Bridged tricyclic carbamoyl pyridinone compounds and uses thereof

Abstract

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

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202380029590.8, filed on April 5, 2023, entitled "Bridged Tricyclic Carbamoylpyridinone Compounds and Their Uses".

[0002] Cross-references

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

[0004] Compounds, compositions, and methods for treating or preventing human immunodeficiency virus (HIV) infection are disclosed. Specifically, novel spirocyclic-substituted bridged tricyclic carbamoylpyridinone compounds, their preparation methods, and their use as therapeutic or preventative agents are disclosed. Background Technology

[0005] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. HIV encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown effectiveness, especially when used in combination, toxicity and the development of drug-resistant strains may limit their usefulness (Palella et al., N. Engl. J Med. (1998) 338:853-860; Richman, DDNature (2001) 410:995-1001). Therefore, new agents to inhibit HIV replication are needed.

[0006] One goal of antiretroviral therapy is to achieve viral suppression in patients with HIV infection. Current treatment guidelines from the U.S. Department of Health and Human Services state that achieving viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. See http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed February 12, 2019). Furthermore, decisions regarding the treatment of HIV-infected patients are complex when they require treatment for other medical conditions (ibid., F-8). Because the standard of care requires the use of multiple different drugs to suppress HIV, and to treat other conditions the patient may be experiencing, the possibility of drug interactions is a criterion for selecting a drug regimen. Therefore, there is a need for antiretroviral therapies with a reduced likelihood of drug interactions.

[0007] In addition, HIV is known to mutate in infected subjects (Tang et al. Drugs (2012) 72(9) e1-e25). Due to the mutability of HIV, there is a need for anti-HIV drugs that are effective against a range of known HIV variants (Hurt et al. HIV / AIDS CID (2014) 58, 423-431).

[0008] For some patients, such as those with limited or difficulty accessing healthcare, adherence to daily oral treatment or preventative regimens can be challenging. Medications offering favorable pharmaceutical properties (e.g., improved potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) can reduce dosing frequency and provide better patient compliance. Such improvements can, in turn, optimize drug exposure and limit the development of resistance. Summary of the Invention

[0009] This disclosure relates to novel compounds with antiviral activity and pharmaceutically acceptable salts thereof. In some embodiments, these compounds can be used to treat HIV infection, inhibit HIV integrase activity, and / or reduce HIV replication. In some embodiments, the compounds disclosed herein are effective against a range of known drug-resistant HIV mutants. In some embodiments, the compounds disclosed herein may 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 at a less than daily frequency, such as once weekly, once monthly, once every three months, once every six months, or at longer intervals.

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

[0011]

[0012] Or its pharmaceutically acceptable salt, wherein:

[0013] R 1 For H, C 6-10 Aryl or 5- to 10-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.

[0014] Where C 6-10 Aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one, two, three, or four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Halogenated alkyl,

[0015] Cyano, –O–C 1-4 Alkyl or C 1-4 Alkyl–O–C 1-4 alkyl;

[0016] R 2 For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0017] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CH2–CH2– or –N(R) a )–;

[0018] W 1 For key or –CR 4a R 4b –;

[0019] W 2 For –CR 5a R5b –、–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)–;

[0020] Y is –C(O)NH–,

[0021] It is a three- to seven-membered spirocycle containing one, two, or three heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, three, or four R atoms. 8 Group substitution;

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

[0023] R 3a and R 3b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or

[0024] R 3a and R 3bTogether with the carbon atoms to which they are attached, they form 3- to 7-membered spirocycles containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally bounded by one, two, or three R atoms. A2 Replace, where each R A2 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

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

[0026] R 5a R 5b R 5c and R 5d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl; or

[0027] R 5a and R 5b or R 5c and R 5d Together with the carbon atoms to which they are attached, they form 3- to 7-membered spirocycles containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally bounded by one, two, or three R atoms. A3 Replace, where each R A3 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or

[0028] R 5a and R 5c or R 5b and R 5d Together with their respective attached carbon atoms, they form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the fused ring is optionally separated by one to three R atoms. A3 Replace, where each R A3 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0029] Each R 6a and R 6b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0030] R 6a and R 6b Together with their respective attached carbon atoms, they form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally surrounded by one, two, three, or four R atoms. A4 Replace, where each R A4 Independently a halogenated or C 1-4 alkyl;

[0031] R 7 For H, C 1-6 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO2R c ;

[0032] Each R 8 Choose independently the following groups:

[0033] (i) Halogen group,

[0034] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein C 6-10 The aryl or 5- to 10-membered heteroaryl group is optionally substituted by 1 to 4 substituents, which are independently selected from C1-C3 alkyl, C1-C3 alkoxy, haloyl, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and tri- to seven-membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0035] (iii)C 1-6 Halogenated alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0036] Where C 6-10 The aryl or 5- to 10-membered heteroaryl group is optionally substituted by 1 to 4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogroup, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and tri- to seven-membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0037] (iv)CN,

[0038] (v) Oxide group,

[0039] (vi)-XR A5

[0040] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0041] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0042] (vii)NHR A6 ,

[0043] Where R A6 It is a C1-C6 alkyl group;

[0044] (viii)NR A7 R A8 ,

[0045] Where R A7 It is a C1-C6 alkyl group; and

[0046] R A8 It is a C1-C6 alkyl group.

[0047] (ix)C 6-10 Aryl groups, which are optionally selected independently from C1, 2, 3 or 4 C2 groups. 1-6 Alkyl, C 1-6 Haloalkyl, halogen, CN, C 3-7 cycloalkyl and C 1-6 Substitution of alkoxy groups;

[0048] Where C 3-7 The cycloalkyl group may optionally be substituted with one, two, three, or four independent halogen groups.

[0049] (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S.

[0050] The 3 to 7-membered rings are optionally composed of one, two, or three independently selected from halogen groups, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Cycloalkyl substituents, and

[0051] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0052] The 5 to 10-membered heteroaryl rings are optionally surrounded by one, two, or three independently selected halogen groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups,

[0053] (xii)-SO2R A13 ,

[0054] R A13 It is a C1-C6 alkyl group or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0055] Where C 1-6 The alkyl group or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halogen, and C1-C6 alkoxy groups.

[0056] (xiii)-SON(R A14 )2,

[0057] Each R A14 Independently for H and C 1-6 Alkyl groups or 3- to 7-membered rings containing 0, 1, or 2 heteroatoms independently selected from N, O, and S;

[0058] Where C 1-6 The alkyl group or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halogen, and C1-C6 alkoxy groups.

[0059] (xiv)C 2-6 The alkynyl group, which may optionally be composed of one, two, three, or four independently selected from C1... 1-6 Alkyl group, OH group, -SO2-(C 1-3 Substitution of alkyl groups, or

[0060] Two Rs 8 Groups are linked to form fused, spiro, or bridged 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S;

[0061] The 3 to 7 membered rings are optionally composed of one, two, or three independently selected from halogen groups, OH groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups; or

[0062] Two Rs on adjacent carbon atoms 8The 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.

[0063] The fused 6- to 10-membered aromatic rings are optionally surrounded by one, two, or three independently selected from halogen groups, OH groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substituents of cycloalkyl groups;

[0064] R 9a R 9b R 9c and R 9d Each independently represents H and C. 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated; or

[0065] R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form 3- to 7-membered spirocycles containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally bounded by one, two, or three R atoms. A9 Replace, where each R A9 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or

[0066] R 9a and R 9c or R 9b and R 9d Together with their respective attached carbon atoms, they form a 3- to 7-membered fused ring containing 0 or 1 heteroatoms selected from N, O, and S, wherein the fused ring is optionally separated by one, two, or three R atoms. A10 Replace, where each R A10 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or

[0067] R 9a R 9b R 9c and R 9d One of them and R 4a R 4b R 5a R 5b and R 7 One of them, together with the atoms to which they are attached, forms a 3- to 7-membered fused ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the fused ring is optionally bounded by one, two, three, or four R atoms. A11Replace, where each R A11 Independently a halogenated or C 1-4 alkyl;

[0068] R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0069] R 10a and R 10b Together with their respective attached carbon atoms, they form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally surrounded by one to four R atoms. A12 Replace, where each R A12 Independently a halogenated or C 1-4 alkyl;

[0070] R a Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R c or SO2R c ;

[0071] R b For H or C 1-4 alkyl;

[0072] R c C 1-4 Alkyl or C 1-4 alkoxy groups; and

[0073] Each n is independently 0, 1, or 2.

[0074] In one embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0075] In another embodiment, a kit or article comprises a compound of formula I or a pharmaceutically acceptable salt thereof, along with instructions for use.

[0076] In another embodiment, a method is provided for treating HIV infection in a person who is infected with HIV or at risk of HIV infection by administering to a person 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.

[0077] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, for treating HIV infection in a person who has HIV infection or is at risk of HIV infection is provided.

[0078] In another embodiment, 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 HIV infection in a person who has or is at risk of HIV infection.

[0079] In another embodiment, a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for use in a medical therapy.

[0080] In another embodiment, a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of HIV infection.

[0081] Other embodiments, objectives, features, and advantages are set forth in the detailed description of the following embodiments and may be apparent in part from the description of the claimed embodiments or may be learned by practice. These objectives and advantages may be realized and obtained by the methods and compositions particularly pointed out in the specification and its claims. The foregoing summary is to be understood as a brief and general summary of some embodiments disclosed herein, provided for the reader's benefit and convenience, and is not intended to limit in any way the scope or equivalents of the appended claims. Detailed Implementation

[0082] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein can be practiced without these details. Several embodiments are described below with the understanding that this disclosure is intended to be illustrative of the claimed subject matter and not to limit the appended claims to the specific embodiments shown. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments exemplified under any heading may be combined with embodiments exemplified under any other heading.

[0083] I. Definition

[0084] Unless the context otherwise requires, throughout this disclosure and the claims, the word “comprising” and its variations such as “including” and “containing” shall be interpreted in an open, inclusive sense, that is, as “including but not limited to”.

[0085] Throughout this specification, the phrase "an embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment disclosed herein. Therefore, the phrases "in an embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner.

[0086] "Amino" refers to the -NH2 group.

[0087] "Hydroxy group" refers to the -OH group.

[0088] As used in this article, the term "C" 1-n "alkyl", where n is an integer, alone or in combination with another group, is intended to refer to a non-cyclic, straight-chain or branched alkyl group containing 1 to n carbon atoms. 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (isopropyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, and hexyl. The abbreviations Me represent methyl; Et represent ethyl; Pr represent propyl; iPr represents 1-methylethyl; Bu represents butyl; and tBu represents 1,1-dimethylethyl.

[0089] "Alkyl" refers to hydrocarbons containing primary, secondary, or tertiary atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20 Alkyl groups, 1 to 10 carbon atoms (i.e., C1-C1) 10 Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, CH2CH3), 1-propyl ( n -Pr、 just -propyl, -CH2CH2CH3), 2-propyl ( i -Pr、 different propyl, CH(CH3)2), 1-butyl ( n -Bu、 just -Butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl ( i -Bu、 differentButyl, -CH2CH(CH3)2), 2-Butyl ( s -Bu、 Uncle -Butyl, CH(CH3)CH2CH3), 2-methyl-2-propyl ( t -Bu、 Uncle Butyl, -C(CH3)3), 1-pentyl ( just -pentyl, CH2CH2CH2CH2CH3), 2-pentyl (CH(CH3)CH2CH2CH3), 3-pentyl (CH(CH2CH3)2), 2-methyl-2-butyl (C(CH3)2CH2CH3), 3-methyl-2-butyl (CH(CH3)CH(CH3)2), 3-methyl-1-butyl (CH2CH2CH(CH3)2), 2-methyl-1-butyl (CH2CH(CH3)CH2CH3), 1-hexyl (CH2CH2CH2CH2CH2CH3), 2-hexyl (CH(CH3)CH2CH2CH2CH3), 3-hexyl (CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (C(CH3)2CH2CH2CH3) 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 group having two monovalent groups at its center derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C10, C20 ... 1-10 Alkyl groups or 1 to 6 carbon atoms (i.e., C46, ​​C56, C66, C 1-6 Alkyl groups or 1 to 3 carbon atoms (i.e., C464, C56, C6 ... 1-3 Alkyl groups. Typical alkyl groups include, but are not limited to, methylene (CH2), 1,1-ethyl (CH(CH3)), 1,2-ethyl (CH2CH2), 1,1-propyl (CH(CH2CH3)), 1,2-propyl (CH2CH(CH3)), 1,3-propyl (CH2CH2CH2), 1,4-butyl (CH2CH2CH2CH2), etc.

[0090] As used herein, the term "alkenyl" refers to a substance containing a primary, secondary, or tertiary carbon atom and having at least one unsaturated site (i.e., carbon-carbon sp). 2Alkenyl groups are straight-chain or branched hydrocarbons with double bonds. For example, the alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C2). 20 alkenyl or C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl or C 2-8 ) or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl or C 2-6 Alkenyl groups. Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CHCH2), allyl (CH2CH=CH2), cyclopentenyl (C5H7) and 5-hexenyl (CH2CH2CH2CH2CH=CH2).

[0091] As used in this article, the term "C" 2-n "Alkenyl", where n is an integer, alone or in combination with another group, is intended to refer to an unsaturated, acyclic, straight-chain or branched group containing two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by double bonds. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise specified, the term "C" is used to refer to... 2-n "Alkenyl" should be understood to include, where possible, individual stereoisomers, including but not limited to (E) and (Z) isomers and mixtures thereof. Unless otherwise stated, when C 2-n When an alkenyl group is substituted, it should be understood that it is substituted on any carbon atom that will have a hydrogen atom, such that the substitution will produce a chemically stable compound, as is recognized by those skilled in the art.

[0092] "Alkyne" is a straight-chain or branched hydrocarbon containing a primary, secondary, or tertiary carbon atom and having at least one unsaturated site (i.e., a carbon-carbon sp triple bond). For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C24-C ... 2-20 acetylsyl group), 2 to 8 carbon atoms (i.e., C64) 2-8 (alkynyl group) or 2 to 6 carbon atoms (i.e., C64) 2-6 Alkyne group). Examples of suitable alkynyl groups include, but are not limited to, acetylene (C). ＝ CH), propynyl (CH2C) ＝ CH), etc.

[0093] As used in this article, the term "C" 2-n "Alynyl", where n is an integer, alone or in combination with another group, is intended to refer to an unsaturated, acyclic, straight-chain or branched group containing two to n carbon atoms, wherein at least two carbon atoms are bonded to each other by a triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. Unless otherwise stated, when C 2-nWhen an alkynyl group is substituted, it should be understood that it is substituted on any carbon atom that will have a hydrogen atom, such that the substitution will produce a chemically stable compound, as is recognized by those skilled in the art.

[0094] "Cyano" or "formonitrile" refers to the -CN group.

[0095] As used in this article, the term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0096] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms are each replaced by a halosubstituent. For example, C 1-6 Haloalkyl is C 1-6 Alkyl groups, wherein one or more hydrogen atoms have been replaced by halogenated substituents. Such a range includes alkyl groups with one halogenated substituent to complete the halogenation of the alkyl group.

[0097] As used in this article, the term "C" 1-n "Halogenated alkyl", where n is an integer, alone or in combination with another group, is intended to refer to an alkyl group as defined above having 1 to n carbon atoms, wherein one or more hydrogen atoms are each replaced by a halogenated substituent. C 1-n Examples of haloalkyl groups include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl.

[0098] As used herein, the term "aryl" refers to a single aromatic ring, or a bicyclic or polycyclic ring. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl groups include phenyl groups or ortho-fused bicyclic or polycyclic groups having about 9 to 14 atoms, wherein at least one ring is aromatic (e.g., an aryl group fused to one or more aryl or carbocyclic rings). Such bicyclic or polycyclic groups may optionally be substituted by one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the bicyclic or polycyclic group. It should be understood that the connection point of a bicyclic or polycyclic group as 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, anthracene, etc.

[0099] As used herein, the terms “heteroaryl,” “heteroaryl ring,” or “heteroaryl ring” refer to monoaryl or polyfused rings. The term includes monoaryl rings having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms, provided the ring is aromatic. Such rings include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. The term also includes polyfused ring systems (e.g., ring systems comprising 2 or 3 rings), wherein a heteroaryl group as defined above may be fused with one or more heteroaryl groups (e.g., naphthidyl), carbocyclic rings (e.g., 5,6,7,8-tetrahydroquinolinyl), or aryl groups (e.g., indazole) to form a polyfused ring. Such polyfused rings may optionally be substituted by one or more (e.g., 1, 2, or 3) oxo groups on the carbocyclic portion of the fused ring. It should be understood that the attachment point of a heteroaryl polycyclic ring as defined above can be at any position on the ring, including the heteroaryl, aryl, or carbocyclic portion of the ring. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiopheneyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, inazolyl, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, and thionyl.

[0100] As used herein, the terms “heterocyclic,” “heterocycle,” or “halocycloalkyl” refer to a monosaturated or partially unsaturated ring or polycyclic ring. This term includes monosaturated or partially unsaturated rings (e.g., 3, 4, 5, 6, or 7-membered rings) containing about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. 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, nitrogen-containing heterocyclic butyl, tetrahydrofuranyl, or piperidinyl. This term also includes polycyclic ring systems (e.g., ring systems containing 2 or 3 rings), wherein a heterocyclic group (as defined above) may be attached to two adjacent atoms via one or more heterocycles (e.g., decahydronaphthyl), heteroaryl (e.g., 1,2,3,4-tetrahydronaphthidyl), carbocyclic (e.g., decahydroquinolinyl), or aryl (fused heterocycle). It should be understood that the attachment point of a heterocyclic polyfused ring as defined above can be at any position on the ring, including the heterocyclic, heteroaryl, aryl, or carbocyclic portion of the ring. Exemplary heterocycles include, but are not limited to, aziridinyl, aziridine, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazine, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, benzodihydropyranyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxazinyl, and 1,4-benzodioxazolyl.

[0101] As used herein, the term "ring" refers to a cycloalkyl or heterocyclic 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.

[0102] As used herein, the terms "fused ring" and "fused" refer to the carbocyclic, heterocyclic, aromatic, or heteroaromatic ring structures described herein, which are connected to existing ring structures in the disclosed compounds via two adjacent atoms shared by the fused ring structure and existing ring structures. For example, the bicyclic compounds described below are respectively incorporated with fused cyclopropane (i.e., the cyclopropane ring is fused with the cyclohexane ring), fused pyrrolidine (i.e., the pyrrolidine ring is fused with the benzene ring), and fused thiophene (i.e., the thiophene ring is fused with the furan ring):

[0103]

[0104] As used in this article, the term "C" 3-m "Cycloalkyl", where m is an integer, alone or in combination with another group, is intended to refer to a cycloalkyl substituent containing 3 to m carbon atoms, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term includes both fully saturated and partially unsaturated rings.

[0105] It should be understood that when a variable is substituted, for example, as in the phrase "C" 1-6 The phrase “alkyl, alone or as part of a group, optionally substituted” describes a variable C. 1-6 Alkyl groups can be substituted when alone, and the variable "C" 1-6 The alkyl group can also be substituted when it is part of a larger group. Similarly, when stated, other variables (e.g., C) can be substituted. 2-6 Alkyne, aryl, heteroaryl, heterocyclic, etc. can also be substituted "alone or as part of a group".

[0106] It should be understood that certain variables of Formula I, which connect two chemical groups, can be oriented in either direction. Therefore, for the X group of Formula I (e.g., O, C(O), C(O)O, S, S(O), SO2, (C1-C6)alkyl O-, (C1-C6)alkyl C(O), (C1-C6)alkyl C(O)O, (C1-C6)alkyl S, (C1-C6)alkyl S(O), and (C1-C6)alkyl SO2), certain asymmetric X values ​​can be oriented in either direction. For example, C(O)O can be oriented as C(O)O or OC(O) relative to the group it is attached to.

[0107] The term "chirality" refers to a molecule that has a non-overlapping property with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0108] The term "stereoisomer" refers to compounds that have the same chemical composition but whose atoms or groups are arranged differently in space.

[0109] A diastereomer is a stereoisomer that has two or more chiral centers or axes and whose molecules are not mirror images of each other. Diastereomers typically have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography.

[0110] "Enantiomers" refer to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0111] The term “treatment” includes, to the extent that it relates to a disease or condition, preventing the occurrence of a disease or condition, suppressing a disease or condition, eliminating a disease or condition, and / or alleviating one or more symptoms of a disease or condition.

[0112] The term "treatment" in relation to treating a patient's disease state includes (i) suppressing or improving the patient's disease state, such as stopping or slowing its progression; or (ii) alleviating the patient's disease state, i.e., causing the remission or cure of the disease state. In the case of HIV, treatment includes reducing the patient's HIV viral load.

[0113] As used herein, the term "treatment" is intended to mean the administration of a compound or composition according to the invention to alleviate or eliminate symptoms of HIV infection and / or reduce the viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the invention after an individual's exposure to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood, to prevent the onset of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to the invention to prevent perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the infant in the first few days of life.

[0114] A "protecting group" is a compound moiety that masks or alters the properties of functional groups or the properties of 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 contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. Functional group protection of a compound alters other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties measurable by commonly used analytical tools. Chemically protected intermediates can themselves be biologically active or inactive.

[0115] Protected compounds can also exhibit alterations both in vitro and in vivo, and in some cases, optimized properties, such as cross-membrane penetration and resistance to enzymatic degradation or chelation. In this role, the protected compound with the intended therapeutic effect may be referred to as a prodrug. Another function of the protecting group is to convert the parent drug into a prodrug, thereby releasing the parent drug during prodrug conversion in vivo. Because the active prodrug may be absorbed more efficiently than the parent drug, the prodrug may have greater potency in vivo. In the case of chemical intermediates, the protecting group is removed in vitro; in the case of prodrugs, the protecting group is removed in vivo. For chemical intermediates, the physiological acceptability of the resulting product (e.g., an alcohol) after deprotection is not particularly important, but generally, it is preferable if these products are pharmacologically harmless.

[0116] Protecting groups are available, generally known, and used, and are optionally used to prevent side reactions with the protecting group during the synthetic procedure (i.e., the route or method for preparing the compounds of the present invention). In most cases, the decision regarding which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will depend on the chemical nature of the reaction to be protected (e.g., acidic, basic, oxidative, reducing, or other conditions) and the intended synthetic direction. If the compound is substituted by multiple PGs, the PGs are not required and are generally not identical. Typically, PGs will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups to prevent side reactions or otherwise promote synthetic efficiency. The deprotection sequence that produces free deprotected groups depends on the intended synthetic direction and the reaction conditions encountered, and can occur in any order determined by a person skilled in the art.

[0117] Various functional groups of the compounds of this invention can be protected. For example, protecting groups of the -OH group (whether hydroxyl, carboxylic acid, phosphoric acid, or other functional groups) include "ether or ester forming groups". In the synthetic embodiments described herein, ether or ester forming groups can act as chemical protecting groups. However, as those skilled in the art will understand, some hydroxyl and thio groups are not ether or ester forming groups and are included in amides, as described below.

[0118] Protective GroupsinOrganic Synthesis Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”) describes a very large number of hydroxyl protecting groups and amide forming groups, as well as the corresponding chemical cleavage reactions. See also Kocienski, Philip J.; P. rotectingGroups(Georg Thieme Verlag Stuttgart, New York, 1994), the entire contents of which are incorporated herein by reference. Specifically, Chapter 1, Protecting Groups: An Overview, pp. 1–20; Chapter 2, Hydroxyl Protecting Groups, pp. 21–94; Chapter 3, Diol Protecting Groups, pp. 95–117; Chapter 4, Carboxyl Protecting Groups, pp. 118–154; Chapter 5, Carbonyl Protecting Groups, pp. 155–184. For protecting groups of carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and other protecting groups of acids, see Greene as described below.

[0119] As used herein, the term “protecting group” is intended to mean a protecting group that may be used during synthetic transformation, including but not limited to the examples listed in Greene, “Protective Groups in Organic Chemistry”, John Wiley & Sons, New York (1981) and its more recent editions.

[0120] The term "solvent" refers to a crystalline solid containing a certain amount of solvent incorporated into its crystal structure. As used herein, the term "solvent" includes hydrates.

[0121] The term "nonsolvent" refers to a crystalline solid in which no solvent molecules occupy specific crystallization sites.

[0122] As used herein, the term "pharmaceutically acceptable" refers to a substance that, within reasonable medical judgment, is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and is effective for its intended use when used in a pharmaceutical composition.

[0123] As used herein, the term "pharmaceutically acceptable salt" is intended to mean a salt of a compound according to the invention, which, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, is generally water-soluble or oil-soluble or dispersible, and is effective for its intended use. This term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A list of suitable salts can be found, for example, in SM Birge et al., J. Pharm. Sci., 1977. 66 Pages 1-19.

[0124] As used herein, the term "pharmaceutically acceptable acid addition salt" is intended to refer to salts formed from inorganic and organic acids that retain the bioavailability and properties of the free base and are not biologically or otherwise undesirable. The inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, nitric acid, and phosphoric acid, while the organic acids include, but are not limited to, acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, and citric acid. Citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphate, hemisulfonic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (hydroxyethanesulfonic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, tris(methyl)toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pyric acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, pentylamino acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.

[0125] As used herein, the term "pharmaceutically acceptable base addition salt" is intended to refer to salts that retain the bioavailability and properties of the free acid and are not biologically or otherwise undesirable salts formed from 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, aluminum, etc.). Particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, primary, secondary, and tertiary amines, quaternary ammonium compounds, substituted amines (including naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, halamine, choline, betaine, ethylenediamine, glucosamine, meglumine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. The preferred organic non-toxic alkaloids are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0126] As used herein, the term "antiviral agent" is intended to mean an agent that effectively inhibits the formation and / or replication of a virus in humans, including but not limited to agents that interfere with the host or viral mechanisms necessary for the formation and / or replication of a virus in humans. The term "antiviral agent" includes, for example, inhibitors of the HIV integrase catalytic site, selected from the group consisting of: retegvir (… Merck); Avira (Gilead); Soltegravir (GSK; ViiV); GSK 1265744 (GSK; ViiV) and Dulutevir; HIV nucleoside reverse transcriptase inhibitors selected from the group consisting of: Abacavir ( GSK); Didanoxin ( BMS); Tenofovir ( Gilead); Enqutabin Gilead); Lamivudine GSK / Shire); Stavudine ( BMS); Zidovudine ( GSK); Avtabin (Achillion); Fentenavir (Oncolys); HIV non-nucleoside reverse transcriptase inhibitors, selected from the group consisting of the following: Nevirapine ( BI); According to the law, Weilen ( BMS); Itravirine ( J&J); Rilpivirine (TMC278, R278474; J&J); Folicidiline (GSK / ViiV); and Lesvirine (Pfizer / ViiV); HIV protease inhibitors selected from the group consisting of: Atazanavir ( BMS); Derrinavir ( J&J); Indinavir ( Merck); Lopinavir Abbott); Nefinavir Pfizer); Saquinavir ( Hoffmann-LaRoche); Tiranavir BI); ritonavir ( Abbott); and fossavir ( GSK / Vertex); HIV entry inhibitors, selected from: Maravero ( Pfizer); Enfvir peptide ( Trimeris; and BMS-663068 (BMS); and HIV maturation inhibitors, selected from Myriad Genetics.

[0127] As used herein, the term "antiviral agent" is intended to mean an agent that effectively inhibits the formation and / or replication of viruses in mammals, including but not limited to agents that interfere with the host or viral mechanisms necessary for the formation and / or replication of viruses in mammals.

[0128] As used in this article, the term "HIV replication inhibitor" is intended to refer to a drug that has the ability to reduce or eliminate HIV replication in host cells, whether in vitro, ex vivo, or in vivo.

[0129] Unless otherwise stated, the term "substituent" as used herein is intended to mean an atom, group, or group that can bond to a carbon atom, heteroatom, or any other atom that is otherwise bonded to at least one hydrogen atom. Substituents considered in the context of a particular molecule or segment thereof are those that produce chemically stable compounds, such as those recognized by those skilled in the art.

[0130] As used in this article, the term "heteroatoms" is intended to refer to O, S, or N.

[0131] The term "OC" can be used interchangeably in this article. 1-n Alkyl or C 1-n "Alkoxy", where n is an integer, alone or in combination with another group, is intended to refer to an oxygen atom further bonded to an alkyl group having 1 to n carbon atoms as defined above. C 1-n Examples of alkoxy groups include, but are not limited to, methoxy (CH3O-), ethoxy (CH3CH2O-), propoxy (CH3CH2CH2O-), 1-methylethoxy (isopropoxy; (CH3)2CHO), and 1,1-dimethylethoxy (tert-butoxy; (CH3)3CO). When C 1-n When an alkoxy group is substituted, it should be understood that it is substituted on its alkyl moiety such that the substitution will produce a chemically stable compound, as is recognized by those skilled in the art.

[0132] As used herein, the term "oxo-substituent" is intended to refer to an oxygen atom attached to a carbon atom via a double bond (=O) as a substituent.

[0133] As used herein, the term "mammal" is intended to encompass humans, as well as non-human mammals susceptible to HIV infection. Non-human mammals include, but are not limited to, domesticated animals such as cattle, pigs, horses, dogs, cats, rabbits, rats, and mice, as well as non-domesticated animals.

[0134] The embodiments disclosed herein are also intended to cover all pharmaceutically acceptable compounds of Formula I that are isotopically labeled having one or more atoms replaced by atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. In some embodiments, these radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or pattern of action or the binding affinity to a pharmacologically important site of action. Certain isotope-labeled compounds of formula I, such as those doped with a radioisotope, can be used for drug and / or substrate tissue distribution studies. Radioisotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) They are particularly suitable for this purpose because they are easy to incorporate and easy to detect.

[0135] In some implementations, heavier isotopes such as deuterium (i.e., 2 H) substitution may offer certain therapeutic advantages due to its greater metabolic stability. For example, it may increase the half-life in vivo or reduce the dosage requirement. Therefore, in some cases, heavier isotopes may be preferred.

[0136] Using positron emission isotopes such as 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds disclosed herein can generally be prepared using techniques known to those skilled in the art, or by methods similar to those described in the examples listed below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0137] The methods, compositions, kits, and articles provided herein use or include compounds (e.g., compounds of formula I) or pharmaceutically acceptable salts thereof, wherein one to n hydrogen atoms attached 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 increase resistance to metabolism and may therefore be used to increase the half-life of the compound or a pharmaceutically acceptable salt thereof when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds may be synthesized by means known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0138] The embodiments disclosed herein are also intended to cover in vivo metabolites of the disclosed compounds. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to the embodiments disclosed herein to a mammal for a period sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound according to the embodiments disclosed herein to an animal (such as a rat, mouse, guinea pig, monkey, or human) at a detectable dose, allowing sufficient time for metabolism and isolating its metabolites from urine, blood, or other biological samples.

[0139] The compounds disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)-, or by amino acid definition as (D)- or (L)-. This disclosure is intended to include all such possible isomers, as well as their racemic, non-racemic, 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 preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomers are also intended to be included.

[0140] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes instances where the event or situation occurs and instances where the event or situation does not occur. For example, "optionally substituted heterocyclic group" means that the heterocyclic group may or may not be substituted, and the description includes substituted heterocyclic groups and unsubstituted heterocyclic groups.

[0141] II.Compounds

[0142] In some embodiments, this disclosure provides a compound of formula I:

[0143]

[0144] Or its pharmaceutically acceptable salt, wherein:

[0145] R 1 For H, C 6-10 Aryl or 5- to 10-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.

[0146] Where C 6-10 Aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one, two, three, or four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Halogenated alkyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkyl–O–C 1-4 alkyl;

[0147] R 2 For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0148] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CH2–CH2– or –N(R) a )–;

[0149] W 1 For key or –CR 4a R 4b –;

[0150] W 2 For –CR 5a R 5b –、–CR 5a R 5b CR 5c R 5d –、–CR 6a=CR 6b –、–N(R 7 )–、–O–、–S(O) n –, –C(O)–, –C(O)O–, –C(O)NH–, –CR 5a R 5b –N(R 7 )–、–CR 5a R 5b –O–、–CR 5a R 5b –S(O) n –、–CR 5a R 5b –C(O)–、–CR 5a R 5b –C(O)O–、–CR 5a R 5b –OC(O)–、-CR 5a R 5b –C(O)NH– or –CR 5a R 5b –NHC(O)–;

[0151] Y is –C(O)NH–,

[0152] It is a three- to seven-membered spirocycle containing one, two, or three heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, three, or four R atoms. 8 Group substitution;

[0153] Z is –CR 9a R 9b –、–CR 9a R 9b CR 9c R 9d –or–CR 10a =CR 10b –;

[0154] R 3a and R 3b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or

[0155] R 3a and R 3b Together with the carbon atoms to which they are attached, they form 3- to 7-membered spirocycles containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally bounded by one, two, or three R atoms. A2 Replace, where each R A2Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0156] R 4a and R 4b Independently for H and C 1-6 Alkyl, C 1-4 Haloalkyl or halogenated groups;

[0157] R 5a R 5b R 5c and R 5d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl; or

[0158] R 5a and R 5b or R 5c and R 5d Together with the carbon atoms to which they are attached, they form 3- to 7-membered spirocycles containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally bounded by one, two, or three R atoms. A3 Replace, where each R A3 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or

[0159] R 5a and R 5c or R 5b and R 5d Together with their respective attached carbon atoms, they form a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the fused ring is optionally separated by one to three R atoms. A3 Replace, where each R A3 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0160] Each R 6a and R 6b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0161] R 6a and R 6bTogether with their respective attached carbon atoms, they form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally surrounded by one, two, three, or four R atoms. A4 Replace, where each R A4 Independently a halogenated or C 1-4 alkyl;

[0162] R 7 For H, C 1-6 Alkyl, C 1-4 Haloalkyl, C(O)R c or SO2R c ;

[0163] Each R 8 Choose independently the following groups:

[0164] (i) Halogen group,

[0165] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein C 6-10 The aryl or 5- to 10-membered heteroaryl group is optionally substituted by 1 to 4 substituents, which are independently selected from C1-C3 alkyl, C1-C3 alkoxy, haloyl, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and tri- to seven-membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0166] (iii)C 1-6 Halogenated alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0167] Where C 6-10 The aryl or 5- to 10-membered heteroaryl group is optionally substituted by 1 to 4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogroup, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and tri- to seven-membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0168] (iv)CN,

[0169] (v) Oxide group,

[0170] (vi)-XR A5

[0171] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0172] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0173] (vii)NHR A6 ,

[0174] Where R A6 It is a C1-C6 alkyl group;

[0175] (viii)NR A7 R A8 ,

[0176] Where R A7 It is a C1-C6 alkyl group;

[0177] And R A8 It is a C1-C6 alkyl group.

[0178] (ix)C 6-10 Aryl groups, which are optionally selected independently from C1, 2, 3 or 4 C2 groups. 1-6 Alkyl, C 1-6 Haloalkyl, halogen, CN, C 3-7 cycloalkyl and C 1-6 Substitution of alkoxy groups;

[0179] Where C 3-7 The cycloalkyl group may optionally be substituted with one, two, three, or four independent halogen groups.

[0180] (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S.

[0181] The 3 to 7-membered rings are optionally composed of one, two, or three independently selected from halogen groups, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Cycloalkyl substituents, and

[0182] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0183] The 5 to 10-membered heteroaryl rings are optionally surrounded by one, two, or three independently selected halogen groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups,

[0184] (xii)-SO2R A13 ,

[0185] R A13 It is a C1-C6 alkyl group or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0186] Where C 1-6 The alkyl group or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halogen, and C1-C6 alkoxy groups.

[0187] (xiii)-SO(NR A14 )2,

[0188] Each R A14 Independently for H and C 1-6 Alkyl groups or 3- to 7-membered rings containing 0, 1, or 2 heteroatoms independently selected from N, O, and S;

[0189] Where C 1-6 The alkyl group or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halogen, and C1-C6 alkoxy groups.

[0190] (xiv)C 2-6 The alkynyl group, which may optionally be composed of one, two, three, or four independently selected from C1... 1-6 Alkyl group, OH group, -SO2-(C 1-3 Substitution of alkyl groups, or

[0191] Two Rs 8 Groups are linked to form fused, spiro, or bridged 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S;

[0192] The 3 to 7 membered rings are optionally composed of one, two, or three independently selected from halogen groups, OH groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups; or

[0193] Two Rs 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.

[0194] The fused 6- to 10-membered aromatic rings are optionally surrounded by one, two, or three independently selected from halogen groups, OH groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups

[0195] Base substitution;

[0196] R 9a R 9b R 9c and R 9d Each independently represents H and C. 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated; or

[0197] R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are attached, they form 3- to 7-membered spirocycles containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the spirocycle is optionally bounded by one, two, or three R atoms. A9 Replace, where each R A9 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or

[0198] R 9a and R 9c or R 9b and R 9d Together with their respective attached carbon atoms, they form a 3- to 7-membered fused ring containing 0 or 1 heteroatoms selected from N, O, and S, wherein the fused ring is optionally separated by one, two, or three R atoms. A10 Replace, where each R A10 Independently halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or

[0199] R 9a R 9b R 9c and R 9d One of them and R 4a R 4b R 5a R 5b and R 7 One of them, together with the atoms to which they are attached, forms a 3- to 7-membered fused ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, wherein the fused ring is optionally bounded by one, two, three, or four R atoms. A11 Replace, where each R A11Independently a halogenated or C 1-4 alkyl;

[0200] R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0201] R 10a and R 10b Together with their respective attached carbon atoms, they form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 or 1 heteroatom selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally surrounded by one to four R atoms. A12 Replace, where each R A12 Independently a halogenated or C 1-4 alkyl;

[0202] R a Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R c or SO2R c ;

[0203] R b For H or C 1-4 alkyl;

[0204] R c C 1-4 Alkyl or C 1-4 alkoxy groups; and

[0205] Each n is independently 0, 1, or 2.

[0206] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, By one, two, three or four R 8 Group substitution; and at least one R 8 The group is selected from the group consisting of the following:

[0207] (i)C 1-6 Alkyl groups, which are reacted with OH and C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0208] Where C 6-10The aryl or 5- to 10-membered heteroaryl group is optionally substituted by 1 to 4 substituents, which are independently selected from C1-C3 alkyl, C1-C3 alkoxy, haloyl, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and tri- to seven-membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0209] (ii)C 1-6 Halogenated alkyl groups, which are reacted with OH, C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0210] Where C 6-10 The aryl or 5- to 10-membered heteroaryl group is optionally substituted by 1 to 4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogroup, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and tri- to seven-membered halocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0211] (iii)CN,

[0212] (iv) Oxide group

[0213] (v)-XR A5

[0214] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0215] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0216] (vi)NHR A6 ,

[0217] Where R A6 It is a C1-C6 alkyl group;

[0218] (vii)NR A7 R A8 ,

[0219] Where R A7 It is a C1-C6 alkyl group and R A8 It is a C1-C6 alkyl group;

[0220] (viii)C 6-10Aryl groups, which are optionally selected independently from C1, 2, 3 or 4 C2 groups. 1-6 Alkyl, C 1-6 Haloalkyl, halogen, CN, C 3-7 cycloalkyl and C 1-6 Alkyl substituents; wherein C 3-7 The cycloalkyl group may optionally be substituted with one, two, three, or four independent halogen groups.

[0221] (ix) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S.

[0222] The 3 to 7-membered rings are optionally composed of one, two, or three independently selected from halogen groups, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Cycloalkyl substituents, and

[0223] (x) Contains 5- to 10-membered heteroaryl rings with 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0224] The 5 to 10-membered heteroaryl rings are optionally surrounded by one, two, or three independently selected halogen groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups,

[0225] (xi)-SO2R A13 ,

[0226] R A13 It is a C1-C6 alkyl group or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0227] Where C 1-6 The alkyl group or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halogen, and C1-C6 alkoxy groups.

[0228] (xii)-SO(NR A14 )2,

[0229] Each R A14 Independently for H and C 1-6 Alkyl groups or 3- to 7-membered rings containing 0, 1, or 2 heteroatoms independently selected from N, O, and S;

[0230] Where C 1-6 The alkyl group or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halogen, and C1-C6 alkoxy groups.

[0231] (xiii)C 2-6 The alkynyl group, which may optionally be composed of one, two, three, or four independently selected from C1... 1-6 Alkyl group, OH group, -SO2-(C 1-3 Substitution of alkyl groups, or

[0232] Two Rs 8 Groups are linked to form fused, spiro, or bridged 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S;

[0233] The 3 to 7 membered rings are optionally composed of one, two, or three independently selected from halogen groups, OH groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups; or

[0234] Two Rs 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.

[0235] The fused 6- to 10-membered aromatic rings are optionally surrounded by one, two, or three independently selected from halogen groups, OH groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups.

[0236] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof It is a six-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, three, or four R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a six-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, or three R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a six-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one or two R atoms. 8 Group substitution.

[0237] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof It is a six-membered spirocycle containing one or two heteroatoms selected from N and O; wherein the spirocycle is optionally bounded by one, two, three or four R atoms. 8Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a six-membered spirocycle containing one or two heteroatoms selected from N and O; wherein the spirocycle is optionally bounded by one, two or three R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a six-membered spirocycle containing one or two heteroatoms selected from N and O; wherein the spirocycle is optionally bounded by one or two R atoms. 8 Group substitution.

[0238] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof It is a five-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, three, or four R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a five-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, or three R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a five-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one or two R atoms. 8 Group substitution.

[0239] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof It is a five-membered spirocycle containing one or two heteroatoms selected from N and O; wherein the spirocycle is optionally bounded by one, two, three or four R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a five-membered spirocycle containing one or two heteroatoms selected from N and O; wherein the spirocycle is optionally bounded by one, two or three R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a five-membered spirocycle containing one or two heteroatoms selected from N and O; wherein the spirocycle is optionally bounded by one or two R atoms. 8 Group substitution.

[0240] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof It is a four-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, three, or four R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a four-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one, two, or three R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a four-membered spirocycle containing one or two heteroatoms selected from N, O, and S; wherein the spirocycle is optionally bounded by one or two R atoms. 8 Group substitution.

[0241] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof It is a four-membered spirocycle containing one or two heteroatoms selected from N and S; wherein the spirocycle is optionally bounded by one, two, three or four R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, A quaternary spirocycle containing one or two heteroatoms selected from N and S, wherein the spirocycle is optionally bounded by one, two or three R atoms. 8 Group substitution. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, It is a four-membered spirocycle containing one or two heteroatoms selected from N and S; wherein the spirocycle is optionally bounded by one or two R atoms. 8 Group substitution.

[0242] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof Choose from the following groups: Where * indicates The attachment point with residual I; R d For H, C 1-4 Alkyl or C 1-4 Haloalkyl; and m is 0, 1, 2, 3 or 4.

[0243] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof Choose from the following groups: Where * indicates The attachment point with residual I; R d For H, C 1-4 Alkyl or C 1-4 Haloalkyl; and m is 0, 1, 2, 3 or 4.

[0244] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof Choose from the following groups: In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes

[0245] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof Choose from the following groups:

[0246] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof yes Where m is 0, 1, 2, or 3. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, yes Where m is 0, 1, 2, or 3. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, yes Where m is 0, 1, 2, 3, or 4. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, yes Where m is 0, 1, 2, or 3. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, yes Where m is 0, 1, 2, or 3. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, yes Where m is 0, 1, 2 or 3.

[0247] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula IA:

[0248]

[0249] IA; where m is 0, 1, 2 or 3.

[0250] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula IB:

[0251]

[0252] IB; where m is 0, 1, 2 or 3.

[0253] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula IC:

[0254]

[0255] Where R d For H, C 1-4 Alkyl or C 1-4 Haloalkyl; and m is 0, 1, 2 or 3.

[0256] In some embodiments of a compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula ID:

[0257]

[0258] Where R d For H, C 1-4 Alkyl or C 1-4 Haloalkyl; and m is 0, 1, 2 or 3.

[0259] In some embodiments of a compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula IE:

[0260]

[0261] Where R d For H, C 1-4 Alkyl or C 1-4 Haloalkyl; and m is 0, 1, 2 or 3.

[0262] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has formula IF:

[0263]

[0264] Where m is 0, 1, 2, 3 or 4.

[0265] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, or IF, or pharmaceutically acceptable salts thereof, R 2 For H or C 1-6 Alkyl group. In some embodiments, R 2 For H. In some implementations, R 2 C 1-6 Alkyl group. In some embodiments, R 2 C 1-3 Alkyl group. In some embodiments, R 2 C 1-4 Halogenated alkyl groups.

[0266] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, or IF, or pharmaceutically acceptable salts thereof, Y is selected from the group consisting of: –C(O)NH–, and In some implementations, Y is –C(O)NH–. In some implementations, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is

[0267] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, or IF, or their pharmaceutically acceptable salts, Y is –C(O)NH– and R 2 Is it H or C? 1-6 alkyl.

[0268] In some embodiments of a compound of formula I or IA, or a pharmaceutically acceptable salt thereof, the compound has formula II-A:

[0269]

[0270] Where m is 0, 1, 2 or 3.

[0271] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, or II-A, or their pharmaceutically acceptable salts, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 For being one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, R 1 The phenyl group is substituted with one, two, three, or four halogens. In some embodiments, R... 1 The phenyl group is substituted with two or three halogens selected from chlorine and fluorine. In some embodiments, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 1 for

[0272] In some implementation schemes, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 1 for

[0273] In some implementation schemes, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 1 for

[0274] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, or II-A, or their pharmaceutically acceptable salts, R 1 To be optionally controlled by one, two, three or four R A1 Substituted pyridinyl groups, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted pyridinyl groups, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 For being one, two, three or four R A1 Substituted pyridinyl groups, wherein each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, R 1 The pyridinyl group is substituted with one, two, three, or four halogens. In some embodiments, R 1 It is a pyridinyl group substituted with two or three halogens selected from chlorine and fluorine. In some embodiments, R 1 for

[0275] In some embodiments of compounds of formula I, IA, or II-A, or pharmaceutically acceptable salts thereof, the compound has formula II-Aa or II-Ab:

[0276]

[0277] Where m is 0, 1, 2 or 3.

[0278] In some embodiments of compounds of formula I, IA, or II-A, or pharmaceutically acceptable salts thereof, the compound has formula II-Aa. In some embodiments of compounds of formula I, IA, or II-A, or pharmaceutically acceptable salts thereof, the compound has formula II-Ab.

[0279] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, or II-Ab, or their pharmaceutically acceptable salts, L is –CR 3a R 3b –; where R 3a and R 3b H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, L is –CR 3a R 3b –; where R 3a and R 3b Independently for H and C 1-6 Alkyl or C 1-4 Halogenated alkyl group. In some embodiments, L is –CR 3a R 3b –; where R 3a and R 3b Independently H or C 1-6 Alkyl group. In some embodiments, L is –CR 3a R 3b –; where R 3a and R 3b All are H. In some embodiments, L is –C(O)–. In some embodiments, L is –SO2–. In some embodiments, L is –CH2–CH2–. In some embodiments, L is or –N(R)–. a In some implementations, L is NH.

[0280] In some embodiments of compounds of formula I, IA, II-A, II-Aa, or II-Ab, the compound has formula III:

[0281]

[0282] Where m is 0, 1, 2 or 3.

[0283] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, or III, the compound has formula IIIa or IIIb:

[0284]

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

[0286] In some embodiments of compounds of formula I, IA, II-A, II-Aa, or III, the compound has formula IIIa. In some embodiments of compounds of formula I, IA, II-A, II-Ab, or III, the compound has formula IIIb.

[0287] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, II-Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl or halogenated. In some embodiments, W 1 For key or –CR 4a R 4b –; where R 4a and R 4b It can be independently H, –CH3, or a halogen group. In some embodiments, W 1 For key or –CR 4a H–; where R 4a For H, C 1-6 Alkyl or halogenated. In some embodiments, W 1 For the bond, –CH2– or –CH(F)–.

[0288] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, IIAa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; and W 1For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl, C 1-4 Haloalkyl or halogenated. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; and W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl or halogenated. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; and W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently, it can be H, –CH3, or a halogen group. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; and W 1 For key or –CR 4a H–; where R 4a For H, C 1-6 Alkyl or halogenated. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; and W 1 For the bond, –CH2– or –CH(F)–.

[0289] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, II-Aa, II-Ab, III, IIIa, or IIIb, or their pharmaceutically acceptable salts, Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4Halogenated alkyl group. In some embodiments, Z is –CH(CH3)– or –CH(CH2F)-.

[0290] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl, C 1-4 Haloalkyl or halogroup; and Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl, C 1-4 Haloalkyl or halogenated. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl or halogenated; and Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently H, –CH3, or a halogroup; and Z is –CR. 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 For H or C1-6 Alkyl; and W 1 For key or –CR 4a H–; where R 4a For H, C 1-6 Alkyl or halogenated; and Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Haloalkyl. In some embodiments, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For a bond, –CH2– or –CH(F)–; and Z is –CH(CH3)– or –CH(CH2F)-.

[0291] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, W 2 For –CR 5a R 5b –or–CR 6a =CR 6b –; where R 5a and R 5b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; and R 6a and R 6b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl group. In some embodiments, W 2 For –CR 5a R 5b –or–CR 6a =CR 6b –; where R 5a and R 5b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated or –O–C 1-4 Alkyl; and R 6a and R 6b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl group. In some embodiments, W 2For –CR 5a R 5b –or–CR 6a =CR 6b –; where R 5a and R 5b Independently for H and C 1-6 Alkyl or halogenated; and R 6a and R 6b Independently H, halogen, or C 1-6 Alkyl group. In some embodiments, W 2 For –CH2– or -CH=CH-. In some implementations, W 2 For –CH2–. In some implementations, W 2 It is -CH=CH-.

[0292] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated; Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated; and W 2 For –CR 5a R 5b –or–CR 6a =CR 6b –; where R 5a and R 5b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; and R 6a and R 6b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl.

[0293] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently for H and C 1-6 Alkyl or halogenated; Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Halogenated alkyl; and W 2 For –CR 5a R 5b –or–CR 6a =CR 6b –; where R 5a and R 5b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated or –O–C 1-4 Alkyl; and R 6a and R 6b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl.

[0294] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For key or –CR 4a R 4b –; where R 4a and R 4b Independently H, –CH3, or a halogroup; Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Halogenated alkyl groups; and W 2 For –CR 5a R 5b–or–CR 6a =CR 6b –; where R 5a and R 5b Independently for H and C 1-6 Alkyl or halogenated; and R 6a and R 6b Independently H, halogen, or C 1-6 alkyl.

[0295] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; and W 1 For key or –CR 4a H–; where R 4a For H, C 1-6 Alkyl or halogenated; Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Halogenated alkyl groups; and W 2 It is –CH2– or -CH=CH-.

[0296] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; and W 1 For key or –CR 4a H–; where R 4a For H, C 1-6 Alkyl or halogenated; Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Halogenated alkyl groups; and W 2 It is –CH2–.

[0297] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R2 For H or C 1-6 Alkyl; and W 1 For key or –CR 4a H–; where R 4a For H, C 1-6 Alkyl or halogenated; Z is –CR 9a R 9b –; where R 9a and R 9b Each independently represents H and C. 1-6 Alkyl or C 1-4 Halogenated alkyl groups; and W 2 It is -CH=CH-.

[0298] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For the bond, –CH2– or –CH(F)–; Z is –CH(CH3– or –CH(CH2F)-; and W 2 It is –CH2– or -CH=CH-.

[0299] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE or IF, II-II-A, Aa, II-Ab, III, IIIa or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For the bond, –CH2– or –CH(F)–; Z is –CH(CH3– or –CH(CH2F)-; and W 2 It is –CH2–.

[0300] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE or IF, II-II-A, Aa, II-Ab, III, IIIa or IIIb, or pharmaceutically acceptable salts thereof, Y is –C(O)NH–; R 2 For H or C 1-6 Alkyl; W 1 For the bond, –CH2– or –CH(F)–; Z is –CH(CH3– or –CH(CH2F)-; and W 2 It is -CH=CH-.

[0301] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, the compound has formula IV:

[0302]

[0303] Where m is 0, 1, 2 or 3.

[0304] In some embodiments of compounds of formula I, IA, II-A, II-Aa, III, IIIa or IV, or pharmaceutically acceptable salts thereof, the compound has formula IVa:

[0305]

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

[0307] In some embodiments of compounds of formula I, IA, II-A, II-Ab, III, IIIb, or IV, or pharmaceutically acceptable salts thereof, wherein the compound has formula IVb:

[0308]

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

[0310] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups.

[0311] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl.

[0312] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a For H, C 1-6 Alkyl or C 1-4 Haloalkyl; and R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl.

[0313] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 9a C 1-6 Alkyl or C 1-4 Halogenated alkyl groups. In some embodiments, R 9a It is -CH3 or -CH2F.

[0314] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 Alkyl or C 1-4 Halogenated alkyl groups. In some embodiments, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5aH, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a It is -CH3 or -CH2F.

[0315] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently:

[0316] (i) Halogen group,

[0317] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0318] (iii)C 1-6 Halogenated alkyl groups,

[0319] (iv)CN,

[0320] (v) Oxide group,

[0321] (vi)-XR A5

[0322] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0323] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0324] (vii)NHR A6 ,

[0325] Where R A6 It is a C1-C6 alkyl group;

[0326] (viii)NR A7 R A8 ,

[0327] Where R A7 It is a C1-C6 alkyl group;

[0328] And RA8 It is a C1-C6 alkyl group.

[0329] (ix)C 6-10 Aryl groups, which are optionally selected independently from C1, 2, 3 or 4 C2 groups. 1-6 Alkyl, C 1-6 Haloalkyl, halogen, CN, C 3-7 cycloalkyl and C 1-6 Substitution of alkoxy groups;

[0330] Where C 3-7 The cycloalkyl group may optionally be substituted with one, two, three, or four independent halogen groups.

[0331] (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S.

[0332] The 3 to 7-membered rings are optionally composed of one, two, or three independently selected from halogen groups, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups, or

[0333] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0334] The 5 to 10-membered heteroaryl rings are optionally surrounded by one, two, or three independently selected halogen groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups, or

[0335] Two Rs 8 Groups are linked to form fused, spiro- or bridged 3- to 7-membered rings containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0336] The 3 to 7 membered rings are optionally composed of one, two, or three independently selected from halogen groups, OH groups, C groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups; or

[0337] Two Rs 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.

[0338] The fused 6- to 10-membered aromatic rings are optionally surrounded by one, two, or three independently selected from halogen groups, OH groups, C groups, etc.1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-7 Substitution of cycloalkyl groups.

[0339] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently:

[0340] (i) Halogen group,

[0341] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0342] (iii)C 1-6 Halogenated alkyl groups,

[0343] (iv)CN,

[0344] (v) Oxide group,

[0345] (vi)-XR A5

[0346] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0347] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0348] (vii)NHR A6 ,

[0349] Where R A6 It is a C1-C6 alkyl group;

[0350] (viii)NR A7 R A8 ,

[0351] Where R A7 It is a C1-C6 alkyl group;

[0352] And RA8 It is a C1-C6 alkyl group.

[0353] (ix)C 6-10 Aryl,

[0354] (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or

[0355] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0356] Two Rs 8 Groups are linked to form fused, spiro- or bridged 3- to 7-membered rings containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0357] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently, it can be Cl, F, Br, oxo group, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CHF2, CH2CF3, (CH2)4Cl, CH2F, CH2CH2F, CH(CH3)F, CF2CH3, CF3.

[0358] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently, it can be Cl, F, Br, oxo group, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl.

[0359] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof,

[0360] R4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0361] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0362] R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated groups; and

[0363] Each R 8 Independently

[0364] (i) Halogen group,

[0365] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0366] (iii)C 1-6 Halogenated alkyl groups,

[0367] (iv)CN,

[0368] (v) Oxide group,

[0369] (vi)-XR A5

[0370] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0371] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0372] (vii)NHR A6 ,

[0373] Where R A6 It is a C1-C6 alkyl group;

[0374] (viii)NR A7 R A8 ,

[0375] Where RA7 It is a C1-C6 alkyl group;

[0376] And R A8 It is a C1-C6 alkyl group.

[0377] (ix)C 6-10 Aryl,

[0378] (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or

[0379] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0380] Two Rs 8 Groups are linked to form fused, spiro- or bridged 3- to 7-membered rings containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0381] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof,

[0382] R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0383] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0384] R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated groups; and

[0385] Each R 8 Independently

[0386] (i) Halogen group,

[0387] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0388] (iii)C 1-6 Halogenated alkyl groups,

[0389] (iv)CN,

[0390] (v) Oxide group,

[0391] (vi)-XR A5

[0392] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0393] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0394] (vii)NHR A6 ,

[0395] Where R A6 It is a C1-C6 alkyl group;

[0396] (viii)NR A7 R A8 ,

[0397] Where R A7 It is a C1-C6 alkyl group;

[0398] And R A8 It is a C1-C6 alkyl group.

[0399] (ix)C 6-10 Aryl,

[0400] (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or

[0401] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0402] Two Rs 8 Groups are linked to form fused, spiro- or bridged 3- to 7-membered rings containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0403] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof,

[0404] R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0405] R 5a H, halogen, C1-4 Halogenated alkyl or C 1-6 alkyl;

[0406] R 9a C 1-6 Alkyl or C 1-4 Halogenated alkyl groups, and

[0407] Each R 8 Independently

[0408] (i) Halogen group,

[0409] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0410] (iii)C 1-6 Halogenated alkyl groups,

[0411] (iv)CN,

[0412] (v) Oxide group,

[0413] (vi)-XR A5

[0414] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0415] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0416] (vii)NHR A6 ,

[0417] Where R A6 It is a C1-C6 alkyl group;

[0418] (viii)NR A7 R A8 ,

[0419] Where R A7 It is a C1-C6 alkyl group;

[0420] And R A8 It is a C1-C6 alkyl group.

[0421] (ix)C6-10 Aryl,

[0422] (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or

[0423] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0424] Two Rs 8 Groups are linked to form fused, spiro- or bridged 3- to 7-membered rings containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0425] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof,

[0426] R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0427] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0428] R 9a It is -CH3 or -CH2F.

[0429] Each R 8 Independently

[0430] (i) Halogen group,

[0431] (ii)C 1-6 Alkyl groups, optionally with OH or C 1-6 Alkoxy, C 6-10 The aryl group or a 5- to 10-membered heteroaryl group containing one, two, or three independent heteroatoms selected from N, O, and S is substituted.

[0432] (iii)C 1-6 Halogenated alkyl groups,

[0433] (iv)CN,

[0434] (v) Oxide group,

[0435] (vi)-XR A5

[0436] Where X is O or S; and R A5 For H, C 1-6 Alkyl or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0437] The C1-C6 alkyl group or 3- to 7-membered ring is optionally substituted by 1, 2, or 3 groups, which are independently selected from CN, halogen, C1-C6 alkoxy, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0438] (vii)NHR A6 ,

[0439] Where R A6 It is a C1-C6 alkyl group;

[0440] (viii)NR A7 R A8 ,

[0441] Where R A7 It is a C1-C6 alkyl group;

[0442] And R A8 It is a C1-C6 alkyl group.

[0443] (ix)C 6-10 Aryl,

[0444] (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or

[0445] (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or

[0446] Two Rs 8 Groups are linked to form fused, spiro- or bridged 3- to 7-membered rings containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

[0447] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently, it can be Cl, F, Br, oxo group, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl.

[0448] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently, it can be -Cl, -F, -Br, oxo group, -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.

[0449] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, two R 8 The connection forms a fused 6-membered ring containing one oxygen atom.

[0450] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof,

[0451] R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0452] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0453] R 9a For H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogenated groups; and

[0454] Each R 8Independently, it can be Cl, F, Br, oxo group, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl.

[0455] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof,

[0456] R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0457] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0458] R 9a C 1-6 Alkyl, C 1-4 Haloalkyl or halogenated groups; and

[0459] Each R 8 Independently, it can be Cl, F, Br, oxo group, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl.

[0460] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof,

[0461] R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0462] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0463] R 9a C 1-6 Alkyl or C 1-4 Halogenated alkyl groups, and

[0464] Each R 8 Independently, it can be Cl, F, Br, oxo group, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl.

[0465] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof,

[0466] R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0467] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0468] R 9a C 1-6 Alkyl or C 1-4 Halogenated alkyl groups, and

[0469] Each R 8 Independently, it can be Cl, F, Br, oxo group, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl.

[0470] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0471] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, the compound has formula V:

[0472]

[0473] Where R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0474] In some embodiments of compounds of formula I, IA, II-A, II-Aa, III, IIIa, IV, IVa or V, or pharmaceutically acceptable salts thereof, the compound has formula Va:

[0475]

[0476] Where R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0477] In some embodiments of compounds of formula I, IA, II-A, II-Ab, III, IIIb, IV, IVb, or V, or pharmaceutically acceptable salts thereof, the compound has formula Vb:

[0478]

[0479] Where R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0480] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, and R 8B H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups. In some embodiments, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, and R 8B For H. In some implementations, R 8A H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, and R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups. In some embodiments, R 8A For H, and R 8B Halogenated, C 1-4Alkyl or C 1-4 Halogenated alkyl groups.

[0481] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups.

[0482] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl.

[0483] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 9a C 1-6 alkyl.

[0484] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups.

[0485] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl.

[0486] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated. In some embodiments, R 9a C 1-6 alkyl.

[0487] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Halogenated, C 1-4Alkyl or C 1-4 Halogenated alkyl; R 8B H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated.

[0488] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 8B For H; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated.

[0489] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated.

[0490] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated.

[0491] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 8B H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated.

[0492] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 8B For H; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated.

[0493] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated.

[0494] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 Alkyl, C 1-4 Halogenated alkyl or halogenated.

[0495] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 8B H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 alkyl.

[0496] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 8B For H; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C1-6 alkyl.

[0497] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 alkyl.

[0498] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and R 9a C 1-6 alkyl.

[0499] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; R 9a C 1-6 Alkyl; and R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 alkyl.

[0500] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; R 9a C 1-6 Alkyl; and R 1 For being one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently a halogenated group or –O–C 1-4 alkyl.

[0501] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; R 9a C 1-6 Alkyl; and R 1 A phenyl group that is substituted with one, two, three, or four halogens.

[0502] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A For H; R 8B Halogenated, C 1-4 Alkyl or C 1-4 Halogenated alkyl; R 4a For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl; R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; R 9a C 1-6 Alkyl; and R 1 It is a phenyl group that is substituted with two or three halogens selected from chlorine and fluorine.

[0503] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -XR A5 Where X is O, and R A5 For H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or 3- to 7-membered rings containing 0, 1, or 2 heteroatoms selected from N, O, and S.

[0504] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof:

[0505] R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -XR A5 Where X is O, and R A5 For H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or 3- to 7-membered rings containing 0, 1, or 2 heteroatoms selected from N, O, and S;

[0506] R 1 A phenyl group substituted with two or three halogens selected from chlorine and fluorine;

[0507] R 4a H, halogen, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0508] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and

[0509] R 9a C 1-6 Alkyl or C 1-4 Halogenated alkyl groups.

[0510] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -XR A5 Where X is O, and R A5 C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0511] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof:

[0512] R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -XR A5 Where X is O, and R A5 C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0513] R 1 A phenyl group substituted with two or three halogens selected from chlorine and fluorine;

[0514] R 4a H, halogen, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0515] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and

[0516] R 9a C 1-6 Alkyl or C 1-4 Halogenated alkyl groups.

[0517] In some embodiments of compounds of formula V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -XR A5 Where X is O, and R A5 C 1-6 alkyl.

[0518] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof:

[0519] R 8A and R 8B Each is independently H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -XR A5 Where X is O, and R A5 C 1-6 alkyl;

[0520] R 1A phenyl group substituted with two or three halogens selected from chlorine and fluorine;

[0521] R 4a H, halogen, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0522] R 5a H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; and

[0523] R 9a C 1-6 Alkyl or C 1-4 Halogenated alkyl groups.

[0524] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0525]

[0526] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0527]

[0528] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0529]

[0530] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0531]

[0532] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0533]

[0534] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0535]

[0536] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0537]

[0538] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0539]

[0540] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0541]

[0542] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is selected from the group consisting of:

[0543]

[0544]

[0545]

[0546]

[0547]

[0548] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is selected from the group consisting of:

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is:

[0559]

[0560]

[0561]

[0562]

[0563] III. Pharmaceutical Composition

[0564] The compounds provided herein are typically administered in the form of pharmaceutical compositions. Therefore, 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 solvents selected from carriers, adjuvants, and excipients are also provided herein. The compounds provided herein may be the sole active ingredient or one of the active ingredients in a pharmaceutical composition. Suitable pharmaceutically acceptable solvents may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition, (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GS Banker and CTRhodes).

[0565] In one aspect, this document provides pharmaceutical compositions 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.

[0566] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0567] The pharmaceutical composition can be administered in single or multiple doses. The pharmaceutical composition can be administered by various methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition can be administered via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0568] One method of administration is parenteral, such as by injection. The pharmaceutical compositions described herein may be incorporated into forms for injection administration, including, for example, aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical solvents.

[0569] Oral administration may be another route of administration for the compounds provided herein. Administration may be via, for example, capsules or enteric-coated tablets. In preparing pharmaceutical compositions comprising at least one compound provided herein or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as the compounds provided herein) is typically diluted with an excipient and / or encapsulated in such a carrier, which may be in the form of capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, acting as a solvent, carrier, or medium for the active ingredient. Therefore, pharmaceutical compositions may be in the form of tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0570] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. Pharmaceutical compositions may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propylparaben; sweeteners; and flavoring agents; or any combination thereof.

[0571] Pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof can be formulated to provide a rapid, sustained, or delayed release of an active ingredient, such as a compound provided herein, upon administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation used in the methods of this disclosure employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a controlled amount of a compound provided herein for continuous or discontinuous infusion. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0572] To prepare solid compositions (such as tablets), a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compound described herein or its pharmaceutically acceptable salts, isomers, or mixtures thereof. When these preformed compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition, making it easy to subdivide the composition into equivalent unit dosage forms such as tablets, pills, and capsules.

[0573] The compounds described herein can be coated or otherwise formulated into tablets or pills to provide a dosage form with the advantage of prolonged action or protection against the acidic conditions of the stomach. For example, tablets or pills may contain an inner dose component and an outer dose component, the latter being a coating on the former. These two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the inner component to enter the duodenum intact or delays release. A variety of materials can be used for this enteric coating or coating, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0574] Pharmaceutical compositions for inhalation or inhalation may include solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or via nasal inhalation to achieve a local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask tent or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0575] IV. Treatment Methods

[0576] In one embodiment, a method of treating HIV infection in a person who has or is at risk of HIV infection (e.g., HIV-1 and / or HIV-2) is provided, the method comprising administering to the person 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.

[0577] In some embodiments, the method further includes administering to a person a therapeutically effective amount of one, two, three, or four adjunctive therapeutic agents. In some embodiments, one or more adjunctive therapeutic agents are anti-HIV agents. In specific embodiments, one or more adjunctive therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb (broadly neutralizing HIV antibody), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, the one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, lenakapavir, or pharmaceutically acceptable salts thereof. In one embodiment, the one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, lenakapavir, GS-5894, islatravir, or pharmaceutically acceptable salts thereof. In some embodiments, the one or more adjunctive therapeutic agents are lenakapavir or islatravir. In some embodiments, the adjunctive therapeutic agent is lenakapavir. In some embodiments, the adjunctive therapeutic agent is islatravir.

[0578] In another embodiment, 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, or 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 the treatment of HIV infection in a person who has HIV (e.g., HIV-1 and / or HIV-2) or is at risk of HIV infection.

[0579] In another embodiment, 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, or 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 a medical therapy.

[0580] In another 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 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 the treatment of HIV infection.

[0581] In another embodiment, 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, or 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 a method of treating HIV infection in a person who has HIV infection or is at risk of HIV infection.

[0582] In another embodiment, 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, or 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 a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering one, two, three, or four additional therapeutic agents to the person.

[0583] In another embodiment, a pharmaceutical composition is provided 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 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, which, in Methods for treating HIV infection in persons who are living with or at risk of HIV infection, wherein the method further includes administering to a person one, two, three, or four additional therapeutic agents 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 capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, one, two, three, or four additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, latency reversal agents, HIV capsid inhibitors, HIV bNAb, TLR7 agonists, and combinations thereof.

[0584] In another embodiment, 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, or 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 a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir disoproxil fumarate and emtricitabine.

[0585] In another embodiment, 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, or 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 a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

[0586] In another embodiment, 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, or 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 a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir disoproxil fumarate.

[0587] In another embodiment, 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, or 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 a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir alafenamide.

[0588] In another embodiment, a method of using 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 in a therapy is provided. Specifically, a method of treating HIV viral replication in a mammal (e.g., a human), treating AIDS, or delaying the onset of AIDS or ARC symptoms is provided, the method 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.

[0589] In another embodiment, 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, is provided for use in methods of treating HIV viral replication in mammals (e.g., humans), treating AIDS, or delaying the onset of AIDS or ARC symptoms.

[0590] In one embodiment, 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, or 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 the prevention of HIV infection.

[0591] For example, in one embodiment, 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, or 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., to prevent HIV infection and / or to prevent the establishment of permanent infection and / or to prevent the development of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood prior to an individual's exposure to HIV.

[0592] In another embodiment, the use of 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, or pharmaceutically acceptable salts thereof, is disclosed for the preparation of a medicament for treating HIV infection in persons who are infected with HIV or at risk of HIV infection.

[0593] In another embodiment, the use of 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, or pharmaceutically acceptable salts thereof, as research tools is disclosed.

[0594] In another embodiment, an article of manufacture is disclosed comprising a composition effective in treating HIV infection; and packaging material including a label indicating that the composition can be used to treat HIV-related infections. Exemplary compositions comprise 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, or pharmaceutically acceptable salts thereof.

[0595] In another embodiment, a method for inhibiting HIV replication is disclosed. The method comprises exposing the virus to 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, under conditions where HIV replication is inhibited.

[0596] In another embodiment, the use of 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, or pharmaceutically acceptable salts thereof, is disclosed for inhibiting the activity of HIV integrase.

[0597] In another embodiment, the use of 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, or pharmaceutically acceptable salts thereof, to inhibit HIV replication is disclosed.

[0598] V. Application

[0599] The compounds disclosed herein (e.g., compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb) may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0600] The compounds disclosed herein may be administered to an individual for the required period of time or duration according to an effective dosing regimen, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compounds are administered on a daily or intermittent schedule throughout the individual's life.

[0601] The specific dose level of the compounds disclosed herein for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. A dose between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dose between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dose between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting doses among subjects with large differences in size (such as when using the drug in children and adults, or when converting an effective dose for a non-human subject, such as a dog, to a dose suitable for a human subject).

[0602] Dosage may also be described as the total amount of the compound described herein administered per dose. The dosage of 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, or their pharmaceutically acceptable salts or pharmaceutically acceptable tautomers, may be between about 1 mg and 4,000 mg, between about 2,000 mg and 4,000 mg, between about 1 mg and 2,000 mg, between about 1 mg and 1,000 mg, between about 10 mg and 500 mg, between about 20 mg and 500 mg, between about 50 mg and 300 mg, between about 75 mg and 200 mg, or between about 15 mg and 150 mg.

[0603] The dosage or frequency of administration of the disclosed compounds may be adjusted during treatment based on the judgment of the physician administering the medication.

[0604] The compounds disclosed herein can be administered in therapeutically effective amounts to an individual (e.g., a person). 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.

[0605] The compounds provided herein may be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of the compounds may include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, the therapeutic amounts of the compounds provided herein include from about 0.3 mg / dose to about 30 mg / dose, or from about 30 mg / dose to about 300 mg / dose, or from about 0.3 μg / dose to about 30 mg / dose, or from about 30 μg / dose to about 300 μg / dose.

[0606] The compounds disclosed herein may be combined with one or more additional therapeutic agents at any dose of the disclosed compounds (e.g., 1 mg to 1000 mg of the compound). Therapeuticly effective doses may include about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective doses of the compounds of Formula I are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose, 450 mg / dose, 475 mg / dose, 500 mg / dose, 525 mg / dose. mg / dose, 550mg / dose, 575mg / dose, 600mg / dose, 625mg / dose, 650mg / dose, 675mg / dose, 700mg / dose, 725mg / dose, 750mg / dose, 775mg / dose, 800mg / dose, 825mg / dose, 850mg / dose, 875mg / dose, 900mg / dose, 925mg / dose, 950mg / dose, 975mg / dose or approximately 1000mg / dose.

[0607] In some embodiments, the method described herein involves administering an initial daily dose of about 1 mg to 500 mg of the compound described herein to a subject, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0608] When administered orally, the total daily dose for human subjects may be between about 1 mg and 1,000 mg, between about 10 mg / day and 500 mg / day, between about 50 mg / day and 300 mg / day, between about 75 mg / day and 200 mg / day, or between about 100 mg / day and 150 mg / day. In some embodiments, the total daily dose for human subjects may be about 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, or 1000 mg / day, administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, or 800 mg / day, administered as a single dose. In some implementations, the total daily dose for human subjects may be approximately 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day, administered as a single dose.

[0609] In some embodiments, the total daily dose for a human subject may be about 100 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 150 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 200 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 250 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 300 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 350 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 400 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 450 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 550 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 600 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 650 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 700 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 750 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 800 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 850 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 900 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 950 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 1000 mg / day, administered as a single dose.

[0610] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose can also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose can also be administered every 1 week, 2 weeks, 3 weeks, or every 4 weeks. In some embodiments, a single dose can be administered weekly. A single dose can also be administered monthly. In some embodiments, the compounds disclosed herein are administered once daily using the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily using the methods disclosed herein.

[0611] In some embodiments, the compound disclosed herein is applied every 10 days. In some embodiments, the compound disclosed herein is applied every 15 days. In some embodiments, the compound disclosed herein is applied every 20 days. In some embodiments, the compound disclosed herein is applied every 10-15 days. In some embodiments, the compound disclosed herein is applied every 15-20 days. In some embodiments, the compound disclosed herein is applied every 10-20 days. In some embodiments, the compound disclosed herein is applied once a month. In some embodiments, the compound disclosed herein is applied every 2 months. In some embodiments, the compound disclosed herein is applied every 3 months. In some embodiments, the compound disclosed herein is applied every 4 months. In some embodiments, the compound disclosed herein is applied every 5 months. In some embodiments, the compound disclosed herein is applied every 6 months. In some embodiments, the compound disclosed herein is applied every 8 months. In some embodiments, the compound disclosed herein is applied every 10 months. In some embodiments, the compound disclosed herein is applied annually.

[0612] The frequency of administration of the compounds disclosed herein will be determined by the individual patient's needs and may be, for example, once daily, once weekly, once every two weeks, once monthly, once every two months, once every three months, once every four months, once every six months, or less. Administration of the compounds will continue as long as treatment for HIV infection is required.

[0613] VI. Reagent kits and products

[0614] In one aspect, this document provides a kit 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, IVa, IVb, V, Va, or Vb) or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit also includes instructions for use. In some embodiments, the kit comprises 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 the indications (including diseases or conditions) described herein.

[0615] In some implementations, the kit also contains one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0616] In one aspect, this document provides articles comprising, in a suitable container, the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures thereof. In some embodiments, the container may be a vial, a wide-mouth bottle, an ampoule, a pre-filled syringe, or an intravenous bag.

[0617] VII. Combination Therapy

[0618] In some embodiments, a method for treating HIV infection is provided, the method comprising administering to a person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In one embodiment, a method for treating HIV infection is provided, the method comprising administering to a person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

[0619] In one embodiment, a pharmaceutical composition is provided comprising a combination of a compound disclosed herein or a pharmaceutically acceptable salt thereof with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0620] In some embodiments, this disclosure provides a method for treating HIV infection, the method comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents suitable for treating HIV infection.

[0621] In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four additional therapeutic agents. In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In still other embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0622] Administration of HIV combination therapy

[0623] In some embodiments, the compounds disclosed herein are administered together with one, two, three, or four additional therapeutic agents. Co-administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally means administering the compounds disclosed herein and one, two, three, or four additional therapeutic agents simultaneously or sequentially, such that therapeutically effective amounts of the compounds disclosed herein and one, two, three, or four additional therapeutic agents are present in the patient. When administered sequentially, the combination may be administered in two or more doses.

[0624] Co-administration includes administering a unit dose of the compound disclosed herein before or after administering a unit dose of one, two, three, or four additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours after administering one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents after several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein after several hours (e.g., 1-12 hours).

[0625] In some embodiments, a kit is provided comprising a compound disclosed herein (e.g., a compound 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., one, two, three, or four) additional therapeutic agents.

[0626] In one specific implementation, the kit comprises the compounds disclosed herein or their pharmaceutically acceptable salts, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor.

[0627] HIV combination therapy

[0628] In the above-described embodiments, one or more additional therapeutic agents may be anti-HIV agents. In some cases, adjunctive therapy may include HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene-editing products (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T-cell CAR-T and engineered T-cell receptor TCR-T, autologous T-cell therapy, engineered B cells, NK cells), latency reversal agents, immunotherapy-based therapies, 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 infection factor inhibitors, HIV-1 Nef modulators, TNFα 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, defensin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grasping non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, anti-HIV peptides, and combinations thereof.

[0629] In some implementations, one or more additional therapeutic agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0630] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0631] In some embodiments, one or more adjunctive therapeutic agents are selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, agonists of HIV bNAb, TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for the treatment of HIV, as well as combinations thereof.

[0632] In some implementations, one or more adjunctive therapeutic agents are selected from dulutegravir, cabotevir, islatrevir, direravir, bicagvir, issavirline, rilpivirline, and lenacapavir, as well as combinations thereof.

[0633] HIV combination therapy

[0634] Examples of combination drugs include, but are not limited to, (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (Ertiravir, Cobistat, Tenofovir disoproxil fumarate and Emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine);

[0635] (Tenofovir alafenamide, emtricitabine, cobistat, and ertirapvir); direravir, tenofovir alafenamide hemifumarate, emtricitabine, and cobistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobistat, and ertirapvir; tenofovir analogues; (Zidovudine and Lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); ( Lopinavir and ritonavir); (Durutvir, Abacavir and Lamivudine); (Bicagvir + Emtricitabine + Tenofovir Alaminamide) (Durutvir + Lamivudine) (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Deruravir and cobistat; Durutvir and rilpivirine; Durutvir and rilpivirine hydrochloride; Durutvir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Rytegvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Durutvir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + lamivudine + tadalavir, lamivudine + tenofovir disoproxil fumarate, ... Mivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine, Tenofovir disoproxil fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lamivudine, Cabotevir + Rilpivirine, 3-BNC117 + Ebovetine, Elpida (Isavirin, VM-1500) and VM-1500A, Lenapapvir + Islatrixvir (oral, injection) and dual-targeting HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0636] Other HIV medications

[0637] Examples of other medications used to treat HIV include, but are not limited to, aspergillin C, acemenopausal, arapovir, BanLec, deferiphenone, Gammune, metenkefalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirima derivatives, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, bryozoin-1, bryozoin analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, fluoro-β-D- Antisense oligonucleotides modified with arabinonucleotide (FANA), FX-101, Griffons, 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 (isratrovir), 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, thrombolytic protein 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 conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, nipamovir, Covimro, and ABBV-1882.

[0638] HIV protease inhibitors

[0639] Examples of HIV protease inhibitors include, but are not limited to, ampravir, atazanavir, becanavir, drenalavir, fossavir, fossavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, ASC-09+ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911.

[0640] Additional examples of HIV protease inhibitors are described, for example, in U.S. Patent Nos. 10,294,234 and U.S. Patent Application Publications Nos. US2020030327 and US2019210978.

[0641] HIVGag protein inhibitors

[0642] Examples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071.

[0643] HIV ribonuclease H inhibitor

[0644] Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC-727447.

[0645] HIV Nef inhibitors

[0646] Examples of HIV Nef inhibitors include, but are not limited to, FP-1.

[0647] HIV reverse transcriptase inhibitors

[0648] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include, but are not limited to, dapiriline, deraviridine, deraviridine mesylate, doravirine, efavirenz, ectrevirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, isavirin (extended-release oral, for HIV infection), doravirine + isavirin (fixed-dose combination / oral tablet formulation, for HIV-1 infection), isavirin (long-acting injectable nanosuspension, for HIV infection), and isavirin (VM-1500).

[0649] Examples of HIV nucleosides or nucleotides in reverse transcriptase include, but are not limited to, adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), and tenofovir disoproxil fumarate. and VIDEX (Didanoxin, DDL), Abacavir, Abacavir sulfate, Alovudine, Alitabin, Cinovine, Didanoxin, Avtabin, Fertinavir, Fivudinetimate, CMX-157, Dapivirine, Doravirine, Etravirine, OCR-5753, Tenofovir disoproxil fumarate, Fivudinetimate, Lamivudine, Phosphatidylcholine, Stavudine, Zacitabine, Zidovudine, Rovafovir-Etalaflavinamide (GS-9131), GS-9148, MK-8504, Isratravir, MK-8583, VM-2500 and KP-1461.

[0650] Additional examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286.

[0651] HIV integrase inhibitors

[0652] Examples of HIV integrase inhibitors include, but are not limited to, Averemvir, Averemvir (extended-release microcapsules), curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine kinase inhibitors, tyrosine kinase inhibitor derivatives, quercetin, quercetin derivatives, retegvir, polyethylene glycol retegvir, dulutexvir, JTK-351, bicagvir, AVX-15567, and carboxylic acid. Bortavir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017.

[0653] Examples of HIV noncatalytic site or allosteric integrase inhibitors (NCINIs) include, but are not limited to, CX-05045, CX-05168, and CX-14442.

[0654] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US20200317689, US20210284642, US2014221356, and US2016016973.

[0655] HIV infection factor inhibitors

[0656] Examples of inhibitors of HIV infectious agents include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0657] HIV entry inhibitors

[0658] Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cineviro, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0659] Examples of CCR5 inhibitors include, but are not limited to, apravirone, vevicvirone, maravirone, maravirone (long-acting injectable nanoemulsion), suniverone, lerolimumab (PRO-140), adatabvir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, celavirone, and vMIP (Haimipu).

[0660] Examples of gp41 inhibitors include, but are not limited to, Abovetine, Enfuvirtide, Griffon (a gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biomodification, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifvirtide.

[0661] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs.

[0662] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbial agents, Radha-108 (receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemsavir (aminobutyric acid), IQP-0831, VVX-004, and BMS-663068.

[0663] Examples of gp160 inhibitors include, but are not limited to, tetrandrine.

[0664] Examples of CXCR4 inhibitors include, but are not limited to, praxavir, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0665] HIV maturation inhibitors

[0666] Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232.

[0667] Latency reversal agent

[0668] Examples of latency reversal agents include, but are not limited to, toll-like receptor (TLR) agonists (including TLR7 agonists such as GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as velcade), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors (such as ZL-0580 and apabelon), iomycin, and IAP antagonists (inhibitors of apoptosis proteins such as APG-1387 and LB). W-242), SMAC mimics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), PMA, SAHA (aminosuccinate or succinyl, aniline and isohydroxamic acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B and ubiquitin inhibitors (such as lagozolar analogs, APH-0812, GSK-343). Examples of PKC activators include, but are not limited to, indolelactam, prostratin, phorbol B and DAG-lactone.

[0669] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.

[0670] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944.

[0671] Histone deacetylase (HDAC) inhibitors

[0672] In some implementations, the agent as described herein is administered together with an inhibitor of histone deacetylases such as histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), remixitana, ricolinostat, romidesin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0673] Capsid inhibitors

[0674] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid-destructive compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, lenakapavir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301 and the AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University) and compounds described in (GSK WO2019 / 087016).

[0675] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030.

[0676] Cytochrome P450 3 inhibitors

[0677] Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553.

[0678] RNA polymerase regulators

[0679] Examples of RNA polymerase regulators include, but are not limited to, those described in U.S. Patent Nos. 10,065,958 and 8,008,264.

[0680] Immune checkpoint modulators

[0681] 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 with one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape by infected cells. Stimulating or activating immune checkpoints can enhance the efficacy of immune checkpoint inhibitors in the treatment of infections. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in the following literature: 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 the following literature: Davis et al., Semin Immunol. (2017) 31:64–75; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0682] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); transmembrane and immunoglobulin domain-containing receptors 2 (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20); CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitors 1 containing V-set domains (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory factors (ICOS, CD278); inducible T cell costimulatory ligands (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 (HVEML, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I peptide-associated sequence A (MICA); MHC Class I polypeptide-associated 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); containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); protein 4 containing T-cell immunoglobulin and mucin domains (TIMD4; TIM4); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactoglucan 9 (LGALS9);Lymphocyte activation 3 (LAG3, CD223); Signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL 16-binding protein 3 (ULBP3); early retinoic acid transcript 1E (RAET1E; ULBP4); early retinoic acid transcript 1G (RAET1G; ULBP5); early retinoic acid transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); cytotoxic cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell lectin-like receptor C1 (KLRC1, NKG) 2A, CD159A); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); cytotoxic lectin-like receptor C2 (KLRC2, CD159c, NKG2C); cytotoxic lectin-like receptor C3 (KLRC3, NKG2E); cytotoxic lectin-like receptor C4 (KLRC4, NKG2F); cytotoxic immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cells Cellular immunoglobulin-like receptors, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors, two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors, three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptor D1 (KLRD1); SLAM family member 7 (SLAMF7); and hematopoietic progenitor cell kinases 1 (HPK1, MAP4K1).

[0683] In various implementation schemes, 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 suppressor immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); and PVR-related immune checkpoint proteins or receptors. Immunoglobulin domains (PVRIG, CD112R); T-cell immune receptors with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactoglobulin 9 (LGALS9); cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and cytotoxic cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In various implementation schemes, the reagents described herein are combined with one or more agonists or activators of one or more T-cell stimulating immune checkpoint proteins or receptors.Examples of T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulators (ICOS, CD278); inducible T-cell costimulator ligands (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); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0684] 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, cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); cytotoxic cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); cytotoxic cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); cytotoxic cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and cytotoxic cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agent as described herein is 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); cytotoxic lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31:64–75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., NatRev Immunol. (2018) 18(11):671-688.

[0685] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitors of CD274 or PDCD1 are selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.

[0686] Examples of CTLA4 inhibitors that can be used co-administered include, but are not limited to: ipilimumab, trimemumab, 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, and ATO. R-1144, PBI-5D3H5, BPI-002, and 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).

[0687] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include, but are not limited to, pembrolizumab, nivolumab, cimetizumab, pildizumab, AMP-224, MEDI0680 (AMP-514), spartazumab, 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-754091. AGEN-2034, JS-001 (Toripalimab), JNJ-63723283, Genomeamarab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181 (Bug's maize), PD1-PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (Dotalimab), 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 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), and PD-L1 (PD-L1 / PD-L1). -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(C TLA4 / 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).

[0688] In various implementation schemes, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058 and AGEN-1307.

[0689] TNF receptor superfamily (TNFRSF) agonists or activators

[0690] In various implementations, the agents described herein are combined with agonists of one or more members of the TNF receptor superfamily (TNFRSF), such agonists being agonists of one or more of the following: TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 355). TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, N TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), ...CD268, NCBI gene ID: 8792), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11 D: 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242) and TNFRSF25 (DR3, NCBI gene ID: 8718).

[0691] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0692] Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0693] In some implementations, the anti-TNFRSF7 (CD27) antibody varigramab (CDX-1127) is co-administered.

[0694] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include, but are not limited to, urinumab, urinumab (PF-05082566), AGEN2373 and ADG-106.

[0695] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include, but are not limited to: MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, an antibody or fragment thereof that co-targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0696] Bispecific and trispecific natural killer (NK) cell adaptors

[0697] In various embodiments, the agent as described herein is combined with a bispecific NK cell adaptor (BiKE) or a trispecific NK cell adaptor (TriKE) (e.g., without Fc) or a bispecific antibody against (e.g., with Fc) of: NK cell activation receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), cytotoxic cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), cytotoxic cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Depending on the application, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell adjuvants that can be co-administered target CD16 and one or more HIV-associated antigens as described herein. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441:333-346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell adjuvants (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe.

[0698] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0699] In various implementations, the agent as described herein is combined with indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, icardolstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0700] Toll-like receptor (TLR) agonists

[0701] In various embodiments, the agent as described herein is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 81793).Examples of TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (vesamote), vesamote analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, remiquimod, 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 US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Ja nssen), WO2014 / 128189(Janssen), US20140350031(Janssen), WO2014 / 023813(Janssen), US20080234251(Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Compounds disclosed in US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, teiramod, and BDB-001.TLR8 agonists include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, remiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), and US20080234251 (Array). The compounds disclosed in US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include rapamod, polyICLC, etc. Apoxxim、 IPH-33, MCT-465, MCT-475, and ND-1.1. TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0702] CDK inhibitors or antagonists

[0703] In some embodiments, the agents described herein are combined with CDK inhibitors or antagonists. In some embodiments, the CDK inhibitors or antagonists are selected from the group consisting of VS2-370.

[0704] STING agonists, RIG-I and NOD2 modulators

[0705] In some embodiments, the agents described herein are combined with interferon gene stimulators (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-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with RIG-1 modulators (such as RGT-100) or NOD2 modulators (such as SB-9200 and IR-103).

[0706] LAG-3 and TIM-3 inhibitors

[0707] In some implementations, the agents described herein are combined with anti-TIM-3 antibodies such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.

[0708] In some embodiments, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation) antibody (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385).

[0709] Interleukin agonists

[0710] In some embodiments, the pharmaceutical agent as described herein is combined with the following substances: interleukin agonists (such as IL-2, IL-7, IL-15, IL-10, IL-12) agonists; examples of IL-2 agonists, such as proleukin (aldeleukin, IL-2); BC-IL (Cel-Sci), PEGylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bepepedin, AIC-284, A Examples of IL-15 agonists include LKS-4230, CUI-101, and Neo-2 / 15; examples of IL-15 agonists include ALT-803, NKTR-255 and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (PEGylated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; examples of IL-7 include, but are not limited to, CYT-107.

[0711] Examples of additional immunotherapies that can be combined with the agents disclosed herein include, but are not limited to, interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ; FLT3 agonists such as CDX-301, GS-3583, gepon, nomfullon, pegylated interferon α-2a, pegylated interferon α-2b and RPI-MN.

[0712] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0713] Examples of PI3K inhibitors include, but are not limited to, adexizib, avocadolixizib, bupalixizib, orotic acid CAI, copanlixizib, duvelixizib, gladalixizib, neratinib, panolixizib, perifoxine, idalixizib, piracexizib, praquitinib mesylate, regoratinib, regoratinib sodium, sonolixizib, tacelilixizib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and DS-7423. , EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-76 66. RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

[0714] α-4 / β-7 antagonists

[0715] Examples of integrin α-4 / β-7 antagonists include, but are not limited to, PTG-100, TRK-170, aliruzumab, ectolizumab, methylcarograss, and vedolzumab.

[0716] HPK1 inhibitors

[0717] Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.

[0718] HIV-targeted antibodies

[0719] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include, but are not limited to, those mentioned above. Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360, TMB-370, and HIV-targeting antibodies Antibodies targeting gp120 or gp41, HIV-targeting antibody recruitment molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef single-domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, recombinant human mAb (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, clone 3 human monoclonal antibodies targeting KLIC (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0720] Various bNAbs can be used. Examples include, but are not limited to, US patents 8673307, 9,493,549, 9,783,594, 10,239,935, US2018371086, US2020223907, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, PCT / US2015 / 41272, and WO2017 / 096221, including antibody 1. 2A12, 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. Other examples include those described in the following literature: Klein et al., Nature, 492(7427):118-22 (2012); Horwitz et al., Proc Natl Acad Sci U SA, 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 Special): DL 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to gp41 MPER); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 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).

[0721] Other broadly neutralizing antibodies that can be used as a second therapeutic agent in combination therapy are, for example, U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594 and WO 2012 / 154312, WO2012 / 158948, WO 2013 / 086533, WO 2013 / 142324, WO2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, WO 2015 / 103549, WO 2015 / 117008, WO2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO2017 / 096221, WO The contents of WO 2017 / 133639 and WO 2017 / 133640 are described herein and are incorporated herein by reference in their entirety for all purposes. Additional examples include, but are not limited to, those described in Sajadi et al., Cell. (2018) 173(7): 1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1): 156-64; Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci 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 Special): DL 133-9 (2014); Mascola et al., Immunol Rev.,254(l):225-44(2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074 and LN01 (all of these combined with gp41 MPER).

[0722] Other examples of antibodies include, but are not limited to, bavirinumab, 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 (epavirinumab), 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, D RVIA7, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

[0723] 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, and 10E8v4 / PGT121-VRC01.

[0724] Examples of in vivo delivered bNAb include, but are not limited to, AAV8-VRC07, mRNA encoding the anti-HIV antibody VRC01, and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med., 2019, 1301).

[0725] Pharmacokinetic enhancers

[0726] Examples of pharmacokinetic enhancers include, but are not limited to, cobistat and ritonavir.

[0727] Additional treatment

[0728] Examples of adjunctive therapeutic agents include, but are not limited to, 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), WO2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US2013 / 0165489 (University of Pennsylvania), US2014 / 0221378 (Japan Tobacco), US2014 / 0221380 (Japan Tobacco), WO Compounds disclosed in WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (PharmaResources), US20140221356 (Gilead Sciences), US20100143301 (Gilead Sciences) and WO2013 / 091096 (Boehringer Ingelheim).

[0729] HIV vaccine

[0730] Examples of HIV vaccines include, but are not limited to, peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors, such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackievirus-based vaccines, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (such as LCMV, Pittend), arenavirus-based vaccines based on bisegmented or trisegmented segments, and arenavirus-based vaccines. HIV-1 vaccines, measles virus-based vaccines, flavivirus-based vaccines, tobacco mosaic virus-based vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopox virus-derived NYVAC, and fowlpox virus-derived ALVAC (canarypox virus) strains); fowlpox virus-based vaccines, rhabdovirus-based vaccines such as VSV and Malabar virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines such as Simelik 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.

[0731] Examples of HIV vaccines include: AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664gp140 adjuvant vaccine, BG505SOSIP.GT1.1 gp140 adjuvant vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA trivalent vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConMSOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAX B / E (gp120), monomeric gp120 HIV-1C subtype 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, Multi-level DNA Recombinant Adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSPISA-51, poly-ICLC adjuvant vaccine, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, and N123-VRC-34 based vaccines.01 HIV vaccines that induce antigens, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 The following vaccines are available: gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vector vaccines expressing SCaVII, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001 and virus-like particle vaccines (such as pseudovirus particle vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, and anti-TAT. HIV vaccines, conjugated peptide vaccines, dendritic cell vaccines (such as DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II antigen heterozygous peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidesin, variant gp120 peptide vaccine, rAd5 gag-pol envA / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer-based vaccines, PD-201401, env(A,B,C,A / E) / gag(C) DNA vaccines, gp120(A,B,C,A / E) protein vaccines, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag primiparous-boost plasmid DNA vaccine, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, arenavirus-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based prophylactic vaccines, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Research Center), TBL-1203HI, CH505 TF chTrimer, CD40 HIVRI Env vaccine, Drep-HIV-PT-1, mRNA-1644, and mRNA-1574.

[0732] Combination therapy with birth control pills

[0733] In some embodiments, the agents described herein are combined with contraceptive or birth control regimens. Therapeutic agents for birth control (contraceptives) that can be combined with the agents disclosed herein include, but are not limited to, cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, nomenoprogesterone acetate, nomeprogesterone acetate, norethindrone, norethindrone, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0734] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four additional therapeutic agents selected from the following: (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (Ertiravir, Cobistat, Tenofovir disoproxil fumarate and Emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistat and erteiravir); (Bicagvir + Emtricitabine + Tenofovir Alamonamide), Adefovir; Adefovir Dipropionate; Cobistat; Emtricitabine; Tenofovir; Tenofovir Alamonamide and Etileravir; Tenofovir Alamonamide + Etileravir (rectal preparation, HIV infection); Tenofovir Disoproxil Fumarate; Tenofovir Disoproxil Fumarate; Tenofovir Alamonamide; Tenofovir Alamonamide Hemifumarate; (Durutexvir, abacavir and lamivudine); Durutvir, abacavir sulfate and lamivudine; Rettagvir; Polyethylene glycol-modified Rettagvir; Rettagvir and lamivudine; Lamivudine + lopinavir + ritonavir + abacavir; Maraviro; Tenofovir + emtricitabine + maraviro, emfvir peptide; Lopinavir and ritonavir); (Zidovudine and Lamivudine; AZT+3TC); Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derreravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertirapvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derreravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefernavir; Nefernavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efaviraxyl, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate.

[0735] In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitory compounds. In further embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetic enhancers. In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0736] In another embodiment, the pharmaceutical agent or pharmaceutical composition thereof disclosed herein is combined with a first adjunctive therapeutic agent and a second adjunctive therapeutic agent, the first adjunctive therapeutic agent being selected from durutevir, cabotevir, islatrevir, direravir, bicagvir, issavirline, rilpivirline, and lenapapvir, and the second adjunctive therapeutic agent being selected from emtricitabine and lamivudine.

[0737] In some embodiments, the pharmaceutical agents or pharmaceutical compositions thereof disclosed herein are combined with a first adjunctive therapeutic agent (contraceptive), the first adjunctive therapeutic agent being selected from the group consisting of: cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etoposide, levonorgestrel, levofloxacin, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, normethylenediamine acetate, norethindrone, norgestrel, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof.

[0738] Gene therapy and cell therapy

[0739] In some implementations, the agents described herein are combined with gene therapy or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modifications that silence genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace most 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 locate and kill infected cells; and gene methods that modify cell activity to further alter the endogenous immune response to infection. Examples of cell therapies include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPCs overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies 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, autologous CD34-positive hematopoietic progenitor cells (HIV-infected / HIV-related lymphoma) transduced with Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoys. In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T-cell therapy or AAV-eCD4-Ig gene therapy.

[0740] Gene-edited products

[0741] In some embodiments, the agents described herein are combined with a gene editor (e.g., an HIV-targeted gene editor). In various embodiments, the genome editing system may be selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and a wide range of nuclease complexes. Exemplary HIV-targeted CRISPR / Cas9 systems include, but are not limited to, EBT-101.

[0742] CAR-T cell therapy

[0743] In some embodiments, the agents described herein may be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains an HIV antigen-binding domain. The HIV antigen includes 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, a N-glycan on gp120, V2 of gp120, and a proximal membrane 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 may be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIVduoCAR-T, anti-CD4CART cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, dual anti-CD4CART-T cell therapy (CD4 CAR+C34-CXCR4 T cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120CAR-T therapy, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide.

[0744] TCR T-cell therapy

[0745] In some embodiments, the agents described herein are combined with a population of TCR-T cells. The TCR-T cells are engineered to target HIV-derived peptides, such as ImmTAV, present on the surface of virus-infected cells.

[0746] B-cell therapy

[0747] In some embodiments, the antibody or antigen-binding fragment described herein is combined with a population of B cells that has been genetically modified to express a broadly neutralizing antibody, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301; Moffett et al., Sci. Immunol. 4, eaax0644 (2019), May 17, 2019).

[0748] The compounds disclosed herein (e.g., any compound of Formula I) may be combined with one, two, three or four additional therapeutic agents at any dose of the compound of Formula I (e.g., 1 mg to 500 mg of the compound).

[0749] In one embodiment, a kit is provided comprising a combination of the compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, one or two or one to three) additional therapeutic agents.

[0750] In one embodiment, one or more additional therapeutic agents in the kit are anti-HIV agents selected from HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing products (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T-cell CAR-T and engineered T-cell receptors, TCR-T, autologous T-cell therapy), compounds targeting the HIV capsid, latency reversal agents, HIV bNAb, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infection factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, defensin modulators, CDK-9 inhibitors, dendritic ICAM-3 grasping non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0751] In some implementations, one or more additional therapeutic agents in the kit are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0752] In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. In another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In yet another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitor. In still another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some 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 yet another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, a nucleoside inhibitor of HIV reverse transcriptase, and an HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAbs. In one specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, and a nucleoside inhibitor of HIV reverse transcriptase.

[0753] Long-term treatment for HIV

[0754] Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotevir, rilpivirine, any integrase LA, VM-1500LAI, maraviro (LAI), tenofovir implant, isratrovir implant, doravirine, retegvir, and long-acting durutvir.

[0755] VII. Examples

[0756] Intermediate A: (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazonine-10-carboxamide

[0757]

[0758] Step 1 : (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-aza Synthesis of 3-amines :

[0759] Add 20 mL of trifluoroacetic acid to (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-aza The reaction mixture was heated to 100°C and held for 4 hours in benzyl 1-carboxylate (6.2 g, 15.7 mmol). The reaction mixture was concentrated and the crude product was used directly in the next step.

[0760] Step 2 : (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6, Synthesis of 7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide :

[0761] Methanol (300 mL) and water (30 mL) were added to methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (6.75 g, 15.7 mmol) and (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-aza -3-amine (from the crude product of the previous step). NaHCO3 (13.2 g, 157 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight at room temperature, then heated to 60 °C and held for 5 hours. The reaction mixture was concentrated, and then ethyl acetate was added, followed by washing with a saturated ammonium chloride solution. The organic layer was concentrated and purified by silica gel chromatography (eluting with 0%–10% MeOH / DCM) to give (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide. MS (m / z) 524.11 [M+H]+.

[0762] Step 3 : (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1, Synthesis of 6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide :

[0763] Selenium dioxide (17.4 g, 157 mmol) was added to a solution of (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (the product of the previous step, 15.7 mmol) in dioxane (160 mL). The reaction mixture was then heated to 105 °C overnight. The reaction mixture was cooled and the solids were filtered off. The filtrate was extracted with ethyl acetate and a saturated ammonium chloride solution. The organic layer was concentrated and purified by silica gel chromatography (eluting with 40%–100% ethyl acetate / hexane) to give (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide. MS (m / z) 538.095 [M+H]+.

[0764] 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide

[0765]

[0766] (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (132 mg, 0.246 mmol) was dissolved in anhydrous THF (3.0 mL), and the resulting mixture was cooled to -20 °C. A 3.0 M ether solution of methyl magnesium bromide (0.41 mL, 1.23 mmol) was added to the stirred and cooled mixture. After stirring for 20 min, the reaction was quenched with saturated NH4Cl. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The product was purified by silica gel chromatography (0-100% EtOAc / hexane). MS(m / z) 553.95 [M+H]+.

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

[0768]

[0769] Step 1 : (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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10- Synthesis of formamide :

[0770] Add (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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (3.15 g, 5.69 mmol) to a round-bottom flask, followed by Fe(acac)3 (1.01 g, 2.85 mmol), EtOH (60 mL), PhSiH3 (2.90 mL, 22.8 mmol), and PhSH (5.69 mL, 2.85 mmol, 0.5 M iPrOH solution). Stir the resulting slurry at room temperature for 48 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by silica gel chromatography (hexane solution of 20% to 100% ethyl acetate), followed by a second purification by reversed-phase chromatography (5% to 100% aqueous acetonitrile solution buffered with 10 mM ammonium formate, pH 3.8). The corresponding fractions were combined, extracted with dichloromethane, and concentrated under vacuum 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide. MS (m / z) 556.4 [M+H]+.

[0771] Step 2 : (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl) (1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide) Synthesis :

[0772] Add (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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (3.20 g, 5.76 mmol) to a round-bottom flask, followed by dichloromethane (90 mL). Add martinithane to the suspension in two portions (8.91 g, 13.2 mmol), and stir the mixture at room temperature for 1 hour. The resulting solution was then concentrated under vacuum, and the residue was purified by reversed-phase chromatography (using 5% to 100% acetonitrile aqueous solution buffered with 10 mM ammonium formate, pH 3.8). The corresponding fractions were separated and lyophilized to obtain (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide. MS (m / z) 538.4 [M+H]+.

[0773] Intermediate D: (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide

[0774]

[0775] This intermediate was prepared in a similar manner to (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (intermediate A), except that methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate was used in step 2. MS (m / z) 520.200 [M+H]+.

[0776] 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide

[0777]

[0778] This intermediate was prepared in a similar manner to (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (intermediate D). MS (m / z) 536.4 [M+H]+.

[0779] 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide

[0780]

[0781] Step 1 : (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo- Synthesis of 1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide become :

[0782] Platinum oxide (IV) (0.72 g, 3.17 mmol, 0.29 equivalents) was added 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (5.90 g, 11.0 mmol, 1 equivalent) in methanol (500 mL) and CH2Cl2 (170 mL). The flask was degassed and backfilled with nitrogen (3x), then degassed and backfilled with hydrogen (3x). The reaction mixture was stirred at room temperature for 16 hours and then backfilled with CH2Cl2. 2- Dilution. Filter the reaction mixture through diatomaceous earth and concentrate. Perform column chromatography (0% to 10% MeOH / CH2Cl). 2-The residue was purified, and the fractions containing the product were combined and concentrated. The residue was ground 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide. MS (m / z) 448.26 [M+H]+.

[0783] Step 2 : (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11- Dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-methyl Synthesis of amides :

[0784] Benzyl bromide (0.957 mL, 8.06 mmol, 3 equivalents) was added 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (1.202 g, 2.69 mmol, 1 equivalent) and potassium carbonate (2.225 g, 16.1 mmol, 6 equivalents) in DMF (27 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0% to 100% EtOAc / hexane) 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide. MS (m / z) 538.11 [M+H]+.

[0785] Step 3 : (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxane 1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide Synthesis :

[0786] Add thionane (3.933 g, 5.85 mmol, 2.5 equivalents) 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide (1.258 g, 2.34 mmol, 1 equivalent) in toluene (15 mL). Heat the reaction mixture to 40 °C, maintain for 1 hour, and concentrate. The residue was purified by column chromatography (0% to 100% EtOAc / hexane) 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide. MS (m / z) 520.12 [M+H]+.

[0787] 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide

[0788]

[0789] Add 1.98 g, 2.94 mmol of thionane 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (0.525 g, 0.98 mmol) (intermediate E) in toluene (10 mL). Stir the reaction mixture at room temperature for 20 min. Dilute the reaction mixture with EtOAc and wash with H2O and brine. Dry the organic phase over MgSO4, filter, and concentrate. 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide. MS (m / z) 518.23 [M+H]+.

[0790] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0791]

[0792] 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]bridged methylenepyrido[1,2-a] [1,4]diazacyclononene]-10'-formamide and (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3, 3'-Dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridge Preparation of methylpyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0793] N-chlorosuccinimide (1.51 g, 11.3 mmol) was added to a solution of acetaldehyde oxime (666 mg, 11.3 mmol) in DMF (50 mL) at room temperature, and then the mixture was heated to 60 °C and held 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]tetradecano-3,6-diene-4-carboxamide (intermediate F) (1.58 g, 3.04 mmol) and triethylamine (1.539 g, 15.2 mmol) were added. The reaction mixture was stirred overnight at room temperature, and the reaction was quenched by adding a saturated NaHCO3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 0% to 100% EtOAc / hexane) to give two separable isomers. MS (m / z) 577.135 [M+H]+ (major); 577.115 [M+H]+ (minor).

[0794] Step 2 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxane -1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1, Preparation of 4]diazacyclic nonene]-10'-formamide :

[0795] TFA (0.5 mL) was added 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (64.7 mg, 0.112 mmol) in toluene (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10% to 90% aqueous acetonitrile solution to give the title compound. MS (m / z) 487.12 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.53 (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,1H ), 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).

[0796] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0797]

[0798] TFA (1 mL) was added 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (396 mg, 0.687 mmol) in toluene (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10% to 90% aqueous acetonitrile solution to give the title compound. MS (m / z) 487.103 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.53 (d, J = 5.8 Hz, 1H), 8.41 (s, 1H), 7.38 (q, J = 7.8 Hz, 1H), 6.95–6.74 (m, 2H), 4.83–4.69 (m, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.25 (s, 1H), 3.77 (dd, J = 15.2, 3.0 Hz, 1H), 3.44 (d,J=15.2Hz,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).

[0799] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0800]

[0801] Step 1 : (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trimethyl) (Fluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2- a][1,4]diazacyclononene]-10'-formamide and (3'S,5R,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1', 11'-Dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2, Preparation of [7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0802] N-chlorosuccinimide (90.5 mg, 0.68 mmol) was added to a solution of acetaldehyde oxime (160 mg, 2.71 mmol) in DMF (5 mL) at room temperature, followed by heating to 60 °C and holding 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (intermediate C) (119 mg, 0.221 mmol) and triethylamine (112 mg, 1.1 mmol) were added. The reaction mixture was stirred overnight at room temperature, and the reaction was quenched by adding a saturated NaHCO3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 0% to 100% EtOAc / hexane) to give two separable isomers. MS (m / z) 595.06 [M+H]+ (major); 595.09 [M+H]+ (minor).

[0803] Step 2 : (3'S,5S,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl) )-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1, Preparation of 4]diazacyclic nonene]-10'-formamide :

[0804] TFA (0.5 mL) was added to a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (72.3 mg, 0.122 mmol) in toluene (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10% to 90% aqueous acetonitrile solution to give the title compound. MS (m / z) 505.129 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.51–10.41(m,1H),8.40(s,1H),6.70(dd,J=8.7,7.5Hz, 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).

[0805] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0806]

[0807] TFA (0.5 mL) was added 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[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (10.8 mg, 0.018 mmol) in toluene (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10% to 90% aqueous acetonitrile solution to give the title compound. MS (m / z) 505.142 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.41(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=15.2,3.0Hz,1H),3.43(d,J=15.5Hz,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).

[0808] 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]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0809]

[0810] Step 1 : (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxane Preparation of 1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide Preparation :

[0811] 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (intermediate E) (0.525 g, 0.98 mmol) in toluene (10 mL), 1.98 g of thionane (2.94 mmol) was added. The reaction mixture was then stirred at room temperature for 20 min. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4. After solvent removal under vacuum, the residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 518.23 [M+H]+.

[0812] Step 2 : (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'- Dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4] Preparation of diazacyclononene]-10'-formamide :

[0813] 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (0.335 g, 0.647 mmol) in DMF (2 mL), (1Z)-N-hydroxyacetimidoyl chloride ((1Z)-N-hydroxyacetimidoyl chloride) (0.303 g, 3.24 mmol) was added, followed by triethylamine (0.655 g, 6.47 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with H2O, 5% LiCl (aqueous solution), and brine. The organic phase was dried over MgSO4. After solvent removal under vacuum, the residue was purified by silica gel chromatography to obtain the title compound. MS(m / z) 575.58 [M+H]+.

[0814] Step 3 : (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-di Methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylene Preparation of pyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0815] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (0.2 g, 0.353 mmol) in i-PrOH (3 ml) and DCM (2 ml), phenylsilane (0.11 g, 1.06 mmol) was added, followed by tris(2,2,6,6-tetramethyl-3,5-heptadecanoic acid)manganese(III) (0.011 g, 0.0018 mmol). The reaction mixture was then stirred for 24 hours under an O2(g) atmosphere. The reaction was quenched by adding 10% sodium thiosulfate, followed by extraction with EtOAc. The organic phase was washed with H2O and brine and dried over MgSO4. After removing the solvent under vacuum, the residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 593.05 [M+H]+.

[0816] Step 4 : (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylene pyridine Preparation of pyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0817] A solution of deoxofluor in toluene (50%, 0.375 mL, 1.01 mmol) was added 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]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (60 mg, 0.101 mmol) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with DCM, the organic phase was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 0%–100% hexane / EtOAc) to give the title compound. MS (m / z) 595.04 [M+H]+.

[0818] Step 5 : (3'S,4'S,5R,7'R)-N-(2,4-difluorobenzyl)-4'-fluoro-12'-hydroxy-3,3'-dimethyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyridyl] Preparation of [1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0819] TFA (1 mL) was added 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (11 mg, 0.0185 mmol) in toluene (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 5%–100% aqueous acetonitrile solution 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,1 H),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).

[0820] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0821]

[0822] Step 1 : ((3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5', 11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononyl] Preparation of tert-butyl 2,4-difluorobenzyl)carbamate (10'-carbonyl)(2,4-difluorobenzyl)carbamate :

[0823] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (631 mg, 1.11 mmol) in toluene (20 ml), di-tert-butyl dicarbonate (1.45 g, 6.64 mmol) and DMAP (608 mg, 4.98 mmol) were added. The reaction mixture was then heated to 110 °C and maintained for 4 hours. After cooling the reactants to room temperature, the reaction was quenched by adding a saturated NaHCO3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 30% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 676.924 [M+H]+.

[0824] Step 2 : (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5' 11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonylene Preparation of 10'-carboxylic acid of olefin :

[0825] At room temperature, 1N NaOH solution (3 mL) was added to a solution of ((3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carbonyl)(2,4-difluorobenzyl)carbamate (590 mg, 0.872 mmol) in MeOH (10 mL). After 1 hour at room temperature, the reaction was quenched by adding 1N HCl solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, and concentrated to give the crude title compound, which was ready for use without purification. MS (m / z) 452.127 [M+H]+.

[0826] Step 3 : (3'S,5S,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3,3'-dimethyl-1', 11'-Dioxo-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1, Preparation of 2-a][1,4]diazacyclic nonene]-10'-formamide :

[0827] At room temperature, 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[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxylic acid (65 mg, 0.144 mmol) in DMF (5 ml) was supplemented with (3-chloro-2,4-difluorophenyl)methylamine (30.7 mg, 0.173 mmol), HATU (98.5 mg, 0.259 mmol), and DEA (149 mg, 1.15 mmol). After 1 hour at room temperature, the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 50% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 611.075 [M+H]+.

[0828] Step 4 : (3'S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'- Dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a] Preparation of [1,4]diazacyclic nonene]-10'-formamide :

[0829] TFA (0.5 mL) was added to a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (88 mg, 0.144 mmol) in toluene (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10% to 90% aqueous acetonitrile solution to give the title compound. MS (m / z) 521.181 [M+H]+. 1 ¹H NMR (400MHz, 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, 1.8Hz, 1H), 4.72 (ddd, J = 19.4, 7.9, 4.5Hz, 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),2.59–2.4 9(m,1H),2.15–1.92(m,6H),1.56(dd,J=14.2,11.2Hz,1H),1.32(d,J=6.6Hz,3H).

[0830] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0831]

[0832] (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide was prepared in a manner similar to that in Example 1, except that isobutyraldehyde oxime was used in step 1. MS (m / z) 515.152 [M+H]+. 1¹H NMR (400MHz, chloroform-d) δ 10.40 (s, 1H), 8.32 (s, 1H), 7.40 (d, J = 7.2Hz, 1H), 6.83 (q, J = 9.7, 9.1Hz, 2H), 4.84–4.75 (m, 1H), 4.67 (t, J = 5.4Hz, 2H), 4.02 (s, 1H), 3.77 (dd, J = 15.2, 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).

[0833] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0834]

[0835] The title compound was prepared in a manner similar to that of Example 1, except that propionaldehyde 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).

[0836] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0837]

[0838] The title compound was prepared in a manner similar to that of Example 3, except that 3,3,3-trifluoropropionaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 573.09 [M+H]+. ¹H NMR (400 MHz, chloroform-d) δ 10.55 (t, J = 5.8 Hz, 1H), 8.55 (s, 1H), 6.76–6.64 (m, 2H), 4.83–4.68 (m, 2H), 4.66 (dd, J = 14.6, 5.6 Hz, 1H), 4.26 (d, J = 2.2 Hz, 1H), 3.86 (dd, J = 15.0, 1H). .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).

[0839] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0840]

[0841] The title compound was prepared in a manner similar to that of Example 3, except that 5-bromopentanal oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 581.223 [M+H]+. 1¹H NMR (400MHz, chloroform-d) δ 10.35 (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=15 .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).

[0842] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0843]

[0844] The title compound was prepared in a manner similar to that of Example 1, except that benzaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 549.127 [M+H]+. 1 ¹H NMR (400MHz, chloroform-d) δ 10.44 (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), 4.32 ( 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,1H ),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).

[0845] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0846]

[0847] The title compound was prepared in a manner similar to that of Example 1, except that 2-phenylacetaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 563.165 [M+H]+. 1 ¹H NMR (400MHz, chloroform-d) δ 10.45 (t, J = 5.9 Hz, 1H), 8.36 (s, 1H), 7.39 (d, J = 6.4 Hz, 1H), 7.36–7.30 (m, 2H), 7.27 (s, 1H), 7.20 (dd, J = 6.9, 1.7 Hz, 2H), 6.95–6.75 (m, 2H), 4.68 (d, J = 6.0 Hz, 3H), 4.18 (s, 1H), 3.93 (d, J = 15.1 Hz, 1H), 3 .84(dd,J=14.9,1.9Hz,1H),3.70(dd,J=14.9,2.7Hz,1H),3.56(d,J=15.1Hz,1H),2.85(d,J=17.6Hz,1H),2.3 5(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).

[0848] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0849]

[0850] The title compound was prepared in a manner similar to that of Example 1, except that N-hydroxypicolinimidoyl chloride was used instead of N-hydroxyacetyliminoyl chloride in step 1. MS (m / z) 550.177 [M+H]+. 1 ¹H NMR (400MHz, 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).

[0851] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0852]

[0853] The title compound was prepared in a manner similar to that of Example 1, except that N-hydroxynicotinimidoyl chloride was used instead of N-hydroxyacetylimide 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).

[0854] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide:

[0855]

[0856] The title compound was prepared in a manner similar to that of Example 1, except that cyclopropylformaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 513.16 [M+H]+. 1 ¹H NMR (400MHz, chloroform-d) δ 10.43 (s, 1H), 8.35 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 6.83 (q, J = 10.0, 9.6 Hz, 2H), 4.83–4.71 (m, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.07 (s, 1H), 3.77 (d, J = 15.8 Hz, 1H), 3.42 (d, J = 15.1 Hz) z,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).

[0857] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0858]

[0859] 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]+. 1 ¹H NMR (400MHz, chloroform-d) δ 10.63 (d, J = 6.0 Hz, 1H), 8.62 (s, 1H), 7.44–7.32 (m, 1H), 6.91–6.71 (m, 2H), 4.73 (dd, J = 14.8, 6.5 Hz, 2H), 4.65–4.49 (m, 2H), 4.37 (d, J = 13.9 Hz, 1H) ),4.28(s,1H),3.87–3.78(m,1H),3.66(d,J=2.7Hz,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).

[0860] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0861]

[0862] Step 1 : Preparation of (E)-2-((tert-butyldiphenylsilyl)oxy)acetaldehyde oxime :

[0863] Hydroxylamine hydrochloride (0.28 g, 4.02 mmol) was added to a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetaldehyde (1 g, 3.35 mmol) in MeOH (15 mL) and H₂O (5 mL), followed by sodium bicarbonate (0.245 g, 4.02 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with H₂O and brine. The organic phase was dried over MgSO₄ and the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give the title compound. MS (m / z) 314.05 [M+H]⁺.

[0864] 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[isoxane] [Azazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide and (3'S,5R,7' R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylene pyridine Preparation of pyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0865] The title compound was prepared in a manner similar to that of 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide was obtained as the major stereoisomer. Furthermore, (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide was obtained as a minor stereoisomer. MS(m / z) 831.12[M+H]+ (major); 831.13[M+H]+ (minor).

[0866] Step 3 : (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyridyl] Preparation of [1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0867] TBAF (1N) (0.578 mL, 0.578 mmol) was added 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (160 mg, 0.193 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with NaHCO3 (saturated) and brine. The organic phase was dried over MgSO4 and the solvent was removed under vacuum. The residue was purified by silica gel chromatography to obtain the title compound. MS(m / z) 593.07 [M+H]+.

[0868] Step 4 : (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyridyl] Preparation of [1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0869] The title compound was prepared in a manner similar to step 4 of Example 5, except that (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diaza Cyclononene]-10'-formamide replaces (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide. MS (m / z) 595.09 [M+H]+.

[0870] Step 5 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1', 11'-Dioxo-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1, Preparation of 2-a][1,4]diazacyclic nonene]-10'-formamide :

[0871] The title compound was prepared in a manner similar to step 2 of Example 1, except that (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1, [4]diazacyclic nonene]-10'-carboxamide replaces (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide. MS (m / z) 505.18 [M+H]+. 1 ¹H NMR (400MHz, 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).

[0872] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0873]

[0874] The title compound was prepared in a manner similar to that used in Example 17 for (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide, except that in step 3, (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',1 1'-Dioxo-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide substituted with (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]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide. MS(m / z)505.18[M+H]+. 1H NMR (400MHz, chloroform-d) δ10.50(t,J=6.0Hz,1H),8.40(s,1H),7.38(q,J=8.1Hz,1H),6.84(q,J=9.0Hz ,2H),5.25(s,1H),5.13(s,1H),4.79(dt,J=10.6,6.7Hz,1H),4.66(d,J=5.8Hz,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).

[0875] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0876]

[0877] The title compound was prepared in a manner similar to that used in Example 17 for (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide, except that in step 2, (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene- 1,11-Dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (intermediate C) substituted with (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (intermediate F). MS (m / z) 523.21 [M+H]+. 1H NMR (400MHz, 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),2.70 (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).

[0878] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0879]

[0880] Step 1 : (3'S,5S,7'R)-12'-(benzyloxy)-3-formyl-3'-methyl-1',11'-dioxo-N-(2, 4,6-Trifluorobenzyl)-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyridine Preparation of [1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0881] Oxaloyl chloride (0.118 ml, 1.39 mmol) was added dropwise to a mixture of DMSO (0.215 ml, 3.03 mmol) in DCM (2 ml) at -78 °C. 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[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide (370 mg, 0.606 mmol) was added dropwise to DCM (2 mL). The resulting reaction mixture was stirred at -78 °C for 15 minutes. Triethylamine (0.426 mL, 3.03 mmol) was added to the reaction mixture, and the cooling bath was removed. The reaction mixture was stirred at room temperature for 30 minutes. EtOAc was added to dilute the reaction mixture, followed by H2O and brine. The organic phase was dried over MgSO4 and the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give the title compound. MS (m / z) 609.09 [M+H]+.

[0882] Step 2 : (3'S,5S,7'R)-12'-(benzyloxy)-3-(difluoromethyl)-3'-methyl-1',11'-dioxo-N- (2,4,6-Trifluorobenzyl)-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyridine Preparation of pyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0883] The title compound was prepared in a manner similar to step 4 of Example 5, except that (3'S,5S,7'R)-12'-(benzyloxy)-3-formyl-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diaza [Cyclononene]-10'-carboxamide replaces (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 631.13 [M+H]+.

[0884] Step 3 : (3'S,5S,7'R)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2, 4,6-Trifluorobenzyl)-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyridine Preparation of [1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0885] The title compound was prepared in a manner similar to step 5 of Example 5, except that (3'S,5S,7'R)-12'-(benzyloxy)-3-(difluoromethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]di [Azacyclic nonene]-10'-carboxamide replaces (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide. MS (m / z) 541.21 [M+H]+. 1H NMR (400MHz, 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).

[0886] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0887]

[0888] The title compound was prepared in a manner similar to that of Example 20, except that in step 1, (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4] [diazacyclononene]-10'-formamide replaces (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-formamide. 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),2.71 (d,J=17.9Hz,1H),2.16–1.96(m,3H),1.70–1.58(m,1H),1.34(d,J=6.6Hz,3H).

[0889] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0890]

[0891] Step 1 : (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)- N-(2,4-Difluorobenzyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-] Preparation of [2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0892] The title compound was prepared in a manner similar to steps 1 to 2 of Example 17, except that (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (intermediate G) was used instead of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (intermediate F). MS (m / z) 829.12 [M+H]+.

[0893] Step 2 : (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl- 1',11'-Dioxo-1',11'-Dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2- Preparation of [1,4]diazacyclic nonene]-10'-formamide :

[0894] The title compound was prepared in a manner similar to step 3 of Example 17, except that (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diaza Cyclononene]-10'-carboxamide replaces (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide. MS (m / z) 591.13 [M+H]+.

[0895] Step 3 : (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(methoxymethyl)-3'-methyl 1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1, Preparation of 2-a][1,4]diazacyclic nonene]-10'-formamide :

[0896] NaH (60% in mineral oil) (5.4 mg, 0.14 mmol) was added to a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxaazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (41 mg, 0.0694 mmol) in DMF (2 ml) at 0 °C, followed by the addition of MeI (0.004 ml, 0.0694 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4 and the solvent was removed under vacuum. The residue was purified by silica gel column chromatography to obtain the title compound. MS (m / z) 605.09 [M+H]+.

[0897] Step 4 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(methoxymethyl)-3'-methyl- 1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyridyl] Preparation of [1,2-a][1,4]diazacyclic nonene]-10'-formamide :

[0898] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (27 mg, 0.045 mmol) and 10% Pd / C (3.8 mg) in EtOH (2 mL) was stirred at room temperature under H2 (g) at 1 atm. After 2 hours, the reaction mixture was filtered, concentrated, and purified by reversed-phase preparative HPLC (5% to 100% MeCN / water containing 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,1 H), 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).

[0899] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0900]

[0901] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0902] A 1M solution of LiHMDS in THF (0.373 ml) was added 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[isoxazol-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (43 mg, 0.075 mmol) in THF (10 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 heating to -20 °C. After 2 hours, the reaction was quenched by adding a saturated NH4Cl solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated and purified by silica gel column chromatography (eluting with 0% to 5% MeOH / EtOAc) to give the title compound. MS(m / z) 591.138 [M+H]+ and MS(m / z) 593.189 [M+H]+.

[0903] Step 2 : (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dihydroxy-3,3',4-trimethyl-1',11'-dihydroxy-3',3',4-trimethyl-1',11'-dihydroxy-3',3',4' ... oxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a] Preparation of [1,4]diazacyclic nonene]-10'-formamide :

[0904] TFA (0.3 mL) was added 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (14 mg, 0.024 mmol) in toluene (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10% to 90% aqueous acetonitrile solution to give the title compound. MS (m / z) 501.282 [M+H] + . 1 ¹H NMR (400MHz, 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),1.58 (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).

[0905] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0906]

[0907] TFA (0.3 mL) was added 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (14 mg, 0.024 mmol) in toluene (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10% to 90% aqueous acetonitrile solution 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).

[0908] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0909]

[0910] Step 1 : (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4, 11'-Trioxo-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1, Preparation of 2-a][1,4]diazacyclic nonene]-10'-formamide :

[0911] At room temperature, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyl-3-(1H)-one (Dies Martin periodane) (10 mg, 0.023 mmol) was added 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (9 mg, 0.0152 mmol) in DCM (3 ml). The reaction was quenched by adding saturated NaHCO3 and Na2SO3 solutions. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 50% to 100% EtOAc / hexane) to give the title compound. MS (m / z) 590.906 [M+H]+.

[0912] Step 2 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-tris ... oxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a] Preparation of [1,4]diazacyclic nonene]-10'-formamide :

[0913] TFA (0.3 mL) was added 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (8.97 mg, 0.0152 mmol) in toluene (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC, eluting with 10% to 90% aqueous acetonitrile solution to give the title compound. MS (m / z) 500.995 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.42 (s, 1H), 8.37 (s, 1H), 7.38 (q, J = 8.1 Hz, 1H), 6.84 (q, J = 9.1, 8.6 Hz, 2H), 4.81 (s, 1H), 4.65 (d, J = 5.8 Hz, 1H), 4.13–3.99 (m, 2H), 3.74 (dd, J = 15.3, 2.8 Hz, 1H), 2.19 (s, 3H), 2.12 (d, J = 15.4 Hz, 1H), 1.94–1.85 (m, 3H), 1.66–1.59 (m, 1H), 1.38 (d, J = 6.7 Hz, 3H).

[0914] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0915]

[0916] (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-carboxamide was prepared in a manner similar to that in 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide substituted 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,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide. 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),6.93–6 .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).

[0917] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide (peak 1) 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]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide (peak 2):

[0918]

[0919] Step 1 : (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'-dimethyl-1', 11'-Dioxo-1',4',5',11'-Tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1, Preparation of 2-a][1,4]diazacyclic nonene]-10'-formamide :

[0920] At 0°C, 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (82 mg, 0.138 mmol) prepared according to Example 26 in DCM (4 ml) was added to bis(2-methoxyethyl)aminosulfur trifluoride (153 mg, 0.692 mmol). After 30 minutes, the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with EtOAc, the organic phase was separated and dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 0% to 100% EtOAc / hexane) to give the title compound as a mixture of stereoisomers. MS (m / z) 595.046

[0921] Step 2 : (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'- Dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a] Preparation of [1,4]diazacyclic nonene]-10'-formamide :

[0922] TFA (1 mL) was added to a solution of a mixture of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclononene]-10'-carboxamide (25.1 mg, 0.0422 mmol) in toluene (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was separated and purified by reversed-phase preparative HPLC, eluting with 10% to 90% aqueous acetonitrile solution to give the title compound.

[0923] Peak 1: MS (m / z) 505.173 [M+H] + . 1 H 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=10.5H z,1H),4.75–4.54(m,3H),3.81(dd,J=4.2,2.3Hz,2H),2.18(d,J=3.3Hz,3 H), 2.09–1.98 (m, 3H), 1.54 (dd, J=15.8, 6.2Hz, 1H), 1.33 (d, J=6.7Hz, 3H).

[0924] Peak 2: MS (m / z) 505.154 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.50 (d, J = 5.9 Hz, 1H), 8.33 (s, 1H), 7.38 (q, J = 8.4, 8.0 Hz, 1H), 6.92–6.78 (m, 2H), 5.34 (d, J = 53.8 Hz, 1H), 4.85–4.59 (m, 3H), 3.93 (dd, J = 14.9, 1.8H) z,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).

[0925] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0926]

[0927] The title compound was prepared in a manner similar to that of Example 24, except that (3'S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a]) was prepared according to Example 26. [1,4]diazacyclic nonene]-10'-formamide replaces (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide. MS (m / z) 503.299 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 11.60 (s, 1H), 9.95–9.84 (m, 1H), 8.33 (s, 1H), 7.40 (q, J = 8.3, 7.8 Hz, 1H), 6.86 (dt, J = 10.2, 6.9 Hz, 2H), 5.16 (s, 1H), 4.86 (td, J = 14.8, 7.2 Hz, 2H), 4.40 (dd, J=14.9,3.9Hz,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).

[0928] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0929]

[0930] The title compound was prepared in a manner similar to that of Example 25, except that (3'S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a]) was prepared according to Example 26. [1,4]diazacyclic nonene]-10'-formamide replaces (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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide. MS (m / z) 500.97 [M+H] + . 1 HNMR (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=15.4,6.2 Hz,1H),4.55(dd,J=15.4,5.4Hz,1H),4.22(s,1H),3.95–3.78(m,2H),2.1 8(s,3H),2.14–2.05(m,2H),1.63(t,J=5.1Hz,2H),1.37(d,J=6.6Hz,3H).

[0931] 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[isoxazo-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide:

[0932]

[0933] 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]bridged methylene pyridine [1,2-a][1,4]diazacyclic nonene]-10'-formamide (peak 1) and (3'S,4R,5R,7'R)-12'-(benzyloxy)- N-(2,4-Difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7' H-spiro[isoxazole-5,6'-[2,7]bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene]-10'-formamide (peak 2) Preparation :

[0934] Sodium borohydride (2.4 mg, 0.064 mmol) was add...

Claims

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

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 。 6. The compound of claim 1, wherein the compound is: 。 7. The compound of claim 1, wherein the compound is: 。 8. The compound of claim 1, wherein the compound is: 。 9. The compound of claim 1, wherein the compound is: 。 10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 10, further comprising one, two, three or four additional therapeutic agents.

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

13. The pharmaceutical composition of any one of claims 10-12, wherein the pharmaceutical composition is an oral or parenteral composition.

14. Use of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 10-13, in the preparation of a medicament for treating HIV infection in a person who has or is at risk of HIV infection.

15. The use according to claim 14, wherein the medicament further comprises one, two, three or four additional therapeutic agents in a therapeutically effective amount.

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

17. The use according to any one of claims 14-16, wherein the drug is an oral, intravenous, subcutaneous, or intramuscular drug.

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