Therapeutic compounds for HIV virus infection

Abstract

This disclosure generally relates to certain compounds, pharmaceutical compositions comprising such compounds, and methods for manufacturing and using such compounds and pharmaceutical compositions. The compounds and compositions provided herein may be used to treat or prevent retroviral infections, including HIV infection.

Description

Technical Field

[0001] This disclosure generally relates to novel compounds and pharmaceutical compositions comprising said compounds for the prevention or treatment of infections caused by Retroviridae viruses, including those caused by Human Immunodeficiency Virus (HIV). This disclosure also relates to methods for manufacturing said compounds and intermediates in the preparation of said compounds. Prior Technology

[0002] Single-stranded RNA viruses, including those of the family Retroviridae, encompass the subfamily Orthoretrovirinae, which causes numerous human and animal diseases, and the genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus. Among lentiviruses, human HIV-1 infection leads to helper T cell depletion and immune dysregulation, resulting in immunodeficiency and susceptibility to opportunistic infections. Highly active antiretroviral therapy (HAART) for HIV-1 infection 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, such 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 active against emerging drug-resistant HIV variants.

[0003] In the field of HIV therapy and treatment, there is also interest in providing patients with regimens that improve pharmacokinetic properties, including, for example, increased potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties. While current HIV treatment regimens have advanced sufficiently that patients no longer need to take multiple medications multiple times a day, patients still require daily medication for the foreseeable future. Therefore, HIV therapies requiring patients to take medication less than once a day (e.g., every few days, once a week, every other week, once a month, etc.) or to take smaller, more effective doses of (multiple) medications daily, weekly, monthly, or for longer periods would be beneficial. Summary of the Invention

[0004] In one embodiment, compounds of formula I are provided herein. Formula I Or a medicinally acceptable salt, in X-groups include C3-7 monocyclic cycloalkyl, 4-7 member monocyclic heterocyclic, phenyl, naphthyl, 5-6 member monocyclic heteroaryl, or 8-10 member fused bicyclic heteroaryl, wherein each of the C3-7 monocyclic cycloalkyl, 4-7 member monocyclic heterocyclic, phenyl, naphthyl, 5-6 member monocyclic heteroaryl, and 8-10 member fused bicyclic heteroaryl is optionally substituted by 1 to 3 R1 groups. Each R1 is independently a -CN, halogen, Ra, Rb, Rc, C1-6 alkyl, or 4 to 7-membered monocyclic heterocyclic group. The C1-6 alkyl group may optionally be substituted by one to three independent groups selected from -CN, halogen, Ra, Rb, Rc, -SR2, and =NR2a. The 4 to 7 member monocyclic heterocyclic group may optionally be substituted by 1 to 3 independent groups selected from -CN, halogen, Ra, Rb, and Rc; Each Ra independently corresponds to -P(O)(OH)₂ or -OP(O)(OH)₂; Each Rb independent system is -C(O)R 2, -C(O)OR 2, -C(O)NR 3R 3, -C(O)C(O)OR 2, -S(O) 2R 2, -S(O) 2NR 3R 3, or -S(O) 2OR 3; Each Rc independently forms -OR 2, -OC(O)R 2, -OC(O)C(O)OR 2, -NR 3R 3, -N +R 3R 3R 3a, -NR 3C(O)R 2, -NR 3C(O)NR 3R 3, -NR 3C(O)OR 2, -NR 3C(O)C(O)OR 2, or -NR 3S(O) 2R 2; Each R2 is independently H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one to three groups independently selected from -CN, halogen, Ra, Rd, and Re; Each R 2a is independently an H or C 1-3 alkyl group; Each R3 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted by one to three groups independently selected from -CN, halogen, Ra, Rd, Re, and =NR3a; Each R 3a is independently an H or C 1-3 alkyl group; Each R d independent system is -C(O)R 4, -C(O)OR 4, -C(O)NR 4R 4, -C(O)C(O)OR 4, -S(O) 2R 4, -S(O) 2NR 4R 4, or -S(O) 2OR 4; Each Re independent system is -OR 4, -OC(O)R 4, -OC(O)C(O)OR 4, -NR 4R 4, -N +R 4R 4R 4a, -NR 4C(O)R 4, -NR 4C(O)NR 4R 4, -NR 4C(O)OR 4, -NR 4C(O)C(O)OR 4, or -NR 4S(O) 2R 4; Each R4 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted by one to three groups independently selected from -OH, CN, halogen, -COOH, and Ra; Each of the four-membered monocyclic heterocyclic groups has one cyclic heteroatom selected from N, O, and S; Each of the 5 to 7 member monocyclic heterocyclic groups has 1 to 2 independently selected cyclic heteroatoms chosen from N, O, and S; and Each of the 5 to 6 monocyclic heteroaryl groups and the 8 to 10 fused bicyclic heteroaryl groups independently has 1 to 4 cyclic heteroatoms independently selected from N, O, and S.

[0005] In one embodiment, this document provides a pharmaceutical composition comprising a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0006] In one embodiment, this document provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient in need, 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.

[0007] In one embodiment, this document provides a method for treating human immunodeficiency virus (HIV) infection in a heavily treatment-experienced patient, the method 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, this document provides a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in a therapy.

[0009] In one embodiment, this document provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient in need, using a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, provided herein. The method comprises administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof to the patient.

[0010] In one embodiment, this document provides a method for treating a human immunodeficiency virus (HIV) infection in a patient undergoing extensive treatment with a compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, comprising administering to the patient a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof. Simple Explanation of the Diagram

[0011] none Implementation

[0012] Cross-referencing of related applications

[0013] This application claims priority to U.S. Provisional Patent Application No. 63 / 285,753, filed December 3, 2021, the entire contents of which are hereby incorporated herein by reference. [I.] [definition]

[0014] The following description is made under the understanding that this disclosure is considered as an example of the claimed claims and is not intended to limit the scope of the accompanying claims to the specific embodiments described. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the scope of the claims in any way. Embodiments described under any heading may be combined with embodiments described under any other heading.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It should be noted that, as used herein and in the appended claims, the singular forms “a / an” and “the” include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “the compound” includes a plural of such compounds, and reference to “the assay” includes one or more assays and their equivalents known to one of ordinary skill in the art, etc.

[0016] As used in this disclosure, the following phrases, words and symbols are generally intended to have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0017] A dash ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -CONH 2 is attached through a carbon atom. Dashes before or at the end of chemical groups are for convenience; chemical groups may or may not be depicted with one or more dashes without losing their usual meaning. Wavy lines drawn through lines in the structure indicate the attachment point of a group. Unless required by chemical or structural rules, the order in which chemical groups are written or named does not indicate or imply directionality. A solid line emanating from the center of a ring (including fused, bridged, or spirocyclic systems) indicates that the attachment point of a substituent on the ring can be at any ring atom. For example, in the following structures, Raa can attach to any of the five carbon ring atoms, or Raa can replace a hydrogen atom attached to a nitrogen ring atom: . As another example, Raaa exists in the following structure: , Raa can be attached to any of the numbered positions shown below: .

[0018] A solid line emanating from the center of a ring (including fused, bridged, or spirocyclic systems) indicates that the attachment point between the ring system and the rest of the compound can be at any ring atom in the fused, bridged, or spirocyclic system. For example, in the following structures: , The monocyclic heterocyclic group may be attached to the remainder of the compound at any of the following numbered positions: .

[0019] As another example, in the following fused bicyclic heterocyclic structure, , The fused bicyclic heterocyclic group can be attached to the remainder of the compound at any of the eight numbered positions shown below: .

[0020] The prefix "C uv" indicates that the following group has u to v carbon atoms. For example, "C 1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "x to y membered" ring, where the values ​​of x and y coefficients range (such as "3 to 12 membered heterocyclic group"), refers to a ring containing x to y atoms (i.e., 3 to 12), of which up to 80% may be heteroatoms such as N, O, S, and P, while the remaining atoms are carbon.

[0021] In addition, certain commonly used alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" and divalent "aryl" can also be referred to as "alkylene / alkylenyl / alkylyl" and "arylene / arylenyl / arylyl", respectively.

[0022] "A compound disclosed herein," "a compound of the present disclosure," "a compound provided herein," or "a compound described herein" refers to a compound of formula I. It also includes specific compounds from Examples 1 to 37.

[0023] This document mentions "about" values ​​or parameters, including (and describing) embodiments for that value or parameter itself. In some embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In some still embodiments, the term "about" includes an indication of ±1%. Furthermore, the term "about X" includes a description of "X".

[0024] "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), 1 to 3 carbon atoms (i.e., C1-3 alkyl), or 1 to 2 carbon atoms (i.e., C1-2 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, dibutyl, isobutyl, terbutyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by a chemical name or determined by a molecular formula, it can cover isomers with all positions having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), secondary butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tertiary butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0025] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0026] "alkynyl" refers to an aliphatic group containing at least one carbon-carbon linkage and having 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term "alkynyl" also includes groups having one linkage and one double bond.

[0027] "alkylene" refers to a divalent and unbranched saturated hydrocarbon chain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C1-20 alkylene), 1 to 12 carbon atoms (i.e., C1-12 alkylene), 1 to 8 carbon atoms (i.e., C1-8 alkylene), 1 to 6 carbon atoms (i.e., C1-6 alkylene), 1 to 4 carbon atoms (i.e., C1-4 alkylene), 1 to 3 carbon atoms (i.e., C1-3 alkylene), or 1 to 2 carbon atoms (i.e., C1-2 alkylene). Examples of alkylene include methylene, ethyl, propyl, butyl, pentyl, and hexyl. In some embodiments, the alkylene may optionally be alkylated. Examples of substituted alkyl groups include -CH(CH 3)CH 2-, -CH 2CH(CH 3)-, -CH 2CH(CH 2CH 3)-, -CH 2C(CH 3) 2-, -C(CH 3) 2CH 2-, -CH(CH 3)CH(CH 3)-, -CH 2C(CH 2CH 3)(CH 3)-, and -CH 2C(CH 2CH 3) 2.

[0028] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, secondary-butoxy, pentoxy, hexoxy, and 1,2-dimethylbutoxy. "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0029] "Acyl" refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, as defined herein. Examples of acyl groups include methylacyl, acetylated, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0030] "Amide" refers to both "C-amido" and "N-amido", where C-amido refers to the group -C(═O)NR yR z and N-amido refers to the group -NR yC(═O)R z, wherein R y and R z are independently selected from the group consisting of: hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclic; each of which may be optionally substituted.

[0031] "Amino" refers to -NR yR z, where R y and R z are independently selected from the group consisting of: hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic; each of which may be optionally substituted.

[0032] "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 groups have 6 to 20 carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon atoms (i.e., C6-12 aryl), or 6 to 10 carbon atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, tyrosyl, and anthracene. However, aryl does not encompass heteroaryl groups as defined below or overlap with them in any way. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is a heteroaryl.

[0033] "Cyano" or "carbonitrile" refers to the -CN group.

[0034] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0035] "Bridged" refers to the ring fusion in which non-adjacent atoms on a ring are connected by a divalent substituent (such as an alkyl group, an alkyl group containing one or two heteroatoms, or a single heteroatom). Examples of pyridyl and adamantyl-based bridged ring systems.

[0036] The term "fused" refers to a ring that is bonded to an adjacent ring.

[0037] "Spiro" refers to a cyclic substituent formed by two bonds bonded together at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane and dimethyl-2-diethylcyclopentane. And 4-benzyl-4-methylpiperidine, wherein cyclopentane and piperidine are spiro-substituents respectively.

[0038] "Halogen" or "halo" includes fluorine, chloro, bromine, and iodine groups. "Haloalkyl" refers to a non-branched or branched alkyl group in which one or more hydrogen atoms have been halogenated, as defined above. For example, in the case where residues are substituted with more than one halogen, it can be designated by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may be, but are not required to be, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0039] "Heteroalkylene" refers to a divalent and unbranched saturated hydrocarbon chain having one, two, or three heteroatoms selected from NH, O, or S. As used herein, heterodialkyl groups have 1 to 20 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-20 heterodialkyl groups); 1 to 8 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-8 heterodialkyl groups); 1 to 6 carbon atoms and one, two, or three heteroatoms selected from NH, O, and SS (i.e., C1-6 heterodialkyl groups); 1 to 4 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-4 heterodialkyl groups); 1 to 3 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-3 heterodialkyl groups); or 1 to 2 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C1-3 heterodialkyl groups). For example, -CH 2O- is a C1 heterodialkyl group, and -CH 2SCH 2- is a C2 heterodialkyl group. Examples of heterodialkyl groups include -CH 2CH 2OCH 2-, -CH 2SCH 2OCH 2-, -CH 2O-, and -CH 2NHCH 2-. In some embodiments, the heterodialkyl group is optionally alkyl-substituted. Examples of substituted heterodialkyl groups include -CH(CH 3)N(CH 3)CH 2-, -CH 2OCH(CH 3)-, -CH 2CH(CH 2CH 3)S-, -CH 2NHC(CH 3) 2-, -C(CH 3) 2SCH 2-, -CH(CH 3)N(CH 3)CH(CH 3)O-, -CH 2SC(CH 2CH 3)(CH 3)-, and -CH 2C(CH 2CH 3) 2NH-.

[0040] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryls include 1 to 20 carbon ring atoms (i.e., C1-20 heteroaryls), 3 to 12 carbon ring atoms (i.e., C3-12 heteroaryls), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryls); and 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryls include pyrimidinyl, purineyl, pyridinyl, and thiazolyl groups. aryl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0041] "Heterocyclyl" or "heterocyclic ring / heterocycle" refers to a non-aromatic cycloalkyl group having one or more independent cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, as used herein, "heterocyclyl" or "heterocyclic" refers to a saturated or partially saturated ring; for example, in some embodiments, "heterocyclyl" or "heterocyclic" refers to a partially saturated ring in specified cases. The term "heterocyclyl" or "heterocyclic ring / heterocycle" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond). Heterocyclic groups can be monocyclic or polycyclic, wherein polycyclic rings can be fused, bridged, or spirocyclic. As used herein, heterocyclic groups have 2 to 20 carbocyclic atoms (i.e., C2-20 heterocyclic groups), 2 to 12 carbocyclic atoms (i.e., C2-12 heterocyclic groups), 2 to 10 carbocyclic atoms (i.e., C2-10 heterocyclic groups), 2 to 8 carbocyclic atoms (i.e., C2-8 heterocyclic groups), 3 to 12 carbocyclic atoms (i.e., C3-12 heterocyclic groups), 3 to 8 carbocyclic atoms (i.e., C3-8 heterocyclic groups), or 3 to 6 carbocyclic atoms (i.e., C3-6 heterocyclic groups); and have 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomum independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include pyrrolidyl, piperidinyl, and piperidine. alkyl, oxetanyl, dioxolanyl, azetidinyl, and Linoyl group. As used herein, the term "bridged-heterocyclyl" refers to a four- to ten-membered ring moiety having at least one or more (e.g., one or two) four- to ten-membered ring moieties connected at two non-adjacent atoms of a heterocyclyl group, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, "bridged-heterocyclyl" includes bicyclic and tricyclic ring systems. Also as used herein, the term "spiro-heterocyclyl" refers to a ring system in which a three- to ten-membered heterocyclyl group has one or more additional rings, wherein the one or more additional rings are three- to ten-membered cycloalkyl groups or three- to ten-membered heterocyclyl groups, wherein each atom of the one or more additional rings is also an atom of the three- to ten-membered heterocyclyl group. Examples of spirocyclic groups include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. As used herein, the terms "heterocycle," "heterocyclyl," and "heterocyclic ring" are used interchangeably. In some embodiments, the heterocyclic group is substituted with a side oxygen group.

[0042] "Hydroxy" refers to the -OH group.

[0043] "Oxo" refers to the group (=O) or (O).

[0044] "Sulphonyl" refers to the group -S(O)2Rbb, where Rbb is an alkyl, haloalkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl group. Examples of sulfonyl groups are methanesulfonyl, ethanesulfonyl, benzenesulfonyl, and toluenesulfonyl.

[0045] Unless otherwise indicated, whenever the graphical representation of a group ends with a single bonded nitrogen atom, the group represents an -NH group. Similarly, unless otherwise indicated, hydrogen atoms are implied and considered to be present, as required by the knowledge of one of ordinary skill in the art, to complete the valence or to provide stability.

[0046] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. Furthermore, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be substituted by any of the atoms other than hydrogen.

[0047] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the replacement does not exceed the normal valence of the specified atom. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acetyl, amino, acetamyl, formamidinyl, aryl, azide, aminomethyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, syloxy, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar infinite structures obtained by defining substituents by an unlimited number of additional substituents (e.g., a substituted aryl group having a substituted alkyl group, the substituted alkyl group itself being substituted by a substituted aryl group, the substituted aryl group being further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, a substituted aryl group that is consecutively substituted with two other substituted aryl groups is limited to an aryl group substituted with ((substituted aryl) substituted) aryl group. Similarly, the above definition is not intended to include prohibited substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such prohibited substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise stated, when a group is described as optionally substituted, any substituted element of that group is itself unsubstituted.

[0048] In some embodiments, the substituted cycloalkyl, substituted heterocyclic, substituted aryl, and / or substituted heteroaryl groups include cycloalkyl, heterocyclic, aryl, and / or heteroaryl groups having substituents on the ring atom, which attach the cycloalkyl, heterocyclic, aryl, and / or heteroaryl group to the remainder of the compound. For example, in the following portions, the cyclopropyl group is methyl-substituted: .

[0049] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, and thus may produce mirror-image isomers, non-mirror-image isomers, and other stereoisomers, which may be defined by absolute stereochemistry as (R)- or (S)-, or by amino acid as (D)- or (L)-. This disclosure is intended 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 a palmitic synthesizer or a palmitic reagent, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual mirror-image isomers include using, for example, palmitic high-pressure liquid chromatography (HPLC) to palmiticly synthesize or resolve racemic products (or racemic products of salts or derivatives) from suitable optically pure precursors. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, it is intended that such compounds include both E and Z geometric isomers. Similarly, it is intended to include all tautomer forms. When a compound is expressed in its scalemic form, it should be understood that the examples cover, but are not limited to, specific non-mirrormic or scalemic isomer enriched forms. When scalemicity is not specified but present, it should be understood that the examples relate to specific non-mirrormic or scalemic isomer enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a non-1:1 ratio.

[0050] "Stereoisomers" refer to compounds composed of identical atoms bonded by the same bonds but with different three-dimensional structures, and these compounds are not interchangeable. This disclosure envisions various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0051] An "enantiomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in ratios other than 1:1 is a "scalemic" mixture.

[0052] A "diastereoisomer" is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

[0053] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomers of any compounds provided herein.

[0054] Some of the compounds described herein exist as tautomers. These tautomers exist in equilibrium with each other. For example, compounds containing acetylamines can exist in equilibrium with imine tautomers. Regardless of the type of tautomers exhibited or the equilibrium nature between them, those skilled in the art will understand that a compound contains both acetylamine and imine tautomers. Therefore, compounds containing acetylamines should be understood to include their imine tautomers. Similarly, compounds containing imines should be understood to include their acetylamine tautomers.

[0055] A "solvate" is formed through 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.

[0056] Any formula or structure provided herein is intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures illustrated by the formulas given herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. Various isotopically labeled compounds disclosed herein are also provided, for example, those incorporating radioactive isotopes (such as 2H, 3H, 13C, and 14C). These isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or receptor tissue distribution detection, or for the treatment of patients with radiation.

[0057] This disclosure also includes compounds of Formula I with one to n hydrogen atoms attached to carbon atoms that have been deuterated, wherein n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and can therefore be used to increase the half-life of any Formula I compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been deuterated.

[0058] The deuterium-labeled or substituted therapeutic compounds disclosed herein may possess improved drug metabolism and pharmacokinetic (DMPK) properties, which are related to absorption, distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18F-labeled compounds can be used in PET or SPECT studies. The isotope-labeled compounds and their prodrugs disclosed herein can generally be prepared by performing the procedures disclosed in the following protocols or examples and preparations, and by replacing unlabeled reagents with readily available isotope-labeled reagents. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I.

[0059] The concentration of this heavier isotope (specifically deuterium) can be defined by the isotope enrichment factor. In the compounds disclosed herein, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally abundant isotopic composition. Therefore, in the compounds disclosed herein, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0060] In many cases, the compounds disclosed herein can form acid salts and / or base salts by means of the presence of amine and / or carboxyl groups or similar groups.

[0061] The term "pharmaceutically acceptable salt" as used for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. Medically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include (by example only) sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary, and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dienylamines, trienylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, mono-, di-, or tricycloalkylamines, mono-, di-, or triarylamines, or mixed amines, and the like. Specific examples of suitable amines include (by way of example only) isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, and piperazine. Piperidine Phosphates, N-ethylpiperidine, and similar compounds.

[0062] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include salts of 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, and the like.

[0063] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics and absorption delay agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any known media or agent is incompatible with the active ingredient, its use in therapeutic compositions is covered. Additional active ingredients may also be incorporated into the composition.

[0064] "Treatment" refers to the methods used to achieve beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: a) suppressing a disease or condition (i.e., reducing one or more symptoms arising from the disease or condition, and / or reducing the severity of the disease or condition); b) slowing or halting the development of one or more clinical symptoms associated with the disease or condition (i.e., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (i.e., metastasis)); and / or c) alleviating the disease, i.e., the cessation of clinical symptoms (i.e., improving the disease state, providing partial or overall relief from the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, improving quality of life, and / or prolonging survival).

[0065] "Prevention" means any treatment that prevents the development of clinical symptoms of a disease or condition. In some embodiments, the compound may be administered to a subject (including humans) who is at risk or has a family history of the disease or condition.

[0066] "Subject" means an animal, such as a mammal (including a human), that has become or will become a subject of treatment, observation, or experimentation. The methods described herein can be used for human therapeutics and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0067] The term "therapeutically effective amount" or "effective amount" as used herein for compounds or their pharmaceutically acceptable salts, isomers, or mixtures means an amount sufficient, when administered to a subject, to achieve therapeutic effect and provide therapeutic benefits (such as improvement of symptoms or slowing of disease progression). For example, a therapeutically effective amount may be an amount sufficient to improve symptoms of retroviral infections, including but not limited to HIV infection. Therapeuticly effective amounts can vary depending on the subject being treated and the disease or condition, the subject's weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by someone skilled in the art. [II.] [Compound]

[0068] In one embodiment, compounds of formula I are provided herein. Formula I Or a medicinally acceptable salt, in X-groups include C3-7 monocyclic cycloalkyl, 4-7 member monocyclic heterocyclic, phenyl, naphthyl, 5-6 member monocyclic heteroaryl, or 8-10 member fused bicyclic heteroaryl, wherein each of the C3-7 monocyclic cycloalkyl, 4-7 member monocyclic heterocyclic, phenyl, naphthyl, 5-6 member monocyclic heteroaryl, and 8-10 member fused bicyclic heteroaryl is optionally substituted by 1 to 3 R1 groups. Each R1 is independently a -CN, halogen, Ra, Rb, Rc, C1-6 alkyl, or 4 to 7-membered monocyclic heterocyclic group. The C1-6 alkyl group may optionally be substituted by one to three independent groups selected from -CN, halogen, Ra, Rb, Rc, -SR2, and =NR2a. The 4 to 7 member monocyclic heterocyclic group may optionally be substituted by 1 to 3 independent groups selected from -CN, halogen, Ra, Rb, and Rc; Each Ra independently corresponds to -P(O)(OH)₂ or -OP(O)(OH)₂; Each Rb independent system is -C(O)R 2, -C(O)OR 2, -C(O)NR 3R 3, -C(O)C(O)OR 2, -S(O) 2R 2, -S(O) 2NR 3R 3, or -S(O) 2OR 3; Each Rc independently forms -OR 2, -OC(O)R 2, -OC(O)C(O)OR 2, -NR 3R 3, -N +R 3R 3R 3a, -NR 3C(O)R 2, -NR 3C(O)NR 3R 3, -NR 3C(O)OR 2, -NR 3C(O)C(O)OR 2, or -NR 3S(O) 2R 2; Each R2 is independently H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one to three groups independently selected from -CN, halogen, Ra, Rd, and Re; Each R 2a is independently an H or C 1-3 alkyl group; Each R3 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted by one to three groups independently selected from -CN, halogen, Ra, Rd, Re, and =NR3a; Each R 3a is independently an H or C 1-3 alkyl group; Each R d independent system is -C(O)R 4, -C(O)OR 4, -C(O)NR 4R 4, -C(O)C(O)OR 4, -S(O) 2R 4, -S(O) 2NR 4R 4, or -S(O) 2OR 4; Each Re independent system is -OR 4, -OC(O)R 4, -OC(O)C(O)OR 4, -NR 4R 4, -N +R 4R 4R 4a, -NR 4C(O)R 4, -NR 4C(O)NR 4R 4, -NR 4C(O)OR 4, -NR 4C(O)C(O)OR 4, or -NR 4S(O) 2R 4; Each R4 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted by one to three groups independently selected from -OH, CN, halogen, -COOH, and Ra; Each of the four-membered monocyclic heterocyclic groups has one cyclic heteroatom selected from N, O, and S; Each of the 5 to 7 member monocyclic heterocyclic groups has 1 to 2 independently selected cyclic heteroatoms chosen from N, O, and S; and Each of the 5 to 6 monocyclic heteroaryl groups and the 8 to 10 fused bicyclic heteroaryl groups independently has 1 to 4 cyclic heteroatoms independently selected from N, O, and S.

[0069] In some embodiments of compounds of formula I or their pharmaceutically acceptable salts, X-groups are C3-7 monocyclic cycloalkyl groups, 4-7-membered monocyclic heterocyclic groups, phenyl groups, or 5-6-membered monocyclic heteroaryl groups, wherein each of the C3-7 monocyclic cycloalkyl group, 4-7-membered monocyclic heterocyclic group, phenyl group, and 5-6-membered monocyclic heteroaryl group is optionally substituted by 1 to 3 R1 groups independently; Each R1 is independently a -CN, halogen, Ra, Rb, Rc, C1-6 alkyl, or 4 to 7-membered monocyclic heterocyclic group. The C1-6 alkyl group may optionally be substituted by one to three independent groups selected from -CN, halogen, Ra, Rb, Rc, -SR2, and =NR2a. The 4 to 7 member monocyclic heterocyclic group may optionally be substituted by 1 to 3 independent groups selected from -CN, halogen, Ra, Rb, and Rc; Each Ra independently corresponds to -P(O)(OH)₂ or -OP(O)(OH)₂; Each Rb independent system is -C(O)R 2, -C(O)OR 2, -C(O)NR 3R 3, -C(O)C(O)OR 2, -S(O) 2R 2, -S(O) 2NR 3R 3, or -S(O) 2OR 3; Each Rc independently forms -OR 2, -OC(O)R 2, -OC(O)C(O)OR 2, -NR 3R 3, -N +R 3R 3R 3a, -NR 3C(O)R 2, -NR 3C(O)NR 3R 3, -NR 3C(O)OR 2, -NR 3C(O)C(O)OR 2, or -NR 3S(O) 2R 2; Each R2 is independently H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra; Each R 2a is independently an H or C 1-3 alkyl group; Each R3 is independently H, -C(O)OR4, or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted by one to three groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a; Each R 3a is independently an H or C 1-3 alkyl group; Each R4 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted by one to three groups independently selected from -OH, CN, halogen, -COOH, and Ra; Each of the four-membered monocyclic heterocyclic groups has one cyclic heteroatom selected from N, O, and S; Each of the 5 to 7 member monocyclic heterocyclic groups has 1 to 2 independently selected cyclic heteroatoms chosen from N, O, and S; and Each of the 5 to 6 monocyclic heteroaryl groups and the 8 to 10 fused bicyclic heteroaryl groups independently has 1 to 4 cyclic heteroatoms independently selected from N, O, and S.

[0070] In some embodiments of compounds of formula I or their pharmaceutically acceptable salts, X-groups are C3-7 monocyclic cycloalkyl groups, 4-7-membered monocyclic heterocyclic groups, phenyl groups, or 5-6-membered monocyclic heteroaryl groups, wherein each of the C3-7 monocyclic cycloalkyl group, 4-7-membered monocyclic heterocyclic group, phenyl group, and 5-6-membered monocyclic heteroaryl group is optionally substituted by 1 to 3 R1 groups independently; Each R1 is independently associated with -OH, -CN, halogen, -C(O)OR2, -NR3R3, -NR3C(O)C(O)OR2, Ra, C1-6 alkyl, or 4 to 7-membered monocyclic heterocyclic groups. The C1-6 alkyl group may optionally be substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR 3R 3, -NR 3C(O)OR 2, Ra, -SR 2, and =NR 2a. The 4 to 7 member monocyclic heterocyclic group may optionally be substituted by 1 to 3 independent groups selected from -OH, -CN, halogen, -C(O)OH, and Ra; Each Ra independently corresponds to -P(O)(OH)₂ or -OP(O)(OH)₂; Each R2 is independently H or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra; Each R 2a is independently an H or C 1-3 alkyl group; Each R3 is independently H, -C(O)OR4, or C1-4 alkyl, wherein the C1-4 alkyl group is optionally substituted by one to three groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a; Each R 3a is independently an H or C 1-3 alkyl group; Each R4 is independently H or C1-3 alkyl, wherein the C1-3 alkyl group is optionally substituted by one to three groups independently selected from -OH, CN, halogen, -COOH, and Ra; Each of the four-membered monocyclic heterocyclic groups has one cyclic heteroatom selected from N, O, and S; Each of the 5 to 7 member monocyclic heterocyclic groups has 1 to 2 independently selected cyclic heteroatoms chosen from N, O, and S; and Each of the 5 to 6 monocyclic heteroaryl groups and the 8 to 10 fused bicyclic heteroaryl groups independently has 1 to 4 cyclic heteroatoms independently selected from N, O, and S.

[0071] As used herein, a 4-membered monocyclic heterocyclic group has one cyclic heteroatom selected from N, O, and S. As used herein, a 5- to 7-membered monocyclic heterocyclic group has one to two cyclic heteroatoms independently selected from N, O, and S. As used herein, a 5- to 6-membered monocyclic heteroaryl group has one to four cyclic heteroatoms independently selected from N, O, and S. As used herein, an 8- to 10-membered fused bicyclic heterocyclic group has one to four cyclic heteroatoms independently selected from N, O, and S.

[0072] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the X-group comprises a C3-7 monocyclic cycloalkyl group, a 4-7 member monocyclic heterocyclic group, a phenyl group, a naphthyl group, a 5-6 member monocyclic heteroaryl group, or an 8-10 member fused bicyclic heteroaryl group, wherein each of the C3-7 monocyclic cycloalkyl group, the 4-7 member monocyclic heterocyclic group, the phenyl group, the naphthyl group, the 5-6 member monocyclic heteroaryl group, and the 8-10 member fused bicyclic heteroaryl group is optionally substituted with 1 to 3 R1 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, the X-group comprises a C3-7 monocyclic cycloalkyl group, a 4-7 member monocyclic heterocyclic group, a phenyl group, or a 5-6 member monocyclic heteroaryl group, wherein each of the C3-7 monocyclic cycloalkyl group, the 4-7 member monocyclic heterocyclic group, the phenyl group, and the 5-6 member monocyclic heteroaryl group is optionally substituted with 1 to 3 R1 groups.

[0073] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X is a C3-7 monocyclic cycloalkyl group, wherein the C3-7 monocyclic cycloalkyl group is optionally substituted with 1 to 3 R1 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X is a C3-7 monocyclic cycloalkyl group, wherein the C3-7 monocyclic cycloalkyl group is optionally substituted with 1 to 2 R1 groups.

[0074] In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, X is a 4- to 7-membered monocyclic heterocyclic group, wherein the 4- to 7-membered monocyclic heterocyclic group is optionally substituted with 1 to 3 R1 groups. In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, X is an acrylyl, pyrrolidyl, piperidinyl, or piperidinyl group. base, or The linyl group, each of which is optionally substituted by one or two R1 groups.

[0075] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X is a phenyl group, wherein the phenyl group is optionally substituted with 1 to 3 R1 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X is a phenyl group, wherein the phenyl group is optionally substituted with 1 to 2 R1 groups.

[0076] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X is a naphthyl group, wherein the naphthyl group is optionally substituted with 1 to 3 R1 groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, X is a naphthyl group, wherein the naphthyl group is optionally substituted with 1 to 2 R1 groups.

[0077] In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, X is a 5- to 6-membered monocyclic heteroaryl group, wherein the 5- to 6-membered monocyclic heteroaryl group is optionally substituted with 1 to 3 R1 groups. In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, X is a pyridyl group, wherein the pyridyl group is optionally substituted with 1 to 2 R1 groups. In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, X is a pyridyl group, wherein the pyridyl group is optionally substituted with 1 to 2 R1 groups.

[0078] In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, X is an 8- to 10-member fused bicyclic heteroaryl group, wherein the 8- to 10-member fused bicyclic heteroaryl group is optionally substituted with 1 to 3 R1 groups. In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, X is an 8- to 10-member fused bicyclic heteroaryl group, wherein the 8- to 10-member fused bicyclic heteroaryl group is optionally substituted with 1 to 2 R1 groups.

[0079] In some embodiments of the compound of formula I or its pharmaceutically acceptable salt, the X group may optionally be substituted with one R1 group.

[0080] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, each R1 is independently a -CN, halogen, Ra, Rb, Rc, C1-6 alkyl, or a 4- to 7-membered monocyclic heterocyclic group. The C1-6 alkyl group may optionally be substituted by one to three independent groups selected from -CN, halogen, Ra, Rb, Rc, -SR2, and =NR2a. The 4 to 7 member monocyclic heterocyclic group may optionally be substituted by 1 to 3 independent groups selected from -CN, halogen, Ra, Rb, and Rc.

[0081] In some embodiments of compounds of formula I or their pharmaceutically acceptable salts, each R1 is independently -OH, -CN, halogen, -C(O)OR2, -NR3R3, -NR3C(O)C(O)OR2, Ra, C1-6 alkyl, or a 4- to 7-membered monocyclic heterocyclic group. The C1-6 alkyl group may optionally be substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR 3R 3, -NR 3C(O)OR 2, Ra, -SR 2, and =NR 2a. The 4 to 7 member monocyclic heterocyclic group may optionally be substituted by 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra.

[0082] In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R1-based compounds are CN. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R1-based halogens are halogens. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R1-based compounds are Ra. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R1-based compounds are Rb. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R1-based compounds are Rc. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R1-based compounds are OH. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R1-based compounds are C(O)OR2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R1-based compounds are NR3R3. In some embodiments of compounds of formula I or their pharmaceutically acceptable salts, one or more R1 series -NR3C(O)C(O)OR2.

[0083] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R1-based C1-6 alkyl groups are included, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -CN, halogen, Ra, Rb, Rc, -SR2, and =NR2a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R1-based C1-6 alkyl groups are included, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR3R3, -NR3C(O)OR2, Ra, -SR2, and =NR2a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one R1-system is a C1-6 alkyl group, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR3R3, -NR3C(O)OR2, Ra, -SR2, and =NH. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R1-system C1-6 alkyl groups are substituted with one to three groups independently selected from -CN, halogen, Ra, Rb, Rc, -SR2, and =NR2a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R1-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR3R3, -NR3C(O)OR2, Ra, -SR2, and =NR2a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one R1-based C1-6 alkyl group is present, wherein the C1-6 alkyl group is substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR3R3, -NR3C(O)OR2, Ra, -SR2, and =NH. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R1-based C1-6 alkyl groups are present.

[0084] In some embodiments of the compound of formula I or its pharmaceutically acceptable salt, an R1 series OH, -NH2, -C(O)OR2, -NR3R3, or -NR3C(O)C(O)OR2.

[0085] In some embodiments of compounds of formula I or their pharmaceutically acceptable salts, an R1 system is included: -C(O)OH, -NH(=NH)NH2, -NHC(O)C(O)OH, or .

[0086] In some embodiments of compounds of formula I or their pharmaceutically acceptable salts, an R1-based methyl group, -CH2NH2, -CH2OH, -CH2SH, -C(=NH)NH2, , , ,or .

[0087] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R1 groups are 4 to 7-membered monocyclic heterocyclic groups, wherein the 4 to 7-membered monocyclic heterocyclic groups are optionally substituted with 1 to 3 groups independently selected from -CN, halogen, Ra, Rb, and Rc. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R1 groups are 4 to 7-membered monocyclic heterocyclic groups, wherein the 4 to 7-membered monocyclic heterocyclic groups are optionally substituted with 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R1 group is a 5 to 6-membered monocyclic heterocyclic group, wherein the 5 to 6-membered monocyclic heterocyclic group is optionally substituted with 1 to 2 groups independently selected from -OH, -C(O)OH, and Ra. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R1 groups are 4 to 7-membered monocyclic heterocyclic groups, wherein the 4 to 7-membered monocyclic heterocyclic group is substituted by 1 to 3 groups independently selected from -CN, halogen, Ra, Rb, and Rc. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R1 groups are 4 to 7-membered monocyclic heterocyclic groups, wherein the 4 to 7-membered monocyclic heterocyclic group is substituted by 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one R1 group is 5 to 6-membered monocyclic heterocyclic group, wherein the 5 to 6-membered monocyclic heterocyclic group is substituted by 1 to 2 groups independently selected from -OH, -C(O)OH, and Ra. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R1 groups are 4 to 7-membered monocyclic heterocyclic groups. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, an R1-based piperidinyl group is present.

[0088] In some embodiments of the compounds of Formula I or their pharmaceutically acceptable salts, each Ra is independently -P(O)(OH)₂ or -OP(O)(OH)₂. In some embodiments of the compounds of Formula I or their pharmaceutically acceptable salts, one or more Ra are -P(O)(OH)₂. In some embodiments of the compounds of Formula I or their pharmaceutically acceptable salts, one or more Ra are -OP(O)(OH)₂.

[0089] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each Rb is independently -C(O)R2, -C(O)OR2, -C(O)NR3R3, -C(O)C(O)OR2, -S(O)2R2, -S(O)2NR3R3, or -S(O)2OR3. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Rb is -C(O)R2. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Rb is -C(O)OR2. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Rb is -C(O)NR3R3. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Rb is -C(O)C(O)OR2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rb-based compounds are represented by S(O)₂R₂. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rb-based compounds are represented by S(O)₂NR₃R₃. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rb-based compounds are represented by S(O)₂OR₃.

[0090] In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, each Rc is independently -OR2, -OC(O)R2, -OC(O)C(O)OR2, -NR3R3, -N+R3R3R3a, -NR3C(O)R2, -NR3C(O)NR3R3, -NR3C(O)OR2, -NR3C(O)C(O)OR2, or -NR3S(O)2R2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rcs are -OR2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rcs are -OC(O)R2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rcs are -OC(O)C(O)OR2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rc-based compounds are NR 3R 3. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rc-based compounds are N +R 3R 3R 3a. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rc-based compounds are NR 3C(O)R 2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rc-based compounds are NR 3C(O)NR 3R 3. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rc-based compounds are NR 3C(O)OR 2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rc-based compounds are NR 3C(O)C(O)OR 2. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more Rc-based compounds are NR 3S(O) 2R 2.

[0091] In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, each R2 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -CN, halogen, Ra, Rd, and Re. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, each R2 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, each R2 is independently H or C1-4 alkyl, wherein the C1-4 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra. In some embodiments of the compound of formula I or its pharmaceutically acceptable salt, each R2 is independently H or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by one or two groups independently selected from -C(O)OH and Ra.

[0092] In some embodiments of compounds of formula I or their pharmaceutically acceptable salts, one or more R2-based H.

[0093] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R2-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -CN, halogen, Ra, Rd, and Re. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R2-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -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 R2-based C1-4 alkyl groups are present, wherein the C1-4 alkyl group is optionally substituted with one to three groups independently selected from -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 R2-based C1-3 alkyl groups are present, wherein the C1-3 alkyl group is optionally substituted with one or two groups independently selected from -C(O)OH and Ra. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R2-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is substituted with one or three groups independently selected from -CN, halogen, Ra, Rd, and Re. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R2-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is substituted with one or three groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R2-based C1-4 alkyl groups are present, wherein the C1-4 alkyl group is substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, and Ra. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R2-based C1-3 alkyl groups are present, wherein the C1-3 alkyl group is substituted with one to two groups independently selected from -C(O)OH and Ra. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R2-based C1-6 alkyl groups are present. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R2-based C1-4 alkyl groups are present. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R2-based C1-3 alkyl groups are present.

[0094] In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, each R 2a is independently H or C1-3 alkyl. In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R 2a are H. In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R 2a are C1-3 alkyl.

[0095] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, each R3 is independently H, Rd, or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -CN, halogen, Ra, Rd, Re, and =NR3a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, each R3 is independently H, -C(O)OR4, or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, each R3 is independently H, -C(O)OR4, or C1-4 alkyl, wherein the C1-4 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, each R3 is independently H, -C(O)OR4, or C1-3 alkyl, wherein the C1-3 alkyl group is optionally substituted with a group selected from -OH, -C(O)OH, -NR4R4, Ra, and =NR3a.

[0096] In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R3-based H. In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R3-based Rd. In some embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R3-based -C(O)OR 4.

[0097] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-6 alkyl groups are included, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -CN, halogen, Ra, Rd, Re, and =NR3a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-6 alkyl groups are included, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-4 alkyl groups are included, wherein the C1-4 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-3 alkyl groups are present, wherein the C1-3 alkyl group is optionally substituted with a group selected from -OH, -C(O)OH, -NR4R4, Ra, and =NR3a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is substituted with one to three independently selected groups selected from -CN, halogen, Ra, Rd, Re, and =NR3a. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is substituted with one to three independently selected groups selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-4 alkyl groups are present, wherein the C1-4 alkyl group is substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-3 alkyl groups are present, wherein the C1-3 alkyl group is substituted with a group selected from -OH, -C(O)OH, -NR4R4, Ra, and =NR3a. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-6 alkyl groups are present. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-4 alkyl groups are present. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more R3-based C1-3 alkyl groups are present.

[0098] In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, each R 3a is independently H or C1-3 alkyl. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R 3a are H. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, one or more R 3a are C1-3 alkyl. In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, R 3a are H.

[0099] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, each Rd is independently -C(O)R4, -C(O)OR4, -C(O)NR4R4, -C(O)C(O)OR4, -S(O)2R4, -S(O)2NR4R4, or -S(O)2OR4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Rds are -C(O)R4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Rds are -C(O)OR4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Rds are -C(O)NR4R4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Rds are -C(O)C(O)OR4. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more Rd-based compounds are represented by S(O)₂R₄. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more Rd-based compounds are represented by S(O)₂NR₄R₄. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more Rd-based compounds are represented by S(O)₂OR₄.

[0100] In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, each Re is independently -OR4, -OC(O)R4, -OC(O)C(O)OR4, -NR4R4, -N+R4R4R4a, -NR4C(O)R4, -NR4C(O)NR4R4, -NR4C(O)OR4, -NR4C(O)C(O)OR4, or -NR4S(O)2R4. In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, one or more Re are -OR4. In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, one or more Re are -OC(O)R4. In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, one or more Re are -OC(O)C(O)OR4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Re-based NR 4R 4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Re-based NR 4R 4R 4a. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Re-based NR 4C(O)R 4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Re-based NR 4C(O)NR 4R 4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Re-based NR 4C(O)OR 4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Re-based NR 4C(O)C(O)OR 4. In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt thereof, one or more Re-based NR 4S(O) 2R 4.

[0101] In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, each R4 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -COOH, and Ra. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, each R4 is independently H or C1-3 alkyl, wherein the C1-3 alkyl group is optionally substituted with one to three groups independently selected from -OH, CN, halogen, -COOH, and Ra. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, each R4 is independently H or C1-3 alkyl, wherein the C1-3 alkyl group is optionally substituted with one to two groups independently selected from -C(O)OH and Ra.

[0102] In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, one or more R4-based H groups are present. In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, one or more R4-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -OH, CN, halogen, -COOH, and Ra. In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, one or more R4-based C1-3 alkyl groups are present, wherein the C1-3 alkyl group is optionally substituted with one to three groups independently selected from -OH, CN, halogen, -COOH, and Ra. In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, one or more R4-based C1-3 alkyl groups are present, wherein the C1-3 alkyl group is optionally substituted with one to two groups independently selected from -C(O)OH and Ra. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R4-based C1-6 alkyl groups are present, wherein the C1-6 alkyl group is substituted with one to three groups independently selected from -OH, -CN, halogen, -COOH, and Ra. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R4-based C1-3 alkyl groups are present, wherein the C1-3 alkyl group is substituted with one to three groups independently selected from -OH, CN, halogen, -COOH, and Ra. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R4-based C1-3 alkyl groups are present, wherein the C1-3 alkyl group is substituted with one to two groups independently selected from -C(O)OH and Ra. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R4-based C1-6 alkyl groups are present. In some embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof, one or more R4-based C1-3 alkyl groups are present.

[0103] In some embodiments of the compounds of Formula I or their pharmaceutically acceptable salts, the compounds provided herein are selected from the group consisting of: , , , , , , , , , , , , ,and , Or a medicinally acceptable salt.

[0104] In some embodiments of the compounds of Formula I, compounds selected from the group consisting of: , , , , , , , , , , , , , , , , , ,and , Or a medicinally acceptable salt.

[0105] In some embodiments of the compounds of Formula I, compounds selected from the group consisting of: , , , ,and , Or a medicinally acceptable salt.

[0106] In some embodiments of the compounds of Formula I, the following compounds are provided herein: , Or a medicinally acceptable salt.

[0107] In some embodiments of the compounds of Formula I, the following compounds are provided herein: , Or a medicinally acceptable salt.

[0108] In some embodiments of the compounds of Formula I, the following compounds are provided herein: , Or a medicinally acceptable salt.

[0109] In some embodiments of the compounds of Formula I, the following compounds are provided herein: , Or a medicinally acceptable salt.

[0110] In some embodiments of the compounds of Formula I, the following compounds are provided herein: , Or a medicinally acceptable salt.

[0111] 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 is therefore administered orally at a lower effective dose than that required for lenacapavir to achieve the same level of exposure to lenacapavir in vivo. [III.] [Components and Sets]

[0112] The compounds or pharmaceutically acceptable salts thereof provided herein are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds or pharmaceutically acceptable salts thereof provided herein, isomers, or mixtures thereof, and one or more pharmaceutically acceptable mediators selected from carriers, adjuvants, and excipients are also provided herein. The compounds or pharmaceutically acceptable salts thereof provided herein may be the sole active ingredient or one of the active ingredients of a pharmaceutical composition. Suitable pharmaceutically acceptable mediators may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GSBanker & CTRhodes, Eds.).

[0113] In one embodiment, this document provides 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.

[0114] In some embodiments, the pharmaceutical composition provided herein further comprises one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0115] In some embodiments, one or more additional therapeutic agents include therapeutic agents for HIV infection. In some embodiments, one or more additional therapeutic agents are anti-HIV agents. In some embodiments, one or more additional therapeutic agents are selected from the group consisting of: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells (CAR-T) and engineered T cell receptors (TCR-T), autologous T cell therapy, engineered B cells, NK cells), latency reversal agents, immunotherapy, 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 modifiers, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef modulators, TNFα ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, 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 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, and reverse transcriptase priming complexes.Inhibitors of complex 1, G6PD and NADH oxidase, 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, anti-HIV peptides, and any combination thereof.

[0116] In some embodiments, one or more additional therapeutic agents are selected from combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, shell inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, and any combination thereof.

[0117] In some embodiments, the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, shell inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, and any combination thereof.

[0118] In some embodiments, one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, agonists of HIV bNAb, TLR7, TLR8, and TLR9, HIV vaccines, intercytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors targeting HIV antigens, pharmacokinetic enhancers, and other drugs for the treatment of HIV, and any combination thereof.

[0119] In some embodiments, one or more additional therapeutic agents are selected from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemiflumethicone, tenofovir alafenamide, and tenofovir alafenamide hemiflumethicone, or pharmaceutically acceptable salts thereof.

[0120] In some embodiments, one or more additional therapeutic agents are selected from dolutegravir, cabotevir, drinenavir, bilutegravir, favirine, rilpivirine, any combination thereof, or pharmaceutically acceptable salts thereof.

[0121] Examples of combination therapies include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (etigavir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA ® (tenofovir alafenamide, emtricitabine, cobicistat, and erticagvir); direnavir, tenofovir alafenamide hemibutenedioic acid, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemibutenedioic acid and emtricitabine; tenofovir alafenamide hemibutenedioic acid, emtricitabine, and rilpivirine; tenofovir alafenamide hemibutenedioic acid, emtricitabine, cobicistat, and erticagvir; tenofovir analogues; 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® (bitelavin + emtricitabine + tenofovir alafenamide), DOVATO® (dotelavin + lamivudine), TRIZIVIR ® (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobicillin; Atazanavir sulfate and cobicillin; Atazanavir sulfate and ritonavir; Derlinavir and cobicillin; Dolutegravir and rilpivirine; Dolutegravir and rilpivirine hydrochloride; Dolutegravir, Abacavir sulfate, and lamivudine; Lamivudine, Nevirapine, and zidovudine; Rettagvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate;Dolutegravir + Lamivudine, Lamivudine + Abacavir + Zidovudine, Lamivudine + Abacavir, Lamivudine + Tenofovir Disoproxil Fumarate, Lamivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine, Tenofovir Disoproxil Fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lamivudine, Cabotevir + Rilpivirine, 3-BNC117 +albuvirtide, elpida (evavirin, VM-1500), and VM-1500A, and dual-target HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0122] In some embodiments, this document provides pharmaceutical compositions comprising a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0123] In some embodiments, the pharmaceutical composition provided herein further comprises one, two, three, or four additional therapeutic agents.

[0124] In some embodiments, the pharmaceutical composition provided herein further comprises one, two, three, or four additional therapeutic agents.The additional treatment agents are selected from the following groups: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, and HIV... Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells (CAR-T) and engineered T cell receptors (TCR-T), autologous T cell therapy, engineered B cells, NK cells), latency reversal agents, immunotherapy, 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 modifiers, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef modulators, TNFα ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, counter-cyclic protein modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 non-integrin 1-grabbing 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 initiation complex inhibitors, G6PD and NADH oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and anti-HIV peptides, or any combination thereof.

[0125] In some embodiments, the pharmaceutical composition provided herein further comprises one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agents are selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, shell inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, bispecific antibodies, "antibody-like" therapeutic proteins, or any combination thereof.

[0126] In some embodiments, the pharmaceutical composition provided herein further comprises one, two, three, or four additional therapeutic agents, wherein the additional therapeutic agents are selected from the group consisting of: dolutegravir, cabotevir, derenavir, bistilavil, ellavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate hemibutenedioic acid, tenofovir alafenamide, and tenofovir alafenamide hemibutenedioic acid, or pharmaceutically acceptable salts thereof.

[0127] The pharmaceutical composition can be administered in a single dose or multiple doses. The pharmaceutical composition can be administered by various methods, including, for example, rectal, buccal, intranasal, and percutaneous routes. In some embodiments, the pharmaceutical composition can be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0128] One mode of administration is parenteral, such as by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oily suspensions, or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical mediators. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and the pharmaceutical compositions disclosed herein are administered by subcutaneous injection.

[0129] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned herein, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as solutions in 1,3-butanediol) or prepared as lyophilized powders. Acceptable mediators and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids (such as oleic acid) may also be used in the preparation of injectable formulations.

[0130] In some embodiments, the sterile injectable formulations disclosed herein may also be sterile injectable solutions or suspensions prepared from lyophilized powders reconstituted in a non-toxic, parenteral-acceptable diluent or solvent, such as solutions in 1,3-butanediol. Acceptable mediators and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids (such as oleic acid) may also be used in the preparation of injectable formulations.

[0131] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the intended recipient's blood; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. In some embodiments, the suspension is a microsuspension. In some embodiments, the suspension is a nanosuspension.

[0132] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will include one or more excipients. The excipients should be compatible with the other components of the formulation and harmless to the recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulation and can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009. Examples of solubilizing excipients in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamer (such as poloxamer 338, 188, or 207).

[0133] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts and pharmaceutical compositions disclosed herein are administered via implantation.

[0134] Oral administration may be another route of administration of the compounds provided herein or their pharmaceutically acceptable salts. Administration may be via, for example, capsules or enteric-coated tablets. In the manufacture of pharmaceutical compositions comprising at least one of the compounds provided herein or its pharmaceutically acceptable salts, isomers, or mixtures, the active ingredient (such as the compounds provided herein) is typically diluted with excipients and / or encapsulated in such carriers, which may be in the form of capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, acting as a mordant, carrier, or medium for the active ingredient. Therefore, pharmaceutical ingredients may take the following forms: tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of an active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0135] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. Pharmaceutical compositions may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents; or any combination thereof.

[0136] Pharmaceutical compositions comprising at least one of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, can be formulated to provide rapid, sustained, or delayed release of an 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 dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation used in the methods disclosed herein employs a percutaneous delivery device (“patch”). Such percutaneous patches can be used to provide continuous or discontinuous infusions of the compounds provided herein in controlled amounts. The construction and use of percutaneous patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured to deliver medication continuously, pulsatilely, or on demand.

[0137] To prepare solid compositions (such as tablets), the main active ingredient may be mixed with pharmaceutical excipients to form a solid preformed composition, which is a homogeneous mixture containing the compound described herein or its pharmaceutically acceptable salts, isomers, or mixtures thereof. When such preformed compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, making it easy to subdivide the composition into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0138] The compounds described herein, or their pharmaceutically acceptable salts, in tablet or pill form, may be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action or to protect it from the effects of gastric acid conditions. For example, tablets or pills may include an internal dose and an external dose component, the latter in the form of an envelope covering the former. These two components may be separated by an enteric coating, which resists disintegration in the stomach and allows the internal component to pass intact into the duodenum or delays release. Various materials may be used for such enteric coatings or enteric layers, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0139] Pharmaceutical compositions for inhalation or inhalation may include solutions and suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or via nasal inhalation to achieve a local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask curtain or an intermittent positive pressure respirator. Solutions, suspensions, or powder compositions may be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.

[0140] In one embodiment, this document provides 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 labeling and / or instructions for use of such compounds for the treatment of indications (including diseases or conditions described herein).

[0141] In some embodiments, the kit further includes one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents or their pharmaceutically acceptable salts.

[0142] In one embodiment, this document provides an article of manufacture which contains, in a suitable container, the compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof. In some embodiments, the container may be a vial, jar, ampoule, pre-loaded syringe, or intravenous bag. [IV.] [method]

[0143] The methods provided herein can be applied to cell populations, both in vivo and in vitro. "In vivo" means within a living individual, such as an animal or human. In this case, the methods provided herein can be used therapeutically in the 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 case, the disclosure can be used for various purposes, including therapeutic and experimental purposes. For example, the disclosure can be used in vitro to determine the optimal scheduling and / or dosage of compounds as disclosed herein for a given cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or in a clinic to establish in vivo therapeutic protocols. Other in vitro applications applicable to this disclosure are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties can be tested using methods familiar to those skilled in the art.

[0144] In one embodiment, this disclosure provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient in need, 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.

[0145] In one embodiment, this disclosure provides a method for treating human immunodeficiency virus (HIV) infection in a patient who has undergone extensive treatment, the method 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.

[0146] In some embodiments, the methods provided herein further include administering a therapeutically effective amount of one, two, three, or four additional therapeutic agents or their pharmaceutically acceptable salts.

[0147] In some embodiments,One, two, three, or four additional treatment agents are selected from the following groups: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells (CAR-T) and engineered T cell receptors (TCR-T), autologous T cell therapy, engineered B cells, NK cells), latency reversal agents, immunotherapy, 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 modifiers, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef modulators, TNFα ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, counter-cyclic protein modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 non-integrin 1-grabbing 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 initiation complex inhibitors, G6PD and NADH oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and anti-HIV peptides, or any combination thereof.

[0148] In some embodiments, one, two, three, or four additional therapeutic agents are selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, shell inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, or any combination thereof.

[0149] In some embodiments, one, two, three, or four additional therapeutic agents are selected from the group consisting of: dolutegravir, cabotevir, derenavir, bilutegravir, ellavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate hemibutenedioic acid, tenofovir alafenamide, and tenofovir alafenamide hemibutenedioic acid, or pharmaceutically acceptable salts thereof.

[0150] In some embodiments of the methods provided herein, the patient is a human.

[0151] In one embodiment, this disclosure provides a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, for use in a therapy.

[0152] In one embodiment, this disclosure provides a method for treating or preventing human immunodeficiency virus (HIV) infection in a patient in need of a compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, by administering to the patient a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.

[0153] In one embodiment, this disclosure provides a method for treating a human immunodeficiency virus (HIV) infection in a patient undergoing extensive treatment with a compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, comprising administering to the patient a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0154] In some embodiments, the uses provided herein further include administering one, two, three, or four additional therapeutic agents or their pharmaceutically acceptable salts in a therapeutically effective amount.

[0155] In some embodiments of the uses provided herein,One, two, three, or four additional treatment agents are selected from the following groups: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells (CAR-T) and engineered T cell receptors (TCR-T), autologous T cell therapy, engineered B cells, NK cells), latency reversal agents, immunotherapy, 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 modifiers, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef modulators, TNFα ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase modulators, mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, IFN antagonists, counter-cyclic protein modulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, dendritic ICAM-3 non-integrin 1-grabbing 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 initiation complex inhibitors, G6PD and NADH oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and anti-HIV peptides, or any combination thereof.

[0156] In some embodiments of the uses provided herein, one, two, three, or four additional therapeutic agents are selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, shell inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, or any combination thereof.

[0157] In some embodiments of the uses provided herein, one, two, three, or four additional therapeutic agents are selected from the group consisting of: dolutegravir, cabotevir, derenavir, bilutegravir, ellavirine, rilpivirine, abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate hemibutenedioic acid, tenofovir alafenamide, and tenofovir alafenamide hemibutenedioic acid, or pharmaceutically acceptable salts thereof.

[0158] In some embodiments of the uses provided herein, the patient is a human. [V.] [Voting]

[0159] The compounds disclosed herein, or their pharmaceutically acceptable salts (also referred to herein as active ingredients), can be administered via any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), and the like. It will be understood that a preferred route may vary depending, for example, on the recipient's condition. The advantage of certain compounds disclosed herein, or their pharmaceutically acceptable salts, is that they are orally bioavailable and can be administered orally.

[0160] The disclosed compounds or pharmaceutically acceptable salts thereof may be administered to an individual for a desired period of time or duration, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or longer, according to an effective dosing regimen. In some embodiments, the compounds or pharmaceutically acceptable salts thereof are administered on a daily or intermittent schedule over the individual's lifespan.

[0161] The specific dosage level of the disclosed compound or its pharmaceutically acceptable salt for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, time of administration, route of administration, and excretion rate, drug combination, and the severity of the specific disease in the subject receiving the therapy. For example, the dosage may be expressed as milligrams (mg / kg) of the compound or its pharmaceutically acceptable salt provided herein per kilogram of subject body weight. Doses between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages between 0.5 and 60 mg / kg may be appropriate. Standardization based on subject weight is particularly useful when adjusting dosages among subjects with wide differences in size, such as when using drugs in both children and adults, or when converting effective doses in non-human subjects (such as dogs) to doses suitable for human subjects.

[0162] Dosage can also be described as the total amount of the compound described herein or its pharmaceutically acceptable salts administered per dose. The dosage or frequency of administration of the disclosed compounds or their pharmaceutically acceptable salts may be adjusted during treatment based on the judgment of the administering physician.

[0163] The disclosed compounds or pharmaceutically acceptable salts thereof can be administered in therapeutically effective amounts to an individual (e.g., a human). In some embodiments, the compounds of Formula I or pharmaceutically acceptable salts thereof are administered once daily, once weekly, once monthly, once every two months, once every three months, or once every six months. In some embodiments, the compounds of Formula I or pharmaceutically acceptable salts thereof are administered once daily. In some embodiments, the compounds of Formula I or pharmaceutically acceptable salts thereof are administered once weekly. In some embodiments, the compounds of Formula I or pharmaceutically acceptable salts thereof are administered once monthly. In some embodiments, the compounds of Formula I or pharmaceutically acceptable salts thereof are administered once every two months. In some embodiments, the compounds of Formula I or pharmaceutically acceptable salts thereof are administered once every three months. In some embodiments, the compounds of Formula I or pharmaceutically acceptable salts thereof are administered once every six months.

[0164] The compounds or their pharmaceutically acceptable salts provided herein may be administered by any available route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of the compounds or their pharmaceutically acceptable salts may include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, therapeutic amounts of the compounds or their pharmaceutically acceptable salts provided herein include 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.

[0165] The compounds disclosed herein or their pharmaceutically acceptable salts may be combined with one or more additional therapeutic agents in any dose of the compounds disclosed herein or their pharmaceutically acceptable salts (e.g., compounds from 1 mg to 1000 mg). Therapeutic effective doses 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 1000 mg per dose. Other therapeutically effective amounts of the compound of Formula I or its pharmaceutically acceptable salts 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 its pharmaceutically acceptable salts 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.

[0166] 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 1000 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 900 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 800 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 700 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 600 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 500 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 400 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 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 15 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 10 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 5 mg.

[0167] 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 a compound of Formula I or a pharmaceutically acceptable salt thereof is about 200 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 250 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 300 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 350 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 400 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 450 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 500 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 550 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 600 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 650 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 700 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 750 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 800 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 850 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 900 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 950 mg.In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1000 mg. In some embodiments, the therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof is about 1050 mg.

[0168] When administered orally, the total weekly dose for human subjects may be between about 1 mg and 1,000 mg / week, between about 10 and 500 mg / week, between about 50 and 300 mg / week, between about 75 and 200 mg / week, or between about 100 and 150 mg / week. In some embodiments, the total weekly dose for human subjects may be a single dose of about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / week. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for human subjects may be a single dose of about 100 mg. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for human subjects may be a single dose of about 150 mg. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 200 mg in a single dose. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 250 mg in a single dose. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 300 mg in a single dose. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 350 mg in a single dose. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 400 mg in a single dose. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 450 mg in a single dose. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 500 mg in a single dose.

[0169] When administered orally, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for human subjects may be between about 500 mg and 1,000 mg / month, between about 600 and 900 mg / month, or between about 700 and 800 mg / month. In some embodiments, the total weekly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for human subjects may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / week as a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for human subjects may be about 500 mg as a single dose. In some embodiments, the total monthly dose for human subjects may be about 550 mg as a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for human subjects may be about 600 mg as a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 650 mg in a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 700 mg in a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 750 mg in a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 800 mg in a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 850 mg in a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 900 mg in a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for a human subject may be about 950 mg in a single dose. In some embodiments, the total monthly dose of a compound of Formula I or a pharmaceutically acceptable salt thereof for human subjects may be approximately 1000 mg in a single dose.

[0170] A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose may be administered once every 1 hour, 2, 3, 4, 6, 8, 12, or 16 hours, or once every 24 hours. A single dose may also be administered once every 1 day, 2, 3, 4, 5, or 6 days, or once every 7 days. A single dose may also be administered once every 1 week, 2, or 3 weeks, or once every 4 weeks. In some embodiments, a single dose may be administered once weekly. A single dose may also be administered once monthly. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered once daily using the methods disclosed herein. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered twice daily using the methods disclosed herein.

[0171] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered once daily using the methods disclosed herein. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered once weekly using the methods disclosed herein. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered once monthly using the methods disclosed herein. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered once every two months using the methods disclosed herein. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered once every three months using the methods disclosed herein. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered once every six months using the methods disclosed herein.

[0172] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 100 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 150 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 200 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 250 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 300 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 350 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 400 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 450 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once weekly in a single dose of about 500 mg.

[0173] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 500 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 550 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 600 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 650 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 700 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 750 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 800 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 850 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 900 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 950 mg. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are administered orally once monthly in a single dose of about 1000 mg.

[0174] The frequency of dosing of the disclosed compound or its pharmaceutically acceptable salt will be determined by the individual patient's needs and may be, for example, once daily, once weekly, once monthly, once every two months, once every three months, or once every six months. The compound or its pharmaceutically acceptable salt may be administered continuously for as long as necessary to treat retroviral infections (including HIV infection) or any other indication described herein. For example, the compound or its pharmaceutically acceptable salt may be administered to humans suffering from retroviral infections (including HIV infection) for the duration of human life.

[0175] The administration may be intermittent, in which the patient receives a daily dose of the disclosed compound or its pharmaceutically acceptable salt for a period of several days or more, followed by a period of several days or more during which the patient does not receive the daily dose of the compound or its pharmaceutically acceptable salt. For example, the patient may receive a dose of the compound or its pharmaceutically acceptable salt every other day or three times a week. Again, as an example, the patient may receive a daily dose of the compound or its pharmaceutically acceptable salt for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive the daily dose of the compound or its pharmaceutically acceptable salt, followed by a subsequent period (e.g., 1 to 14 days) during which the patient again receives the daily dose of the compound or its pharmaceutically acceptable salt. Depending on clinical needs for treating the patient, alternating periods of administration of the compound or its pharmaceutically acceptable salt followed by non-administration of the compound or its pharmaceutically acceptable salt may be repeated.

[0176] The compounds disclosed herein, or their pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein, may be administered once, twice, three, or four times daily in any of the suitable modes described above. Furthermore, administration of the compounds or their pharmaceutically acceptable salts, or treatment with the compounds or their pharmaceutically acceptable salts, may continue for several days; for example, for a treatment cycle, treatment typically lasts at least 7, 14, or 28 days. Treatment cycles for retroviral infections (including HIV infection) are well known. In some embodiments, treatment cycles are often alternated between cycles with rest periods of about 1 to 28 days, typically about 7 days or about 14 days. In other embodiments, treatment cycles may also be continuous. [VI.] [Combination therapy]

[0177] Patients treated with the compounds provided herein or their pharmaceutically acceptable salts often exhibit diseases or conditions that benefit from treatment with other therapeutic agents, including agents for treating retroviral infections (including HIV infection). In some embodiments, the other therapeutic agents are agents for treating HIV infection. Therefore, one aspect of this disclosure is a method of treating HIV infection comprising administering to a subject in need (particularly a human subject) a combination of the compounds disclosed herein or their pharmaceutically acceptable salts with one or more compounds that can be used to treat HIV infection.

[0178] In some embodiments, the disclosed compound or its pharmaceutically acceptable salt system is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the disclosed compound or its pharmaceutically acceptable salt system is combined with two additional therapeutic agents. In some embodiments, the disclosed compound or its pharmaceutically acceptable salt system is combined with three additional therapeutic agents. In some embodiments, the disclosed compound or its pharmaceutically acceptable salt system 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 type of therapeutic agents, and / or may be therapeutic agents selected from different types.

[0179] In some embodiments, when a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or more administrations.

[0180] In some embodiments, the disclosed compounds or their pharmaceutically acceptable salts are combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, such as as a solid dosage form for oral administration.

[0181] In some embodiments, the disclosed compound or its pharmaceutically acceptable salts are co-administered with one or more additional therapeutic agents.

[0182] Co-administration includes administering a unit dose of the compound disclosed herein or a pharmaceutically acceptable salt thereof before or after administering a unit dose of one or more additional therapeutic agents. The compound provided herein or a pharmaceutically acceptable salt thereof may be administered within seconds, minutes, or hours after administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound provided herein or a pharmaceutically acceptable salt thereof is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound provided herein or a pharmaceutically acceptable salt thereof within seconds or minutes. In some embodiments, a unit dose of the compound provided herein or thereof is administered first, followed by a unit dose of one or more additional therapeutic agents after a period of several hours (i.e., 1 to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound provided herein or a pharmaceutically acceptable salt thereof, after a period of several hours (i.e., 1 to 12 hours).

[0183] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is formulated into a tablet, which may optionally contain one or more other compounds that can be used to treat the disease to be treated. In some embodiments, the tablet may contain another active ingredient for treating retroviral infections, including 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. In some embodiments, such tablets are suitable for once-every three months. In some embodiments, such tablets are suitable for once-every six months.

[0184] This article also provides a method of treatment in which a compound of Formula I or its tautomers or a pharmaceutically acceptable salt thereof is administered to a patient in combination with one or more additional therapeutic agents or therapies. In some embodiments, for human subjects, the total daily dose of the compound of Formula I or its tautomers or a pharmaceutically acceptable salt thereof may be about 1 to about 500 mg administered in a single dose. HIV combination therapy

[0185] In the above embodiments, one or more additional therapeutic agents may be anti-HIV drugs. In some embodiments, additional therapeutic agents may be HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells (CAR-T) and engineered T cell receptors (TCR-T), autologous T cell therapy, engineered B cells, NK cells), latency reversal agents, immunotherapy, 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 regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modifiers, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef regulators, TNFα ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase regulators, mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, IFN antagonists, countercyclic protein regulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 regulators, dendritic ICAM-3 non-integrin 1 capture inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, anti-HIV peptides, and combinations thereof.

[0186] In some embodiments, one or more additional therapeutic agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, shell inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0187] In some embodiments, the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, shell inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0188] In some embodiments, one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, agonists of HIV bNAb, TLR7, TLR8, and TLR9, HIV vaccines, intercytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other drugs for the treatment of HIV, and combinations thereof.

[0189] In some embodiments, one or more additional therapeutic agents are selected from dolutegravir, cabotegravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof. HIV combination therapy

[0190] Examples of combination therapies include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (etigavir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA ® (tenofovir alafenamide, emtricitabine, cobicistat, and erticagvir); direnavir, tenofovir alafenamide hemibutenedioic acid, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemibutenedioic acid and emtricitabine; tenofovir alafenamide hemibutenedioic acid, emtricitabine, and rilpivirine; tenofovir alafenamide hemibutenedioic acid, emtricitabine, cobicistat, and erticagvir; tenofovir analogues; 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® (bitelavin + emtricitabine + tenofovir alafenamide), DOVATO® (dotelavin + lamivudine), TRIZIVIR ® (Abacavir sulfate, Zidovudine, and Lamivudine; ABC+AZT+3TC); Atazanavir and Cobicillin; Atazanavir sulfate and Cobicillin; Atazanavir sulfate and Ritonavir; Derlinavir and Cobicillin; Dolutegravir and Rilpivirine; Dolutegravir and Rilpivirine Hydrochloride; Dolutegravir, Abacavir sulfate, and Lamivudine; Lamivudine, Nevirapine, and Zidovudine; Rettagvir and Lamivudine; Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate; Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate;Dolutegravir + Lamivudine, Lamivudine + Abacavir + Zidovudine, Lamivudine + Abacavir, Lamivudine + Tenofovir Disoproxil Fumarate, Lamivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine, Tenofovir Disoproxil Fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lamivudine, Cabotevir + Rilpivirine, 3-BNC117 +albuvirtide, elpida (evavirin, VM-1500), and VM-1500A, and dual-target HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors. Other HIV medications

[0191] Examples of other medications used to treat HIV include, but are not limited to, aspergillin C, acemannan, alisporivir, BanLec, deferiprone, gamimune, metenkefalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, H1 viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, bevirimat derivatives, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, and bryozoxin-1. (bryostatin-1), bryostatin analogs, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, antisense oligonucleotides modified with fluoro-β-D-arabinose (FANA), FX-101, griffithsin, GSK-3739937, GSK-3739937 (long-acting), HGTV-43, HPH-116, HS-10234, hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, 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-9011 0. TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-44 67. 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. HIV protease inhibitors

[0192] Examples of HIV protease inhibitors include, but are not limited to, amprenavir, atazanavir, becanavir, derenavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC-09 + ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911. Additional examples of HIV protease inhibitors are described, for example, in U.S. Patent No. 10,294,234 and U.S. Patent Application Publication Nos. US2020030327 and US2019210978. HIV Gag protein inhibitors

[0193] Examples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071. HIV ribonuclease H inhibitor

[0194] Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC-727447. HIV Nef inhibitors

[0195] Examples of HIV Nef inhibitors include, but are not limited to, FP-1. HIV reverse transcriptase inhibitors

[0196] Examples of non-nucleoside or non-nucleotide reverse transcriptase inhibitors for HIV 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, favirine (continuously released oral, for HIV infection), favirine (long-acting injectable nano-suspension, for HIV infection), and favirine (VM-1500). Additional non-limiting examples of non-nucleoside or non-nucleotide reverse transcriptase inhibitors include compounds disclosed in U.S. Patent No. 10,548,898.

[0197] Examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include, but are not limited to, adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemibutenediate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir octadecoxyethyl ester (AGX-1009), tenofovir disoproxil fumarate hemibutenediate, VIDEX® and VIDEX EC. ® (didanosine, DDL), abacavir, abacavir sulfate, alovudine, aprikitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapiriline, doravirine, etravirine, OCR-5753, tenofovir disoproxil fumarate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8583, VM-2500, and KP-1461.

[0198] Additional examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include, but are not limited to, those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356, and WO04096286. HIV integrase inhibitors

[0199] Examples of HIV integrase inhibitors include, but are not limited to, elvitegravir, elvitegravir (extended-release microcapsules), curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, phenethyl caffeate, phenethyl caffeate derivatives, tyrphostin, tyramine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, raltegravir, pegylated raltegravir, dolutegravir, JTK-351, bitegravir, AVX-15567, cabotevir (long-acting injection), and diketoquinoline-4-1 derivatives. Biological, integrase-LEDGF inhibitors, ledgin, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017. Additional non-limiting examples of HIV integrase inhibitors include compounds disclosed in U.S. Patent No. 11,084,832.

[0200] Examples of HIV non-catalytic site (or ectopic) integrase inhibitors (NCINIs) include, but are not limited to, CX-05045, CX-05168, and CX-14442. HIV infection factor inhibitors

[0201] Examples of HIV infection factor inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L. HIV entry inhibitors

[0202] Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0203] Examples of CCR5 inhibitors include, but are not limited to, aplaviroc, vicriviroc, maraviro, maraviro (long-acting injectable nanoemulsion), cineviro, leronlimab (PRO-140), adastatin (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, thioraviroc, and vMIP (Haimipu).

[0204] Examples of gp41 inhibitors include, but are not limited to, enfuvirtide, griffithsine (a gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and sifuvirtide.

[0205] Examples of CD4 attachment inhibitors include, but are not limited to, ibalizumab and CADA analogs.

[0206] Examples of gp120 inhibitors include, but are not limited to, anti-HIV microbial agents, Radha-108 (receptol), 3B3-PE38, BMS818251, BanLec, bentonite-based nanoparticles, fostemsavir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0207] Examples of gp160 inhibitors include, but are not limited to, fangchinoline.

[0208] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). HIV maturation inhibitors

[0209] Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232. Latency reversal agent

[0210] Examples of latency reversal agents include, but are not limited to, TLR receptor (TLR) agonists (including TLR7 agonists (e.g., GS-9620), TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as Velcade), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-Bromovirex 4 (BRD4) inhibitors (such as ZL-0580, apabetalone), ionomycin, IAP antagonists (apoptosis protein inhibitors, such as APG-1387, LBW-242), SMAC mimics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), PMA, and SAHA (suberanilohydroxamic acid). Examples of PKC activators include, but are not limited to, indolactam, prostratin, ingenol B, and DAG-lactone. Other PKC activators include, but are not limited to, indolactam, prostratin, ingenol B, and DAG-lactone. NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins, and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (such as lagazole analogs, APH-0812, and GSK-343).

[0211] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2010143301.

[0212] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. US2017071944. Histone deacetase (HDAC) inhibitors

[0213] In some embodiments, the agents described herein are combined with inhibitors of histone deacetase, such as histone deacetase 1, histone deacetase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, and quisinostat. (JNJ-26481585), resminostat, ricolinostat, romidepsin, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamustine, resminostat, and entetasestat. Shell inhibitors

[0214] Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid disruption compounds, HIV nucleocapsid protein p7 (NCp7) inhibitors (such as azodimethicone), HIV p24 capsid protein inhibitors, linacapvir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University), and compounds described in (GSK WO2019 / 087016).

[0215] Additional examples of shell inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030.

[0216] Additional examples of HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publication Nos. US2014221356 and US2016016973. Cytochrome P450 3 inhibitors

[0217] Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553. RNA polymerase regulators

[0218] Examples of RNA polymerase regulators include, but are not limited to, those described in U.S. Patents 10,065,958 and 8,008,264. Immune checkpoint modulators

[0219] In various embodiments, the agents described herein are combined with one or more inhibitors or blockers of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune escape by infected cells. Activating or stimulating stimulating immune checkpoints can amplify the effects of immune checkpoint inhibitors in infection treatments. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., 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., reviewed in Davis et al., Semin Immunol. (2017) 31:64–75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0220] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC type I peptide-associated sequence A (MICA); MHC type I peptide-associated sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; connexin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); containing PVR-associated immunoglobulin domain (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); containing T-cell immunoglobulin and mucin domains 4 (TIMD4; TIM4);Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galactoglobulin 9 (LGALS9); lymphocyte activation 3 (LAG3, CD223); signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); early retinoic acid transcript 1E (RAET1E; ULBP4); early retinoic acid transcript 1G (RAET1G; ULBP5); early retinoic acid transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); Killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); Killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); Killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); Killer cell lectin-like receptor C3 (KLRC3, NKG2E); Killer cell lectin-like receptor C4 (KLRC4, NKG2F); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); Killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); SLAM family member 7 (SLAMF7); and hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1).

[0221] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T-cell suppressive immune checkpoint proteins or receptors. Exemplary T-cell suppressor immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); and PVR-associated immunoglobulin domain-containing (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galactoglobulin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more T-cell stimulating immune checkpoint proteins or receptors.Examples of T-cell stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T-cell costimulator (ICOS, CD278); inducible T-cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; connexin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0222] 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, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Exemplary NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31:64–75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0223] In some embodiments, one or more immune checkpoint inhibitors comprise protein (e.g., antibody or fragment thereof, or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors comprise small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitors of CD274 or PDCD1 are selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0224] Examples of co-administerable CTLA4 inhibitors include, but are not limited to, ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), and 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).

[0225] Examples of co-administerable PD-L1 (CD274) or PD-1 (PDCD1) inhibitors include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), and AK-103. (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (budigalimab), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

[0226] In various embodiments, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058, and AGEN-1307. TNF receptor superfamily (TNFRSF) members, agonists or activators

[0227] In various embodiments, the agents described herein are combined with agonists of one or more members of the TNF receptor superfamily (TNFRSF), such as one or more of the following agonists: 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), TNFR SF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID: 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: 939), TNFRSF9 (CD262, DR5, TRAILR2 ... Due to ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 1 15650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242), and TNFRSF25 (DR3, NCBI gene ID: 8718).

[0228] Examples of co-administerable anti-TNFRSF4 (OX40) antibodies include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0229] Examples of co-administerable anti-TNFRSF5 (CD40) antibodies include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0230] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) can be co-administered.

[0231] Examples of co-administerable anti-TNFRSF9 (4-1BB, CD137) antibodies include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0232] Examples of co-administerable anti-TNFRSF18 (GITR) antibodies include, but are not limited to, those described in MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibody systems are described, for example, in WO2017096179 and WO2018089628. Bispecific and trispecific natural killer (NK) cell connectors

[0233] In various embodiments, the agents described herein are combined with bispecific NK cell connectors (BiKE) or trispecific NK cell connectors (TriKE) (e.g., without Fc) or bispecific antibodies (e.g., with Fc) targeting the following: NK cell activation receptors (e.g., CD16A), C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Depending on the application, anti-CD16 binding bispecific molecules may or may not have an Fc. Explanatory bispecific NK cell adjuvants that can be co-delivered 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 adjuvants (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitor

[0234] In various embodiments, the pharmaceutical agents described herein are combined with the following inhibitor: indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivative (SN-35837), reminolta, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. TLR receptor agonists

[0235] In various embodiments, the agents described herein are combined with agonists of TLR receptors (TLRs), such as agonists of TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 81793).Exemplary TLR7 agonists that can be co-administered include, but are not limited to, AL-034, DSP-0509, GS-9620 (vesatolimod), vesatolimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and the compounds disclosed below: US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences). Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx The following are listed as patents: US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, telratolimod, and BDB-001.TLR8 agonists include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resimimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed below: US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). TLR9 agonists include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042.Examples of TLR3 agonists include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. TLR4 agonists include, but are not limited to, G-100 and GSK-1795091. CDK inhibitors or antagonists

[0236] In some embodiments, the agents described herein are in combination with CDK inhibitors or antagonists. In some embodiments, the CDK inhibitors or antagonists are selected from the group consisting of VS2-370. STING enhancer, RIG-I and NOD2 modifier

[0237] In some embodiments, the agents described herein are in combination with interferon gene stimulators (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of: ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethyl Keto-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP), and cyclic-di-AMP. In some embodiments, the agents described herein are in combination with RIG-I modifiers (such as RGT-100) or NOD2 modifiers (such as SB-9200 and IR-103). LAG-3 and TIM-3 inhibitors

[0238] In some embodiments, the agents described herein are combined with anti-TIM-3 antibodies (such as TSR-022, LY-3321367, MBG-453, INCAGN-2390).

[0239] In some embodiments, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation) antibody (such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385). Interleukin agonist

[0240] In some embodiments, the pharmaceutical agents described herein are combined with interleukin agonists (such as IL-2, IL-7, IL-15, IL-10, and IL-12 agonists); examples of IL-2 receptor agonists include proleukin (aldeleukin, IL-2); BC-IL (Cel-Sci), PEGylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), beempegaldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2 / 15; examples of IL-15 agonists include, but are not limited to, ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 synthorin (PEGylated IL-15), P-22339, and IL-15-PD-1 fusion protein N-809; examples of IL-7 include, but are not limited to, CYT-107.

[0241] Examples of additional immunotherapy that can be combined with the agents disclosed herein include, but are not limited to, interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ; FLT3 agonists such as CDX-301, GS-3583, Gepon, Normferon, pegylated interferon α-2a, pegylated interferon α-2b, and RPI-MN. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0242] Examples of PI3K inhibitors include, but are not limited to, idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, and puquitinib mesylate. mesylate), rigosertib, rigosertib sodium, sonoxixib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-22 69577, 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. α-4 / β-7 antagonists

[0243] Examples of integrin α-4 / β-7 antagonists include, but are not limited to, PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab. HPK1 inhibitors

[0244] Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057. Antibodies targeting HIV

[0245] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include, but are not limited to, DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360, TMB-370, and antibodies targeting HIV gp120 or gp41, HIV antibody-recruiting molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef single-domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, camel-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, and human recombinant mAbs. (PGT-121), PGT121.414.LS, Ibarizumab, Ibarizumab (second generation), Immuglo, MB-66, Human monoclonal antibody targeting KLIC strain 3 (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB.

[0246] Various bNAb can be used. Examples include, but are not limited to, those described in the following: U.S. Patents Nos. 8,673,307, 9,493,549, 9,783,594, 10,239,935, US 2018,371,086, US 2020,223,907, WO 2014 / 063,059, WO 2012 / 158,948, WO 2015 / 117,008, PCT / US 2015 / 41,272, and WO 2017 / 0962. 21, including antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include those described in the following: Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci 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), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (all of which bind to gp41 MPER); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 2G12 (which binds to exogenous glycans); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to CD4 binding sites).

[0247] Additional broadly neutralizing anti-inflammatory systems that can be used as a second therapeutic agent in combination therapy are described, for example, in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594; and WO 2012 / 154312; WO2012 / 158948; WO 2013 / 086533; WO 2013 / 142324; WO2014 / 063059; WO 2014 / 089152, WO 2015 / 048462; WO 2015 / 103549; WO 2015 / 117008; WO2016 / 014484; WO 2016 / 154003; WO 2016 / 196975; WO 2016 / 149710;WO2017 / 096221;WO 2017 / 133639;WO 2017 / 133640, the full text of which are hereby incorporated herein by reference for all purposes. Additional examples include, but are not limited to, those described in the following: 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):Dl 133-9 (2014), Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074, and LN01 (all of which are combined with gp41 MPER).

[0248] Examples of additional antibodies include, but are not limited to, bavituximab, UB-421, BF520.1, BiIA-SG, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, Cl3hmAb, GS-9722 (elipovimab), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, and PGT-12. 1.60, PGT-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (Ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (Ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, D RVIA7, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

[0249] Examples of HIV bispecific and trispecific antibodies include, but are not limited to, MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, and 10E8v4 / PGT121-VRC01.

[0250] Examples of in vivo delivery of bNAb include, but are not limited to, AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and engineered B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301). Pharmacokinetic enhancers

[0251] Examples of pharmacokinetic enhancers include, but are not limited to, cobicistat and ritonavir. Additional treatment

[0252] Examples of additional therapeutic agents include, but are not limited to, the compounds disclosed in the following: WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim). HIV vaccine

[0253] Examples of HIV vaccines include, but are not limited to, peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors, such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackievirus-based vaccines, enterovirus-based vaccines, chimpanzee adenovirus vaccines, lentiviral vector-based vaccines, and salivirus vaccines (such as LCMV, Pichind...). e) Vaccines based on two- or three-segment salamander viruses, HIV-1 vaccines based on trimers, measles virus vaccines, flavivirus vector vaccines, tobacco mosaic virus vector vaccines, varicella-zoster virus vaccines, human parainfluenza virus type 3 (PIV3) vaccines, poxvirus vaccines (modified Ankara vaccinia virus (MVA), orthopox virus-derived NYVAC, and fowlpox virus-derived ALVAC (canarypox virus) strain); fowlpox virus vaccines; rhabdovirus vaccines, such as VSV and marabavirus; recombinant human CMV (rhCMV) vaccines; alpha virus 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-modified mRNA-based therapeutic vaccines; LNP-modified self-replicating RNA / self-amplifying RNA vaccines.

[0254] Examples of vaccines include: AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvant vaccine, BG505 SOSIP.GT1.1 gp140 adjuvant vaccine, ChAdOx1.tHIVconsv1 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, Contre Virus, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multi-channel 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 adjuvant 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, based on N123-VRC-34.01. Inducible Epitopes for 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, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, VIR-1111, IHV-001, and virus-like particle vaccines (such as pseudovirus particle vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccines, conjugate peptide vaccines, dendritic cell vaccines (such as DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC type II epitope heterozygous peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-dose Env vaccine, MVA vaccine, Pennvax-GP, HCMV vector HIV gag vaccine lacking pp71, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidesin, variant gp120 peptide vaccine, rAd5 gag-pol 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; vaccines based on eOD-GT8 60mer, PD-201401, env (A, B, C, A / E) / gag (C) DNA vaccine, gp120 (A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag primiparous-booster plasmid DNA vaccine, anti-CD4 vaccine stimulating HIV-1 iglb12 neutralizing VRC-01 antibody, vaccines based on isotropic virus vectors (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, mRNA-based disease prevention vaccines, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Center), TBL-1203HI, CH505 TF chTrimer, CD40 HIVRI Env vaccine, Drep-HIV-PT-1, mRNA-1644, and mRNA-1574. Fertility control (contraception) combination therapy

[0255] In some embodiments, the agents described herein are combined with fertility control or contraceptive regimens. Therapeutic agents for fertility control (contraception) that can be combined with the agents disclosed herein include, but are not limited to, cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, norethindrone, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, and nomegestrol acetate. Acetate), methylprogesterone, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combination thereof.

[0256] In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, or four additional therapeutic agents selected from the following: ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (etigavir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA ® (tenofovir alafenamide, emtricitabine, cobicistat, and erticagvir); BIKTARVY® (biteravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir alafenamide and erticagvir; tenofovir alafenamide + erticagvir (rectal formula, HIV infection); tenofovir disoproxil fumarate; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemibutenedioic acid; TRIUMEQ ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; retegvir; polyethylene glycol retegvir; retegvir and lamivudine; lamivudine + lopinavir + ritonavir + abacavir; maraviro; tenofovir + emtricitabine + maraviro, enfuvirdi; 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; Derrenavirvir and Cobicistat; Atazanavir; Atazanavir sulfate; Dolutegravir; Eticagvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derrenavirvir; Lamivudine; Pralastine; Fosanavir; Fosanavir calcium Efaviraxyl; Etravirine; Nefenavir; Nefenavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde; Zacitabine; Telanavir; Ampravir; Deraviridine; Deraviridine mesylate; Radha-108 (Reciputa); Lamivudine and Tenofovir disoproxil fumarate;Efaviraxyl, lamivudine, and tenofovir disoproxil fumarate; fosfilz; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0257] In some embodiments, the pharmaceutical agents or pharmaceutical compositions disclosed herein are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV non-nucleoside reverse transcriptase inhibitors. In another specific embodiment, the pharmaceutical agents or pharmaceutical compositions disclosed herein are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV protease inhibitory compounds. In an additional embodiment, the pharmaceutical agents or pharmaceutical compositions disclosed herein are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, and pharmacokinetic enhancers. In some embodiments, the pharmaceutical agents or pharmaceutical compositions disclosed herein are combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the pharmaceutical agents or pharmaceutical compositions disclosed herein are combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors.

[0258] In another embodiment, the pharmaceutical agent or its pharmaceutical composition disclosed herein is combined with a first additional therapeutic agent and a second additional therapeutic agent, wherein the first additional therapeutic agent is selected from dolutegravir, cabotevir, durenavir, bitelavir, ellavirine, rilpivirine, and linacapvir, and the second additional therapeutic agent is selected from emtricitabine and lamivudine.

[0259] In some embodiments, the pharmaceutical agents or their pharmaceutical components disclosed herein are combined with a first additional therapeutic agent (contraceptive) selected from the group consisting of: cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, norethindrone, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, and nomegestrol. Acetate), methylprogesterone, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combination thereof. Gene therapy and cell therapy

[0260] In some embodiments, the agents described herein are combined with gene or cell therapy regimens. Gene therapy and cell therapy include, but are not limited to, gene modification of silencing genes; gene methods for directly killing infected cells; infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; gene methods for modifying cell activity to further alter endogenous immune reactivity against infection. Examples of cell therapies include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPCs overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies include, but are not limited to, AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T and SB-728-HSPC. CCR5 gene inhibitors include, but are not limited to, Cal-1 and autologous CD34-positive hematopoietic progenitor cells (HIV-infected / HIV-related lymphoma) transduced with lentiviral vector CCR5 shRNA / TRIM5α / TAR decoys. In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103-transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy. Gene editor

[0261] In some embodiments, the agents described herein are combined with a gene editor, such as an HIV-targeted gene editor. In various embodiments, the gene editing system may be selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and broad-spectrum nuclease complexes. Illustrative HIV-targeted CRISPR / Cas9 systems include (but are not limited to) EBT-101. CAR-T cell therapy

[0262] In some embodiments, the agents described herein may be co-administered with a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR includes an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4-binding site on gp120, a CD4-inducible binding site on gp120, N-glycans on gp120, V2 of gp120, and a juxtamembranous region on gp41. The immune effector cell line is a T cell or NK cell. In some embodiments, the T cell line is a CD4+ T cell, a CD8+ T cell, or a combination thereof. The cells may be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CAR-T, anti-HIV duoCAR-T, anti-CD4 CAR-T cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, dual anti-CD4 CAR-T cell therapy (CD4 CAR+C34-CXCR4 T cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide. TCR-T cell therapy

[0263] In some embodiments, the agents described herein are combined with a TCR-T cell population. The TCR-T cell line is engineered to target HIV-derived peptides, such as ImmTAV, present on the surface of virus-infected cells. B-cell therapy

[0264] In some embodiments, the antibody or antigen-binding fragment described herein is combined with a genetically modified B cell population to express a broadly neutralizing antibody, such as 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301, Moffett et al., Sci. Immunol). [4], eaax0644 (2019) 17 May 2019.

[0265] The compounds disclosed herein (e.g., any compound of Formula I) can be combined with one, two, three, or four additional therapeutic agents at any dose of the compound of Formula I (e.g., compounds from 1 mg to 500 mg).

[0266] In one embodiment, a kit is provided comprising a combination of the compound disclosed herein or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0267] In one embodiment, one or more additional therapeutic agents in the kit are anti-HIV agents selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells (CAR-T) and engineered T cell receptors (TCR-T), autologous T cell therapy), compounds targeting the HIV capsid, latency reversal agents, HIV bNAb, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins. 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 modifiers, Vif dimerization antagonists, HIV viral infection factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, countercyclic protein modulators, CDK-9 inhibitors, dendritic ICAM-3 non-integrin 1 capture inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0268] In some embodiments, one or more additional therapeutic agents in the kit are selected from combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, shell inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0269] In one specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide reverse transcriptase inhibitor. In another specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide reverse transcriptase inhibitor, and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, and an HIV protease inhibitor. In an additional embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In some embodiments, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide reverse transcriptase inhibitors. In one specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, and an HIV capsid inhibitor. In one specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside reverse transcriptase inhibitor, and an HIV capsid inhibitor. In one specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor. In one specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAbs. In one specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor. In one specific embodiment, the kit includes 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 reverse transcriptase inhibitor. Long-term HIV therapy

[0270] Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotevir, rilpivirine, any integrase LA, VM-1500 LAI, maraviro (LAI), tenofovir implant, doravirine, retegvir, and long-acting dolutegravir. [VII.] [Compound Preparation]

[0271] Some embodiments disclosed herein relate to procedures and intermediates that can be used to prepare the compounds provided herein or their pharmaceutically acceptable salts.

[0272] The compounds described herein can be purified by any means known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases and ion exchange resins. Most generally, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0273] During any procedure used to prepare the compounds provided herein, it may be necessary and / or desired to protect any sensitive or reactive groups on the molecule of interest. This can be achieved by means of known protecting groups, as described in standard operating procedures, such as TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis,” 4 thed., Wiley, New York 2006. Protecting groups can be removed at a convenient subsequent stage using methods known from the art to which they pertain.

[0274] Exemplary chemical entities that can be used in the methods described in the examples will now be described with reference to the illustrative synthetic schemes of the general preparation described herein and subsequent specific examples. Those skilled in the art will appreciate that, in order to obtain the various compounds described herein, starting materials may be suitably selected such that the reaction scheme will carry the final desired substituent (with or without proper protection) to produce the desired product. Alternatively, it may be necessary or desirable to use a suitable group to replace the final desired substituent, which can be carried by the reaction scheme and suitably replaced with the desired substituent. Furthermore, those skilled in the art will appreciate that the conversions shown in the following schemes can be performed in any order compatible with the functionality of the particular side-attached groups. The reactions depicted in the general schemes are preferably run at a temperature from about 0°C to the reflux temperature of the organic solvent used. The isolation of the final compound can be performed by various methods known to those skilled in the art, but is preferably reverse-phase HPLC followed by lyophilization from various organic solvents. Repeated lyophilization may optionally be performed to reduce the amount of residual acid modifier produced by the purification process. In some embodiments, the final compounds provided herein are isolated as mono- or ditrifluoroacetates.

[0275] The method disclosed herein typically provides a specific mirror-image or non-mirror-image isomer as the desired product, although the stereochemistry of the mirror-image or non-mirror-image isomer is not always determined. When the stereochemistry of a specific stereocenter in a mirror-image or non-mirror-image isomer is not determined, the compound is plotted as not showing any stereochemistry at that specific stereocenter, even if the compound may be substantially mirror-image or non-mirror-image pure.

[0276] Representative synthetic systems of the compounds disclosed herein are described in the following schemes and subsequent specific examples. List of abbreviations and initials Abbreviations / initials significance 1,2-EDT 1,2-Ethylenedithiol Ac Acetate ACN or MeCN Acetonitrile AcOH Acetic acid aq. Aqueous solution Ar Argon Bn benzyl BnBr benzyl bromide BnOH benzyl alcohol Boc Tertiary butoxycarbonyl Boc 2O Dibutyl dicarbonate Bu 4N Tetrabutylammonium C18 18-base bonded silicone support C 5H 4N Pyridine CH 2N 4 1-H-tetrazole COMU (1-Cyano-2-ethoxy-2-sideoxyethyleneaminooxy)dimethylamino-N- linyl-carbomony hexafluorophosphate DBDMH 1,3-Dibromo-5,5-dimethylhydantoin DCE 1,2-Dichloroethane DCM dichloromethane DIEA or DIPEA N,N-Diisopropylethylamine DMAc N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO dimethyl monoxide EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ESI Electro-ionization Et Ethyl Et 3N Triethylamine EtOAc Ethyl acetate h or hr(s) (Multiple) hours HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High-performance liquid chromatography i-Pr Isopropyl LCMS Liquid chromatography-mass spectrometry Me methyl MEK Methyl ethyl ketone MeOH methanol MeSO₃H / MsOH mesylate MeTHF or 2-MeTHF 2-Methyltetrahydrofuran Min minute MS Mass spectrometry MsCl Methylsulfonyl chloride m / z mass-to-charge ratio NaOAc Sodium acetate NMR Nuclear magnetic resonance spectroscopy NMM 4-Methyl phyto NMI 1-Methylimidazole OMs Methanesulfonates OTs p-Pyridonium p-toluenesulfonate PhG α-Phenylglycine PhMe Toluene Ra-Ni Rabble nickel RBF round-bottom flask RT or rt room temperature sat. or satd. saturation T3P Propylphosphonic anhydride t-Bu or tBu Grade III Butyl TBAI Tetrabutylammonium iodide TBSCl Tertiary butyldimethylsilyl chloride TCFH N'-Tetramethylformamidin hexafluorophosphate TEA Triethylamine TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxy Tf 2O Trifluoromethanesulfonic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran General synthesis scheme

[0277] General reaction schemes 1 to 4 are provided as further embodiments of this disclosure and illustrate general methods for preparing certain compounds of this disclosure and for preparing additional compounds of this disclosure. The various variables (e.g., R1, R2, R3, R4) of the compounds disclosed in general synthetic schemes 1 to 6 are as defined herein.

[0278] The compounds disclosed herein can be prepared using the methods disclosed herein and their conventional modifications, which will be apparent to those skilled in the art based on the disclosure herein and methods well-known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of typical compounds described herein can be carried out as illustrated in the following examples. Reagents can be commercially available, for example, from Sigma Aldrich or other chemical suppliers, if available. Generally, the compounds described herein are stable and can be isolated at room temperature and pressure.

[0279] Typical embodiments of the compounds disclosed herein can be synthesized using the general reaction schemes described below. As will be apparent to those skilled in the art from the description herein, these general schemes can be altered by substituting the starting materials with other substances having similar structures to produce correspondingly different products. The following description of the synthesis will provide several examples of how the starting materials can be modified to provide corresponding products. For the desired product with defined substituents, the necessary starting materials can usually be determined by testing. Starting materials are generally obtained from commercial sources or synthesized using publicly available methods. For the synthesis of the compounds of the specific examples disclosed herein, examination of the structure of the compound to be synthesized will provide the identification of each substituent. Given the examples herein, the identification of the final product usually becomes apparent through a simple testing procedure that makes the identification of the necessary starting materials obvious.

[0280] The terms "solvent," "inert organic solvent," or "inert solvent" refer to solvents that are inert under the conditions of the reactions described therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, dichloromethane, diethyl ether, methanol, and the like). Unless otherwise stated, the solvents used in the reactions disclosed herein are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon. [General Synthesis Scheme 1]

[0281] Compound A3 can be prepared according to general synthetic scheme 1, wherein A is a C3-7 monocyclic cycloalkyl, 4-7 member monocyclic heterocyclic group, phenyl, naphthyl, 5-6 member monocyclic heteroaryl, or 8-10 member fused bicyclic heteroaryl; G1 is H, -C(O)OH, C1-6 alkyl, -NH2, or 4-7 member monocyclic heterocyclic group, wherein the C1-6 alkyl group is optionally substituted by 1 to 3 groups independently selected from -C(O)OH, -NH2, and -SH, any of which can be protected by a protecting group known in the art; and W is a general detached group, which includes, but is not limited to, halogens or -OH. According to general synthetic scheme 1, it can be prepared by... [Intermediate substance] [5] or [Intermediate substance] [5E] The reaction of compound A1 with a compound under various basic conditions yields compound A3. Non-limiting illustrative conditions include the use of common coupling agents such as HATU, COMU, TCFH, or EDC in the presence of a base and at suitable solvents and temperatures. Alternatively, compound A3 can be obtained by... [23C] Preparation by reaction with a compound of formula A2. Non-limiting illustrative conditions include reaction at an appropriate temperature in the presence of a base (such as DIPEA). In the above conditions, compounds of formula A1 and A2 may contain protecting groups, which are respectively reacted with... [Intermediate substance] [5 / ] [Intermediate item 5E] or [23C] is removed after the reaction to expose a functional group, which can optionally be further processed by reacting with various electrophilic agents (such as xylene chloride or N,N'-di-Boc-1H-pyrazole-1-carboxamidine) and subsequently deprotecting, if appropriate. The compounds of formulas A1 and A2 are commercially available or readily synthesized by one of ordinary skill in the art from known materials and reagents in one or more steps. [General Synthesis Scheme 2.]

[0282] Compounds of formulas B3, B6, and B8 can be prepared according to general synthetic scheme 2, wherein R1 is as defined herein; A is a C3-7 monocyclic cycloalkyl, 4-7 member monocyclic heterocyclic, phenyl, naphthyl, 5-6 member monocyclic heteroaryl, or 8-10 member fused bicyclic heteroaryl; G2 is Ra, Rb, Rc, -SR2, or =NR2a, wherein Ra, Rb, Rc, R2, and R2a are as defined herein; PG is an alcohol or carboxylic acid protecting group known in the art; PG' is a phosphate protecting group known in the art; PG'' is an amine protecting group known in the art; and L is H or -O, or both L are combined with the carbons to which they are attached to form C=O. According to general synthetic scheme 2, compounds of formulas B1 or B4 can be reacted with phosphorylating agents under various conditions to give compounds of formulas B2 or B5, respectively. Non-limiting illustrative reagents include N,N-dialkylphosphamide reagents or dialkylchlorophosphates. Compound B2 can be deprotected and oxidized under conditions known in the art, where both L and L are H, to give compound B3. Compound B5 can be deprotected under suitable conditions known in the art to provide compound B6. Compound B7 can be... [Intermediate substance] [5 / ] [Intermediate 5E] is obtained by reacting [intermediate 5E] with a compound of formula B3, or by reacting [intermediate 5E] with a compound of formula B6. The reaction between [23C] yields the compound. Compound B7 can be deprotected under conditions known in the art to give compound B8. Compounds B1 and B4 are commercially available or readily synthesized by one of ordinary skill in the art in one or more steps using conditions known in the art. [General Synthesis Scheme 3.]

[0283] Compounds of formulas C3, C6, and C8 can be prepared according to general synthetic scheme 3, wherein R1 is as defined herein; A is a C3-7 monocyclic cycloalkyl, 4-7 member monocyclic heterocyclic, phenyl, naphthyl, 5-6 member monocyclic heteroaryl, or 8-10 member fused bicyclic heteroaryl; G2 is Ra, Rb, Rc, -SR2, or =NR2a, wherein Ra, Rb, Rc, R2, and R2a are as defined herein; PG is an alcohol or carboxylic acid protecting group known in the art; PG' is a phosphate protecting group known in the art; PG'' is an amine protecting group known in the art; and L is H or -O, or both L are combined with the carbons to which they are attached to form C=O. According to general synthetic scheme 3, compounds of formulas C1 or C4 can be reacted with alkyl phosphate reagents under various conditions to give compounds of formulas C2 or C5, respectively. Non-limiting illustrative reagents include di- and tributyl chloromethyl phosphate. Compound C2 can be deprotected and oxidized under conditions known in the art, where both L and H are H, to yield compound C3. Compound C5 can be deprotected under suitable conditions known in the art to provide compound C6. Compound C7 can be... [Intermediate substance] [5 / ] [Intermediate 5E] is obtained by reacting a compound of formula C3, or by reacting a compound of formula C6 with... The reaction between [23C] yields the compound. Compound C7 can be deprotected under conditions known in the art to give compound C8. Compounds C1 and C4 are commercially available or readily synthesized by one of ordinary skill in the art in one or more steps using conditions known in the art. [General Synthesis Scheme 4.]

[0284] Compounds of formulas D4, D8, and D10 can be prepared according to general synthetic scheme 4, wherein R1 and R3 are as defined herein; A is a C3-7 monocyclic cycloalkyl, 4-7 member monocyclic heterocyclic, phenyl, naphthyl, 5-6 member monocyclic heteroaryl, or 8-10 member fused bicyclic heteroaryl; G2 is Ra, Rb, Rc, -SR2, or =NR2a, wherein Ra, Rb, Rc, R2, and R2a are as defined herein; PG is an alcohol or carboxylic acid protecting group known in the art; PG' is a phosphate protecting group known in the art; PG'' is an amine protecting group known in the art; and L is H or -O, or both L are combined with the carbons to which they are attached to form C=O. According to general synthetic scheme 4, compounds of formula D1 or D5 can be reacted with methyl chloroformate under various conditions to give compounds of formula D2 or D6, respectively. Compounds D2 or D6 can react with dialkyl phosphate reagents to give D3 or D7, respectively. Non-limiting illustrative reagents for this transformation include potassium di- and tributyl phosphate and tetrabutylammonium di- and tributyl phosphate. Compound D3 can be deprotected and oxidized under conditions known in the art, with both L and L being H, to give compound D4. Compound D7 can be deprotected under suitable conditions known in the art to provide compound D8. Compound D9 can be... [Intermediate substance] [5 / ] [Intermediate 5E] is obtained by reacting [intermediate 5E] with a compound of formula D4, or by reacting [intermediate 5E] with a compound of formula D8. The reaction between [23C] yields the compound. Compound D9 can be deprotected under conditions known in the art to give compound D10. Compounds D1 and D5 are commercially available or readily synthesized in one or more steps using conditions known in the art. [VIII.] [Example]

[0285] The exemplary chemical systems disclosed herein are provided in the following specific examples. Those skilled in the art will understand that, in order to obtain the various compounds described herein, starting materials can be suitably selected such that the desired final substituent (with or without proper protection) is incorporated through a reaction scheme to produce the desired product. Alternatively, it may be necessary or desirable to use a suitable group to replace the desired final substituent, which can be incorporated through a reaction scheme and suitably 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 compatible with the functionality of the particular side-attached groups.

[0286] The examples provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that different batches of the compounds can be combined and then used in the next synthetic step.

[0287] 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 implement certain embodiments of this disclosure. Other embodiments may be utilized, and other logical variations may be made without departing from the scope of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure. [Intermediate item:] Intermediate item 1.

[0288] [( , S , )-1-(3,6- ] [Dibromopyridine-2-] [base)-2-(3,5-] [Difluorophenyl] [B-1-] [aminoacetyl-d-] [Leucine salt (intermediate 1)] [) of synthesis:] will [Intermediate substance] A mixture of [1A] (30.8 mmol, 1.00 equivalent), 2-methyltetrahydrofuran (75 mL), water (45 g), and NaOH (37.9 mmol, 1.23 equivalent) 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 in toluene, distilled to a final volume of 3 mL / g, and then diluted with toluene (224 mL). N-acetylated-d-leucine (43.3 mmol), zinc oxide (6.25 mmol), and 2-pyridinecarboxaldehyde (1.6 mmol) were added to the solution. 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), filtered through diatomaceous earth (7.5 g), and rinsed with toluene (30 mL) in the forward direction. The aqueous phase was discarded, and the organic phase was washed three times with water (75 mL). EtOH (15 mL), water (7.5 mL), toluene (76 mL), and N-acetylglucosinolate (27.7 mmol) were added to the organic phase. The mixture was cooled to 0 °C and filtered. The filter cake was washed with toluene (76 mL) and dried under vacuum to yield the title compound. [Intermediate substance] [1]. 1H NMR (400 MHz, DMSO- d 6) δ 8.03 (d, J= 8.0 Hz, 1H), 7.95 (d, J= 8.3 Hz, 1H), 7.49 (d, J= 8.3 Hz, 1H), 7.03 (tt, J= 9.5, 2.4 Hz, 1H), 6.87 (dtd, J= 8.4, 6.2, 2.2 Hz, 2H), 5.49 (s, 3H), 4.42 (dd, J= 7.9, 5.9 Hz, 1H), 4.18 (q, J= 7.8 Hz, 1H), 2.93 (dd, J= 13.3, 5.9 Hz, 1H), 2.85 (dd, J= 13.2, 8.0 Hz, 1H), 1.83 (s, 3H), 1.71 – 1.54 (m, 1H), 1.47 (dd, J= 8.4, 6.2 Hz, 2H), 0.88 (d, J= 6.6 Hz, 3H), 0.83 (d, J= 6.5 Hz, 3H) ppm. 13C NMR (101 MHz, DMSO- d 6) δ 174.72, 169.03, 162.07 (dd, J= 245.5, 13.3 Hz), 161.79, 143.51, 142.82 (t, J= 9.4 Hz), 139.72, 128.39, 119.30, 113.36 – 111.39 (m), 101.73 (t, J= 25.7 Hz), 55.19, 50.69, 41.74 (d, J= 2.3 Hz), 40.51, 24.36, 22.91, 22.44, 21.46ppm. Intermediate 2.

[0289] [(1, R , ,5 , R , , E , )-3-( ] [Hydroquinone] [Dual Ring [3.1.0]] [F-2-] [Ketone (intermediate 2B)] Synthesis of [ ]: [ ] at 5℃ to ketone [Intermediate substance] [2A] (111 mmol) and ethyl trifluoroacetate (121 mmol) in 2-methyltetrahydrofuran (50 mL) were added to a mixture of 2 M potassium tributoxide (62.4 mL, 1.2 equivalents) in 2-methyltetrahydrofuran. After 1 h, the solution was warmed to 20 °C and stirred for 3 h. The mixture was cooled to 5 °C and 86% phosphoric acid (133 mmol) in water (50 mL) 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 2-methyltetrahydrofuran (80 mL, 80 mL, and 50 mL). The combined organic phases were distilled to 3 mL / g, then exchanged in acetic acid and distilled to a total volume of 5 mL / g to provide the title compound. [Intermediate substance] [2B] solution. ¹H NMR (400 MHz, DMSO-d 6) δ 12.26 (s, 1H), 2.73 (d, J = 18.5 Hz, 1H), 2.63 (ddd, J = 18.6, 5.3, 2.0 Hz, 1H), 2.17 – 2.01 (m, 2H), 1.34 (dddd, J = 9.2, 7.1, 4.9, 2.0 Hz, 1H), 0.77 (td, J = 4.6, 3.4 Hz, 1H) ppm.

[0290] [(1, R , ,5 , R , , E , )- ] [screw[] [Dual Ring [3.1.0]] [hexane-2,2'-[1,3]] [Dithia] []-3-] [Ketooxime (intermediate 2C)] [) Synthesis:] At 20℃, to [Intermediate substance] [2B] 102 mmol was added to a solution of acetic acid (total volume 55 mL) containing 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 washed with a mixture of 2 parts of 2-propanol (24 mL) and water (6 mL) and dried under vacuum to provide the title compound. [Intermediate substance] [2C]. 1H NMR (400 MHz, DMSO- d 6) δ 10.93 (s, 1H), 3.63 – 3.51 (m, 2H), 3.51 – 3.42 (m, 1H), 3.39 – 3.31 (m, 1H), 2.83 (d, J= 17.4 Hz, 1H), 2.59 – 2.52 (m, 1H), 1.87 (ddd, J= 8.0, 6.2, 3.7 Hz, 1H), 1.65 (dddd, J= 7.7, 6.2, 5.2, 3.9 Hz, 1H), 0.93 (tdd, J= 7.6, 5.5, 1.7 Hz, 1H), 0.02 (dt, J= 5.5, 3.8 Hz, 1H) ppm.

[0291] [(1, R , ,5 , R , )- ] [screw[] [Dual Ring [3.1.0]] [hexane-2,2'-[1,3]] [Dithia] []-3-] [Ketone (intermediate 2D)] Synthesis of [ ):] p-Toluenesulfonic acid (0.90 g) was loaded into a container containing [Intermediate substance] [2C] (2.5 mmol) was added to a container in a suspension of methyl ethyl ketone (2.5 mL) and water (2.5 mL). The mixture was stirred at about 85°C until the reaction was complete. By cooling to about 20°C, water (2.50 mL) was added, and the mixture was cooled to about 0°C to isolate the product from the reaction mixture. The slurry was filtered, and the filter cake was washed with water and then thoroughly deliquored to provide the title compound. [Intermediate substance] [2D]. 1H NMR (400 MHz, DMSO- d 6) δ 3.55 – 3.37 (m, 3H), 3.28 – 3.13 (m, 1H), 3.03 (ddd, J= 18.5, 5.6, 2.2 Hz, 1H), 2.20 (d, J= 18.5 Hz, 1H), 1.84 (ddd, J= 8.0, 7.0, 3.8 Hz, 1H), 1.66 (tdd, J= 7.2, 5.6, 4.1 Hz, 1H), 1.03 (tdd, J= 7.9, 5.9, 2.1 Hz, 1H), 0.06 (dt, J= 6.0, 4.0 Hz, 1H).

[0292] [Diisopropylammonium( , Z , )-2,2,2- ] [trifluoro-1-((1, R , ,5 , S , )-3- ] [Side-oxygen spirochete] [Dual Ring [3.1.0]] [hexane-2,2'-[1,3]] [Dithia] []-4-] [Subunit] [B-1-] [Alkoxide (Intermediate 2)] Synthesis of [ ]: Intermediate 2D] (756 mg) was loaded into a container and dissolved in 2-methyltetrahydrofuran (7.6 mL). Ethyl trifluoroacetate (0.57 g) was added to this mixture, and the reaction was cooled to about 0 °C. Hexamethyldisilamide lithium (4.5 g in 1.0 M solution in THF) was added 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 added, and the reaction was then heated 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 combined organic layers were concentrated and N,N-diisopropylamine (0.5 g) was added. The product was crystallized by adding heptane (11 mL). The reaction was filtered, and the filter cake was washed with heptane, then thoroughly dehydrated and dried to provide the title compound. [Intermediate substance] [2]. 1H NMR (400 MHz, acetonitrile-d 3) δ 7.84 (m, 2H), 3.58 (d, J= 8.7 Hz, 2H), 3.47 – 3.27 (m, 4H), 2.20 (s, 1H), 1.81 – 1.68 (m, 1H), 1.24 (dd, J= 6.5, 0.6 Hz, 12H), 0.99 (q, J= 6.5 Hz, 1H), 0.13 (s, 1H). Intermediate item 3.

[0293] [2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [Ethyl acetate (intermediate 3B)] Synthesis of [ ):] Acetyl chloride (940 mmol) was added to EtOH (324 g) to produce anhydrous HCl in EtOH. 2-Ethylhydrazyl acetate HCl (293 mmol), LiCl (850 mmol), and [ ] were added to the solution. [Intermediate substance] [2] (235 mmol), and EtOH (36 g). The mixture was stirred for 44 h, then concentrated to a volume of 2 mL / g, and then diluted with dichloromethane (1170 g). The mixture was washed with water (450 g), then with a solution of sodium bicarbonate (428 mmol) in water (451 g) and a solution of NaCl (50.7 g) in water (452 ​​g). The organic phase was treated with silicone (45.1 g), filtered, and azeotropically distilled to a volume of 2 mL / g, then diluted with dichloromethane (451 g). Crude [Intermediate substance] [3A] is used in the following steps.

[0294] At –13°C, 70% w / w pyridine hydrogen fluoride (2652 mmol) was added to a mixture of dibromodimethylhydantoin (93.5 mmol) and dichloromethane (170 mL). The resulting mixture was then loaded into crude dichloromethane (50 mL). [Intermediate substance] [3A] (27.4 mmol). After 2.5 h, water (105 mL), sodium metabisulfite (109 mmol) in water (159 g), and 45% KOH solution (128 g) were added to the mixture sequentially. The mixture was heated to 20 °C, and the aqueous phase was separated and discarded. The organic phase was washed with 35% HCl (113 mmol) in water (103 g) and NaCl (5.2 g) in water (105 g). The organic solution was exchanged for 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 min. The mixture was filtered and rinsed with additional EtOH (42 mL) in the forward direction. 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 provide the title compound. [Intermediate substance] [3B]. 1H NMR (400 MHz, DMSO- d 6) δ 5.31 – 5.04 (m, 2H), 4.17 (q, J= 7.1 Hz, 2H), 2.78 – 2.57 (m, 2H), 1.47 (dddd, J= 8.5, 7.1, 5.5, 1.4 Hz, 1H), 1.19 (t, J= 7.1 Hz, 3H), 1.04 (tdt, J= 5.3, 4.0, 1.8 Hz, 1H). 13C NMR (101 MHz, DMSO- d 6) δ 166.79, 143.15 (t, J= 29.4 Hz), 134.65 (q, J= 39.0 Hz), 132.99, 121.05 (q, J= 268.4 Hz), 120.52 (t, J= 243.3 Hz), 62.09, 52.49, 27.95 (dd, J= 34.7, 29.0 Hz), 23.82 (d, J= 2.6 Hz), 14.25, 12.14 (t, J= 3.1 Hz). 19F NMR (376 MHz, DMSO- d 6) δ -60.47, -79.68 (dd, J= 253.5, 13.2 Hz), -103.09 (dd, J= 253.3, 9.8 Hz) ppm.

[0295] [2-((3b , S , ,4a , R , )-5,5- ] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydrogen-1H-] [Circular C[3,4]] [Cyclopentaenoic acid[1,2-c]] [Pyrazole-1-] [base)] [Acetic acid (intermediate 3)] [) of synthesis:] towards [intermediate] [3B] 64.6 mmol was added to a mixture of EtOH (9.3 g) and water (80.3 g), followed by the addition of 130 mmol of 45% KOH and heating the mixture to 50 °C. After 17 h, the solution was added to a mixture of 170 mmol of 35% HCl and 102 g of water. The reaction was filtered, and the filter cake was washed with water (120 g) and dried under vacuum to provide the title compound. [Intermediate substance] [3]. 1H NMR (400 MHz, DMSO- d 6) δ 13.50 (s, 1H), 5.14 – 4.81 (m, 2H), 2.82 – 2.56 (m, 2H), 1.46 (dddd, J= 8.5, 7.1, 5.5, 1.4 Hz, 1H), 1.08 – 1.00 (m, 1H). 13C NMR (101 MHz, DMSO- d 6) δ 168.16, 143.05 (t, J= 29.4 Hz), 134.40 (q, J= 38.9 Hz), 132.80, 121.11 (q, J= 268.4 Hz), 120.55 (t, J= 243.3 Hz), 52.54, 27.97 (dd, J= 34.7, 29.0 Hz), 23.81 (d, J= 2.5 Hz), 12.13 (t, J= 3.1 Hz). 19F NMR (376 MHz, DMSO- d 6) δ -60.39 (d, J= 1.4 Hz), -79.83 (dd, J= 253.2, 13.1 Hz), -102.97 (dd, J= 253.2, 9.8 Hz). Intermediate item 4.

[0296] [4-] [Chloride-7-(4,4,5,5-)] [Tetramethyl-1,3,2-] [Dioxaborane-2-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [Amine (Intermediate 4)] Synthesis of [ ]: Bis(triphenylphosphine)palladium(II) dichloride (0.46 mmol), bis(pinacolyl)diboron (33 mmol), [Intermediate substance] A mixture of [4A] (30.5 mmol), potassium propionate (89.3 mmol), toluene (44 g), and DMF (29 g) was degassed and then heated to 107 °C. After 7 h, the mixture was cooled to 60 °C, 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 diatomaceous earth, and forward 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 forward rinsed with additional EtOAc (80 g). The solution was exchanged for 2-propanol and distilled to a final volume of 4 mL / g. The mixture was diluted with n-heptane (41 g), heated 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 provide the title compound. [Intermediate substance] [4]. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (dd, J = 7.6, 1.0 Hz, 1H), 7.07 (dd, J = 7.6, 1.0 Hz, 1H), 5.58 (s, 2H), 5.46 (q, J = 9.1 Hz, 2H), 1.32 (s, 12h). 5. Intermediate item.

[0297] [( , S , )-1-(3- ] [bromo-6-(3-)] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-2-] [base)-2-(3,5-] [Difluorophenyl] [B-1-] [Amine (Intermediate 5B)] [) of synthesis:] will [Intermediate substance] [1] (35.33 mmol, 1.00 equivalent) [Intermediate substance] A mixture of [5A] (39.7 mmol, 1.12 equivalents), bis(triphenylphosphine)palladium(II) dichloride (0.54 mmol, 0.015 equivalents), and triethylamine (178.7 mmol, 5.06 equivalents) in MeCN (64 g) was heated at 70 °C for 6 h. Water (10.1 g) was added, and the mixture was cooled to 50 °C. N-acetylg-l-cysteine ​​(0.60 g) was added, and the mixture was cooled to RT. 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 substance] [5B]. 1H NMR (400 MHz, DMSO- d 6) δ 8.05 (d, J= 8.2 Hz, 1H), 7.42 (d, J= 8.2 Hz, 1H), 7.01 (tt, J= 9.5, 2.4 Hz, 1H), 6.97 – 6.84 (m, 2H), 4.41 (dd, J= 8.5, 5.2 Hz, 1H), 3.20 (s, 3H), 2.93 (dd, J= 13.3, 5.2 Hz, 1H), 2.79 (dd, J= 13.3, 8.5 Hz, 1H), 1.99 (s, 2H), 1.68 (s, 6H). 13C NMR (101 MHz, DMSO- d 6) δ 162.25, 162.00 (dd, J= 245.2, 13.4 Hz), 143.88 (t, J= 9.4 Hz), 141.09, 139.72, 127.51, 120.08, 112.58 – 112.12 (m), 101.45 (t, J= 25.7 Hz), 87.94, 84.25, 57.24, 55.90, 42.57, 34.99, 22.19.

[0298] [, N , -(( , S , )-1-(3- ] [bromo-6-(3-)] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-2-] [base)-2-(3,5-] [Difluorophenyl] [ethyl)-2-((3b, S , ,4a , R , )-5,5- ] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1, H , - ] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [Acetamide (intermediate 5C)] [) of synthesis:] towards [Intermediate substance] [5B] (43.8 mmol, 1.00 equivalent) [Intermediate substance] [3] A mixture of triethylamine (48.1 mmol, 1.10 equivalents) and MeCN (100 g) in MeCN was mixed with 50% (w / w) T3P / DMF solution (132 mmol, 1.5 equivalents) and stirred for 3 h. DMF (20.1 g) and water (50.1 g) were then added, followed by the title compound. [Intermediate substance] [5C] seed crystals (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 yield the title compound. [Intermediate substance] [5C]. 1H NMR (400 MHz, DMSO- d 6) δ9.19 (d, J= 8.3 Hz, 1H), 8.12 (d, J= 8.3 Hz, 1H), 7.50 (d, J= 8.3 Hz, 1H), 7.07 (tt, J= 9.4, 2.4 Hz, 1H), 6.96 – 6.87 (m, 2H), 5.52 (td), J= 8.8, 5.3 Hz, 1 H), 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 (100 MHz, DMSO-d 6): δ 164.42, 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.

[0299] [, N , -(( , S , )-1-(3-(3- ] [amino-4-] [Chloride-1-(2,2,2-)] [trifluoroethyl)-1H-] [Indazole-7-] [base)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-2-] [base)-2-(3,5-] [Difluorophenyl] [Ethyl)-2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [Acetamide (intermediate 5D)] [) of synthesis:] will [Intermediate substance] [5C] (88.0 mmol, 1.00 equivalent) [Intermediate substance] [4] A mixture of 105 mmol (1.19 equivalents), potassium bicarbonate (266 mmol, 3.03 equivalents), palladium(II) chloride (1.3 mmol, 0.015 equivalents), and cyclohexyldiphenylphosphine (2.7 mmol, 0.030 equivalents) in 2-methyltetrahydrofuran (449 g) and water (130 g) was heated at 70 °C for 15 h, and then cooled to 40 °C. N-acetylglycine (19.5 g), water (202 g), NaOH (6.5 g), and EtOH (48.7 g) were added, and the mixture was stirred for 1 h. The aqueous phase was removed, and the organic phase was washed with a mixture of N-acetylg-l-cysteine ​​(19.5 g), water (429 g), NaOH (6.5 g), and EtOH (48.8 g), followed by washing with 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-exchanged in EtOH and distilled to approximately 4 ml / g. Methanesulfonic acid (39.1 mmol) and the title compound were added. [Intermediate substance] [5D] seed crystals (0.06 g) were added, followed by the addition of 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 yield the title compound. [Intermediate substance] [5D] 1H NMR (400 MHz, DMSO-d 6) δ 9.19 (d, J = 8.3 Hz, 2H), 7.84 – 7.69 (m, 4H), 7.11 (d, J = 7.7 Hz, 2H), 7.07 – 6.95 (m, 3H), 6.82 (d, J = 7.7 Hz, 2H), 6.54 – 6.40 (m, 4H), 4.90 (d, J = 16.4 Hz, 2H), 4.76 – 4.60 (m, 4H), 4.15 (dq, J = 16.6, 8.4 Hz, 2H), 3.75 (dt, J = 16.3, 8.7 Hz, 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 = 2.1 Hz, 13H), 0.93 (dd, J = 6.1, 3.9 Hz, 2H).

[0300] [, N , -(( , S) , -1-(3-(3- ] [amino-4-] [Chloride-1-(2,2,2-)] [Trifluoroethyl)-1, H , - ] [Indazole-7-] [base)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-2-] [base)-2-(3,5-] [Difluorophenyl] [ethyl)-2-((3b, S , ,4a , R , )-5,5- ] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydrogen-1, H , - ] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [Acetamide (intermediate 5E)] [) of synthesis:] will [Intermediate substance] The mixture of [5D] (17.8 mmol, 1.00 equivalent) in 2-methyltetrahydrofuran (181 g) was washed with a solution of sodium carbonate (38 mmol, 2.1 equivalent) 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 equivalent) and sodium chloride (4.0 g) in water (200 g). The organic phase was azeotropically distilled with additional 2-methyltetrahydrofuran, followed by distillation to approximately 3 ml / g. Additional 2-methyltetrahydrofuran (240 g) was added, the temperature was adjusted to 10 °C, and triethylamine (112 mmol, 6.3 equivalent) and methanesulfonyl chloride (52 mmol, 2.9 equivalent) 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 equivalents) in water (60 g) and heated to 35°C. The aqueous phase was discarded, and the organic phase was washed with water (60 g), followed by azeotropic distillation with additional 2-methyltetrahydrofuran, solvent exchanged with EtOH, and distilled to approximately 3 ml / g. Additional EtOH (32 g) was added, 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 give the title compound. [Intermediate substance] [5E]。 1H NMR (400 MHz, DMSO- d 6) δ 9.09 (d, J= 8.0 Hz, 1H), 8.93* (d, J= 8.5 Hz), 7.80 – 7.72* (m), 7.71 (s, 2H), 6.99 (tt, J= 9.5, 2.4 Hz, 1H), 6.94 (d, J= 7.6 Hz, 1H), 6.90* (d, J= 6.3 Hz), 6.69 (d, J= 7.6 Hz, 1H), 6.57 – 6.51* (m), 6.48 – 6.40 (m, 2H), 4.90 (d, J= 16.5 Hz, 1H), 4.77 (d, J= 16.4 Hz, 1H), 4.70 (td, J= 8.3, 5.2 Hz, 1H), 4.63* (d, J= 16.5 Hz), 4.22 (dq, J= 16.7, 8.4 Hz, 1H), 3.90 – 3.75 (m, 1H), 3.26 (s, 3H), 2.92 (td, J= 13.8, 8.5 Hz, 2H), 2.83* (s), 2.80 (s, 3H), 2.64 – 2.51 (m, 2H), 1.74 (d, J= 2.2 Hz, 6H), 1.44 – 1.34 (m, 1H), 0.94 (dq, J= 6.0, 3.7 Hz, 1H); 13C NMR (100 MHz, dmso) δ 164.39, 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 generated by minor transisomers. 13C NMR data for mixtures of transisomers are recorded.

[0301] [, N , -(( , S , )-1-(3-(4- ] [Chloride-3-()] [methylsulfonamide]-1-(2,2,2-) [Trifluoroethyl)-1, H , - ] [Indazole-7-] [base)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-2-] [base)-2-(3,5-] [Difluorophenyl] [ethyl)-2-((3b, S , ,4a , R , )-5,5- ] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1, H , - ] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [Acetamide (Intermediate 5)] [) of synthesis:] will [Intermediate substance] [5E] (1.0 g) and glacial acetic acid (2.1 g) were mixed and stirred at about 20°C until dissolved. The resulting solution was transferred to a reactor containing water (15 g) over about 1 hour. The resulting slurry was further stirred for about 1 hour and filtered. The filter cake was washed with water (2 × 5 g), dehydrated, and dried under vacuum at about 60°C to provide the title compound. [Intermediate substance] [5] It is also known as Linakapavir. ¹H NMR (400 MHz, δ 6-DMSO; 5:1 mixture of resistive isomers) δ 10.11* (s), 10.00 (s, ¹H), 9.25 (d, J = 8.0 Hz, ¹H), 8.92* (d, J = 8.4 Hz), 7.90* (d, J = 7.6 Hz), 7.81 (d, J = 8.0 Hz, ¹H), 7.76 (d, J = 8.0 Hz, ¹H), 7.32 (d, J = 7.6 Hz, ¹H), 7.23* (d, J = 8.0 Hz), 7.19* (d, J = 8.0 Hz), 7.02 (tt, J = 9.4, 2.4 Hz, ¹H), 6.94* (m), 6.86 (d, J= 7.6 Hz, 1 H), 6.54* (m), 6.48 (m, 2 H), 4.92 (d, J= 16.4 Hz, 1 H), 4.77* (d, J= 16.4 Hz), 4.71 (d, J= 16.4 Hz, 1 H), 4.68* (m), 4.51 (dq, J= 16.4, 8.3 Hz, 1 H), 4.19* (dq, J= 16.4, 8.2 Hz), 3.96 (dq, J= 16.8, 8.4 Hz, 1 H), 3.27 (s, 3 H), 3.24* (s), 3.17 (s, 3 H), 3.11* (dd, J= 13.0, 3.4 Hz), 3.02 (dd, J= 13.6, 5.6 Hz, 1 H), 2.95 (dd, J= 13.8, 8.6 Hz, 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); 13C NMR (100 MHz, δ 6-DMSO; a 5:1 mixture of isomers) δ 164.5, 163.4*, 162.1 (dd, J= 246.0, 13.4 Hz), 162.0* (dd, J= 246.1, 13.4 Hz), 158.8, 158.1*, 142.7 (t, J= 29.3 Hz), 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= 38.7 Hz), 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= 268.3 Hz), 119.9 (t, J= 243.4 Hz), 119.0, 118.7*, 117.5*, 117.4, 112.0 (m), 102.1 (t, J= 25.6 Hz), 101.9* (m), 88.5*, 88.4, 84.5, 57.3, 52.8, 52.7, 52.4*, 50.2 (q, J= 33.3 Hz), 50.0 (m), 41.4*, 41.2, 39.8, 38.7, 35.1, 27.5 (dd, J= 35.1, 29.0 Hz), 23.2, 22.4, 22.3, 22.2*, 11.6. . [, * , ] Signals generated by secondary blocking isomers. [Final Example:] Example 1.

[0302] [N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydrogen-1H-] [Circular C[3,4]] [Cyclopentaenoic acid[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-4-] [Methyl-N-()] [Methylsulfonylurea] [Pipeline] [-1-] [Carboxymethylamine (1)] [The synthesis:] Towards [Intermediate substance] [5] A solution containing 0.052 mmol of 4-methylpiperazine was sequentially added to DCM (0.5 mL). -1-carbonyl chloride (0.310 mmol), N,N-diisopropylethylamine (0.155 mmol), and 4-dimethylaminopyridine (0.310 mmol). The reaction mixture was then sealed, heated to 35°C, and stirred for 16 h. After completion, the reaction mixture was concentrated, diluted in DMF, filtered, and purified by reverse-phase HPLC. The fraction containing the product was collected and lyophilized to give the title compound as a mixture of transisomers. [1]. 1H NMR (400 MHz, methanol-d 4 ) δ 9.18 (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). 19F 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.

[0303] [N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-N-(] [Methylsulfonylurea)-[1,4'-] [Bipiperidine]-1'-] [Carboxylamine(2)] [Synthesis:] At 0°C, pyridine (0.155 mmol) and 4-dimethylaminopyridine (1 mg) were added to... [Intermediate substance] [5] (0.052 mmol) was added to a cooled solution in dichloromethane (1 ml). 4-piperidinylpiperidin-1-carbonyl chloride (24 mg 0.1 mmol) was added and the mixture was stirred at room temperature for 2 hours, followed by heating to 38°C overnight. After completion, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (using methanol elution from ethyl acetate) to provide the title compound. [2] A mixture of transtransfer isomers. 1H NMR (400 MHz, methanol-d4) δ 7.78 (d, J = 8.1 Hz), 7.71 (d, J = 8.0 Hz), 7.29 (d, J = 7.6 Hz), 6.76 (tt, J = 9.2, 2.4 Hz), 6.55 (d, J = 7.7 Hz), 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, 8.1 Hz), 2.87 (dd, J = 13.1, 6.6 Hz), 2.64 – 2.15 (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, 3.6 Hz). MS (m / z): 1163.77 [M+H] +. Example 3.

[0304] [N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-2-] [Methyl-N-()] [Methylsulfonylurea] [Benzylamine (3)] [The synthesis:] Towards [Intermediate substance] [5] 0.2 mmol of 2-methylbenzoic acid chloride and 0.62 mmol of N,N-diisopropylethylamine (0.2 mmol) and 4-dimethylaminopyridine (0.2 mmol) were added to a solution of 2-methylbenzoic acid chloride (0.62 mmol) in DCM (3 mL). The reaction mixture was sealed and stirred for 1 hour. After completion, the reaction mixture was concentrated, diluted in DMF, filtered, and purified by reverse-phase HPLC. The fraction containing the product was collected and lyophilized to give the title compound as a mixture of the transisomers. [3]. 1H NMR (400 MHz, CDCl3) δ 7.58 – 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). 19F NMR (377 MHz, 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.

[0305] [N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-N-(] [Methylsulfonylurea] [Nicotinamide)(4)] [Synthesis:] Add to a vial with a stir bar [Intermediate substance] [5] (0.0826 mmol), pyridine-3-carbonyl chloride hydrochloride (0.117 g, 7.95 equivalents), and N,N-diisopropylethylamine (0.160 g, 15 equivalents). Dichloromethane (0.75 mL) was added and the reaction was stirred at 40 °C. After completion, the reaction was concentrated under reduced pressure and purified by reverse-phase HPLC. The fraction containing the product was collected and lyophilized to give the title compound as a mixture of transisomers. [4] 1H NMR (400 MHz, methanol-d 4 ) δ 8.90 (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.

[0306] [3-((4-] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Aya-1-] [Tributyl carboxylate (5)] [The synthesis:] Towards [Intermediate substance] [5] (0.165 mmol), [5A] (0.496 mmol, 3 equivalents) and DMAP (0.496 mmol, 3 equivalents) were added to a solution of DMF (2 mL) with EDC (0.496 mmol, 3 equivalents). After completion, the reaction system was partitioned between EtOAc (10 mL) and 0.1 M HCl (10 mL). The organic fraction was collected, dried over Na₂SO₄ and concentrated under reduced pressure to provide the title compound. A mixture of transisomers of [5B], used without purification. MS (m / z) 1151.55 [M+H]+.

[0307] [N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-N-(] [Methylsulfonylurea] [Aya-3-] [Carboxymethylamine (5)] [The synthesis:] Towards [5B] (0.026 mmol) of TFA (0.2 mL) was added to a solution in DCM (1 mL). When the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by reverse-phase HPLC. The fraction containing the product was collected and lyophilized to provide the title compound as a mixture of inhibited isomers. [5]. 1H NMR (400 MHz, DMSO- d 6 ) δ 9.38 (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. 19F NMR (375 MHz, DMSO- d 6 ) 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.

[0308] [((E)-((] [Tri-butoxycarbonyl] [amino)(3-((4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Aya-1-] [base)] [methylene] [Tributyl carbamate (6A)] [The synthesis:] Towards [5] N,N'-di-Boc-1H-pyrazole-1-formamidin (0.116 mmol) and DIPEA (0.174 mmol) were sequentially added to a solution in MeCN (0.2 mL), and the resulting mixture was stirred for 30 minutes. After completion, the mixture was transferred to a separatory funnel using DCM (20 mL), and the organic layer was continuously washed with 0.1 M HCl (10 mL). The organic fraction was collected, dried over Na₂SO₄, and concentrated under reduced pressure to provide the title compound. [6A], which was used without purification. MS (m / z) 1293.65 [M+H]+.

[0309] [1-] [methamidinyl-N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-N-(] [Methylsulfonylurea] [Aya-3-] [Carboxymethylamine (6)] [The synthesis:] Towards [6A] (0.058 mmol) was added to a solution of trifluoroacetic acid (0.5 mL) in DCM (3 mL). After completion, the reaction was concentrated under reduced pressure and purified by reverse-phase HPLC. The fraction containing the product was collected and lyophilized to give the title compound as a mixture of inhibited isomers. [6]. 1H NMR (400 MHz, DMSO- d 6 ) δ 9.24 (dd), 7.92 (d), 7.85 – 7.77 (m), 7.49 (dd), 7.36 (d), 7.27 (d), 7.01 (ddt), 6.49 (ddd), 5.00 (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. 19F NMR (375 MHz, DMSO- d 6 ) 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.

[0310] [(] [Trans)-3-] [amino-N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-N-(] [Methylsulfonylurea] [Cyclobutane-1-] [Carboxymethylamine (7)] [Synthesis:] Based on the synthesis example 5 [5] The method presented uses trans-1-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid instead of [5A] to prepare a mixture of the transisomers of the title compound. 1H NMR (400 MHz, DMSO- d 6 ) δ 9.65 – 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. 19F NMR (375 MHz, DMSO- d6) δ -60.78 (d), -60.84, -60.94, -69.23 (t), -70.15 (t), -74.29, -79.75 (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.

[0311] [2-(] [Trans-3-((4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclobutyl] [amino)-2- [Glyoxylic acid (8)] [Synthesis of:] At -78℃, to [7] 0.065 mmol of oxalic acid (0.129 mmol, 2 equivalents) was added to a solution in DCM (2 mL), followed by the addition of DIPEA (0.323 mmol, 5 equivalents). After 30 min, the reaction was quenched with an aqueous acetonitrile solution (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. The fraction containing the product was collected and lyophilized to provide the title compound. [8] A mixture of transtransfer isomers. 1H NMR (400 MHz, DMSO- d 6 ) δ 9.65 – 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. 19F NMR (375 MHz, DMSO- d6) δ -60.78 (d), -60.84, -60.94, -69.23 (t), -70.15 (t), -74.29, -79.75 (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.

[0312] [trans-N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-3-] [guanidino-N-() [Methylsulfonylurea] [Cyclobutane-1-] [Carboxylamine (9)] [Synthesis:] Based on the synthesis example 6 [6] The method presented utilizes [7] Replace [5] to prepare a mixture of the title compound’s transisomers. 1H NMR (400 MHz, DMSO- d 6 ) δ 9.26 (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. 19F NMR (375 MHz, DMSO- d 6 ) 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.

[0313] [(1s,3R)-3-] [amino-N-(4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)-N-(] [Methylsulfonylurea] [Cyclobutane-1-] [Carboxylamine (10)] [Synthesis:] Based on the synthesis example 5 [5] The method presented uses cis-3-(tertiary butoxycarbonylamino)cyclobutanecarboxylic acid instead of [5A] to prepare a mixture of the transisomers of the title compound. 1H NMR (400 MHz, methanol-d4) δ 8.99 (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 (dd), 3.04 – 2.92 (m, 1H), 2.73 – 2.41 (m, 3H), 2.33 (q, J = 9.7 Hz, 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.

[0314] [(1R,2S)-2-(] [Hydroxymethyl] [Cyclopropane-1-] [Benzyl carboxylate (11A)] [Synthesis:] At 0 °C, a solution of a borane-dimethyl sulfide complex (10.0 M, 10.9 mL, 2 equivalents) was added dropwise to a solution of (1S,2R)-2-((benzyloxy)carbonyl)cyclopropane-1-carboxylic acid (54.4 mmol) in 105 mL THF. When complete conversion was observed, the reaction was quenched with 20 mL MeOH, concentrated under reduced pressure, and purified by silica gel chromatography. The fraction containing the product was collected and lyophilized to give the title compound. [11A]. 1H NMR (CDCl 3, 400 MHz): δ 7.32 – 7.37 (m, 5H), 5.14 (s, 2H), 3.94 (dd, J = 12 Hz, J = 5.6 Hz, 1H), 3.74 (dd, J = 12 Hz, J = 5.6 Hz, 1H), 2.25 (s, 1H), 1.82 – 1.84 (m, 1H), 1.52 – 1.54 (m, 1H), 1.13 – 1.17 (m, 2H) ppm.

[0315] [(1R,2S)-2-(((] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [methyl)] [Cyclopropane-1-] [Benzyl carboxylate (11B)] [Synthesis:] Add THF and MeCN (4 mL, 3:1 v / v) sequentially to the mixture. [11A] (46.0 mmol), di-tert-butyl-diisopropylphosphonamide (92.1 mmol, 2 equivalents), and 1H-tetrazole (115 mmol, 10.2 mL, 2.5 equivalents). The reaction was stirred at RT until the starting material was completely consumed by LCMS, then cooled to 0°C and 30% hydrogen peroxide solution (115.0 mmol, 4.0 equivalents) was slowly added. The mixture was stirred at 0°C until the reaction was complete, at which point the reaction mixture was transferred to a separatory funnel using 150 mL of EtOAc and washed 3x with saturated sodium thiosulfate solution (90 mL × 3). The organic fraction was dried over sodium sulfate, concentrated, and purified by silica gel chromatography. The fraction containing the product was collected and concentrated under reduced pressure to give the title compound. [11B]. 1H NMR (CDCl 3, 400 MHz) δ 7.35 (m, 5H), 5.15 (dd, J = 26.0 Hz, J = 12.8 Hz 2H), 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]+.

[0316] [(1R,2S)-2-(((] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [methyl)] [Cyclopropane-1-] [Carboxylic acid (11C)] [The synthesis:] will [11B] (2.51 mmol) in 8 mL EtOAc was purged with Ar for 5 min. Pd / C (10% activated carbon-supported Pd, 0.25 mmol, 0.1 equivalent) was then carefully added to the solution. The resulting mixture was then purged with H₂ for 5 min, followed by stirring at 1 atm H₂ for 2 h. After completion, the reaction was diluted with 10 mL EtOAc and purged with Ar for 5 min before filtration through a Celite® filter. The filter cake was washed with 3 × 10 mL EtOAc, and the organic filtrate was concentrated under reduced pressure to give the title compound. [11C]. 1H NMR (CDCl 3, 400 MHz) δ 4.37 – 4.26 (m, 1H), 4.12 (dt, J = 11.1, 8.4 Hz, 1H), 1.93 – 1.71 (m, 2H), 1.50 (s, 18H), 1.19 (ddd, J = 13.0, 7.7, 5.1 Hz, 2H) ppm. MS (m / z) 309.21 [M+H] +.

[0317] [(((1S,2R)-2-((4-] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclopropyl] [Methoxy] [Methyl dihydrogen phosphate (11)] [Synthesis:] Based on the synthesis example 5 [5] The method presented utilizes [11C] replaces [5A] and [Intermediate substance] [5E] replaces [Intermediate substance] [5], to prepare a mixture of the title compound’s transisomers. 1H NMR (400 MHz, DMSO- d 6 ) 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. 19F NMR (375 MHz, DMSO- d 6 ) 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.

[0318] [(1R,2S)-2-((] [benzyloxy] [Carbonyl] [Cyclopropane-1-] [Carboxylic acid (12A)] [Synthesis:] At -55 °C, benzyl alcohol (133 mmol, 3 equivalents) was added dropwise to a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (44.6 mmol) and quinidine (50.4 mmol, 1.13 equivalents) in toluene (230 mL). The resulting mixture was stirred at -55 °C for 96 h, then quenched with 5 mL of water and concentrated under reduced pressure, and partitioned between saturated NaHCO3 (200 mL) and EtOAc (200 mL). The organic fraction was collected, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound. [12A], which was used without purification. ¹H NMR (CDCl 3400 MHz): δ 7.38–7.23 (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.

[0319] [2-((()] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [Methyl)(1S,2R)-] [Cyclopropane-1,2-] [Dicarboxylic acid 1-] [Benzyl ester (12B)] [Synthesis:] Towards [12A] (26.1 mmol) was added sequentially to a solution of Cs₂CO₃ (78.5 mmol, 3 equivalents) and KI (35.3 mmol, 1.35 equivalents) in DMSO (40 mL). Next, di- and tri-butylchloromethyl phosphate was added to the reaction, and the temperature was raised to 40 °C. After completion, the reaction was quenched with 10 mL of water and partitioned between EtOAc (100 mL) and brine (100 mL). The organic fraction was collected, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to provide the title compound. [12B]. 1H NMR (CDCl 3400 MHz): δ 7.37-7.33 (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.

[0320] [(1S,2R)-2-(((()] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [Methoxy] [Carbonyl] [Cyclopropane-1-] [Carboxylic acid (12C)] [Synthesis:] Based on the synthesis example 11 The method presented in [11C] utilizes [12B] Replaces [11B] was used to prepare the title compound.

[0321] [(] [phosphonoyloxy] [Methyl(1R,2S)-2-((4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclopropane-1-] [Carboxylic acid ester (12)] [Synthesis:] Based on the synthesis example 5 [5] The method presented utilizes [12C] replaces [5A] and [Intermediate substance] [5E] replaces [Intermediate substance] [5], to prepare a mixture of the title compound’s transisomers. 1H NMR (400 MHz, DMSO) δ 9.31 – 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 – 2.55 (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). 19F NMR (376 MHz, 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.

[0322] [(1S,3r)-3-((4-] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclobutane-1-] [Carboxylic acid(13)] [Synthesis:] Based on the synthesis example 5 [5] The method presented uses trans-cyclobutane-1,4-dicarboxylic acid instead of [5A] and [Intermediate substance] [5E] replaces [Intermediate substance] [5], to prepare a mixture of the title compound’s transisomers. 1H NMR (400 MHz, DMSO- d 6 ) δ 9.20 (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 – 4.66 (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. 19F NMR (375 MHz, DMSO- d 6 ) δ -58.25 – -63.52 (m), -66.76 – -83.50 (m), -100.32 – -106.48 (m), -110.65 (dt), -219.04 ppm. MS (m / z): 1094.28 [M+H]+. Example 14.

[0323] [((1R,3s)-3-((4-] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclobutane-1-] [Carboxylic acid) (14) [Synthesis:] Based on the synthesis example 5 [5] The method presented uses cis-cyclobutane-1,3-dicarboxylic acid instead of [5A] and [Intermediate substance] [5E] replaces [Intermediate substance] [5], to prepare a mixture of the transisomers of the title compound. ¹H NMR (400 MHz, methanol-d4) δ 8.95 (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.

[0324] [Cipherical-] [Citric -1,3,5-] [pair(] [Tri-butoxycarbonyl] [Cyclohexane-1-] [Carboxylic acid (15A)] [Synthesis:] 2-Tributyl-1,3,5-tricarboxylic acid (2.31 mmol) was added to a solution of cis-cis-cyclohexane-1,3,5-tricarboxylic acid in DCM (5 mL) along with 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 fraction containing the product was collected and concentrated under reduced pressure to give the title compound. [15A]. 1H NMR (400 MHz, CDCl 3) δ 2.55 – 2.35 (m, 1H), 2.35 – 2.14 (m, 5H), 1.62 – 1.47 (m, 3H), 1.45 (s, 18H) ppm.

[0325] [(1R,3S,5r)-5-((4-] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclohexane-1,3-] [Dicarboxylic acid (15)] [Synthesis:] Based on the synthesis example 5 [5] The method presented utilizes [15A] Replace [5A] to prepare a mixture of the transisomers of the title compound. 1H NMR (400 MHz, DMSO- d 6 ) δ 12.15 (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. 19F NMR (375 MHz, DMSO- d 6 ) 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.

[0326] [(1R,2R)-2-(] [Tri-butoxycarbonyl] [Cyclopropane-1-] [Carboxylic acid (16A)] [Synthesis:] 2-Tributyl-1,3-diisopropylurea (1.54 mmol, 1 equivalent) was added to a solution of (1R,2R)-cyclopropane-1,2-dicarboxylic acid (1.54 mmol) in 5 mL DCM. When complete conversion was observed, the reaction was concentrated under reduced pressure and purified by silica gel chromatography. The fraction containing the product was collected and concentrated under reduced pressure to give the title compound. [16A]. 1H NMR (400 MHz, CDCl 3) δ 2.20 – 1.98 (m, 1H), 1.47 (s, 9H), 1.51 – 1.39 (m, 1H), 1.35 – 1.25 (m, 1H), 1.18 (d, J = 6.4 Hz, 1H) ppm.

[0327] [(1R,2R)-2-((4-] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclopropane-1-] [Carboxylic acid(16)] [Synthesis:] Based on the synthesis example 5 [5] The method presented utilizes [16A] Replace [5A] and [Intermediate substance] [5E] replaces [Intermediate substance] [5], to prepare a mixture of the title compound’s transisomers. 1H NMR (400 MHz, DMSO- d 6 ) 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. 19F NMR (375 MHz, DMSO- d 6 ) 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.

[0328] [(1R,2S)-2-((4-] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclopropane-1-] [Carboxylic acid (17)] [Synthesis:] Based on the synthesis example 5 The method presented in [5] uses (1S,2R)-2-(tertiary butoxycarbonyl)cyclopropane-1-carboxylic acid instead of [5A] and [Intermediate substance] [5E] replaces [Intermediate substance] [5], to prepare a mixture of the title compound’s transisomers. 1H NMR (400 MHz, DMSO- d 6) δ 10.01 (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= 16.4 Hz), 4.77 – 4.67 (m), 4.67 – 4.44 (m), 4.08 – 3.88 (m), 2.04 – 1.95 (m), 1.76 – 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.

[0329] [1-((4-] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclopropane-1-] [Carboxylic acid (18)] [Synthesis:] Based on the synthesis example 5 The method presented in [5] uses 1-(tert-butoxycarbonyl)cyclopropane-1-carboxylic acid instead of [5A] and [Intermediate substance] [5E] replaces [Intermediate substance] [5], to prepare a mixture of the title compound’s transisomers. 1H NMR (400 MHz, DMSO- d 6 ) δ 9.25 – 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. 19F NMR (375 MHz, DMSO- d 6 ) 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.

[0330] [2-((] [benzyloxy] [Carbonyl] [benzoic acid (19A)] [Synthesis:] BnBr (21.2 mmol, 1.1 equivalent) was added to a solution of phthalic acid (19.3 mmol) and DIPEA (23.1 mmol, 1.2 equivalents) in 8 mL of DMF, and the mixture was stirred at rt. When complete conversion was observed, the reaction mixture was transferred to a separatory funnel using Et₂O (250 mL) and 5% LiCl solution (100 mL). The organic layer was further extracted with 5% LiCl solution (2 × 100 mL), collected, dried over Na₂SO₄, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound. [19A]. MS (m / z): 257.30 [M+H]+.

[0331] [((()] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [methyl)] [Benzyl phthalate (19B)] [The synthesis:] Towards [19A] (5.46 mmol) and potassium bicarbonate (6.56 mmol, 1.2 equivalents) were added to a mixture of di-tert-butyl chloromethyl phosphate (7.10 mmol, 1.3 equivalents) in 6.5 mL of DMF, and the mixture was heated to 40 °C. After the reaction was complete, the contents were transferred to a separatory funnel using Et₂O (100 mL) and 5% LiCl solution (50 mL). The organic layer was further extracted with 5% LiCl solution (3 × 50 mL), collected, dried over Na₂SO₄, 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] +.

[0332] [2-((()] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [Methoxy] [Carbonyl] [benzoic acid (19C)] [Synthesis:] Based on the synthesis example 11 The method presented in [11C] utilizes [19B] instead [11B] to prepare the title compound. ¹H NMR (400 MHz, DMSO-d 6 ) δ ¹H NMR (400 MHz, Chloroform-d) δ 7.88 – 7.75 (m, 2H), 7.64 – 7.51 (m, 2H), 5.83 (d, J = 14.8 Hz, 2H), 1.53 (s, 18H) ppm.

[0333] [(()] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [Methyl 2-((4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Benzoester (19D)] [The synthesis:] Towards [19C] (0.74 mmol) and [Intermediate substance] [5E] (0.59 mmol, 1.2 equivalents) was added to a mixture in MeCN (3.5 mL) with 1-methylimidazole (1.0 mmol, 2.1 equivalents). After stirring for 2 min, TCFH (0.51 mmol, 1.05 equivalents) was added in a single fraction. The reaction was then concentrated under reduced pressure and purified by reverse-phase HPLC. The fractions containing the product were collected and lyophilized to give the title compound as a mixture of transisomers. [19D]. MS (m / z) 1360.30 [M+Na] +.

[0334] [(] [phosphonoyloxy] [Methyl 2-((4-)] [Chloride-7-(2-((S)-1-(2-((3bS,4aR)-5,5-] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Phenylate (19)] [The synthesis:] Towards [19D] (0.492 mmol) was added to 5 mL of DCM solution with 0.38 mL of TFA. When complete conversion was observed, the reaction was concentrated under reduced pressure and purified by reverse-phase HPLC. The fraction containing the product was collected and lyophilized to give the title compound as a mixture of the inhibited isomers.

[19] . 1H NMR (400 MHz, DMSO- d 6 ) δ 9.22 – 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. 19F NMR (375 MHz, DMSO- d 6 ) 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, -110.79 ppm. MS (m / z) 1225.30 [M+H]+. Example 20.

[0335] [(1S,2R)-2-(((] [Methylsulfonylurea] [Oxygen group] [methyl)] [Cyclopropane-1-] [Benzyl carboxylate (20A)] [Synthesis:] A solution of (1S,2R)-2-(hydroxymethyl)cyclopropane-1-carboxylic acid benzyl ester (6.24 mmol) and triethylamine (12.5 mmol) in DCM (50.0 mL) was cooled to 0 °C. Methylsulfonyl chloride (9.36 mmol) was added, and the reaction was stirred at 0 °C for 90 min. The reaction was quenched at 0 °C with 1N HCl, diluted with water, and extracted with DCM (3x). The combined organic layers were washed with saturated NaHCO3 (aq) and brine, dried over MgSO4, filtered, and concentrated. The crude material was diluted with EtOAc and concentrated (repeated 2x) to remove residual DCM, placed under high vacuum for 48 h, and used without further purification to provide the title compound. [20A]. 1H NMR (400 MHz, DMSO- d 6) δ 7.45 – 7.27 (m, 5H), 5.21 – 5.05 (m, 2H), 4.55 (dd, J= 10.7, 6.1 Hz, 1H), 4.20 (dd, J= 10.7, 9.4 Hz, 1H), 3.09 (d, J= 0.9 Hz, 3H), 1.99 (td, J= 8.1, 5.7 Hz, 1H), 1.87-1.73 (m, 1H), 1.30-1.22 (m, 1H), 1.09-1.00 (m, 1H) ppm.

[0336] [(1, S , ,2 , R , )-2-( ] [Azidemethyl] [Cyclopropane-1-] [Benzyl carboxylate (20B)] [The synthesis:] will A solution of [20A] (5.48 mmol) and sodium azide (8.77 mmol) in DMF (25.0 mL) was heated at 60 °C for 2 hours. The reaction mixture was diluted with water (200 mL) and extracted with 25% EtOAc / hexane (3x). The combined organic layers were washed with 5% LiCl (aq), dried over MgSO4, filtered, and concentrated to provide [20B], which was used without further purification. ¹H NMR (400 MHz, DMSO-d6) δ 7.45 – 7.29 (m, 5H), 5.19 – 5.04 (m, 2H), 3.64 (dd, J= 13.1, 5.9 Hz, 1H), 3.43 – 3.34 (m, 1H), 1.94 (td, J= 8.2, 5.5 Hz, 1H), 1.71 (dt, J= 9.3, 6.7 Hz, 1H), 1.22 (td, J= 8.2, 4.5 Hz, 1H), 1.03 – 0.92 (m, 1H) ppm.

[0337] [(1, S , ,2 , R , )-2-( ] [aminomethyl] [Cyclopropane-1-] [Benzyl carboxylate (20C)] [The synthesis:] Towards [20B] (5.24 mmol) was added to a solution of triphenylphosphine (8.38 mmol) in THF (20.0 mL), followed by the addition of water (2.00 mL). The reaction was stirred at RT for 18 hours, concentrated, diluted with 1N HCl (10 mL), and extracted with diethyl ether (3x). The aqueous layer was concentrated and lyophilized to provide the HCl salt. [20C]. The title compound was used without further purification. MS (m / z) [M+H] +205.98.

[0338] [(1, S , ,2 , R , )-2-(((( ] [Chloromethoxy] [Carbonyl] [Amine group] [methyl)] [Cyclopropane-1-] [Benzyl carboxylate (20D)] [Synthesis:] To present HCl salts [20C] (2.85 mmol) was added to a solution of triethylamine (9.96 mmol) in DCM (14.0 mL). The solution was cooled to 0°C, and methyl chloroformate (3.70 mmol) was added dropwise. The reaction was gradually heated to RT and stirred for 2 hours. The reaction was quenched with saturated NH4Cl (aq) and extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to provide the title compound. [20D], which was used without purification. MS (m / z) 319.91 [M+Na]+.

[0339] [(1, S , ,2 , R , )-2-(((((( ] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [Methoxy] [Carbonyl] [Amine group] [methyl)] [Cyclopropane-1-] [Benzyl carboxylate (20E)] [The synthesis:] Towards [20D] Tetrabutylammonium di-tertiary phosphate (4.84 mmol) was added to a solution of DME (10.0 mL). The reaction was heated at 80 °C for 2 hours. The reaction was concentrated, diluted with EtOAc, washed with water (2x) and brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel chromatography to provide the title compound. [20E]. MS (m / z)493.95) [M+Na] +.

[0340] [(1, S , ,2 , R , )-2-(((((( ] [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [Methoxy] [Carbonyl] [Amine group] [methyl)] [Cyclopropane-1-] [Carboxylic acid (20F)] [Synthesis:] Purge with nitrogen / vacuum (3x) A solution of [20E] (0.878 mmol) in EtOH (10.0 mL) was added. Palladium on carbon (10%, 0.176 mmol) was added and the reaction was purged with nitrogen / vacuum (3x). The flask was equipped with a hydrogen balloon, and the reaction was purged with hydrogen / vacuum (3x) and stirred at RT and 1 atm for 1 h. The reaction was purged with nitrogen, filtered through diatomaceous earth and concentrated to provide the title compound. [20F], which was used without further purification. MS (m / z) 403.93 [M+Na]+.

[0341] [(] [phosphonoyloxy] [methyl(((1 , R , ,2 , S , )-2-((4- ] [Chloride-7-(2-((S)-1-(2-((3b , S , ,4a , R , )-5,5- ] [Difluoro-3-() [trifluoromethyl)-3b,4,4a,5-] [Tetrahydro-1H-] [Cyclopropionate[3,4]] [Cyclopenta[1,2-c]] [Pyrazole-1-] [base)] [acetamino)-2-(3,5-] [Difluorophenyl] [Ethyl)-6-(3-] [Methyl-3-() [Methylsulfonylurea] [Ding-1-] [Alkyne-1-] [base)] [Pyridine-3-] [base)-1-(2,2,2-] [trifluoroethyl)-1H-] [Indazole-3-] [base)(] [Methylsulfonylurea] [Aminomethyl] [Cyclopropyl] [methyl)] [Carbamate (20)] [Synthesis:] Based on the synthesis example 19 The method presented in

[19] utilizes [20F] Replace [19C] to prepare a mixture of transisomers of the title compound. 1H NMR (400 MHz, DMSO- d 6) 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). 19F NMR (376 MHz, DMSO- d 6) 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). 31P NMR (162 MHz, DMSO- d 6) δ -2.86 (t), -3.39 (t). MS (m / z) 1219.20 [M+H]+. Example 21.

[0342] [2-((()] [Tri-butoxycarbonyl] [Amine group] [methyl)] [Methyl benzoate (21A)] [Synthesis:] Triethylamine (35.2 mmol) was added to an ice-cold solution of (2-methoxycarbonylphenyl)methylammonium chloride (32.0 mmol) and di-tributyl dicarbonate (35.2 mmol) in DCM (168 mL). The reaction mixture was sealed, allowed to reach room temperature, and stirred for 1 hour. After completion, the reaction mixture 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 fraction was collected, dried over Na₂SO₄, concentrated, and purified by silica gel chromatography. The fraction containing the product was collected and concentrated to yield the title compound. [21A]. MS (m / z): 288.20 [M+Na] +.

[0343] [(2-()] [Hydroxymethyl] [Benzyl) [Tributyl carbamate (21B)] [The synthesis:] Towards [21A] (28 mmol) was added to a solution of 2M lithium borohydride (89 mmol) in THF (61 mL). The reaction mixture was sealed, heated to 50 °C, and stirred for 16 hours. After completion, the reaction mixture was cooled to 0 °C and quenched with water (60 mL), saturated NH4Cl (20 mL), and water (350 mL). The solution was transferred to a separatory funnel and extracted 3x with EtOAc (100 mL). The organic fraction was collected, dried over Na2SO4, concentrated, and purified by silica gel chromatography. The fraction containing the product was collected and concentrated to yield the title compound. [21B]. MS (m / z): 260.20 [M+Na] +.

[0344] [(2-(()] [allyloxy] [methyl)] [Benzyl) [Tributyl carbamate (21C)] [Synthesis:] Add DMF (10 mL) to an ice-cold flask containing sodium hydride (9.7 mmol). Stir the mixture at room temperature for 15 minutes, then cool it back to 0°C. [21B] (9.3 mmol) was added to the reaction. The reaction mixture was sealed, allowed to reach room temperature, and stirred for 1 hour. Then, allyl bromide (10 mmol) was added to the reaction. After completion, the reaction was quenched with water (10 mL) and saturated NH4Cl (10 mL). The solution was transferred to a separating funnel containing EtOAc (100 mL) and water (100 mL), and the aqueous layer was extracted with EtOAc (100 mL). The organic fraction was collected, washed with water (100 mL), 5% wt / v LiCl (50 mL), and saturated NaCl (50 mL), dried over Na2SO4, concentrated, and purified by silica gel chromatography. The fraction containing the product was collected and concentrated to yield the title compound. [21C]. MS (m / z): 300.20 [M+Na] +.

[0345] [[2-(] [allyloxymethyl) [Phenyl] [Methylammonium chloride (21D)] [Synthesis:] Add to the flask [21C] (4.0 mmol), DCM (20 mL), and in two 4M HCl in 10 mL of alkane. The reaction mixture was sealed and stirred for 1 hour. After completion, the reaction mixture was concentrated, dissolved in MeCN, and lyophilized to provide the title compound. [21D]. MS (m / z): 178.20 [M+H]+.

[0346] [3-[[2-(] [allyloxymethyl) [Phenyl] [Methylamino] [Tributyl propionate (21E)] [The synthesis:] Towards [21D] (6.7 mmol) and triethylamine (7.35 mmol) in a solution of MeOH (13 mL) were mixed with 587 µL of tributyl acrylate. The reaction was sealed and stirred for 16 hours. After completion, the reaction was concentrated and dissolved in EtOAc (70 mL). The solution was transferred to a separatory funnel and washed twice with saturated NaHCO3 (35 mL). The organic fraction was collected, dried over Na2SO4, concentrated, and purified by silica gel chromatography. The fraction containing the product was collected and concentrated to yield the title compound. [21E]. MS (m / z): 306.30 [M+H]+.

[0347] [3-((2-(()] [allyloxy] [methyl)] [benzyl)(((()) [two-] [Tri-butoxyphosphatidyl] [Oxygen group] [Methoxy] [Carbonyl] [Amine group] [Tributyl propionate (21F)] [Synthesis:] Based on the synthesis example 20 The method presented in [20E] utilizes [21E] Replace The title compound was prepared by [20C]. MS (m / z): 594.30 [M+Na]+.

[0348] [3-[] [di- and tertiary butoxyphosphatoxymethoxycarbonyl-[[2-( [Hydroxymethyl] [Phenyl] [methyl]] [Amine group] [Tributyl propionate (21g)] [Synthesis:] Tetra(triphenylphosphine)palladium (0) was added to a solution purged with argon gas containing tributyl 3-[[2-(allyloxymethyl)phenyl]methyl-(di-tert-butoxyphosphatoxymethoxycarbonyl)amino]propionate (1.24 mmol), 1,3-dimethylbarbituric acid (2.48 mmol), and MeOH (3.7 mL). The reaction mixture was sealed, heated to 40 °C, and stirred for 1 hour. After completion, the reaction mixture was concentrated and purified by silica gel chromatography. The fraction containing the product was collected and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.39 (t, 1H), 7.31 – 7.18 (m, 3H), 5.64 (t, 2H), 4.73 – 4.67 (m, 4H), 3.51 (t, 2H), 2.47 (t, 2H), 2.14 (s, 1H), 1.49 (d, 18H), 1.42 (s, 9H).

[0349] [3-[] [di- and tertiary butoxyphosphatoxymethoxycarbonyl-[(2-]] [methoxyphenyl] [methyl]] [Amine group] [Tributyl propionate (21H)] [The synthesis:] Towards Add 80% sodium chlorite (0.70 mmol) and 8% sodium hypochlorite (0.564 mmol) solution to a solution of [21G] (0.47 mmol), TEMPO (0.10 mmol), 0.2 M KH₂PO₄ (2.3 mL), and MeCN (2.3 mL). Seal and stir the reaction mixture for 1 hour. After completion, cool the reaction mixture to 0 °C and quench it with saturated Na₂SO₃ (2.3 mL). Transfer the solution to a separatory funnel containing water (10 mL) and extract 3x with EtOAc (20 mL). Collect the organic fraction, dry it with Na₂SO₄, and concentrate it to yield the title compound. [21H]. MS (m / z): 552.30 [M+Na] +.

[0350] [2-[[(3-)] [Tri-butoxy-3-] [Side group-] [propyl)-( [Di- and Tri-butoxyphosphatoxymethoxycarbonyl] [Amine group] [methyl]] [benzoic acid (21I)] [The synthesis:] Towards 80% sodium chlorite (0.91 mmol) was added to an ice-cold solution of [21H] (0.453 mmol), 30% H₂O₂ (0.68 mmol), KH₂PO₄ (0.18 mmol), and 1:1 water / MeCN (2 mL). The reaction mixture was sealed, allowed to reach room temperature, and stirred for 1 hour. After completion, the reaction was cooled to 0 °C, quenched with saturated Na₂SO₃ (2 mL), and acidified with 1 M HCl (4 mL). The solution was transferred to a separatory funnel and extract...

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein X is a C3-7 monocyclic cycloalkyl group, a 4- to 7-membered monocyclic heterocyclic group, a phenyl group, or a pyridyl group, wherein the C3-7 monocyclic cycloalkyl group and the 4- to 7-membered monocyclic heterocyclic group are each optionally substituted by 1 to 2 R1 groups, and wherein the phenyl group is optionally substituted by 1 R1 group; each R1 group is independently -CN, halogen, Ra, Rb, Rc, C1-6 alkyl group, or a 4- to 7-membered monocyclic heterocyclic group, wherein the C1-6 alkyl group is optionally substituted by 1 to 3 groups independently selected from -CN, halogen, Ra, Rb, Rc, -SR2, and =NR2a, wherein the 4- to 7-membered monocyclic heterocyclic group is optionally substituted by 1 to 3 groups independently selected from -CN, halogen, Ra, Rb, and Rc; each Ra group is independently -P(O)(OH)2 or -OP(O)(OH)2; Each Rb is independently -C(O)R2, -C(O)OR2, -C(O)NR3R3, -C(O)C(O)OR2, -S(O)2R2, -S(O)2NR3R3 or -S(O)2OR3; Each Rc is independently -OR2, -OC(O)R2, -OC(O)C(O)OR2, -NR3R3, -N+R3R3R3a, -NR3C(O)R2, -NR3C(O)NR3R3, -NR3C(O)OR2, -NR3C(O)C(O)OR2 or -NR3S(O)2R2; Each R2 is independently H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by 1 to 3 groups independently selected from -CN, halogen, Ra, Rd and Re; Each R2a is independently H or C1-3 alkyl; Each R3 is independently H, -C(O)OR4, or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted by 1 to 3 groups independently selected from -CN, halogen, Ra, Rd, Re, and =NR3a; each R3a is independently H or C1-3 alkyl; each Rd is independently -C(O)R4, -C(O)OR4, -C(O)NR4R4, -C(O)C(O)OR4, -S(O)2R4, -S(O)2NR4R4, or -S(O)2OR4; Each Re is independently of -OR4, -OC(O)R4, -OC(O)C(O)OR4, -NR4R4, -N+R4R4R4a, -NR4C(O)R4, -NR4C(O)NR4R4, -NR4C(O)OR4, -NR4C(O)C(O)OR4 or -NR4S(O)2R4; each R4 is independently of H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted by 1 to 3 groups independently selected from -OH, CN, halogen, -COOH and Ra; wherein each 4-membered monocyclic heterocyclic group has 1 cyclic heteroatom selected from N, O and S; wherein each 5 to 7-membered monocyclic heterocyclic group has 1 to 2 cyclic heteroatoms independently selected from N, O and S;Furthermore, each of the 5 to 6 monocyclic heteroaryl groups and the 8 to 10 fused bicyclic heteroaryl groups independently possesses 1 to 4 cyclic heteroatoms independently selected from N, O, and S.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R1 is independently -CN, halogen, Ra, Rb, Rc, C1-6 alkyl or 4 to 7-membered monocyclic heterocyclic group, wherein the C1-6 alkyl group is optionally substituted by 1 to 3 groups independently selected from -CN, halogen, Ra, Rb, Rc, -SR2 and =NR2a, wherein the 4 to 7-membered monocyclic heterocyclic group is optionally substituted by 1 to 3 groups independently selected from -CN, halogen, Ra, Rb and Rc; each Ra is independently -P(O)(OH)2 or -OP(O)(OH)2; each Rb is independently -C(O)R2, -C(O)OR2, -C(O)NR3R3, -C(O)C(O)OR2, -S(O)2R2, -S(O)2NR3R3 or -S(O)2OR3; Each Rc is independently -OR2, -OC(O)R2, -OC(O)C(O)OR2, -NR3R3, -N+R3R3R3a, -NR3C(O)R2, -NR3C(O)NR3R3, -NR3C(O)OR2, -NR3C(O)C(O)OR2 or -NR3S(O)2R2; each R2 is independently H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OH and Ra; each R2a is independently H or C1-3 alkyl; Each R3 is independently H, -C(O)OR4, or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted with 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra, and =NR3a; each R3a is independently H or C1-3 alkyl; each R4 is independently H or C1-6 alkyl, wherein the C1-6 alkyl group is optionally substituted with 1 to 3 groups independently selected from -OH, CN, halogen, -COOH, and Ra; each 4-membered monocyclic heterocyclic group has 1 heteroatom selected from N, O, and S; each 5 to 7-membered monocyclic heterocyclic group has 1 to 2 heteroatoms independently selected from N, O, and S; and each 5 to 6-membered monocyclic heteroaryl and 8 to 10-membered fused bicyclic heteroaryl independently has 1 to 4 heteroatoms independently selected from N, O, and S.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R1 is independently -OH, -CN, halogen, -C(O)OR2, -NR3R3, -NR3C(O)C(O)OR2, Ra, C1-6 alkyl or 4 to 7 member monocyclic heterocyclic group, wherein the C1-6 alkyl group is optionally substituted by 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR3R3, -NR3C(O)OR2, Ra, -SR2 and =NR2a, wherein the 4 to 7 member monocyclic heterocyclic group is optionally substituted by 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OH and Ra; each Ra is independently -P(O)(OH)2 or -OP(O)(OH)2; Each R2 is independently H or C1-4 alkyl, wherein the C1-4 alkyl group is optionally substituted by 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OH and Ra; each R2a is independently H or C1-3 alkyl; each R3 is independently H, -C(O)OR4 or C1-4 alkyl, wherein the C1-4 alkyl group is optionally substituted by 1 to 3 groups independently selected from -OH, -CN, halogen, -C(O)OR4, -NR4R4, Ra and =NR3a; each R3a is independently H or C1-3 alkyl; each R4 is independently H or C1-3 alkyl, wherein the C1-3 alkyl group is optionally substituted by 1 to 3 groups independently selected from -OH, CN, halogen, -COOH and Ra; wherein each 4-membered monocyclic heterocyclic group has 1 cyclic heteroatom selected from N, O and S; Each of the 5 to 7 member monocyclic heterocyclic groups has 1 to 2 independently selected cyclic heteroatoms chosen from N, O and S; and each of the 5 to 6 member monocyclic heteroaryl groups and the 8 to 10 member fused bicyclic heteroaryl groups has 1 to 4 independently selected cyclic heteroatoms chosen from N, O and S.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a C3-7 monocyclic cycloalkyl group, wherein the C3-7 monocyclic cycloalkyl group is optionally substituted with one or two R1 groups.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a 4- to 7-membered monocyclic heterocyclic group, wherein the 4- to 7-membered monocyclic heterocyclic group is optionally substituted with 1 to 2 R1 groups.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a phenyl group, wherein the phenyl group is optionally substituted with one R1 group.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a pyridyl group.

8. A salt acceptable for use in the compound or medicine of claim 1, wherein one of R1 is -OH, -NH2, -C(O)OR2, -NR3R3 or -NR3C(O)C(O)OR2.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein one of R1 is a C1-6 alkyl group, wherein the C1-6 alkyl group is optionally substituted with one to three groups independently selected from -OH, -CN, halogen, -C(O)OH, -NR3R3, -NR3C(O)OR2, Ra, -SR2 and =NH.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein one of R1 is a 5- or 6-membered monocyclic heterocyclic group, wherein the 5- or 6-membered monocyclic heterocyclic group is optionally substituted by one or two independently selected groups selected from -OH, -C(O)OH and Ra.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R2 is independently H or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by one or two independently selected groups selected from -C(O)OH and Ra.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R3 is independently H, -C(O)OR4, or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with a group selected from -OH, -C(O)OH, -NR4R4, Ra, and =NR3a.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R4 is independently H or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by one or two independently selected groups selected from -C(O)OH and Ra.

14. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , and.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , and.

16. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of: , , , and.

17. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 16 of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17 further comprises one, two, three or four additional therapeutic agents.

19. Use of a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of human immunodeficiency virus (HIV) infection.

20. Use of any compound of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating human immunodeficiency virus (HIV) infection in heavily treated patients.

21. The use of any of claims 19 to 20, wherein the drug further comprises one, two, three or four additional therapeutic agents or pharmaceutically acceptable salts thereof, or is used in combination with one, two, three or four additional therapeutic agents or pharmaceutically acceptable salts thereof.

22. As requested in paragraph 21, wherein the one, two, three or four additional therapeutic agents are selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, and immunotherapy or any combination thereof.

23. As claimed in paragraph 21, wherein the one, two, three, or four additional therapeutic agents are selected from the group consisting of: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors, cell therapy, latency reversal agents, 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 regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modifiers, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef regulators, TNFα ligand inhibitors, HIV Nef inhibitors, Hck tyrosine kinase regulators, mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, IFN antagonists, countercyclic protein regulators, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, CDK-9 inhibitors, cytochrome P450 3 inhibitors, CXCR4 regulators, dendritic ICAM-3 non-integrin 1 capture inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein regulators, RNA polymerase regulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and anti-HIV peptides or any combination thereof.

24. As claimed in paragraph 21, wherein the one, two, three, or four additional therapeutic agents are selected from the group consisting of: gene editors selected from CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, and TALEN; and cell therapies selected from chimeric antigen receptor T cells (CAR-T), engineered T cell receptors (TCR-T), autologous T cell therapy, engineered B cells, and NK cells.

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