Therapeutic compounds for HIV viral infection

Abstract

Providing methods of treating diseases SOLUTION: The present disclosure relates generally to certain compounds, pharmaceutical compositions comprising the compounds, and methods of making and using the compounds and pharmaceutical compositions. The compounds and compositions provided herein may be used in the treatment or prevention of Retroviridae infections, including HIV infections. As explained in detail and demonstrated specifically herein, surprisingly, according to the invention, a significant effect is achieved, which the person skilled in the art could not have easily predicted from the prior art.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 285,753, filed December 3, 2021, the entire contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates generally to novel compounds and pharmaceutical compositions containing such compounds for use in the prevention or treatment of Retroviridae viral infections, including infections caused by human immunodeficiency virus (HIV). The disclosure also relates to methods of making such compounds and intermediates in the preparation of such compounds. [Background technology]

[0003] Positive-stranded single-stranded RNA viruses, including the Retroviridae family, include the subfamily Orthoretrovirus and the genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus, which cause numerous human and animal diseases. Human infection with HIV-1, a lentivirus, leads to T helper cell depletion and immune dysfunction, resulting in immunodeficiency and susceptibility to opportunistic infections. Treatment of HIV-1 infection with highly active antiretroviral therapy (HAART) has been shown to be effective in reducing viral load and significantly delaying disease progression (Hammer, SM, et al.; JAMA 2008, 300:555-570). However, these treatments may lead to the emergence of HIV strains resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, RJ, et al., Science 2010, 327:697-701). Therefore, there is an urgent need to discover new antiretroviral agents that are active against newly drug-resistant HIV mutants. Also of interest in the field of HIV therapy and treatment is providing patients with regimens with improved pharmacokinetic properties, including, for example, enhanced efficacy, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties. Although current regimens for treating HIV have advanced enough that patients no longer need to take tablets multiple times a day, today's patients still need to take tablets every day for the foreseeable course of their lives. Therefore, it would be beneficial to have an HIV therapy that requires patients to take the drug less than once a day (e.g., once every two days, once a week, once every two weeks, once a month, etc.), or to take a lower effective dose of the drug on a daily, weekly, monthly, or longer basis. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Hammer,SM,et al.;JAMA 2008,300:555-570 [Non-patent document 2] Taiwo, B., International Journal of Infectious Diseases 2009,13:552-559 [Non-patent document 3] Smith,RJ,et al.,Science 2010,327:697-701 Summary of the Invention

[0005] In one embodiment, a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is C 3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered fused bicyclic heteroaryl, wherein C 3~7Monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered fused bicyclic heteroaryl each independently represent 1 to 3 R 1 optionally substituted with a group, Each R 1 are independently -CN, halogen, R a , R b , R c , C 1~6 alkyl, or 4- to 7-membered monocyclic heterocyclyl; where C 1~6 Alkyl is -CN, halogen, R a , R b , R c , -SR 2 and =NR 2a and optionally substituted with 1 to 3 groups independently selected from Here, the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —CN, halogen, and R a , R b and R c and optionally substituted with 1 to 3 groups independently selected from Each R a are independently —P(O)(OH) or —OP(O)(OH), Each R b are independently -C(O)R 2 , -C(O)OR 2 , -C(O)NR 3 R 3 , -C(O)C(O)OR 2 , -S(O)2R 2 , -S(O)NR 3 R 3 , or -S(O)2OR 3 and Each R c are independently -OR 2 , -OC(O)R 2 , -OC(O)C(O)OR 2 , -NR 3 R 3 , -N + R 3 R 3 R 3a , -NR3 C(O)R 2 , -NR 3 C(O)NR 3 R 3 , -NR 3 C(O)OR 2 , -NR 3 C(O)C(O)OR 2 , or -NR 3 S(O)2R 2 and Each R 2 are independently H or C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R d and R e and optionally substituted with 1 to 3 groups independently selected from Each R 2a are independently H or C 1~3 is alkyl, Each R 3 are independently H or C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R d , R e and =NR 3a and optionally substituted with 1 to 3 groups independently selected from Each R 3a are independently H or C 1~3 is alkyl, Each R d are independently -C(O)R 4 , -C(O)OR 4 , -C(O)NR 4 R 4 , -C(O)C(O)OR 4 , -S(O)2R 4 , -S(O)NR 4 R 4 , or -S(O)2OR 4 and Each R e are independently -OR 4 , -OC(O)R 4 , -OC(O)C(O)OR 4 , -NR4 R 4 , -N + R 4 R 4 R 4a , -NR 4 C(O)R 4 , -NR 4 C(O)NR 4 R 4 , -NR 4 C(O)OR 4 , -NR 4 C(O)C(O)OR 4 , or -NR 4 S(O) 2nd Round 4 and Each R 4 are independently H or C 1~6 alkyl, where C 1~6 Alkyl is -OH, CN, halogen, -COOH and R a and optionally substituted with 1 to 3 groups independently selected from each 4-membered monocyclic heterocyclyl has one ring heteroatom selected from N, O, and S; each 5- to 7-membered monocyclic heterocyclyl has 1 to 2 ring heteroatoms independently selected from N, O, and S; wherein each 5-6 membered monocyclic heteroaryl and 8-10 membered fused bicyclic heteroaryl independently has 1-4 ring heteroatoms independently selected from N, O and S; Provided herein are compounds of Formula I, or pharmaceutically acceptable salts thereof:

[0006] In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In one embodiment, provided herein is a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0008] In one embodiment, provided herein is a method of treating human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0009] In one embodiment, provided herein is a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in therapy.

[0010] In one embodiment, there is provided a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to the patient.

[0011] In one embodiment, there is provided a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in a method of treating human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, the method comprising administering to the patient a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition. DETAILED DESCRIPTION OF THE INVENTION

[0012] I. Definition The following description is made with the understanding that the present disclosure should be considered as an example of claimed subject matter and is not intended to limit the scope of the appended claims to the particular embodiments illustrated. Headings used throughout this disclosure are for convenience only and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0013] Unless otherwise defined, all technical and scientific terms used herein are understood by those of ordinary skill in the art. " has the same meaning as commonly understood by the term "a," "and," and "the." As used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0014] As used in this disclosure, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment for a substituent. For example, -CONH2 is attached through a carbon atom. Dashes before or after chemical groups are for convenience; chemical groups may be designated with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. No directionality is indicated or implied by the order in which chemical groups are written or named, unless chemically or structurally required. A solid line extending from the center of a ring (including fused, bridged, or spirocyclic ring systems) indicates that the point of attachment of a substituent to that ring may be at any ring atom. For example, R in the following structure: aamay be attached to any of the five carbon ring atoms, or the hydrogen attached to the nitrogen ring atom may be attached to R aa may be replaced by: [ka] As another example, R in the following structure: aa So, [ka] R aa can be attached at any of the numbered positions shown below: [ka]

[0016] A solid line projecting from the center of a ring (including fused, bridged, or spirocyclic ring systems) indicates that the point of attachment of the ring system to the remainder of the compound can be at any ring atom of the fused, bridged, or spirocyclic ring system. For example, in the structure: [ka] Monocyclic heterocyclyls are compounds that are bonded to the ring at any of the numbered positions shown below. Can be attached to the rest of the thing: [ka] As another example, in the following fused bicyclic heterocyclic structure: [ka] The fused bicyclic heterocyclyl can be attached to the rest of the compound at any of the eight numbered positions shown below: [ka]

[0017] "C u~vThe prefix "" indicates that the following group has carbon atoms u through v. For example, "C 1~6 "Alkyl group" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "xy-membered" ring, where x and y are numerical ranges (e.g., "3-12-membered heterocyclyl"), refers to a ring having x to y (i.e., 3 to 12) atoms, up to 80% of which may be heteroatoms such as N, O, S, P, etc., and the remaining atoms are carbon.

[0018] Also, certain commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups, or alkylyl groups, "arylene" or "arylenyl" groups, or aryl groups, respectively.

[0019] "Compounds disclosed herein" or "compounds of the disclosure" or "compounds provided herein" or "compounds described herein" refer to compounds of Formula I. Also included are the specific compounds of Examples 1-37.

[0020] Reference herein to "about" a value or parameter includes (and describes) embodiments related to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Additionally, the term "about X" includes the description of "X."

[0021] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1~20 alkyl), having 1 to 12 carbon atoms (i.e., C 1~12 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), having 1 to 6 carbon atoms (i.e., C1~6 alkyl), having 1 to 4 carbon atoms (i.e., C 1~4 alkyl), having 1 to 3 carbon atoms (i.e., C 1~3 alkyl), or having 1 to 2 carbon atoms (i.e., C 1~2 alkyl). Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbon atoms is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0022] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), having 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), having 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or having 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an aliphatic group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0023] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), having 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), having 2 to 6 carbon atoms (i.e., C2~6 alkynyl), or having 2 to 4 carbon atoms (i.e., C 2~4 alkynyl), an aliphatic group. The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0024] "Alkylene" refers to a divalent unbranched saturated hydrocarbon chain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C 1~20 alkylene), having 1 to 12 carbon atoms (i.e., C 1~12 alkylene), having 1 to 8 carbon atoms (i.e., C 1~8 alkylene), having 1 to 6 carbon atoms (i.e., C 1~6 alkylene), having 1 to 4 carbon atoms (i.e., C 1~4 alkylene), having 1 to 3 carbon atoms (i.e., C 1~3 alkylene), or having 1 to 2 carbon atoms (i.e., C 1~2 alkylene). Examples of alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. In some embodiments, alkylene is optionally substituted with an alkyl group. Substituted alkylene groups include -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH(CH2CH3)-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH(CH3)CH(CH3)-, -CH2C(CH2CH3)(CH3)-, and -CH2C(CH2CH3)2.

[0025] "Alkoxy" refers to an "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. "Haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms have been replaced by halogen.

[0026] "Acyl" refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, Examples of acyl include aryl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0027] "Amide" is -C(=O)NR y R z "C-amido" refers to the group, and -NR y C(=O)R z "N-amide group" refers to both the y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl, each of which can be optionally substituted.

[0028] "Amino" is -NR y R z refers to a group, wherein R y and R z is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which can be optionally substituted.

[0029] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), having 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), or having 6 to 10 carbon ring atoms (i.e., C 6~10Aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

[0030] "Cyano" or "carbonitrile" refers to the group --CN.

[0031] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0032] "Bridged" refers to a ring fusion in which non-adjacent atoms on the rings are joined by a divalent substituent such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0033] The term "fused" refers to rings that are joined to adjacent rings.

[0034] "Spiro" refers to a ring substituent joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine, respectively, are spiro substituents.

[0035] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Alkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms have been replaced by a halogen. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0036] "Heteroalkylene" refers to a divalent unbranched saturated hydrocarbon chain having 1, 2, or 3 heteroatoms selected from NH, O, or S. As used herein, heteroalkylene refers to a heterocyclic group having 1 to 20 carbon atoms and 1, 2, or 3 heteroatoms selected from NH, O, and S (i.e., C 1~20 heteroalkylene; 1 to 8 carbon atoms and 1, 2, or 3 heteroatoms selected from NH, O, and S (i.e., C 1~8 heteroalkylene; 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms selected from NH, O, and S (i.e., C 1~6 heteroalkylene; 1 to 4 carbon atoms and 1, 2, or 3 heteroatoms selected from NH, O, and S (i.e., C 1~4 heteroalkylene; 1 to 3 carbon atoms and 1, 2, or 3 heteroatoms selected from NH, O, and S (i.e., C 1~3heteroalkylene); or 1 to 2 carbon atoms and 1, 2, or 3 heteroatoms selected from NH, O, and S (i.e., C 1~3 Heteroalkylene groups include -CH2CHO-, -CH2SCH2-, -CH2CHOCH2-, -CH2NHCH2-, and -CH2NHCH2-. In some embodiments, heteroalkylene is optionally substituted with an alkyl group. Examples of substituted heteroalkylene groups include -CH(CH3)N(CH3)CH2-, -CHOCH(CH3)-, -CH2CH(CH2CH3)S-, -CH2NHC(CH3)2-, -C(CH3)2SCH2-, -CH(CH3)N(CH3)CH(CH3)O-, -CH2SC(CH2CH3)(CH3)-, and -CH2C(CH2CH3)2NH-.

[0037] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having 1 to 20 carbon ring atoms (i.e., C 1~20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C 3~12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3~8 Heteroaryl) and contains 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass and does not overlap with aryl, as defined above.

[0038] "Heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a non-aromatic cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, "heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a saturated or partially saturated ring unless otherwise specified. For example, in some embodiments, "heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a partially saturated ring when specified. The term "heterocyclyl" or "heterocyclic ring" or "heterocycle" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond). A heterocyclyl may be monocyclic or polycyclic, and polycyclic rings may be fused, bridged, or spiro. As used herein, a heterocyclyl is , having 2 to 20 carbon ring atoms (i.e., C 2~20 heterocyclyl), having 2 to 12 carbon ring atoms (i.e., C 2~12 heterocyclyl), having 2 to 10 carbon ring atoms (i.e., C 2~10 heterocyclyl), having 2 to 8 carbon ring atoms (i.e., C 2~8 heterocyclyl), having 3 to 12 carbon ring atoms (i.e., C 3~12 heterocyclyl), having 3 to 8 carbon ring atoms (i.e., C 3~8 heterocyclyl), or having 3 to 6 carbon ring atoms (i.e., C 3~6Heterocyclyl; having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclyl" refers to a 4- to 10-membered ring moiety connected at two non-adjacent atoms of a heterocyclyl having one or more (e.g., one or two) 4- to 10-membered ring moieties, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. As used herein, "bridged heterocyclyl" includes bicyclic and tricyclic ring systems. As used herein, the term "spiroheterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, wherein the one or more additional rings are 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, and a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyls include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. As used herein, the terms "heterocycle," "heterocyclyl," and "heterocyclic ring" are used interchangeably. In some embodiments, the heterocyclyl is substituted with an oxo group.

[0039] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0040] "Oxo" refers to the (=O) or (O) radical.

[0041] "Sulfonyl" is -S(O)R bb refers to a group, wherein R bbis alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0042] Whenever a group illustration terminates in a single bonded nitrogen atom, that group represents an -NH group unless otherwise indicated. Similarly, unless otherwise stated, hydrogen atoms are implied and considered to be present when needed to complete valence or provide stability, given the knowledge of those skilled in the art.

[0043] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not. Also, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0044] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents may include alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, or the like. Examples of substituents include, but are not limited to, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonate, alkylsulfonyl, thiocyanato, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining a substituent with an infinite number of additional substituents (e.g., a substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl." Unless otherwise specified, if a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

[0045] In some embodiments, the substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and / or substituted heteroaryl includes a cycloalkyl, heterocyclyl, aryl, and / or heteroaryl having a substituent on a ring atom, where the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl is attached to the remainder of the compound. For example, in the moiety below, the cyclopropyl is substituted with a methyl group: [ka]

[0046] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, with respect to absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0047] "Stereoisomers" refer to compounds made up of the same atoms connected by the same bonds but with different, not interchangeable, three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0048] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scalemic" mixture.

[0049] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0050] "Tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compounds provided herein.

[0051] Some of the compounds provided herein exist as tautomeric isomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compounds include both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0052] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds provided herein are also provided. Hydrates of the compounds provided herein are also provided.

[0053] Any formula or structure provided herein is also intended to represent unlabeled and isotopically labeled forms of the compound.Isotopically labeled compounds have the structure shown by the formula provided herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure include, but are not limited to, 2 H, 3 H, 13 C and 14 1C, which incorporate a radioactive isotope, also provided herein. Such isotopically labeled compounds are useful for metabolic studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays. Such techniques may be useful in detection or imaging techniques such as radiotherapy, or in the radiation treatment of patients.

[0054] The present disclosure also includes compounds of Formula I in which 1 to n hydrogens attached to carbon atoms have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be prepared by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium. It is synthesized.

[0055] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure exhibit improved DMPK (drug metabolism and pharmacokinetics) properties related to absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may afford certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0056] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have that hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0057] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0058] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, mono-, di-, or tricycloalkylamines, mono-, di-, or triarylamines, or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0059] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0060] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Such vehicles and excipients for pharmaceutically active substances are not intended to be limiting. The use of pharmaceutical agents is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0061] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting the disease or condition (i.e., reducing one or more symptoms resulting from the disease or condition and / or attenuating the severity of the disease or condition), b) slowing or arresting the onset of one or more clinical symptoms associated with the disease or condition (i.e., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (i.e., metastasis) of the disease or condition), and / or c) palliating the disease, i.e., causing regression of clinical symptoms (i.e., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0062] "Prevention" or "preventing" means any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0063] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0064] The terms "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, means an amount sufficient to effect treatment and provide a therapeutic benefit, such as amelioration of symptoms or slowing of disease progression, when administered to a subject. For example, a therapeutically effective amount can be an amount sufficient to ameliorate the symptoms of a Retroviridae virus infection, including, but not limited to, an HIV infection. A therapeutically effective amount may vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0065] II. Compounds In one embodiment, a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is C 3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered fused bicyclic heteroaryl, wherein C 3~7 Monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered fused bicyclic heteroaryl each independently represent 1 to 3 R 1optionally substituted with a group, Each R 1 are independently -CN, halogen, R a , R b , R c , C 1~6 alkyl, or 4- to 7-membered monocyclic heterocyclyl; where C 1~6 Alkyl is -CN, halogen, R a , R b , R c , -SR 2 and =NR 2a and optionally substituted with 1 to 3 groups independently selected from Here, the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —CN, halogen, and R a , R b and R c and optionally substituted with 1 to 3 groups independently selected from Each R a are independently —P(O)(OH) or —OP(O)(OH), Each R b are independently -C(O)R 2 , -C(O)OR 2 , -C(O)NR 3 R 3 , -C(O)C(O)OR 2 , -S(O)2R 2 , -S(O)NR 3 R 3 , or -S(O)2OR 3 and Each R c are independently -OR 2 , -OC(O)R 2 , -OC(O)C(O)OR 2 , -NR 3 R 3 , -N + R 3 R 3 R 3a , -NR 3 C(O)R 2 , -NR 3 C(O)NR 3 R 3 , -NR 3 C(O)OR2 , -NR 3 C(O)C(O)OR 2 , or -NR 3 S(O)2R 2 and Each R 2 are independently H or C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R d and R e and optionally substituted with 1 to 3 groups independently selected from Each R 2a are independently H or C 1~3 is alkyl, Each R 3 are independently H or C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R d , R e and =NR 3a and optionally substituted with 1 to 3 groups independently selected from Each R 3a are independently H or C 1~3 is alkyl, Each R d are independently -C(O)R 4 , -C(O)OR 4 , -C(O)NR 4 R 4 , -C(O)C(O)OR 4 , -S(O)2R 4 , -S(O)NR 4 R 4 , or -S(O)2OR 4 and Each R e are independently -OR 4 , -OC(O)R 4 , -OC(O)C(O)OR 4 , -NR 4 R 4 , -N + R 4 R 4 R 4a , -NR 4 C(O)R4 , -NR 4 C(O)NR 4 R 4 , -NR 4 C(O)OR 4 , -NR 4 C(O)C(O)OR 4 , or -NR 4 S(O)2R 4 and Each R 4 are independently H or C 1~6 alkyl, where C 1~6 Alkyl is -OH, CN, halogen, -COOH and R a and optionally substituted with 1 to 3 groups independently selected from each 4-membered monocyclic heterocyclyl has one ring heteroatom selected from N, O, and S; each 5- to 7-membered monocyclic heterocyclyl has 1 to 2 ring heteroatoms independently selected from N, O, and S; Provided herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein each 5-6 membered monocyclic heteroaryl and 8-10 membered fused bicyclic heteroaryl independently has 1-4 ring heteroatoms independently selected from N, O, and S.

[0066] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is C 3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, where C 3~7 Monocyclic cycloalkyl, 4- The 7-membered monocyclic heterocyclyl, phenyl, and 5- to 6-membered monocyclic heteroaryl each independently have 1 to 3 R 1 optionally substituted with a group, Each R 1 are independently -CN, halogen, R a , R b , R c , C 1~6 alkyl, or 4- to 7-membered monocyclic heterocyclyl; where C1~6 Alkyl is -CN, halogen, R a , R b , R c , -SR 2 and =NR 2a and optionally substituted with 1 to 3 groups independently selected from Here, the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —CN, halogen, and R a , R b and R c and optionally substituted with 1 to 3 groups independently selected from Each R a are independently —P(O)(OH) or —OP(O)(OH), Each R b are independently -C(O)R 2 , -C(O)OR 2 , -C(O)NR 3 R 3 , -C(O)C(O)OR 2 , -S(O)2R 2 , -S(O)NR 3 R 3 , or -S(O)2OR 3 and Each R c are independently -OR 2 , -OC(O)R 2 , -OC(O)C(O)OR 2 , -NR 3 R 3 , -N + R 3 R 3 R 3a , -NR 3 C(O)R 2 , -NR 3 C(O)NR 3 R 3 , -NR 3 C(O)OR 2 , -NR 3 C(O)C(O)OR 2 , or -NR 3 S(O)2R 2 and Each R 2 are independently H or C 1~6 alkyl, where C1~6 Alkyl is -OH, -CN, halogen, -C(O)OH and R a and optionally substituted with 1 to 3 groups independently selected from Each R 2a are independently H or C 1~3 is alkyl, Each R 3 are independently H, -C(O)OR 4 , or C 1~6 alkyl, where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OR 4 , -NR 4 R 4 , R a , and =NR 3a and optionally substituted with 1 to 3 groups independently selected from Each R 3a are independently H or C 1~3 is alkyl, Each R 4 are independently H or C 1~6 alkyl, where C 1~6 Alkyl is -OH, CN, halogen, -COOH and R a and optionally substituted with 1 to 3 groups independently selected from each 4-membered monocyclic heterocyclyl has one ring heteroatom selected from N, O, and S; each 5- to 7-membered monocyclic heterocyclyl has 1 to 2 ring heteroatoms independently selected from N, O, and S; wherein each 5-6 membered monocyclic heteroaryl and 8-10 membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.

[0067] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is C 3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, where C 3~7Monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, and 5- to 6-membered monocyclic heteroaryl each independently represent 1 to 3 R 1 optionally substituted with a group, Each R 1 are independently -OH, -CN, halogen, -C(O)OR 2 , -NR 3 R 3 , -NR 3 C(O)C(O)OR 2 , R a , C 1~6 alkyl, or 4- to 7-membered monocyclic heterocyclyl; where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH, -NR 3 R 3 , -NR 3 C(O)OR 2 , R a , -SR 2 and =NR 2a and optionally substituted with 1 to 3 groups independently selected from Here, the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —OH, —CN, halogen, —C(O)OH and R a and optionally substituted with 1 to 3 groups independently selected from Each R a are independently —P(O)(OH) or —OP(O)(OH), Each R 2 are independently H or C 1~4 alkyl, where C 1~4 Alkyl is -OH, -CN, halogens, -C(O)OH and R a and optionally substituted with 1 to 3 groups independently selected from Each R 2a are independently H or C 1~3 is alkyl, Each R 3 are independently H, -C(O)OR 4 , or C 1~4 alkyl, where C 1~4Alkyl is -OH, -CN, halogen, -C(O)OR 4 , -NR 4 R 4 , R a , and =NR 3a and optionally substituted with 1 to 3 groups independently selected from Each R 3a are independently H or C 1~3 is alkyl, Each R 4 are independently H or C 1~3 alkyl, where C 1~3 Alkyl is -OH, CN, halogen, -COOH and R a and optionally substituted with 1 to 3 groups independently selected from each 4-membered monocyclic heterocyclyl has one ring heteroatom selected from N, O, and S; each 5- to 7-membered monocyclic heterocyclyl has 1 to 2 ring heteroatoms independently selected from N, O, and S; wherein each 5-6 membered monocyclic heteroaryl and 8-10 membered fused bicyclic heteroaryl independently has 1 to 4 ring heteroatoms independently selected from N, O and S.

[0068] As used herein, a 4-membered monocyclic heterocyclyl has 1 ring heteroatom selected from N, O, and S. As used herein, a 5- to 7-membered monocyclic heterocyclyl has 1 to 2 ring heteroatoms independently selected from N, O, and S. As used herein, a 5- to 6-membered monocyclic heteroaryl has 1 to 4 ring heteroatoms independently selected from N, O, and S. As used herein, an 8- to 10-membered fused bicyclic heteroaryl has 1 to 4 ring heteroatoms independently selected from N, O, and S.

[0069] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is C 3~7monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered fused bicyclic heteroaryl, wherein C 3~7 Monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, and 8- to 10-membered fused bicyclic heteroaryl each independently represent 1 to 3 R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is optionally substituted with a C group. 3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, where C 3~7 Monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, and 5- to 6-membered monocyclic heteroaryl each independently represent 1 to 3 R 1 is optionally substituted with a group.

[0070] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is C 3~7 is a monocyclic cycloalkyl, C 3~7 Monocyclic cycloalkyl has 1 to 3 R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is optionally substituted with a C group. 3~7 is a monocyclic cycloalkyl, C 3~7 Monocyclic cycloalkyl has 1 to 2 R 1 is optionally substituted with a group.

[0071] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is a 4- to 7-membered monocyclic heterocyclyl, wherein the 4- to 7-membered monocyclic heterocyclyl is selected from 1 to 3 R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, the compound is a 4- to 7-membered monocyclic heterocyclyl, wherein the 4- to 7-membered monocyclic heterocyclyl is optionally substituted with one to two R 1In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is optionally substituted with a group. , piperazinyl, or morpholinyl, each of which is selected from the group consisting of 1 to 2 R 1 is optionally substituted with a group.

[0072] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is phenyl, and the phenyl is selected from 1 to 3 R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is phenyl, and the phenyl is optionally substituted with one to two R 1 is optionally substituted with a group.

[0073] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is naphthalenyl, and the naphthalenyl is selected from 1 to 3 R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is naphthalenyl, and the naphthalenyl is optionally substituted with one to two R 1 is optionally substituted with a group.

[0074] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is a 5-6 membered monocyclic heteroaryl, and the 5-6 membered monocyclic heteroaryl is selected from 1 to 3 R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is a 5-6 membered monocyclic heteroaryl, and the 5-6 membered monocyclic heteroaryl is optionally substituted with one to two R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is pyridinyl, and the pyridinyl is optionally substituted with one to two R 1 is optionally substituted with a group.

[0075] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is an 8- to 10-membered fused bicyclic heteroaryl, and the 8- to 10-membered fused bicyclic heteroaryl is selected from 1 to 3 R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is an 8- to 10-membered fused bicyclic heteroaryl, and the 8- to 10-membered fused bicyclic heteroaryl is optionally substituted with one to two R 1 is optionally substituted with a group.

[0076] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, X is one R 1 is optionally substituted with a group.

[0077] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 1 are independently -CN, halogen, R a , R b , R c , C 1~6 alkyl, or 4- to 7-membered monocyclic heterocyclyl; where C 1~6 Alkyl is -CN, halogen, R a , R b , R c , -SR 2 and =NR 2a and optionally substituted with 1 to 3 groups independently selected from Here, the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —CN, halogen, and R a , R b and R c and optionally substituted with 1 to 3 groups independently selected from:

[0078] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 1 are independently -OH, -CN, halogen, -C(O)OR 2 , -NR 3 R 3 , -NR 3 C(O)C(O)OR 2 , Ra , C 1~6 alkyl, or 4- to 7-membered monocyclic heterocyclyl; where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH, -NR 3 R 3 , -NR 3 C(O)OR 2 , R a , -SR 2 and =NR 2a and optionally substituted with 1 to 3 groups independently selected from Here, the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —OH, —CN, halogen, —C(O)OH and R a and optionally substituted with 1 to 3 groups independently selected from:

[0079] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is -CN. Some embodiments of compounds of formula I or pharmaceutically acceptable salts thereof So, one or more R 1 is halogen. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is R b In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is R c In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 -C(O)OR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is -NR 3 R 3In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 Ha-NR 3 C(O)C(O)OR 2 is.

[0080] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R b , R c , -SR 2 and =NR 2a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is C 1~6 alkyl, where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH, -NR 3 R 3 , -NR 3 C(O)OR 2 , R a , -SR 2 , and =NR 2a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R 1 is C 1~6 alkyl, C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH, -NR 3 R 3 , -NR 3 C(O)OR 2 , R a , -SR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a, R b , R c , -SR 2 and =NR 2a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is C 1~6 alkyl, where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH, -NR 3 R 3 , -NR 3 C(O)OR 2 , R a , -SR 2 , and =NR 2a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R 1 is C 1~6 alkyl, C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH, -NR 3 R 3 , -NR 3 C(O)OR 2 , R a , -SR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is C 1~6 It is alkyl.

[0081] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R 1 -OH, -NH2, -C(O)OR 2 , -NR 3 R 3 , or -NR 3 C(O)C(O)OR 2 is.

[0082] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R 1 is -C(O)OH, -NH(=NH)NH2, -NHC(O)C(O)OH, or [ka] is.

[0083] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R 1 is methyl, -CH2NH2, -CH2OH, -CH2SH, -C(=NH)NH2, [ka] is.

[0084] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is a 4- to 7-membered monocyclic heterocyclyl, where the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —CN, halogen, R a , R b and R c In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is a 4- to 7-membered monocyclic heterocyclyl, where the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —OH, —CN, halogen, —C(O)OH, and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R 1 is a 5- to 6-membered monocyclic heterocyclyl, where the 5- to 6-membered monocyclic heterocyclyl is selected from the group consisting of —OH, —C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is a 4- to 7-membered monocyclic heterocyclyl, where the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —CN, halogen, R a , R b and R cIn some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is a 4- to 7-membered monocyclic heterocyclyl, where the 4- to 7-membered monocyclic heterocyclyl is selected from the group consisting of —OH, —CN, halogen, —C(O)OH, and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R 1 is a 5- to 6-membered monocyclic heterocyclyl, where the 5- to 6-membered monocyclic heterocyclyl is selected from the group consisting of —OH, —C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 1 is a 4- to 7-membered monocyclic heterocyclyl. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R 1 is piperidinyl.

[0085] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R a is independently —P(O)(OH) or —OP(O)(OH). In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R a is —P(O)(OH). In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R a is -OP(O)(OH)2.

[0086] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R b are independently -C(O)R 2 , -C(O)OR 2 , -C(O)NR 3 R 3 , -C(O)C(O)OR 2 , -S(O)2R 2 , -S(O)NR 3 R 3 , or -S(O)2OR 3In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R b HA-C(O)R 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R b -C(O)OR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R b is -C(O)NR 3 R 3 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R b -C(O)C(O)OR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R b -S(O)2R 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R b is -S(O)2NR 3 R 3 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R b -S(O)2OR 3 is.

[0087] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R c are independently -OR 2 , -OC(O)R 2 , -OC(O)C(O)OR 2 , -NR 3 R 3 , -N + R 3 R 3 R 3a , -NR 3 C(O)R 2 , -NR 3 C(O)NR 3 R 3 , -NR 3 C(O)OR 2 , -NR 3 C(O)C(O)OR 2, or -NR 3 S(O)2R 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c HA-OR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c Ha-OC(O)R 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c -OC(O)C(O)OR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c Ha-NR 3 R 3 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c Ha-N + R 3 R 3 R 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c is -NR 3 C(O)R 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c is -NR 3 C(O)NR 3 R 3 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c Ha-NR 3 C(O)OR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c is -NR 3 C(O)C(O)OR 2 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R c Ha-NR 3 S(O)2R 2 is.

[0088] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 2 are independently H or C 1~6 alkyl, C 1~6 Alkyl is -CN, halogen, R a , R d and R e In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 2 are independently H or C 1~6 alkyl, C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 2 are independently H or C 1~4 alkyl, C 1~4 Alkyl is -OH, -CN, halogen, -C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 2 are independently H or C 1~3 alkyl, C 1~3 Alkyl is —C(O)OH and R a is optionally substituted with 1 to 2 groups independently selected from

[0089] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is H.

[0090] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R d and R eIn some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~6 alkyl, where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~4 alkyl, where C 1~4 Alkyl is -OH, -CN, halogen, -C(O)OH and R a and optionally substituted with 1 to 3 groups independently selected from In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~3 alkyl, where C 1~3 Alkyl is —C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R d and R e In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~6 alkyl, where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~4 alkyl, where C 1~4 Alkyl is -OH, -CN, halogen, -C(O)OH and Ra In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~3 alkyl, where C 1~3 Alkyl is —C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~6 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2 is C 1~3 It is alkyl.

[0091] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 2a are independently H or C 1~3 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2a is H. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 2a is C 1~3 It is alkyl.

[0092] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 3 are independently H, R d or C 1~6 alkyl, C 1~6 Alkyl is -CN, halogen, R a , R d , R e and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 3 are independently H, -C(O)OR 4, or C 1~6 alkyl, C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OR 4 , -NR 4 R 4 , R a , and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 3 are independently H, -C(O)OR 4 , or C 1~4 alkyl, where C 1~4 Alkyl is -OH, -CN, halogen, -C(O)OR 4 , -NR 4 R 4 , R a , and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 3 are independently H, -C(O)OR 4 , or C 1~3 alkyl, where C 1~3 Alkyl is -OH, -C(O)OH, -NR 4 R 4 , R a , and =NR 3a and optionally substituted with one group selected from:

[0093] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is H. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is R d In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is -C(O)OR 4 is.

[0094] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R d , R e and =NR 3a and optionally substituted with 1 to 3 groups independently selected from In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~6 alkyl, where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OR 4 , -NR 4 R 4 , R a and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~4 alkyl, where C 1~4 Alkyl is -OH, -CN, halogen, -C(O)OR 4 , -NR 4 R 4 , R a and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~3 alkyl, where C 1~3 Alkyl is -OH, -C(O)OH, -NR 4 R 4 , R a and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~6 alkyl, where C 1~6 Alkyl is -CN, halogen, R a , R d , R e and =NR 3aIn some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~6 alkyl, where C 1~6 Alkyl is -OH, -CN, halogen, -C(O)OR 4 , -NR 4 R 4 , R a and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~4 alkyl, where C 1~4 Alkyl is -OH, -CN, halogen, -C(O)OR 4 , -NR 4 R 4 , R a and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~3 alkyl, where C 1~3 Alkyl is -OH, -C(O)OH, -NR 4 R 4 , R a and =NR 3a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~6 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3 is C 1~3 It is alkyl.

[0095] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 3a are independently H or C1~3 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3a is H. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 3a is C 1~3 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, R 3a is H.

[0096] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R d are independent of each other, C(O)R 4 , -C(O)OR 4 , -C(O)NR 4 R 4 , -C(O)C(O)OR 4 , -S(O)2R 4 , -S(O)NR 4 R 4 , or -S(O)2OR 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R d HA-C(O)R 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R d -C(O)OR 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R d is -C(O)NR 4 R 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R d is -C(O)C(O)OR 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R d is -S(O)2R 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R d is -S(O)NR 4 R 4In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R d -S(O)2OR 4 is.

[0097] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R e is German Stand up, -OR 4 , -OC(O)R 4 , -OC(O)C(O)OR 4 , -NR 4 R 4 , -N + R 4 R 4 R 4a , -NR 4 C(O)R 4 , -NR 4 C(O)NR 4 R 4 , -NR 4 C(O)OR 4 , -NR 4 C(O)C(O)OR 4 , or -NR 4 S(O)2R 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e HA-OR 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e is -OC(O)R 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e is -OC(O)C(O)OR 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e is -NR 4 R 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e -N + R 4 R 4 R 4aIn some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e is -NR 4 C(O)R 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e is -NR 4 C(O)NR 4 R 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e is -NR 4 C(O)OR 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e is -NR 4 C(O)C(O)OR 4 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R e is -NR 4 S(O)2R 4 is.

[0098] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 4 are independently H or C 1~6 alkyl, C 1~6 Alkyl is -OH, CN, halogen, -COOH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 4 are independently H or C 1~3 alkyl, where C 1~3 Alkyl is -OH, CN, halogen, -COOH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each R 4 are independently H or C 1~3 alkyl, C 1~3 Alkyl is —C(O)OH and R ais optionally substituted with 1 to 2 groups independently selected from

[0099] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is H. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is C 1~6 alkyl, C 1~6 Alkyl is -OH, CN, halogen, -COOH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is C 1~3 alkyl, where C 1~3 Alkyl is -OH, CN, halogen, -COOH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is C 1~3 alkyl, where C 1~3 Alkyl is —C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is C 1~6 alkyl, where C 1~6 Alkyl is -OH, CN, halogen, -COOH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is C 1~3 alkyl, where C 1~3 Alkyl is -OH, CN, halogen, -COOH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is C 1~3alkyl, where C 1~3 Alkyl is —C(O)OH and R a In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is C 1~6 In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R 4 is C 1~3 It is alkyl.

[0100] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts thereof, provided herein is a compound selected from the group consisting of: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments of the compounds of Formula I, provided herein is a compound selected from the group consisting of: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments of the compounds of Formula I, provided herein is a compound selected from the group consisting of: [ka] or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments of the compounds of Formula I, provided herein are compounds that are: [ka] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments of the compounds of Formula I, provided herein are compounds that are: [ka] or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments of the compounds of Formula I, provided herein are compounds that are: [ka] or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments of the compounds of Formula I, provided herein are compounds that are: [ka] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments of the compounds of Formula I, provided herein are compounds that are: [ka] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, administration of a compound of Formula I results in the formation of lenacapavir, which is known to be active against HIV, as disclosed, for example, in U.S. Patent No. 10,071,985. In some embodiments, the compound of Formula I is converted to lenacapavir in the gastrointestinal tract. In some embodiments, the compound of Formula I is more soluble than lenacapavir and therefore is orally administered at a lower effective oral dose than that required for lenacapavir to achieve the same level of exposure of lenacapavir in vivo.

[0109] III. Compositions and Kits The compounds provided herein or their pharmaceutically acceptable salts are usually administered in the form of pharmaceutical compositions.Therefore, pharmaceutical compositions comprising one or more of the compounds provided herein or their pharmaceutically acceptable salts, isomers, or mixtures and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and additives are also provided herein.The compounds provided herein or their pharmaceutically acceptable salts may be the only active ingredient or one of the active ingredients of the pharmaceutical composition.Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants.Such compositions are prepared in a manner well known in the pharmaceutical arts. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T.Rhodes, Eds.).

[0110] In one aspect, provided herein is a pharmaceutical composition comprising a compound provided herein (i.e., a compound of Formula I) 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.

[0111] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (i.e., 1, 2, 3, 4; 1 or 2; 1 to 3; or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (i.e., 1, 2, 3, 4; 1 or 2; 1 to 3; or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0112] In some embodiments, the one or more additional therapeutic agents comprise an agent for the treatment of HIV viral infection. In some embodiments, the one or more additional therapeutic agents are anti-HIV agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, an HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells, etc.), latent infection reactivators, immune system therapeutics, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF α ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P4503 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein modulators, RNA polymerase modulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and anti-HIV peptides, or any combination thereof.

[0113] In some embodiments, the additional therapeutic agent or agents are selected from HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and any combination thereof.

[0114] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and any combination thereof.

[0115] In some embodiments, the additional therapeutic agent or agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reactivators, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, HIV antigen-targeting chimeric T cell receptors, pharmacokinetic enhancers, and other drugs for treating HIV, and any combination thereof.

[0116] In some embodiments, the additional therapeutic agent or agents are selected from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the additional therapeutic agent or agents are selected from dolutegravir, cabotegravir, darunavir, vitegravir, elsulfavirine, rilpivirine, and any combination thereof, or a pharmaceutically acceptable salt thereof.

[0118] Examples of combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCO VY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine Mivudine; Tenofovir alafenamide and emtricitabine; Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; Tenofovir analogs; COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); KALETR A® (ALUVIA®, lopinavir and ritonavir), TRIUMEQ® (dolutegravir, abacavir, and lamivudine); BIKTARVY® (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO® (dolutegravir + lamivudine), TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir;Darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dollar; Tegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitab These include, but are not limited to, 3-BNC117 plus rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir plus ritonavir plus abacavir + lamivudine, lamivudine, cabotegravir + rilpivirine, 3-BNC117 plus albuvirtide, elpida (elsulfavirine, VM-1500), and VM-1500A, and dual-targeted HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0119] In one embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0120] In some embodiments, the pharmaceutical compositions provided herein further comprise one, two, three, or four additional therapeutic agents.

[0121] In some embodiments, the pharmaceutical compositions provided herein further comprise one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agents are a combination medication for HIV, another drug for treating HIV, an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, an HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells, etc.), latent infection reactivators, immune system therapeutics, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF α ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P4503 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein modulators, RNA polymerase modulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccine The antibody may be selected from the group consisting of an anti-HIV peptide, an anti-proliferative agent ...

[0122] In some embodiments, the pharmaceutical compositions provided herein further comprise one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agents are selected from the group consisting of a combination medication for HIV, another drug for treating HIV, an HIV protease inhibitor, an HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry (fusion) inhibitor, an HIV maturation inhibitor, a latency reactivator, a capsid inhibitor, an immune system therapeutic, a PI3K inhibitor, an HIV antibody, a bispecific antibody, an "antibody-like" therapeutic protein, or any combination thereof.

[0123] In some embodiments, the pharmaceutical compositions provided herein further comprise one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agents are selected from the group consisting of dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt thereof.

[0124] The pharmaceutical compositions may be administered in either a single dose or multiple doses. The pharmaceutical compositions may be administered by a variety of methods, including, for example, rectal, oral, intranasal, and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0125] One mode of administration is parenteral, for example, by injection.The form that the pharmaceutical composition described in the present disclosure can be incorporated into for administration by injection includes, for example, aqueous suspension or oil suspension, or emulsion containing sesame oil, corn oil, cottonseed oil or peanut oil, or elixir, mannitol, dextrose or sterile aqueous solution and similar pharmaceutical vehicle.In some embodiments, the compound disclosed herein or its pharmaceutically acceptable salt and pharmaceutical composition are administered by subcutaneous injection.

[0126] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents described herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0127] In some embodiments, the sterile injectable preparations disclosed herein may also be sterile injectable solutions or suspensions prepared from lyophilized powders dissolved in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butane-diol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectables.

[0128] Formulations suitable for parenteral administration include those which are isotonic with the blood of the intended recipient. These include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. In certain embodiments, the suspension is a microsuspension. In certain embodiments, the suspension is a nanosuspension.

[0129] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) contain one or more additives. The additive must be compatible with the other components of the formulation and physiologically harmless to the recipient. Examples of suitable additives are well known to those skilled in the art of parenteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009. Examples of solubilizing additives in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338, 188, or 207).

[0130] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions are administered with an implant.

[0131] Oral administration may be another route for administering the compounds provided herein, or pharmaceutically acceptable salts thereof. Administration may be, for example, via capsules or enteric-coated tablets. When preparing pharmaceutical compositions containing at least one compound provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as the compounds provided herein) is typically diluted with an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), e.g., ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile-packaged powders.

[0132] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. The pharmaceutical composition can further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents, or any combination thereof.

[0133] Pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, can be formulated to provide rapid, sustained, or delayed release of the active ingredient (such as the compounds provided herein) after administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and solution-based systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are provided in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0134] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient may be dispersed evenly throughout the composition, so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0135] Tablets or pills of the compounds provided herein, or their pharmaceutically acceptable salts, may be coated or otherwise formulated to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dosage and an outer dosage, the latter being in the form of an envelope covering the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0136] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives, as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be atomized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0137] In one embodiment, provided herein is a kit comprising a compound provided herein (i.e., a compound of Formula I), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (i.e., a compound of Formula I), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for use of the compound in treating an indication, including a disease or condition described herein.

[0138] In some embodiments, the kit further comprises one or more (i.e., 1, 2, 3, 4; 1 or 2; 1 to 3; or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0139] In one embodiment, provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, in a suitable container, hi some embodiments, the container may be a vial, jar, ampoule, pre-filled syringe, or infusion bag.

[0140] IV. Method The methods provided herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods provided herein may be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and their biopsies. In this context, the present disclosure can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present disclosure can be used ex vivo to determine optimal schedules and / or dosages of administration of the compounds disclosed herein for a given cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or to design protocols for in vivo treatment in the clinic. Other ex vivo uses for which the present disclosure may be suitable are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to determine safety or tolerated doses in human or non-human subjects. Such properties can be determined using methods commonly known to those skilled in the art.

[0141] In one embodiment, the present disclosure provides a method of treating or preventing human immunodeficiency virus (HIV) infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0142] In one embodiment, the present disclosure provides a method of treating human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, comprising administering to the patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0143] In some embodiments, the methods provided herein further comprise administering therapeutically effective amounts of one, two, three, or four additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0144] In some embodiments, the one, two, three, or four additional therapeutic agents are a combination medication for HIV, another drug for treating HIV, an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, an HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells, etc.), latent infection reactivators, immune system therapeutics, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulator, Vif dimerization antagonist, HIV-1 viral infectivity factor inhibitor, HIV-1 Nef modulator, TNF α ligand inhibitor, H IV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV The inhibitor is selected from the group consisting of a POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, an HPK1 (MAP4K1) inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, an mTOR complex 1 inhibitor, an mTOR complex 2 inhibitor, a P-glycoprotein modulator, an RNA polymerase modulator, a TAT protein inhibitor, a prolyl endopeptidase inhibitor, a phospholipase A2 inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, an HIV vaccine, and an anti-HIV peptide, or any combination thereof.

[0145] In some embodiments, the one, two, three, or four additional therapeutic agents are selected from the group consisting of HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, or any combination thereof.

[0146] In some embodiments, the one, two, three, or four additional therapeutic agents are selected from the group consisting of dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments of the methods provided herein, the patient is a human.

[0148] In one embodiment, the present disclosure provides a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in therapy.

[0149] In one embodiment, the present disclosure provides a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0150] In one embodiment, the present disclosure provides a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in a method of treating human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, the method comprising administering to the patient a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0151] In some embodiments, the uses provided herein include a therapeutically effective amount of one, two, three, or more The method further comprises administering one or four additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0152] In some embodiments of the uses provided herein, the one, two, three, or four additional therapeutic agents are a combination medication for HIV, another drug for treating HIV, an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, an HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells, etc.), latent infection reactivators, immune system therapeutics, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF α ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIVThe inhibitor is selected from the group consisting of a GAG protein inhibitor, an HIV POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, an HPK1 (MAP4K1) inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, an mTOR complex 1 inhibitor, an mTOR complex 2 inhibitor, a P-glycoprotein modulator, an RNA polymerase modulator, a TAT protein inhibitor, a prolyl endopeptidase inhibitor, a phospholipase A2 inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, an HIV vaccine, and an anti-HIV peptide, or any combination thereof.

[0153] In some embodiments of the uses provided herein, the one, two, three, or four additional therapeutic agents are selected from the group consisting of HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, or any combination thereof.

[0154] In some embodiments of the uses provided herein, the one, two, three, or four additional therapeutic agents are dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil hemifumarate, tenofovir sulphate ... The compound is selected from the group consisting of nofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments of the uses provided herein, the patient is a human.

[0156] V. Administration The compounds of the present disclosure, or pharmaceutically acceptable salts thereof (also referred to herein as active ingredients), can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein, or pharmaceutically acceptable salts thereof, is that they are orally bioavailable and can be administered orally.

[0157] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be administered to an individual according to an effective dosing regimen for a desired period of time or duration, e.g., 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, or pharmaceutically acceptable salts thereof, are administered on a daily or intermittent schedule for the duration of the individual's life.

[0158] The specific dosage level of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject undergoing therapy. For example, dosages may be expressed as milligrams of a compound provided herein, or a pharmaceutically acceptable salt thereof, per kilogram of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing by subject body weight is particularly useful when adjusting dosages between subjects of widely different sizes, such as occurs when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0159] Dosage amounts may also be described as the total amount of a compound described herein, or a pharmaceutically acceptable salt thereof, administered per dose. The amount or frequency of administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, may be adjusted over the course of treatment based on the judgment of the administering physician.

[0160] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily, once weekly, once monthly, once every two months, once every three months, or once every six months. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once weekly. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once monthly. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once every two months. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once every three months. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once every six months.

[0161] The compounds provided herein, or pharmaceutically acceptable salts thereof, can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, e.g., from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 μg to about 30 mg per day, or from about 30 μg to about 300 μg per day.

[0162] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be combined with one or more additional therapeutic agents at any dosage of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof (e.g., 1 mg to 1000 mg of compound). A therapeutically effective amount may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose, or such as from about 0.01 mg per dose to about 1000 mg per dose, or such as from about 0.01 mg per dose to about 100 mg per dose, or such as from about 0.1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose, or such as from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of the compound of Formula I or a pharmaceutically acceptable salt thereof are about 50, 100, 125, 150, 175, 200, 225, 250, 275, or 300 mg per dose. Other therapeutically effective amounts of the compound of Formula I or a pharmaceutically acceptable salt thereof are about 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0163] In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 900 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 800 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 700 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 600 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 500 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 400 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 300 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 200 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 100 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 75 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 50 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 25 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 20 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 20 mg. A therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 15 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 10 mg. In some embodiments, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 5 mg.

[0164] In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, or about 1050 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 5 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 100 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 150 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 200 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 250 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 300 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 350 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 400 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 450 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 500 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 550 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 600 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 650 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 700 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 750 mg.In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 800 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 850 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 900 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 950 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1000 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1050 mg.

[0165] When administered orally, the total weekly dosage for a human subject can be about 1 mg to 1,000 mg per week, about 10 to 500 mg per week, about 50 to 300 mg per week, about 75 to 200 mg per week, or about 100 to 150 mg per week. In some embodiments, the total weekly dosage for a human subject can be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg per week administered in a single dose. In some embodiments, the total weekly dosage for a human subject of the compound of Formula I or a pharmaceutically acceptable salt thereof can be about 100 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of the compound of Formula I or a pharmaceutically acceptable salt thereof can be about 150 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of the compound of Formula I or a pharmaceutically acceptable salt thereof can be about 200 mg administered in a single dose. In some embodiments, the total weekly dosage of the compound of formula I or a pharmaceutically acceptable salt thereof for a human subject can be about 250 mg administered in a single dose. The total weekly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 300 mg administered in a single dose. In some embodiments, the total weekly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 350 mg administered in a single dose. In some embodiments, the total weekly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 400 mg administered in a single dose. In some embodiments, the total weekly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 450 mg administered in a single dose. In some embodiments, the total weekly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 500 mg administered in a single dose.

[0166] When administered orally, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 500 mg to 1,000 mg per month, about 600 to 900 mg per month, or about 700 to 800 mg per month. In some embodiments, the total weekly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 mg per week administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 500 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 550 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 600 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 650 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 700 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 750 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 800 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 850 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof to a human subject can be about 900 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject can be about 950 mg administered in a single dose. In some embodiments, the total monthly dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject can be about 1000 mg administered in a single dose.

[0167] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once every week. A single dose can also be administered once every month. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once daily in the methods disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered twice daily in the methods disclosed herein.

[0168] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once daily in the methods disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once weekly in the methods disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once daily in the methods disclosed herein. or a pharmaceutically acceptable salt thereof is administered once per month in the methods disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once every two months in the methods disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once per three months in the methods disclosed herein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered once per six months in the methods disclosed herein.

[0169] In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 100 mg. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 150 mg. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 200 mg. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 250 mg. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 300 mg. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 350 mg. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 400 mg. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 450 mg. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered once per week in a single dose of about 500 mg.

[0170] In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 500 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 550 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 600 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 650 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 700 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 750 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 800 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 850 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 900 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 950 mg once per month. In some embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is orally administered in a single dose of about 1000 mg once per month.

[0171] The frequency of administration of the compound of the present disclosure or a pharmaceutically acceptable salt thereof is determined by the needs of the individual patient and may be, for example, once a day, once a week, once a month, once every two months, once every three months, or once every six months. Administration of the compound or a pharmaceutically acceptable salt thereof continues as long as necessary to treat a retroviral infection, including HIV infection, or any other indication described herein. For example, administration of the compound or a pharmaceutically acceptable salt thereof may be continued as long as necessary to treat a retroviral infection, including HIV infection, or any other indication described herein. can be administered to humans suffering from retroviral infections, including HIV infection, for the duration of the human's life.

[0172] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for a period of several days or more, followed by a period of several days or more during which the patient does not receive a daily dose of the compound, or a pharmaceutically acceptable salt thereof. For example, the patient can receive a dose of the compound, or a pharmaceutically acceptable salt thereof, every other day or three times per week. As a further example, the patient can receive a dose of the compound, or a pharmaceutically acceptable salt thereof, daily for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, or a pharmaceutically acceptable salt thereof, followed by a subsequent period (e.g., 1 to 14 days) during which the patient again receives a daily dose of the compound, or a pharmaceutically acceptable salt thereof. Alternating periods of administration of the compound, or a pharmaceutically acceptable salt thereof, followed by non-administration of the compound, or a pharmaceutically acceptable salt thereof, can be repeated as clinically needed to treat the patient.

[0173] The compound or pharmaceutically acceptable salt thereof of the present disclosure, or the pharmaceutical composition of the present disclosure, may be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compound or pharmaceutically acceptable salt thereof may also continue for several days; for example, treatment will typically continue for at least 7, 14, or 28 days per treatment cycle. Treatment cycles are well known for retroviral infections, including HIV infection. In some embodiments, treatment cycles alternate periodically, with a rest period of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. Treatment cycles may also be continuous in other embodiments.

[0174] VI. Combination Therapy Patients treated by administration of a compound provided herein, or a pharmaceutically acceptable salt thereof, often exhibit a disease or condition that would benefit from treatment with another therapeutic agent, including an agent therapeutic for a retroviridae infection, including an HIV infection. In some embodiments, the other therapeutic agent is an agent therapeutic for an HIV infection. Accordingly, one aspect of the present disclosure is a method of treating an HIV infection, comprising administering to a subject, particularly a human subject, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more compounds useful in the treatment of an HIV infection.

[0175] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, 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 may be selected from different classes of therapeutic agents.

[0176] In some embodiments, when a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or as a sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0177] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a patient, e.g., as a solid dosage form for oral administration.

[0178] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more additional therapeutic agents.

[0179] Co-administration includes administration of a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, before or after administration of a unit dose of one or more additional therapeutic agents. The compound provided herein, or a pharmaceutically acceptable salt thereof, can be administered within seconds, minutes, or hours of administration of the one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered first, followed several hours (i.e., 1 to 12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed several hours (i.e., 1-12 hours) later by a unit dose of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is formulated as a tablet, which may optionally contain one or more other compounds useful in treating the disease being treated. In certain embodiments, the tablet may contain another active ingredient for treating a retroviridae infection, including an HIV infection. In some embodiments, such tablets are suitable for once-daily administration. In some embodiments, such tablets are suitable for once-weekly administration. In some embodiments, such tablets are suitable for once-monthly administration. In some embodiments, such tablets are suitable for once-every-two-months administration. In some embodiments, such tablets are suitable for once-every-three-months administration. In some embodiments, such tablets are suitable for once-every-six-months administration.

[0181] Also provided herein are methods of treatment in which a compound of Formula I, or a tautomer or pharmaceutically acceptable salt thereof, is administered to a patient in combination with one or more additional therapeutic agents or therapies. In some embodiments, the total daily dosage of the compound of Formula I, or a tautomer or pharmaceutically acceptable salt thereof, is from about 1 to about 500 mg, which may be administered in a single dose for a human subject.

[0182] HIV combination therapy In the above embodiments, the additional therapeutic agent or agents may be anti-HIV agents. In some examples, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an HIV capsid inhibitor, a nucleocapsid protein 7 (NCp7) inhibitor, an HIV Tat or Rev inhibitors, inhibitors of Tat-TAR-P-TEFb, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapy (chimeric antigen receptor T cells, T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells, etc.), latent infection reactivators, immune system therapeutics, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomers enzyme A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, HIV-1 Nef modulators, TNF α ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, retrocyclin modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV The inhibitor may be a POL protein inhibitor, a complement factor H modulator, a ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, an HPK1 (MAP4K1) inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, an mTOR complex 1 inhibitor, an mTOR complex 2 inhibitor, a P-glycoprotein modulator, an RNA polymerase modulator, a TAT protein inhibitor, a prolyl endopeptidase inhibitor, a phospholipase A2 inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, an HIV vaccine, and an anti-HIV peptide, and combinations thereof.

[0183] In some embodiments, the additional therapeutic agent or agents are selected from HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0184] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutics, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0185] In some embodiments, the additional therapeutic agent or agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latent infection reactivators, HIV bNAbs, agonists of TLR7, TLR8, and TLR9, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, HIV antigen-targeting chimeric T cell receptors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0186] In some embodiments, the additional therapeutic agent or agents are selected from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0187] HIV combination drugs Examples of concomitant medications include ATRIPLA® (efavirenz, tenofovir proxil fumarate, and emtricitabine; COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY (registered trademark) GENVOYA® (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (Tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); Darunavir, Tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; Efavirenz, Lamivudine, and Tenofovir disoproxil fumarate; Lamivudine and Tenofovir disoproxil fumarate; Tenofovir and Lamivudine; Tenofovir alafenamide and emtricitabine; Tenofovir alafenamide hemifumarate tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; tenofovir analogs; COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); KALETRA® (ALUVIA®, lopinavir and ritonavir), TRIUMEQ® (dolutegravir, abacavir, and lamivudine); BIKTARVY® (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO® (dolutegravir + lamivudine), TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride;Dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir These include, but are not limited to, abacavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotegravir + rilpivirine, 3-BNC117 + albuvirtide, elpida (elsulfavirine, VM-1500), and VM-1500A, and dual-targeted HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors;

[0188] Other HIV drugs Examples of other drugs for treating HIV include, but are not limited to, aspernigrin C, acemannan, alisporivir, BanLec, deferiprone, Gamimune, methenkephalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicamoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, Bevirimat derivative, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, bryostatin-1, bryostatin analog, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, fluoro-beta-D-arabinose nucleic acid (FANA)-modified antisense oligonucleotide, FX-101, Griffithin, 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, 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, Fas nall, Immuglo, 2-CLIPS peptide, HRF-4467, thrombospondin analogues, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugates (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, Nipamovir, Covimro and ABBV-1882.

[0189] HIV protease inhibitors Examples of HIV protease inhibitors include, but are not limited to, amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC-09 plus ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911. Additional examples of HIV protease inhibitors are described, for example, in U.S. Pat. No. 10,294,234, and U.S. Patent Application Publication No. 2020 / 030327, and U.S. Patent Application Publication No. 2019 / 210978.

[0190] HIV Gag protein inhibitors Examples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071.

[0191] HIV ribonuclease H inhibitors Examples of HIV RNase H inhibitors include, but are not limited to, NSC-727447.

[0192] HIV Nef inhibitors Examples of HIV Nef inhibitors include, but are not limited to, FP-1.

[0193] HIV reverse transcriptase inhibitors Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include, but are not limited to, dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, elsulfavirine (sustained-release oral form, HIV infection), elsulfavirine (long-acting injectable nanosuspension, HIV infection), and elsulfavirine (VM-1500). Further non-limiting examples of non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include the compounds disclosed in U.S. Pat. No. 10,548,898.

[0194] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir disoproxil hemifumarate, VIDEX® and VIDEXEC® (didanosine, ddl), ...defovir alafenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefovir alfenamide fumarate, adefo These include, but are not limited to, vacacvir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, ethidovudine lavirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8583, VM-2500, and KP-1461.

[0195] Additional examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include, but are not limited to, those described in U.S. Patent Application Publication No. 2007 / 049754, U.S. Patent Application Publication No. 2016 / 250215, U.S. Patent Application Publication No. 2016 / 237062, U.S. Patent Application Publication No. 2016 / 251347, U.S. Patent Application Publication No. 2002 / 119443, U.S. Patent Application Publication No. 2013 / 065856, U.S. Patent Application Publication No. 2013 / 090473, U.S. Patent Application Publication No. 2014 / 221356, and WO 04096286.

[0196] HIV integrase inhibitors Examples of HIV integrase inhibitors include elvitegravir, elvitegravir (sustained-release microcapsules), curcumin, curcumin derivatives, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, pegylated raltegravir, dolutegravir, JTK-351, bictegravir, Examples of HIV integrase inhibitors include, but are not limited to, AVX-15567, cabotegravir (long-acting injectable solution), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017. Further non-limiting examples of HIV integrase inhibitors include the compounds disclosed in U.S. Pat. No. 11,084,832.

[0197] HIV non-catalytic site or allosteric integrase inhibitors or allosteric, integrase inhibitor, NCINI) is an example of CX-050 45, CX-05168, and CX-14442.

[0198] HIV viral infectivity factor inhibitors Examples of HIV viral infectivity inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0199] HIV entry inhibitors Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0200] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, maraviroc (long-acting injectable nanoemulsion), cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc, and vMIP (Hai mipu).

[0201] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, and gp41 inhibitors. These include rififiscin (gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biobetter, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifuvirtide. Not limited.

[0202] Examples of CD4 binding inhibitors include, but are not limited to, ibalizumab and CDA analogs.

[0203] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbicides, Radha-108 (receptor) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, fostemasavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0204] Examples of gp160 inhibitors include, but are not limited to, fangchinoline.

[0205] Examples of CXCR4 inhibitors include, but are not limited to, plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0206] HIV maturation inhibitors Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232.

[0207] Latent infection reactivator Examples of latent infection reactivators include toll-like receptors (TLRs) ) agonists (including TLR7 agonists, e.g., GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors, e.g., Velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BET-bromodomain 4, BRD4) inhibitors (e.g., ZL-0580, apabetalone), ionomycin, IAP antagonists (inhibitors of apoptotic proteins such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), PMA, SAHA (suberoylanilide hydroxamic acid or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 modulating antibodies (IL-15, IL-15 fusion proteins, and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, APH-0812, and GSK Examples of PKC activators include, but are not limited to, indolactam, prostratin, ingenol B, and DAG-lactone.

[0208] Additional examples of TLR7 agonists include, but are not limited to, those described in US Patent Application Publication No. 2010 / 143301.

[0209] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. 2017 / 071944.

[0210] Histone deacetylase (HDAC) inhibitors In some embodiments, the agents described herein are further combined with an inhibitor of histone deacetylase, e.g., histone deacetylase 1, histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0211] Capsid inhibitors Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, lenacavir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitor (HIV-1 infection, Shandong University), and compounds described in (GSK WO 2019 / 087016).

[0212] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication No. 2018 / 051005 and U.S. Patent Application Publication No. 2016 / 108030.

[0213] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication No. 2014 / 221356 and U.S. Patent Application Publication No. 2016 / 016973.

[0214] Cytochrome P450 3 inhibitors Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in US Pat. No. 7,939,553.

[0215] RNA polymerase modulators Examples of RNA polymerase modulators include, but are not limited to, those described in US Pat. No. 10,065,958 and US Pat. No. 8,008,264.

[0216] Immune Checkpoint Modulators In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can effectively regulate T cell or NK cell activation and prevent immune leakage of infected cells. Activation or stimulation of stimulatory immune checkpoints can enhance the effects of immune checkpoint inhibitors in infection treatments. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., as reviewed in Davis et al., Semin Immunol. (2017) 31:64-75, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0217] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane domain and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T-cell activation inhibitory factor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BT) LA); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing (PVRIG, CD112R);T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Lymphocyte activation 3 (LAG3, CD223); Signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SL AMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16-binding protein 1 (ULBP1); UL16-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, 3 Ig receptors; killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2 Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); SLAM family member 7 (SLAMF7); and hematopoietic progenitor kinase 1 (HPK1, MAP4K1).

[0218] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, agents as described herein are combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0219] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, Killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulatory immune checkpoint proteins or receptors. Exemplary NK cell-stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang et al., Semin Immunol. (2017) 31:37-54, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0220] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0221] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, and PBI -5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0222] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (budigalimab), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostallimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 ( Examples of suitable anti-PD-1 antibodies include, but are not limited to, PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

[0223] In various embodiments, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058, and AGEN-1307.

[0224] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In various embodiments, the agents described herein are agonists of one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID 7132), TNFRSF1B (NCBI Gene ID 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID; 7293), TNFRSF5 (CD40; NCBI Gene ID; 958), TNFRSF6 (FAS, NCBI Gene ID; 355), TNFRSF7 (CD 27, NCBI Gene ID; 939), TNFRSF8 (CD30, NCBI Gene ID; 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID; 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID; 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID; 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID; 8794), TN FRSF10D (CD264, TRAILR4, NCBI gene ID; 8793), TNFRSF11A (CD265, RANK, NCBI gene ID; 8792), TNFRSF11B (NCBI gene ID; 4982), TNFRSF12A (CD266, NCBI gene ID; 51330), TNFRSF13B (CD267, NCBI gene ID; 23495), TNFRSF13C (CD268, NCBI gene ID; 115650), TNFRSF16 (NG and TNFRSF25 (DR3, NCBI gene ID; 8718), TNFRSF16 (BCMA, 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).

[0225] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include MEDI6469, MEDI6383, MEDI0562 (tabolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in WO 2016179517, WO 2017096179, WO 2017096182, WO 2017096281, and WO 2018089628. Examples of antibodies include, but are not limited to, the antibodies described above.

[0226] Examples of anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0227] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0228] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0229] 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 WO 2017 / 096179, WO 2017 / 096276, WO 2017 / 096189, and WO 2018 / 089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO 2017 / 096179 and WO 2018 / 089628.

[0230] Bispecific and trispecific natural killer (NK) cell engagement Ja In various embodiments, the agents described herein bind to NK cell activating receptors, e.g., CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (which mediate antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and the like. and a bi-specific NK cell engager against CD137 (41BB) The anti-CD16 binding bispecific molecule may be combined with a CD16-binding NK cell engager (BiKE) or trispecific NK cell engager (TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that may be co-administered target CD16 and one or more HIV-associated antigens, as described herein. BiKE and TriKE are described, for example, in Felices et al., Methods Mol Biol. (2016) 1441:333-346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell inducers (TRiKEs) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3TriKE.

[0231] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In various embodiments, the agents described herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, and pyranonaphthoquinone derivatives. Examples of anti-cancer drugs include, but are not limited to, benzodiazepine (SN-35837), resminostat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0232] Toll-like receptor (TLR) agonists In some embodiments, an agent described herein is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Exemplary TLR7 agonists that may be co-administered include AL-034, DSP-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and those disclosed in U.S. Patent Application Publication Nos. 20100143301 (Gilead Sciences), 20110098248 (Gilead Sciences), and U.S. Patent Application Publication Nos. 20100143301 (Gilead Sciences), 20110098248 (Gilead Sciences), and 20110098248 (Gilead Sciences). Sciences), and No. 20090047249 (Gilead Sciences), 20140045849 (Janssen), 20140073642 (Janssen), WO 2014 / 056953 (Janssen), 2014 / 076221 (Janssen), 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), 20080306050 (Array Biopharma), 20100029585 (Ventirx Pharma), 20110092485 (Ventirx Pharma), No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Pharma), 20140088085 (Ventirx Pharma), 20140275167 (Novira Therapeutics), and 20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, telluritolimod, and BDB-001. Examples of TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in U.S. Patent Application Publication No. 20140045849 (Janssen) and U.S. Patent Application Publication No. 20140073642 (J Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Examples of compounds disclosed in U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042. Examples of TLR3 agonists include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0233] CDK inhibitors or antagonists In some embodiments, an agent described herein is combined with an inhibitor or antagonist of a CDK, hi some embodiments, the inhibitor or antagonist of a CDK is selected from the group consisting of VS2-370.

[0234] STING agonists, RIG-I and NOD2 modulators In some embodiments, an agent described herein is combined with a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic di-AMP. In some embodiments, an agent described herein is combined with a RIG-I modulator such as RGT-100, or a NOD2 modulator such as SB-9200 and IR-103.

[0235] LAG-3 and TIM-3 inhibitors In certain embodiments, the agents described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, or INCAGN-2390.

[0236] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with an anti-LAG-3 (lymphocyte activating) antibody, such as leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, or INCAGN2385.

[0237] Interleukin agonists In certain embodiments, the agents described herein are interleukin agonists, such as IL-2, IL-7, IL-15, IL-10, and IL-12 agonists; examples of IL-2 agonists include Proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214), modified variants of IL-2 (e.g., THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2 / 15; ALT-803, NKTR-255 and examples of IL-15 agonists such as hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 symbolin (PEGylated IL-15), P-22339, and IL-15-PD-1 fusion protein N-809; examples of IL-7 include, but are not limited to, CYT-107.

[0238] Examples of additional immune system therapeutics that can be combined with the agents of the present disclosure include, but are not limited to, interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma; FLT3 agonists such as CDX-301, GS-3583, Gapion, Nucleoferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, and RPI-MN.

[0239] Phosphatidylinositol 3-kinase (PI3K) inhibitors Examples of PI3K inhibitors include idelalisib, alpelisib, bupallisib, CAI orotate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonoliside, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and DS-742. 3, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

[0240] Alpha-4 / beta-7 antagonists Examples of integrin alpha-4 / beta-7 antagonists include, but are not limited to, PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0241] HPK1 inhibitors Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.

[0242] HIV targeting antibody Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAbs (broadly neutralizing HIV-1 antibodies), TMB-360, TMB-370, and HIV These include, but are not limited to, antibodies targeting gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), PGT121.414.LS, ibalizumab, ibalizumab (second generation), Immuglo, MB-66, KLIC-targeting clone 3 human monoclonal antibody (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0243] A variety of bNAbs can be used, see, for example, U.S. Patent No. 8,673,307; U.S. Patent No. 9,493,549, U.S. Patent No. 9,783,594, U.S. Patent No. 10,239,935, U.S. Patent Application Publication No. 2018 / 371086, U.S. Patent Application Publication No. 2020 / 223907, WO 2014 / 063059, WO 2012 / 158948, WO 2015 / 117008, and International Application Nos. PCT / US2015 / 41272 and WO 2017 / 096221. Examples include, but are not limited to, antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include Klein et al., Nature, 492(7427):118-22(2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41):16538-43(2013); Scheid et al., Science, 333:1633-1637(2011); Scheid et al., Nature, 458:636-640(2009); Eroshkin et al., Nucleic Acids Res., 42(Database Issue):Dl 133-9(2014); Mascola et al., Immunol Rev., 254(l):225-44(2013), for example, 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to the V1V2-glycan), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site).

[0244] Additional broadly neutralizing antibodies that can be used as second therapeutic agents in combination therapy are described in, for example, U.S. Pat. Nos. 8,673,307, 9,493,549, and 9,783,594, and WO 2012 / 154312, 2012 / 158948, 2013 / 086533, 2013 / 142324, 2014 / 063059, 2014 / 089152, and WO 2015 / 048 Nos. 462, 2015 / 103549, 2015 / 117008, 2016 / 014484, 2016 / 154003, 2016 / 196975, 2016 / 149710, 2017 / 096221, 2017 / 133639, and 2017 / 133640, which are incorporated by reference in their entireties for all purposes. Further examples include, but are not limited to, Sajadi et al., Cell. (2018) 173(7): 1783-1795; Sajadi, et al., J Infect Dis. (2016) 213(1): 156-64; Klein et al., Nature, 492(7427): 118-22(2012), Horwitz et al., Proc Natl Acad Sci USA,110(41):16538-43(2013),Scheid et al., Science, 333: 1633-1637 (2011), Scheid et al., Nature, 458: 636-640 (2009), Eroshkin et al., Nucleic Acids Res., 42 (Database issue): D1 133-9 (2014), Mascola et al., Immunol Rev., 254(1): 225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074, and LN01 (all of which bind to the MPER of gp41).

[0245] Examples of additional antibodies include bavituximab, UB-421, BF520.1, and BiIA. -SG、CH01、CH59、C2F5、C4E10、C2F5+C2G12+C4E10、CAP256V2LS、3 BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074- LS, Cl3hmAb, GS-9722(Link), DH411-2, BG18, GS-9721, GS-972 3. PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, P.S GT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-1 、PGT-135、PGT-128、PGT-136、PGT-137、PGT-138、PGT-139、MDX01 0(Dutch) DH511 DH511-2 N6 N6LS N49P6 N49P7 N49P7.1 N4 9P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCD N-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (Carl) VRC01, VRC-01-LS, A32. 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v 4 BMI-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, VRC-HIVMAB080-0 0-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33. 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08C AP256-VRC26.09, CAP256-VRC26.25, PCT64-24E, and VRC38.01, PGT-151, CAP248-2 B、35O22、ACS202、VRC34くびVRC34.01、10E8、10E8v4、10E8-5R-100cF、4E10、DH511.These include, but are not limited to, 11P, 2F5, 7b2, and LN01.

[0246] Examples of HIV bispecific and trispecific antibodies include, but are not limited to, MGD014, B12BiTe, BiIA-SG, TMB bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121-VRC01.

[0247] Examples of in vivo delivered bNAbs include, but are not limited to, AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and genetically engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301).

[0248] Pharmacokinetic enhancers Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir.

[0249] Additional therapeutic agents Examples of additional therapeutic agents include those described in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), and the like. sciences), U.S. Patent Application Publication No. 2013 / 0165489 (University of Pennsylvania), U.S. Patent Application Publication No. 2014 / 0221378 (Japan Tobacco), U.S. Patent Application Publication No. 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharmaceutical Resources), U.S. Patent Application Publication No. 20140221356 (Gilead Sciences), U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim).

[0250] HIV vaccine Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors such as Ad5, Ad26, or Ad35), simian adenovirus vaccines (chimpanzee, gorilla, rhesus macaque, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), coxsackievirus-based vaccines, and Enterovirus-based vaccines, gorilla adenovirus vaccines, lentivirus-vectored vaccines, arenavirus vaccines (e.g., LCMV, Pichinde), two-segmented or three-segmented arenavirus-based vaccines, trimerized HIV-1 vaccines, measles virus-based vaccines, flavivirus-vectored vaccines, tobacco mosaic virus-vectored vaccines, varicella-zoster virus-based vaccines, human parainfluenza virus 3 (PIV3)-based vaccines, poxvirus-based vaccines (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, avipox, etc.) ALVAC (Canarypox virus) strains derived from variola viruses; fowlpox virus-based vaccines, rhabdovirus-based vaccines, such as VSV and Maraba virus; recombinant human CMV (rhCMV)-based vaccines, alphavirus-based vaccines, such as , Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128 / CVI.00298-16); LNP-formulated mRNA-based therapeutic vaccines; and LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0251] Examples of vaccines include AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1 gp140 adjuvanted vaccine, ChAdOx1.tHIV consv1 vaccine, CMV-MVA triple vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAX B / E (gp120), monomeric gp120 HIV-1 subtype C vaccine, MPER-656 liposomal subunit vaccine, Remune, ITV-1, and Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC Ajuva Concentrated vaccine, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, N123-VRC-34.01 (including epitope-based HIV vaccines), NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX -B21, GOVX-C55, TVI-HIV-1, Ad-4 (Ad4-env clade C + Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 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.Virus-like particle vaccines such as HIV+MVA mosaic vaccine+gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001, and pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine (e.g., DermaVir), gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, -rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980, eOD-GT8 60-mer vaccine, PD-201401, env (A, B, C, A / E) / gag (C) DNA vaccine, gp120 (A, B, C, A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE immunostimulation), HIV p24gag basal-enhanced plasmid DNA vaccine, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, arenavirus vector-based vaccine (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based prophylactic vaccine, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Center), TBL-1203HI, CH505 TF Examples include, but are not limited to, chTrimer, CD40.HIVRI.Env vaccine, Drep-HIV-PT-1, mRNA-1644, and mRNA-1574.

[0252] Combined birth control (contraceptive) therapy In certain embodiments, the agents described herein are combined with birth control or contraceptive regimens. Therapeutic agents used for birth control (contraception) that can be combined with the agents of the present disclosure include cyproterone acetate, desostril, ethinyl estradiol, ethynodiol, etonogestrill, levomycin, levonorgestrel, linepolistin, misoprostrol, nomedistrol acetate, norelgestromin, norethindrone, noregestrol, norelgestromin, norethoxyfene, sedisterone acetate. and any combination thereof.

[0253] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate, TDF+FTC; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY® (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir Tenofovir; Tenofovir alafenamide and elvitegravir; Tenofovir alafenamide + elvitegravir (rectal formulation, HIV infection), Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); Dolutegravir, abacavir sulfate, and lamivudine; Raltegravir; Pegylated raltegravir; Raltegravir and lamivudine; Lamivudine + lopinavir + ritonavir + abacavir; Malategravir Viroc; tenofovir + emtricitabine + maraviroc, enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat;Atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium; efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevira in combination with one, two, three, or four additional therapeutic agents selected from: benzodiazepine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazides; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0254] In some embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In an additional embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, an agent disclosed herein, or a pharmaceutical composition thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. I'm fooled.

[0255] In another embodiment, a drug disclosed herein or a pharmaceutical composition thereof is combined with a first additional therapeutic agent selected from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0256] In some embodiments, the agents disclosed herein, or pharmaceutical compositions thereof, are combined with a first additional therapeutic agent (contraceptive) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, norethynodrel, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof.

[0257] Gene Therapy and Cell Therapy In certain embodiments, the agents described herein are combined with gene or cell therapy regimens. Gene therapy and cell therapy include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches to modify cell activity to further alter endogenous immune responsiveness to infection. Examples of cell therapy include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPC-overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapy. Examples of dendritic cell therapy include, but are not limited to, AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T and SB-728-HSPC. CCR5 gene inhibitors include, but are not limited to, Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy transduced autologous CD34-positive hematopoietic progenitor cells (HIV infection / HIV-associated lymphoma). In some embodiments, C34-CCR5 / C34-CXCR4-expressing CD4-positive T cells are co-administered with one or more multispecific antigen binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy.

[0258] Gene Editor In certain embodiments, the agents described herein are combined with a gene editor, such as an HIV-targeting gene editor. In various embodiments, the genome editing system can be selected from the group consisting of a CRISPR / Cas9 complex, a zinc finger nuclease complex, a TALEN complex, a homing endonuclease complex, and a meganuclease complex. Exemplary HIV targets for the CRISPR / Cas9 system include, but are not limited to, EBT-101.

[0259] CAR-T cell therapy In some embodiments, the agents described herein are immune effector cells engineered to express a chimeric antigen receptor (CAR). The CAR can be co-administered with a population of HIV antigens, wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen can be an HIV envelope protein or a portion thereof, gp120 or a portion thereof, gp1 The immune effector cells include a CD4 binding site on gp120, a CD4-induced binding site on gp120, an N-glycan on gp120, V2 of gp120, and a membrane proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic. Examples of HIV CAR-Ts include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-CD4 CAR cell therapy, and CD4 CAR+C34-CXCR4+CCR5 ZFN. These include T cells, dual anti-CD4 CAR T cell therapy (CD4 CAR + C34-CXCR4 T cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, for HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR, and C46 peptide.

[0260] TCR-T cell therapy In certain embodiments, the agents described herein are combined with a population of TCR-T cells that are genetically engineered to target an HIV-derived peptide, e.g., ImmTAV, present on the surface of virally infected cells.

[0261] B cell therapy In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells engineered to express broadly neutralizing antibodies, such as 3BNC117 (Hartweger et al, J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol. 4, eaax0644 (2019) 17 May 2019).

[0262] A compound disclosed herein (e.g., any compound of Formula I) may be combined with one, two, three, or four additional therapeutic agents in any dosage relative to the compound of Formula I (e.g., 1 mg to 500 mg of compound).

[0263] In one embodiment, a kit is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1; 2; 3; 1 or 2; or 1 to 3) additional therapeutic agents.

[0264] In one embodiment, the additional therapeutic agent or agents in the kit are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapies (such as chimeric antigen receptor T cells, T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapies, etc.), compounds targeting the HIV capsid, latency reactivators, capsid polymerization inhibitors, HIV bNAbs, immune system therapeutics, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicin and anti-HIV agents selected from: HIV nuclease inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0265] In some embodiments, the additional therapeutic agent or agents in the kit are selected from HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0266] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitor compound. In an additional embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside inhibitor of reverse transcriptase and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and an HIV capsid inhibitor. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and one, two, three, or four HIV bNAbs. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor.In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, and an HIV nucleoside inhibitor of reverse transcriptase.

[0267] HIV long-acting therapy Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, doravirine, raltegravir, and long-acting dolutegravir.

[0268] VII. Compound Preparation Some embodiments of the present disclosure are directed to processes and intermediates useful for preparing the compounds provided herein, or pharmaceutically acceptable salts thereof.

[0269] The compounds described herein can be purified by any of the techniques known in the art, including chromatographic techniques such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0270] During any of the processes for the preparation of the compounds provided herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is further described in T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," 4 th This can be achieved by conventional protecting groups, as described in standard works such as "Protective Groups for the Synthesis of Novel Compounds," ed., Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0271] Exemplary chemicals useful in the methods of the embodiments will now be described by reference to exemplary synthetic schemes for their general preparation herein and the specific examples below. To obtain the various compounds herein, the skilled artisan will recognize that starting materials can be appropriately selected to obtain the desired product, such that the ultimately desired substituents are carried through the reaction schemes, with or without protection as necessary. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is carried through the reaction scheme and can be appropriately replaced with the desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions shown in the general schemes is preferably carried out at a temperature from about 0°C to the reflux temperature of the organic solvent used. Isolation of the final compounds can be achieved by a variety of methods known to those skilled in the art, but is most preferably by reverse-phase HPLC, followed by lyophilization from various organic solvents. Repeated lyophilization may optionally be performed to reduce the amount of residual acidic modifiers resulting from the purification process. In some embodiments, the final compounds provided herein were isolated as mono- or bis-trifluoroacetic acid salts.

[0272] Although the methods of the present disclosure generally provide a particular enantiomer or diastereomer as the desired product, the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is derived without indicating the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0273] Representative syntheses of compounds of the present disclosure are described in the following schemes and specific examples below. [Table 2-1] [Table 2-2]

[0274] General synthetic scheme General Reaction Schemes 1-4 are provided as further embodiments of the present disclosure and illustrate general methods that can be used to prepare certain compounds of the present disclosure and to prepare additional compounds of the present disclosure. Each of the variables (e.g., R 1 , R 2 , R 3 , R 4 ) are as defined herein.

[0275] The compounds of the present disclosure may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent to those skilled in the art in light of the disclosures herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may also be used. Synthesis of exemplary compounds described herein can be achieved as illustrated in the following examples. Where available, reagents may be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers. In general, the compounds described herein are typically stable and isolatable at room temperature and pressure.

[0276] Exemplary embodiments of the compounds disclosed herein can be prepared according to the general reaction schemes described below. The compounds may be synthesized using the same scheme. Given the description herein, it will be apparent to one skilled in the art that the general scheme can be modified by substituting starting materials with other materials having similar structures, resulting in correspondingly different products. The synthetic description then provides numerous examples of how starting materials can be varied to provide the corresponding products. Given a desired product with defined substituents, the necessary starting materials can generally be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. To synthesize a compound that is an embodiment disclosed in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent. The identity of the final product will generally be apparent by a simple inspection process of the necessary starting materials, given the examples herein.

[0277] The terms "solvent," "inert organic solvent," or "inert solvent" refer to a solvent that is inert under the conditions of the reaction being described (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, etc. Unless specified to the contrary, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon. General synthetic scheme 1 [ka]

[0278] Compounds of formula A3 can be prepared according to general synthetic scheme 1, where A is C 3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered fused bicyclic heteroaryl; G 1 are H, -C(O)OH, C 1~6 alkyl, -NH2, or 4- to 7-membered monocyclic heterocyclyl, where C1~6 The alkyl is optionally substituted with 1 to 3 groups independently selected from -C(O)OH, -NH2, and -SH, any of which can be protected with protecting groups known in the art, and W is a common leaving group, including, but not limited to, halogen or -OH. According to General Synthetic Scheme 1, compounds of Formula A3 can be obtained by reacting intermediate 5 or intermediate 5E with compounds of Formula A1 under various basic conditions. Non-limiting exemplary conditions include the use of common coupling reagents such as HATU, COMU, TCFH, or EDC in the presence of a base under appropriate solvent and temperature conditions. Alternatively, compounds of Formula A3 can be prepared from the reaction of 23C with compounds of Formula A2. Non-limiting exemplary conditions include the use of a base such as DIPEA in the presence of a base. Examples include reaction at an appropriate temperature under a low temperature. In the above cases, compounds of formula A1 and A2 may contain protecting groups that are removed after reaction with intermediate 5 / intermediate 5E or 23C, respectively, to reveal functional groups that can be optionally further elaborated by reaction with various electrophiles, such as oxalyl chloride or N,N'-di-Boc-1H-pyrazole-1-carboxamidine, followed by deprotection as needed. Compounds of formula A1 and A2 can be commercially available or can be easily synthesized in one or more steps by one skilled in the art from known materials and reagents. General synthetic scheme 2. [ka]

[0279] Compounds of formula B3, B6 and B8 can be prepared according to general synthetic scheme 2, where R 1 is as defined herein, and A is C 3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered fused bicyclic heteroaryl; G 2 is R a , R b , R c , -SR 2 or =NR2a where R a , R b , R c , R 2 and R 2a is as defined herein, PG is a protecting group known in the art for alcohols and carboxylic acids, PG' is a protecting group known in the art for phosphates, PG" is a protecting group known in the art for amines, and L is H or -O, or both L's together with the carbon to which they are attached form C=O. According to General Synthetic Scheme 2, compounds of formula B1 or B4 can be reacted with phosphorylating reagents under various conditions to provide compounds of formula B2 or B5, respectively. Non-limiting exemplary reagents include N,N-dialkyl phosphoramidite reagents or di-alkyl chlorophosphates. Compounds of formula B2 can be deprotected and, if both L's are H, oxidized to provide compounds of formula B3 using conditions known in the art. Compounds of formula B5 can be deprotected under appropriate conditions known in the art to provide compounds of formula B6. Compounds of formula B7 can be obtained by either reacting intermediate 5 / intermediate 5E with compounds of formula B3 or by reacting compounds of formula B6 with 23C. Compounds of formula B7 can be deprotected under conditions known in the art to give compounds of formula B8. Compounds of formula B1 and B4 are commercially available or can be readily synthesized in one or more steps by one skilled in the art using conditions known in the art. General synthetic scheme 3 [ka]

[0280] Compounds of formula C3, C6 and C8 can be prepared according to general synthetic scheme 3, where R 1 is as defined herein, and A is C 3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered fused bicyclic heteroaryl; G 2 is Ra , R b , R c , -SR 2 , or =NR 2a where R a , R b , R c , R 2 , and R 2a is as defined herein, and PG is a compound known in the art for alcohols and carboxylic acids. wherein PG' is a protecting group known in the art for phosphates, PG" is a protecting group known in the art for amines, and L is H or -O, or both L's taken together with the carbon to which they are attached form C=O. According to General Synthetic Scheme 3, compounds of formula C1 or C4 can be reacted with an alkyl phosphate reagent under various conditions to give compounds of formula C2 or C5, respectively. A non-limiting exemplary reagent includes di-tert-butyl chloromethyl phosphate. Compounds of formula C2 can be deprotected and, if both L's are H, oxidized to give compounds of formula C3 using conditions known in the art. Compounds of formula C5 can be deprotected under appropriate conditions known in the art to give compounds of formula C6. Compounds of formula C7 can be obtained by either reacting intermediate 5 / intermediate 5E with compounds of formula C3 or by reacting compounds of formula C6 with 23C. Compounds of formula C7 can be deprotected under conditions known in the art to give compounds of formula C8. Compounds of formula C1 and C4 are commercially available or can be readily synthesized in one or more steps by one skilled in the art using conditions known in the art. General synthetic scheme 4 [ka]

[0281] Compounds of formula D4, D8 and D10 can be prepared according to general synthetic scheme 4. In the formula, R 1 and R 3 is as defined herein, and A is C3~7 monocyclic cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, naphthalenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered fused bicyclic heteroaryl; G 2 is R a , R b , R c , -SR 2 or =NR 2a where R a , R b , R c , R 2 and R 2a is as defined herein, PG is a protecting group known in the art for alcohols and carboxylic acids, PG' is a protecting group known in the art for phosphates, PG" is a protecting group known in the art for amines, and L is H or -O, or both L's together with the carbon to which they are attached form C=O. According to General Synthetic Scheme 4, compounds of formula D1 or D5 can be reacted with chloromethyl chloroformate under various conditions to give compounds of formula D2 or D6, respectively. Compounds of D2 or D6 can be reacted with a dialkyl phosphate reagent to give compounds D3 or D7, respectively. Non-limiting exemplary reagents for this transformation include potassium di-tert-butyl phosphate and tetrabutylammonium di-tert-butyl phosphate. Compounds of formula D3 can be deprotected and, if both L's are H, oxidized using conditions known in the art to give compounds of formula D4. Compounds of formula D7 can be deprotected under appropriate conditions known in the art to give compounds of formula D8. The compound of formula D9 can be obtained by either the reaction of intermediate 5 / intermediate 5E with a compound of formula D4 or the reaction of a compound of formula D8 with 23C. The compound of formula D9 can be deprotected under conditions known in the art to obtain a compound of formula D10. Compounds of formula D1 and D5 are commercially available or can be readily synthesized in one or more steps using conditions known in the art.

[0282] VIII. Working Examples Exemplary chemicals of the present disclosure are provided in the specific examples below. Those skilled in the art will understand that to obtain the various compounds described herein, starting materials can be suitably selected so that the ultimately desired substituents are carried through the reaction scheme, with or without protection as necessary, to obtain the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that can be carried through the reaction scheme and appropriately replaced with the desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular pendant groups.

[0283] The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It is understood that the individual steps described herein can be combined. It is also understood that separate batches of compounds can be combined and then carried forward to the next synthetic step.

[0284] In the following description of examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of the present disclosure. Therefore, the following description is not intended to limit the scope of the present disclosure. Intermediates: Intermediate 1. [ka]

[0285] Synthesis of (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amineacetyl-D-leucinate (Intermediate 1): A mixture of Intermediate 1A (30.8 mmol, 1.00 equiv.), 2-methyltetrahydrofuran (75 mL), water (45 g), and NaOH (37.9 mmol, 1.23 equiv.) was stirred for 2 h. The aqueous phase was discarded, and the organic phase was washed twice with water (45 mL). The organic phase was solvent-exchanged into toluene, distilled to a final volume of 3 mL / g, and then diluted with toluene (224 mL). To this solution was added N-acetyl-D-leucine (43.3 mmol), zinc oxide (6.25 mmol), and 2-pyridinecarboxaldehyde (1.6 mmol). The mixture was stirred at 35 °C for 157 h and then cooled to 20 °C. The mixture was treated with a solution of NaOH (45 mmol) in water (75 mL) and then filtered through celite (7.5 g) and rinsed with toluene (30 mL). The aqueous phase was discarded, and the organic phase was washed three times with water (75 mL). To the organic phase were added EtOH (15 mL), water (7.5 mL), toluene (76 mL), and N-acetyl-D-leucine (27.7 mmol). The mixture was cooled to 0° C. and filtered. The filter cake was washed with toluene (76 mL) and dried under vacuum to give the title compound, Intermediate 1. 1 H NMR(400MHz,DMSO-d6)δ8.03(d,J=8.0Hz,1H),7.95(d,J=8.3Hz,1H),7.49(d,J=8.3Hz,1H),7.03 (tt,J=9.5,2.4Hz,1H),6.87(dtd,J=8.4,6.2,2.2Hz,2H),5.49(s,3H),4.42(dd,J=7.9,5.9Hz,1H ),4.18(q,J=7.8Hz,1H),2.93(dd,J=13.3,5.9Hz,1H),2.85(dd,J=13.2,8.0Hz,1H),1.83(s,3H) ,1.71-1.54(m,1H),1.47(dd,J=8.4,6.2Hz,2H),0.88(d,J=6.6Hz,3H),0.83(d,J=6.5Hz,3H)ppm. 13C NMR(101MHz,DMSO-d6)δ174.72,169.03,162.07(dd,J=245.5,13.3Hz),161.79,143.51,142.82(t,J=9.4Hz),139.72,128.39 ,119.30,113.36-111.39(m),101.73(t,J=25.7Hz),55.19,50.69,41.74(d,J=2.3Hz),40.51,24.36,22.91,22.44,21.46ppm. Intermediate 2. [ka]

[0286] Synthesis of (1R,5R,E)-3-(hydroxyimino)bicyclo[3.1.0]hexan-2-one (intermediate 2B): ketone intermediate 2A (111 mmol) and ethyl methyl ... To a mixture of 121 mmol of 2-methyltetrahydrofuran trifluoroacetate in 50 mL of 2-methyltetrahydrofuran was added 2 M potassium t-butoxide in 2-methyltetrahydrofuran (62.4 mL, 1.2 equiv.). After 1 h, the solution was warmed to 20° C. and stirred for 3 h. The mixture was cooled to 5° C., and a solution of 86% phosphoric acid (133 mmol) in 50 mL of water was added. The mixture was warmed to 20° C., and sodium nitrite (122 mmol) was added. After 16 h, water (100 mL) was added, and the aqueous phase was separated. The aqueous phase was back-extracted with three portions of 80 mL, 80 mL, and 50 mL of 2-methyltetrahydrofuran. The combined organic phase was distilled to 3 mL / g, then exchanged with acetic acid and distilled to a total volume of 5 mL / g to give a solution of the title compound, Intermediate 2B. 1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H),2.73(d,J=18.5Hz,1H),2.63(ddd,J=18.6,5.3,2.0Hz,1 H),2.17-2.01(m,2H),1.34(dddd,J=9.2,7.1,4.9,2.0Hz,1H),0.77(td,J=4.6,3.4Hz,1H)ppm.

[0287] Synthesis of (1R,5R,E)-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dithiolane]-3-one oxime (Intermediate 2C): To a solution of Intermediate 2B (102 mmol) in acetic acid (total volume 55 mL) at 20°C was added 1,2-ethanedithiol (117 mmol) and p-toluenesulfonic acid (42 mmol). After 20 h, water (60 mL) was added and the mixture was cooled to 5°C. After 3 h, the reaction was filtered, and the filter cake was then washed with two portions of a mixture of 2-propanol (24 mL) and water (6 mL) and dried under vacuum to provide the title compound, Intermediate 2C. 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),3.63-3.51(m,2H),3.51-3.42(m,1H),3.39-3.31(m,1H),2.83(d,J=17.4Hz,1H),2.59-2.52(m,1H),1 .87(ddd,J=8.0,6.2,3.7Hz,1H),1.65(dddd,J=7.7,6.2,5.2,3.9Hz,1H),0.93(tdd,J=7.6,5.5,1.7Hz,1H),0.02(dt,J=5.5,3.8Hz,1H)ppm.

[0288] Synthesis of (1R,5R)-spiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dithiolane]-3-one (Intermediate 2D): para-Toluenesulfonic acid (0.90 g) was charged to a vessel containing a suspension of Intermediate 2C (2.5 mmol) in methyl ethyl ketone (2.5 mL) and water (2.5 mL). The mixture was stirred at about 85°C until the reaction was complete. The product was isolated from the reaction mixture by cooling to about 20°C, adding water (2.50 mL), and cooling to about 0°C. The slurry was filtered, and the filter cake was washed with water and then thoroughly dried to provide the title compound, Intermediate 2D. 1H NMR(400MHz,DMSO-d6)δ3.55-3.37(m,3H),3.28-3.13(m,1H),3.03(ddd,J=18.5,5.6,2.2Hz,1H),2.20(d,J=18.5Hz,1H),1.84 (ddd,J=8.0,7.0,3.8Hz,1H),1.66(tdd,J=7.2,5.6,4.1Hz,1H),1.03(tdd,J=7.9,5.9,2.1Hz,1H),0.06(dt,J=6.0,4.0Hz,1H).

[0289] Synthesis of diisopropylammonium (Z)-2,2,2-trifluoro-1-((1R,5S)-3-oxospiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dithiolan]-4-ylidene)ethane-1-olate (Intermediate 2): Intermediate 2D (756 mg) was charged to a vessel and dissolved in 2-methyltetrahydrofuran (7.6 mL). To this mixture was charged ethyl trifluoroacetate (0.57 g), and the reaction was cooled to about 0°C. Lithium hexamethyldisilazide (4.5 g of a 1.0 M solution in THF) was charged over about 60 minutes, and the reaction was stirred until complete. A solution of sulfuric acid (2.0 g) in water (5.6 mL) was charged, and the reaction was then warmed to about 20°C and stirred for about 20 minutes. The layers were separated and the aqueous layer was extracted twice with 2-methyltetrahydrofuran (5.3 mL). The mixture was concentrated and charged with N,N-diisopropylamine (0.5 g). The product was crystallized by the addition of heptane (11 mL). The reaction was filtered, the filter cake was washed with heptane, and then thoroughly dehydrated and dried to give the title compound, Intermediate 2. 1 H NMR(400MHz,Acetonitrile-d3)δ 7.84(m,2H),3.58(d,J=8.7Hz,2H),3.47-3.27(m,4H),2.20(s,1H),1.81-1. 68(m,1H),1.24(dd,J=6.5,0.6Hz,12H),0.99(q,J=6.5Hz,1H),0.13(s,1H). Intermediate 3. [ka]

[0290] Synthesis of ethyl 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (Intermediate 3B): Acetyl chloride (940 mmol) was added to EtOH (324 g) to give a solution of anhydrous HCl in EtOH. To this solution was charged 2-ethylhydrazinoacetate HCl (293 mmol), LiCl (850 mmol), Intermediate 2 (235 mmol), and EtOH (36 g). The mixture was stirred for 44 h, then concentrated to a volume of 2 mL / g and diluted with dichloromethane (1170 g). The mixture was washed with water (450 g), followed by a solution of sodium bicarbonate (428 mmol) in water (451 g) and NaCl (50.7 g) in water (452 ​​g). The organic phase was treated with silica gel (45.1 g), filtered, azeotropically distilled to a volume of 2 mL / g, and then diluted with dichloromethane (451 g). The crude intermediate 3A was used in the next step.

[0291] A mixture of dibromodimethylhydantoin (93.5 mmol) and dichloromethane (170 mL) was charged with 70% w / w hydrogen fluoride pyridine (2652 mmol) at −13° C. To the resulting mixture was charged crude Intermediate 3A (27.4 mmol) in dichloromethane (50 mL). After 2.5 h, water (105 mL), a solution of sodium metabisulfite (109 mmol) in water (159 g), and a solution of 45% KOH (128 g) were added sequentially to the mixture. The mixture was warmed to 20° C., and the aqueous phase was separated and discarded. The organic phase was washed with a solution of 35% HCl (113 mmol) in water (103 g) and a solution of NaCl (5.2 g) in water (105 g). The organic solution was exchanged with EtOH and distilled to a final volume of 8.2 mL / g. Activated carbon (3.0 g) was added to the solution and stirred for 30 minutes. The mixture was filtered and rinsed with additional EtOH (42 mL). The solution was distilled to a volume of 5.5 mL / g, and water (50 mL) was added. The reaction was filtered, and the filter cake was washed with a mixture of EtOH (20 mL) and water (20 L) and dried under vacuum to give the title compound, Intermediate 3B.1 H NMR(400MHz,DMSO-d6)δ5.31-5.04(m,2H),4.17(q,J=7.1Hz,2H),2.78-2.57(m,2H),1.47( dddd,J=8.5,7.1,5.5,1.4Hz,1H),1.19(t,J=7.1Hz,3H),1.04(tdt,J=5.3,4.0,1.8Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ166.79,143.15(t,J=29.4Hz),134.65(q,J=39.0Hz),132.99,121.05(q,J=268.4Hz),12 0.52(t,J=243.3Hz),62.09,52.49,27.95(dd,J=34.7,29.0Hz),23.82(d,J=2.6Hz),14.25,12.14(t,J=3.1Hz). 19 F NMR(376MHz,DMSO-d6)δ-60.47,-79.68(dd,J=253.5,13 .2Hz),-103.09(dd,J=253.3,9.8Hz)ppm.

[0292] Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (Intermediate 3): To a mixture of Intermediate 3B (64.6 mmol) in EtOH (9.3 g) and water (80.3 g) was added 45% KOH (130 mmol) and the mixture was warmed to 50° C. After 17 h, the solution was added to a mixture of 35% HCl (170 mmol) in water (102 g). The reaction was filtered, and the filter cake was washed with water (120 g) and dried under vacuum to give the title compound, Intermediate 3. 1 H NMR(400MHz,DMSO-d6)δ13.50(s,1H),5.14-4.81(m,2H),2.82-2.56(m,2H),1.46(dddd,J=8.5,7.1,5.5,1.4Hz,1H),1.08-1.00(m,1H). 13C NMR(101MHz,DMSO-d6)δ168.16,143.05(t,J=29.4Hz),134.40(q,J=38.9Hz),132.80,121.11(q,J=268.4 Hz),120.55(t,J=243.3Hz),52.54,27.97(dd,J=34.7,29.0Hz),23.81(d,J=2.5Hz),12.13(t,J=3.1Hz). 19 F NMR (376MHz, DMSO-d6) δ-60.39(d,J=1.4Hz),-79.83(dd,J=253.2,13.1Hz),-102.97(dd,J=253.2,9.8Hz). Intermediate 4. [ka]

[0293] Synthesis of 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (Intermediate 4): A mixture of bis(triphenylphosphine)palladium(II) dichloride (0.46 mmol), bis(pinacolato)diboron (33 mmol), Intermediate 4A (30.5 mmol), potassium propionate (89.3 mmol), toluene (44 g), and DMF (29 g) was degassed and then warmed to 107 °C. After 7 h, the mixture was cooled to 60 °C and treated with a solution of N-acetylcysteine ​​(6.1 mmol) in water (20 g) and stirred for 18 h. The mixture was cooled to 20 °C, diluted with EtOAc (50 g), filtered through celite, and rinsed with additional EtOAc (40 g). The aqueous phase was discarded, and the organic phase was washed three times with a solution of LiCl (6.0 g) in water (60 g). The organic phase was treated with activated carbon and rinsed with additional EtOAc (80 g). The solution was exchanged into 2-propanol and distilled to a final volume of 4 mL / g. The mixture was diluted with n-heptane (41 g), warmed to 82° C., and then cooled to 15° C. The mixture was filtered, and the filter cake was washed with 2-propanol (32 g) and dried under vacuum to give the title compound, intermediate 4. 1H NMR (400MHz, DMSO-d6) δ7.70(dd,J=7.6,1.0Hz,1H),7.07(dd,J=7.6,1.0Hz,1H),5.58(s,2H),5.46(q,J=9.1Hz,2H),1.32(s,12h). Intermediate 5. [ka]

[0294] Synthesis of (S)-1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (Intermediate 5B): A mixture of Intermediate 1 (35.33 mmol, 1.00 equiv.), Intermediate 5A (39.7 mmol, 1.12 equiv.), bis(triphenylphosphine)palladium(II) dichloride (0.54 mmol, 0.015 equiv.), and triethylamine (178.7 mmol, 5.06 equiv.) in MeCN (64 g) was heated at 70° C. for 6 hours. Water (10.1 g) was added, and the mixture was cooled to 50° C. N-acetyl-L-cysteine ​​(0.60 g) was added, and the mixture was cooled to room temperature. Water (150 g) was added, and the reaction was filtered. The filter cake was washed with a mixture of MeCN (20 g) and water (52 g) and dried under vacuum to give the title compound Intermediate 5B. 1 H NMR(400MHz,DMSO-d6)δ8.05(d,J=8.2Hz,1H),7.42(d,J=8.2Hz,1H),7.01(tt,J=9.5,2.4Hz,1H),6.97-6.84(m,2H),4.41 (dd,J=8.5,5.2Hz,1H),3.20(s,3H),2.93(dd,J=13.3,5.2Hz,1H),2.79(dd,J=13.3,8.5Hz,1H),1.99(s,2H),1.68(s,6H). 13C NMR(101MHz,DMSO-d6)δ162.25,162.00(dd,J=245.2,13.4Hz),143.88(t,J=9.4Hz),141.09,139.72,127 .51,120.08,112.58-112.12(m),101.45(t,J=25.7Hz),87.94,84.25,57.24,55.90,42.57,34.99,22.19.

[0295] N-((S)-1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c] Synthesis of pyrazol-1-ylacetamide (Intermediate 5C): To a mixture of Intermediate 5B (43.8 mmol, 1.00 equivalents), Intermediate 3 (48.1 mmol, 1.10 equivalents), and triethylamine (65.3 mmol, 1.49 equivalents) in MeCN (100 g) was added a 50% (w / w) T3P / DMF solution (132 mmol, 1.5 equivalents), and the mixture was stirred for 3 hours. DMF (20.1 g) and water (50.1 g) were added, followed by seed crystals of the title compound, Intermediate 5C (0.06 g). Water (90.0 g) was added, and the reaction was filtered. The filter cake was washed with a mixture of MeCN (70.0 g) and water (90.1 g) and dried under vacuum to give the title compound, Intermediate 5C. 1 H NMR(400MHz,DMSO-d6)δ9.19(d,J=8.3Hz,1H),8.12(d,J=8.3Hz,1H),7.50(d,J=8.3Hz,1H),7.07(tt,J=9.4,2.4Hz,1H),6.96-6.87(m,2H),5.52( td), J=8.8,5.3Hz,1H),4.93-4.73(m,2H),3.22(s,3H),3.11-2.90(m,2H) ),2.66-2.52(m,2H),1.69(s,6H),1.45-1.36(m,1H),1.02-0.93(m,1H). 13C NMR(100MHz,DMSO-d6):δ164.42,163.62,163.49,161.17,161.04,158.19,142.92,142.20,142.10,142.01,141.63,140.23,134.11,133.73,132.14,128.66,122.23,120.49,119.56,112.49,112.25,104.75,102.25,88.62,84.20,57.44,53.85,53.03,35.21,23.41,22.46,22.40,11.79。

[0296] N-((S)-1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole Synthesis of (-1-yl)acetamide (Intermediate 5D): A mixture of Intermediate 5C (88.0 mmol, 1.00 equiv.), Intermediate 4 (105 mmol, 1.19 equiv.), potassium bicarbonate (266 mmol, 3.03 equiv.), palladium(II) chloride (1.3 mmol, 0.015 equiv.), and cyclohexyldiphenylphosphine (2.7 mmol, 0.030 equiv.) in 2-methyltetrahydrofuran (449 g) and water (130 g) was heated at 70° C. for 15 hours and then cooled to 40° C. N-acetyl-L-cysteine ​​(19.5 g), water (202 g), NaOH (6.5 g), and EtOH (48.7 g) were added, and the mixture was stirred for 1 hour. The aqueous phase was removed, and the organic phase was washed with a mixture of N-acetyl-L-cysteine ​​(19.5 g), water (429 g), NaOH (6.5 g), and EtOH (48.8 g), followed by a solution of water (293 g) and sodium dihydrogen phosphate (32.5 g). A portion of the organic phase (97.5 g) was azeotropically distilled with additional 2-methyltetrahydrofuran, then solvent-switched to EtOH and distilled to a volume of approximately 4 mL / g. Methanesulfonic acid (39.1 mmol) and seed crystals (0.06 g) of the title compound Intermediate 5D were added, followed by di-n-butyl ether (86.3 g). The reaction was filtered, and the filter cake was washed twice with a mixture of di-n-butyl ether (24 g) and ethanol (5.0 g) and dried under vacuum to give the title compound Intermediate 5D. 1 H NMR(400MHz,DMSO-d6)δ9.19(d,J=8.3Hz,2H),7.84-7.69(m,4H),7.11(d,J=7.7Hz,2H),7.07-6.95(m,3H),6.82(d,J=7.7Hz,2H),6.54-6.40(m,4H) ,4.90(d,J=16.4Hz,2H),4.76-4.60(m,4H),4.15(dq,J=16.6,8.4Hz,2H),3.75(dt,J=16.3,8.7Hz,2H),3.25(s,7H),2.99-2.86(m,4H),2.63-2.50(m,3H),2.41(s,14H),1.73(d,J=2.1Hz,13H),0.93(dd,J=6.1,3.9Hz,2H)。

[0297] Synthesis of N-((S)-1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (Intermediate 5E): A mixture of Intermediate 5D (17.8 mmol, 1.00 equiv) in 2-methyltetrahydrofuran (181 g) was washed with a solution of sodium carbonate (38 mmol, 2.1 equiv) in water (200 g). The aqueous phase was discarded, and the organic phase was washed twice with a solution of sodium carbonate (38 mmol, 2.1 equiv.) and sodium chloride (4.0 g) in water (200 g). The organic phase was azeotropically distilled with additional 2-methyltetrahydrofuran, followed by distillation to a volume of approximately 3 mL / g. Additional 2-methyltetrahydrofuran (240 g) was added, the temperature was adjusted to 10 °C, and triethylamine (112 mmol, 6.3 equiv.) and methanesulfonyl chloride (52 mmol, 2.9 equiv.) were added. After 1.5 h, the mixture was washed with water (100 g). The organic phase was treated with a solution of sodium hydroxide (61 mmol, 3.4 equiv.) in water (60 g) and warmed to 35 °C. The aqueous phase was discarded, and the organic phase was washed with water (60 g) and then azeotroped with additional 2-methyltetrahydrofuran, followed by a solvent switch to EtOH and distillation to a volume of approximately 3 mL / g. Additional EtOH (32 g) was charged, followed by n-heptane (69 g). The reaction was filtered, and the filter cake was washed with a mixture of n-heptane (34 g) and ethanol (40 g) and dried under vacuum to provide the title compound, Intermediate 5E. 1 H NMR(400MHz,DMSO-d6)δ9.09(d,J=8.0Hz,1H),8.93 *( d, J = 8.5 Hz), 7.80-7.72 * (m),7.71(s,2H),6.99(tt,J=9.5,2.4Hz,1H),6.94(d,J=7.6Hz,1H),6.90 *(d,J=6.3Hz),6.69(d,J=7.6Hz,1H),6.57-6.51 * (m),6.48-6.40(m,2H),4.90(d,J=16.5Hz,1H),4.77(d,J=16.4Hz,1H),4.70(td,J=8.3,5.2Hz,1H),4.63 * (d,J=16.5Hz),4.22(dq,J=16.7,8.4Hz,1H),3.90-3.75(m,1H),3.26(s,3H),2.92(td,J=13.8,8.5Hz,2H),2.83 * (s),2.80(s,3H),2.64-2.51(m,2H),1.74(d,J=2.2Hz,6H),1.44-1.34(m,1H),0.94(dq,J=6.0,3.7Hz,1H); 13 C NMR(100MHz,dmso)δ164.39,163.43,163.39,163.25,160.94,160.91,160.81,158.93,158.22,152.64,151.94,142.92,142.72,142.63,142.43,142.34,142.19,142.10,142.00,141.43,141.14,139.55,139.36,133.95,133.56,133.17,132.12,131.93,131.68,129.66,129.56,128.17,127.91,126.86,126.76,125.02,122.35,122.21,122.08,122.05,119.93,119.88,119.38,118.88,118.18,117.54,117.21,117.04,112.18,112.02,111.95,111.84,111.78,102.28,102.03,101.81,88.14,88.00,84.69,84.65,57.33,53.22,52.96,52.76,52.44,40.15,39.94,39.73,39.52,39.31,39.10,38.97,38.89,38.65 ,35.10,35.08,27.86,27.56,27.52,27.23,23.19,22.42,22.41,22.30,22.28,11.63. *Signals arising from minor atropisomers. 13 C NMR data is reported for a mixture of atropisomers.

[0298] Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (Intermediate 5): Intermediate 5E (1.0 g) and glacial acetic acid (2.1 g) were combined at about 20° C. and stirred until dissolved. The resulting solution was transferred to a reactor containing water (15 g) over about 1 hour. The resulting slurry was stirred for an additional hour and filtered. The filter cake was washed with water (2 x 5 g), dewatered, and dried under vacuum at about 60°C to give the title compound intermediate 5, also known as lenacapavir. 1 H NMR (400 MHz, δ 6-DMSO; 5:1 mixture of atropisomers) δ 10.11 * (s),10.00(s,1 H),9.25(d,J=8.0Hz,1 H),8.92 * (d,J=8.4Hz),7.90 * (d,J=7.6Hz),7.81(d,J=8.0Hz,1 H),7.76(d,J=8.0Hz,1 H), 7.32(d, J=7.6Hz, 1 H), 7.23 * (d,J=8.0Hz), 7.19 * (d,J=8.0Hz),7.02(tt,J=9.4,2.4Hz,1H),6.94 * (m), 6.86(d, J=7.6Hz, 1 H), 6.54 * (m),6.48(m,2 H),4.92(d,J=16.4Hz,1 H),4.77 * (d,J=16.4Hz),4.71(d,J=16.4Hz,1H),4.68 *(m),4.51(dq,J=16.4,8.3Hz,1 H),4.19 * (dq,J=16.4,8.2Hz),3.96(dq,J=16.8,8.4Hz,1 H),3.27(s,3 H),3.24 * (s), 3.17(s, 3 H), 3.11 * (dd,J=13.0,3.4Hz),3.02(dd,J=13.6,5.6Hz,1 H),2.95(dd,J=13.8,8.6Hz,1 H),2.92 * (m),2.60(m,1 H),2.55(m,1 H),1.74(s,6 H),1.40(m,1 H),0.96(m,1 H); 13 C NMR (100MHz, δ6-DMSO; 5:1 アトロプisotropic mixture) δ 164.5, 163.4 * ,162.1(dd,J=246.0,13.4Hz),162.0 * (dd,J=246.1,13.4Hz),158.8,158.1 * ,142.7(t,J=29.3Hz),142.3,142.1 * (m), 141.9 (t, J = 9.5 Hz), 141.7 * 140.2 * 140.0 * 139.8 * ,139.5,139.3,139.2,133.8(q,J=38.7Hz),132.0(m),131.7 * ,131.1,130.3 * ,130.0,126.8,126.4,126.2 * 123.0 * (m), 122.9 (q, J = 281.7 Hz), 122.7 * ,122.1,120.7(q,J=268.3Hz),119.9(t,J=243.4Hz),119.0,118.7 * 117.5 * ,117.4,112.0(m),102.1(t,J=25.6Hz),101.9 * (m), 88.5 * ,88.4,84.5,57.3,52.8,52.7,52.4 *,50.2(q,J=33.3Hz),50.0(m),41.4 * ,41.2,39.8,38.7,35.1,27.5(dd,J=35.1,29.0Hz),23.2,22.4,22.3,22.2 * ,11.6. * Signals arising from minor atropisomers. Final Example: Example 1 [ka]

[0299] N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2, Synthesis of 2-trifluoroethyl)-1H-indazol-3-yl)-4-methyl-N-(methylsulfonyl)piperazine-1-carboxamide (1): To a solution of intermediate 5 (0.052 mmol) in DCM (0.5 mL) was added 4-methylpiperazine-1-carbonyl chloride (0.310 mmol), N,N-diisopropylethylamine (0.155 mmol), and 4-dimethylaminopyridine (0.310 mmol) sequentially. The reaction was then sealed, heated to 35° C., and stirred for 16 hours. Upon completion, the reaction mixture was concentrated, diluted with DMF, filtered, and purified by reverse-phase HPLC. Product-containing fractions were pooled and lyophilized to afford the title compound 1 as a mixture of atropisomers. 1H NMR (400MHz, methanol-d4) δ9.18(d),7.86-7.72(m),7.40(d),6.91-6.80(m),6.69(d),6.34-6.21(m),4.04(dq) ,3.63(q),3.49(s),3.38(s),3.26(s),3.11(dd),2.96(dd),2.60(d),1.85(s),1.50(q),1.20(t),1.09(dt). 19 F NMR (376 MHz, methanol-d4) δ -63.40, -72.54 (t), -77.51, -82.30, -104.92, -105.61, -111.97. MS (m / z) 1094.46 [M+H] + . Example 2. [ka]

[0300] N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)-[ Synthesis of 1,4'-bipiperidine]-1'-carboxamide (2): Pyridine (0.155 mmol) and 4-dimethylaminopyridine (1 mg) were added to a cooled solution of intermediate 5 (0.052 mmol) in methylene chloride (1 mL) at 0 °C. 4-Piperidinopiperidine-1-carbonyl chloride (24 mg 0.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours and then heated to 38 °C overnight. Upon completion, the reaction was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with methanol in ethyl acetate to give the atropisomeric mixture of the title compound 2.1 H NMR (400MHz, methanol-d4) δ7.78(d,J=8.1Hz),7.71(d,J=8.0Hz),7.29(d,J=7.6Hz),6.76 (tt,J=9.2,2.4Hz),6.55(d,J=7.7Hz),6.30-6.10(m),4.92-4.75(m),4.76-4.61(m),4 .25-3.84(m,),3.23(s),3.04(dd,J=13.1,8.1Hz),2.87(dd,J=13.1,6.6Hz),2.64-2.1 5(m),1.81(s),1.74-1.48(m),1.48-1.34(m),1.32-1.10(m),1.05(dq,J=6.0,3.6Hz). MS(m / z):1163.77[M+H] + . Example 3. [ka]

[0301] N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridine Synthesis of (3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-2-methyl-N-(methylsulfonyl)benzamide (3): To a solution of intermediate 5 (0.2 mmol) and 2-methylbenzoyl chloride (0.62 mmol) in DCM (3 mL) was added N,N-diisopropylethylamine (0.2 mmol) and 4-dimethylaminopyridine (0.2 mmol). The reaction was sealed and stirred for 1 h. Upon completion, the reaction mixture was concentrated, diluted with DMF, filtered, and purified by reverse-phase HPLC. Product-containing fractions were pooled and lyophilized to afford the title compound 3 as a mixture of atropisomers. 1H NMR(400MHz,CDCl3)δ7.58-7.34(m),7.13(d),7.07-6.98(m),6.93(p),6.88 -6.79(m),6.73(d),6.63(t),6.23(d),6.16(dd),6.08(d),5.88(d),4.79-4 .66(m),4.52-4.22(m),3.90-3.69(m),3.62(d),3.16(d),2.79-2.70(m),2. 58-2.45(m),2.41(s),1.92(s),1.84(d),1.46(h),1.25(s),1.18-1.09(m). 19 F NMR (377MHz, CDCl3) δ-61.86--62.44(m),-69.82--71.84(m),-76.06,-81.35(ddd),-104.06(ddd),-109.76(dt). MS(m / z):1186.30[M+H] + . Example 4. [ka]

[0302] (N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl) Synthesis of (2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)nicotinamide (4): To a vial equipped with a stir bar was added Intermediate 5 (0.0826 mmol), pyridine-3-carbonyl chloride hydrochloride (0.117 g, 7.95 equiv.), and N,N-diisopropylethylamine (0.160 g, 15 equiv.). Dichloromethane (0.75 mL) was added, and the reaction was stirred at 40 °C. Upon completion, the reaction was concentrated under reduced pressure and purified by reverse-phase HPLC. Product-containing fractions were pooled and lyophilized to afford the title compound 4 as a mixture of atropisomers.1 H NMR (400MHz, methanol-d4) δ8.90(dd),8.70(s),8.50(d),8.37(d),7.99(dt),7.91 -7.69(m),7.73-7.62(m),7.61(dt),7.41-7.30(m),7.25(dd),6.98(dd),6.87-6 .69(m),6.58(d),6.55-6.41(m),6.21(ddd),4.82-4.55(m),3.92(ddq),3.68(s ),3.65(s),3.47(s),3.24(d),3.09-2.83(m),2.57(ddq),1.83(d),1.45(p)ppm. MS(m / z) 1073.32[M+H] + . Example 5. [ka]

[0303] tert-Butyl 3-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yne-1 Synthesis of (2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)azetidine-1-carboxylate (5): To a solution of intermediate 5 (0.165 mmol), 5A (0.496 mmol, 3 equiv.), and DMAP (0.496 mmol, 3 equiv.) in DMF (2 mL) was added EDC (0.496 mmol, 3 equiv.). Upon completion, the reaction was partitioned between EtOAc (10 mL) and 0.1 M HCl (10 mL). The organic fractions were collected, dried over NaSO, and concentrated under reduced pressure to give the atropisomeric mixture of title compound 5B, which was used without purification. MS (m / z) 1151.55 [M+H] + .

[0304] Synthesis of N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)azetidine-3-carboxamide (5): To a solution of 5B (0.026 mmol) in DCM (1 mL) was added TFA (0.2 mL). Upon completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase HPLC. The product-containing fractions were pooled and lyophilized to give the title compound 5 as a mixture of atropisomers. 1 H NMR(400MHz,DMSO-d6)δ9.38(d),8.81(s),7.90(d),7.86-7.74(m),7.48(dd),7.13-6.98(m),6.81(d),6.56-6.40(m),5.01(d),4.82- 4.52(m),4.30-4.09(m),4.09-3.81(m),3.62(d),3.28(d),3.17-2.86(m),2.71-2.56(m),1.75(d),1.51-1.33(m),1.08-0.92(m)ppm. 19 F NMR(375MHz,DMSO-d6)δ-60.92(d),-69.09(t),-69.59--70.08(m),-74.52,-79.43(d),-79.79(d) ,-80.11(d),-80.46(d),-102.75,-103.18(d),-103.41(d),-103.86(d),-110.39--111.07(m)ppm. MS(m / z)1051.861[M+H] + . Example 6 [ka]

[0305] tert-Butyl((E)-((tert-butoxycarbonyl)amino)(3-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yne-1 Synthesis of N,N'-di-Boc-1H-pyrazole-1-carboxamidine (0.116 mmol) and DIPEA (0.174 mmol) were added sequentially to a solution of 5 (0.058 mmol) in MeCN (0.2 mL), and the resulting mixture was stirred for 30 minutes. Upon completion, the mixture was transferred to a separatory funnel with DCM (20 mL), and the organic layer was washed successively with 0.1 M HCl (10 mL). The organic fractions were collected, dried over NaSO, and concentrated under reduced pressure to give the title compound 6A, which was used without further purification. MS (m / z) 1293.65 [M+H] + .

[0306] Synthesis of 1-carbamimidoyl-N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)azetidine-3-carboxamide (6): To a solution of 6A (0.058 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.5 mL). Upon completion, the reaction was concentrated under reduced pressure and purified using reverse-phase HPLC. The product-containing fractions were pooled and lyophilized to give the title compound 6 as a mixture of atropisomers. 1 H NMR(400MHz,DMSO-d6)δ9.24(dd),7.92(d),7.85-7.77(m),7.49(dd),7.36(d),7.27(d),7.01(ddt),6.49(ddd),5.0 0(d),4.79-4.55(m),4.33-4.06(m),3.28(d),3.14-2.88(m),2.57(dd),1.75(d),1.47-1.37(m),1.06-0.91(m)ppm. 1 9 F NMR(375MHz,DMSO-d6)δ-60.90(d),-69.06--69.38(m),-69.88(t),-74.83 ,-80.17(d),-80.85(d),-103.28,-103.89(dd),-110.49--110.94(m)ppm. MS(m / z)1093.28[M+H] + . Example 7 [ka]

[0307] (trans)-3-amino-N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yne) Synthesis of (2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)cyclobutane-1-carboxamide (7): The atropisomeric mixture of the title compound was prepared following the procedure presented for the synthesis of 5 in Example 5, utilizing trans-1-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid in place of 5A. 1 H NMR(400MHz,DMSO-d6)δ9.65-8.78(m),7.99-7.69(m),7.39(d),7.12-6.96(m),6.67(d),6.52-6.43(m),6.40-6.31(m),5.08(d),4.99-4.82 (m),4.82-4.68(m),4.63-4.49(m),4.11(tt),3.57(d),3.28(d),3.04 -2.89(m),2.10-1.86(m),1.79-1.69(m),1.41(dq),1.08-0.95(m)ppm. 19 F NMR(375MHz,DMSO-d6)δ-60.78(d),-60.84,-60.94,-69.23(t),-70.15(t),-74.29,-79.7 5(dd),-80.47(d),-102.77,-103.22,-103.43(d),-103.88(d),-110.48--110.61(m)ppm. MS(m / z)1066.039[M+H] + . Example 8 [ka]

[0308] Synthesis of 2-(trans-3-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3 -methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)cyclobutyl)amino)-2-oxoacetic acid (8): To a solution of 7 (0.065 mmol) in DCM (2 mL) at −78° C., oxalyl chloride (0.129 mmol, 2 equiv.) was added, followed by DIPEA (0.323 mmol, 5 equiv.). After 30 min, the reaction was quenched with aqueous acetonitrile (1 mL of a 1:1 v / v mixture). The solvent was then removed under reduced pressure, and the residue was purified by reverse-phase HPLC. Product-containing fractions were pooled and lyophilized to afford the atropisomeric mixture of the title compound 8. 1 H NMR(400MHz,DMSO-d6)δ9.65-8.78(m),7.99-7.69(m),7.39(d),7.12-6.96(m),6.67(d),6.52-6.43(m),6.40-6.31(m),5.08(d),4.99-4.82 (m),4.82-4.68(m),4.63-4.49(m),4.11(tt),3.57(d),3.28(d),3.04 -2.89(m),2.10-1.86(m),1.79-1.69(m),1.41(dq),1.08-0.95(m)ppm. 19 F NMR(375MHz,DMSO-d6)δ-60.78(d),-60.84,-60.94,-69.23(t),-70.15(t),-74.29,-79.7 5(dd),-80.47(d),-102.77,-103.22,-103.43(d),-103.88(d),-110.48--110.61(m)ppm. MS(m / z)1161.25[M+Na] + . Example 9. [ka]

[0309] Synthesis of trans-N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-3-guanidino-N-(methylsulfonyl)cyclobutane-1-carboxamide (9): The atropisomeric mixture of the title compound was prepared according to the method presented for the synthesis of 6 in Example 6, utilizing 7 instead of 5. 1 H NMR(400MHz,DMSO-d6)δ9.26(dd),7.91(d),7.88-7.81(m),7.81-7.75(m ),7.53-7.44(m),7.39(d),7.09-7.00(m),6.70(d),6.54-6.43(m),6.38- 6.28(m),5.07(d),4.88(dd),4.76(dd),4.57(p),4.09(ddq),3.28(d),3 .12-2.86(m),2.81-2.57(m),1.88(dq),1.75(d),1.40(dq),0.99(s)ppm. 19 F NMR(375MHz,DMSO-d6)δ-60.72--60.87(m),-61.02,-69.31(t),-69.78(t),-70.20(t),-74.52,-79.46( d),-79.78(d),-80.13(d),-80.46(d),-102.75(d),-103.42(d),-103.89(d),-110.53--110.64(m)ppm. MS(m / z)1108.02[M+H] + . Example 10. [ka]

[0310] (1s,3R)-3-amino-N-(4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1- Synthesis of (in-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)cyclobutane-1-carboxamide (10): The atropisomeric mixture of the title compound was prepared following the procedure presented for the synthesis of 5 in Example 5, utilizing cis-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid in place of 5A. 1 H NMR (400MHz, methanol-d4) δ8.99(d),8.10(s),7.86(d),7.81-7.70(m),7.39-7.28(m) ,6.83(tt),6.52(d),6.28(h),4.00(dq),3.68-3.55(m),3.46(s),3.29(d),3.21(d d),3.04-2.92(m,1H),2.73-2.41(m,3H),2.33(q,J=9.7Hz,1H),2.20(ddd)2.08-1. 93(m),1.85(s),1.84(t),1.49(q1.20(t),1.13-1.04(m)ppm.MS(m / z)1065.24[M+H] + . Example 11 [ka]

[0311] Synthesis of benzyl (1R,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (11A): (1S,2R)-2-((benzyloxy)carbonyl)cyclopropane To a solution of 105 mL of 1-chloropropane-1-carboxylic acid (54.4 mmol) in 105 mL of THF was added dropwise a borane-dimethyl sulfide complex solution (10.0 M, 10.9 mL, 2 equiv.) at 0° C. When complete conversion was observed, the reaction was quenched with 20 mL of MeOH, concentrated under reduced pressure, and purified by silica gel chromatography. The product-containing fractions were pooled and lyophilized to give the title compound 11A. 1 H NMR(CDCl3,400MHz):δ7.32-7.37(m,5H),5.14(s,2H),3.94(dd,J=12Hz,J=5.6Hz,1H),3.74(dd, J=12Hz,J=5.6Hz,1H),2.25(s,1H),1.82-1.84(m,1H),1.52-1.54(m,1H),1.13-1.17(m,2H)ppm.

[0312] Synthesis of benzyl (1R,2S)-2-(((di-tert-butoxyphosphoryl)oxy)methyl)cyclopropane-1-carboxylate (11B): To a mixture of THF and MeCN (4 mL, 3:1 v / v) were added 11A (46.0 mmol), di-tert-butyl-diisopropylphosphoramidite (92.1 mmol, 2 equiv), and 1H-tetrazole (115 mmol, 10.2 mL, 2.5 equiv) sequentially. The reaction was stirred at room temperature until complete consumption of the starting material was observed by LCMS. It was then cooled to 0 °C and 30% hydrogen peroxide solution (115.0 mmol, 4.0 equiv) was slowly added. The following mixture was stirred at 0 °C until the reaction was complete, at which point it was transferred to a separatory funnel with 150 mL of EtOAc and washed three times with saturated sodium thiosulfate solution (90 mL × 3). The organic fraction was dried over sodium sulfate, concentrated, and purified using silica gel chromatography. The product-containing fractions were pooled and concentrated under reduced pressure to give the title compound 11B. 1 H NMR(CDCl3,400MHz)δ7.35(m,5H),5.15(dd,J=26.0Hz,J=12.8Hz2H),4.32(m ,1H),4.08(m,1H),1.90(m,1H),1.75(m,1H),1.50(m,18H),1.15(m,2H)ppm. MS(m / z):287[M+H]+ .

[0313] Synthesis of (1R,2S)-2-(((di-tert-butoxyphosphoryl)oxy)methyl)cyclopropane-1-carboxylic acid (11C): A solution of 11B (2.51 mmol) in 8 mL of EtOAc was flushed with Ar for 5 minutes. Pd / C (10% Pd on activated carbon, 0.25 mmol, 0.1 equiv.) was then carefully added to the solution. The resulting mixture was then flushed with H for 5 minutes and then stirred under 1 atm of H for 2 hours. Upon completion, the reaction was diluted with 10 mL of EtOAc and flushed with Ar for 5 minutes before filtering through Celite®. The filter cake was carefully washed with 3×10 mL of EtOAc, and the organic filtrate was concentrated under reduced pressure to provide the title compound 11C. 1 H NMR (CDCl3,400MHz)δ4.37-4.26(m,1H),4.12(dt,J=11.1,8.4Hz,1H),1.93-1.71(m,2H),1.50(s,18H),1.19(ddd,J=13.0,7.7,5.1Hz,2H)ppm. MS(m / z)309.21[M+H] + .

[0314] Synthesis of (((1S,2R)-2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)cyclopropyl)methoxy)methyl dihydrogenphosphate (11): An atropisomeric mixture of the title compound was prepared following the method proposed for the synthesis of 5 in Example 5, utilizing 11C instead of 5A and intermediate 5E instead of intermediate 5. 11H NMR (400 MHz, DMSO-d6) δ 9.25 - 8.99 (m), 8.02 - 7.91 (m), 7.86 - 7.75 (m), 7.47 (dd), 7.01 (ddq), 6.85 (d), 6.50 (td), 6.38 (ddt), 5.02 - 4.85 (m ), 4.88 - 4.72 (m), 4.75 - 4.49 (m), 4.13 - 4.05 (m), 4.10 - 3.97 (m), 4.01 - 3.89 (m), 3.92 - 3.83 (m), 3.88 - 3.77 (m), 3.71 - 3.50 (m), 3.30 - 3.24 (m), 3.06 - 2.84 (m), 2.59 (s), 2.64 - 2.53 (m), 1.75 (q), 1.57 (ddd), 1.46 - 1.35 (m), 1.38 - 1.17 (m), 1.22 - 0.95 (m), 0.96 (s), 0.85 (dt), 0.69 (td) ppm. 19 19F NMR (375 MHz, DMSO-d6) δ -60.61 - -61.07 (m), -69.27 - -70.08 (m), -75.24, -75.28 (d, J = 19.2 Hz), -79.80, -79.93 - -80.61 (m), -80.95 (dd, J = 91.6, 12.9 Hz), -102.73 - -104.22 (m), -110.42 - -111.59 ppm. MS (m / z) 1146.72 [M+H] + . Example 12. [Chemical formula]

[0315] Synthesis of (1R,2S)-2-((benzyloxy)carbonyl)cyclopropane-1-carboxylic acid (12A): To a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (44.6 mmol) and quinidine (50.4 mmol, 1.13 equiv) in toluene (230 mL) was added benzyl alcohol (133 mmol, 3 equiv) dropwise at −55° C. The resulting mixture was stirred at −55° C. for 96 h, then quenched with 5 mL of water, concentrated under reduced pressure, and partitioned between saturated NaHCO (200 mL) and EtOAc (200 mL). The organic fractions were collected, dried over NaSO, and concentrated under reduced pressure to provide the title compound 12A, which was used without purification. 1 H NMR (CDCl3400MHz): δ7.38-7.23(m,5H),5.14(s,2H),2.20-2.16(m,1H),2.11-2.09(m,1H),1.75-1.73(m,1H),1.36-1.35(m,1H)ppm.

[0316] Synthesis of 1-benzyl 2-((((di-tert-butoxyphosphoryl)oxy)methyl)(1S,2R)-cyclopropane-1,2-dicarboxylate (12B): To a solution of 12A (26.1 mmol) in DMSO (40 mL) was added CsCO (78.5 mmol, 3 equiv.) and KI (35.3 mmol, 1.35 equiv.) sequentially. Then, di-t ert-Butyl-chloromethyl phosphate was added to the reaction, and the temperature was raised to 40 °C. Upon completion, the reaction was quenched with 10 mL of water and partitioned between EtOAc (100 mL) and brine (100 mL). The organic fractions were collected, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to provide the title compound 12B. 1 H NMR(CDCl3400MHz):δ7.37-7.33(m,5H),5.58-5.54(m,1H),5.47-5.24(m,1H),5.13 (s,2H),2.17-2.11(m,2H),1.77-1.76(m,1H),1.49(s,18H),1.43-1.26(m,1H)ppm.

[0317] Synthesis of (1S,2R)-2-((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)cyclopropane-1-carboxylic acid (12C): The title compound was prepared following the method presented for the synthesis of 11C in Example 11, utilizing 12B instead of 11B.

[0318] Synthesis of (phosphonooxy)methyl (1R,2S)-2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)cyclopropane-1-carboxylate (12): The atropisomeric mixture of the title compound was prepared according to the method presented for the synthesis of 5 in Example 5, utilizing 12C instead of 5A and intermediate 5E instead of intermediate 5. 1 H NMR(400MHz,DMSO)δ9.31-9.10(m),8.00-7.91(m),7.89-7.71(m),7.61-7.43(m) ),7.12-6.88(m),6.59-6.33(m),5.53(dt),5.38(dt),4.96(dd),4.89-4.65(m), 4.66-4.41(m),3.96(ddd),3.53(q),3.49(d),3.28(d),3.04-2.88(m),2.62-2.5 5(m),2.53-2.48(m),1.76(d),1.66-1.49(m),1.44-1.34(m),1.01(s),0.76(s). 19 F NMR (376MHz, DMSO) δ-59.28--61.85(m),-68.81--70.37(m),-80.68(dd),-103.23(d),-109.27--112.20(m). MS(m / z):1191.345[M+H] + . Example 13 [ka]

[0319] (1S,3r)-3-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl) Synthesis of (phenyl)carbamoyl)cyclobutane-1-carboxylic acid (13): The atropisomeric mixture of the title compound was prepared following the procedure presented for the synthesis of 5 in Example 5, utilizing trans-cyclobutane-1,4-dicarboxylic acid in place of 5A and intermediate 5E in place of intermediate 5. 1 H NMR(400MHz,DMSO-d6)δ9.20(dd),7.87-7.73(m),7.35(dd),7.06-6.95(m),6.66(d),6.46(ddd),6.35(qd),4.98(d),4.87(d),4.82-4.6 6(m),4.63-4.47(m),4.22-4.08(m),3.99(dd),3.28(d),3.12-2.87(m),2.36(td),1.96(tt),1.80-1.72(m),1.39(p),1.03-0.95(m)ppm. 19 F NMR (375MHz, DMSO-d6) δ-58.25--63.52(m),-66.76--83.50(m),-100.32--106.48(m),-110.65(dt),-219.04ppm. MS(m / z):1094.28[M+H] + . Example 14. [ka]

[0320] ((1R,3s)-3-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yne-1- Synthesis of (methylsulfonyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)cyclobutane-1-carboxylic acid (14): The atropisomeric mixture of the title compound was prepared following the method proposed for the synthesis of 5 in Example 5, utilizing cis-cyclobutane-1,3-dicarboxylic acid instead of 5A and intermediate 5E instead of intermediate 5. 1 H NMR (400MHz, methanol-d4) δ8.95(d),7.93-7.81(m),7.75(d),7.42-7.23(m),6.77(tt),6.59(d),6.30(qd),4.71(d),3.97(dq),3.55 (d),3.46(s),3.26(s),3.25(d),3.12(dd),2.98(dt),2.81(p),2.73-2.31(m),1.85(s),1.98-1.71(m),1.44(td),1.03(ddd)ppm. MS(m / z)1094.19[M+H] + . Example 15. [ka]

[0321] Synthesis of cis-cis-1,3,5-bis(tert-butoxycarbonyl)cyclohexane-1-carboxylic acid (15A): To a solution of cis-cis-cyclohexane-1,3,5-tricarboxylic acid (2.31 mmol) in DCM (5 mL) was added 2-tert-butyl-1,3-diisopropylurea (4.63 mmol, 2 equivalents). Upon completion of the reaction, the mixture was filtered, and the mother liquor was concentrated under reduced pressure and purified by silica gel chromatography. The product-containing fractions were pooled and concentrated under reduced pressure to give the title compound 15A.1 H NMR (400MHz, CDCl3) δ 2.55-2.35 (m, 1H), 2.35-2.14 (m, 5H), 1.62-1.47 (m, 3H), 1.45 (s, 18H) ppm.

[0322] Synthesis of (1R,3S,5r)-5-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)cyclohexane-1,3-dicarboxylic acid (15): The atropisomeric mixture of the title compound was prepared according to the method presented for the synthesis of 5 in Example 5, utilizing 15A instead of 5A. 1 H NMR(400MHz,DMSO-d6)δ12.15(s),9.23(d),9.02(d),7.90(d),7.85-7.79(m),7.78(s),7.49(dd),7.36(dd),7.06-6.90(m),6.56(d),6.50-6.43 (m),6.32-6.21(m),5.04(dd),4.75(m),4.65-4.53(m),4.08(m),3.55(d ),3.28(d),3.00(dd),2.88(dd),1.99(dd),1.75(d),1.57-0.90(m)ppm. 19 F NMR(375MHz,DMSO-d6)δ-60.68,-60.84(d),-69.37(t),-69.59(t),-69.87(t),-70.24(t),-74.16,-79.74(d),-80.25(d),-80. 41(d),-80.92(d),-102.14,-102.82,-103.22(d),-103.80--103.94(m),-110.42(t),-110.57(q),-110.70(t),-110.82(t)ppm. MS(m / z)1165.990[M+H] + . Example 16. [ka]

[0323] Synthesis of (1R,2R)-2-(tert-butoxycarbonyl)cyclopropane-1-carboxylic acid (16A): To a solution of (1R,2R)-cyclopropane-1,2-dicarboxylic acid (1.54 mmol) in 5 mL of DCM was added 2-tert-butyl-1,3-diisopropylurea (1.54 mmol, 1 equivalent). Upon complete conversion, the reaction was concentrated under reduced pressure and purified by silica gel chromatography. The product-containing fractions were pooled and concentrated under reduced pressure to give the title compound 16A. 1 H NMR (400MHz, CDCl3) δ2.20-1.98(m,1H),1.47(s,9H),1.51-1.39(m,1H),1.35-1.25(m,1H),1.18(d,J=6.4Hz,1H)ppm.

[0324] Synthesis of (1R,2R)-2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)cyclopropane-1-carboxylic acid (16): An atropisomeric mixture of the title compound was prepared following the method proposed for the synthesis of 5 in Example 5, utilizing 16A instead of 5A and intermediate 5E instead of intermediate 5. 11H NMR (400 MHz, DMSO-d6) δ 12.51 (s), 9.25 - 9.05 (m), 7.90 - 7.73 (m), 7.56 - 7.45 (m), 7.40 - 7.25 (m), 7.11 - 6.95 (m), 6.46 (ddd), 6.45 - 6.32 (m), 5.00 (d), 4.93 - 4.80 (m), 4.83 - 4.67 (m), 4.61 (s), 4.67 - 4.49 (m), 4.25 - 3.97 (m), 3.28 (d), 2.97 (tdd), 2.14 - 1.97 (m), 1.89 (d), 1.78 - 1.72 (m), 1.61 (s), 1.54 - 1.34 (m), 1.40 (s), 1.30 - 1.22 (m), 1.16 (dt), 0.99 (s) ppm. 19 19F NMR (375 MHz, DMSO-d6) δ -60.75 - -61.00 (m), -69.43 - -70.13 (m), -75.10, -79.60 (d), -79.77 (d), -80.28 (d), -80.45 (d), -102.76 (d), -103.23, -103.72 - -103.96 (m), -110.44 - -110.66 (m), -110.77 ppm. MS (m / z) 1080.80 [M+H] + . Example 17. [Chemical formula] <0002​​​​(1R,2S)-2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3- Synthesis of (1S,2R)-2-(tert-butoxycarbonyl)cyclopropane-1-carboxylic acid (17): The atropisomeric mixture of the title compound was prepared according to the method presented for the synthesis of 5 in Example 5, utilizing (1S,2R)-2-(tert-butoxycarbonyl)cyclopropane-1-carboxylic acid instead of 5A and intermediate 5E instead of intermediate 5. 1 H NMR(400MHz,DMSO-d6)δ10.01(s),9.29-9.22(m),7.84-7.71(m),7.34-7.25(m),7.08-6.99(m),6.89-6.82(m),6.56-6.41(m),4.92(m,J=16. 4Hz),4.77-4.67(m),4.67-4.44(m),4.08-3.88(m),2.04-1.95(m),1.7 6-1.71(m), 1.49-1.38(m), 1.30-1.23(m), 1.21-1.07(m), 0.96(s)ppm. MS(m / z)1079.80[M+H] + . Example 18. [ka]

[0326] 1-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3- Synthesis of (methylsulfonyl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)cyclopropane-1-carboxylic acid (18): The atropisomeric mixture of the title compound was prepared following the method proposed for the synthesis of 5 in Example 5, utilizing 1-(tert-butoxycarbonyl)cyclopropane-1-carboxylic acid instead of 5A and intermediate 5E instead of intermediate 5. 1 H NMR(400MHz,DMSO-d6)δ9.25-9.18(m),9.05-8.92(m),7.90-7.68(m),7.45 -7.22(m),7.09-6.97(m),6.99-6.86(m),6.65-6.57(m),6.53-6.44(m),4.98-4.82(m),4.83-4.69(m),4.72-4.55(m),4.23-4.02(m) ),3.62-3.54(m),3.27(s),3.17-2.79(m),2.67-2.51(m),1.79-1.72(m),1.54-1.26(m),1.36(s),1.14-1.03(m),1.02-0.93(m)ppm. 19 F NMR(375MHz,DMSO-d6)δ-60.55--61.13(m),-68.82--69.34(m),-69.55--69.92(m),-75.09 ,-79.61--81.05(m),-102.84--103.31(m),-103.52--103.98(m),-110.43--110.88(m)ppm. MS(m / z)1080.09[M+H] + . Example 19. [ka]

[0327] Synthesis of 2-((benzyloxy)carbonyl)benzoic acid (19A): To a solution of phthalic acid (19.3 mmol) and DIPEA (23.1 mmol, 1.2 equiv.) in 8 mL of DMF, BnBr (21.2 mmol, 1.1 equiv.) was added and stirred at room temperature. Once complete conversion was observed, the reaction contents were transferred to a separatory funnel with EtO (250 mL) and 5% LiCl solution (100 mL). The organic layer was further extracted with 5% LiCl solution (2×100 mL), then collected, dried over NaSO, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound 19A. MS (m / z): 257.30 [M+H] + .

[0328] Synthesis of benzyl ((((di-tert-butoxyphosphoryl)oxy)methyl) phthalate (19B): 19A (5.46 mmol) and potassium bicarbonate (6.56 mmol, To a mixture of 19B (1.2 equiv.) in 6.5 mL of DMF was added di-tert-butyl chloromethyl phosphate (7.10 mmol, 1.3 equiv.) and the mixture was heated to 40 °C. Upon completion of the reaction, the contents were transferred to a separatory funnel with EtO (100 mL) and 5% LiCl solution (50 mL). The organic layer was further extracted with 5% LiCl solution (3 × 50 mL), then collected, dried over NaSO, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound 19B. MS (m / z) 369.11 [M-2-t-Bu] + .

[0329] Synthesis of 2-((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)benzoic acid (19C): The title compound was prepared following the method proposed for the synthesis of 11C in Example 11, utilizing 19B instead of 11B. 1 H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,Chloroform-d)δ7.88-7.75(m,2H),7.64-7.51(m,2H),5.83(d,J=14.8Hz,2H),1.53(s,18H)ppm.

[0330] ((Di-tert-butoxyphosphoryl)oxy)methyl 2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methyl Synthesis of (methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)benzoate (19D): To a mixture of 19C (0.74 mmol) and Intermediate 5E (0.59 mmol, 1.2 equiv.) in MeCN (3.5 mL) was added 1-methylimidazole (1.0 mmol, 2.1 equiv.). After stirring for 2 minutes, TCFH (0.51 mmol, 1.05 equiv.) was added in one portion. Upon completion, the reaction was concentrated under reduced pressure and purified by reverse-phase HPLC. Product-containing fractions were pooled and lyophilized to afford the title compound 19D as a mixture of atropisomers. MS (m / z) 1360.30 [M+Na] + .

[0331] Synthesis of (phosphonooxy)methyl 2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)benzoate (19): To a solution of 19D (0.492 mmol) in 5 mL of DCM was added 0.38 mL of TFA. Upon complete conversion, the reaction was concentrated under reduced pressure and purified by reverse-phase HPLC. The product-containing fractions were pooled and lyophilized to give the title compound 19 as a mixture of atropisomers. 1H NMR(400MHz,DMSO-d6)δ9.22-9.11(m),7.96-7.85(m),7.88-7.64(m),7.58-7.44(m),7.47-7.39(m) ,7.43-7.20(m),7.15-7.04(m),7.06-6.95(m),6.97-6.88(m),6.49-6.39(m),5.88-5.76(m),5.79-5 .57(m),4.89-4.70(m),4.67-4.40(m),4.37(s),4.17(s),4.05-3.84(m),3.74-3.63(m),3.28-3.22 (m),2.99-2.84(m),2.68-2.52(m),1.79-1.70(m),1.48-1.33(m),1.11-1.03(m),1.02-0.95(m)ppm. 19 F NMR(375MHz,DMSO-d6)δ-60.72--60.94(m),-69.62--69.82(m),-75.19--75.72(m),-75.51,-79.76--79.94(m) ,-80.43--80.61(m),-102.94,-103.20--103.36(m),-103.52--103.68(m),-103.97,-110.46--110.61(m),-110.57,-110.79ppm. MS(m / z)1225.30[M+H] + . Example 20. [ka]

[0332] Synthesis of benzyl (1S,2R)-2-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (20A): A solution of benzyl (1S,2R)-2-(hydroxymethyl)cyclopropane-1-carboxylate (6.24 mmol), triethylamine (12.5 mmol) in DCM (50.0 mL) was cooled to 0° C. Methanesulfonyl chloride (9.36 mmol) was added and the reaction was stirred at 0° C. for 90 minutes. The reaction was quenched with 1N HCl at 0° C., diluted with water, and extracted with DCM (3×). The combined organic layers were washed with saturated NaHCO 3 3(水溶液), washed with brine, dried over MgSO, filtered, and concentrated. The crude material was diluted with EtOAc, concentrated (repeated twice) to remove residual DCM, placed under high vacuum for 48 hours, and used without further purification to give the title compound 20A. 1 H NMR(400MHz,DMSO-d6)δ7.45-7.27(m,5H),5.21-5.05(m,2H),4.55(dd,J=10.7,6.1Hz,1H),4.20(dd,J=10.7,9.4Hz, 1H),3.09(d,J=0.9Hz,3H),1.99(td,J=8.1,5.7Hz,1H),1.87-1.73(m,1H),1.30-1.22(m,1H),1.09-1.00(m,1H)ppm.

[0333] Synthesis of benzyl (1S,2R)-2-(azidomethyl)cyclopropane-1-carboxylate (20B): A solution of 20A (5.48 mmol), sodium azide (8.77 mmol) in DMF (25.0 mL) was heated at 60° C. for 2 h. The reaction was diluted with water (200 mL) and extracted with 25% EtOAc / hexanes (3×). The combined organic layers were washed with 5% LiCl (水溶液) The mixture was washed with HCl, dried over MgSO4, filtered and concentrated to give 20B, which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ7.45-7.29(m,5H),5.19-5.04(m,2H),3.64(dd,J=13.1,5.9Hz,1H),3.43-3.34(m,1H) ,1.94(td,J=8.2,5.5Hz,1H),1.71(dt,J=9.3,6.7Hz,1H),1.22(td,J=8.2,4.5Hz,1H),1.03-0.92(m,1H)ppm.

[0334] Synthesis of benzyl (1S,2R)-2-(aminomethyl)cyclopropane-1-carboxylate (20C): To a solution of 20B (5.24 mmol) in THF (20.0 mL) was added triphenylphosphine (8.38 mmol), followed by water (2.00 mL). The reaction was stirred at room temperature for 18 hours, concentrated, diluted with 1 N HCl (10 mL), and extracted with ether (3×). The aqueous layer was concentrated and lyophilized to give 20C as the HCl salt. The title compound was used without further purification. MS (m / z) [M+H] + 205.98.

[0335] Synthesis of benzyl (1S,2R)-2-((((chloromethoxy)carbonyl)amino)methyl)cyclopropane-1-carboxylate (20D): To a solution of 20C (2.85 mmol) as the HCl salt in DCM (14.0 mL) was added triethylamine (9.96 mmol). The solution was cooled to 0° C. and chloromethyl chloroformate (3.70 mmol) was added dropwise. The reaction was allowed to warm gradually to room temperature and stirred for 2 h. The reaction was diluted with saturated NH4Cl (水溶液) The mixture was quenched with HCl and extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound 20D, which was used without purification. MS (m / z) 319.91 [M+Na] + .

[0336] Synthesis of benzyl (1S,2R)-2-(((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)amino)methyl)cyclopropane-1-carboxylate (20E): To a solution of 20D in DME (10.0 mL) was added tetra-n-butylammonium di-tert-butylphosphate (4.84 mmol). The reaction was heated at 80° C. for 2 h. The reaction was concentrated, diluted with EtOAc, washed with water (2×), brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound 20E. MS (m / z) 493.95) [M+Na] + .

[0337] Synthesis of (1S,2R)-2-((((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)amino)methyl)cyclopropane-1-carboxylic acid (20F): A solution of 20E (0.878 mmol) in EtOH (10.0 mL) was purged with nitrogen / vacuum (3x). Palladium on carbon (10%, 0.176 mmol) was added and the reaction was purged with nitrogen / vacuum (3x). A hydrogen balloon was attached to the flask and the reaction was purged with hydrogen / vacuum (3x) and stirred under 1 atm of hydrogen at room temperature for 1 hour. The reaction was purged with nitrogen, filtered through Celite, and concentrated to give the title compound 20F, which was used without further purification. MS (m / z) 403.93 [M+Na] + .

[0338] (Phosphonooxy)methyl(((1R,2S)-2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[3,4]pyridoxal]) Synthesis of [1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)cyclopropyl)methyl)carbamate (20): The atropisomeric mixture of the title compound was prepared following the method proposed for the synthesis of 19 in Example 19, utilizing 20F instead of 19C. 11H NMR (400 MHz, DMSO-d6) δ 9.28 (d), 9.18 (d), 7.98 (d), 7.83 (d), 7.79 (s), 7.75 (d), 7.57 (d), 7.50 (d), 7.16 (d), 7.09 - 6.94 (m), 6.75 (t), 6.55 - 6.45 (m), 6.26 (d), 5.46 - 5.28 (m), 4.95 (d), 4.90 - 4.59 (m), 4.55 (q), 4.31 - 4.15 (m), 4.11 - 3.94 (m), 3.62 - 3.54 (m), 3.48 (s), 3.44 (s), 3.16 - 2.92 (m), 2.83 (d), 2.62 - 2.47 (m), 1.74 (d), 1.47 - 1.32 (m), 1.20 - 1.09 (m), 1.09 - 0.87 (m), 0.85 - 0.74 (m). 19 19F NMR (376 MHz, DMSO-d6) δ -60.86, -61.01, -69.49 (t), -70.07 (t), -79.79 (d), -80.32 - -80.57 (m), -81.08 (d), -103.05 (d), -103.22 (d), -103.72 (d), -103.89 (d), -110.59 (t), -110.91 (t). 31 31P NMR (162 MHz, DMSO-d6) δ -2.86 (t), -3.39 (t). MS (m / z) 1219.20 [M+H] + . Example 21. [Chemistry]

[0339] Synthesis of methyl 2-(((tert-butoxycarbonyl)amino)methyl)benzoate (21A): To an ice-cold solution of (2-methoxycarbonylphenyl)methylammonium chloride (32.0 mmol) and di-tert-butyl dicarbonate (35.2 mmol) in DCM (168 mL) was added triethylamine (35.2 mmol). The reaction was sealed, brought to room temperature, and stirred for 1 h. Upon completion, the reaction was diluted with water (50 mL). The solution was transferred to a separatory funnel, and the aqueous layer was extracted with DCM (100 mL). The organic fractions were collected, dried over Na2SO4, concentrated, and purified by silica chromatography. Fractions containing product were pooled and concentrated to give the title compound 21A. MS (m / z): 288.20 [M+Na] + .

[0340] Synthesis of tert-butyl (2-(hydroxymethyl)benzyl)carbamate (21B): To a solution of 21A (28 mmol) in THF (61 mL) was added 2 M lithium borohydride (89 mmol). The reaction was sealed, heated to 50 °C, and stirred for 16 h. Upon completion, the reaction was cooled to 0 °C and quenched with water (60 mL), saturated NH Cl (20 mL), and water (350 mL). The solution was transferred to a separatory funnel and extracted three times with EtOAc (100 mL). The organic fractions were collected, dried over Na SO , concentrated, and purified by silica chromatography. The product-containing fractions were pooled and concentrated to give the title compound 21B. MS (m / z): 260.20 [M+Na] + .

[0341] Synthesis of tert-butyl (2-((allyloxy)methyl)benzyl)carbamate (21C): To an ice-cooled flask containing sodium hydride (9.7 mmol) was added DMF (10 mL). The mixture was stirred at room temperature for 15 minutes and then cooled to 0°C. 21B (9.3 mmol) was added to the reaction. The reaction was sealed, brought to room temperature, and stirred for 1 hour. Allyl bromide (10 mmol) was then added to the reaction. Upon completion, the reaction was quenched with water (10 mL), saturated NH4Cl (10 mL). The solution was transferred to a separatory funnel with EtOAc (100 mL) and water (100 mL), and the aqueous layer was extracted with EtOAc (100 mL). The organic fractions were collected, washed with water (100 mL), 5% wt / v LiCl (50 mL), saturated NaCl (50 mL), dried over NaSO, concentrated, and purified by silica chromatography. The product-containing fractions were pooled and concentrated to give the title compound 21C. MS (m / z): 300.20 [M+Na] + .

[0342] Synthesis of [2-(allyloxymethyl)phenyl]methylammonium chloride (21D): To a flask was added 21C (4.0 mmol), DCM (20 mL), and 4 M HCl in dioxane (10 mL). The reaction was sealed and stirred for 1 h. Upon completion, the reaction was concentrated, dissolved in MeCN, and lyophilized to give the title compound 21D. MS (m / z): 178.20 [M+H] + .

[0343] Synthesis of tert-butyl 3-[[2-(allyloxymethyl)phenyl]methylamino]propanoate (21E): To a solution of 21D (6.7 mmol) and triethylamine (7.35 mmol) in MeOH (13 mL) was added tert-butyl acrylate (587 μL). The reaction was sealed and stirred for 16 hours. Upon completion, the reaction was concentrated and dissolved in EtOAc (70 mL). The solution was transferred to a separatory funnel and washed twice with saturated NaHCO (35 mL). The organic fractions were collected, dried over NaSO, concentrated, and purified by silica chromatography. Fractions containing the product were pooled and concentrated to give the title compound 21E. MS (m / z): 306.30 [M+H] + .

[0344] Synthesis of tert-butyl 3-((2-((allyloxy)methyl)benzyl)((((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)amino)propanoate (21F): The title compound was prepared by the procedure described in Example 20 using 21E instead of 20C. Prepared according to the method proposed for the synthesis of E. MS (m / z): 594.30 [M+Na] + .

[0345] Synthesis of tert-butyl 3-[ditert-butoxyphosphoryloxymethoxycarbonyl-[[2-(hydroxymethyl)phenyl]methyl]amino]propanoate (21G): To an argon-purged solution of tert-butyl 3-[[2-(allyloxymethyl)phenyl]methyl-(ditert-butoxyphosphoryloxymethoxycarbonyl)amino]propanoate (1.24 mmol), 1,3-dimethylbarbituric acid (2.48 mmol), and MeOH (3.7 mL), tetrakis(triphenylphosphine)palladium(0) was added. The reaction was sealed, heated to 40 °C, and stirred for 1 hour. Upon completion, the reaction was concentrated and purified by silica chromatography. Product-containing fractions were pooled and concentrated to provide the title compound. 1H NMR(400MHz,CDCl3)δ7.39(t,1H),7.31-7.18(m,3H),5.64(t,2H),4.73-4.6 7(m,4H),3.51(t,2H),2.47(t,2H),2.14(s,1H),1.49(d,18H),1.42(s,9H).

[0346] Synthesis of tert-butyl 3-[ditert-butoxyphosphoryloxymethoxycarbonyl-[(2-formylphenyl)methyl]amino]propanoate (21H): To a solution of 21G (0.47 mmol), TEMPO (0.10 mmol), 0.2 M KH2PO4 (2.3 mL), and MeCN (2.3 mL) was added 80% sodium chlorite (0.70 mmol) and 8% sodium hypochlorite solution (0.564 mmol). The reaction was sealed and stirred for 1 h. Upon completion, the reaction was cooled to 0 °C and quenched with saturated Na2SO3 (2.3 mL). The solution was transferred to a separatory funnel containing water (10 mL) and extracted three times with EtOAc (20 mL). The organic fractions were collected, dried over Na2SO4, and concentrated to give the title compound 21H. MS (m / z): 552.30 [M + Na] + .

[0347] Synthesis of 2-[[(3-tert-butoxy-3-oxo-propyl)-(di-tert-butoxyphosphoryloxymethoxycarbonyl)amino]methyl]benzoic acid (21I): To an ice-cold solution of 21H (0.453 mmol), 30% HO (0.68 mmol), KHPO (0.18 mmol), and 1:1 water / MeCN (2 mL) was added 80% sodium chlorite (0.91 mmol). The reaction was sealed, brought to room temperature, and stirred for 1 h. Upon completion, the reaction was cooled to 0 °C, quenched with saturated NaSO (2 mL), and acidified with 1 M HCl (4 mL). The solution was transferred to a separatory funnel and extracted three times with EtOAc (20 mL). The organic fractions were collected, dried over NaSO, and concentrated to give the title compound 21I. MS (m / z): 568.30 [M + Na] + .

[0348] Synthesis of 3-((2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)benzyl)(((phosphonooxy)methoxy)carbonyl)amino)propanoic acid (21): The atropisomeric mixture of the title compound was prepared following the method proposed for the synthesis of 19 in Example 19, utilizing 21I instead of 19C. 1 H NMR(400MHz,CD3CN)δ7.74-7.67(m),7.64-7.52(m),7.42-7.22(m),7.11(d),7.06(t),7.01-6.94(m),6.93-6.67(m),6 .60(dd),6.25-6.16(m),6.13-6.05(m),5.67-5.49(m),4.87-4.51(m),4.38(s),3.94(ddd),3.64(d),3.58(d),3.55-3. 40(m),3.15(s),2.98-2.75(m),2.61-2.43(m),1.76(s),1.40(p),1.12-1.01(m). 19 F NMR (377MHz, CD3CN) δ-62.55(d),-71.58(d),-77.36,-81.84(ddd),-104.07--105.73(m),-111.89(tt). MS(m / z):1327.30[M+H] + . Example 22. [ka]

[0349] Synthesis of (2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)methanol (22A): To a solution of 1,2-phenylenedimethanol (29 mmol) in 90 mL of THF was added NaH (60% mineral oil dispersion, 29 mmol, 1 equiv.) portionwise at 0° C. The resulting suspension was stirred overnight, and then TBSCl (29 mmol, 1 equiv.) was added portionwise. Once complete conversion was observed, the reaction was concentrated under reduced pressure, and the residue was transferred to a separatory funnel with the aid of EtOAc (200 mL) and water (50 mL). The organic layer was washed with 0.1 M HCl solution (200 mL), and then the organic fractions were collected, dried over NaSO, concentrated under reduced pressure, and purified by silica gel chromatography. The product-containing fractions were pooled and concentrated under reduced pressure to give the title compound 22A. 1 H NMR(400MHz,DMSO-d6)7.42-7.35(m,2H),7.30-7.21(m,2H),5.05(td,J=5.4,1.0Hz,1H ),4.75(s,2H),4.53(d,J=5.5Hz,2H),0.91(d,J=1.0Hz,9H),0.08(d,J=1.0Hz,6H)ppm.

[0350] Synthesis of di-tert-butyl(2-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)phosphate (22B): The title compound was prepared according to the method proposed for the synthesis of 11B in Example 11, utilizing 22A instead of 11A and changing the solvent from THF / MeCN to DMF. MS (m / z) 446.30 [M+H] + .

[0351] Synthesis of di-tert-butyl(2-(hydroxymethyl)benzyl)phosphate (22C): A solution of 22B (5.94 mmol) in 15 mL of THF was diluted with TBAF (1 mL in THF). M, 5.94 mmol, 1 equiv) was added. Once complete conversion was observed, the reaction was concentrated under reduced pressure and transferred to a separatory funnel with the aid of DCM (100 mL) and water (100 mL). The organic layer was washed with brine (4 x 100 mL), dried over NaSO, and concentrated under reduced pressure to provide the title compound 22C, which was used without purification.1 H NMR (400MHz, DMSO-d6) δ7.46-7.42(m,1H),7.39-7.26(m,3H),5.17(t,J=5.4Hz,1H),4.99(d,J=7.1Hz,2H),4.59(d,J=5.4Hz,2H),1.41(s,18H)ppm.

[0352] Synthesis of di-tert-butyl(2-formylbenzyl)phosphate (22D): The title compound was prepared following the procedure presented for the synthesis of 21H in Example 21, utilizing 22C instead of 21G. MS (m / z) 351.20 [M+Na] + .

[0353] Synthesis of 2-(((di-tert-butoxyphosphoryl)oxy)methyl)benzoic acid (22E): The title compound was prepared following the procedure presented for the synthesis of 21I in Example 21, utilizing 22D instead of 21H. MS (m / z) 367.20 [M+Na] + .

[0354] Synthesis of 2-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)benzyl dihydrogen phosphate (22): The atropisomeric mixture of the title compound was prepared according to the method proposed for the synthesis of 19 in Example 19, utilizing 22E instead of 19C. 1H NMR(400MHz,DMSO-d6)δ9.22-9.13(m),7.85-7.65(m),7.61-7.54(m),7.51-7.41(m),7.41-7.1 7(m),7.15-6.87(m),6.54-6.27(m),5.22-4.98(m),5.02-4.88(m),4.86(s),4.83-4.70(m),4. 70-4.41(m),4.35-4.24(m),4.10-3.95(m),3.97-3.82(m),3.78-3.71(m),3.63(s),3.28-3.22 (m),2.95-2.83(m),2.69-2.52(m),1.79-1.70(m),1.47-1.34(m),1.23(s),1.04-0.94(m)ppm. 19 F NMR(375MHz,DMSO-d6)δ-60.74--60.93(m),-69.71--69.95(m),-70.07--70.22(m),-75.42,-79.66--79.85(m),-80.25--80.53(m),-1 02.85--102.95(m),-103.20--103.30(m),-103.53--103.62(m),-103.88--103.97(m),-110.49--110.70(m),-111.14--111.25(m)ppm. MS(m / z)1182.20[M+H] + . Example 23. [ka]

[0355] Synthesis of 4-benzyl 3-(((di-tert-butoxyphosphoryl)oxy)methyl)(S)-morpholine-3,4-dicarboxylate (23A): The title compound was prepared following the procedure presented for the synthesis of 19B in Example 19, utilizing (S)-4-((benzyloxy)carbonyl)morpholine-3-carboxylic acid in place of 19A. MS (m / z) 510.20 [M+Na] + .

[0356] Synthesis of ((di-tert-butoxyphosphoryl)oxy)methyl (S)-morpholine-3-carboxylate (23B): The title compound was prepared according to the procedure set forth for the synthesis of 11C in Example 11, utilizing 23A instead of 11B. MS (m / z) 353.99 [M+H] + .

[0357] Synthesis of (4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamic chloride (23C): To a vial containing Intermediate 5 (0.103 mmol) and triphosgene (0.309 mmol), DCM (2 mL) was added and the reaction was cooled to 0° C. in an ice bath. To the mixture was then added DIPEA (0.309 mmol) and the reaction was stirred for 15 minutes. Upon completion, the reaction was concentrated under reduced pressure to give the atropisomeric mixture of the title compound 23C, which was used without purification. MS (m / z) 1030.81 [M+H] + .

[0358] ((Di-tert-butoxyphosphoryl)oxy)methyl(S)-4-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3 Synthesis of -(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)morpholine-3-carboxylate (23D): To a solution of 23C (0.776 mmol) in DCM (8 mL) was added 23B (1.55 mmol, 2 equiv.) and DIPEA (1.55 mmol, 2 equiv.) sequentially. Upon completion, the reaction was partitioned between DCM (20 mL) and 0.1 M HCl (20 mL). The organic fractions were collected, dried over NaSO, and concentrated under reduced pressure to afford the atropisomeric mixture of the title compound 23D, which was used without purification. MS (m / z) 1291.68 [Mt-Bu + 2H] + .

[0359] Synthesis of (phosphonooxy)methyl (S)-4-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)morpholine-3-carboxylate (23): To a solution of 23D (0.776 mmol) in DCM (5 mL) was added TFA (2 mL). Upon completion, the reaction was concentrated under reduced pressure and purified by reverse phase HPLC. The product-containing fractions were pooled and lyophilized to give the title compound 23 as a mixture of atropisomers. 1H NMR(400MHz,DMSO-d6)δ9.30-9.23(m),7.94-7.87(m),7.86-7.78(m),7.52-7.45(m),7.0 2(tt,J=9.4,2.4Hz),6.98-6.91(m),6.39-6.32(m),6.10(s),5.60-5.51(m),5.07-4.96( m),4.89-4.68(m),4.57-4.50(m),4.42(s),4.06-3.93(m),3.40(s),3.12-3.04(m),2.94 (s),2.94-2.86(m),2.65-2.52(m),2.08(s),1.75(s),1.46-1.36(m),1.03-0.95(m)ppm. 19 F NMR (375MHz, DMSO-d6) δ-60.42--61.21(m),-69.50--70.33(m),-75.34,-80.74,-81.42,-102.49,-103.14,-110.84ppm. MS(m / z)1135.20[M+H] + . Example 24. [ka]

[0360] 1-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2- Synthesis of (trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)azetidine-3-carboxylic acid (24): The atropisomeric mixture of the title compound was prepared following the procedure presented for the synthesis of 23 in Example 23, utilizing 3-(tert-butoxycarbonyl)azetidin-1-ium acetate instead of 23B. 1H NMR (400MHz, methanol-d4) δ 8.95-8.87 (m), 7.87-7.76 (m), 7.76-7.68 (m), 7.33-7.27 (m), 6.82-6.71 (m), 6.53-6.46 (m), 6.29-6.19 (m), 4.93-4.84 (m), 4.84-4.69 (m), 4 .01-3.94(m),3.79-3.74(m),3.53-3.48(m),3.43(s),3.26-3.21(m),3.11-2.97(m ),2.97-2.87(m),2.61-2.50(m),1.85-1.80(m),1.49-1.38(m),1.10-1.01(m)ppm. MS(m / z):1095.43[M+H] + . Example 25. [ka]

[0361] 1-((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pi Synthesis of)(lysin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)(methylsulfonyl)carbamoyl)piperidine-4-carboxylic acid (25): The atropisomeric mixture of the title compound was prepared according to the method presented for the synthesis of 23 in Example 23, utilizing 4-(tert-butoxycarbonyl)piperidin-1-ium acetate instead of 23B. 1H NMR (400 MHz, methanol-d4) δ 9.01-8.93 (m), 7.92-7.85 (m), 7.85-7.78 (m), 7.43-7.34 (m), 6.92-6.81 (m), 6.63-6.56 (m), 6.39-6.29 (m), 5.03-4.93 (m), 4.93-4.83 (m), 4.83-4.77 (m), 4.11-3.96 (m), 3.96 -3.89(m),3.36-3.31(m),3.18-3.07(m),3.07-2.99(m),2.99-2.83(m),2.69-2.54(m),2.33(d,J=9 .7Hz),1.95-1.90(m),1.78-1.68(m),1.65-1.56(m),1.56-1.49(m),1.45-1.40(m),1.19-1.10(m). MS(m / z):1123.40[M+H] + . Example 26. [ka]

[0362] Synthesis of ((4-chloro-7-(2-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4...

Claims

[Claim 1] The invention described in the specification.

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