoro; or (f) R 1 is, 【Transformation 7】 is, or (g) R 1 is, 【Transformation 8】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. The compound has formula II-Aa or II-Ab, 【Chemistry 9】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or 3.

6. The compound according to claim 1 or 2, wherein L is -CH2-, or a pharmaceutically acceptable salt thereof.

7. The compound has formula III, 【Chemistry 10】 In the formula, m is 0, 1, 2, or 3; or The compound has formula IIIa or IIIb, 【Chemistry 11】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or 3.

8. (a) (i) W1 is a bond or -CR4aR4b-, where R4a and R4b are independently H, C1-6 alkyl, C1-4 haloalkyl, or halo; or (ii) W1 is a bond or -CR4aR4b-, where R4a and R4b are independently H, C1-6 alkyl, or halo; or (iii) W1 is a bond or -CR4aR4b-, where R4a and R4b are independently H, -CH3, or halo; or (iv) W1 is a bond or -CR4aH-; or (v) W1 is a bond, -CH2- or -CH(F)-; and / or (b) (i) Z is -CR9aR9b-, where R9a and R9b are each independently H, C1-6 alkyl, C1-4 haloalkyl, or halo; or (ii) Z is -CR9aR9b-, where R9a and R9b are each independently H, C1-6 alkyl, or C1-4 haloalkyl; or (iii) Z is -CH(CH3)- or -CH(CH2F)-; and / or (c) (i) W2 is -CR5aR5b- or -CR6a=CR6b-, where R5a and R5b are independently H, C1-6 alkyl, C1-4 haloalkyl, halo, hydroxyl, cyano, -O-C1-4 alkyl, or C1-4 alkylene-O-C1-4 alkyl, and R6a and R6b are independently H, halo, C1-4 haloalkyl, or C1-6 alkyl; or (ii) W2 is -CR 5a R 5b- or -CR 6a = CR 6b-, where R 5a and R 5b are independently H, C1-6 alkyl, C1-4 haloalkyl, halo, or -O-C1-4 alkyl, and R 6a and R 6b are independently H, halo, C1-4 haloalkyl, or C1-6 alkyl; or (iii) W2 is -CR 5a R 5b- or -CR 6a = CR 6b-, where R 5a and R 5b are independently H, C1-6 alkyl, or halo, and R 6a and R 6b are independently H, halo, or C1-6 alkyl; or (iv) The compound according to claim 1 or 2, wherein W2 is -CH2- or -CH=CH-, or a pharmaceutically acceptable salt thereof.

9. (a) The compound has formula IV, 【Chemistry 12】 In the formula, m is 0, 1, 2, or 3; or (b) The compound has formula IVa, 【Chemistry 13】 In the formula, m is 0, 1, 2, or 3; or (c) The compound has formula IVb, 【Chemistry 14】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or 3.

10. (a) R 4a is H, C1-6 alkyl, or C1-4 haloalkyl; and / or (b) R 5a is H, halo, C1-4 haloalkyl, or C1-6 alkyl; and / or (c) R 9a, (i) H, C1-6 alkyl, C1-4 haloalkyl, or halo; or (ii) C1-6 alkyl, C1-4 haloalkyl, or halo; or (iii) C1-6 alkyl or C1-4 haloalkyl; or (iv)-CH3 or-CH2F The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

11. Each R8 is independently Cl, F, Br, oxo, methyl, ethyl, CH₂Ph, CH₂OH, CH₂OMe, NHMe, NMe₂, OH, OMe, OCH₂CF₃, OCH₂CHF₂, SMe, CH₂F, CHF₂, CH₂CF₃, and 【Chemistry 15】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

12. m is 0, 1, or 2, and optionally m is (i) 0; or (ii) 1; or (iii) 2 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

13. (a) The compound has formula V, 【Chemistry 16】 In the formula, R 8A and R 8B are each independently H, Cl, F, Br, methyl, ethyl, CH 2 F, CHF 2, CH 2 CF 3, CH 2 CH 2 F, CH(CH 3) F, CF 2 CH 3, CF 3, OH, OMe, OCH 2 CF 3, or OCH 2 CHF 2, and optionally, R1 is a phenyl compound substituted with two or three halogens selected from chloro and fluoro. R 4a is H, halo, C1-6 alkyl, or C1-4 haloalkyl. R 5a is H, halo, C1-4 haloalkyl, or C1-6 alkyl. R 9a is a C1-6 alkyl or C1-4 haloalkyl; or (b) The compound has formula V, 【Chemistry 17】 In the formula, R 8A and R 8B are each independently H, Cl, F, Br, methyl, ethyl, CH₂F, CHF₂, CH₂CF₃, CH₂CH₂F, CH(CH₃)F, CF₂CH₃, CF₃, OMe, OCH₂CF₃, or OCH₂CHF, and optionally, R1 is a phenyl compound substituted with two or three halogens selected from chloro and fluoro. R 4a is H, halo, C1-6 alkyl, or C1-4 haloalkyl. R 5a is H, halo, C1-4 haloalkyl, or C1-6 alkyl. R 9a is a C1-6 alkyl or C1-4 haloalkyl; or (c) The compound has formula V, [Chemistry 18] In the formula, R 8A and R 8B are each independently H, Cl, F, Br, methyl, ethyl, CH₂F, CHF₂, CH₂CF₃, CH₂CH₂F, CH(CH₃)F, CF₂CH₃, CF₃, or OMe, and are optionally selected. R1 is a phenyl compound substituted with two or three halogens selected from chloro and fluoro. R 4a is H, halo, C1-6 alkyl, or C1-4 haloalkyl. R 5a is H, halo, C1-4 haloalkyl, or C1-6 alkyl. R 9a is a C1-6 alkyl or C1-4 haloalkyl; or (d) The compound has formula V, 【Chemistry 19】 In the formula, R 8A and R 8B are each independently H, Cl, F, Br, methyl, ethyl, CH₂F, CHF₂, CH₂CF₃, CH₂CH₂F, CH(CH₃)F, CF₂CH₃, or CF₃; or (e) The compound has formula Va, 【Chemistry 20】 In the formula, R 8A and R 8B are each independently H, Cl, F, Br, methyl, ethyl, CH₂F, CHF₂, CH₂CF₃, CH₂CH₂F, CH(CH₃)F, CF₂CH₃, or CF₃; or (f) The compound has formula Vb, 【Chemistry 21】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 8A and R 8B are each independently H, Cl, F, Br, methyl, ethyl, CH 2 F, CHF 2, CH 2 CF 3, CH 2 CH 2 F, CH(CH 3)F, CF 2 CH 3, or CF 3.

14. (a) (i) R 8A is Cl, F, Br, methyl, ethyl, CH₂F, CHF₂, CH₂CF₃, CH₂CH₂F, CH(CH₃)F, CF₂CH₃, or CF₃, and R 8B is H, Cl, F, Br, methyl, ethyl, CH₂F, CHF₂, CH₂CF₃, CH₂CH₂F, CH(CH₃)F, CF₂CH₃, or CF₃; or (ii) R 8A is Cl, F, Br, methyl, ethyl, CH₂F, CHF₂, CH₂CF₃, CH₂CH₂F, CH(CH₃)F, CF₂CH₃, or CF₃, and R 8B is H; or (iii) R 8A is H, Cl, F, Br, methyl, ethyl, CH 2 F, CHF 2, CH 2 CF 3, CH 2 CH 2 F, CH (CH 3) F, CF 2 CH 3, or CF 3, and R 8B is Cl, F, Br, methyl, ethyl, CH 2 F, CHF 2, CH 2 CF 3, CH 2 CH 2 F, CH (CH 3) F, CF 2 CH 3, or CF 3; or (iv) R 8A is H, and R 8B is Cl, F, Br, methyl, ethyl, CH 2 F, CHF 2, CH 2 CF 3, CH 2 CH 2 F, CH(CH 3) F, CF 2 CH 3, or CF 3; and / or (b) R 4a is H, C1-6 alkyl, or C1-4 haloalkyl; and / or (c) R 5a is H, halo, C1-4 haloalkyl, or C1-6 alkyl; and / or (d) R 9a is, (i) H, C1-6 alkyl, C1-4 haloalkyl, or halo; or (ii) C1-6 alkyl, C1-4 haloalkyl, or halo; or (iii) C1-6 alkyl is; and / or (e) (i) R1 is a phenyl molecule optionally substituted with 1, 2, 3, or 4 R A1s, each R A1 independently being a halo, C1-4 alkyl, C1-4 haloalkyl, or -O-C1-4 alkyl; or (ii) R1 is a phenyl molecule substituted with 1, 2, 3, or 4 R A1s, each R A1 independently being a halo or -O-C1-4 alkyl group; (iii) R 1 is a phenyl substituted with 1, 2, 3, or 4 halogens; or (iv) The compound according to claims 13(d) to (f), or a pharmaceutically acceptable salt thereof, wherein R 1 is a phenyl substituted with two or three halogens selected from chloro and fluoro.

15. The compound is (a) 【Chemistry 22】 or (b) 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 or (c) 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of pharmaceutically acceptable salts thereof. 【Request Item 16】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof. 【Request Item 17】 【Chemistry 37】 The compound according to claim 16, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. Further comprising one, two, three, or four additional therapeutic agents, optionally (i) The additional therapeutic agent is an anti-HIV agent; or (ii) The additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent infection reactivator, a capsid polymerization inhibitor, an HIV bNAbs, a TLR7 agonist, a pharmacokinetic enhancer, another agent for treating HIV, or a combination thereof; or (iii) The additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buto-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide, or a pharmaceutically acceptable salt thereof; and / or The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is for oral or parenteral administration.

20. A composition for use in medical therapy, comprising the compound described in claim 1 or 2, or a pharmaceutically acceptable salt thereof.

21. A composition for use in the treatment of HIV infection, comprising the compound described in claim 1 or 2, or a pharmaceutically acceptable salt thereof.

22. (a) The compound or a pharmaceutically acceptable salt thereof is used together with one, two, three, or four additional therapeutic agents in a therapeutically effective amount, wherein the additional therapeutic agents are optionally (i) Anti-HIV agents; or (ii) HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latent infection reactivators, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other agents for the treatment of HIV, or combinations thereof; or (iii) Abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buto-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide, or pharmaceutically acceptable salts thereof is; and / or (b) The composition according to claim 21, wherein the administration is by oral, intravenous, subcutaneous, or intramuscular means.

Images