Tetracyclic compounds for the treatment of HIV infection

Abstract

The present disclosure as a whole relates to certain tetracyclic compounds, pharmaceutical compositions comprising the compounds, and methods for preparing the compounds and pharmaceutical compositions. The compounds of the present disclosure can be used to treat or prevent human immunodeficiency virus (HIV) infection. (Formula (I))

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefits of U.S. Provisional Application No. 62 / 980,857, filed February 24, 2020; U.S. Provisional Application No. 63 / 036,268, filed June 8, 2020; and U.S. Provisional Application No. 63 / 128,670, filed December 21, 2020. The entire contents of these applications are incorporated herein by reference. Technical Field

[0003] This disclosure relates in its entirety to certain tetracyclic compounds, pharmaceutical compositions comprising said compounds, and methods for preparing and using said compounds and pharmaceutical compositions. Background Technology

[0004] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. HIV encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown effectiveness, especially when used in combination, toxicity and the development of drug-resistant strains may limit their usefulness (Palella et al., N. Engl. J Med. (1998) 338:853–860; Richman, DDNature (2001) 410:995–1001). Therefore, new agents to inhibit HIV replication are needed.

[0005] One goal of antiretroviral therapy is to achieve viral suppression in patients with HIV infection. Current treatment guidelines from the U.S. Department of Health and Human Services state that achieving viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Website: https: / / files.aidsinfo.nih.gov / contentfiles / lvguidelines / AdultandAdolescentGL.pdf. Accessed February 20, 2020). Furthermore, decisions regarding the treatment of HIV-infected patients are complex when they require treatment for other medical conditions. Because the standard of care requires the use of multiple different drugs to suppress HIV, as well as to treat other conditions the patient may be experiencing, the possibility of drug interactions is a criterion for selecting a drug regimen. Therefore, there is a need for antiretroviral therapies with a reduced likelihood of drug interactions.

[0006] In addition, HIV is known to mutate in infected subjects (Tang et al., Drugs (2012) 72(9)e1-e25). Due to the mutability of HIV, there is a need for anti-HIV drugs that are effective against a range of known HIV variants (Hurt et al., HIV / AIDS CID (2014) 58, 423-431).

[0007] For some patients, such as those with limited or difficulty accessing healthcare, adherence to daily oral treatment or preventative regimens can be challenging. Medications offering favorable pharmaceutical properties (e.g., improved potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) can reduce dosing frequency and provide better patient compliance. Such improvements can, in turn, optimize drug exposure and limit the development of resistance. Summary of the Invention

[0008] In one respect, this article provides a compound of formula I:

[0009]

[0010] Or its pharmaceutically acceptable salt, wherein

[0011] R1 For H, C 6-10 Aryl or C 6-10 heteroaryl, wherein the C 6-10 Aryl or C 6-10 Heteroaryl groups are selectively bound by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 alkyl;

[0012] Y is selected from the following groups: –C(O)NH–,

[0013] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CR 3a R 3b –CR 3c R 3d –or–N(R) a )–;

[0014] W 1 For chemical bonds or –CR 4a R 4b –;

[0015] W 2 For –CR 5a R 5b –、–CR 5a R 5b CR 5c R 5d –、–CR 6a =CR 6b –、–N(R 7 )–、–O–、–S(O) n –、–C(O)NR e –、–CR 5a R 5b –N(R 7 )–、–CR 5a R 5b –O–、–CR 5a R 5b –S(O) n –、-CR 5a R 5b –C(O)NRe –、–CR 5a R 5b –NR e –C(O)–、 –S(O) n N(R e )–CR 5a R 5b –or–N(R) e )–S(O) n –CR 5a R 5b –;

[0016] X represents a chemical bond or –CR 8a R 8b –;

[0017] Z is –CR 9a R 9b –、–CR 9a R 9b CR 9c R 9d –or–CR 10a =CR 10b –;

[0018] T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d And U is –NR 11 –、–CR 12a R 12b –、–S(O) n –, –C(O)– or –O–; or T and U together are

[0019] R 2a R 2b R 2c R 2d R 12a and R 12b Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(Ra )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a -;or

[0020] (i)R 2a and R 2b (ii)R 2c and R 2d Or (iii)R 12a and R 12b Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0021] R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or

[0022] (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally surrounded by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0023] R 4a R 4b R 5a R 5bR 5c R 5d R 8a R 8b R 9a R 9b R 9c and R 9d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl; or

[0024] (i)R 4a and R 4b (ii)R 5a and R 5b (iii)R 5c and R 5d (iv)R 5a and R 5c (v)R 5b and R 5d 、(vi)R 8a and R 8b (vii)R 9a and R 9b (viii)R 9c and R 9d 、(ix)R 9a and R 9c 、(x)R 9b and R 9d 、(xi)R 8b and R 5a R 5b R 5c R 5d and R 7 One of them or (xii)R 9a R 9b R 9c and R 9d One of them and R 4a R 4b R 5a R 5b and R 7 Any one of these, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C3-6 cycloalkyl or –OR e ;

[0025] Each R 6a R 6b R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0026] (i)R 6a and R 6b Or (ii)R 10a and R 10b Any of the following, together with the carbon atoms to which they are attached, forms (i) a 5- to 10-membered carbon ring, (ii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (iii) a 6- to 10-membered aromatic ring, or (iv) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring, the 5- to 10-membered heterocycle, the 6- to 10-membered aromatic ring, or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A4 Replace, where each R A4 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0027] R 7 For H, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R c or SO2R c ;

[0028] R 11 For H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, –C(O)–R a –S(O) n –R a –CH2–R a ;

[0029] Each R a Independently for (i)H, (ii)C 1-6 Alkyl, (iii)C 3-6Cycloalkyl, (iv) 5 to 10-membered carbon ring, (v) 5 to 10-membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S, (vi) 6 to 10-membered aromatic ring or (iv) 5 to 10-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0030] Wherein C 1-6 Alkyl, C 3-6 The cycloalkyl, 5- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, 6- to 10-membered aromatic, or 5- to 10-membered heteroaromatic rings are optionally substituted by 0 to 4 substituents, said substituents being independently selected from the group consisting of: (i) oxo, (ii) halogen, (iii) cyano, (iv) –O–C 1-4 Alkyl, (v)C 1-6 Alkyl, (vi)–OR e (vii) a 3- to 10-membered carbon ring, (viii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (ix) a 6- to 10-membered aromatic ring, or (x) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S; wherein the 3- to 10-membered carbon ring, 5- to 10-membered heterocycle, 6- to 10-membered aromatic ring, or 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A5 Replace, where each R A5 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0031] R b For H, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 cycloalkyl;

[0032] R f H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0033] Each R c Independently for H and C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R d Or –SO2R d ;

[0034] Each R d Independently C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, –NRe 2 or –OR e ;

[0035] Each R e H and C independently 1-4 Alkyl or C 3-6 cycloalkyl, wherein each C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with a halogen or cyano group; and

[0036] Each n can be 0, 1, or 2.

[0037] In another embodiment, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0038] In another embodiment, this disclosure provides a kit containing a compound of the disclosure or a pharmaceutically acceptable salt thereof, along with instructions for use.

[0039] In another embodiment, this disclosure provides a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method comprises administering to the person a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0040] In another embodiment, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for treating HIV infection in persons who have or are at risk of HIV infection.

[0041] In another aspect, this disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for use in medical therapies.

[0042] In another embodiment, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for the treatment of HIV infection.

[0043] In another aspect, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of a medicament for treating HIV infection in a person who has or is at risk of HIV infection. Detailed Implementation

[0044] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein can be practiced without these details. Several embodiments are described below with the understanding that this disclosure is intended to be illustrative of the claimed subject matter and not to limit the appended claims to the specific embodiments shown. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments exemplified under any heading may be combined with embodiments exemplified under any other heading.

[0045] I. Definition

[0046] Unless the context otherwise requires, throughout this disclosure and the claims, the word “comprising” and its variations such as “including” and “containing” shall be interpreted in an open, inclusive sense, that is, as “including but not limited to”.

[0047] Throughout this specification, the phrase "an embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment disclosed herein. Therefore, the phrases "in an embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner.

[0048] "Amino" refers to the -NH2 group.

[0049] "Hydroxy group" refers to the -OH group.

[0050] "O-substituent" refers to the =O substituent.

[0051] Prefixes such as "C" u-v "or (C u -C v The ) 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.

[0052] "Alkyl" refers to a straight-chain or branched hydrocarbon group composed of carbon and hydrogen atoms. This group is saturated and has one to twelve carbon atoms (C1 to C2). 1-12 Alkyl groups, in some embodiments having one to eight carbon atoms (C64- ... 1-8 Alkyl groups or one to six carbon atoms (C 1-6 Alkyl groups or one to four carbon atoms (C46- ... 1-4Alkyl group, which is attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, etc.

[0053] "Alkylene" refers to a saturated, branched, straight-chain, or cyclic hydrocarbon group having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, alkylenes can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), and 1,4-butyl (-CH2CH2CH2CH2-).

[0054] "Aryl" or "aromatic ring" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings comprising a fused system (e.g., bicyclic or tricyclic). As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C24 carbon atoms). 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group or 6 to 10 carbon ring atoms (i.e., C46) 6-10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl does not cover heteroaryl groups as defined below or overlap with them in any way.

[0055] "Cyano" or "formonitrile" refers to the -CN group.

[0056] "Cycloalkyl" or "carbocyclic" refers to a saturated or partially saturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C14 carbon atoms). 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12) 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C145-C ... 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C14 and C24) 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Halocycloalkyl" refers to a cycloalkyl group that has been substituted with one or more halogens.

[0057] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine.

[0058] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted by one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0059] "Heteroaryl" or "heteroary ring" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryls include 5 to 20 ring atoms (5 to 20-membered heteroaryl rings), 5 to 12 ring atoms (5 to 12-membered heteroaryl rings), 5 to 10 ring atoms (5 to 10-membered heteroaryl rings), or 5 to 6 ring atoms (5 to 6-membered heteroaryl rings); and 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryls do not encompass aryl groups as defined above or overlap with them.

[0060] "Heterocyclic group" or "heterocycle" refers to a non-aromatic group or ring having three to fifteen atoms, wherein one to six atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur and are attached to the remainder of the molecule by single bonds. In some embodiments, the "heterocyclic group" has three to ten atoms, wherein one to four atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or has three to seven atoms, wherein one to two atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized. As used herein, unless otherwise specified, "heterocyclic group" or "heterocycle" refers to a saturated ring, for example, in some embodiments, "heterocyclic group" or "heterocycle" refers to a saturated or partially saturated ring in specified cases. Examples of such heterocyclic groups include, but are not limited to, dioxolane, imidazoalkyl, isothiazolyl, and isothiazoalkyl. azolealkyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidylalkyl Azolyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, trithiacyclohexyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.

[0061] The embodiments disclosed herein are also intended to cover all pharmaceutically acceptable compounds of Formula I that are isotopically labeled having one or more atoms replaced by atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. In some embodiments, these radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or pattern of action or binding affinity to a pharmacologically important site of action. Certain isotope-labeled compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb (e.g., those doped with a radioisotope) can be used for drug and / or substrate tissue distribution studies. The radioisotope tritium (i.e.... 3 H) and carbon-14 (i.e. 14 C) They are particularly suitable for this purpose because they are easy to incorporate and easy to detect.

[0062] In some implementations, heavier isotopes such as deuterium (i.e., 2 H) substitution may offer certain therapeutic advantages due to its greater metabolic stability. For example, it may increase the half-life in vivo or reduce the dosage requirement. Therefore, in some cases, heavier isotopes may be preferred.

[0063] Using positron emission isotopes such as 11 C 18 F, 15 O and 13N-substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb can be prepared using techniques known to those skilled in the art or through processes similar to those described in the examples set forth below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0064] The methods, compositions, kits, and articles provided herein use or include compounds (e.g., compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb) or pharmaceutically acceptable salts thereof, wherein one to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds increase resistance to metabolism and are therefore used to increase the half-life of the compound or its pharmaceutically acceptable salt when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0065] The embodiments disclosed herein are also intended to cover in vivo metabolites of the disclosed compounds. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to the embodiments disclosed herein to a mammal for a period sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound according to the embodiments disclosed herein to an animal (such as a rat, mouse, guinea pig, monkey, or human) at a detectable dose, allowing sufficient time for metabolism and isolating its metabolites from urine, blood, or other biological samples.

[0066] “Mammals” include humans as well as livestock (such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits)) and non-livestock (such as wild animals).

[0067] The terms "optional" or "optionally" mean that the event or situation subsequently described may or may not occur, and the description includes instances where said event or situation occurs and instances where said event or situation does not occur. For example, "optionally substituted heterocyclic group" means that the heterocyclic group may or may not be substituted, and the description includes substituted heterocyclic groups and unsubstituted heterocyclic groups.

[0068] "Pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substance formulated in combination with the pharmacologically active ingredient of the pharmaceutical composition and compatible with other components of the formulation and suitable for human or animal use without undue toxicity, irritation, allergic reactions, etc.

[0069] Examples of pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX4. + (where X is C) 1-4 Salts of alkyl groups. Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, salts of the following: organic carboxylic acids, such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphate, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, ethanesulfonic acid, lactobionic acid, nicotinic acid, oxalic acid, dihydroxynaphthyl acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, pentanoic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and aminosulfonic acid. Pharmaceutically acceptable salts of compounds with hydroxyl groups include the anion of the compound with a suitable cation such as Na+. + and NX4 + (where X is independently selected from H or C) 1-4 Combinations of alkyl groups.

[0070] For therapeutic use, salts of the active ingredients of the compounds disclosed herein will generally be pharmaceutically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be used, for example, to prepare or purify compounds of Formula I or other compounds of the embodiments disclosed herein. All salts (whether or not derived from physiologically acceptable acids or bases) are within the scope of the embodiments disclosed herein.

[0071] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to the embodiments disclosed herein. An example of a metal salt prepared in this manner is one containing Li. + Na + and K + Salts with low solubility can be precipitated from solutions of salts with high solubility by adding a suitable metal compound.

[0072] Additionally, salts can be formed by the addition of certain organic and inorganic acids (e.g., HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids) to an acid with a basic center (typically an amine). Finally, it should be understood that the compositions herein comprise both unionized and zwitterionic forms of the compounds disclosed herein.

[0073] "Pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). Such a medium includes all pharmaceutically acceptable excipients.

[0074] "Effective amount" or "therapeutic effective amount" means an amount of a compound according to the embodiments disclosed herein that is sufficient to treat the disease state, symptom, or disorder disclosed herein when administered to a patient in need. Such an amount would be sufficient to elicit a biological or medical response in the tissue system or in the patient as sought by the researcher or clinician. The amount of a compound according to the embodiments disclosed herein that constitutes a therapeutically effective amount will vary depending on factors such as: the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the excretion rate of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, the drugs used in combination with or concurrently with the compound according to the embodiments disclosed herein, and the patient's age, weight, general health condition, sex, and diet. Such a therapeutically effective amount can be determined by someone skilled in the art after taking into account their own knowledge, prior art, and the content of this disclosure.

[0075] As used herein, the term "treatment" is intended to mean the administration of a compound or composition according to embodiments of the invention disclosed herein to alleviate or eliminate one or more symptoms of HIV infection and / or reduce the viral load in a patient. In some embodiments, the term "treatment" also encompasses the administration of a compound or composition according to embodiments of the invention disclosed herein after an individual's exposure to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood, to prevent the onset of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to embodiments of the invention disclosed herein to prevent perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the infant in the first few days of life. The term "treatment" also encompasses the administration of a compound or composition according to embodiments of the invention disclosed herein (also known as pre-exposure prophylaxis or PrEP) before an individual's exposure to the virus to prevent HIV infection from taking hold and / or to prevent the establishment of permanent infection and / or to prevent the onset of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood. The term "treatment" also covers the administration of compounds or compositions according to embodiments of the invention disclosed herein, both before and after an individual's exposure to a virus.

[0076] As used herein, the term "prevention" refers to the administration of a compound, composition, or pharmaceutically acceptable salt according to this disclosure before or after exposure to a virus, but before the onset of disease symptoms and / or before the virus is detected in the blood. The term also refers to prevention of the onset of disease symptoms and / or prevention of the virus reaching detectable levels in the blood. The term includes pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and event-driven or "on-demand" prophylaxis. The term also refers to prevention of perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the infant during the first few days of life. The term also refers to prevention of HIV transmission via blood transfusion.

[0077] As used herein, the term "antiviral agent" is intended to mean an agent (compound or biological agent) that effectively inhibits the formation and / or replication of a virus in humans, including but not limited to agents that interfere with the host or viral mechanisms necessary for the formation and / or replication of a virus in humans.

[0078] As used in this article, the term "HIV replication inhibitor" is intended to refer to agents that can reduce or eliminate HIV replication in host cells, whether in vitro, ex vivo, or in vivo.

[0079] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers as well as their racemic, non-racemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomers are also intended to be included.

[0080] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other. In any embodiment disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

[0081] "Partially unsaturated" refers to a cyclic group containing at least one double bond but not an aromatic group.

[0082] II.Compounds

[0083] This article discloses compounds of formula I:

[0084]

[0085] Or its pharmaceutically acceptable salt, wherein

[0086] R 1 For H, C 6-10 Aryl or C 6-10 heteroaryl, wherein the C 6-10 Aryl or C 6-10 Heteroaryl groups are selectively bound by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkyl–O–C 1-4alkyl;

[0087] Y is selected from the following groups: –C(O)NH–,

[0088] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CR 3a R 3b –CR 3c R 3d –or–N(R) a )–;

[0089] W 1 For chemical bonds or –CR 4a R 4b –;

[0090] W 2 For –CR 5a R 5b –、–CR 5a R 5b CR 5c R 5d –、–CR 6a =CR 6b –、–N(R 7 )–、–O–、–S(O) n –、–C(O)NR e –、–CR 5a R 5b –N(R 7 )–、–CR 5a R 5b –O–、–CR 5a R 5b –S(O) n –、-CR 5a R 5b –C(O)NR e –or–CR 5a R 5b –NR e –C(O)–、–S(O) n N(R e )–CR 5a R 5b –、–N(R e )–S(O) n –CR 5a R 5b –、–N(R e )–C(O)–CR 5a R 5b –or–CR 5a R 5b–NR e –C(O)–;

[0091] X represents a chemical bond or –CR 8a R 8b –;

[0092] Z is –CR 9a R 9b –、–CR 9a R 9b CR 9c R 9d –or–CR 10a =CR 10b –;

[0093] T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d And U is –NR 11 –、–CR 12a R 12b –、–S(O) n –、–C(O)– or –O–; or T and U together are

[0094] R 2a R 2b R 2c R 2d R 12a and R 12b H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a -;or

[0095] (i)R 2a and R 2b (ii)R 2c and R 2d Or (iii)R 12a and R 12b Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0096] R 3a and R 3b H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or

[0097] (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally surrounded by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0098] R 4a R 4b R 5a R 5b R 5c R 5d R 8a R 8b R 9a R 9b R 9c and R 9d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4Alkylene –O–C 1-4 Alkyl; or

[0099] (i)R 4a and R 4b (ii)R 5a and R 5b (iii)R 5c and R 5d (iv)R 5a and R 5c (v)R 5b and R 5d 、(vi)R 8a and R 8b (vii)R 9a and R 9b (viii)R 9c and R 9d 、(ix)R 9a and R 9c 、(x)R 9b and R 9d 、(xi)R 8b , and R 5a R 5b R 5c R 5d and R 7 One of them or (xii)R 9a R 9b R 9c and R 9d One of them and R 4a R 4b R 5a R 5b and R 7 Any one of these, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing 0 or 2 heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0100] Each R 6a R 6b R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0101] (i)R 6aand R 6b Or (ii)R 10a and R 10b Any of the following, together with the carbon atoms to which they are attached, forms (i) a 5- to 10-membered carbon ring, (ii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (iii) a 6- to 10-membered aromatic ring, or (iv) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring, the 5- to 10-membered heterocycle, the 6- to 10-membered aromatic ring, or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A4 Replace, where each R A4 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0102] R 7 For H, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R c or SO2R c ;

[0103] R 11 For H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, –C(O)–R a –S(O) n –R a –CH2–R a ;

[0104] Each R a Independently for (i)H, (ii)C 1-6 Alkyl, (iii)C 3-6 (iv) a cycloalkyl group, (v) a 5- to 10-membered carbon ring, (v) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (vi) a 6- to 10-membered aromatic ring, or (iv) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S; wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, 5- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, 6- to 10-membered aromatic, or 5- to 10-membered heteroaromatic rings are optionally substituted by 0 to 4 substituents, said substituents being independently selected from the group consisting of: (i) oxo, (ii) halogen, (iii) cyano, (iv) –O–C 1-4 Alkyl, (v)C 1-6Alkyl, (vi)–OR e (vii) a 3- to 10-membered carbon ring, (viii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (ix) a 6- to 10-membered aromatic ring, or (x) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S; wherein the 3- to 10-membered carbon ring, 5- to 10-membered heterocycle, 6- to 10-membered aromatic ring, or 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A5 Replace, where each R A5 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0105] R b For H, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 cycloalkyl;

[0106] R f H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0107] Each R c Independently for H and C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R d Or –SO2R d ;

[0108] Each R d Independently C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, –NR e 2 or –OR e ;

[0109] Each R e Independently for H and C 1-4 Alkyl or C 3-6 cycloalkyl, wherein each C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with a halogen or cyano group; and

[0110] Each n can be 0, 1, or 2.

[0111] In some embodiments of the compound of formula I, R 1 For H, C 6-10 Aryl or C6-10 heteroaryl, wherein the C 6-10 Aryl or C 6-10 Heteroaryl groups are selectively bound by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 alkyl;

[0112] Y is selected from the following groups: –C(O)NH–,

[0113] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CR 3a R 3b –CR 3c R 3d –or–N(R) a )–;

[0114] W 1 For chemical bonds or –CR 4a R 4b –;

[0115] W 2 For –CR 5a R 5b –、–CR 5a R 5b CR 5c R 5d –、–CR 6a =CR 6b –、–N(R 7 )–、–O–、–S(O) n –、–C(O)NR e –、–CR 5a R 5b –N(R 7 )–、–CR 5a R 5b –O–、–CR 5a R 5b –S(O) n –、-CR 5a R 5b –C(O)NR e –、–CR 5a R 5b –NRe –C(O)–、–S(O) n N(R e )–CR 5a R 5b –or–N(R) e )–S(O) n –CR 5a R 5b –;

[0116] X represents a chemical bond or –CR 8a R 8b –;

[0117] Z is –CR 9a R 9b –、–CR 9a R 9b CR 9c R 9d –or–CR 10a =CR 10b –;

[0118] T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d U is –NR 11 –、–CR 12a R 12b –、–S(O) n –、–C(O)– or –O–; or T and U together are

[0119] R 2a R 2b R 2c R 2d R 12a and R 12b H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a–、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a -;or

[0120] (i)R 2a and R 2b (ii)R 2c and R 2d Or (iii)R 12a and R 12b Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0121] R 3a R 3b R 3c and R 3d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 alkyl;

[0122] R 4a R 4b R 5a R 5b R 5c R 5d R 8a R 8b R 9a R 9b R 9c and R 9d H and C independently 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 alkyl;

[0123] Each R 6a R 6b R10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0124] R 7 For H, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R c or SO2R c ;

[0125] R 11 For H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, –C(O)–R a –S(O) n –R a –CH2–R a ;

[0126] Each R a Independently for (i)H, (ii)C 1-6 Alkyl, (iii)C 3-6 Cycloalkyl, (iv) 5 to 10-membered carbon ring, (v) 5 to 10-membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S, (vi) 6 to 10-membered aromatic ring or (iv) 5 to 10-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0127] Wherein C 1-6 Alkyl, C 3-6 The cycloalkyl, 5- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, 6- to 10-membered aromatic, or 5- to 10-membered heteroaromatic rings are optionally substituted by 0 to 4 substituents, said substituents being independently selected from the group consisting of: (i) oxo, (ii) halogen, (iii) cyano, (iv) –O–C 1-4 Alkyl, (v)C 1-6 Alkyl, (vi)–OR e (vii) a 3- to 10-membered carbon ring, (viii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (ix) a 6- to 10-membered aromatic ring, or (x) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S; wherein the 3- to 10-membered carbon ring, 5- to 10-membered heterocycle, 6- to 10-membered aromatic ring, or 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A5 Replace, where each R A5 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group.1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0128] R b For H, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 cycloalkyl;

[0129] R f H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0130] Each R c Independently for H and C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R d Or –SO2R d ;

[0131] Each R d Independently C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, –NR e 2 or –OR e ;

[0132] Each R e Independently for H and C 1-4 Alkyl or C 3-6 cycloalkyl, wherein each C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with a halogen or cyano group; and

[0133] Each n can be 0, 1, or 2.

[0134] In some embodiments of the compound of formula I:

[0135] R 1 For H, C 6-10 Aryl or C 6-10 heteroaryl, wherein the C 6-10 Aryl or C 6-10 Heteroaryl groups are selectively bound by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 alkyl;

[0136] Y is selected from the following groups: –C(O)NH–,

[0137] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CR 3a R 3b –CR 3c R 3d –or–N(R) a )–;

[0138] W 1 For chemical bonds or –CR 4a R 4b –;

[0139] W 2 For –CR 5a R 5b –、–CR 5a R 5b CR 5c R 5d –、–CR 6a =CR 6b –、–N(R 7 )–、–O–、–S(O) n –、–C(O)NR e –、–CR 5a R 5b –N(R 7 )–、–CR 5a R 5b –O–、–CR 5a R 5b –S(O) n –、-CR 5a R 5b –C(O)NR e –、–CR 5a R 5b –NR e –C(O)–、–S(O) n N(R e )–CR 5a R 5b –or–N(R) e )–S(O) n –CR 5a R 5b –;

[0140] X represents a chemical bond or –CR 8a R 8b –;

[0141] Z is –CR 9a R 9b –、–CR 9a R 9b CR 9c R 9d –or–CR 10a =CR 10b –;

[0142] T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d U is –NR 11 –、–CR 12a R 12b –、–S(O) n –, –C(O)– or –O–; or T and U together are

[0143] R 2a R 2b R 2c R 2d R 12a and R 12b Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –;

[0144] R 3a R 3bR 3c and R 3d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or

[0145] (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally surrounded by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0146] R 4a R 4b R 5a R 5b R 5c R 5d R 8a R 8b R 9a R 9b R 9c and R 9d H and C independently 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 alkyl;

[0147] Each R 6a R 6b R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0148] R 7 For H, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R c or SO2Rc ;

[0149] R 11 For H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, –C(O)–R a –S(O) n –R a –CH2–R a ;

[0150] Each R a Independently for (i)H, (ii)C 1-6 Alkyl, (iii)C 3-6 Cycloalkyl, (iv) 5 to 10-membered carbon ring, (v) 5 to 10-membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S, (vi) 6 to 10-membered aromatic ring or (iv) 5 to 10-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0151] Wherein C 1-6 Alkyl, C 3-6 The cycloalkyl, 5- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, 6- to 10-membered aromatic, or 5- to 10-membered heteroaromatic rings are optionally substituted by 0 to 4 substituents, said substituents being independently selected from the group consisting of: (i) oxo, (ii) halogen, (iii) cyano, (iv) –O–C 1-4 Alkyl, (v)C 1-6 Alkyl, (vi)–OR e (vii) a 3- to 10-membered carbon ring, (viii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (ix) a 6- to 10-membered aromatic ring, or (x) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S; wherein the 3- to 10-membered carbon ring, 5- to 10-membered heterocycle, 6- to 10-membered aromatic ring, or 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A5 Replace, where each R A5 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0152] R b For H, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 cycloalkyl;

[0153] R f H, halogen, C 1-4 Alkyl or C1-4 alkyl halide;

[0154] Each R c H and C independently 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R d Or –SO2R d ;

[0155] Each R d Independently for C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, –NR e 2 or –OR e ;

[0156] Each R e H and C independently 1-4 Alkyl or C 3-6 cycloalkyl, wherein each C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with a halogen or cyano group; and

[0157] Each n can be 0, 1, or 2.

[0158] In some embodiments of the compound of formula I:

[0159] R 1 For H, C 6-10 Aryl or C 6-10 heteroaryl, wherein the C 6-10 Aryl or C 6-10 Heteroaryl groups are selectively bound by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 alkyl;

[0160] Y is selected from the following groups: –C(O)NH–,

[0161] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CR3a R 3b –CR 3c R 3d – or –N(R a )–;

[0162] W 1 is a chemical bond or –CR 4a R 4b –;

[0163] W 2 is –CR 5a R 5b –, –CR 5a R 5b CR 5c R 5d –, –CR 6a =CR 6b –, –N(R 7 )–, –O–, –S(O) n –, –C(O)NR e –, –CR 5a R 5b –N(R 7 )–, –CR 5a R 5b –O–, –CR 5a R 5b –S(O) n –, -CR 5a R 5b –C(O)NR e –, –CR 5a R 5b –NR e –C(O)–, –S(O) n N(R e )–CR 5a R 5b – or –N(R e )–S(O) n –CR 5a R 5b –;

[0164] X is a chemical bond or –CR 8a R 8b –;

[0165] Z is –CR 9a R 9b –, –CR 9a R 9b CR 9c R 9d – or –CR 10a =CR 10b –;

[0166] T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d U is –NR 11 –、–CR 12a R 12b –、–S(O) n –、–C(O)– or –O–; or T and U together are

[0167] R 2a R 2b R 2c R 2d R 12a and R 12b H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a -;or

[0168] R 3a R 3b R 3c and R 3d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or

[0169] R 4a R 4b R 5a R 5b R 5c R 5dR 8a R 8b R 9a R 9b R 9c and R 9d H and C independently 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl; or

[0170] (i)R 4a and R 4b (ii)R 5a and R 5b (iii)R 5c and R 5d (iv)R 5a and R 5c (v)R 5b and R 5d 、(vi)R 8a and R 8b (vii)R 9a and R 9b (viii)R 9c and R 9d 、(ix)R 9a and R 9c 、(x)R 9b and R 9d 、(xi)R 8b and R 5a R 5b R 5c R 5d and R 7 One of them or (xii)R 9a R 9b R 9c and R 9d One of them and R 4a R 4b R 5a R 5b and R 7 Any one of these, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6Alkyl, C 3-6 cycloalkyl or –OR e ;

[0171] Each R 6a R 6b R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl;

[0172] R 7 For H, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R c or SO2R c ;

[0173] R 11 For H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, –C(O)–R a –S(O) n –R a –CH2–R a ;

[0174] Each R a Independently for (i)H, (ii)C 1-6 Alkyl, (iii)C 3-6 Cycloalkyl, (iv) 5 to 10-membered carbon ring, (v) 5 to 10-membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S, (vi) 6 to 10-membered aromatic ring or (iv) 5 to 10-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0175] Wherein C 1-6 Alkyl, C 3-6 The cycloalkyl, 5- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, 6- to 10-membered aromatic, or 5- to 10-membered heteroaromatic rings are optionally substituted by 0 to 4 substituents, said substituents being independently selected from the group consisting of: (i) oxo, (ii) halogen, (iii) cyano, (iv) –O–C 1-4 Alkyl, (v)C 1-6 Alkyl, (vi)–OR e(vii) a 3- to 10-membered carbon ring, (viii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (ix) a 6- to 10-membered aromatic ring, or (x) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S; wherein the 3- to 10-membered carbon ring, 5- to 10-membered heterocycle, 6- to 10-membered aromatic ring, or 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A5 Replace, where each R A5 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0176] R b For H, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 Cycloalkyl;

[0177] R f H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0178] Each R c H and C independently 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R d Or –SO2R d ;

[0179] Each R d Independently for C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, –NR e 2 or –OR e ;

[0180] Each R e H and C independently 1-4 Alkyl or C 3-6 cycloalkyl, wherein each C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with a halogen or cyano group; and

[0181] Each n can be 0, 1, or 2.

[0182] In some embodiments of the compound of formula I:

[0183] R 1 For H, C 6-10 Aryl or C6-10 heteroaryl, wherein the C 6-10 Aryl or C 6-10 Heteroaryl groups are selectively bound by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 alkyl;

[0184] Y is selected from the following groups: –C(O)NH–,

[0185] L is –CR 3a R 3b –, –C(O)–, –SO2–, –CR 3a R 3b –CR 3c R 3d –or–N(R) a )–;

[0186] W 1 For chemical bonds or –CR 4a R 4b –;

[0187] W 2 For –CR 5a R 5b –、–CR 5a R 5b CR 5c R 5d –、–CR 6a =CR 6b –、–N(R 7 )–、–O–、–S(O) n –、–C(O)NR e –、–CR 5a R 5b –N(R 7 )–、–CR 5a R 5b –O–、–CR 5a R 5b –S(O) n –、-CR 5a R 5b –C(O)NR e –、–CR 5a R 5b –NRe –C(O)–、–S(O) n N(R e )–CR 5a R 5b –or–N(R) e )–S(O) n –CR 5a R 5b –;

[0188] X represents a chemical bond or –CR 8a R 8b –;

[0189] Z is –CR 9a R 9b –、–CR 9a R 9b CR 9c R 9d –or–CR 10a =CR 10b –;

[0190] T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d U is –NR 11 –、–CR 12a R 12b –、–S(O) n –、–C(O)– or –O–; or T and U together are

[0191] R 2a R 2b R 2c R 2d R 12a and R 12b H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a–、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –;

[0192] R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 alkyl;

[0193] R 4a R 4b R 5a R 5b R 5c R 5d R 8a R 8b R 9a R 9b R 9c and R 9d Independently for H and C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 alkyl;

[0194] Each R 6a R 6b R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0195] (i)R 6a and R 6b Or (ii)R 10a and R 10bAny of the following, together with the carbon atoms to which they are attached, forms (i) a 5- to 10-membered carbon ring, (ii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (iii) a 6- to 10-membered aromatic ring, or (iv) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring, the 5- to 10-membered heterocycle, the 6- to 10-membered aromatic ring, or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A4 Replace, where each R A4 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0196] R 7 For H, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R c or SO2R c ;

[0197] R 11 For H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, –C(O)–R a –S(O) n –R a –CH2–R a ;

[0198] Each R a Independently for (i)H, (ii)C 1-6 Alkyl, (iii)C 3-6 Cycloalkyl, (iv) 5 to 10-membered carbon ring, (v) 5 to 10-membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S, (vi) 6 to 10-membered aromatic ring or (iv) 5 to 10-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0199] Wherein C 1-6 Alkyl, C 3-6 The cycloalkyl, 5- to 10-membered carbocyclic, 5- to 10-membered heterocyclic, 6- to 10-membered aromatic, or 5- to 10-membered heteroaromatic rings are optionally substituted by 0 to 4 substituents, said substituents being independently selected from the group consisting of: (i) oxo, (ii) halogen, (iii) cyano, (iv) –O–C 1-4 Alkyl, (v)C 1-6 Alkyl, (vi)–OR e(vii) a 3- to 10-membered carbon ring, (viii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (ix) a 6- to 10-membered aromatic ring, or (x) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S; wherein the 3- to 10-membered carbon ring, 5- to 10-membered heterocycle, 6- to 10-membered aromatic ring, or 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A5 Replace, where each R A5 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e ;

[0200] R b For H, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 Cycloalkyl;

[0201] R f H, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0202] Each R c H and C independently 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C(O)R d Or –SO2R d ;

[0203] Each R d Independently for C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, –NR e 2 or –OR e ;

[0204] Each R e H and C independently 1-4 Alkyl or C 3-6 cycloalkyl, wherein each C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with a halogen or cyano group; and

[0205] Each n can be 0, 1, or 2.

[0206] In some embodiments, the compound of formula I is the same as the compound of formula Ia:

[0207]

[0208] In some embodiments, the compound of formula I is a compound of formula Ib:

[0209]

[0210] In some embodiments of compounds of formula I, Ia, or Ib, Y is selected from the group consisting of: –C(O)NH–,

[0211] In some embodiments of compounds of formula I, Ia, or Ib, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementation schemes, Y is In some implementations, for compounds of formula I, Ia, or Ib, Y is –CONH–.

[0212] In some embodiments, the compound of formula I is the compound of formula II:

[0213]

[0214] In some embodiments, the compound of formula I, Ia, or II is a compound of formula IIa:

[0215]

[0216] In some embodiments, the compound of formula I, Ib, or II is a compound of formula IIb:

[0217]

[0218] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or (i)R 2a and R 2b Or (ii)R 2c and R 2d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0219] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R2b R 2c and R 2d H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or (i)R 2a and R 2b Or (ii)R 2c and R 2d Any of the atoms in the group, together with the carbon atoms to which they are attached, forms a 3- to 7-membered carbon ring, wherein the 3- to 7-membered carbon ring is optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0220] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2ORa –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or (i)R 2a and R 2b Or (ii)R 2c and R 2d Any of the atoms in the group, together with the carbon atoms to which they are attached, forms a 3- to 5-membered carbon ring, wherein the 3- to 5-membered carbon ring is optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0221] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)Ra –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or (i)R 2a and R 2b Or (ii)R 2c and R 2d Any of the atoms in the group, together with the carbon atoms to which they are attached, forms a ternary carbon ring, wherein the ternary carbon ring is optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0222] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or (i)R 2a and R2b Or (ii)R 2c and R 2d Any one of them, together with the carbon atoms to which they are attached, forms a ternary carbon ring.

[0223] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or (i)R 2a and R 2b Or (ii)R 2c and R 2d Any of the following, together with the carbon atoms to which they are attached, forms a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycle is optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0224] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –. In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a – or – NR e –C(O)R a –. In some implementations, T is –CR2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2OR a or –OR a In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, or cyano. In some embodiments, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R2d H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or C 3-6 Halogenated cycloalkyl. In some embodiments, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ; where each R 2a R 2b R 2c and R 2d H and C independently 1-6 Alkyl or C 3-6 Cycloalkyl.

[0225] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d ;where R 2a R 2b R 2c and R 2d H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –OR a Or –NHR a In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, T is –CR2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl or halogenated. In some embodiments, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently, it can be H or a halogen group. In some embodiments, T is –CR. 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently H, –C(O)–NH(R) a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a –、–S(O) n –R a –or –O–C(O)–NHR a In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d H and –OR independently a –NHR a–C(O)–NH(R) a ), –NR e –C(O)R a Or –NR e –S(O) n R a In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d H and –OR independently a Or –O–C(O)–NHR a In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently for H, –S(O) n –NH(R a ) or –S(O) n –R a –. In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently H, halogen, cyano, –NHR a –or –OR a In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently for H or –NHR a In some implementations, T is –CR 2a R2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently H, halo, cyano, or –OR a In some implementations, T is –CR 2a R 2b –or–CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d It can be either an H or a cyano group.

[0226] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0227] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3 to 7-membered carbon rings, wherein the 3 to 7-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0228] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2bTogether with the carbon atoms to which they are attached, they form 3- to 5-membered carbon rings, wherein the 3- to 5-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0229] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2b Together with the carbon to which they are attached, they form 3 to 5-membered carbon rings, wherein the 3 to 5-membered carbon rings are...

[0230] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2b Together with the carbon atoms to which they are attached, they form 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0231] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2b Together with the carbon atoms to which they are attached, they form 4- to 5-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 4- to 5-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0232] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2b Together with the carbon atoms to which they are attached, they form 4- to 5-membered heterocycles containing one or two heteroatoms selected from N, O, and S.

[0233] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2b H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –OR a Or –NHR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently for H, C1 -6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl or halogenated. In some embodiments, T is –CR 2a R 2b –, where R 2a and R 2b H and C independently 1-6 Alkyl, C 3-6 Cycloalkyl or halogenated. In some embodiments, T is –CR 2a R 2b –, where R 2a and R 2b Independently, it can be H or a halogen group. In some embodiments, T is –CR. 2a R 2b –, where R 2a and R 2b Independently H, –C(O)–NH(R) a )–、–NR e –C(O)R a –、–NR e –S(O)n R a –、–S(O) n –NH(R a –、–S(O) n –R a –or –O–C(O)–NHR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b H and –OR independently a –NHR a –C(O)–NH(R) a ), –NR e –C(O)R a Or –NR e –S(O) n R a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b H and –OR independently a Or –O–C(O)–NHR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently for H, –S(O) n –NH(R a ) or –S(O) n –R a –. In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently H, halogen, cyano, –NHR a –or –OR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently for H or –NHR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently H, halo, cyano, or –OR a In some implementations, T is –CR 2a R 2b –, where R2a and R 2b Independently, it is either H or cyano. In some embodiments, T is –CR 2a R 2b –, where R 2a and R 2b Each is represented by H.

[0234] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –; where each R 2a and R 2b Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0235] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –; where each R 2a and R 2b Independently for H and C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3- to 7-membered carbon rings, wherein the 3- to 7-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0236] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –; where each R 2a and R 2b Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NRe –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3- to 5-membered carbon rings, wherein the 3- to 5-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0237] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –; where each R 2a and R 2b Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form a 3-membered carbon ring, wherein the 3-membered carbon ring is optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0238] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –; where each R 2a and R 2b Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form a ternary carbon ring.

[0239] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –, where R 2a and R 2b Independently H, halogen, or –OR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently H, halogen, or –OR a And each R a Independently H or C 1-6 Alkyl group. In some embodiments, T is –CR 2a R 2b –, where R 2a and R 2b Independently H, halogen, or –OR a And each R aIndependently H or C 1-3 Alkyl group. In some embodiments, T is –CR 2a R 2b –, where R 2a and R 2b Independently H, halogen, or –OR a And each R a It can be H or methyl on its own.

[0240] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –CR 2c R 2d ;where R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –OR a Or –NHR a In some implementations, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl or halogenated. In some embodiments, T is –CR2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently for H and C 1-6 Alkyl, C 3-6 Cycloalkyl or halogenated. In some embodiments, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently, it can be H or a halogen group. In some embodiments, T is –CR. 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently H, –C(O)–NH(R) a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a –、–S(O) n –R a –or –O–C(O)–NHR a In some implementations, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d H and –OR independently a –NHR a –C(O)–NH(R) a ), –NR e –C(O)R a Or –NR e –S(O) n R a In some implementations, T is –CR 2a R 2b –CR 2c R2d , where R 2a R 2b R 2c and R 2d H and –OR independently a Or –O–C(O)–NHR a In some implementations, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently for H, –S(O) n –NH(R a ) or –S(O) n –R a –. In some implementations, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently H, halogen, cyano, –NHR a –or –OR a In some implementations, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently for H or –NHR a In some implementations, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently H, halo, cyano, or –OR a In some implementations, T is –CR 2a R 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Independently, it is either H or cyano. In some embodiments, T is –CR 2aR 2b –CR 2c R 2d , where R 2a R 2b R 2c and R 2d Each is represented by H.

[0241] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, T is –CR 2a R 2b –CR 2c R 2d –; where R 2a R 2b R 2c and R 2d Independently H, halogen, or –OR a In some implementations, T is –CR 2a R 2b –CR 2c R 2d –, where R 2a R 2b R 2c and R 2d Independently H, halogen, or –OR a And each R a Independently H or C 1-6 Alkyl group. In some embodiments, T is –CR 2a R 2b –CR 2c R 2d –, where R 2a R 2b R 2c and R 2d Independently H, halogen, or –OR a And each R a Independently H or C 1-3 Alkyl group. In some embodiments, T is –CR 2a R 2b –CR 2c R 2d –, where R 2a R 2b R 2c and R 2d Independently H, halogen, or –OR a And each R a It can be H or methyl on its own.

[0242] In some embodiments, the compound of formula I or II is a compound of formula III:

[0243]

[0244] In some embodiments, the compounds of formula I, Ia, II, or IIa are compounds of formula IIIa:

[0245]

[0246] In some embodiments, compounds of formula I, Ib, II, or IIb are compounds of formula IIIb:

[0247]

[0248] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, U is –NR. 11 –、–CR 12a R 12b –, –S–, –S(O)–, –S(O)2–, –C(O)–, or –O–. In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, U is –NR. 11 –CR 12a R 12b –C(O)– or –O–. In some implementations, U is –NR. 11 –CR 12a R 12b Or –O–. In some implementations, U is –NR. 11 Or –CR 12a R 12b In some implementations, U is –NR 11 .

[0249] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, U is –O–, –C(O)–, –S–, –S(O)–, or –S(O)2–. In some embodiments, U is –O– or –C(O)–. In some embodiments, U is –S–, –S(O)–, or –S(O)2–. In some embodiments, U is –S–. In some embodiments, U is –S(O)–. In some embodiments, U is –S(O)2–. In some embodiments, U is –C(O)–. In some embodiments, U is –O–.

[0250] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, R 11 For H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6Cycloalkyl, C 3-6 Halogenated cycloalkyl, –C(O)–R a –S–R a –S(O)–R a –S(O)2–R a –CH2–R a In some implementations, R 11 It can be H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl. In some embodiments, R 11 It is H, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl. In some embodiments, R 11 It is H, C1-C4 alkyl, or C1-C4 haloalkyl. In some embodiments, R 11 It is an H or C1-C4 alkyl group. In some embodiments, R 11 It is a C3-C6 halocycloalkyl group. In some embodiments, R 11 It is a C3-C6 cycloalkyl group. In some embodiments, R 11 It is a C1-C4 haloalkyl group. In some embodiments, R 11 It is a C1-C4 alkyl group. In some embodiments, R 11 For H. In some implementations, R 11 –C(O)–R a –S–R a –S(O)–R a –S(O)2–R a –CH2–R a .

[0251] In some embodiments, compounds of formula I, II, or III have formula IV:

[0252]

[0253] In some embodiments, compounds of formula I, Ia, II, IIa, III, IIIa or IV have formula IVa:

[0254]

[0255] In some embodiments, compounds of formula I, Ib, II, IIb, III, IIIb, or IV have formula IVb:

[0256]

[0257] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R 2b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0258] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3 to 7-membered carbon rings, wherein the 3 to 7-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0259] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3- to 5-membered carbon rings, wherein the 3- to 5-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0260] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R 2a and R 2b Together with the carbon to which they are attached, they form 3 to 5-membered carbon rings, wherein the 3 to 5-membered carbon rings are...

[0261] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R 2a and R 2b Together with the carbon atoms to which they are attached, they form 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0262] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3- to 5-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 5-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently oxo, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, or –OR e .

[0263] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3 to 5-membered heterocycles containing one or two heteroatoms selected from N, O, and S.

[0264] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R 2a and R 2b H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –OR a Or –NHR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b H and C independently 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b H and C independently 1-6 Alkyl, C3-6 Cycloalkyl or halogenated. In some embodiments, T is –CR 2a R 2b –, where R 2a and R 2b Independently, it can be H or a halogen group. In some embodiments, T is –CR. 2a R 2b –, where R 2a and R 2b Independently H, –C(O)–NH(R) a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a –、–S(O) n –R a –or –O–C(O)–NHR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b H and –OR independently a –NHR a –C(O)–NH(R) a ), –NR e –C(O)R a Or –NR e –S(O) n R a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b H and –OR independently a Or –O–C(O)–NHR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently for H, –S(O) n –NH(R a ) or –S(O) n –R a –. In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently H, halogen, cyano, –NHR a–or –OR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently for H or –NHR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently H, halo, cyano, or –OR a In some implementations, T is –CR 2a R 2b –, where R 2a and R 2b Independently, it is either H or cyano. In some embodiments, T is –CR 2a R 2b –, where R 2a and R 2b Each is represented by H.

[0265] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R 2a and R 2b Independently for H and C 1-6 Alkyl, C 3-6 cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0266] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R 2a and R 2b H and C independently 1-6 Alkyl, C 3-6 cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3- to 7-membered carbon rings, wherein the 3- to 7-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0267] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R 2a and R 2b H and C independently 1-6 Alkyl, C 3-6 cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a–O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form 3- to 5-membered carbon rings, wherein the 3- to 5-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0268] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R 2a and R 2b H and C independently 1-6 Alkyl, C 3-6 cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form a 3-membered carbon ring, wherein the 3-membered carbon ring is optionally separated by one to three R atoms. A2 Replace, where each R A2Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0269] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R 2a and R 2b Independently for H and C 1-6 Alkyl, C 3-6 cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Together with the carbon atoms to which they are attached, they form a ternary carbon ring.

[0270] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R 12a and R 12b H and –OR independently a Or –O–C(O)–NHR a In some implementations, R 12a and R 12b Independently for H, –NHR a –C(O)–NH(R) a ), –NR e –C(O)R a –NR e –S(O) n R a In some implementations, R 12a and R 12b Independently for H, –S(O) n–NH(R a ) or –S(O) n –R a –. In some implementations, R 12a and R 12b Independently H, halogen, cyano, –NHR a –or –OR a In some implementations, R 12a and R 12b Independently for H or –NHR a In some implementations, R 12a and R 12b Independently H, halogen, cyano, or –OR a In some implementations, R 12a and R 12b It can be H or cyano independently. In some embodiments, R 12a and R 12b Independent of H or –OR a In some implementations, R 12a and R 12b Independent of H or –OR a And R a C 3-6 Cycloalkyl. In some embodiments, R 12a and R 12b Independent of H or –OR a And R a C 1-4 Halogenated alkyl groups. In some embodiments, R 12a and R 12b Independent of H or –OR a And R a For optional use by –O–C 1-4 Alkyl substituted C 1-4 alkyl.

[0271] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 cycloalkyl or –OR e .

[0272] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form 3- to 7-membered carbon rings, wherein the 3- to 7-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 cycloalkyl or –OR e .

[0273] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 cycloalkyl or –OR e .

[0274] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 1-6 Cycloalkyl.

[0275] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 3- to 5-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 5-membered carbon rings or the 3- to 5-membered heterocycles are optionally surrounded by one or three R atoms. A2 Replace, where each RA2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 1-6 Cycloalkyl.

[0276] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form (i) 3 to 7-membered carbon rings or (ii) 3 to 5-membered heterocycles containing one or two heteroatoms selected from N, O and S.

[0277] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form 3- to 5-membered carbon rings, wherein the 3- to 5-membered carbon rings are optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 1-6 Cycloalkyl.

[0278] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form 3- to 5-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 5-membered heterocycles are optionally separated by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 1-6 Cycloalkyl.

[0279] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form 3 to 5-membered carbon rings.

[0280] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form 3- to 5-membered heterocycles containing one or two heteroatoms selected from N, O, and S.

[0281] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, R 12a and R 12b Together with the carbon atoms to which they are attached, they form a ternary carbon ring.

[0282] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, each R 2a R 2b R 12a and R 12b Independently H, halogen, or –OR a In some implementations, each R 2a R 2b R 12a and R 12b Independently H, halogen, or –OR a And each R a Independently H or C 1-6 Alkyl group. In some embodiments, each R 2a R 2b R 12a and R 12b Independently H, halogen, or –OR a And each R a Independently H or C 1-3 Alkyl group. In some embodiments, each R 2a R 2b R 12a and R 12b Independently H, halogen, or –OR a And each R a It can be H or methyl on its own.

[0283] In some embodiments, the compound of formula I or II has formula V:

[0284]

[0285] In some embodiments, the compounds of formula I, Ia, II, or IIa have formula Va:

[0286]

[0287] In some embodiments, compounds of formula I, Ib, II, or IIb have formula Vb:

[0288]

[0289] In some embodiments of compounds of formulas V, Va, and Vb, R 2a and R 12a Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –OR a Or –NHR a In some implementations, R 2a and R 12a Independently for H and C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, R 2a and R 12a Independently for H and C 1-6 Alkyl, C 3-6 Cycloalkyl or halogenated. In some embodiments, R 2a and R 12a Independently, it can be an H or a halogen group. In some embodiments, R 2a and R 12a Independently H, –C(O)–NH(R) a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a –、–S(O) n –R a –or –O–C(O)–NHR a In some implementations, R 2a and R 12a H and –OR independently a –NHR a –C(O)–NH(R) a ), –NR e –C(O)R a Or –NR e –S(O) n R a In some implementations, R 2a and R 12a H and –OR independently aOr –O–C(O)–NHR a In some implementations, R 2a and R 12a Independently for H, –S(O) n –NH(R a ) or –S(O) n –R a –. In some implementations, R 2a and R 12a Independently H, halogen, cyano, –NHR a –or –OR a In some implementations, R 2a and R 12a Independently for H or –NHR a In some implementations, R 2a and R 12a Independently H, halo, cyano, or –OR a In some implementations, R 2a and R 12a It can be H or cyano independently. In some embodiments, R 2a and R 12a Each is represented by H.

[0290] In some embodiments of compounds of formulas V, Va, and Vb, R 2a and R 12a H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –

[0291] In some embodiments of compounds of formulas V, Va, and Vb, R 2a and R12a Independently for H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, halogenated, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –

[0292] In some embodiments of compounds of formulas V, Va, and Vb, R 2a and R 12a Independently for H and C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –

[0293] In some embodiments of compounds of formulas V, Va, and Vb, R 2a and R 12a Independently for H and C 1-6 Alkyl, C 3-6Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –

[0294] In some embodiments of compounds of formulas V, Va, and Vb, R 2a and R 12a H and C independently 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –

[0295] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W 1 For chemical bonds or –CR 4a R 4b –R 4a ;where R 4b and R 4b H and C independently 1-6 Alkyl, C1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl; or R 4a and R 4b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W 1 For chemical bonds or –CR 4a R 4b –R 4a , where R 4a and R 4b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl group. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –R 4a , where R 4a and R 4b Independently for H and C 1-6 Alkyl, halogen, C 1-4 Halogenated alkyl or cyano. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –R 4a , where R 4a and R 4b Independently for H and C 1-6 Alkyl, halo, or cyano groups. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –R 4a , where R 4a and R 4b Independently, it is H, a halogroup, or a C1-C4 alkyl group. In some embodiments, W 1For chemical bonds or –CR 4a R 4b –R 4a , where R 4a and R 4b Independently, it is H, fluorine, chlorine, or C1-C4 alkyl. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –R 4a , where R 4a and R 4b It can be independently H or cyano. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –R 4a , where R 4a and R 4b Independently H or C 1-4 Halogenated alkyl groups.

[0296] In some implementation schemes, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing 0 to 2 heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some implementation schemes, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –R 4a , where R 4a and R 4bTogether with the carbon atoms to which they are attached, they form 3- to 7-membered carbon rings, wherein the 3- to 7-membered carbon rings are optionally separated by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form 3 to 7-membered carbon rings.

[0297] In some implementation schemes, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form a group optionally bounded by one to three R atoms. A3 Replaced 3-membered carbon rings, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl.

[0298] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W 1 For –CR 4a R 4b –, where R 4b and R4b H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl; or R 4a and R 4b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W 1 For –CR 4a R 4b –, where R 4a and R 4b H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl group. In some embodiments, W 1 For –CR 4a R 4b –, where R 4a and R 4b Independently H, C1-C6 alkyl, halogen, C 1-4 Halogenated alkyl or cyano. In some embodiments, W 1 For –CR 4a R 4b –, where R 4a and R 4b Independently, it is H, C1-C6 alkyl, halogroup, or cyanogroup. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Independently, it is H, a halogroup, or a C1-C4 alkyl group. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –, where R 4aand R 4b Independently, it is H, fluorine, chlorine, or C1-C4 alkyl. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b It can be independently H or cyano. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Independently H or C 1-4 Halogenated alkyl groups.

[0299] In some implementation schemes, W 1 For –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some implementation schemes, W 1 For –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon rings or the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, W 1 For –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form 3- to 7-membered carbon rings, wherein the 3- to 7-membered carbon rings are optionally separated by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6Cycloalkyl. In some embodiments, W 1 For –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycles are optionally separated by one or three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, W 1 For –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form (i) 3- to 7-membered carbon rings or (ii) 4- to 7-membered heterocycles containing one or two heteroatoms selected from N, O, and S. In some embodiments, W 1 For chemical bonds or –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form 3 to 7-membered carbon rings. In some embodiments, W 1 For –CR 4a R 4b –, where R 4a and R 4b Together with the carbon atoms to which they are attached, they form a group optionally bounded by one to three R atoms. A3 Replaced 3-membered carbon rings, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl.

[0300] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W 1 It is a chemical bond;

[0301] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W 2 For –CR 5a R 5b –;

[0302] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W 2 For -CR 6a =CR 6b -, where R 6a and R 6b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl group. In some embodiments, W 2 For -CR 6a =CR 6b -, where each R 6a and R 6b Together with the carbon atoms to which they are attached, they form (i) a 5- to 10-membered carbon ring, (ii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (iii) a 6- to 10-membered aromatic ring, or (iv) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring, the 5- to 10-membered heterocycle, the 6- to 10-membered aromatic ring, or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R atoms. A4 Replace, where each R A4 Independently a halogenated or C 1-4 alkyl.

[0303] In some implementation schemes, W 2 For -CR 6a =CR 6b -, where each R 6a and R 6b Together with the carbon atoms to which they are attached, they form (i) a 6- to 10-membered aromatic ring or (ii) a 5- to 10-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, and S, wherein the 6- to 10-membered aromatic ring or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R atoms. A4 Replace, where each R A4 Independently a halogenated or C 1-4 alkyl.

[0304] In some implementation schemes, W 2 For -CR 6a =CR 6b -, where each R 6a and R 6b Together with the carbon atoms to which they are attached, they form (i) a 5- to 10-membered carbon ring or (ii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring or the 5- to 10-membered heterocycle is optionally surrounded by one to four R atoms. A4 Replace, where each R A4 Independently a halogenated or C1-4 alkyl.

[0305] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, X is a chemical bond; in some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, X is –CR 8a R 8b –

[0306] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, Z is –CR 9a R 9b –

[0307] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, Z is -CR 10a =CR 10b -, where R 10a and R 10b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl group. In some embodiments, Z is -CR 10a =CR 10b -, where each R 10a and R 10b Together with the carbon atoms to which they are attached, they form (i) a 5- to 10-membered carbon ring, (ii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, (iii) a 6- to 10-membered aromatic ring, or (iv) a 5- to 10-membered heteroaromatic ring containing one to three heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring, the 5- to 10-membered heterocycle, the 6- to 10-membered aromatic ring, or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R atoms. A4 Replace, where each R A4 Independently a halogen group, oxo group, cyano group, or C 1-4 Alkyl group. In some embodiments, Z is -CR 10a =CR 10b -, where each R 10a and R 10b Together with the carbon atoms to which they are attached, they form (i) a 6- to 10-membered aromatic ring or (ii) a 5- to 10-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, and S, wherein the 6- to 10-membered aromatic ring or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R atoms.A4 Replace, where each R A4 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, Z is -CR 10a =CR 10b -, where each R 10a and R 10b Together with the carbon atoms to which they are attached, they form (i) a 5- to 10-membered carbon ring or (ii) a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring or the 5- to 10-membered heterocycle is optionally surrounded by one to four R atoms. A4 Replace, where each R A4 Independently a halogenated or C 1-4 alkyl.

[0308] In some embodiments, compounds of formula I, II, III, or IV have formula VI:

[0309]

[0310]

[0311] Where m is 0, 1, 2, 3, or 4; and

[0312] Each R 2 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a ;or

[0313] Two Rs on the same carbon atom 2 Together with the carbon atoms attached to both, they form (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms.A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0314] In some embodiments, compounds of formula I, Ia, II, IIa, III, IIIa, IV, or IVa have formula VIa:

[0315]

[0316] Where m is 0, 1, 2, 3, or 4; and

[0317] Each R 2 Independently for C 1-6 Alkyl or C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a ;

[0318] Or two R atoms on the same carbon atom 2 Together with the carbon atoms attached to both, they form (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0319] In some embodiments, compounds of formula I, Ib, II, IIb, III, IIIb, IV, or IVb have formula VIb:

[0320]

[0321] Where m is 0, 1, 2, 3, or 4; and

[0322] Each R 2 Independently for C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a ;or

[0323] Two Rs on the same carbon atom 2 Together with the carbon atoms attached to both, they form (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0324] In some embodiments, for compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is –CR 3a R 3b –, –C(O)–, –SO2–, –CR 3a R 3b –CR 3c R 3d –or–N(R) a In some implementations, L is –CR. 3a R 3b –、–C(O)–、–CR 3a R3b –CR 3c R 3d – or –SO2. In some implementations, L is –CR. 3a R 3b –、–C(O)– or –CR 3a R 3b –CR 3c R 3d –. In some implementations, L is –CR 3a R 3b –or–CR 3a R 3b –CR 3c R 3d – In some implementations, L is –C(O)–. In some implementations, L is –SO2–. In some implementations, L is –CR 3a R 3b –CR 3c R 3d –. In some implementations, L is –N(R a In some implementations, L is –CR. 3a R 3b –

[0325] In some embodiments, for compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally surrounded by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some implementations, R 3a R 3b R 3c and R 3dIndependently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally separated by one or two R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the atoms in the group, together with the carbon atoms to which they are attached, forms a ternary carbon ring, wherein the ternary carbon ring is optionally separated by one or two R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of these atoms, together with the carbon atoms to which they are attached, forms a ternary carbon ring. In some embodiments, R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 3a R3b R 3c and R 3d H and C independently 1-3 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-3 Alkyl group. In some embodiments, R 3a R 3b R 3c and R 3d Independently H or C 1-3 Alkyl group. In some embodiments, R 3a R 3b R 3c and R 3d Each is represented by H.

[0326] In some embodiments, for compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is –CR 3a R 3b –or–CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally surrounded by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some implementations, L is –CR 3a R 3b –or–CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R3d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally separated by one or two R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, L is –CR 3a R 3b –or–CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the atoms in the group, together with the carbon atoms to which they are attached, forms a ternary carbon ring, wherein the ternary carbon ring is optionally separated by one or two R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, L is –CR 3a R 3b –or–CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R3c and R 3d Any of these atoms, together with the carbon atoms to which they are attached, forms a ternary carbon ring. In some embodiments, L is –CR 3a R 3b –or–CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 3a R 3b R 3c and R 3d Independently for H and C 1-3 Alkyl, C 1-3 Halogenated alkyl or –O–C 1-3 Alkyl group. In some embodiments, L is –CR 3a R 3b –or–CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Independently H or C 1-3 Alkyl group. In some embodiments, R 3a R 3b R 3c and R 3d Each is represented by H.

[0327] In some embodiments, for compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is –CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3bOr (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally surrounded by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some implementations, L is –CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally separated by one or two R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, L is –CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the atoms in the group, together with the carbon atoms to which they are attached, forms a ternary carbon ring, wherein the ternary carbon ring is optionally separated by one or two R atoms. A2 Replace, where each R A2Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, L is –CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of these atoms, together with the carbon atoms to which they are attached, forms a ternary carbon ring. In some embodiments, L is –CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 3a R 3b R 3c and R 3d Independently for H and C 1-3 Alkyl, C 1-3 Halogenated alkyl or –O–C 1-3 Alkyl group. In some embodiments, L is –CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Independently H or C 1-3 Alkyl group. In some embodiments, L is –CR 3a R 3b –CR 3c R 3d –, where R 3a R 3b R 3c and R 3d Each is represented by H.

[0328] In some embodiments, for compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is –CR 3a R 3b –, where R 3a and R 3b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally surrounded by one or three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some implementations, L is –CR 3a R 3b –, where R 3a and R 3b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 3- to 7-membered heterocycle is optionally separated by one or two R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, L is –CR 3a R 3b –, where R 3a and R 3b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R3b Or (ii)R 3c and R 3d Any of the atoms in the group, together with the carbon atoms to which they are attached, forms a ternary carbon ring, wherein the ternary carbon ring is optionally separated by one or two R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, L is –CR 3a R 3b –, where R 3a and R 3b H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl; or (i)R 3a and R 3b Or (ii)R 3c and R 3d Any of these atoms, together with the carbon atoms to which they are attached, forms a ternary carbon ring. In some embodiments, L is –CR 3a R 3b –, where R 3a and R 3b H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, L is –CR 3a R 3b –, where R 3a and R 3b H and C independently 1-3 Alkyl, C 1-3 Halogenated alkyl or –O–C 1-3 Alkyl group. In some embodiments, L is –CR 3a R 3b –, where R 3a and R 3b Independently H or C 1-3 Alkyl group. In some embodiments, L is –CR 3a R 3b –, where R 3a and R 3b Each is represented by H.

[0329] In some embodiments, compounds of formula I, II, III, IV, or VI have formula VII:

[0330]

[0331] In some embodiments, compounds of formula I, Ia, II, IIa, III, IIIa, IV, IVa, VI, or VIa have formula VIIa:

[0332]

[0333] In some embodiments, compounds of formula I, Ib, II, IIb, III, IIIb, IV, IVb, VI, or VIb have formula VIIb:

[0334]

[0335] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, and VIIb, R 1 For H, C 6-10 Aryl or C 6-10 heteroaryl, wherein the C 6-10 Aryl or C 6-10 Heteroaryl groups are selectively bound by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 alkyl.

[0336] In some implementation schemes, R 1 The phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is H, wherein the phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optionally surrounded by one to four R A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 The phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optionally surrounded by one, two, three, or four R. A1 Replace, where each R A1 Independently halogenated, C1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 Independently halogenated, C 1-4 Alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, R 1 It is a phenyl, pyridinyl, pyridazine, pyrazine, or pyrimidine substituted with one, two, three, or four halogens. In some embodiments, R 1 It is a phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with two or three halogens. In some embodiments, R 1 It is a phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with two or three halogens selected from chlorine and fluorine.

[0337] In some implementation schemes, R 1 It is H, phenyl, or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl or pyridyl, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl or pyridyl, wherein each R A1 Independently halogenated, C 1-4 Alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl or pyridyl, wherein each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl or pyridyl, wherein each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, R 1 The phenyl or pyridyl group is substituted with one, two, three, or four halogens. In some embodiments, R 1 It is a phenyl or pyridyl group substituted with two or three halogens. In some embodiments, R 1 It is a phenyl or pyridyl group substituted with two or three halogens selected from chlorine and fluorine.

[0338] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa or VIIb, R 1 For H or C 6-10 Aryl, wherein the C 6-10 Aryl groups are selectively bound by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 It is H or phenyl, wherein the phenyl is optionally surrounded by one to four R A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently halogenated, C1-4 Alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl groups, wherein each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, R 1 The phenyl group is substituted with one, two, three, or four halogens. In some embodiments, R... 1 The phenyl group is substituted with two or three halogens. In some embodiments, R... 1 It is a phenyl group that is substituted with two or three halogens selected from chlorine and fluorine.

[0339] In some implementation schemes, R 1 Choose from the following groups: In some implementation schemes, R 1 Choose from the following groups: In some implementation schemes, R 1 Choose from the following groups:

[0340] In some implementation schemes, R 1 To be optionally controlled by one, two, three or four R A1 Substituted pyridinyl groups, wherein each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted pyridinyl groups, wherein each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted pyridinyl groups, wherein each RA1 Independently halogenated, C 1-4 Alkyl or –O–C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted pyridinyl groups, wherein each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted pyridinyl groups, wherein each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, R 1 The pyridinyl group is substituted with one, two, three, or four halogens. In some embodiments, R 1 The pyridinyl group is substituted with two or three halogens. In some embodiments, R 1 It is a pyridinyl group substituted with two or three halogens selected from chlorine and fluorine.

[0341] In some embodiments, compounds of formula I, II, III, IV, VI, or VII have formula VIII:

[0342]

[0343]

[0344] Where p is 2 or 3.

[0345] In some embodiments, compounds of formula I, Ia, II, IIa, III, IIIa, IV, IVa, VI, VIa, VII, or VIIa have formula VIIIa:

[0346]

[0347] Where p is 2 or 3.

[0348] In some embodiments, compounds of formula I, Ib, II, IIb, III, IIIb, IV, IVb, VI, VIb, VII, or VIIb have formula VIIIb:

[0349]

[0350] Where p is 2 or 3.

[0351] In some embodiments, for compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, each R A1 Independently halogenated, C 1-4 Alkyl or –O–C 1-4 Alkyl group. In some embodiments, each R A1 Independently halogenated, C 1-4 Alkyl, cyano, or –O–C 1-4 Alkyl group. In some embodiments, each R A1 Independently a halogenated, cyanoated, or C group 1-4 Alkyl group. In some embodiments, each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, each R A1 Independently a halogenated, cyanoated, or –O–C group 1-4 Alkyl group. In some embodiments, each RA1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, each R A1 Independently halogenated. In some implementations, each R... A1 It can be chlorine or fluorine on its own.

[0352] In some embodiments, for compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, R 4a R 4b R 5a R 5b R 8a R 8b R 9a and R 9b Each independently represents H and C. 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, –O–C 1-4 Alkyl or C 1-4 Alkylene –O–C 1-4 Alkyl group. In some embodiments, R 4a R 4b R 5a R 5b R 8a R 8b R 9a and R 9b Each is independently H, C1-C6 alkyl, halogroup, or cyanogroup. In some embodiments, R 4a R 4b R 5a R 5b R 8a R 8b R 9a and R 9b Each is independently H, a halogroup, or a C1-C4 alkyl group. In some embodiments, R 4a R 4b R 5a R 5b R 8a R 8b R 9a and R 9b Each is independently H, fluorine, chlorine, or C1-C4 alkyl. In some embodiments, R 4a R 4b R 5a R 5b R 8a R8b R 9a and R 9b Each is independently an H or cyano group. In some embodiments, R 4a R 4b R 5a R 5b R 8a R 8b R 9a and R 9b Each independently is H or C 1-4 Halogenated alkyl groups.

[0353] In some embodiments, for compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, (i)R 4a and R 4b (ii)R 5a and R 5b (iii)R 8a and R 8b or (iv)R 9a and R 9b Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e In some implementations, (i)R 4a and R 4b (ii)R 5a and R 5b (iii)R 8a and R 8b or (iv)R 9a and R 9b Any of the following, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 4- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 7-membered carbon ring or the 4- to 7-membered heterocycle is optionally surrounded by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, (i)R4a and R 4b (ii)R 5a and R 5b (iii)R 8a and R 8b or (iv)R 9a and R 9b Any of the atoms in the group, together with the carbon atoms to which they are attached, forms a 3- to 7-membered carbon ring, wherein the 3- to 7-membered carbon ring is optionally separated by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, (i)R 4a and R 4b (ii)R 5a and R 5b (iii)R 8a and R 8b or (iv)R 9a and R 9b Any of the three to seven members together with the carbon atoms to which they are attached forms a four- to seven-membered heterocycle containing one or two heteroatoms selected from N, O, and S, wherein the three to seven-membered carbon rings or the four to seven-membered heterocycles are optionally separated by one to three R atoms. A3 Replace, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, (i)R 4a and R 4b (ii)R 5a and R 5b (iii)R 8a and R 8b or (iv)R 9a and R 9b Any of these, together with the carbon atoms to which they are attached, forms (i) a 3- to 7-membered carbon ring or (ii) a 3- to 7-membered heterocycle containing one or two heteroatoms selected from N, O, and S. In some embodiments, (i) R 4a and R 4b (ii)R 5a and R 5b (iii)R 8a and R 8b or (iv)R 9a and R 9b Any of them, together with the carbon atoms to which they are attached, can optionally be formed by one to three R A3 Replaced 3-membered carbon rings, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6Alkyl or C 3-6 Cycloalkyl. In some embodiments, (i)R 4a and R 4b (ii)R 5a and R 5b (iii)R 8a and R 8b or (iv)R 9a and R 9b Any of these, together with the carbon atoms to which they are attached, forms a 3- to 7-membered carbon ring. In some embodiments, R 4a and R 4b Together with the carbon atoms to which they are attached, they form a group optionally bounded by one to three R atoms. A3 Replaced 3-membered carbon rings, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 5a and R 5b Together with the carbon atoms to which they are attached, they form a group optionally bounded by one to three R atoms. A3 Replaced 3-membered carbon rings, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form a group optionally bounded by one to three R atoms. A3 Replaced 3-membered carbon rings, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 9a and R 9b Together with the carbon atoms to which they are attached, they form a group optionally bounded by one to three R atoms. A3 Replaced 3-membered carbon rings, where each R A3 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 4a and R 4b Together with the carbon atoms to which they are attached, they form a ternary carbon ring. In some embodiments, R 5a and R 5b Together with the carbon atoms to which they are attached, they form a ternary carbon ring. In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form a ternary carbon ring. In some embodiments, R 9a and R 9bTogether with the carbon atoms to which they are attached, they form a ternary carbon ring.

[0354] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0355] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R 2 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or two R atoms on the same carbon atom 2 Together with the carbon atoms attached to both of them, they form a 3- to 7-membered carbon ring, wherein the 3- to 7-membered carbon ring is optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0356] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R 2 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n Ra –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or R 2a and R 2b Or two R atoms on the same carbon atom 2 Together with the carbon atoms attached to both of them, they form a 3- to 5-membered carbon ring, wherein the 3- to 5-membered carbon ring is optionally separated by one to three R atoms. A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0357] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R 2 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or two R atoms on the same carbon atom 2 Together with the carbon atoms attached to both of them, they form a 3-membered carbon ring, wherein the 3-membered carbon ring is optionally separated by one to three R atoms.A2 Replace, where each R A2 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 3-6 cycloalkyl or –OR e .

[0358] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIb, each R 2 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –CH2–S(O) n R a –、–OR a –O–C(O)–NHR a –NHR a –、–C(O)–NH(R a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a – or – S(O) n –R a –; or two R atoms on the same carbon atom 2 Together with the carbon atoms attached to both of them, they form a ternary carbon ring.

[0359] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each R 2 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –OR a Or –NHR a In some implementations, each R 2 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, each R 2 Independently C1-6 Alkyl, C 3-6 Cycloalkyl or halogenated. In some embodiments, each R 2 Independently a halogen group. In some implementations, each R... 2 Independently –C(O)–NH(R) a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a –、–S(O) n –R a –or –O–C(O)–NHR a In some implementations, each R 2 Independently for –OR a –NHR a –C(O)–NH(R) a ), –NR e –C(O)R a Or –NR e –S(O) n R a In some implementations, each R 2 Independently for –OR a Or –O–C(O)–NHR a In some implementations, each R 2 Independently for –S(O) n –NH(R a ) or –S(O) n –R a –. In some implementations, each R 2 Independently halogenated, cyanoated, –NHR a –or –OR a In some implementations, each R 2 For –NHR a In some implementations, each R 2 Independently a halogenated, cyanoated, or -OR group a In some implementations, each R 2 It is cyano. In some embodiments, each R 2 Independently for –OR a In some implementations, each R 2 Independently for –OR a And each R aIndependently, it is a C3-C6 cycloalkyl group optionally substituted with one to two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, and –O–C1-C4 alkyl. In some embodiments, each R 2 Independently for –OR a ; where each R a Independently, it is a C1-C6 alkyl group optionally substituted with one to two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, –O–C1-C4 alkyl. In some embodiments, each R 2 Independently for –OR a ; where each R a Independently, optionally –O–C 1-4 Alkyl or halogen-substituted C1-C6 alkyl groups. In some embodiments, each R 2 Independently for –OR a ; where each R a Independently, optionally –O–C 1-4 Alkyl-substituted C1-C6 alkyl groups.

[0360] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 2, and for each R 2 Independently for C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –OR a Or –NHR a In some implementations, m is 2, and each R 2 Independently for C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, m is 2, and each R 2 Independently for C 1-6 Alkyl, C 3-6 Cycloalkyl or halogenated. In some embodiments, m is 2, and each R 2 Independently a halogen group. In some embodiments, m is 2, and each R 2 Independently –C(O)–NH(R) a )–、–NR e –C(O)R a –、–NR e –S(O) n Ra –、–S(O) n –NH(R a –、–S(O) n –R a –or –O–C(O)–NHR a In some implementations, m is 2, and each R 2 Independently for –OR a –NHR a –C(O)–NH(R) a ), –NR e –C(O)R a Or –NR e –S(O) n R a In some implementations, m is 2, and each R 2 Independently for –OR a Or –O–C(O)–NHR a In some implementations, m is 2, and each R 2 Independently for –S(O) n –NH(R a ) or –S(O) n –R a –. In some implementations, m is 2, and each R 2 Independently halogenated, cyanoated, –NHR a –or –OR a In some implementations, m is 2, and each R 2 Independently for –NHR a In some implementations, m is 2, and each R 2 Independently a halogenated, cyanoated, or -OR group a In some implementations, m is 2, and each R 2 It is cyano. In some embodiments, m is 2, and each R 2 Independently a halogen group. In some embodiments, m is 2, and each R 2 Independently for –OR a In some implementations, m is 2, and each R 2 Independently for –OR a And each R a Independently, it is a C3-C6 cycloalkyl group optionally substituted with one to two substituents, said substituents being independently selected from the group consisting of: halogens, cyano groups, and –O–C1-C4 alkyl groups. In some embodiments, m is 2, and each R 2 Independently for –OR a ; where each R aIndependently, it is a C1-C6 alkyl group optionally substituted with one to two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, –O–C1-C4 alkyl. In some embodiments, m is 2, and each R 2 Independently for –OR a ; where each R a Independently, optionally –O–C 1-4 Alkyl or halogen-substituted C1-C6 alkyl groups. In some embodiments, each m is 2, and R 2 Independently for –OR a ; where each R a Independently, optionally –O–C 1-4 Alkyl-substituted C1-C6 alkyl groups.

[0361] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 1, and R 2 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a –OR a Or –NHR a In some implementations, m is 1, and R 2 C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, cyano, –CH2R a –、–CH2OR a or –OR a In some implementations, m is 1, and R 2 C 1-6 Alkyl, C 3-6 Cycloalkyl or halogenated. In some embodiments, m is 1, and R 2 It is a halogen group. In some embodiments, m is 1, and R 2 Independently –C(O)–NH(R) a )–、–NR e –C(O)R a –、–NR e –S(O) n R a –、–S(O) n –NH(R a –、–S(O) n –R a –or –O–C(O)–NHR a In some implementations, m is 1, and R2 For –OR a –NHR a –C(O)–NH(R) a ), –NR e –C(O)R a Or –NR e –S(O) n R a In some implementations, m is 1, and R 2 For –OR a Or –O–C(O)–NHR a In some implementations, m is 1, and R 2 For –S(O) n –NH(R a ) or –S(O) n –R a –. In some implementations, m is 1, and R 2 Halogenated, cyano, –NHR a –or –OR a In some implementations, m is 1, and R 2 For –NHR a In some implementations, m is 1, and R 2 Halogenated, cyano, or -OR a In some implementations, m is 1, and R 2 It is a cyano group. In some embodiments, m is 1, and R 2 It is a halogen group. In some embodiments, m is 1, and R 2 For –OR a In some implementations, m is 1, and R 2 For –OR a , and R a The substituent is a C3-C6 cycloalkyl group selectively substituted with one or two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, and –O–C1-C4 alkyl. In some embodiments, m is 1, and R 2 For –OR a ;where R a The C1-C6 alkyl group is optionally substituted with one to two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, –O–C1-C4 alkyl. In some embodiments, m is 1, and R 2 For –OR a ;where R a For optional use by –O–C 1-4 Alkyl or halogen-substituted C1-C6 alkyl groups. In some embodiments, each m is 1, and R 2 For –ORa ; where each R a For optional use by –O–C 1-4 Alkyl-substituted C1-C6 alkyl groups.

[0362] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 1 or 2, and each R 2 Independent of halogen or –OR a And each R a Independently H or C1-C6 alkyl. In some embodiments, m is 1 or 2, each R 2 Independent of halogen or –OR a And each R a Independently, it is an H or C1-C3 alkyl group. In some embodiments, m is 1 or 2, and each R 2 Independent of halogen or –OR a And each R a Independently, it is H or methyl. In some embodiments, m is 1 or 2, each R 2 Independent of halogen or –OR a And each R a For H. In some implementations, m is 1 or 2, and for each R 2 Independent of halogen or –OR a And each R a It is a methyl group.

[0363] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 1, R 2 Halogenated or –OR a , and R a It is H or C1-C6 alkyl. In some embodiments, m is 1, R 2 Halogenated or –OR a , and R a It is H or C1-C3 alkyl. In some embodiments, m is 1, R 2 Halogenated or –OR a , and R a It is H or methyl. In some embodiments, m is 1, R 2 Halogenated or –OR a , and R a For H. In some implementations, m is 1, R 2 Halogenated or –OR a , and R a It is a methyl group.

[0364] In some embodiments, for compounds of formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, m is 2, and each R 2 Independent of halogen or –OR a And each R a Independently, it is an H or C1-C6 alkyl group. In some embodiments, m is 2, and each R 2 Independent of halogen or –OR a And each R a Independently, it is an H or C1-C3 alkyl group. In some embodiments, m is 2, and each R 2 Independent of halogen or –OR a And each R a Independently H or methyl. In some embodiments, m is 2, each R 2 Independent of halogen or –OR a And each R a For H. In some implementations, m is 2, and for each R 2 Independent of halogen or –OR a And each R a It is a methyl group.

[0365] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each R a Independently for H and C 1-6 Alkyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with 0 to 4 substituents, said substituents being independently selected from the group consisting of: halogen, cyano, –O–C. 1-4 Alkyl groups, 5- to 10-membered carbon rings, 5- to 10-membered heterocycles containing one or two heteroatoms selected from N, O, and S, 6- to 10-membered aromatic rings, and 5- to 10-membered heteroaromatic rings containing one or three heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring, the 5- to 10-membered heterocycle, the 6- to 10-membered aromatic ring, or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A5 Replace, where each R A5 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 cycloalkyl or –OR e .

[0366] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each R a C1-C6 alkyl groups, independently of H, C1-C6 alkyl groups, or optionally substituted with 1 to 2 substituents. 3- C6 cycloalkyl, wherein the substituents are independently selected from the group consisting of: halogen, cyano, –O–C 1- C4 alkyl, 5 to 10-membered carbon rings and 5 to 10-membered heterocycles containing one or two heteroatoms selected from N, O and S.

[0367] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each R a Independently H, C1-C4 alkyl, or C3-C6 cycloalkyl optionally substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of: halogen, cyano, and –O–C1-C4 alkyl.

[0368] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each R a Independently, it is a C3-C6 cycloalkyl group optionally substituted with one or two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, and –O–C1-C4 alkyl.

[0369] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each R a Independently, it is a C1-C6 alkyl group optionally substituted with one or two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, –O–C1-C4 alkyl.

[0370] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each R a Independently, optionally –O–C 1-4 C substituted with alkyl or halogen groups 1-6 alkyl.

[0371] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each R a Independently comprising a 5- to 10-membered carbon ring, a 5- to 10-membered heterocycle containing one or two heteroatoms selected from N, O, and S, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring containing one or three heteroatoms selected from N, O, and S, wherein the 5- to 10-membered carbon ring, the 5- to 10-membered heterocycle, the 6- to 10-membered aromatic ring, or the 5- to 10-membered heteroaromatic ring is optionally surrounded by one to four R... A4 Replace, where each R A4 Independently, it can be an oxo group, a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 cycloalkyl or –OR e .

[0372] In some embodiments of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each R e Independently for H and C 1-4 Alkyl or C 3-6 Cycloalkyl, and each C 1-4 Alkyl or C 3-6 The cycloalkyl group is optionally replaced by a halogenated or cyano group. In some embodiments, each R e Independently for H and C 1-4 Alkyl or C 3-6 Cycloalkyl. In some embodiments, each R e Independently H or C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally replaced by a halogen or cyano group. In some embodiments, each R e Independently H or C 3-6 cycloalkyl, wherein each C 3-6The cycloalkyl group is optionally replaced by a halogenated or cyano group. In some embodiments, each R e Independently H or C 1-4 Alkyl group. In some embodiments, each R e Independently H or C 3-6 Cycloalkyl. In some embodiments, each R e For H. In some implementations, each R e Independently for C 1-4 Alkyl group. In some embodiments, each R e Independently for C 3-6 Cycloalkyl.

[0373] In some embodiments, for compounds of formulas VIII, VIIIa, and VIIIb, p is 2 or 3, and for each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, p is 2 or 3, and each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, p is 2 or 3, and each R A1 Independently halogenated, C 1-4 Alkyl or –O–C 1-4 Alkyl group. In some embodiments, p is 2 or 3, and each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, p is 2 or 3, and each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, p is 2 or 3, and each R A1 Independently halogenated. In some embodiments, p is 2 or 3, and each R A1 It is independently selected from chlorine and fluorine.

[0374] In some embodiments, for compounds of formulas VIII, VIIIa, and VIIIb, p is 2, and for each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, p is 2, and each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, p is 2, and each R A1 Independently halogenated, C 1-4 Alkyl or –O–C 1-4 Alkyl group. In some embodiments, p is 2, and each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, p is 2, and each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, p is 2, and each R A1 Independently halogenated. In some implementations, p is 2, and each R A1 It is independently selected from chlorine and fluorine.

[0375] In some embodiments, for compounds of formulas VIII, VIIIa, and VIIIb, p is 3, and for each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, –O–C 1-4 Alkyl, –O–C 3-6 cycloalkyl or C 1-4 Alkyl–O–C 1-4 Alkyl group. In some embodiments, p is 3, and each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or –O–C 1-4 Alkyl group. In some embodiments, p is 3, and each R A1 Independently halogenated, C 1-4 Alkyl or –O–C 1-4 Alkyl group. In some embodiments, p is 3, and each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, p is 3, and each R A1 Independent of a halogen group or –O–C 1-4 Alkyl group. In some embodiments, p is 3, and each R A1 Independently halogenated. In some implementations, p is 3, and each R A1 It is independently selected from chlorine and fluorine.

[0376] In some embodiments of compounds of formula IV, IVa, or IVb:

[0377]

[0378]

[0379] X is –CR 8a R 8b –;

[0380] W 1 For chemical bonds or –CR 4a R 4b –;

[0381] W 2 For –CR 5a R 5b –or–CR 6a =CR 6b –;

[0382] Z is –CR 9a R 9b –;

[0383] L stands for –CH2–;

[0384] R 2a R 2b R 12a and R 12b H and C independently 1-6 Alkyl, halogen, –OR a –or–CH2OR a ;

[0385] R a For H or C 1-6 alkyl;

[0386] R 4a R 4b R 5a R 5b R 8a R 8b R 9a R 9b Independently H, hydroxyl, C 1-6 Alkyl or –O–C 1-4 alkyl;

[0387] R 6a and R 6b Both are H; and

[0388] R 1 To be arbitrarily selected by one to four R A1 Replacement C6-10 Aryl, where each R A1 It can be either fluorine or chlorine.

[0389] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb are compounds selected from the group consisting of:

[0390] Or its pharmaceutically acceptable salt.

[0391] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb are compounds selected from the group consisting of:

[0392] Or its pharmaceutically acceptable salt.

[0393] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb are compounds selected from the group consisting of:

[0394] Or its pharmaceutically acceptable salt.

[0395] III. Composition and Packaging

[0396] The compounds provided herein are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds provided herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, and one or more pharmaceutically acceptable solvents selected from carriers, adjuvants, and excipients are also provided herein. The compounds provided herein may be the sole active ingredient or one of the active ingredients in a pharmaceutical composition. Suitable pharmaceutically acceptable solvents may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition, (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GS Banker & C.T. Rhodes).

[0397] In one aspect, this document provides pharmaceutical compositions comprising compounds provided herein (e.g., compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients or carriers. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients or carriers.

[0398] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0399] The pharmaceutical composition can be administered in single or multiple doses. The pharmaceutical composition can be administered by various methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition can be administered via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0400] One method of administration is parenteral, such as by injection. The pharmaceutical compositions described herein may be incorporated into forms for injection administration, including, for example, aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical solvents.

[0401] Oral administration may be another route of administration for the compounds provided herein. Administration may be via, for example, capsules or enteric-coated tablets. In preparing pharmaceutical compositions comprising at least one compound provided herein or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as the compounds provided herein) is typically diluted with an excipient and / or encapsulated in such a carrier, which may be in the form of capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, acting as a solvent, carrier, or medium for the active ingredient. Thus, pharmaceutical compositions may be in the form of tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0402] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. Pharmaceutical compositions may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propylparaben; sweeteners; and flavoring agents; or any combination thereof.

[0403] Pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof can be formulated to provide a rapid, sustained, or delayed release of an active ingredient, such as a compound provided herein, upon administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation used in the methods of this disclosure employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a controlled amount of a compound provided herein for continuous or discontinuous infusion. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0404] To prepare solid compositions (such as tablets), a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compound described herein or its pharmaceutically acceptable salts, isomers, or mixtures thereof. When these preformed compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition, making it easy to subdivide the composition into equivalent unit dosage forms such as tablets, pills, and capsules.

[0405] The compounds described herein can be coated or otherwise formulated into tablets or pills to provide a dosage form with the advantage of prolonged action or protection against the acidic conditions of the stomach. For example, tablets or pills may contain an inner dose component and an outer dose component, the latter being a coating on the former. These two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the inner component to enter the duodenum intact or delay release. A variety of materials can be used for such enteric coatings or coatings, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0406] Pharmaceutical compositions for inhalation or inhalation may include solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or via nasal inhalation to achieve a local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a mask tent or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0407] In one aspect, this document provides a medicine box comprising a compound provided herein (e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb) or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvation thereof, and suitable packaging. In some embodiments, the medicine box also includes instructions for use. In some embodiments, the medicine box comprises a compound provided herein (e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb) or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvation thereof, and a label and / or instructions for use of the compound in treating the indications (including diseases or conditions) described herein.

[0408] In some embodiments, the pillbox may also include one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or their pharmaceutically acceptable salts.

[0409] In one aspect, this document provides articles comprising, in a suitable container, the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures thereof. In some embodiments, the container may be a vial, a wide-mouth bottle, an ampoule, a pre-filled syringe, or an intravenous bag.

[0410] IV. Methods

[0411] In one embodiment, a method of treating HIV infection in a person who has or is at risk of HIV infection (e.g., HIV-1 and / or HIV-2) is provided, the method comprising administering to the person a therapeutically effective amount of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof.

[0412] In some embodiments, the method further includes administering to a person a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are anti-HIV agents. In specific embodiments, one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb (broadly neutralizing HIV antibody), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, one or more adjunctive therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-l-(3-(4-chloro-3-(methanesulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazole-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropyl[3,4]cyclopent[l,2-c]pyrazol-l-yl)acetamide or a pharmaceutically acceptable salt thereof.

[0413] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, is provided for the treatment of HIV infection in a person who has HIV (e.g., HIV-1 and / or HIV-2) or is at risk of HIV infection.

[0414] In another embodiment, a pharmaceutical composition is provided of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, for use in a medical therapy.

[0415] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, is provided for the treatment of HIV infection.

[0416] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has HIV infection or is at risk of HIV infection.

[0417] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, is provided for a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering one, two, three, or four additional therapeutic agents to the person.

[0418] In another embodiment, a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIb is provided. A pharmaceutical composition of a compound of Ib or a pharmaceutically acceptable salt thereof, used for treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to a person one, two, three, or four additional therapeutic agents selected from the group consisting of: HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, one, two, three, or four additional therapeutic agents are selected from HIV protease inhibitors, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, latency reversal agents, HIV capsid inhibitors, HIV bNAb, TLR7 agonists, and combinations thereof.

[0419] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, is provided for a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir disoproxil fumarate and emtricitabine.

[0420] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, is provided for a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

[0421] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, is provided for a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir disoproxil fumarate.

[0422] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, is provided for a method of treating HIV infection in a person who has or is at risk of HIV infection, wherein the method further comprises administering to the person a therapeutically effective amount of tenofovir alafenamide.

[0423] In another embodiment, a method of using a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb in treatment is provided. Specifically, a method of treating HIV viral replication in mammals (e.g., humans), treating AIDS, or delaying the onset of AIDS or ARC symptoms is provided, the method comprising administering to the mammal a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0424] In another embodiment, a composition comprising a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, is provided for use in methods of treating HIV viral replication in mammals (e.g., humans), treating AIDS, or delaying the onset of AIDS or ARC symptoms.

[0425] In one embodiment, a pharmaceutical composition is provided of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, for the prevention of HIV infection.

[0426] For example, in one embodiment, a pharmaceutical composition is provided of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb or a pharmaceutically acceptable salt thereof, for use in pre-exposure prophylaxis (PrEP), i.e., preventing viral infection from taking root and / or establishing permanent infection and / or preventing the onset of disease symptoms and / or preventing the virus from reaching detectable levels in the blood prior to an individual's exposure to HIV.

[0427] In another embodiment, the use of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or pharmaceutically acceptable salts thereof, is disclosed in the preparation of a medicament for treating HIV infection in persons who are infected with HIV or at risk of HIV infection.

[0428] In another embodiment, the use of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or pharmaceutically acceptable salts thereof, as research tools are disclosed.

[0429] In another embodiment, an article of manufacture is disclosed comprising a composition effective in treating HIV infection; and packaging material including a label indicating that the composition can be used to treat HIV infection. Exemplary compositions comprise compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or pharmaceutically acceptable salts thereof.

[0430] In another embodiment, a method for inhibiting HIV replication is disclosed. The method comprises exposing the virus to an effective amount of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, or a salt thereof, under conditions that inhibit HIV replication.

[0431] In another embodiment, the use of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb to inhibit the activity of HIV integrase is disclosed.

[0432] In another embodiment, the use of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or salts thereof, for inhibiting HIV replication is disclosed.

[0433] V. Application

[0434] The compounds disclosed herein (also referred to herein as the active ingredients) may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0435] The compounds disclosed herein may be administered to an individual for the required period of time or duration according to an effective dosing regimen, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compounds are administered on a daily or intermittent schedule throughout the individual's life.

[0436] The specific dose level of the compounds disclosed herein for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. A dose between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dose between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dose between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting doses among subjects with large differences in size (such as when using the drug in children and adults, or when converting an effective dose for a non-human subject, such as a dog, to a dose suitable for a human subject).

[0437] The daily dose may also be described as the total amount of the compounds described herein administered per dose or per day. The daily dose of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, or their pharmaceutically acceptable salts or pharmaceutically acceptable tautomers, may be between about 1 mg and 4,000 mg, between about 2,000 and 4,000 mg / day, between about 1 and 2,000 mg / day, between about 1 and 1,000 mg / day, between about 10 and 500 mg / day, between about 20 and 500 mg / day, between about 50 and 300 mg / day, between about 75 and 200 mg / day, or between about 15 and 150 mg / day.

[0438] The dosage or frequency of administration of the disclosed compounds may be adjusted during treatment based on the judgment of the physician administering the medication.

[0439] The compounds disclosed herein can be administered in therapeutically effective amounts to an individual (e.g., a human). In some embodiments, the compounds are administered once daily.

[0440] The compounds provided herein may be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of the compounds may include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, therapeutic amounts of the compounds provided herein include from about 0.3 mg to about 30 mg / day, or from about 30 mg to about 300 mg / day, or from about 0.3 μg to about 30 mg / day, or from about 30 μg to about 300 μg / day.

[0441] The compounds disclosed herein may be combined with one or more additional therapeutic agents in any dose of the compounds disclosed herein (e.g., 1 mg to 1000 mg of compounds). Therapeuticly effective amounts may include about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective doses of compounds of formulas I, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb are about 1 mg / dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg / dose. Other therapeutically effective amounts of the compounds disclosed herein are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975 or about 1000 mg per dose.

[0442] In some embodiments, the method described herein involves administering an initial daily dose of about 1 mg to 500 mg of the compound described herein to a subject, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0443] When administered orally, the total daily dose for human subjects may be between about 1 mg and 1,000 mg, between about 10-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or between about 100-150 mg / day. In some embodiments, the total daily dose for human subjects may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / day as a single dose. In some embodiments, the total daily dose for human subjects may be about 200, 300, 400, 500, 600, 700, or 800 mg / day as a single dose. In some embodiments, the total daily dose for human subjects may be about 300, 400, 500, or 600 mg / day as a single dose.

[0444] In some embodiments, the total daily dose for a human subject may be about 100 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 150 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 200 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 250 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 300 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 350 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 400 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 450 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 550 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 600 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 650 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 700 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 750 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 800 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 850 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 900 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 950 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 1000 mg / day, administered as a single dose.

[0445] A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose may be administered every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or every 24 hours. A single dose may also be administered every 1, 2, 3, 4, 5, or 6 days, or every 7 days. A single dose may also be administered every 1, 2, or 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly. In some embodiments, the compounds disclosed herein are administered once daily using the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily using the methods disclosed herein.

[0446] The frequency of dosage of the compounds disclosed herein will be determined by the individual patient's needs and may be, for example, once daily or twice daily or more. Administration of the compounds may continue for the duration required to treat HBV infection, HIV infection, cancer, proliferative disorders, or any other indication described herein. For example, the compounds may be administered to individuals infected with HBV for a period of 20 to 180 days, or for a period of, for example, 20 to 90 days, or for example, 30 to 60 days.

[0447] Administration may be intermittent, with the patient receiving a daily dose of the disclosed compound for periods of several days or more, followed by periods of several days or more without receiving a daily dose of the compound. For example, the patient may receive a dose of the compound every other day or three times a week. Again, by way of example, the patient may receive a daily dose of the compound for periods of 1 to 14 days, followed by periods of 7 to 21 days without receiving a dose of the compound, followed by periods of receiving a daily dose of the compound again in subsequent periods (e.g., 1 to 14 days). The alternating periods of administration followed by non-administration of the compound may be repeated as needed to treat the patient's clinical needs.

[0448] The compounds or pharmaceutical compositions thereof disclosed herein may be administered once, twice, three or four times daily in any of the suitable modes described above. Furthermore, administration of the compound or treatment may continue for multiple days; for example, for a treatment cycle, treatment typically continues for at least 7, 14, or 28 days. Treatment cycles are well known in cancer chemotherapy and typically alternate with rest periods of approximately 1 to 28 days, typically approximately 7 or 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0449] VI. Combination Therapy

[0450] In some embodiments, a method for treating or preventing HIV infection in a person who is infected with HIV or at risk of HIV infection is provided, the method comprising administering to a person a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one, two, three, one or two, or one to three) supplemental therapeutic agents. In one embodiment, a method for treating HIV infection in a person who is infected with HIV or at risk of HIV infection is provided, the method comprising administering to a person a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one, two, three, one or two, or one to three) supplemental therapeutic agents.

[0451] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0452] In some embodiments, this disclosure provides a method for treating HIV infection, the method comprising administering to a patient in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents suitable for treating HIV infection.

[0453] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with three additional therapeutic agents. In still other embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0454] Administration of HIV combination therapy

[0455] In some embodiments, the compounds disclosed herein are administered together with one or more additional therapeutic agents. Co-administration of the compounds disclosed herein with one or more additional therapeutic agents generally means administering the compounds disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that therapeutically effective amounts of the compounds disclosed herein and one or more additional therapeutic agents are present in the patient. When administered sequentially, the combination may be administered in two or more doses.

[0456] Co-administration includes administering a unit dose of the compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours after administering one or more additional therapeutic agents. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents several hours (e.g., 1-12 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 disclosed herein several hours (e.g., 1-12 hours).

[0457] In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, as a solid dosage form for oral administration.

[0458] In some embodiments, the compounds of Formula I are formulated into tablets, which may optionally contain one or more other compounds that can be used to treat HIV. In some embodiments, the tablets may contain another active ingredient for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0459] In some implementations, such tablets are suitable for once-daily administration.

[0460] HIV combination therapy

[0461] In the above implementation scheme, the additional treatment agent may be an anti-HIV agent. HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T-cell CAR-T and engineered T-cell receptor TCR-T, autologous T-cell therapy), latency reversal agents, compounds targeting the HIV capsid, 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, HIV Vif gene modulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, CD4 modulators, CD4 antagonists, HIV ribonuclease H inhibitors, defensin modulators, CDK-9 inhibitors, CCR5 chemokine antagonists, CCR5 gene modulators, dendritic ICAM-3 grasping non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, hyaluronidase inhibitors, Nef antagonists, Nef inhibitors, protease-activated receptor-1 antagonists, TNFα ligand inhibitors, PDE4 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.

[0462] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0463] HIV combination therapy

[0464] Examples of combination drugs include (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (Bimetiravir, Emtricitabine and Tenofovir Alambutamide); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistat and erteiravir); (Direravir, Tenofovir Alamonamide hemifumarate, Emtricitabine, and Cobistat); SYMFITM (Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate); CIMDUTM (Lamivudine and Tenofovir Disoproxil Fumarate); Tenofovir and Lamivudine; Tenofovir Alamonamide and Emtricitabine; Tenofovir Alamonamide hemifumarate and Emtricitabine; Tenofovir Alamonamide hemifumarate, Emtricitabine, and Rilpivirine; Tenofovir Alamonamide hemifumarate, Emtricitabine, Cobistat, and Aviravir; (zidovudine and lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); ( lopinavir and ritonavir); (Durutvir, Abacavir and Lamivudine); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Deruravir and cobistat; Dulutegravir and rilpivirine; Dulutegravir and rilpivirine hydrochloride; Dulutegravir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Rettagvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Dapivirine + levonorgestrel, Dulutegravir + lamivudine Durutvir + Emtricitabine + Tenofovir Alamenosamine, Alfavirine + Emtricitabine + Tenofovir Disoproxil Fumarate, 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, and Lamivudine.

[0465] Other HIV medications

[0466] Examples of other medications used to treat HIV include acetaminophen, arapovir, atorvastatin, BanLec, CC-11050, deferiphenone, gamimune, grenoferrin, mitfalin, naltrexone, prolastin, REP 9, RPI-MN, Vorapaxar, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, MK-8527, BlockAide, PSC-RANTES, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, and IMO. -3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SC Y-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

[0467] HIV protease inhibitors

[0468] Examples of HIV protease inhibitors include ampravir, atazanavir, becanavir, drenellavir, fossavir, fossavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911.

[0469] HIV reverse transcriptase inhibitors

[0470] Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include dapirine, deraviridine, deraviridine mesylate, doravirine, efavirenz, ectrevirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, and isavirin (VM-1500).

[0471] Examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate. and VIDEX (Didanovic, DDL), Abacavir, Abacavir sulfate, Alovudine, Alitabin, Cinovudine, Didanovic, Avtabin, Fertinavir, Fivudinetimate, CMX-157, Dapivirine, Doravirine, Etravirine, OCR-5753, Tenofovir disoproxil fumarate, Fivudinetimate, Islatravir, Lamivudine, Azoxyphosphine, Stavudine, Zacitabine, Zidovudine, Rovafovir-Etalaflavinamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500 and KP-1461.

[0472] HIV integrase inhibitors

[0473] Examples of HIV integrase inhibitors include avermectin, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine kinase inhibitors, tyrosine kinase inhibitor derivatives, quercetin, quercetin derivatives, retegvir, dulutexvir, JTK-351, bicretiravir, AVX-15567, and BMS-98. 6197, Cabotevir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and Cabotevir.

[0474] Examples of HIV noncatalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442.

[0475] HIV entry inhibitors

[0476] Examples of HIV entry (fusion) inhibitors include cineviro, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors.

[0477] Examples of CCR5 inhibitors include apravirone, vevicvirone, maravirone, sinevicvirone, leronlimab (PRO-140), adatavir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu).

[0478] Examples of gp41 inhibitors include EbvoVita, Enfvirtide, BMS-986197, Enfvirtide biomodifiers, Enfvirtide biosimilars, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and Sifvirtide.

[0479] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0480] Examples of gp120 inhibitors include Radha-108 (receptor alcohol) 3B3-PE38, BanLec, bentonite-based nanomedicine, Fostersavir tromethamine, IQP-0831, and BMS-663068.

[0481] Examples of CXCR4 inhibitors include plexafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0482] HIV maturation inhibitors

[0483] Examples of HIV maturation inhibitors include BMS-955176, BMS-986197, GSK-3640254, and GSK-2838232.

[0484] Latency reversal agents

[0485] Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as velcade and ixazomib citrate), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-Bromo domain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (saturated aniline hydroxamic acid or saturated aniline, aniline and hydroxamic acid), IL-15 modulatory antibodies, JQ1, disulfiram, amphotericin B and ubiquitin inhibitors (such as lagozolar analogs), as well as APH-0812 and GSK-343.

[0486] Examples of HDAC inhibitors include romidesin, vorinostat, and pabistat.

[0487] Examples of PKC activators include indolinamide, prostratin, phorbol B, and DAG-lactone.

[0488] Capsid inhibitors

[0489] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-destroying compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, and the GS-6207, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

[0490] Immunotherapy

[0491] Examples of immunotherapy-based therapies include Toll-like receptor modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; hydroxychloroquine (hydroxychloroquine); prazolam (aldeleukin, IL-2); interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivatives. MMF; Ribavirin; Polyethyleneimine (PEI); Gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107; Interleukin-15 / Fc fusion protein; AM-0015; ALT-803; NIZ-985; NKTR-255; NKTR-262; NKTR-214; Norfloxacin; Pegylated Interferon α-2a; Pegylated Interferon α-2b; Recombinant Interleukin-15; Xmab-24306; RPI-MN; STING modulator; RIG-I modulator; NOD2 modulator; SB-9200; and IR-103.

[0492] Examples of TLR agonists: Vesamimod (GS-9620), GS-986, IR-103, Lefemod, Tilsotolimod, Rintatlimod, DSP-0509, AL-034, G-100, Cobitolimod, AST-008, Motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, Telratolimod.RO-7020531.

[0493] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0494] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, orotic acid (CAI), copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifoxine, pictilisib, pilaralisib, praquitinib mesylate, regoratinib, regoratinib sodium, sonolisib, and taselisib. , AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY -3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

[0495] α-4 / β-7 antagonists

[0496] Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, alirumab, itralizumab, carotegrast methyl, and vedolzumab.

[0497] HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0498] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include: Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bnAB (broadly neutralizing HIV-1 antibody), BMS-936559, TMB-360 and antibodies targeting HIV gp120 or gp41, HIV-targeting antibody recruitment molecules, anti-CD63 monoclonal antibodies, CD3 bispecific antibodies, CD16 bispecific antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, recombinant human mAb (PGT-121), ibalizumab, Immuglo, MB-66.

[0499] Examples of antibodies that target HIV in this way include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, D1D2, 10-1074, 10-1074-LS, GS-9722, DH411-2, BG18, PGT145, and PG. T121, PGT122, PGT-151, PGT-133, PGT-135, PGT-128, 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, PG9, PG16, 8ANC195, 2Dm2m, 4Dm2m, 6Dm2m, VRC-01, VRC-01-LS, PGDM1400, A32, 7B2 , 10E8, 10E8VLS, 3810109, 10E8v4, 10E8.4 / iMab, VRC-01 / PGDM-1400 / 10E8v4, IMC-HIV, i Examples of HIV bispecific antibodies include Mabm36, 10E8v4 / PGT121-VRC01, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples of HIV bispecific antibodies include MGD014 and TMB bispecific antibodies.

[0500] Examples of in vivo delivered bnAB include AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01.

[0501] Pharmacokinetic enhancers

[0502] Examples of pharmacokinetic enhancers include cobistat and ritonavir.

[0503] Additional therapeutic agents

[0504] Examples of additional therapeutic agents include WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (GileadSciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728(Gilead Sciences), WO2013 / 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 Compounds disclosed in WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (PharmaResources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0505] HIV vaccine

[0506] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines using viral vectors (such as arenavirus, lymphocytic choriomeningovirus (LCMV), Pitender virus, modified vaccinia ani virus (MVA), adenovirus, adeno-associated virus (AAV), vesicular stomatitis virus (VSV), and chimpanzee adenovirus (ChAd)), DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, BG505 SOSIP.664gp140, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, and Contre Vir, Ad4-Env145NFL, Ad5-ENVA-48, HB-500, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, Vacc-CRX, VVX-004, VAC-3S, Multi-level DNA Recombinant Adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, Poly-ICLC Adjuvanted Vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1 , NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, 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, IHV-001 and virus-like particle vaccines (such as pseudovirus vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-stage Env vaccine, MVA vaccine, Pennvax-GP, pp71 defective HCMV vector HIV GAG vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidesin, variant gp120 peptide vaccine, rAd5gag-pol env A / B / C vaccine, DNA.HTI, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; based on eOD-GT8 60mer vaccines, PD-201401, env(A, B, C, A / E) / gag(C) DNA vaccines, gp120(A, B, C, A / E) protein vaccines, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccines (GLA-SE adjuvant), HIV p24gag primary-boost plasmid DNA vaccines, isanoxic virus vector-based immunotherapies (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimens, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV gp120, mRNA-based prophylactic vaccines, TBL-1203HI, VRC-HIVRGP096-00-VP, VAX-3S, and HIV MAG DNA vaccines.

[0507] HIV combination therapy

[0508] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents selected from the following: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistatin and ertiravir); Adefovir; Adefovir dipyridamole; Cobistatin; Emtricitabine; Tenofovir; Tenofovir disoproxil fumarate; Tenofovir disoproxil fumarate; Tenofovir alafenamide hemifumarate; (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derreravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertirapvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derreravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefernavir; Nefernavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efaviraxyl, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate.

[0509] Those skilled in the art will understand that the additional therapeutic agents listed above may include more than one of the categories listed above. Specific categories are not intended to limit the function of the compounds listed in those categories.

[0510] In one specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitor. In yet another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In yet another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0511] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are used in combination with HIV capsid inhibitors and / or nucleoside reverse transcriptase translocation inhibitors. In some embodiments, the compounds disclosed herein are used in combination with lenacapavir and / or isilavir. In some embodiments, the compounds disclosed herein are used in combination with lenacapavir. In some embodiments, the compounds disclosed herein are used in combination with isilavir.

[0512] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide fumarate.

[0513] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate.

[0514] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a first adjunctive therapeutic agent and a second adjunctive therapeutic agent, the first adjunctive therapeutic agent being selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and the second adjunctive therapeutic agent being selected from the group consisting of emtricitabine and lamivudine.

[0515] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a first adjunctive therapeutic agent and a second adjunctive therapeutic agent, the first adjunctive therapeutic agent being selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, wherein the second adjunctive therapeutic agent is emtricitabine.

[0516] Compounds disclosed herein (e.g., any compound of Formula I) may be combined with one or more additional therapeutic agents at any dose of a compound of Formula I (e.g., 1 mg to 500 mg of compound).

[0517] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemisphericate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemisphericate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemisphericate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. Compounds disclosed herein (e.g., compounds of Formula I) may be combined with the pharmaceutical agents provided herein in any dosage (e.g., 1 mg to 500 mg of the compound), as each combination of dosages is specifically and individually listed.

[0518] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate and 200 mg of emtricitabine. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate and 200 mg of emtricitabine. Compounds disclosed herein (e.g., compounds of formula I) may be combined with the pharmaceutical agents provided herein in any dosage (e.g., 1 mg to 500 mg of the compound), as each combination of dosages is specifically and individually listed.

[0519] In one embodiment, a kit is provided comprising a combination of the compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0520] Birth control (contraceptive pill) combination therapy

[0521] Therapeutic agents (contraceptives) used to control birth include cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etogestene, levonorgestrel, levonorgestrel, linegestrel, medroxyprogesterone acetate, ethinylestradiol methyl ether, mifepristone, misoprostol, nomexone acetate, noregestrel, norethindrone, olmexifen, segestersone acetate, ullistat acetate, and any combination thereof.

[0522] Gene therapy and cell therapy

[0523] Gene therapy and cell therapy include genetic modification of silent genes; gene methods that directly kill infected cells; infusion of immune cells designed to replace most of the patient’s own immune system to enhance the immune response to infected cells, or to activate the patient’s own immune system to kill infected cells, or to locate and kill infected cells; and gene methods that modify cell activity to further alter the endogenous immune response to infection.

[0524] Examples of dendritic cell therapy include AGS-004.

[0525] Examples of CCR5 gene-editing drugs include SB-728T.

[0526] Examples of CCR5 gene inhibitors include Cal-1.

[0527] CD4-positive T cells expressing C34-CCR5 / C34-CXCR4.

[0528] AGT-103-transduced autologous T-cell therapy.

[0529] AAV-eCD4-Ig gene therapy.

[0530] Gene-edited products

[0531] Genome editing systems were selected from the following groups: CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and large-scale nuclease system.

[0532] Examples of HIV targeting the CRISPR / Cas9 system include EBT-101.

[0533] CAR-T cell therapy

[0534] The immune effector cell population is engineered to express a chimeric antigen receptor (CAR), wherein the CAR contains an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-induced binding site on gp120, an N-glycan on gp120, V2 of gp120, and a proximal membrane region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic.

[0535] Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CART cell therapy, and autologous hematopoietic stem cells genetically engineered to express CD4CAR and C46 peptides.

[0536] TCR-T cell therapy

[0537] TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells.

[0538] VII. Examples

[0539] Exemplary chemical entities of this disclosure are provided in the following specific embodiments. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, the starting materials may be suitably selected such that the final desired substituent will be carried out in a reaction scheme, with or without 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 out in the reaction scheme and, if appropriate, substituted with the desired substituent. Furthermore, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the particular side groups.

[0540] The examples provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare these compounds. It should be understood that the various steps described herein can be combined. It should also be understood that individual batches of compounds can be combined and then continued in the next synthesis step.

[0541] In the following examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of the present disclosure. Therefore, the following description is not intended to limit the scope of the present disclosure.

[0542] Example 1: ((6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, Preparation of nitrogen-indene-9-carboxamide (1) in 10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0543]

[0544] Step 1. Synthesis of tert-butyl 1-amino-3-cyanozyrazine-heptane-1-carboxylate (1a) :

[0545] 3-oxazacycloheptan-1-carboxylic acid tert-butyl ester (3.5 g, 16.4 mmol), potassium cyanide (1.60 g, 24.6 mmol), and ammonium chloride (1.32 g, 24.6 mmol) in ammonium hydroxide (19.5 mL), ethanol (20 mL), and water (6.5 mL) were heated overnight at 60 °C. The reaction mixture was concentrated to about 30 mL and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and purified by CombiFlash (80 g, ethyl acetate / hexane) to give the title compound. MS (m / z) 239.82 [M+H] + .

[0546] Step 2: Synthesis of tert-butyl 3-((tert-butoxycarbonyl)amino)-3-cyanozyrazine-1-heptane-1-carboxylate (1b) :

[0547] To a solution of tert-butyl 3-amino-3-cyano-azacycloheptan-1-carboxylate (1a, 3.3 g, 13.8 mmol) in ethyl acetate (20 mL), saturated sodium carbonate (5 mL) and di-tert-butyl dicarbonate (4.51 g, 20.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was extracted with dichloromethane (3×), dried (MgSO4), filtered, and concentrated. The residue was purified via CombiFlash (80 g, ethyl acetate / hexane) to give the title compound and the recovered starting material. MS (m / z) 339.9 [M+H] + .

[0548] Step 3: Synthesis of 3-((tert-butoxycarbonyl)amino)-3-formylazetane-1-carboxylic acid tert-butyl ester (1c) become :

[0549] tert-butyl 3-((tert-butoxycarbonyl)amino)-3-cyanozazirconium-1-carboxylate (1b, 0.952 g, 2.81 mmol) was added to a solution of 3-(tert-butoxycarbonyl)amino)-3-cyanozazirconium-1-carboxylate in dichloromethane (14.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 20 h. Further addition of bis(cyclopentadienyl)zirconia(IV) hydride (1.45 g, 5.61 mmol) was added, and the reaction mixture was warmed to room temperature over 3 h. The reaction mixture was adsorbed onto silica gel, loaded into a dry loading tube, and purified by CombiFlash (120 g, 0-30% EtOAc / Hex) to give the title compound. MS (m / z) 342.73 [M+H] + .

[0550] Step 4: 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-3- Synthesis of tert-butyl (tert-butoxycarbonyl)amino)azacycloheptan-1-carboxylate (1d) :

[0551] A solution of 1.0 M lithium diisopropylamino in THF / hexane (2.30 mL, 2.30 mmol) was added dropwise to a solution of methyl 3-(benzyloxy)-6-((dimethoxyphosphoryl)methyl)-4-oxo-4H-pyran-2-carboxylate (prepared according to WO2018102485) (0.826 g, 2.16 mmol) in THF (15 mL) at -78 °C. The reaction mixture was stirred for 60 min, and then a solution of tert-butyl 3-((tert-butoxycarbonyl)amino)-3-carboxylated aziridine-1-carboxylate (1 c, 0.370 g, 1.08 mmol) in THF (5.0 mL) was added. The reaction mixture was stirred at -78 °C for 0.5 h, and then warmed to -40 °C. After 1 h, the reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched with 1 N HCl, brine was added, and the mixture was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, concentrated, and purified by CombiFlash (120 g, 0-60% EtOAc / Hex) to give the title compound. MS (m / z) 598.88 [M+H] + .

[0552] Step 5: 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-3- Synthesis of (tert-butoxycarbonyl)amino)azacycloheptan-1-carboxylic acid tert-butyl ester (1e) :

[0553] A solution of 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-3-((tert-butoxycarbonyl)amino)azacycloheptane-1-carboxylate tert-butyl ester (1 day, 490 mg, 0.80 mmol) and 20% wet carbon-supported palladium hydroxide (114 mg) in THF (20 mL) was stirred for 1 hour. The reaction mixture was filtered through a diatomaceous earth pad, washed with ethyl acetate, and concentrated to give 3-((tert-butoxycarbonyl)amino)-3-(2-(5-hydroxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)azacycloheptane-1-carboxylate tert-butyl ester, which was used in the next step without further purification.

[0554] 0.427 g of tert-butyl 3-((tert-butoxycarbonyl)amino)-3-(2-(5-hydroxy-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)azacycloheptan-1-carboxylate was dissolved in DMF (8 mL), and benzyl bromide (193 μL, 1.63 mmol) and potassium carbonate (0.451 g, 3.26 mmol) were added. The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% LiCl solution (3×) and brine, dried (MgSO4), and filtered. Concentration and purification (40 g, 0-60% EtOAc / Hex) gave the title compound. MS (m / z) 600.83 [M+H] + .

[0555] Step 6: 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9, Synthesis of indene-1,10-dione (1f) from 1,2-cd] :

[0556] A solution of tert-butyl 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)ethyl)-3-((tert-butoxycarbonyl)amino)azacycloheptan-1-carboxylate (1e, 0.252 g, 0.410 mmol) and trifluoroacetic acid (2.0 mL) in dichloromethane (10.0 mL) was stirred at 0 °C for 2 hours, and then warmed to room temperature over 4 hours. The reaction mixture was concentrated and dried under high vacuum overnight.

[0557] The methyl 6-(2-(3-aminoazacycloheptan-3-yl)ethyl)-3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylate ester was dissolved in ethanol (10 mL) and heated at 90 °C for 5 hours. The reaction mixture was concentrated and purified by CombiFlash (24 g, 0-20% MeOH / CH2Cl2) to give the title compound. MS (m / z) 351.28 [M+H] + .

[0558] Step 7: 11-(benzyloxy)-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonane Synthesis of N-indene-1,10-dione in [9,1,2-cd] :

[0559] To a solution of 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]-indene-1,10-dione (1f, 260 mg, 0.626 mmol) in anhydrous methanol (6.3 mL), 3-chloroperoxybenzoic acid (0.432 g, 2.51 mmol) was added, followed by N-iodosuccinimide (0.564 g, 2.51 mmol). The reaction mixture was heated at 70 °C for 15 min. The reaction mixture was diluted with dichloromethane and washed with 10% sodium sulfite. The aqueous layer was back-extracted, and the combined organic layers were dried (MgSO4), filtered, and concentrated. The title compound was purified by CombiFlash (40 g, 0-10% MeOH / CH2Cl2). MS (m / z) 477.14 [M+H] + .

[0560] Step 8: 11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octadecyl Synthesis of indene-9-carboxamide (1 g) from hydrogen-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0561] To a solution of 11-(benzyloxy)-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]-indene-1,10-dione (210 mg, 0.441 mmol) in DMSO (6.5 mL), 2,4,6-trifluorobenzylamine (355 mg, 2.20 mmol), N,N-diisopropylethylamine (384 μL, 2.20 mmol), and tetra(triphenylphosphine)palladium (25.5 mg, 0.022 mmol) were added. The reaction mixture was degassed under vacuum and backfilled with CO (3×). The reaction mixture was slowly aerated with CO using a 22-gauge needle connected to a CO-filled gas bag and heated at 80 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 0.05 N HCl, saturated sodium bicarbonate solution, and brine, dried (MgSO4), and concentrated. The residue was purified by CombiFlash (40 g, 0-100% EtOAc / Hex) to obtain the desired product. MS (m / z) 538.15 [M+H] + .

[0562] Step 9: (6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, 10-Octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (1h-1) and (6aS)- 11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene Resolution of indene-9-carboxamide (1h-2) in [1,4]diazanonacyclo[9,1,2-cd] :

[0563] The racemic 11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (119 mg) was resolved using chiral SFC (IB, 30% MeOH).

[0564] (6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide: Peak 1, MS (m / z) 538.16 [M+H] + .

[0565] (6aS)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide: Peak 2, MS (m / z) 538.18 [M+H] + .

[0566] Step 10: (6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10- Synthesis of nitro-indene-9-carboxamide (1) in octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0567] Trifluoroacetic acid (1.0 mL) was added to a solution of (6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]-indene-9-carboxamide (1 h⁻¹, 37 mg, 0.069 mmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was aged in a refrigerator for 30 h. The reaction mixture was concentrated and purified by Gilson HPLC (Gemini 5-100% ACN / H₂O + 0.1% TFA), and lyophilized to give the title compound. MS (m / z) 448.24 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.07–6.79 (m, 2H), 4.73–4.54 (m, 2H), 4.35 (dt, J = 13.4, 8.0 Hz, 1H), 3.98–3.73 (m, 3H), 3.49 (ddd, J = 18.8, 11.2, 7.7 Hz, 1H), 3.19 (ddd, J = 13.2, 7.0, 3.4 Hz, 1H), 2.31–2.07 (m, 3H), 2.07–1.85 (m, 3H), 1.79 (dd, J = 15.6, 6.9 Hz, 1H), 1.39–1.23 (m, 1H).

[0568] Example 2: (6aS)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, Preparation of nitrogen-indene-9-carboxamide (2) in 10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0569]

[0570] (6aS)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (1) was prepared in a similar manner to (6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (2), except in step 10 Using (6aS)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (1h-2) instead of (6aR)-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (1h-1). MS (m / z) 448.19 [M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 10.79 (t, J = 5.0 Hz, 1H), 8.77 (s, 1H), 6.75–6.59 (m, 2H), 4.65 (qd, J = 14.4, 5.4 Hz, 2H), 4.44 (dt, J = 13.7, 8.1 Hz, 1H), 4.10 (dd, J = 18.9, 8.3 Hz, 1H), 3.81–3.61 (m, 2H) ),3.53(ddd,J=19.0,11.5,7.7Hz,1H),3.14(ddd,J=13.7,7.2,3.3Hz,1H),2.15(dddd,J=3 1.2, 18.6, 11.4, 5.4Hz, 4H), 1.83 (dddd, J=23.1, 16.1, 12.3, 5.0Hz, 3H), 1.42–1.26 (m, 1H).

[0571] Example 3: (6aR)-N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10- Preparation of nitro-indene-9-carboxamide (3) in octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0572]

[0573] (6aR)-N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (3) was prepared in a similar manner to (6aR)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (3), except that 2,4-difluorobenzylamine was used instead of 2,4,6-trifluorobenzylamine in step 8. MS (m / z) 430.30 [M+H] + . 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.44 (q, J = 8.4 Hz, 1H), 7.02–6.88 (m, 2H), 4.68–4.54 (m, 2H), 4.37 (dt, J = 13.6, 7.9 Hz, 1H), 3.99–3.74 (m, 3H), 3.57–3.44 (m, 1H), 3.24–3.13 (m, 1H), 2.29–2.06 (m, 3H), 2.04–1.86 (m, 3H), 1.86–1.72 (m, 1H), 1.32 (q, J = 12.7, 12.2 Hz, 1H).

[0574] Example 4: (6aS)-N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10- Preparation of 4-nitrogen-indene-9-carboxamide in octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0575]

[0576] (6aS)-N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (4) was prepared in a similar manner to (6aR)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (4), except that 2,4-difluorobenzylamine was used instead of 2, 4,6-Trifluorobenzylamine, and in step 10, (6aS)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (1h-2) instead of (6aR)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (1h-1). MS (m / z) 430.31 [M+H] + . 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.44 (q, J = 8.3 Hz, 1H), 7.05–6.87 (m, 2H), 4.68–4.55 (m, 2H), 4.37 (dt, J = 13.5, 8.0 Hz, 1H), 3.98–3.75 (m, 3H), 3.51 (ddd, J = 18.7, 11.5, 7.7 Hz, 1H), 3.24–3.14 (m, 1H), 2.30–2.09 (m, 3H), 2.09–1.86 (m, 3H), 1.81 (dd, J = 15.8, 6.5 Hz, 1H), 1.39–1.25 (m, 1H).

[0577] Example 5: (6aR)-N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10- Preparation of nitro-indene-9-carboxamide (5) in octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0578]

[0579] (6aR)-N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (5) was prepared in a similar manner to (6aR)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (5), except that 3-chloro-2-fluorobenzylamine was used instead of 2,4,6-trifluorobenzylamine in step 8. MS (m / z) 446.30 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.43–7.38(m,1H),7.35(t,J=7.2Hz,1H),7.14(t,J=7. 8Hz,1H),4.69(dd,J=15.4,5.3Hz,2H),4.37(dt,J=13.7,8.1Hz,1H),3.98–3 .74(m,3H),3.58–3.44(m,1H),3.20(ddd,J=12.3,7.0,3.7Hz,1H),2.31–2.0 9(m,3H),2.08–1.86(m,3H),1.86–1.73(m,1H),1.32(q,J=12.8,12.4Hz,1H).

[0580] Example 6: (6aS)-N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10- Preparation of nitro-indene-9-carboxamide (6) in octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0581]

[0582] (6aS)-N-(3-chloro-2-fluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (6) was prepared in a similar manner to (6aR)-11-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (6), except that 3-chloro-2-fluorobenzylamine was used instead of 2, 4,6-Trifluorobenzylamine, and in step 10, (6aS)-11-(benzyloxy)-N-(3-chloro-2-fluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (1h-2) instead of (6aR)-11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (1h-1). MS (m / z) 446.30 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.43–7.38(m,1H),7.35(t,J=7.2Hz,1H),7.14(t,J=7. 8Hz,1H),4.69(dd,J=15.4,5.3Hz,2H),4.37(dt,J=13.7,8.1Hz,1H),3.98–3 .74(m,3H),3.58–3.44(m,1H),3.20(ddd,J=12.3,7.0,3.7Hz,1H),2.31–2.0 9(m,3H),2.08–1.86(m,3H),1.86–1.73(m,1H),1.32(q,J=12.8,12.4Hz,1H).

[0583] Example 7: ((6aR)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, Preparation of nitrogen-indene-9-carboxamide (7) in 10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0584]

[0585] Step 1: 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1, Synthesis of methyl indene-9-carboxylate (7a) in diazanonacyclo[9,1,2-cd] :

[0586] N,N-diisopropylethylamine (185 μL, 1.06 mmol) and tetrakis(triphenylphosphine)palladium (0.021, 0.018 mmol) were added to a solution of 7-benzyloxy-5-iodo-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadecyl-4,7-diene-6,9-dione (0.169 g, 0.355 mmol) in anhydrous tetrahydrofuran (2.0 mL) and anhydrous methanol (2.0 mL). The reaction mixture was degassed under vacuum and backfilled with CO (3×). The reaction mixture was aerated with CO using an 18-gauge needle connected to a CO-filled gas bag and heated at 65 °C for 18 hours. Add additional methanol (4.0 mL) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.029 g, 0.0355 mmol), and heat the reaction mixture under a CO atmosphere (1 atm) for 24 hours. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with 0.05 N HCl, saturated sodium bicarbonate solution, and brine. Dry (MgSO4) and concentrate. Purify the crude product using CombiFlash (40 g, 0-100% EtOAc / Hept) to obtain the desired product. MS (m / z) 409.1 [M+H] + .

[0587] Step 2: 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1, Synthesis of indene-9-carboxylic acid (7b) in diazanonacyclo[9,1,2-cd] :

[0588] A solution of methyl indene-9-carboxylate (7a) (46 mg, 0.113 mmol) of 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]-indene (7a) (5 M, 68 μL, 0.338 mmol) in THF (1.0 mL) and methanol (0.5 mL) was heated at 45 °C for 2 hours. The reaction mixture was acidified with 1 M HCl and extracted with ethyl acetate (3 ×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the desired product, which could be used in the next step without further purification. MS (m / z) 395.05 [M+H] + .

[0589] Step 3: 11-(benzyloxy)-1,10-dioxo-N'-(2-(2,4,6-trifluorophenyl)thioacetyl)-1,3, 4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]monazine-9-carbonylhydrazine (7d) Synthesis :

[0590] N-methylmorpholine (49 μL, 0.446 mmol) and isobutyl chloroformate (19 μL, 0.145 mmol) were added to a solution of 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]-indene-9-carboxylic acid (7b) (44 mg, 0.112 mmol) in anhydrous THF (2.0 mmol) at 0 °C. The reaction mixture was stirred for 2 h. 2-(2,4,6-trifluorophenyl)thioacetylhydrazine TFA salt (7c) (55.9 mg, 0.167 mmol) was added, followed by N-methylmorpholine (49 μL, 0.446 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was diluted with ethyl acetate, washed with saturated bicarbonate, dried (MgSO4), filtered, and concentrated. The reaction product can be used in the next step without further purification. MS (m / z) 596.93 [M+H] + .

[0591] Step 4: 11-(benzyloxy)-9-(5-(2,4,6-trifluorobenzyl)-1,3,4-thiadiazol-2-yl)-3,4,5,6,7, Synthesis of indene-1,10-dione (7e) in 8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0592] 11-(benzyloxy)-1,10-dioxo-N'-(2-(2,4,6-trifluorophenyl)thioacetyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]nidene-9-carbazide (7d) (approximately 0.0033 mmol) was dissolved in acetic acid (1.5 mL) and heated at 100 °C for 7 hours. The reaction mixture was concentrated, purified by Gilson HPLC (Gemini, 5-100% ACN / H₂O + 0.1% TFA), and lyophilized to give the desired product. MS (m / z) 489.36 [M+H] + .

[0593] Step 5: 11-Hydroxy-9-(5-(2,4,6-trifluorobenzyl)-1,3,4-thiadiazol-2-yl)-3,4,5,6,7,8-hexadecyl Synthesis of N-indene-1,10-dione (7) in hydrogen-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0594] A solution of 7-benzyloxy-5-[5-[(2,4,6-trifluorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-10,15-diazatetracyclo[6.6.1.11,10.04,15]hexadec-4,7-diene-6,9-dione (7e) (1.5 mg, 0.0026 mmol) and trifluoroacetic acid (0.5 mL) in toluene (1.0 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and purified by Gilson HPLC (Gemini, 5-100% ACN / H2O + 0.1% TFA), followed by lyophilization to give the desired product. MS (m / z) 579.04 [M+H]+ . 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.05–6.88 (m, 2H), 4.52 (s, 2H), 4.38 (dt, J = 13.3, 8.1 Hz, 1H), 4.05 (dd, J = 18.5, 7.6 Hz, 1H), 3.96 (d, J = 14.2 Hz, 1H), 3.86 (d, J = 14.1 Hz, 1H), 3.67 (ddd) ,J=18.7,10.9,8.0Hz,1H),3.23(dq,J=9.9,3.5Hz,1H),2.47–2.18(m,3H),1.99(ddd, J=32.1,14.1,6.8Hz,3H),1.83(dd,J=13.7,5.7Hz,1H),1.33(q,J=11.2,10.7Hz,1H).

[0595] Example 8: (6aS,8S)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (8-1) and (6aR,8R)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2, Preparation of nitro-indene-9-carboxamide (8-2) in 6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0596]

[0597] Step 1. 11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonane Synthesis of indene-1,10-dione (8a) from [9,1,2-cd] :

[0598] Under Ar(g) conditions, N-fluorobenzenesulfonamide (0.135 g, 0.428 mmol) was added to a solution of 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] in an indene-1,10-dione (0.050 g, 0.143 mmol) in THF (3 mL) prepared according to intermediate 1f in Example 1. The reaction mixture was cooled to -78 °C and a 1.0 M solution of LiHMDS in THF (0.428 mL, 0.428 mmol) was added dropwise. After stirring for 0.5 hours, the reaction was warmed to room temperature and stirred overnight. Methanol was added for quenching, and the solution was concentrated. The residue was purified by column chromatography (0-20% MeOH / CH2Cl2) to give 11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione. MS (m / z) 369.26 [M+H] + .

[0599] Step 2. 11-(benzyloxy)-8-fluoro-9-iodine-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazide Synthesis of N-indene-1,10-dione (8b) in heterocyclic [9,1,2-cd] :

[0600] To a solution of 11-(benzyloxy)-8-fluoro-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] inden-1,10-dione (0.022 g, 0.059 mmol) in anhydrous methanol (0.5 mL), 77% m-CPBA (m-chloroperbenzoic acid) (0.053 g, 0.237 mmol) and N-iodosuccinimide (0.053 g, 0.237 mmol) were added. The reaction mixture was heated at 80 °C for 24 hours and cooled to room temperature. The solution was diluted with CH2Cl2 and washed with 10% Na2SO3 aqueous solution. The aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% MeOH / CH2Cl2) to give 11-(benzyloxy)-8-fluoro-9-iodide-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione. MS (m / z) 495.10 [M+H] + .

[0601] Step 3. 11-(benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8, Synthesis of indene-9-carboxamide (8c) in 10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0602] To a solution of 11-(benzyloxy)-8-fluoro-9-iodide-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] in DMSO (1 mL), 2,4,6-trifluorobenzylamine (0.042 g, 0.263 mmol), i-Pr2NEt (0.046 mL, 0.263 mmol), and Pd(PPh3)4 (0.003 g, 0.003 mmol) were added. The reaction flask was evacuated and backfilled three times with CO(g), and then heated to 80 °C for 4 hours at 1 atm of CO(g). After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with 0.05N HCl (1×), saturated NaHCO3 aqueous solution (1×), and brine (1×). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-100% EtOAc / heptane) to give 11-(benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide. MS (m / z) 556.17 [M+H] + .

[0603] Step 4. (6aS,8S)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (8-1) and (6aR,8R)-8-fluoro-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2, Synthesis of indene-9-carboxamide (8-2) in 6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0604] Racemic -(6aR,8S)-11-(benzyloxy)-8-fluoro-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]nidene-9-carboxamide was isolated into its individual enantiomers using a preparative SFC on an AD-H column with 40% MeOH cosolvent, yielding two isolated enantiomers. Each isolated enantiomer was dissolved in 1:1 toluene / TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in MeCN and purified by preparative HPLC (column, Gemini 10μC18 110A, AXI / ; 250 × 21.2 mm), eluting over 30 minutes with 5–100% acetonitrile (0.1% TFA) and water (0.1% TFA). The combined fractions were lyophilized to give the title compound. Absolute configuration was not confirmed.

[0605] Peak 1: MS (m / z) 466.24 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ10.83(t,J=5.7Hz,1H),7.30–7.16(m,2H),6.84–6.69(m,1H),4.61( dd,J=14.5,5.8Hz,1H),4.52(dd,J=14.6,5.5Hz,1H),4.19(dt,J=12.8,7.4Hz,1H),3.86(d,J =14.3Hz,1H),3.68(d,J=14.2Hz,1H),3.05(dt,J=12.3,5.7Hz,1H),2.44(d,J=2.9Hz,1H),2 .38(s,1H),2.16–2.00(m,2H),1.83(dd,J=15.6,8.1Hz,2H),1.74–1.65(m,1H),1.24(s,1H). 19 F NMR (376MHz, DMSO-d6) δ-109.31 (ddd, J=15.5, 9.3, 6.4Hz), -112.48 (t, J=7.2Hz), -167.67 (ddd, J=50.1, 35.0, 24.1Hz).

[0606] Peak 2: MS (m / z) 466.27 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.82(t,J=5.7Hz,1H),7.31–7.13(m,2H),6.85–6.63(m,1H),4.60(dd,J=14.6,5.9Hz,1H),4.51(dd,J=14.5,5.5Hz,1H),4.19(dt,J=14.0,7.4Hz,1H),3.86(d,J=14.3Hz,1H),3.67(d,J=14.2Hz,1H),3.04(dt,J=12.5,5.8Hz,1H),2.44(d,J=3.0Hz,1H),2.40–2.29(m,1H),2.16–1.98(m,2H),1.90–1.77(m,2H),1.69(d,J=16.1Hz,1H),1.33–1.18(m,1H)。 19 F NMR(376MHz,DMSO-d6)δ-109.31(tt,J=9.4,6.4Hz),-112.48(t,J=7.2Hz),-167.67(ddd,J=50.0,35.1,24.2Hz)。

[0607] Example 9: (6aS,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (9-1), (6aR,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2, 6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (9-2), (6aS,8S)-8,11-dihydroxy 1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]di Inza-indene-9-carboxamide (9-3) and (6aR,8S)-8,11-dihydroxy-1,10-dioxo-N- inzanonacyclo[9,1,2-cd] (2,4,6-Trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2- Preparation of nitrogen-indene-9-carboxamide (9-4) in cd] :

[0608]

[0609] Step 1. 11-(benzyloxy)-8-hydroxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanin Synthesis of indene-1,10-dione (9a) in cyclo[9,1,2-cd] :

[0610] Under Ar(g) conditions, a solution of 0.100 g (0.285 mmol) of 11-(benzyloxy)-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] in indene-1,10-dione in THF in Ar(g) was cooled to -78 °C. A 1.0 M solution of LiHMDS in THF (0.856 mL, 0.856 mmol) was added dropwise. After 10 minutes, a solution of 2-(benzenesulfonyl)-3-phenyl-oxaprodiidine (0.164 g, 0.628 mmol) in THF (1 mL) was added. The reaction mixture was warmed to room temperature and stirred for 3 hours. Methanol was added for quenching, and the solution was concentrated. The residue was purified by column chromatography (0-20% MeOH / CH2Cl2) to give 11-(benzyloxy)-8-hydroxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione, a mixture of diastereomers. MS (m / z) 367.27 [M+H] + .

[0611] Step 2. 11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]di Synthesis of indene-1,10-dione (9b) in azanonacyclo[9,1,2-cd] :

[0612] To a solution of 11-(benzyloxy)-8-hydroxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]-indene-1,10-dione (0.057 g, 0.155 mmol) in anhydrous methanol (1 mL), 77% m-CPBA (0.139 g, 0.620 mmol) and N-iodosuccinimide (0.140 g, 0.620 mmol) were added. The reaction mixture was heated at 80 °C for 1 hour and cooled to room temperature. The solution was diluted with CH2Cl2 and washed with 10% Na2SO3 aqueous solution. The aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% MeOH / CH2Cl2) to obtain 11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione. MS (m / z) 493.11 [M+H] + .

[0613] Step 3. 11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7, Synthesis of indene-9-carboxamide (9c) in 8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0614] To a solution of 11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] in DMSO (2 mL), 2,4,6-trifluorobenzylamine (0.084 g, 0.524 mmol), i-Pr2NEt (0.091 mL, 0.524 mmol), and Pd(PPh3)4 (0.006 g, 0.005 mmol) were added. The reaction flask was evacuated and backfilled three times with CO(g), and then heated to 80 °C at 1 atm of CO(g) for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with 0.05N HCl (1×), saturated NaHCO3 aqueous solution (1×), and brine (1×). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-100% EtOAc / heptane) to give 11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide. MS (m / z) 554.21 [M+H] + .

[0615] Step 4. (6aS,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, 7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (9-1), (6aR,8R)-8,11-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2, 6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (9-2), (6aS,8S)-8,11-dihydroxy 1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]di Inzazanecacyclo[9,1,2-cd], there are indene-9-carboxamide (9-3) and (6aR,8S)-8,11-dihydroxy-1,10-dioxo-N- (2,4,6-Trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2- Synthesis of nitrogen-indene-9-carboxamide (9-4) in cd] :

[0616] The nitrogen-9-carboxamide in 11-(benzyloxy)-8-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] was separated into its individual stereoisomers using a preparative SFC on an AD-H column with a cosolvent of 50% i-PrOH (containing 0.1% NH3). Four separate peaks were obtained, numbered 1 to 4 according to the elution order. Peaks 1 and 4 are enantiomers; peaks 2 and 3 are enantiomers. The absolute configuration was not confirmed.

[0617] The separated stereoisomers were each dissolved in a 1:1 toluene / TFA solution (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in MeCN and purified by preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm), eluting over 30 minutes with 5–100% acetonitrile (0.1% TFA) and water (0.1% TFA). The combined fractions were lyophilized to give the title compound. The absolute configuration was not confirmed.

[0618] Peak 1: MS (m / z) 464.25 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.52(t,J=5.7Hz,1H),7.23(t,J=8.6Hz,2H),6.85(s,1H),5 .60(dd,J=9.4,7.0Hz,1H),4.66(dd,J=14.6,5.9Hz,1H),4.55(dd,J=14.5,5.5Hz,1H ),4.16(dt,J=13.8,7.3Hz,1H),3.83(s,2H),3.09–3.00(m,1H),2.61(dd,J=12.2,7. 1Hz,1H),2.02–1.90(m,2H),1.88–1.76(m,3H),1.70–1.55(m,1H),1.21–1.07(m,1H). 19 F NMR (376MHz, DMSO-d6) δ -108.99 (td, J = 9.3, 4.4Hz), -112.44 (t, J = 7.2Hz).

[0619] Peak 2: MS (m / z) 464.26 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.88 (t, J = 5.7 Hz, 1H), 7.32–7.16 (m, 2H), 5.68 (d, J = 6.7 Hz, 1H), 4.62 (dd, J = 14.5, 5.8 Hz, 1H), 4.54 (dd, J = 14.6, 5.6 Hz, 1H), 4.18 (dt, J = 14.3, 7.4 Hz, 1H), 3.81 (d, J = 14.2 Hz, 1H), 3.65 (d, J = 14.1 Hz, 1H), 3.03 (dt, J = 12.1, 5.7 Hz, 1H), 2.25 (dd, J = 13.5, 6.9 Hz, 1H), 2.21–2.07 (m, 2H), 2.04 (d, J = 13.4 Hz, 1H), 1.89–1.76 (m, 2H), 1.73–1.59 (m, 1H), 1.30–1.14 (m, 1H). 19 19F NMR (376 MHz, DMSO-d6) δ -109.24 (ddd, J = 15.5, 9.2, 6.2 Hz), -112.44 (t, J = 7.2 Hz).

[0620] Peak 3: MS (m / z) 464.26 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.88 (t, J = 5.7 Hz, 1H), 7.32–7.13 (m, 2H), 5.68 (d, J = 6.7 Hz, 1H), 4.62 (dd, J = 14.5, 5.8 Hz, 1H), 4.54 (dd, J = 14.5, 5.6 Hz, 1H), 4.18 (dt, J = 14.1, 7.4 Hz, 1H), 3.81 (d, J = 14.2 Hz, 1H), 3.65 (d, J = 14.1 Hz, 1H), 3.03 (dt, J = 12.3, 5.5 Hz, 1H), 2.25 (dd, J = 13.4, 6.8 Hz, 1H), 2.21–2.07 (m, 2H), 2.04 (d, J = 13.4 Hz, 1H), 1.90–1.76 (m, 2H), 1.73–1.59 (m, 1H), 1.31–1.13 (m, 1H). 19 19F NMR (376 MHz, DMSO-d6) δ -109.24 (ddd, J = 15.6, 9.5, 6.3 Hz), -112.44 (t, J = 7.1 Hz).

[0621] Peak 4: MS (m / z) 464.22 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.52(t,J=5.6Hz,1H),7.23(t,J=8.7Hz,2H),6.86(s,1H),5.61(dd,J=9.4,7.1Hz,1H),4.66(dd,J=14.5,6.0Hz,1H),4.56(dd,J=14.7,5.5Hz,1H),4.17(dt,J=14.5,7.6Hz,1H),3.84(s,2H),3.06(dt,J=12.5,5.7Hz,1H),2.62(dd,J=12.2,7.0Hz,1H),2.03–1.90(m,2H),1.87–1.78(m,3H),1.69–1.55(m,1H),1.23–1.08(m,1H)。 19 F NMR(376MHz,DMSO-d6)δ-108.87–-109.12(m),-112.44(t,J=7.3Hz)。

[0622] Example 10: (6aS,8R)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6, 7,8,10-Octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide(10-1), (6aR,8R)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a- Bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (10-2), (6aS,8S)-N-(2,4-difluoro (benzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diaza The nonacyclo[9,1,2-cd] contains indene-9-carboxamide (10-3) and (6aR,8S)-N-(2,4-difluorobenzyl)-8,11-dihydroxy- 1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] Preparation of indene-9-carboxamide (10-4) :

[0623]

[0624] Step 1. 11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8, Synthesis of indene-9-carboxamide (10a) in 10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] :

[0625] A solution of 11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione (0.091 g, 0.185 mmol), i-Pr2NEt (0.161 mL, 0.924 mmol), and Pd(PPh3)4 (0.011 g, 0.009 mmol) in DMSO (3.7 mL) was prepared according to the preparation of intermediate 9b in Example 9. The reaction flask was evacuated and backfilled with CO(g) three times, and then heated to 80 °C at 1 atm of CO(g) for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with 0.05N HCl (1×), saturated NaHCO3 aqueous solution (1×), and brine (1×). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-100% EtOAc / heptane) to give 11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide. MS (m / z) 536.16 [M+H] + .

[0626] Step 2. (6aS,8R)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7, 8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (10-1), (6aR, 8R)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged Methyl[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (10-2), (6aS,8S)-N-(2,4-difluorobenzyl) )-8,11-dihydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanona The cyclo[9,1,2-cd]-indene-9-carboxamide (10-3) and (6aR,8S)-N-(2,4-difluorobenzyl)-8,11-dihydroxy-1, 10-Dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] with nitrogen Synthesis of indene-9-carboxamide (10-4) :

[0627] The nitrogen-indene-9-carboxamide in 11-(benzyloxy)-N-(2,4-difluorobenzyl)-8-hydroxy-1,10-dioxo-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] was isolated into its individual stereoisomers using a preparative SFC on an AD-H column with a cosolvent of 50% i-PrOH (containing 0.1% NH3). Four separate peaks were obtained, numbered 1 to 4 according to the elution order. Peaks 1 and 4 are enantiomers; peaks 2 and 3 are enantiomers. The absolute configuration was not confirmed.

[0628] The separated stereoisomers were each dissolved in 1:1 toluene / TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in MeCN and purified by preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm), eluting with 5–100% acetonitrile (0.1% TFA) and water (0.1% TFA) solution over 30 minutes. The combined fractions were lyophilized to give the title compound. The absolute configuration was not confirmed.

[0629] Peak 1: MS (m / z) 446.23 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.44(t,J=5.8Hz,1H),7.45(td,J=8.6,6.6Hz,1H),7.33–7.19(m ,1H),7.09(td,J=8.6,2.6Hz,1H),5.61(dd,J=9.4,7.1Hz,1H),4.60(qd,J=15.0,5.7Hz,2H ),4.18(dt,J=14.1,7.4Hz,1H),3.85(s,2H),3.07(dt,J=12.5,5.7Hz,1H),2.63(dd,J=12. 2,7.0Hz,1H),2.04–1.92(m,2H),1.89–1.77(m,3H),1.71–1.55(m,1H),1.22–1.08(m,1H). 19 F NMR (376MHz, DMSO-d6) δ -112.03 (p, J = 8.1Hz), -114.77 (q, J = 8.9Hz).

[0630] Peak 2: MS (m / z) 446.27 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.80 (t, J = 5.8 Hz, 1H), 7.44 (td, J = 8.7, 6.6 Hz, 1H), 7.26 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.08 (td, J = 8.5, 2.6 Hz, 1H), 5.68 (d, J = 6.7 Hz, 1H), 4.63–4.52 (m, 2H), 4.19 (dt, J = 13.2, 7.5 Hz, 1H), 3.83 (d, J = 14.2 Hz, 1H), 3.68 (dd, J = 14.1, 1.4 Hz, 1H), 3.05 (ddd, J = 13.3, 6.6, 4.7 Hz, 1H), 2.28 (dd, J = 13.5, 6.9 Hz, 1H), 2.20 (dd, J = 15.5, 6.4 Hz, 1H), 2.15–2.08 (m, 1H), 2.06 (d, J = 13.5 Hz, 1H), 1.91–1.77 (m, 2H), 1.73–1.62 (m, 1H), 1.30–1.16 (m, 1H). 19 19F NMR (376 MHz, DMSO-d6) δ -112.32 (p, J = 7.7 Hz), -114.96 (q, J = 8.8 Hz).

[0631] Peak 3: MS (m / z) 446.26 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.80 (t, J = 5.9 Hz, 1H), 7.50–7.37 (m, 1H), 7.26 (td, J = 10.0, 2.6 Hz, 1H), 7.08 (td, J = 8.5, 2.5 Hz, 1H), 5.68 (d, J = 6.8 Hz, 1H), 4.64–4.51 (m, 2H), 4.19 (dt, J = 14.1, 7.5 Hz, 1H), 3.83 (d, J = 14.2 Hz, 1H), 3.68 (d, J = 14.1 Hz, 1H), 3.05 (dt, J = 12.3, 5.5 Hz, 1H), 2.28 (dd, J = 13.5, 6.8 Hz, 1H), 2.20 (dd, J = 15.4, 6.4 Hz, 1H), 2.16–2.09 (m, 1H), 2.06 (d, J = 13.4 Hz, 1H), 1.92–1.78 (m, 2H), 1.74–1.62 (m, 1H), 1.30–1.15 (m, 1H). 19 19F NMR (376 MHz, DMSO-d6) δ -112.32 (p, J = 7.6 Hz), -114.96 (q, J = 8.5 Hz).

[0632] Peak 4: MS (m / z) 446.24 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (t, J = 5.8 Hz, 1H), 7.44 (td, J = 8.7, 6.6 Hz, 1H), 7.26 (td, J = 9.9, 2.6 Hz, 1H), 7.08 (td, J = 8.5, 2.7 Hz, 1H), 5.61 (dd, J = 9.4, 7.1 Hz, 1H), 4.59 (qd, J = 14.9, 5.8 Hz, 2H), 4.17 (dt, J = 14.2, 7.4 Hz, 1H), 3.84 (s, 2H), 3.05 (dd, J = 12.8, 5.9 Hz, 1H), 2.62 (dd, J = 12.2, 7.1 Hz, 1H), 2.03–1.92 (m, 2H), 1.89–1.76 (m, 3H), 1.69–1.57 (m, 1H), 1.22–1.08 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -112.03 (p, J = 8.2 Hz), -114.77 (q, J = 8.9 Hz).

[0633] Example 11: (6aR,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1, 3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (11-1), (6aS,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7, 8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (11-2), (6aR, 7R,8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2, 6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (11-3) and (6aS,7R,8R)-7,8, 11-Trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene Preparation of [1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (11-4) :[[]]END]]

[0634]

[0635] Step 1. 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)-1,2-dihydroxy Synthesis of tert-butyl heptane-1-carboxylate (11a) (-ethyl)-3-((tert-butoxycarbonyl)amino)azacycloheptan-1-carboxylate :[[]]END]]

[0636] NMO (0.233 g, 1.99 mmol) and a solution of 2.5% OsO4 in tBuOH (0.125 mL, 0.010 mmol) were added to a solution of (E)-3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)vinyl)-3-((tert-butoxycarbonyl)amino)azacycloheptan-1-carboxylic acid tert-butyl ester (0.595 g, 0.994 mmol) in 1:1 acetone / water (14.3 mL). The reaction mixture was stirred at room temperature for 24 hours, quenched with a saturated aqueous solution of sodium thiosulfate and NaHCO3, and stirred for 1 hour. The mixture was concentrated and CH2Cl2 was added. The phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×). The combined organic phases were dried over Na₂SO₄, filtered, concentrated, and purified by column chromatography (0-80% EtOAc / hexane) to obtain tert-butyl 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)-1,2-dihydroxyethyl)-3-((tert-butoxycarbonyl)amino)azacycloheptan-1-carboxylate. MS (m / z) 632.87 [M+H] + .

[0637] Step 2. 11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazo Synthesis of N-indene-1,10-dione (11b) in heterocyclic [9,1,2-cd] :

[0638] Trifluoroacetic acid (4.00 mL, 50.5 mmol) was added to a solution of 0.519 g (0.821 mmol) of 3-(2-(5-(benzyloxy)-6-(methoxycarbonyl)-4-oxo-4H-pyran-2-yl)-1,2-dihydroxyethyl)-3-((tert-butoxycarbonyl)amino)azacycloheptan-1-carboxylic acid tert-butyl ester in CH2Cl2 (20 mL) at 0 °C. The reaction mixture was stirred for 2 h, warmed to room temperature, concentrated, and dried under high vacuum for 1 h. The residue was dissolved in ethanol (20 mL) and heated at 90 °C for 3 h. The reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography to give 11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione. MS (m / z) 383.26 [M+H] + .

[0639] Step 3. 11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1, Synthesis of 11c (11-dione) of diazanonacyclo[9,1,2-cd] :

[0640] To a solution of 11-(benzyloxy)-7,8-dihydroxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]-indene-1,10-dione (0.100 g, 0.261 mmol) in anhydrous methanol (2 mL), 77% m-CPBA (0.234 g, 1.05 mmol) and N-iodosuccinimide (0.235 g, 1.05 mmol) were added. The reaction mixture was heated at 80 °C for 0.5 h and cooled to room temperature. The solution was diluted with CH2Cl2 and washed with 10% Na2SO3 aqueous solution. The aqueous phase was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% MeOH / CH2Cl2) to give 11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione. MS (m / z) 509.09 [M+H] + .

[0641] Step 4. 11-(benzyloxy)-7,8-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5, 6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (11d) synthesis :

[0642] To a solution of 11-(benzyloxy)-7,8-dihydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] in DMSO (2 mL), 2,4,6-trifluorobenzylamine (0.043 g, 0.266 mmol), i-Pr2NEt (0.046 mL, 0.266 mmol), and Pd(PPh3)4 (0.003 g, 0.003 mmol) were added. The reaction flask was evacuated and backfilled three times with CO(g), and then heated to 80 °C at 1 atm of CO(g) for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with 0.05N HCl (1×), saturated NaHCO3 aqueous solution (1×), and brine (1×). The organic phase was dried over Na2SO4, filtered, concentrated, and purified by column chromatography (0-20% MeOH / CH2Cl2) to give 11-(benzyloxy)-7,8-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide. MS (m / z) 570.21 [M+H] + .

[0643] Step 5. (6aR,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4, 5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (11- 1) (6aS,7S,8S)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10- Octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (11-2), (6aR,7R, 8R)-7,8,11-trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a- Bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (11-3) and (6aS,7R,8R)-7,8,11- Trihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1, Synthesis of indene-9-carboxamide (11-4) in diazanonacyclo[9,1,2-cd] :

[0644] The nitrogen-9-carboxamide in 11-(benzyloxy)-7,8-dihydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] was isolated into its individual stereoisomers using a preparative SFC on an IB column with 40% MeOH cosolvent. Four separate peaks were obtained, numbered 1 to 4 according to the elution order. Peaks 1 and 4 are enantiomers; peaks 2 and 3 are enantiomers. The absolute configuration was not confirmed.

[0645] The separated stereoisomers were each dissolved in 1:1 toluene / TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in MeCN and purified by preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm), eluting with 5–100% acetonitrile (0.1% TFA) and water (0.1% TFA) solution over 30 minutes. The combined fractions were lyophilized to give the title compound. The absolute configuration was not confirmed.

[0646] Peak 1: MS (m / z) 480.20 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.86(t,J=5.7Hz,1H),7.22(t,J=8.6Hz,2H),5.74(s,1H),5.53(s,1H ),4.57(qd,J=14.6,5.7Hz,2H),4.20(dt,J=13.7,6.9Hz,1H),4.06(s,1H),3.79(d,J=14.6Hz, 1H),3.65(d,J=14.6Hz,1H),3.03(dt,J=12.6,6.0Hz,1H),2.49–2.43(m,1H),2.17–2.06(m,1H ), 2.00(dd,J=15.5,7.1Hz,1H),1.86–1.75(m,2H),1.78–1.59(m,1H),1.25(d,J=15.5Hz,1H). 1919F NMR (376 MHz, DMSO-d6) δ -109.28 (ddd, J = 15.6, 9.3, 6.2 Hz), -112.43 (t, J = 7.2 Hz).

[0647] Peak 2: MS (m / z) 480.21 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 11.50 (t, J = 5.7 Hz, 1H), 7.23 (t, J = 8.6 Hz, 2H), 6.98 (s, 1H), 5.10 (d, J = 8.0 Hz, 1H), 4.65 (dd, J = 14.6, 5.8 Hz, 1H), 4.55 (dd, J = 14.6, 5.4 Hz, 1H), 4.15 (dt, J = 13.5, 6.9 Hz, 1H), 4.06 (d, J = 7.9 Hz, 1H), 3.83–3.70 (m, 2H), 3.05 (dt, J = 12.8, 6.0 Hz, 1H), 2.32–2.25 (m, 1H), 1.86–1.74 (m, 2H), 1.75–1.69 (m, 1H), 1.69–1.59 (m, 1H), 1.50 (dd, J = 15.1, 7.2 Hz, 1H), 1.34–1.26 (m, 1H). 19 19F NMR (376 MHz, DMSO-d6) δ -108.87–-109.08 (m), -112.43 (t, J = 7.4 Hz).

[0648] Peak 3: MS (m / z) 480.22 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 11.51 (t, J = 5.7 Hz, 1H), 7.28–7.18 (m, 2H), 6.99 (s, 1H), 5.10 (d, J = 8.0 Hz, 1H), 4.66 (dd, J = 14.7, 5.8 Hz, 1H), 4.56 (dd, J = 14.6, 5.5 Hz, 1H), 4.21–4.11 (m, 1H), 4.07 (d, J = 8.2 Hz, 1H), 3.81–3.72 (m, 2H), 3.10–3.02 (m, 1H), 2.33–2.25 (m, 1H), 1.88–1.70 (m, 3H), 1.70–1.59 (m, 1H), 1.51 (dd, J = 14.6, 7.5 Hz, 1H), 1.32–1.24 (m, 1H). 19 19F NMR (376 MHz, DMSO-d6) δ -108.87–-109.07 (m), -112.43 (t, J = 7.2 Hz).

[0649] Peak 4: MS (m / z) 480.20 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.86 (t, J = 5.7 Hz, 1H), 7.28–7.13 (m, 2H), 5.74 (s, 1H), 5.53 (s, 1H), 4.57 (qd, J = 14.5, 5.7 Hz, 2H), 4.20 (dt, J = 13.4, 6.8 Hz, 1H), 4.06 (s, 1H), 3.79 (d, J = 14.5 Hz, 1H), 3.65 (d, J = 14.6 Hz, 1H), 3.03 (dt, J = 13.0, 6.1 Hz, 1H), 2.17–2.06 (m, 1H), 2.00 (dd, J = 15.4, 7.3 Hz, 1H), 1.85–1.74 (m, 2H), 1.74–1.61 (m, 1H), 1.35–1.24 (m, 1H). 19 19F NMR (376 MHz, DMSO-d6) δ -109.28 (ddd, J = 9.4, 6.5, 3.0 Hz), -112.43 (t, J = 7.1 Hz).

[0650] Example 12: (6aS,8R)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1, 3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (12-1), (6aR,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7, 8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (12-2), (6aS, 8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2, 6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-9-carboxamide (12-3) and (6aR,8R)-11-hydroxy 8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene Preparation of indene-9-carboxamide (12-4) from [1,4]diazanonacyclo[9,1,2-cd] :

[0651]

[0652] Step 1. 11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4] Synthesis of indene-1,10-dione (12a) from diazanonacyclo[9,1,2-cd] :

[0653] At room temperature, a solution of 11-(benzyloxy)-8-hydroxy-9-iodo-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione (0.035 g, 0.071 mmol) prepared according to the preparation of intermediate 9b in Example 9 was treated with 60% sodium hydride (0.004 g, 0.107 mmol) in DMF (1 mL). After 5 minutes, iodomethane (0.009 mL, 0.142 mmol) was added. The reaction was stirred for 2 hours, quenched with MeOH, concentrated, and purified by column chromatography (0-10% MeOH / CH2Cl2). The impure residue was further purified by column chromatography (20-100% EtOAc / hexane) to obtain 11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] indene-1,10-dione. MS (m / z) 507.10 [M+H] + .

[0654] Step 2. 11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6, Synthesis of indene-9-carboxamide (12b) in 7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] become :

[0655] To a solution of 11-(benzyloxy)-9-iodo-8-methoxy-3,4,5,6,7,8-hexahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd] in DMSO (1 mL), 2,4,6-trifluorobenzylamine (0.026 g, 0.160 mmol), i-Pr2NEt (0.028 mL, 0.160 mmol), and Pd(PPh3)4 (0.002 g, 0.002 mmol) were added. The reaction flask was evacuated and backfilled three times with CO(g), and then heated to 80 °C at 1 atm of CO(g) for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with 0.05N HCl (1×), saturated NaHCO3 aqueous solution (1×), and brine (1×). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% MeOH / CH2Cl2) to give 11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide, which are two separable stereoisomers.

[0656] Peak 1 (major): MS (m / z) 568.15 [M+H] + .

[0657] Peak 2 (minor): MS (m / z) 568.18 [M+H] + .

[0658] Step 3. (6aS,8R)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4, 5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (12- 1) (6aR,8S)-11-hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10- Octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide (12-2), (6aS,8S)- 11-Hydroxy-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridge Indene-9-carboxamide (12-3) and (6aR,8R)-11-hydroxy-8-methyl in methylene[1,4]diazanonacyclo[9,1,2-cd] oxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4] Synthesis of indene-9-carboxamide (12-4) from diazanonacyclo[9,1,2-cd] :

[0659] The major diastereomeric derivative (peak 1 from 12b) of 11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide was isolated as its individual stereoisomers using a preparative SFC on an AD-H column with a 40% MeOH cosolvent, yielding two separate peaks. The isolated stereoisomers were each dissolved in 1:1 toluene / TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in MeCN and purified by preparative HPLC (column, Gemini 10μC18 110A, AXI / ; 250 × 21.2 mm), eluting over 30 min with 5–100% acetonitrile (0.1% TFA) and water (0.1% TFA). The combined fractions were lyophilized to give the title compound. The absolute configuration was not confirmed.

[0660] Peak 1: MS (m / z) 478.19 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.83(t,J=5.6Hz,1H),7.32–7.13(m,2H),5.68(d,J=5.6Hz,1H),4. 63(dd,J=14.4,6.1Hz,1H),4.47(dd,J=14.4,5.1Hz,1H),4.18(dt,J=13.6,7.1Hz,1H),3.81( d,J=14.2Hz,1H),3.63(d,J=14.3Hz,1H),3.39(s,3H),3.02(dt,J=12.7,5.7Hz,1H),2.27(d ,J=13.5Hz,1H),2.13–2.02(m,3H),1.87–1.76(m,2H),1.72–1.61(m,1H),1.31–1.24(m,1H). 19F NMR (376MHz, DMSO-d6) δ -109.34 (tt, J = 9.7, 6.4Hz), -112.45 (t, J = 7.3Hz).

[0661] Peak 2: MS (m / z) 478.18 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ10.83(t,J=5.6Hz,1H),7.26–7.16(m,2H),5.68(d,J=5.6Hz,1H),4. 63(dd,J=14.5,6.0Hz,1H),4.47(dd,J=14.5,5.2Hz,1H),4.18(dt,J=13.8,7.1Hz,1H),3.81( d,J=14.2Hz,1H),3.63(d,J=14.3Hz,1H),3.39(s,3H),3.02(dt,J=12.5,5.7Hz,1H),2.27(d ,J=13.5Hz,1H),2.13–2.03(m,3H),1.86–1.76(m,2H),1.71–1.62(m,1H),1.31–1.24(m,1H). 19 F NMR (376MHz, DMSO-d6) δ-109.34 (ddd, J=9.0, 6.4, 2.9Hz), -112.45 (t, J=7.2Hz).

[0662] The minor diastereomeric derivative (peak 2 from 12b) of 11-(benzyloxy)-8-methoxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,10-octahydro-2,6a-bridged methylene[1,4]diazanonacyclo[9,1,2-cd]indene-9-carboxamide was isolated as a separate stereoisomer by preparative SFC on an OJ-H column using 20% ​​EtOH cosolvent. Two separate peaks were obtained. The isolated stereoisomers were each dissolved in 1:1 toluene / TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in MeCN and purified by preparative HPLC (column, Gemini 10μC18 110A, AXI / ; 250 × 21.2 mm), eluting over 30 min with 5–100% acetonitrile (0.1% TFA) and water (0.1% TFA). The combined fractions were lyophilized to give the title compound. The absolute configuration was not confirmed.

[0663] Peak 1: MS (m / z) 478.12 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 9.66 (t, J = 5.6 Hz, 1H), 7.22–7.14 (m, 2H), 5.37 (t, J = 7.6 Hz, 1H), 4.55 (dd, J = 14.3, 6.2 Hz, 1H), 4.41 (dd, J = 14.5, 5.1 Hz, 1H), 4.16 (dt, J = 14.2, 7.6 Hz, 1H), 3.85–3.74 (m, 2H), 3.27 (s, 3H), 3.09–3.00 (m, 1H), 2.76 (dd, J = 12.4, 7.2 Hz, 1H), 1.89–1.72 (m, 5H), 1.67–1.56 (m, 1H), 1.16–1.05 (m, 1H). 19 19F NMR (376 MHz, DMSO-d6) δ -109.64 (ddd, J = 9.4, 6.4, 3.0 Hz), -112.09 (t, J = 7.1 Hz).

[0664] Peak 2: MS (m / z) 478.13 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.67 (t, J = 5.6 Hz, 1H), 7.25–7.17 (m, 2H), 5.37 (t, J = 7.6 Hz, 1H), 4.56 (dd, J = 14.2, 6.1 ...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 C 6-10 Aryl, wherein the C 6-10 The aryl group is optionally substituted by two to four R A1 Substitute, where each R A1 are independently halo; Y is selected from the group consisting of: –C(O)NH– and L is –CH2–; W 1 is a chemical bond or –CR 4a R 4b – W 2 is –CR 5a R 5b – or –CR 6a =CR 6b –; X is –CR 8a R 8b – Z is –CR 9a R 9b –; T is -CR 2a R 2b –; U is –CR 12a R 12b –; R 2a , R 2b , R 12a and R 12b Independently H, C 1-6 Alkyl, halide, –CH2OR a , or –OR a ; R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , R 9a and R 9b Independently H, C 1-6 Alkyl, hydroxyl, –O–C 1-4 alkyl; Each R 6a and R 6b are independently H or C 1-6 Alkyl; and Each R a are independently (i) H or (ii) C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula Ia: Among them, Z, W 1 , W 2 , X, L, T, U, Y, and R 1 As defined in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula Ib: Among them, Z, W 1 , W 2 , X, L, T, U, Y, and R 1 As defined in claim 1.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y is 5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently H, halo or –OR a .

6. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently H, halo or –OR a ; and where R a are independently H or C 1-3 alkyl.

7. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently H, halo or –OR a ; and where R a is independently H or methyl.

8. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Independently H, C 1-6 Alkyl or halide.

9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently H or halo.

10. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b independently H or –OR a .

11. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R a It is H or C1-C4 alkyl.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IV: Among them, Z, W 1 , W 2 , X, L, R 2a , R 2b , R 12a , R 12b and R 1 As defined in any one of claims 1 to 11.

13. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IVa: Among them, Z, W 1 , W 2 , X, L, R 2a , R 2b , R 12a , R 12b and R 1 As defined in any one of claims 1 to 11.

14. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IVb: Among them, Z, W 1 , W 2 , X, L, R 2a , R 2b , R 12a , R 12b and R 1 As defined in any one of claims 1 to 11.

15. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: R 1 is optionally represented by two to four R A1 Substituted C 6-10 Aryl, where each R A1 are independently fluorine or chlorine.

16. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 12a and R 12b are independently H, halo or –OR a .

17. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 12a and R 12b independently H or –OR a .

18. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 12a and R 12b independently H or –OR a ; and each R a H or C 1-3 alkyl.

19. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 12a and R 12b independently H or –OR a ; and each R a It is H or methyl.

20. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W 1 For chemical bonds.

21. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W 1 For –CR 4a R 4b –.

22. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W 2 For –CR 5a R 5b –.

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula VI: Where m is 0, 1, 2, 3 or 4; Each R 2 Independently for C 1-6 Alkyl, halide, –CH2OR a OR a ;and R 9a , R 9b , R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , L and R 1 As defined in any one of claims 1 to 11.

24. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula VIa: Where m is 0, 1, 2, 3 or 4; Each R 2 Independently for C 1-6 Alkyl, halide, cyano, –CH2OR a OR a ;and R 9a , R 9b , R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , L and R 1 As defined in any one of claims 1 to 11.

25. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula VIb: Where m is 0, 1, 2, 3 or 4; Each R 2 Independently for C 1-6 Alkyl, halide, –CH2OR a OR a ;and R 9a , R 9b , R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , L and R 1 As defined in any one of claims 1 to 11.

26. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted by two, three or four halogens.

27. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted by two or three halogens selected from chlorine and fluorine.

28. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 Select from the group consisting of:

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula VIII: Where p is 2 or 3; R 9a , R 9b , R 4a , R 4b , R 5a , R 5b , R 8a , R 8b and R A1 As defined in any one of claims 1 to 11; and m and R 2 As defined in any one of claims 23 to 25.

30. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula VIIIa: Where p is 2 or 3; R 9a , R 9b , R 4a , R 4b , R 5a , R 5b , R 8a , R 8b and R A1 As defined in any one of claims 1 to 11; and m and R 2 As defined in any one of claims 23 to 25.

31. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula VIIIb: Where p is 2 or 3; R 9a , R 9b , R 4a , R 4b , R 5a , R 5b , R 8a , R 8b and R A1 As defined in any one of claims 1 to 11; and m and R 2 As defined in any one of claims 23 to 25.

32. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , R 9a and R 9b Each is independently H, C1-C6 alkyl or –O–C 1-4 alkyl.

33. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , R 9a and R 9b Each is independently H or C1-C6 alkyl.

34. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , R 9a and R 9b Each is independently H or C1-C4 alkyl.

35. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , R 9a and R 9b For H.

36. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , R 9a and R 9b Each is independently H or -CH3.

37. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b , R 5a , R 5b , R 8a , R 8b , R 9a and R 9b Each is independently H, -CH3 or -OCH3.

38. The compound of claim 23, wherein m is 0, 1 or 2.

39. The compound of claim 23, wherein m is 0.

40. The compound of claim 23, wherein m is 1.

41. The compound of claim 23, wherein m is 2.

42. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen group.

43. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently halo or –OR a .

44. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently halo or –OR a ; where each R a are independently H or C1-C3 alkyl.

45. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently halo or –OR a ; where each R a is independently H or methyl.

46. ​​The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein each R 2 Independently for –OR a .

47. The compound according to claim 29, wherein p is 3, and each R A1 are independently halo.

48. The compound according to claim 29, wherein p is 2, and each R A1 are independently halo.

49. according to the compound described in any one of claims 1-3, wherein each R A1 are independently fluorine or chlorine.

50. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

51. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

52. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

53. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

54. The pharmaceutical composition of claim 53, further comprising one, two, three or four additional therapeutic agents.

55. The pharmaceutical composition of claim 54, wherein the one or more additional therapeutic agents are anti-HIV agents.

56. A pharmaceutical composition according to claim 54 or 55, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

57. The pharmaceutical composition of claim 54 or 55, wherein the one or more additional therapeutic agents comprises an HIV capsid inhibitor.

58. The pharmaceutical composition of claim 54 or 55, wherein the one or more additional therapeutic agents comprises lenacapvir.

59. The pharmaceutical composition of claim 54 or 55, wherein the one or more additional therapeutic agents comprises a nucleoside reverse transcriptase translocation inhibitor.

60. The pharmaceutical composition of claim 54 or 55, wherein the one or more additional therapeutic agents comprises islatravir.

61. The pharmaceutical composition of claim 54 or 55, wherein the one or more additional therapeutic agents comprise an HIV capsid inhibitor and a nucleoside reverse transcriptase translocation inhibitor.

62. The pharmaceutical composition of claim 54 or 55, wherein the one or more additional therapeutic agents comprise lenacapvir and islatravir.

63. The pharmaceutical composition of claim 54 or 55, wherein the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide or a pharmaceutically acceptable salt thereof.

64. The pharmaceutical composition of claim 54 or 55, wherein the pharmaceutical composition is for oral or parenteral administration.

65. A kit comprising a compound according to any one of claims 1-52 or a pharmaceutically acceptable salt thereof and instructions for use.

66. The kit of claim 65, further comprising one, two, three or four additional therapeutic agents.

67. The kit of claim 66, wherein the one or more additional therapeutic agents are anti-HIV agents.

68. The kit of any one of claims 66 or 67, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

69. The kit of claim 66 or 67, wherein the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide or a pharmaceutically acceptable salt thereof.

70. Use of a composition comprising a compound according to any one of claims 1-52 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53-64, in the preparation of a medicament for treating HIV infection in a person suffering from or at risk of HIV infection.

71. The use according to claim 70, characterized in that The compositions are administered in combination with one, two, three, or four additional therapeutic agents.

72. The use according to claim 71, wherein the one or more additional therapeutic agents are anti-HIV agents.

73. The use according to claim 71 or 72, wherein the one or more additional therapeutic agents are HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

74. The use of claim 71 or 72, wherein the one or more additional therapeutic agents comprises an HIV capsid inhibitor or a nucleoside reverse transcriptase translocation inhibitor.

75. The use of claim 71 or 72, wherein the one or more additional therapeutic agents include lenacapvir and islatravir.

76. The use of claim 71 or 72, wherein the one or more additional therapeutic agents comprises an HIV capsid inhibitor.

77. The use of claim 71 or 72, wherein the one or more additional therapeutic agents comprises lenacapvir.

78. The use of claim 71 or 72, wherein the one or more additional therapeutic agents comprises a nucleoside reverse transcriptase translocation inhibitor.

79. The use of claim 71 or 72, wherein the one or more additional therapeutic agents comprises islatravir.

80. The use according to claim 71 or 72, wherein the one or more additional therapeutic agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide or a pharmaceutically acceptable salt thereof.

81. The use according to claim 71 or 72, wherein the administration is oral, intravenous, subcutaneous or intramuscular.

82. Use of a composition comprising a compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53 to 64, in the preparation of a medicament for treating HIV infection.

83. Use of a composition comprising a compound according to any one of claims 1-52 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 53-64, in the preparation of a medicament for treating HIV infection in a person suffering from or at risk of HIV infection.

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