Compounds, compositions and methods

Abstract

This disclosure generally relates to small molecule inhibitors of the 1 (SARM1) protein containing sterile α and TIR motifs, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, methods of their preparation, intermediates, and methods of their use.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 580,981, filed September 6, 2023, pursuant to 35 USC § 119(e), the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0002] This disclosure generally relates to small molecule regulators of the 1 (SARM1) protein containing sterile α and TIR motifs and their use as therapeutic agents. Background Technology

[0003] Neurodegenerative diseases are a group of progressive neurological disorders in which nerve cells malfunction and eventually die. Neuronal degeneration in patients with neurodegenerative diseases can manifest as a variety of symptoms, including changes in mood and behavior, irritability, sensory disturbances, motor and cognitive difficulties, and memory loss. These symptoms may progress to immobility or speech impairment, dementia, and ultimately death.

[0004] Axonal degeneration has been identified as an important pathological feature in most neurodegenerative diseases. Axons are susceptible to both mechanical damage (Wallerian degeneration) and disease (Wallerian-like degeneration).

[0005] In healthy axons, the N-terminus of SARM1 interacts with the TIR domain, preventing TIR dimerization and subsequent NAD. + Enzymatic cleavage of SARM1. However, under conditions of neuronal injury or disease, the N-terminal TIR domain interaction of SARM1 is disrupted, leading to TIR polymerization, followed by rapid loss of NAD+ and related axonal degeneration. Summary of the Invention

[0006] This article provides compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that may be used to treat and / or prevent diseases at least in part mediated by SARM1.

[0007] In some implementations, compounds that inhibit SARM1 are provided.

[0008] In another embodiment, a pharmaceutical composition is provided comprising a compound as described herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers or a prodrug, and a pharmaceutically acceptable carrier.

[0009] In another embodiment, a method is provided for treating a disease or ailment at least partially mediated by SARM1, the method comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0010] This disclosure also provides compositions, including pharmaceutical compositions; kits comprising the said compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof; methods of using (or administering) and preparing the said compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug thereof; and intermediates thereof.

[0011] This disclosure further provides a method of using a compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers or a prodrug thereof, or a composition thereof, for treating a disease, condition or ailment at least in part mediated by SARM1.

[0012] Furthermore, this disclosure provides the use of the said compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers or a prodrug thereof, or a composition thereof, in the manufacture of a medicament for treating at least partially SARM1-mediated diseases, conditions or disorders.

[0013] The inventive summary herein describes exemplary embodiments of the present technology. However, it should be understood that such inventive summary is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0014] 1. Definition A dash ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -C(O)NH2 is connected by a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group can be depicted with or without one or more dashes without losing its general meaning. A wavy or dashed line drawn through a line in the structure indicates the designated connection point of the group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0015] prefix "C" u-v "Indicates that the following group has u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0016] In this document, references to “about” for a value or parameter include (and describe) embodiments relating to said value or parameter itself. In some embodiments, the term “about” includes an indication of ±10%. In other embodiments, the term “about” includes an indication of ±5%. In some other embodiments, the term “about” includes an indication of ±1%. Furthermore, the term “about X” includes a description of “X”. Unless the context clearly specifies otherwise, the singular forms “a” and “said” also include plural indicators. Thus, for example, a reference to “compound” includes a variety of such compounds, and a reference to “test” includes reference to one or more tests and their equivalents known to those skilled in the art.

[0017] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C64) 1-12 Alkyl groups, 1 to 8 carbon atoms (i.e., C64) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4 Alkyl groups. Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or identified by a molecular formula, it may encompass all positional isomers having said number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0018] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl", divalent "aryl", and divalent heteroaryl may also be referred to as "alkylene" or "alkylenyl" (e.g., methylene, ethylene, and propylene), "arylene" or "arylenyl" (e.g., phenylene or naphthylene, or quinolinyl for heteroaryl). Furthermore, unless otherwise explicitly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last group mentioned contains the atoms used to attach that moiety to the remainder of the molecule.

[0019] "Alkenyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C20-20 carbon atoms).2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C) 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkyl groups (alkenyl). Examples of alkenyl groups include, for example, vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "Alkyne" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon linkage and having 2 to 20 carbon atoms (i.e., C20). 2-20 alkynyl group), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl group), 2 to 8 carbon atoms (i.e., C64) 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkyl groups (alkynyl). The term "alkynyl" also includes those groups having one ternary bond and one double bond.

[0021] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl".

[0023] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0024] "Acyl" refers to the group -C(O)R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein. Examples of acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0025] "Amide group" refers to "C-amide group" (which refers to the group -C(O)NR). y R z ) and "N-amide group" (which refers to the group -NR) y C(O)R z Both, of which R y and R zIndependently hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein, or R y and R z Together they form cycloalkyl or heterocyclic groups; each of which may optionally be substituted as defined herein.

[0026] "Amino" refers to the -NR group. y R z , where R y and R z It is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0027] "Formamidinyl" refers to -C(NR) y (NR) z 2), where R y and R z It is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0028] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 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, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups in no way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is heteroaryl, regardless of the connection point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is heterocyclic, regardless of the connection point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is cycloalkyl, regardless of the connection point.

[0029] "Arylalkyl" or "arylalkyl" refers to the group "aryl-alkyl-".

[0030] "Carbamoyl" refers to "O-carbamoyl" (which refers to the group -OC(O)NR). y R z ) and "N-carbamoyl" (which refers to the group -NR) y C(O)OR z Both, of which R y and R zIt is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0031] "Carboxylic ester" or "ester" refers to -OC(O)R x and -C(O)OR x Of the two, R x It is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl group; each of which may optionally be substituted as defined herein.

[0032] "Cyanoalkyl" refers to an alkyl group as defined above, wherein one or more (e.g., 1 or 2) hydrogen atoms are replaced by a cyano (-CN) group.

[0033] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings (including fused, bridged, and spirocyclic systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cycloalkenyl groups having at least one sp... 3 A carbon-ring fused ring system (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C164 ... 3-20 cycloalkyl groups, 3 to 14 cyclic carbon atoms (i.e., C14) 3-12 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. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to cover any non-aromatic ring that can fused to an aryl ring, regardless of its connection to the rest of the molecule. Additionally, cycloalkyl also includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom, such as spiro[2.5]octyl, spiro[4.5]dodecyl, or spiro[5.5]undecyl.

[0034] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

[0035] "Imine" refers to the group -C(NR) y )R z , where R y and R zEach is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each may optionally be substituted as defined herein.

[0036] "Imidin group" refers to the group -C(O)NR y C(O)R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each may optionally be substituted as defined herein.

[0037] "Halogen" or "halogenated group" refers to an atom that occupies group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0038] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are substituted with a halogen. For example, if a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may be (but are not necessarily) the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0039] "Haloalkoxy" refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are halogenated.

[0040] "Haloalkoxyalkyl" refers to an alkoxyalkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are halogenated.

[0041] "Hydroxyalkyl" means an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by hydroxyl groups.

[0042] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently substituted with the same or different heteroatom groups, provided that the connection point to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently substituted with the same or different heteroatom groups. Heteroatom groups include (but are not limited to) -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., among which R yIt is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2OCH3, etc.), and amines (e.g., -CH2NR). y CH3、-CH(CH3)NR y CH3、-CH2CH2NR y CH3、-CH2CH2NR y CH2CH2NR y CH3, etc., of which R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein. As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom.

[0043] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 cyclic carbon atoms (i.e., C atoms). 1-20 heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C) 3-8The heteroaryl group comprises a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each independently having a 1-4 membered ring, a 1-3 membered ring, a 1-2 membered ring, or a 1 membered ring, selected independently from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, Imidazolyl, indazole, indolyl, indazole, isoindolyl, isoquinolinyl, isoxazolyl, nitryl, oxadiazolyl, oxazolyl, 1-pyridyloxy, 1-pyrimidinyloxy, 1-pyrazinyloxy, 1-pyridazinyloxy, phenazinyl, phthalazinyl, pteridineyl, purine, pyrroleyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include (but are not limited to) benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl, and imidazo[1,5-a]pyridyl, wherein the heteroaryl group can be linked through any ring of the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of the connection of the rest of the molecule (i.e., linked through any of the fused rings). Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0044] "Heteroarylenealkyl" refers to the group "heteroarylene-alkyl-".

[0045] "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocoupled, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) atoms. -The term "heterocyclic group" refers to a non-aromatic ring containing at least one heteroatom, regardless of its connection (i.e., bonding via carbon atoms or heteroatoms). Furthermore, the term "heterocyclic group" is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of the connection to the rest of the molecule. As used herein, a heterocyclic group has 2 to 20 ring carbon atoms (i.e., C64 carbon atoms). 2-20 Heterocyclic groups), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic groups), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C 3-6 Heterocyclic groups; having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 cyclic heteroatoms independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azirrocyclobutyl, azirroyl, benzo[b][1,4]dioxaneheptyl, 1,4-benzodioxyl, benzopyranyl, benzodioxanehenyl, benzopyranone, benzofuranone, dioxanecyclo, dihydropyranyl, hydropyranyl, thiophene[1,3]dithiazinyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazoalkyl, indololinyl, inazinyl, isoindololinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl The terms "heterocyclic group" include: dolyl, 2-oxohexahydropyrazinyl, 2-oxohexahydropyridinyl, 2-oxopyrrolidinyl, oxazolyl, epoxyethyl, oxacyclobutyl, phenthiazinyl, phenoxazinyl, hexahydropyridinyl, hexahydropyrazinyl, 4-hexahydropyridinoneyl, pyrrolidinyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, tetrahydropyranyl, trithiazinyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When two substitution positions exist on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl, wherein the heterocyclic group can be linked through any ring of the fused system.

[0046] "Heterocyclic alkyl" refers to the group "heterocyclic-alkyl-".

[0047] "Oxime" refers to the group -CR y (=NOH), where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0048] "Sulfonyl" refers to the group -S(O)2R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0049] "Sulinate group" refers to the group -S(O)R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each may optionally be substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0050] "Sulfanamide group" refers to the group -SO2NR. y R z and -NR y SO2R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each may optionally be substituted as defined herein.

[0051] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both the scenario where the event or situation occurs and the scenario where the event or situation does not occur. Similarly, the term “optionally substituted” means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the specified atom or group may be partially substituted with hydrogen atoms or may not be partially substituted with hydrogen atoms.

[0052] As used herein, the term "substituted" means any of the above-mentioned groups (i.e., alkyl, alkenyl, alkynylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is substituted with a non-hydrogen atom, such as (but not limited to) alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, formamidinyl, aryl, aralkyl, azide, carbamoyl, carboxyl Carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidinyl, halogroup, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, -NHNH2, =NNH2, imino, imide, hydroxyl, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thionyl, N-oxide or -Si(R y )3, where each R y It can be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic.

[0053] In some embodiments, "substituted" includes any of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently substituted with: deuterium, haloyl, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR g R h -NR g C(O)R h -NR g C(O)NR g R h -NR g C(O)OR h -NR g S(O) 1-2 R h -C(O)R g -C(O)OR g -OC(O)OR g -OC(O)R g -C(O)NR g R h -OC(O)NR g R h -OR g -SR g -S(O)R g -S(O)2R g -OS(O) 1-2R g -S(O) 1-2 OR g -NR g S(O) 1-2 NR g R h =NSO2R g =NOR g -S(O) 1-2 NR g R h -SF5, -SCF3, or -OCF3. In some embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are substituted via -C(O)R g -C(O)OR g -C(O)NR g R h -CH2SO2R g or -CH2SO2NR g R h Permutation. In the preceding text, R... g and R h These are the same or different groups, and independently comprised of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, heterocyclic alkyl, heteroaryl, and / or heteroarylalkyl. In some embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are substituted with bonds of amino, cyano, hydroxy, imino, nitro, oxo, thionyl, haloyl, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, and / or heteroarylalkyl; or R g and R h and R i The two atoms in the mixture together with the atoms they are attached to form a heterocyclic ring, which is optionally substituted with an oxo, a halogroup, or an alkyl group optionally substituted with an oxo, a halogroup, an amino group, a hydroxyl group, or an alkoxy group.

[0054] This document is not intended to include polymers or similar indeterminate structures obtained by defining substituents by an unlimited number of additional substituents (e.g., a substituted aryl group having a substituted alkyl group, which itself is substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise noted, the maximum number of successive substitutions in the compounds described herein is three. For example, a successive substitution of a substituted aryl group with two other substituted aryl groups is limited to an aryl group substituted by ((substituted aryl)-substituted)-aryl. Similarly, the above definitions are not intended to include prohibited substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such prohibited substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein.

[0055] In some implementations, as used herein, the phrase "one or more species" refers to one to five species. In some implementations, as used herein, the phrase "one or more species" refers to one to three species.

[0056] Any compound or structure presented herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. These compound forms may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures illustrated herein, except that one or more atoms have been replaced with atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example… 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Various isotope-labeled compounds disclosed herein, such as radioisotopes (e.g., 3 H and 14 C) Those compounds incorporated therein. Such isotopically labeled compounds can be used for metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays) or for the radiotherapy of patients.

[0057] The term “isotope-enriched analogues” includes “deuterated analogues” of the compounds described herein, wherein one or more hydrogen atoms are replaced by deuterium (e.g., hydrogen on a carbon atom). Such compounds exhibit increased resistance to metabolism when administered to mammals (humans in particular) and can therefore be used to extend the half-life of any compound. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol.Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials with one or more hydrogen atoms replaced by deuterium.

[0058] The deuterated or substituted therapeutic compounds disclosed herein may possess improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (e.g., deuterium) can provide certain therapeutic advantages due to enhanced metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F, 3 H or 11 C-labeled compounds can be used in PET or SPECT or other imaging studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing unlabeled reagents with readily available isotopically labeled reagents by performing the procedures disclosed in the protocols or in the examples and preparations described below. It should be understood that deuterium is considered a substituent in the compounds described herein.

[0059] The concentration of such heavier isotopes (specifically deuterium) can be defined by isotope enrichment coefficients. In the compounds disclosed herein, any atom not specifically designated as a particular isotope refers to any stable isotope representing that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position should be understood to have hydrogen in its natural abundance isotopic composition. Therefore, in the compounds disclosed herein, any atom specifically designated as deuterium (D) refers to deuterium.

[0060] In many cases, the compounds of this disclosure are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0061] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical components suitable for veterinary or human pharmaceutical use.

[0062] The term "pharmaceutically acceptable salt" for the given compounds refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing the acid salt solution. Conversely, if the product is a free base, the addition salt, specifically a pharmaceutically acceptable addition salt, can be produced according to the conventional procedure for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include (but are not limited to) salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trienylamines (i.e., N(alkenyl)3), and substituted alkenylamines (i.e., NH2(substituted alkenyl)). Di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include (by way of example only) isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, hexahydropyrazine, hexahydropyridine, morpholine, N-ethylhexahydropyridine, etc.

[0063] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with their imine tautomers. Regardless of which tautomer is exhibited or the nature of the equilibrium between the tautomers, it will be understood by those skilled in the art that a compound comprises both its amide and imine tautomers. Therefore, amide-containing compounds should be understood to include their imine tautomers. Similarly, imine-containing compounds should be understood to include their amide tautomers.

[0064] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, include an asymmetric center and thereby give rise to enantiomers, diastereomers, and other stereoisomers, which can be defined according to the absolute stereochemical definition (…). R )-or( S (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), ( R )-and( S (D)- and (L)- isomers can be prepared using palmite synthons or palmite reagents, or resolved using conventional techniques (e.g., chromatography and / or fractional crystallization). Conventional techniques for the preparation / separation of individual enantiomers include palmite synthesis from suitable optically pure precursors or resolution of racemic products (or racemic products of salts or derivatives) using, for example, palmite high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise specified, the intended compounds include both the E and Z geometric isomers.

[0065] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but with different (non-interchangeable) three-dimensional structures. This disclosure contemplates various stereoisomers or mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0066] A "diastereomer" is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

[0067] Use the “thick bond” style (thick lines or parallel lines) to graphically indicate the relative centers of compounds as illustrated in this article, and use wedge bonds (thick lines or parallel lines) to illustrate absolute stereochemistry.

[0068] "Prodrug" means any compound that releases an active parent drug according to the structure described herein in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein in a manner that allows the modification to cleave in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in compounds in a manner that allows the modification to cleave into the parent compound under normal operating conditions or in vivo. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl, or thiol groups in the compounds described herein are respectively bonded to any group that can cleave in vivo to regenerate a free hydroxyl, amino, or thiol group. Examples of prodrugs include (but are not limited to) esters (e.g., acetates, formates, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc., of the hydroxyl functional group in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in the following literature: T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14; “Design of Prodrugs,” edited by H. Bundgaard, Elsevier, 1985; and “Bioreversible Carriers in Drug Design,” edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated in its entirety by reference.

[0069] 2. Compounds This document provides compounds as inhibitors of SARM1. In some embodiments, compounds of formula I are provided: I Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11)2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13)2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0070] In some embodiments, a compound of formula I is provided: I Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R is -NR 2 R 3 -OR7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11-S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals.1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The condition is that at least one of A, B, C, D, or E occurs: A. X 1 It is N and X 2 It is NR 8b ;and a. When R is C 1-6 Alkyl; C 1-6 Alkyl groups via halogenation or C 3-10 cycloalkyl groups and optional one to four Z 1 Replace; and / or b. R 8b Not hydrogen; and / or c. When R is -OR 7 When; then R 7 Not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9 H -fluorene-9-ylmethyl; And the compound is not:

[0071] B. X 2 Yes or NR 8b And R is -NR 2 R 3 ;and a. R 2 and R 3 Not both methyl; and / or b. When X 1 When it is O, then R 8b R 8c R 6c Or R 6d At least one of them is not hydrogen; And the compound is not:

[0072] C. X1 Is it N or CR? 6a X 2 It is O, X 3 Is it N or CR? 6c And X 4 It is N; and a. In R is C 1-6 In the case of alkyl groups, C 1-6 Alkyl groups with one to five Z 1 Replace; and / or b. R 6c Not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl, or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridyl]amino]-5-thiazolyl; and / or c. When R is -OR 7 When, then R 7 Not isobutyl or tert-butyl; And the compound is not:

[0073] D. X 1 It is O, X 2 Is it N or CR? 6b X 3 It is CR 6c X 4 It is N, R 6c It is not hydrogen; and R is -NR. 2 R 3 , where R 2 and R 3 Together they form a heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 Replace; and at least one of the following a. through d. appears: a. X 2 It is N; or b. R 1 Not methyl; or c. R 2 and R 3 Forming an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; or d. R 2 and R 3 Form a optionally substituted monocyclic 7-membered heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; And the compound is not:

[0074] and / or E. R is , where q is 0, 1, 2, 3, 4 or 5; and p is 0, 1, 2 or 3.

[0075] In some embodiments, compounds of formula II are provided: II Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 3 Is it N or CR? 6c ; X 4 Is it N or CR? 6d ; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein C 1-6 Alkyl groups via halogenation or C 3-10 cycloalkyl groups and optional one to four Z 1 Replace; and where C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals.1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 8b It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8b and R 6c 、or R 6c and R 6dTogether they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: When R is -OR 7 When; then R 7 Not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9 H -fluorene-9-ylmethyl; and the compound is not:

[0076] In some embodiments, compounds of formula III are provided: III Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 Is it N or NR? 8b ; X 3 It is N, NR 8c or CR 6c ; X4 Is it N or CR? 6d ; The condition is that it contains X 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 6a and R 8b R 8b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: R 2 and R 3 Not both methyl; When X1 When it is O, then R 8b R 8c R 6c Or R 6d At least one of them is not hydrogen; and The compound is not:

[0077] In some embodiments, a compound of formula IV is provided: IV Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 Is it N or CR? 6a ; X 3 Is it N or CR? 6c ; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein C 1-6 Alkyl groups with one to five Z 1 Replace; and where C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a and R 6c Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11-S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: R 6c Not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridinyl]amino]-5-thiazolyl; When R is -OR 7 When, then R 7 Not isobutyl or tert-butyl; and the compound is not:

[0078] In some embodiments, a compound of formula V is provided: V Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 2 Is it N or CR? 6b ; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11-S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6b It contains hydrogen, halogen, cyano, -NO2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 6c It is a halogenated group, a cyano group, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 6b and R 6c Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The condition is that one or more of the following occur: X 2 It is N; R 1 Not methyl; R 2 and R 3 Forming an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; or R 2 and R 3 Form a optionally substituted monocyclic 7-membered heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; And the compound is not:

[0079] In some implementations, R or part yes It can be optionally fused to a C6 aryl group; wherein: q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; X is CH2, CHZ 1 C(Z) 1 2. NR 9 , O or S; and R 9 Is it H or Z? 1 .

[0080] In some embodiments, a compound of formula VI is provided: VI Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; q is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11-NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13-C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0081] In some embodiments of the formula disclosed herein, each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R)12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, -SF5, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0082] In some embodiments, a compound of formula VI is provided: VI Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3and X 4 The ring is from the Aromatic tribe; q is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C.1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, -SF5, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0083] In some implementations, R, part or part yes ;in: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 Replace; and L 1 It is key, C 1-4 Alkylene, C 2-4 imide or C 2-4 Alynyl group.

[0084] In some implementations, R, part or part yes ;in: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1b Replace; and L 1 It is key, C 1-4 Alkylene, C 2-4 imide or C 2-4 Alynyl group.

[0085] In some implementations, p is 1.

[0086] In some implementations, q is 1 or 2.

[0087] In some implementations, R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl, optionally substituted with cyano or methyl.

[0088] In some implementations, R 1 It is fluorine, chlorine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclobutyl, or cyclopropyl, optionally substituted with cyano or methyl.

[0089] In some implementations, R 1 It is chloro, cyano, or trifluoromethyl.

[0090] In some implementations, L 1 Is it a key or C? 1-4 Alkylene. In some embodiments, L 1 Is it a key or C? 1-2 Alkylene. In some embodiments, L 1 It is a key or -CH2-. In some implementations, L 1 It is a key.

[0091] In some implementations, ring B is optionally routed through one to five Z-shaped paths. 1a Substituted heteroaryl groups. In some embodiments, ring B is optionally substituted with one to five Z-terminal groups. 1a Substituted heteroaryl groups, and L 1 Is it a key or C? 1-2 Alkylene. In some embodiments, ring B is optionally cyclic to one to five Zn groups. 1a Substituted heteroaryl groups, and L 1 It is a bond or CH2. In some embodiments, ring B is a heteroaryl group and L1 It is key. In some implementations, ring B is optionally connected via one to five Z-axis rings. 1a Substituted heteroaryl, L 1 It is a key, q is 1, and Z is... 1 It is C 1-6 alkyl.

[0092] In some implementations, ring B is optionally routed through one to five Z-shaped paths. 1b Substituted heteroaryl groups. In some embodiments, ring B is optionally substituted with one to five Z-terminal groups. 1b Substituted heteroaryl groups, and L 1 Is it a key or C? 1-2 Alkylene. In some embodiments, ring B is optionally cyclic to one to five Zn groups. 1b Substituted heteroaryl groups, and L 1 It is a bond or CH2. In some embodiments, ring B is a heteroaryl group and L 1 It is key. In some implementations, ring B is optionally connected via one to five Z-axis rings. 1b Substituted heteroaryl, L 1 It is a key, q is 1, and Z is... 1 It is C 1-6 alkyl.

[0093] In some implementations, R 4 Is it hydrogen or C? 1-6 alkyl.

[0094] In some implementations, R 4 It is either hydrogen or methyl.

[0095] In some implementations, R 5 It is either hydrogen or a halogroup.

[0096] In some implementations, R 5 It is either hydrogen or fluorine.

[0097] In some implementations, part yes , , , , , , , , , , , , , , , , , , , , , , , or .

[0098] In some implementations, part yes , , , , , , , , , , , , or .

[0099] In some implementations, part yes .

[0100] In some implementations, part yes , , , , , , , , , or .

[0101] In some implementations, R 6a R 6b R 6c and R 6d Each is independently hydrogen, halogroup, cyanogroup, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 Cycloalkyl.

[0102] In some implementations, part yes , , , , , , , , , , , , or And R 6a R 6b R 6c and R 6d Each is independently hydrogen, halogroup, cyanogroup, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 Cycloalkyl.

[0103] In some implementations, part yes , , , , , , , , , or And R 6a R 6b R 6c and R 6d Each is independently hydrogen, halogroup, cyanogroup, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 Cycloalkyl.

[0104] In some implementations, R 6a R 6b R 6c and R 6d Each can be independently hydrogen, fluorine, cyano, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, cyclopropyl or cyclopropylmethyl.

[0105] In some implementations, each Z 1 Independently halogenated, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, heteroaryl groups, -OR 12 or -C(O)OR 12 ; where each C 1-6 Alkyl, C 1-6 The haloalkyl or heteroaryl groups are optionally substituted independently with one to five hydroxyl, methoxy, or methyl groups.

[0106] In some implementations, R is -OR 7 .

[0107] In some implementations, R is -OR 7 And R 7 It is benzyl or cyclobutyl.

[0108] In some implementations, R is -NR 2 R 3 .

[0109] In some implementations, R is -NR 2 R 3 And R 2 and R 3 Together they form a heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace.

[0110] In some implementations, R is -NR 2 R 3 And R 2 and R 3 Together they form a heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 Replace; where each Z 1 It is independently fluorine, bromine, cyano, methyl, trifluoromethyl, methoxy, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pent-1-yl or phenyl.

[0111] In some implementations, R is optionally via one to five Z. 1 Replacement C 1-6 alkyl.

[0112] In some implementations, R is optionally via one to five Z. 1 Replacement C 1-6 Alkyl; wherein each Z 1 Independently, it is fluorine, methyl, trifluoromethyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pent-1-yl, phenyl or pyridyl.

[0113] In some implementations, each Z 1 Independently halogenated, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, heteroaryl groups, C 1-6 Alkyl group or -C(O)OC 1-6 Alkyl; wherein each C 1-6 Alkyl, C 1-6 The haloalkyl or heteroaryl groups are optionally substituted independently with one to five hydroxyl, methoxy, or methyl groups.

[0114] In some embodiments, compounds of formula IIA are provided: IIA Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 3 Is it N or CR? 6c ; X 4 Is it N or CR? 6d ; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8b It is hydrogen, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8b and R 6c 、or R 6c and R 6d Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13)2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0115] In some embodiments, compounds of formula IIB are provided: IIB Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; X 3 Is it N or CR? 6c ; X 4Is it N or CR? 6d ; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8b It is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8b and R 6c 、or R 6c and R 6d Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0116] In some embodiments, compounds of formula IIC are provided: IIC Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; L 1 It is key, C 1-4 Alkylene, C 2-4 imide or C 2-4 Ethyne group; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1b replace; X 3 Is it N or CR? 6c ; X 4 Is it N or CR? 6d ; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11)2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8b It is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8b and R 6c 、or R 6c and R 6d Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13-SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0117] In some implementations, L 1 It is a key.

[0118] In some implementations, R 1 It is a C-type halogenated group or optionally substituted with one to five halogenated groups. 1-6 alkyl.

[0119] In some implementations, R 1 Is it a halogenated group or C 1-6 Halogenated alkyl groups. In some embodiments, R 1 It is a halogenated group or CF3.

[0120] In some implementations, R 4 It is hydrogen.

[0121] In some implementations, R 5 It is either hydrogen or a halogroup.

[0122] In some implementations, X 3 It is CR 6c .

[0123] In some implementations, X 4 It is N.

[0124] In some implementations, X 3 It is CR 6c And X 4 It is N.

[0125] In some implementations, R 8b It is C 1-6 Alkyl group. In some embodiments, R 8b It is a methyl group.

[0126] In some embodiments, a compound of formula IID is provided: IID Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; L 1 It is key, C 1-4 Alkylene, C 2-4 imide or C 2-4 Ethyne group; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1b replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 5 It is a hydrogen or halogroup; R 8b It is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0127] In some embodiments, compounds of formula IIE are provided: IIE Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1b replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 5 It is a hydrogen or halogroup; R 8b It is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0128] In some implementations, R 8b It is C 1-6 Alkyl group. In some embodiments, R 8b It is a methyl group.

[0129] In some implementations, ring B is optionally routed through one to five Z-shaped paths. 1b Substituted oxadiazole.

[0130] In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 0. In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2. In some implementations, q is 3.

[0131] In some embodiments, compounds of formula IIF are provided: IIF Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 5 It is a hydrogen or halogroup; R 8b It is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C.1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C.1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Z 1c Is it hydrogen or Z? 1b ; Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0132] In some implementations, each Z 1 Independently halogenated, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, heteroaryl groups, -OR 12 or -C(O)OR 12 ; where each C 1-6 Alkyl, C 1-6 The haloalkyl or heteroaryl groups are optionally substituted independently with one to five hydroxyl, methoxy, or methyl groups.

[0133] In some implementations, each Z 1b Independently halogenated, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl; wherein each C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with a hydroxyl or methoxy group independently.

[0134] In some embodiments, compounds of formula IIG are provided: IIG Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 The cycloalkyl group is optionally substituted with one to five halogroups; R 5 It is a hydrogen or halogroup; Z 1c Is it hydrogen or Z? 1b ; Z 1b It is a halogenated group, cyano group, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0135] In some embodiments, compounds selected from Table 1 or pharmaceutically acceptable salts, isotopically enriched analogs, prodrugs, stereoisomers, or mixtures of stereoisomers are provided: Table 1 In some embodiments, compounds selected from Table 2 or pharmaceutically acceptable salts thereof are provided.

[0136] Table 2 3. Methods "Treatment" is a method of achieving a beneficial or desired outcome (including clinical outcomes). A beneficial or desired clinical outcome may include one or more of the following: a) suppressing a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder and / or alleviating the severity of the disease or disorder); b) slowing or halting the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder and / or preventing or delaying the spread of the disease or disorder (e.g., metastasis)); and / or c) alleviating the disease, even if clinical symptoms subside (e.g., improving the disease state, providing partial or overall remission of the disease or disorder, enhancing the effect of another drug therapy, delaying the progression of the disease, improving quality of life and / or prolonging survival).

[0137] "Prevention / preventing" means any treatment that prevents the development of clinical symptoms of the disease or ailment. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of the disease or ailment or have a family history of the disease or ailment.

[0138] "Subject" means an animal, such as a mammal (including humans), that has been or will be the subject of treatment, observation, or experimentation. The methods described herein are applicable to human therapeutics and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0139] The term "therapeutic effective amount" or "effective amount" for a compound or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug described herein means an amount sufficient, when administered to a subject, to achieve therapeutic effect and provide therapeutic benefit (e.g., improvement of symptoms or slowing of disease progression). For example, a therapeutic effective amount may be an amount sufficient to alleviate symptoms of a disease or ailment as described herein. Therapeutic effective amounts can vary depending on the subject to be treated and the disease or ailment, the subject's weight and age, the severity of the disease or ailment, and the method of administration, and can be readily determined by one of ordinary skill in the art.

[0140] The methods described herein can be applied to cell populations, either in vivo or in vitro. “In vivo” means within a living individual, such as an animal or human. In this case, the methods described herein can be used therapeutically within the individual. “In vitro” means outside a living individual. Examples of in vitro cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained using methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this case, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro to determine the optimal administration schedule and / or dosing of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental purposes or in a clinic to establish medical protocols for in vivo treatment. Other in vitro uses of the compounds and compositions described herein that may be suitable are described below or will become apparent to those skilled in the art. The compounds may be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties can be examined using methods commonly known to those skilled in the art.

[0141] In some embodiments, compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, are provided that inhibit the activity of a 1 (SARM1) protein containing a sterile α and TIR motif. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, inhibit SARM1.

[0142] In some embodiments, a method for inhibiting SARM1 activity is provided, which includes contacting cells with an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug. Inhibition may be performed in vitro or in vivo.

[0143] In some embodiments, compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof are provided for inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0144] In some embodiments, this disclosure provides for the use of compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, in the manufacture of pharmaceutical agents for inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0145] In some embodiments, a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided for inhibiting the NADase activity of SARM1. In some embodiments, a method is provided for inhibiting SARM1 NADase activity in a subject of need and / or treating neurodegeneration or neurological disorders or conditions, comprising administering to a subject of need a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0146] In some embodiments, a method for treating a disease or ailment at least partially mediated by SARM1 is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0147] In some embodiments, a method for treating a disease or ailment at least partially mediated by SARM1 is provided, comprising administering a therapeutically effective amount of a compound of formula I to a subject in need: I Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl or heterocyclic groups; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Alkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-3 Alkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R)11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11-NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R6d Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0148] In some embodiments, a method of treating axonal degeneration in a subject of need is provided, comprising administering to the subject of need a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug. In some embodiments, the compound thereof, or a pharmaceutically acceptable salt thereof, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug, inhibits axonal degeneration, including axonal degeneration caused by reduction or depletion of NAD+. In some embodiments, the compound thereof, or a pharmaceutically acceptable salt thereof, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug, prevents axonal degeneration distal to axonal injury.

[0149] In some embodiments, a method for treating degeneration of neurons or a portion thereof in the peripheral nervous system is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0150] In some embodiments, a method for treating degeneration of neurons or a portion thereof in the central nervous system is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0151] In some implementations, treatment includes reducing one or more symptoms or characteristics of neurodegeneration.

[0152] In some embodiments, a method for inhibiting axonal degeneration is provided, the method comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0153] In some embodiments, a method for treating neurodegeneration or neurological diseases or conditions is provided, the method comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug.

[0154] In some embodiments, methods are provided for treating neurodegeneration or neurological diseases or conditions associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI) (see Ziogas et al., J. Neuroscience, 2018, 38(16):4031-4032 and WO2020191257), leukoencephalopathy, or leukodystrophy, said methods comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0155] In some embodiments, a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided for the treatment of a subject in need of a disease or disorder at least partially mediated by SARM1.

[0156] In some embodiments, a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is provided for inhibiting axonal degeneration in a subject of need.

[0157] In some embodiments, this disclosure provides the use of compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, in the manufacture of a medicament for inhibiting axonal degeneration in a subject of need.

[0158] In some embodiments, this disclosure provides the use of compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, in the manufacture of medicaments for treating neurodegeneration or neurological diseases or conditions, such as those associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukodystrophy, or leukodystrophy.

[0159] In some implementations, the disease or ailment is an acute illness. In other implementations, the disease or ailment is a chronic illness.

[0160] In some implementations, the disease or ailment is characterized by axonal degeneration in the central nervous system, peripheral nervous system, optic nerve, cranial nerve, or a combination thereof.

[0161] In some embodiments, the disease or ailment is or includes acute injury to the central nervous system, such as, but not limited to, spinal cord injury and / or traumatic brain injury (TBI). In some embodiments, the disease or ailment is or includes chronic injury to the central nervous system, such as, but not limited to, spinal cord injury, traumatic brain injury (TBI), and / or traumatic axonal injury (TAI). In some embodiments, the disease or ailment is or includes chronic traumatic encephalopathy (CTE).

[0162] In some implementations, the disease or ailment is a chronic disorder affecting the central nervous system, such as, but not limited to, Parkinson's disease (see, for example, Sajadi, A. et al.). Curr. Biology 2004, 14 , 326-330; and Hasbani, DM et al. Exp. Neurology. 2006, 202 , 93-99), amyotrophic lateral sclerosis (see, for example, White, MA et al. Acta Neuropath. Comm. 2019, 7(1), 166), multiple sclerosis, Huntington's disease, or Alzheimer's disease.

[0163] In some implementations, the disease or ailment is acute peripheral neuropathy. In some implementations, the disease or ailment is chemotherapy-induced peripheral neuropathy (CIPN). See, for example... ， Geisler, S. et al. Brain 2016, 139 , 3092-3108; Turkiew, E. et al. J. Peripher. Nerv. Syst 2017, 22 , 162-171; Geisler, S. et al. JCI Insight. 2019, 4 (17), e129920; and Cetinkaya-Fisgin, A. et al. Sci. Rep. 2020, 21889. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of acute peripheral neuropathy that can be associated with a variety of drugs, such as, but not limited to, thalidomide, epothilone (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), or platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0164] In some implementations, the disease or ailment is a chronic condition affecting the peripheral nervous system, such as, but not limited to, diabetic neuropathy, HIV neuropathy, Charcot Marie Tooth disease, or amyotrophic lateral sclerosis.

[0165] In some implementations, the disease or ailment is glaucoma (see, for example, Ko, KW et al.) J. Cell Bio. 2020, 219 (8), e201912047).

[0166] In some implementations, the disease or ailment is an acute condition affecting the optic nerve, such as, but not limited to, diabetic optic neuropathy, acute optic neuropathy (AON), or acute angle-closure glaucoma.

[0167] In some implementations, the disease or ailment is a chronic condition affecting the optic nerve, such as, but not limited to, diabetic optic neuropathy, Leber congenital amaurosis, Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma, or autosomal dominant optic atrophy.

[0168] In some implementations, the disease or disorder is associated with retinal degeneration. In some implementations, the disease or disorder is Lebe's congenital amaurosis, such as Lebe's congenital amaurosis type 9 (LCA9) (see, for example, Sasaki, Y. et al.). eLife 2020, 9 (e62027).

[0169] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat one or more neurodegenerative diseases, conditions, or disorders selected from the group consisting of neuropathy or axonopathy. In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat neuropathy or axonopathy associated with axonopathy. In some embodiments, the neuropathy associated with axonopathy is a hereditary or congenital neuropathy or axonopathy. In some embodiments, the neuropathy associated with axonopathy is caused by a de novo mutation or somatic mutation. In some embodiments, the neuropathy associated with axonopathy is selected from the list contained herein. In some embodiments, the neuropathy or axonopathy is associated with axonopathy, including but not limited to Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, focal ischemia, stroke, chemical injury, thermal injury, or AIDS.

[0170] In some embodiments, one or more compounds or compositions as described herein are characterized by reducing one or more symptoms or features of neurodegeneration when administered to a subject population. For example, in some embodiments, the associated symptoms or features may be selected from the group consisting of: the degree, rate, and / or timing of neuronal damage. In some embodiments, neuronal damage may be or include axonal degeneration, synaptic loss, dendritic loss, loss of synaptic density, loss of dendritic dendrite formation, loss of axonal branching, loss of neuronal density, loss of myelination, loss of neuronal cell body, loss of synaptic enhancement, loss of action potential difference, loss of cytoskeleton stability, loss of axonal transport, loss of ion channel synthesis and switching, loss of neurotransmitter synthesis, loss of neuronal release and reuptake capacity, loss of axonal potential propagation, neuronal hyperexcitability, and / or neuronal hypoexcitability. In some embodiments, neuronal damage is characterized by the inability to maintain an appropriate resting neuronal membrane potential. In some embodiments, neuronal damage is characterized by the presence of inclusion bodies, plaques, and / or neurofibrillary tangles. In some embodiments, neuronal damage is characterized by the presence of stress granules. In some embodiments, neuronal destruction is characterized by intracellular activation of one or more members of the cysteine-aspartic protease (caspase) family. In some embodiments, neuronal destruction is characterized by neurons undergoing programmed cell death (e.g., apoptosis, telogen effluvium, ferruginous apoptosis, and / or necrosis) and / or inflammation.

[0171] In some implementations, neurodegeneration or neurological diseases or conditions are associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by leukodystrophy, or leukodystrophy. In some implementations, neurodegeneration or neurological diseases or conditions include spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukodystrophy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus-Merzbacher disease, periventricular leukomalacia, Krabbe's disease, Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS), and Lou Gehrig's disease. Diseases including Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, Gaucher's disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (e.g., chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, glaucoma, retinitis pigmentosa, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), and Leber congenital amaurosis (e.g.,Lebe's congenital amaurosis type 9 (LCA9), neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Shamadousin disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia (ataxia), hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonal neuropathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, infectious cavernous encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic hemiplegia, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, or nonalcoholic steatohepatitis (NASH).

[0172] In some embodiments, this disclosure provides SARM1 activity inhibitors for treating neurodegeneration or neurological diseases or conditions involving axonal degeneration or axonal lesions. This disclosure also provides methods for using SARM1 activity inhibitors to treat, prevent, or improve axonal degeneration, axonal lesions, and neurodegeneration or neurological diseases or conditions involving axonal degeneration. In some embodiments, this disclosure provides methods for inhibiting axonal degeneration, the methods comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug.

[0173] In some embodiments, this disclosure provides methods for treating neurodegeneration or nervous system diseases or conditions associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by leukodystrophy, or leukodystrophy.

[0174] In some implementations, neuropathy and axonopathy include any disease or disorder involving neurons and / or supporting cells such as glial cells, muscle cells, or fibroblasts, particularly those involving axonal damage. Axonal damage can be caused by traumatic injury or non-mechanical injury resulting from disease, condition, or exposure to toxic molecules or drugs. The consequences of such damage can be axonal degeneration or dysfunction, as well as loss of functional neuronal activity. Diseases and disorders that produce or are associated with such axonal damage are among a large number of neuropathic diseases and disorders. Such neuropathy can include peripheral neuropathy, central neuropathy, or a combination thereof. Furthermore, peripheral neuropathy can result from diseases primarily affecting the central nervous system, while central nervous system manifestations can result from diseases that are essentially peripheral or systemic.

[0175] In some implementations, peripheral neuropathy may involve damage to the peripheral nerves and / or may be caused by neurological disorders or be a result of systemic diseases. Some such diseases include diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiencies such as vascular or collagen diseases of atherosclerosis, or autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. In some implementations, peripheral neuropathy is caused by traumatic (mechanical) damage to the nerves as well as chemical or thermal damage. Such peripheral nerve disorders include compression or entrapment injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fractures, or dislocations; pressure involving superficial nerves (ulnar, radial, or peroneal nerves), which may be caused by prolonged use of crutches or maintaining one posture for too long, or tumors; intraneural hemorrhage; local ischemia; exposure to cold or radiation, or certain drugs or toxic substances, such as herbicides or pesticides. Specifically, nerve damage may be caused by chemical damage resulting from cytotoxic anticancer agents such as paclitaxel, cisplatinin, proteasome inhibitors, or vinca alkaloids, such as vincristine. Typical symptoms of this type of peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, itching, tingling, or numbness), and pain in the arms, hands, legs, and / or feet. In some implementations, the neuropathy is associated with mitochondrial dysfunction. This type of neuropathy may manifest as decreased energy levels, specifically decreased NAD and ATP levels.

[0176] In some implementations, peripheral neuropathy is a metabolic and endocrine neuropathy that encompasses a wide range of peripheral neuropathy symptoms associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes mellitus, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia vera, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiencies, or mitochondrial diseases. A common hallmark of these diseases is the involvement of peripheral nerves due to structural or functional alterations in myelin sheaths and axons resulting from metabolic pathway dysregulation.

[0177] In some implementations, neuropathy includes optic neuropathy, such as glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and external retinal neuropathy; optic neuritis and / or degeneration, including those associated with multiple sclerosis; traumatic injury to the optic nerve, which may include, for example, injury during tumor resection; hereditary optic neuropathy, such as Kjer's disease and Leber's hereditary optic neuropathy (LHON); focal ischemic optic neuropathy, such as those secondary to giant cell arteritis; metabolic optic neuropathy, such as neurodegenerative diseases, including Leber's neuropathy; nutritional deficiencies, such as vitamin B12 or folic acid deficiency; and poisoning, such as poisoning by ethambutol or cyanide; neuropathy caused by adverse drug reactions and neuropathy caused by vitamin deficiencies. Focal ischemic optic neuropathy also includes non-arterial anterior focal ischemic optic neuropathy.

[0178] In some implementations, neurodegenerative diseases associated with neuropathy or axonal lesions in the central nervous system encompass a variety of conditions. These include those involving: progressive dementia, such as Alzheimer's disease, senile dementia, Pick's disease, and Huntington's disease; central nervous system diseases affecting muscle function, such as Parkinson's disease; motor neuron diseases and progressive ataxia, such as amyotrophic lateral sclerosis (ALS); demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as those caused by enteroviruses, arboviruses, and herpes simplex viruses; and prion disease. Mechanical injuries (such as glaucoma or traumatic injuries to the head and spine) also cause nerve damage and degeneration in the brain and spinal cord. Furthermore, local ischemia and stroke, as well as conditions such as nutritional deficiencies and chemical toxicity (e.g., chemotherapeutic agents), can cause central nervous system neuropathy.

[0179] In some embodiments, this disclosure provides methods for treating neuropathies or axonal lesions associated with axonal degeneration. In some embodiments, the neuropathies or axonal lesions associated with axonal degeneration may be any of a variety of neuropathies or axonal lesions, such as those that are hereditary or congenital, or those associated with Parkinson's disease, Alzheimer's disease, herpes infections, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemic stroke, chemical injury, thermal injury, and AIDS. Furthermore, neurodegenerative diseases not mentioned above, as well as subsets of the aforementioned diseases, may also be treated using the methods of this disclosure. Such subsets of diseases may include Parkinson's disease or Alzheimer's disease.

[0180] In some embodiments, the method includes administering an effective amount of the compound and / or composition described herein (e.g., compound of formula I) to a subject in need. In some such embodiments, the subject is at risk of developing a disease characterized by axonal degeneration. In some embodiments, the subject has a disease characterized by axonal degeneration. In some embodiments, the subject has been diagnosed with a disease characterized by axonal degeneration. In some embodiments, the subject is at risk of developing a disease characterized by axonal degeneration. In some embodiments, for example, the subject is identified as being at risk of axonal degeneration based on the subject's genotype, diagnosis of a disease associated with axonal degeneration, and / or exposure to agents and / or diseases that induce axonal degeneration.

[0181] In some embodiments, the subject is at risk of developing neurodegenerative diseases. In some embodiments, the subject is elderly. In some embodiments, the subject is known to have genetic risk factors for neurodegeneration. In some embodiments, the subject has a family history of neurodegenerative diseases. In some embodiments, the subject exhibits one or more copies of a known genetic risk factor for neurodegeneration. In some embodiments, the subject comes from a population with a high incidence of neurodegeneration. In some embodiments, the subject has a hexanucleotide repeat amplification in open reading frame 72 of chromosome 9. In some embodiments, the subject has one or more copies of the ApoE4 allele.

[0182] In some embodiments, the neurodegenerative disease, condition, or disorder may be or include traumatic neuronal injury. In some embodiments, traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to concussion and / or explosive forces, or penetrating injury to the brain cavity or areas innervated by nerves. In some embodiments, traumatic neuronal injury is a force that causes axonal deformation, stretching, compression, or tearing. In some embodiments, the disease or condition is traumatic brain injury (TBI).

[0183] In some implementations, the subject has engaged in or is engaged in activities identified as risk factors for neuronal degeneration, such as contact sports or occupations with a high chance of traumatic neuronal injury or TBI.

[0184] In some embodiments, a method of treating a neurodegenerative disease, condition, or disorder is provided, comprising administering to a patient in need one or more of the compounds described herein and DLK inhibitors or NAMPT inhibitors. In some embodiments, a combination therapy is provided comprising the compounds described herein and DLK inhibitors and / or NAMPT inhibitors. In some embodiments, a combination therapy is provided comprising the compounds described herein, DLK inhibitors, and one or more additional therapeutic agents. In some embodiments, a combination therapy is provided comprising the compounds described herein, NAMPT inhibitors, and one or more additional therapeutic agents. In some embodiments, a combination therapy is provided comprising the compounds described herein, DLK inhibitors, NAMPT inhibitors, and one or more additional therapeutic agents.

[0185] In some embodiments, the DLK inhibitor is a small molecule, peptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or aptamer), antibody, dominant / negative inhibitor, or ribozyme. In some embodiments, the DLK inhibitor is a small molecule. In some embodiments, the DLK inhibitor is siRNA. In some embodiments, the DLK inhibitor is an antisense oligonucleotide. In some embodiments, the DLK inhibitor is a peptide. In some embodiments, the DLK inhibitor is a peptide fragment. In some embodiments, the DLK inhibitor is a nucleic acid. In some embodiments, the DLK inhibitor is an antisense oligonucleotide.

[0186] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, WO2014177060, WO2015091889, WO2016142310, US20180057507, WO2018107072, WO2019241244, WO2020168111 and CN104387391A, all of which are hereby incorporated herein by reference in their entirety.

[0187] In some embodiments, the NAMPT inhibitor is a small molecule, peptide, peptide fragment, nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or aptamer), antibody, dominant / negative inhibitor, or ribozyme. In some embodiments, the NAMPT inhibitor is a small molecule. In some embodiments, the NAMPT inhibitor is siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In some embodiments, the NAMPT inhibitor is a peptide. In some embodiments, the NAMPT inhibitor is a peptide fragment. In some embodiments, the NAMPT inhibitor is a nucleic acid. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide.

[0188] In some implementations, NAMPT inhibitors prevent the formation of nicotinamide mononucleotide (NMN). In some implementations, NAMPT inhibition suppresses the mammalian NAD+ rescue pathway.

[0189] In some embodiments, a composition comprising compounds as described herein is provided, which is formulated for administration to a subject in combination with a DLK inhibitor and / or a NAMPT inhibitor.

[0190] In some embodiments, a composition comprising compounds as described herein is provided for use in combination with DLK inhibitors and / or NAMPT inhibitors. In some embodiments, such a composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0191] In some implementations, the subject may be a subject who has received, is receiving, or has been prescribed chemotherapy related to peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilone (e.g., ixaprazole), taxanes (e.g., paclitaxel and docetaxel), vinblastine alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), and platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0192] In some embodiments, SARM1 inhibition as described herein may be used in combination with one or more other therapies to treat an associated disease, condition, or disorder. In some embodiments, the administration of the SARM1 inhibitor is altered when used in combination therapy compared to when it is administered as a monotherapy; alternatively or additionally, the therapy administered in combination with SARM1 inhibition as described herein is administered according to a different regimen or medical protocol than when administered alone or in combination with one or more therapies other than SARM1 inhibition. In some embodiments, a composition includes additional therapeutic agents, which, together with the provided compounds, may act synergistically. In some embodiments, one or both therapies utilized in the combination regimen are administered at a lower level or less frequently than when used as monotherapy.

[0193] In some embodiments, the compounds provided herein, or their pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs or components, are associated with NAD+. + or NAD + Precursors (e.g., nicotinamide riboside (NR), nicotinic acid (NA), nicotinic acid ribose (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), tryptophan (TRP), nicotinic acid adenine dinucleotide (NAAD), or vitamin B3) are administered in combination.

[0194] In some embodiments, compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof are provided for inhibiting the activity of protein 1 (SARM1) containing sterile α and TIR motifs (e.g., in vitro or in vivo).

[0195] In some embodiments, this disclosure provides compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for the manufacture of protein 1 (SARM1) containing sterile α and TIR motifs (e.g., in vitro or in vivo) and for supplementing axonal NAD. + Uses in horizontal pharmaceutical preparations.

[0196] Axonal degeneration is associated with various types of neurodegenerative diseases and is considered an important indicator of disease progression and an attractive target for therapeutic treatment of these diseases. Similarly, axonal degeneration has also been observed in subjects with traumatic brain injury and peripheral neuropathy.

[0197] In some embodiments, a method for treating a disease or ailment at least partially mediated by SARM1 is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or a prodrug with NAD. + or NAD + A combination of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0198] In some embodiments, this disclosure provides a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug with NAD. + or NAD + Use of combinations of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3) in the manufacture of pharmaceutical agents for the treatment or prevention of neurodegenerative diseases in subjects in need.

[0199] In some embodiments, a method for treating any disease caused by SARM1 activity is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or a prodrug with NAD. + or NAD + A combination of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0200] In some implementations, the disease or ailment may be a disease or ailment of the central nervous system, and / or may be caused by or related to a pathogen or traumatic injury. It should be understood that these general implementations, defined according to broad categories of diseases, symptoms, and ailments, are not mutually exclusive.

[0201] In some embodiments, a method for treating neurodegenerative diseases is provided, comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or a prodrug with NAD. + or NAD + A combination of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0202] Other embodiments include the use of the compounds disclosed in this invention in therapeutic applications.

[0203] 4. Reagent kit This document also provides a kit comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers, or a prodrug, and suitable packaging. In some embodiments, the kit also includes instructions for use. In one aspect, the kit comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers, or a prodrug, and labeling and / or instructions regarding the indications for treatment with the compound (including the diseases or ailments described herein).

[0204] This document also provides articles comprising the compounds described herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, contained in suitable containers. Containers may be vials, cans, ampoules, pre-filled syringes, or intravenous bags.

[0205] 5. Drug composition and administration method The compounds described herein are typically administered as pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, and one or more pharmaceutically acceptable media selected from carriers, adjuvants, and excipients are also provided herein. Suitable pharmaceutically acceptable media may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in pharmaceutical technology. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GS Banker and CT Rhodes).

[0206] The drug composition can be administered in a single dose or multiple doses. The drug composition can be administered via various methods, including, for example, rectal, buccal, intranasal, and percutaneous routes. In some embodiments, the drug composition can be administered via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0207] One mode of administration is parenteral administration, such as by injection. Forms that may be incorporated into the pharmaceutical compositions described herein for administration by injection include, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical carriers.

[0208] Oral administration may be another route of administration for the compounds described herein. Administration may be carried out, for example, in capsules or enteric-coated tablets. In the preparation of pharmaceutical compositions comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, the active ingredient is typically diluted with and / or encapsulated within 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, serving as a medium, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0209] Some examples of suitable excipients include, for example, 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. Formulations may also include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0210] Compositions including at least one compound described herein or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug can be formulated using procedures known in the art to provide rapid, sustained, or delayed release of the active ingredient upon administration to a subject. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation used in the methods disclosed herein employs a percutaneous delivery device (“patch”). Such percutaneous patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of percutaneous patches for delivering pharmaceutical agents are well known in the art. Such patches can be configured for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0211] To prepare solid compositions (e.g., tablets), a major active ingredient may be mixed with a pharmaceutical excipient to form a homogeneous mixture of the compound described herein or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug. When these preformed compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition, allowing for easy subdivision into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0212] The tablets or pills of the compounds described herein may be coated or otherwise formulated 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 comprise an internal dose component and an external dose component, the latter in the form of a coating over the former. The two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to enter the duodenum intact or with delayed release. A wide variety of substances can be used for such enteric coatings or coatings, including various polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0213] Compositions for inhalation or blowing may include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered via the oral or nasal respiratory route for local or systemic action. 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 connected to a face mask tent or intermittent positive pressure ventilation machine. In one embodiment, the solution, suspension, or powder composition may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0214] The amount of compounds in a pharmaceutical composition or formulation can vary within the full range employed by those skilled in the art. Typically, based on weight percentage (wt%), the formulation will contain about 0.01-99.99 wt% of the compounds disclosed herein, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compounds are present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described below.

[0215] Formulation Example 1 - Tablet Formulation Mix the following ingredients thoroughly and compress them into single-score tablets.

[0216] Formulation Example 2 - Capsule Formulation Mix the following ingredients thoroughly and load them into hard-shell gelatin capsules.

[0217] Formulation Example 3 - Suspension Formulation Mix the following ingredients to form a suspension for oral administration.

[0218] Formulation Example 4 - Injectable Formulation Mix the following ingredients to form an injectable formulation.

[0219] Formulation Example 5 - Suppository Formulation A suppository with a total weight of 2.5 g was prepared by mixing the disclosed compound with Wiptsol® H-15 (a triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York), and it has the following composition:

[0220] 6. Administration The specific dosage level of the compounds in this application 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 dosage may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of the subject's body weight. Doses between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 to 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 and 60 mg / kg may be appropriate. In some embodiments, doses of about 0.0001 to about 100 mg / kg body weight, about 0.001 to about 50 mg compound / kg body weight, or about 0.01 to about 10 mg compound / kg body weight per day may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting the dose among subjects with significantly different body sizes, such as when the drug is used in both children and adults, or when converting an effective dose for a non-human subject (e.g., a dog) to a dose suitable for a human subject.

[0221] 7. Synthesis of Compounds Compounds can be prepared using the methods disclosed herein and their conventional modifications (which will be obvious given the disclosure herein and methods well known in the art). In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of typical compounds described herein can be carried out as illustrated in the following examples. Reagents and starting materials, if available, can be commercially available from (e.g.) Sigma Aldrich or other chemical suppliers.

[0222] It should be understood that, unless otherwise stated, other process conditions may be used even when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0223] Furthermore, conventional protecting groups (“PG”) may be necessary to prevent certain functional groups from undergoing unwanted reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in Wuts, PGM, Greene, TW, and Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the references cited therein. Protecting groups for alcohols, such as hydroxyl groups, include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsiloxymethyl (TOM), and triisopropylsilyl (TIPS) ether), which can be removed by acids or fluoride ions such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups used for alcohols include acetyl, removed by acid or base; benzoyl, removed by acid or base; benzyl, removed by hydrogenation; methoxyethoxymethyl ether, removed by acid; dimethoxytriphenylmethyl, removed by acid; methoxymethyl ether, removed by acid; tetrahydropyranyl or tetrahydrofuranyl, removed by acid; and triphenylmethyl, removed by acid. Examples of protecting groups used for amines include benzyloxycarbonyl, removed by hydrolysis; p-methoxybenzylcarbonyl, removed by hydrolysis; tert-butoxycarbonyl, removed by concentrated strong acid (e.g., HCl or CF3COOH) or by heating to above about 80°C; 9-fluorenylmethyloxycarbonyl, removed by a base (e.g., hexahydropyridine); acetyl, removed by treatment with a base; benzoyl, removed by treatment with a base; benzyl, removed by hydrolysis; carbamate, removed by acid and gentle heating; p-methoxybenzyl, removed by hydrolysis; 3,4-dimethoxybenzyl, removed by hydrolysis; p-methoxyphenyl, removed by cerium ammonium nitrate (IV); toluenesulfonyl, removed by concentrated acid (e.g., HBr or H2SO4) and a strong reducing agent (sodium or naphthyl sodium in liquid ammonia); troc (trichloroethyl chloroformate), removed by Zn insertion in the presence of acetic acid; and sulfonamides (Nosyl and Nps), removed by samarium iodide or tributyltin hydride.

[0224] Furthermore, the compounds disclosed herein may contain one or more palmate centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures of enriched stereoisomers, if desired. Unless otherwise stated, all such stereoisomers (and enriched mixtures) are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, palmate column chromatography, palmate resolving agents, etc.

[0225] The starting materials used in the following reactions are typically known compounds, or can be prepared by known procedures or their obvious modifications. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other preparations can be made using procedures described in, for example, the following standard references or their obvious modifications: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989), organic Reactions, Volumes 1–40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0226] General Synthesis Scheme I illustrates a general method that can be used to synthesize the compounds described herein (e.g., Formula I), wherein X 1 X 2 X 3 X 4 , R, R 1 R 4 and R5 Each is independently defined as described herein, and each LG is independently a detachable group (e.g., halogenated, alkoxy, etc.).

[0227] Option I In Scheme I, the compound of formula I can be prepared by contacting compound I-1 with compound I-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection if desired. Alternatively, the compound of formula I can be prepared by contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, followed by optional functionalization or deprotection if desired. Alternatively, the compound of formula I can be prepared by contacting compound I-5 with a portion of a suitable functionalized precursor of A under suitable coupling reaction conditions, followed by optional functionalization or deprotection if desired. After each reaction is complete, each of the intermediates or the final compound can be recovered and optionally purified by conventional techniques (e.g., neutralization, extraction, precipitation, chromatography, filtration, etc.).

[0228] Further derivatization of the compound or any intermediate provided by the steps outlined in Scheme I provides additional Formula I compounds. It should be understood that any of the compounds or intermediates shown in Scheme I can be prepared using conventional methods or purchased from commercial sources. Furthermore, any intermediate or product obtained by the process outlined in Scheme I can be derivatized at any step to provide various Formula I compounds. In some embodiments, various substituents of the compounds or intermediates used in Scheme I are as defined for Formula I.

[0229] In some embodiments, the compound of formula I (where R is -OR) 7 Compounds of formula IA or IB can be prepared according to scheme II, wherein X 1 X 2 X 3 X 4 R 1 R 2 R 3 R 4 R 5 and R 7 Each is independently defined as described herein, and each LG is independently a detachable group (e.g., halogenated, alkoxy, etc.).

[0230] Option II In scheme II, the compound of formula IA can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide an acylation intermediate, followed by contacting the acylation intermediate with compound II-2 or a salt thereof. Compound I (where R is -OR)7 Compound II-4 can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide an acylation intermediate, followed by contacting the acylation intermediate with compound II-3. After each reaction is completed, each of the intermediates or the final compound can be recovered and optionally purified by conventional techniques (e.g., neutralization, extraction, precipitation, chromatography, filtration, etc.).

[0231] It should be understood that any of the compounds or intermediates shown in Scheme II can be prepared using conventional methods or obtained from commercial sources. Furthermore, any intermediate or product obtained by the process outlined in Scheme II can be derivatized at any step to provide compounds of various formulas I or IA. In some embodiments, various substituents of the compounds or intermediates used in Scheme II are as defined for formulas I or IA.

[0232] After each reaction is completed, each of the intermediates or final compounds can be recovered and optionally purified using conventional techniques (such as neutralization, extraction, precipitation, chromatography, filtration, etc.).

[0233] In some embodiments, a process for providing a compound of formula I is provided, comprising: 1) Make compound I-1: I-1 With compound of formula I-2: I-2 Contact under conditions sufficient to provide compound I; wherein X 1 X 2 X 3 X 4 , R, R 1 R 4 and R 5 Each is independent as defined in this article.

[0234] In some embodiments, a process for providing a compound of formula I is provided, comprising: 1) Make compound I-1: I-1 Compounds of formula IA-2: IA-2 Contact under conditions sufficient to provide compound of formula IA; wherein X 1 X 2 X 3 X 4 R 1 R 2 R 3 R4 and R 5 Each is independent as defined herein. In some embodiments, the conditions include a phosgene reagent, such as triphosgene.

[0235] Example The following embodiments are included to illustrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, those skilled in the art will understand that, based on this disclosure, many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this disclosure, and similar or analogous results can still be obtained.

[0236] General experimental methods All solvents used are commercially available and can be used without further purification. Anhydrous solvents are typically used in the reaction under an inert nitrogen atmosphere.

[0237] NMR spectroscopy: Implementation using one of the following instruments: a Bruker Avance III or lower, equipped with a BBFO 300 MHz probe and operating at 300 MHz. 1 1H nuclear magnetic resonance (NMR) spectroscopy: Bruker Avance 400 instrument equipped with DUAL 400 MHz S1 probe, and 6 S1 400 MHz 5mm probe. 1 H- 13 The instrument includes a Bruker Avance 400 instrument with C ID, a Bruker Avance III 400 instrument with a nanobay equipped with a Broadband BBFO 5 mm direct probe, and a Bruker Mercury Plus 400 NMR spectrometer operating at 400 MHz equipped with a Bruker 400 BBO probe. All deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal (for...). 1 H and 13 C (both are set at δ 0.00). In some cases, unless otherwise specified, the solvent is used with a Bruker Advance 400 instrument running at 400 MHz at approximately room temperature. 1 1H nuclear magnetic resonance (NMR) spectroscopy. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) were given in parts per million using conventional abbreviations of the main peak names: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doubletet; dt, doubletet; br, broad peak.

[0238] Thin-layer chromatography (TLC): In cases where TLC is used, this refers to silica gel TLC using silica gel F254 (Merck) plates. Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography is performed on a silica gel column using an automated flash chromatography system or on a C18 column in the case of reversed-phase chromatography. Alternatively, TLC is performed on Alugram® (silica gel 60 F254) from Mancherey-Nagel, and UV is typically used to visualize the spots. Other visualization methods are also employed in some cases. In these cases, iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (generated by adding 25 g of (NH4)6Mo7O4) is used. 24 (The compound was prepared by thoroughly mixing 4H2O and 5 g (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4. The mixture was then developed on a TLC plate to visualize the compound.

[0239] Liquid chromatography-mass spectrometry and HPLC analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system with a photodiode array detector and a Luna-C18(2) 2.0 × 50 mm (5 µm column) at a flow rate of 1.2 mL / min using a gradient solvent mobile phase A (MPA, H2O + 0.037 % (v / v) TFA): mobile phase B (MPB, ACN + 0.018 % (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS or evaporative light scattering (ELSD) detection and positive electrospray ionization (MS) were performed at 220 nm and 254 nm. Semi-preparative HPLC was performed under acidic or neutral conditions. Acidic: Luna C18 100 × 30 mm, 5 μm; MPA: HCl / H2O = 0.04% or formic acid / H2O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150 × 25, 5 μm; MPA: 10 mM NH4HCO3 in H2O; MPB: ACN. Gradients for both conditions: 10% MPB over 12 min to 80% MPB at a flow rate of 20 mL / min, followed by 100% MPB over 2 min, then 10% MPB over 2 min, with a UV detector. SFC analysis was performed on a Thar analytical SFC system using a UV / Vis detector and a series of palmar columns, including AD, AS-H, OJ, OD, AY, and IC, 4.6 × 100 mm, 3 µm columns, at a flow rate of 4 mL / min, using a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.05 % (v / v) IPA) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56–5 min, 10% MPB).Preparative SFC was performed on a Thar 80 preparative SFC system equipped with a UV / Vis detector and a series of palmar preparative columns (including AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, 30 × 250 mm, 5 μm columns) at a flow rate of 65 mL / min using a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.1 % (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1–10 min, 10% MPB). LC-MS data were also collected using a UPLC-MS Acquity™ system equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization modes. The column used was a Cortecs UPLC C18, 1.6 µm, 2.1 × 50 mm. A linear gradient was applied, starting with 95% A (A: 0.1% formic acid in water) and ending with 95% B (B: 0.1% formic acid in MeCN), lasting 2.0 min, for a total run time of 2.5 min. The column temperature was 40 °C, and the flow rate was 0.8 mL / min.

[0240] Example The following embodiments are included to illustrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, those skilled in the art will understand that, based on this disclosure, many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this disclosure, and similar or analogous results can still be obtained.

[0241] General experimental methods The following embodiments are included to illustrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, those skilled in the art will understand that, based on this disclosure, many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this disclosure, and similar or analogous results can still be obtained.

[0242] General experimental methods All solvents used are commercially available and can be used without further purification. Anhydrous solvents are typically used in the reaction under an inert nitrogen atmosphere.

[0243] NMR spectroscopy: Implementation using one of the following instruments: a Bruker Avance III or lower, equipped with a BBFO 300 MHz probe and operating at 300 MHz. 1 1H nuclear magnetic resonance (NMR) spectroscopy: Bruker Avance 400 instrument equipped with DUAL 400 MHz S1 probe, and 6 S1 400 MHz 5mm probe. 1 H- 13 The instrument includes a Bruker Avance 400 instrument with C ID, a Bruker Avance III 400 instrument with a nanobay equipped with a Broadband BBFO 5 mm direct probe, and a Bruker Mercury Plus 400 NMR spectrometer operating at 400 MHz equipped with a Bruker 400 BBO probe. All deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal (for...). 1 H and 13 C (both are set at δ 0.00). In some cases, unless otherwise specified, the solvent is used with a Bruker Advance 400 instrument running at 400 MHz at approximately room temperature. 1 1H nuclear magnetic resonance (NMR) spectroscopy. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) were given in parts per million using conventional abbreviations of the main peak names: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doubletet; dt, doubletet; br, broad peak.

[0244] Thin-layer chromatography (TLC): In cases where TLC is used, this refers to silica gel TLC using silica gel F254 (Merck) plates. Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography is performed on a silica gel column using an automated flash chromatography system or on a C18 column in the case of reversed-phase chromatography. Alternatively, TLC is performed on Alugram® (silica gel 60 F254) from Mancherey-Nagel, and UV is typically used to visualize the spots. Other visualization methods are also employed in some cases. In these cases, iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (generated by adding 25 g of (NH4)6Mo7O4) is used. 24(The compound was prepared by thoroughly mixing 4H2O and 5 g (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4. The mixture was then developed on a TLC plate to visualize the compound.

[0245] Liquid chromatography-mass spectrometry and HPLC analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system with a photodiode array detector and a Luna-C18(2) 2.0 × 50 mm (5 µm column) at a flow rate of 1.2 mL / min using a gradient solvent mobile phase A (MPA, H2O + 0.037 % (v / v) TFA): mobile phase B (MPB, ACN + 0.018 % (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS or evaporative light scattering (ELSD) detection and positive electrospray ionization (MS) were performed at 220 nm and 254 nm. Semi-preparative HPLC was performed under acidic or neutral conditions. Acidic: Luna C18 100 × 30 mm, 5 μm; MPA: HCl / H2O = 0.04% or formic acid / H2O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150 × 25, 5 μm; MPA: 10 mM NH4HCO3 in H2O; MPB: ACN. Gradients for both conditions: 10% MPB over 12 min to 80% MPB at a flow rate of 20 mL / min, followed by 100% MPB over 2 min, then 10% MPB over 2 min, with a UV detector. SFC analysis was performed on a Thar analytical SFC system using a UV / Vis detector and a series of palmar columns, including AD, AS-H, OJ, OD, AY, and IC, 4.6 × 100 mm, 3 µm columns, at a flow rate of 4 mL / min, using a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.05 % (v / v) IPA) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56–5 min, 10% MPB).Preparative SFC was performed on a Thar 80 preparative SFC system equipped with a UV / Vis detector and a series of palmar preparative columns (including AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, 30 × 250 mm, 5 μm columns) at a flow rate of 65 mL / min using a gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.1 % (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1–10 min, 10% MPB). LC-MS data were also collected using a UPLC-MS Acquity™ system equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization modes. The column used was a Cortecs UPLC C18, 1.6 µm, 2.1 × 50 mm. A linear gradient was applied, starting with 95% A (A: 0.1% formic acid in water) and ending with 95% B (B: 0.1% formic acid in MeCN), lasting 2.0 min, with a total run time of 2.5 min. The column temperature was 40 °C, and the flow rate was 0.8 mL / min.

[0246] intermediate Intermediate 1 4-Methyl-3-(1-methyl-1-yl) H -1,2,4-triazol-3-yl)aniline At 25 °C and under N2, Pd(dppf)Cl2 (314 mg, 0.429 mmol) and K2CO3 (1.78 g, 12.87 mmol) were added to a mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)aniline (1 g, 4.29 mmol) and 3-bromo-1-methyl-1,2,4-triazole (834 mg, 5.15 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL). The mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was then diluted with H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 189.1 [M+H] + .

[0247] Intermediate 2 2-Cyclobutyl- N -(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)acetamide At 0 °C and under N2, TEA (1.74 g, 17.16 mmol) and 2-cyclobutylacetyl chloride (1.37 g, 10.30 mmol) were added to a mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (2 g, 8.58 mmol) in DCM (20 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was then diluted with H2O (30 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to give the title compound. LCMS: m / z = 330.3 [M+H] + .

[0248] Intermediate 3 4-Methyl-3-(5-methyl-1-yl) H -1,2,4-triazol-3-yl)aniline 2-Methyl-5-nitrobenzoylhydrazide: NH₂NH₂•H₂O (2.56 g, 51.24 mmol, 2.49 mL) was added to a mixture of methyl 2-methyl-5-nitrobenzoate (2 g, 10.25 mmol) in EtOH (20 mL) at 25 °C under N₂. The mixture was heated to 85 °C and stirred for 16 h. The mixture was then concentrated under reduced pressure to give the title compound.

[0249] 5-Methyl-3-(2-methyl-5-nitrophenyl)-1 H -1,2,4-Triazole: K₂CO₃ (1.90 g, 13.73 mmol) was added to a mixture of 2-methyl-5-nitrobenzoylhydrazine (1.34 g, 6.87 mmol) and acetamidine hydrochloride (649 mg, 6.87 mmol) in H₂O (20 mL) at 25 °C under N₂. The mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was filtered and the solid was dried under reduced pressure to give the title compound.

[0250] 4-Methyl-3-(5-methyl-1-yl) H -1,2,4-triazol-3-yl)aniline: at 25°C, to 5-methyl-3-(2-methyl-5-nitrophenyl)-1 H 1,2,4-triazole (200 mg, 0.92 mmol) was added to a solution of EtOAc (5 mL) with 10% Pd / C (50 mg, 0.92 mmol). The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 25 °C under H2 (15 psi) for 0.5 h. After stirring, the mixture was analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 189.0 [M+H] + .

[0251] Intermediate 4 4-Methyl-3-(1-(trifluoromethyl)-1 H- pyrazol-3-yl)aniline 3-(2-methyl-5-nitrophenyl)-1 H -Pyrazole: 2-iodo-1-methyl-4-nitrobenzene (5 g, 19.01 mmol), (1 H A mixture of pyrazol-3-yl)boronic acid (4.25 g, 38.02 mmol), K₂CO₃ (5.25 g, 38.02 mmol), and Pd(dppf)Cl₂ (1.39 g, 1.90 mmol) in 1,4-dioxane (100 mL) and H₂O (10 mL) was degassed and purged three times with N₂. The mixture was heated to 90 °C and stirred under N₂ for 16 h. The mixture was then analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 204.3 [M+H] + .

[0252] 1-(bromodifluoromethyl)-3-(2-methyl-5-nitrophenyl)-1 H -Pyrazole: At 0°C and under N2, to 3-(2-methyl-5-nitrophenyl)-1 HA mixture of pyrazole (580 mg, 2.85 mmol) in DMF (10 mL) was mixed with NaH (457 mg, 11.42 mmol, 60%, in mineral oil). The mixture was stirred at 0 °C for 0.5 h, followed by the addition of dibromo(difluoro)methane (3.59 g, 17.13 mmol) at 0 °C and stirring for another 1 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 332.0, 334.0 [M+H] + .

[0253] 3-(2-methyl-5-nitrophenyl)-1-(trifluoromethyl)-1 H -Pyrazole: At -78°C and under N2, to 1-(bromodifluoromethyl)-3-(2-methyl-5-nitrophenyl)-1 H β-pyrazole (1.5 g, 4.52 mmol) was added to a mixture of DCM (20 mL) and MeCN (4 mL) with silver tetrafluoroborate (2.64 g, 13.55 mmol). The mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was adjusted to pH 7–8 by adding saturated aqueous NaHCO3 solution and then extracted with DCM (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 272.1 [M+H] + .

[0254] 4-Methyl-3-(1-(trifluoromethyl)-1 H- Pyrazol-3-yl)aniline: At 25°C, 3-(2-methyl-5-nitrophenyl)-1-(trifluoromethyl)-1 H 10% Pd / C (30 mg, 0.13 mmol) was added to a solution of pyrazole (70 mg, 0.26 mmol) in EtOAc (2 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was then stirred at 25 °C with H2 (15 psi) for 1 h. The solution was analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 242.2 [M+H] + .

[0255] Intermediate 5 ( S )-2,2-difluoro- N -(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)cyclopropane-1-carboxamide At 25°C and under N2, a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)aniline (1 g, 4.29 mmol) in pyridine (10 mL) was added. S 2,2-Difluorocyclopropanecarboxylic acid (628.42 mg, 5.15 mmol) and EDCI (1.64 g, 8.58 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 9:1) to give the title compound. LCMS: m / z = 338.1 [M+H] + .

[0256] Intermediate 6 3-(1-methyl-1-yl) H -pyrazole-3-yl)-4-(1-methylcyclopropyl)aniline 2-Bromo-4-nitro-1-(prop-1-en-2-yl)benzene: At 25 °C under N2, K2CO3 (16.86 g, 121.99 mmol) and Pd(dppf)Cl2•CH2Cl2 (4.98 g, 6.10 mmol) were added to a mixture of 2-bromo-1-iodo-4-nitro-benzene (20 g, 60.99 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (11.27 g, 67.09 mmol) in 1,4-dioxane (200 mL) and H2O (20 mL). The mixture was heated to 80 °C and stirred for 12 h. (The results were obtained via Celite.) ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE) to give the title compound.

[0257] 2-Bromo-1-(2,2-dibromo-1-methylcyclopropyl)-4-nitrobenzene: At 25 °C under N2, NaOH (33.05 g, 413 mmol, 25 mL, 50% purity, in H2O) and benzyltriethylammonium chloride (188 mg, 0.826 mmol) were added to a mixture of 2-bromo-1-isopropenyl-4-nitrobenzene (5 g, 20.66 mmol) in bromoform (50 mL). The reaction mixture was heated to 50 °C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH = 7–8 by adding HCl (2 M), followed by extraction with MTBE (3 × 20 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:MTBE = 1:0 to 10:1) to obtain the title compound.

[0258] 3-Bromo-4-(1-methylcyclopropyl)aniline: Zn (30.81 g, 471 mmol) and NH4Cl (33.60 g, 628 mmol) were added to a mixture of 2-bromo-1-(2,2-dibromo-1-methylcyclopropyl)-4-nitrobenzene (13 g, 31.41 mmol) in EtOH (100 mL) at 25 °C under N2. The mixture was heated to 90 °C and stirred for 5 h. (The result was obtained via Celite...) ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 250 × 70 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 40%–70%, 10 min) to give the title compound. LCMS: m / z = 226.1, 228.1 [M+H] + .

[0259] 3-(1-methyl-1-yl) H3-Bromo-4-(1-methylcyclopropyl)aniline: At 25 °C under N2, K2CO3 (367 mg, 2.65 mmol) and Pd(dppf)Cl2 (97 mg, 0.133 mmol) were added to a mixture of 3-bromo-4-(1-methylcyclopropyl)aniline (300 mg, 1.33 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (414 mg, 1.99 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL). The mixture was heated to 100 °C and stirred for 10 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 228.1 [M+H] + .

[0260] Intermediate 7 N -(4-Cyclopropyl-3-(1-Methyl-1 H -pyrazole-3-yl)phenyl)-1 H -Imidazole-1-formamide At -40°C and under N2, 4-cyclopropyl-3-(1-methyl-1-dioxane) was added to a mixture of CDI (91 mg, 0.56 mmol) and DCM (3 mL) in DCM (3 mL). H -pyrazol-3-yl)aniline (100 mg, 0.469 mmol). The mixture was stirred at -40 °C for 1 h and the reaction mixture was used directly in the next step.

[0261] Intermediate 8 3-Fluoro-5,8-dihydro-5,8-cycloiminoquinoline hydrochloride 4-Bromo-5-fluoro-3-(trimethylsilyl)pyridin-2-ol: LDA (22.92 mmol, 2 M, 11.46 mL in THF) was added to a mixture of 4-bromo-5-fluoropyridin-2-ol (2 g, 10.42 mmol) in THF (25 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 30 min, then the reaction mixture was heated to 0 °C and TMSCl (2.26 g, 20.83 mmol) was added and stirred at 0 °C for 4 h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 264.0, 266.0 [M+H] + .

[0262] 5-Fluoro-3-(trimethylsilyl)pyridin-2-ol: 10% Pd / C (100 mg, 3.21 mmol) was added to a mixture of 4-bromo-5-fluoro-3-(trimethylsilyl)pyridin-2-ol (847 mg, 3.21 mmol) in MeOH (10 mL) at 20 °C. The mixture was stirred at 20 °C under H2 (15 psi) for 2 h. (Solution via Celite) ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 186.2 [M+H] + .

[0263] 5-Fluoro-3-(trimethylsilyl)pyridin-2-yl ester of trifluoromethanesulfonic acid: Tf₂O (1.37 g, 4.86 mmol) was added to a mixture of 5-fluoro-3-(trimethylsilyl)pyridin-2-ol (450 mg, 2.43 mmol) and pyridine (5 mL) at 20 °C under N₂. The mixture was heated to 20 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was adjusted to pH 7–8 by adding saturated aqueous NaHCO₃ and then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE) to give the title compound. LCMS: m / z = 318.1 [M+H]+ .

[0264] 3-Fluoro-5,8-dihydro-5,8-cycloiminoquinoline-9-carboxylic acid tert-butyl ester: At 20°C and under N2, 5-fluoro-3-(trimethylsilyl)pyridin-2-yl ester of trifluoromethanesulfonate (200 mg, 0.63 mmol) and 1 H CsF (191 mg, 1.26 mmol) was added to a mixture of tert-butyl pyrrole-1-carboxylate (527 mg, 3.15 mmol) in MeCN (5 mL). The mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO₂, PE:EtOAc = 3:1) to give the title compound. LCMS: m / z = 263.2 [M+H] + .

[0265] 3-Fluoro-5,8-dihydro-5,8-cycloiminoquinoline hydrochloride: A mixture of tert-butyl 3-fluoro-5,8-dihydro-5,8-cycloiminoquinoline-9-carboxylate (50 mg, 0.19 mmol) in HCl / EtOAc (3 mL, 4 M) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 163.0 [M+H] + .

[0266] Intermediate 9 4-Cyclopropyl-3-(1-methyl-1-yl) H -pyrazole-3-yl)aniline 3-Bromo-4-cyclopropylaniline: At 20 °C and under N2, a solution of 3-bromo-4-iodoaniline (10 g, 33.57 mmol) in toluene (160 mL) and H2O (8 mL) was supplemented with cyclopropylboronic acid (4.32 g, 50.35 mmol), K3PO4 (21.37 g, 100.70 mmol), tricyclohexylphosphine (1.88 g, 6.71 mmol, 2.18 mL), and Pd(OAc)2 (753 mg, 3.36 mmol). The mixture was heated to 120 °C and stirred for 12 h. (The results were obtained via Celite.) ®The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 212.1, 214.1 [M+H] + .

[0267] 4-Cyclopropyl-3-(1-methyl-1-yl) H 3-Bromo-4-cyclopropylaniline: 3-Bromo-4-cyclopropylaniline (5.5 g, 25.93 mmol), Pd(dppf)Cl2 (1.90 g, 2.59 mmol), and K2CO3 (7.17 g, 51.87 mmol) were added to a solution of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazole (13.49 g, 64.83 mmol) in 1,4-dioxane (30 mL) and H2O (3 mL) at 25 °C under N2. The mixture was heated to 100 °C and stirred for 12 h. (The results were obtained via Celite.) ® The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 214.2 [M+H] + .

[0268] Intermediate 10 cis-3-(3,3-difluoroazacyclobutan-1-yl)cyclobutan-1-carboxylic acid cis-3-(3,3-difluoroazacyclobutane-1-yl)cyclobutane-1-carboxylate: At 25 °C under N2, TEA (990 mg, 9.79 mmol) and HOAc (588 mg, 9.79 mmol) were added to a mixture of 3-oxocyclobutanecarboxylate (1 g, 4.90 mmol) and 3,3-difluoroazacyclobutane (1.27 g, 9.79 mmol) in a DCE (10 mL). The mixture was heated to 25 °C and stirred for 30 min, then cooled to 0 °C and NaBH3CN (923 mg, 14.69 mmol) was added. The reaction mixture was heated to 25 °C and stirred for 2 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound.

[0269] Cis-3-(3,3-difluoroazacyclobutan-1-yl)cyclobutane-1-carboxylic acid: At room temperature and under N2, 10% Pd / C (20 mg) was added to a solution of cis-3-(3,3-difluoroazacyclobutan-1-yl)cyclobutane-1-carboxylic acid benzyl ester (200 mg, 0.71 mmol) in THF (10 mL). The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was then stirred at 25 °C for 3 h under H2 (15 psi). The solution was analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 192.1 [M+H] + .

[0270] Intermediate 11 3-(1-methyl-1-yl) H -pyrazole-3-yl)-4-(trans-2-methylcyclopropyl)aniline ( E 2-Bromo-4-nitro-1-(prop-1-en-1-yl)benzene: At 25 °C, under N2, 2-bromo-1-iodo-4-nitro-benzene (4 g, 12.20 mmol) and [( E [-propenyl]boronic acid (1.05 g, 12.20 mmol) was added to a mixture of 1,4-dioxane (60 mL) and H2O (6 mL) along with K2CO3 (5.06 g, 36.60 mmol) and Pd(dppf)Cl2 (892 mg, 1.22 mmol). The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was then analyzed by Celite. ® The reaction mixture was filtered through a filter pad, and the filtrate was diluted with H₂O (40 mL) and extracted with MTBE (3 × 25 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE) to give the title compound.

[0271] 2-Bromo-1-((trans)-2,2-dibromo-3-methylcyclopropyl)-4-nitrobenzene: at 25°C under N2, towards ( EA mixture of 2-bromo-4-nitro-1-(prop-1-en-1-yl)benzene (3 g, 12.39 mmol) in bromoform (30 mL) was mixed with NaOH (15 g, 0.375 mol, 50% w / w, 15 mL H2O) and benzyltriethylammonium chloride (112 mg, 0.49 mmol). The mixture was heated to 50 °C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 7-8 with HCl (2 M) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE) to give the title compound.

[0272] 2-Bromo-1-(trans-2-methylcyclopropyl)-4-nitrobenzene: At 25 °C under N2, Zn (7.82 g, 119.60 mmol) and NH4Cl (8.53 g, 159.46 mmol) were added to a mixture of 2-bromo-1-[(trans)-2,2-dibromo-3-methylcyclopropyl]-4-nitrobenzene (3.3 g, 7.97 mmol) in EtOH (30 mL). The mixture was heated to 90 °C and stirred for 5 h. The product was analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 226.1, 228.1 [M+H] + .

[0273] 3-(1-methyl-1-yl) H 1-Pyrazol-3-yl)-4-(trans-2-methylcyclopropyl)aniline: At 25 °C, under N2, K2CO3 (501 mg, 3.63 mmol) and Pd(dppf)Cl2 (132 mg, 0.18 mmol) were added to a mixture of 2-bromo-1-(trans-2-methylcyclopropyl)-4-nitrobenzene (410 mg, 1.81 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxane (6 mL) and H2O (0.6 mL) to form 1,4-dioxane (6 mL). The mixture was heated to 100 °C and stirred for 16 h. (By Celite) ®The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: NH4HCO3 in water, B: MeCN; B%: 25%–55%, 10 min) to give the title compound. LCMS: m / z = 228.2 [M+H] + .

[0274] Intermediate 12 4-Cyclobutyl-3-(1-methyl-1-yl) H -pyrazole-3-yl)aniline hydrochloride 3-(2-bromo-5-nitrophenyl)-1-methyl-1 H -Pyrazole: At 20 °C, under N2, to 1-bromo-2-iodo-4-nitrobenzene (4 g, 12.20 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1 H β-pyrazole (2.8 g, 13.42 mmol) was added to a mixture of 1,4-dioxane (70 mL) and H2O (7 mL) along with K2CO3 (5 g, 36.60 mmol) and Pd(dppf)Cl2 (892 mg, 1.22 mmol). The mixture was heated to 100 °C and stirred for 12 h. The solution was obtained via Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 282.2, 284.2 [M+H] + .

[0275] 4-Bromo-3-(1-methyl-1- H -pyrazol-3-yl)aniline: at 20°C, 3-(2-bromo-5-nitrophenyl)-1-methyl-1 H β-pyrazole (1.2 g, 4.25 mmol) was added to a mixture of EtOH (10 mL) and H2O (2 mL) along with Fe (950 mg, 17.02 mmol) and NH4Cl (455 mg, 8.51 mmol). The mixture was heated to 80 °C and stirred for 2 h. The solution was then analyzed by Celite. ®The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the title compound. LCMS: m / z = 252.1, 254.1 [M+H] + .

[0276] (4-bromo-3-(1-methyl-1) H 3-Pyrazol-3-yl)phenyl)tert-butyl carbamate: At 20°C, 4-bromo-3-(1-methyl-1-yl)-(2 ... H (-pyrazol-3-yl)aniline (700 mg, 2.78 mmol) was added to a mixture of 1,4-dioxane (4 mL) and H₂O (6 mL), followed by (Boc)₂O (908 mg, 4.16 mmol) and NaOH (5.55 mL, 2 M), and the mixture was stirred for 12 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 352.1, 354.1 [M+H] + .

[0277] (4-Cyclobutyl-3-(1-methyl-1) H -Pyrazol-3-yl)phenyl)tert-butyl carbamate: (4-bromo-3-(1-methyl-1) HA solution of 300 mg (0.85 mmol) of pyrazol-3-yl)phenyl)carbamate tert-butyl ester (DMA) in DMA (1 mL) was supplemented with potassium cyclobutyltrifluoroborate (179 mg, 1.11 mmol), Na₂CO₃ (180 mg, 1.70 mmol), NiCl₂•glycol dimethyl ether (9 mg, 0.04 mmol), dtbbpy (11 mg, 0.04 mmol), and Ir[dF(CF₃)ppy]₂(dtbpy)(PF₆) (47 mg, 0.04 mmol). The reaction mixture was stirred at 25 °C for 16 h under two 34 W blue LEDs (the vial was approximately 6 cm from the light source). The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the title compound. LCMS: m / z = 328.2 [M+H] + .

[0278] 4-Cyclobutyl-3-(1-methyl-1-yl) H -pyrazol-3-yl)aniline hydrochloride: (4-cyclobutyl-3-(1-methyl-1) H A mixture of 140 mg (0.42 mmol) pyrazol-3-yl)phenyl)carbamate tert-butyl ester in HCl / EtOAc (5 mL, 4 M) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 228.2 [M+H] + .

[0279] Intermediate 13 3-(5,6-dihydro-4) H -pyrrolo[1,2- b ]pyrazol-2-yl)-4-methylaniline At 25°C and under N2, 3-iodo-4-methylaniline (352 mg, 1.51 mmol) and 2-(tributyltinyl)-5,6-dihydro-4 H -pyrrolo[1,2- bPyrazole (500 mg, 1.26 mmol) was added to a mixture of bis(tri-tert-butylphosphine) (64 mg, 0.13 mmol) in DMF (8 mL). The reaction mixture was heated to 110 °C and stirred for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 214.2 [M+H] + .

[0280] Intermediate 14 3-(2-methyl-2-) H -1,2,3-triazol-4-yl)-4-(trifluoromethyl)aniline 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-4-(trifluoromethyl)aniline: At 25 °C under N2, KOAc (5.11 g, 52.08 mmol) and Pd(dppf)Cl2 (1.52 g, 2.08 mmol) were added to a mixture of 3-bromo-4-(trifluoromethyl)aniline (5 g, 20.83 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentanane (7.93 g, 31.25 mmol) in DMSO (50 mL). The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was diluted with H2O (20 mL) and treated with EtOAc (3 × 20⁻⁶). Extracted with 10 mL of brine. The combined organic layers were washed with 10 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 288.0 [M+H] + .

[0281] 3-(2-methyl-2-) H -1,2,3-triazol-4-yl)-4-(trifluoromethyl)aniline: At 25 °C under N2, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-4-(trifluoromethyl)aniline (1 g, 3.48 mmol) and 4-bromo-2-methyl-2 H-1,2,3-triazole (846 mg, 5.22 mmol) was added to a mixture of DMF (20 mL) and H2O (2 mL) with K2CO3 (1.44 g, 10.45 mmol) and Pd(PPh3)4 (403 mg, 0.35 mmol). The reaction mixture was heated to 110 °C and stirred for 16 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 243.2 [M+H] + .

[0282] Intermediate 15 4-Chloro-3-(2-methyl-2-) H -1,2,3-triazol-4-yl)aniline 4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline: At 20 °C under N2, KOAc (1.6 g, 15.78 mmol) and Pd(dppf)Cl2 (577 mg, 0.78 mmol) were added to a mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentanane) (8 g, 31.56 mmol) and 3-bromo-4-chloroaniline (4 g, 15.78 mmol) in DMF (80 mL). The reaction mixture was heated to 95 °C and stirred under N2 for 2 h. The reaction mixture was diluted with H2O (160 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 254.1 [M+H] + .

[0283] 4-Chloro-3-(2-methyl-2-) H -1,2,3-triazol-4-yl)aniline: At 20 °C under N2, 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (1 g, 3.94 mmol) and 4-bromo-2-methyl-2 H-1,2,3-triazole (638 mg, 3.94 mmol) was added to a mixture of DMF (10 mL) and H2O (1 mL) with K2CO3 (1.64 g, 11.83 mmol) and Pd(PPh3)4 (455 mg, 0.39 mmol). The reaction mixture was heated to 100 °C and stirred under N2 for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 209.1 [M+H] + .

[0284] Intermediate 16 4-Cyclopropyl-3-(2-methyl-2-) H -1,2,3-triazol-4-yl)aniline At 25 °C and under N2, cyclopropylboronic acid (247 mg, 2.88 mmol), K3PO4 (610 mg, 2.88 mmol), phosphonium tris(cyclohexyl)tetrafluoroborate (106 mg, 0.29 mmol), and Pd(OAc)2 (32 mg, 0.14 mmol) were added to a solution of 4-chloro-3-(2-methyltriazol-4-yl)aniline (300 mg, 1.44 mmol) in toluene (5 mL) and H2O (0.5 mL). The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc = 1:1) to obtain the title compound. LCMS m / z = 215.0 [M+H] + .

[0285] Intermediate 17 4-Cyclopropyl-3-(1-methyl-1-yl) H -1,2,4-triazol-3-yl)aniline 4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)aniline: At 25 °C under N2, KOAc (5.94 g, 60.54 mmol) and Pd(dppf)Cl2 (1.77 g, 2.42 mmol) were added to a solution of 3-bromo-4-chloro-aniline (5 g, 24.22 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (9.22 g, 36.33 mmol) in DMSO (50 mL). The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (PE:EtOAc = 10:1 to 5:1) to give the title compound. LCMS: m / z = 254.1 [M+H] + .

[0286] 4-Chloro-3-(1-methyl-1-) H -1,2,4-triazol-3-yl)aniline: At room temperature, under N2, K2CO3 (1.64 g, 11.83 mmol) and Pd(dppf)Cl2 (289 mg, 0.40 mmol) were added to a solution of 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)aniline (1 g, 3.94 mmol) and 3-bromo-1-methyl-1,2,4-triazole (639 mg, 3.94 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 209.1 [M+H] + .

[0287] 4-Cyclopropyl-3-(1-methyl-1-yl) H -1,2,4-triazol-3-yl)aniline: under N2, to 4-chloro-3-(1-methyl-1 HPd(OAc)₂ (26 mg, 0.11 mmol), Cs₂CO₃ (1.17 g, 3.59 mmol), and bis(1-adamantyl)-butylphosphine (85 mg, 0.23 mmol) were added to a mixture of 1,4-triazol-3-yl)aniline (250 mg, 1.20 mmol) and potassium cyclopropyltrifluoroborate (531 mg, 3.59 mmol) in 1,4-dioxane (3 mL). The reaction mixture was heated to 120 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 10:1) to give the title compound. LCMS: m / z = 215.0 [M+H] + .

[0288] Intermediate 18 4-Amino-2-(1-methyl-1-amino ... H -pyrazol-3-yl)benzyl nitrile At 20 °C and under N2, 4-amino-2-bromobenzyl nitrile (500 mg, 2.55 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1 H -Pyrazole (581 mg, 2.79 mmol) was added to a solution of 1,4-dioxane (12 mL) and H2O (1.2 mL) along with K2CO3 (877 mg, 6.34 mmol) and Pd(dppf)Cl2 (186 mg, 0.25 mmol). The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the title compound.

[0289] Intermediate 19 3-(1-(cyclopropylmethyl)-1 H -pyrazole-3-yl)-4-methylaniline 3-(2-Methyl-5-nitrophenyl)-1H-pyrazole: At 25 °C under N2, K2CO3 (9.46 g, 68.43 mmol) and Pd(dppf)Cl2 (2.50 g, 3.42 mmol) were added to a mixture of 2-iodo-1-methyl-4-nitro-benzene (9 g, 34.22 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (9.96 g, 51.32 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL). The mixture was heated to 100 °C and stirred for 16 h. The resulting residue was diluted with H2O (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 204.1 [M+H] + .

[0290] 1-(cyclopropylmethyl)-3-(2-methyl-5-nitrophenyl)-1 H -Pyrazole: At 20°C and under N2, to 3-(2-methyl-5-nitrophenyl)-1 H A mixture of pyrazole (1 g, 4.92 mmol) and bromomethylcyclopropane (797 mg, 5.91 mmol) in DMF (10 mL) was supplemented with Cs₂CO₃ (4.01 g, 12.30 mmol) and KI (81 mg, 0.49 mmol). The mixture was heated to 50 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 1:1) to give the title compound.

[0291] 3-(1-(cyclopropylmethyl)-1 H -pyrazol-3-yl)-4-methylaniline: At 20°C and under N2, to 1-(cyclopropylmethyl)-3-(2-methyl-5-nitrophenyl)-1 Hβ-pyrazole (600 mg, 2.33 mmol) was added to a mixture of EtOH (6 mL) and H₂O (1.5 mL) along with Fe (261 mg, 4.66 mmol) and NH₄Cl (499 mg, 9.33 mmol). The mixture was heated to 80 °C and stirred for 2 h. The solution was then analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 0:1) to give the title compound. LCMS: m / z = 228.2 [M+H] + .

[0292] Intermediate 20 4-Methyl-3-(1-methyl-1-yl) H -pyrazole-3-yl)aniline At 20 °C and under N2, 3-bromo-4-methylaniline (2 g, 10.75 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1 H 1,4-pyrazole (3.58 g, 12.90 mmol) was added to a solution of 1,4-dioxane (20 mL) and H₂O (2 mL) along with K₂CO₃ (2.97 g, 21.50 mmol) and Pd(dppf)Cl₂ (786 mg, 1.07 mmol). The mixture was heated to 110 °C and stirred for 12 h. The solution was analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the title compound. LCMS: m / z = 188.3 [M+H] + .

[0293] Intermediate 21 4-Methyl-3-(1-(trifluoromethyl)-1 H -1,2,4-triazol-3-yl)aniline 2-Methyl-5-nitrobenzamide: DMF (121 mg, 1.66 mmol) was added to a mixture of 2-methyl-5-nitrobenzic acid (15 g, 82.81 mmol) in SOCl2 (100 mL) at 25 °C under N2. The mixture was heated to 70 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The resulting residue (10 g, 50.10 mmol) was mixed with NH3•H2O (100 mL) and stirred at 70 °C for 4 h. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give the title compound. LCMS: m / z = 181.1 [M+H] + .

[0294] N 2-((dimethylamino)methylene)-2-methyl-5-nitrobenzamide: 2-Methyl-5-nitrobenzamide (7.3 g, 40.52 mmol) was added to DMF•DMA (80 mL) at 25 °C under N2. The mixture was heated to 120 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 236.1 [M+H] + .

[0295] 3-(2-methyl-5-nitrophenyl)-1 H -1,2,4-triazole: at 25°C, under N2, to N 9.5 g (40.38 mmol) of -((dimethylamino)methylene)-2-methyl-5-nitrobenzamide was added to a mixture of -(dimethylamino)methylene)-2-methyl-5-nitrobenzamide (100 mL) in AcOH, followed by the addition of N₂H₄•H₂O (2.22 g, 44.42 mmol, 98% purity). The mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was cooled to rt and H₂O (50 mL) was added. The solid was collected by filtration and dried under reduced pressure to give the title compound. LCMS: m / z = 205.1 [M+H] + .

[0296] 1-(bromodifluoromethyl)-3-(2-methyl-5-nitrophenyl)-1 H -1,2,4-triazole: at 0°C and under N2, to 3-(2-methyl-5-nitrophenyl)-1 HNaH (1.18 g, 29.39 mmol, 60% in mineral oil) was added to a mixture of -1,2,4-triazole (3 g, 14.69 mmol) in DMF (30 mL), and the mixture was stirred at 0 °C for 30 min. Dibromo(difluoro)methane (9.25 g, 44.08 mmol) was added at 0 °C under N2, and the mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 333.1, 335.1 [M+H] + .

[0297] 3-(2-methyl-5-nitrophenyl)-1-(trifluoromethyl)-1 H -1,2,4-triazole: at 25°C under N2, to 1-(bromodifluoromethyl)-3-(2-methyl-5-nitrophenyl)-1 H AgF (952.19 mg, 7.51 mmol) was added to a mixture of -1,2,4-triazole (500 mg, 1.50 mmol) and DMSO (5 mL). The mixture was heated to 140 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO₂, PE:EtOAc = 3:1) to give the title compound. LCMS: m / z = 273.1 [M+H] + .

[0298] 4-Methyl-3-(1-(trifluoromethyl)-1 H -1,2,4-triazol-3-yl)aniline: at 25°C under N2, to 3-(2-methyl-5-nitrophenyl)-1-(trifluoromethyl)-1 H -1,2,4-triazole (100 mg, 367.40 mmol) was added to a mixture of EtOH (2 mL) and H2O (0.5 mL) along with NH4Cl (98 mg, 1.84 mmol) and Fe (103 mg, 1.84 mmol). The mixture was heated to 80 °C and stirred for 2 h. The solution was then analyzed by Celite. ®The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 243.0 [M+H] + .

[0299] Intermediate 22 Cis- N -(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide 2-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)aniline: At 20 °C and under N2, KOAc (14.43 g, 147.03 mmol) and Pd(dppf)Cl2 (3.59 g, 4.90 mmol) were added to a mixture of 5-bromo-2-fluoro-4-methylaniline (10 g, 49.01 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (18.67 g, 73.52 mmol) in 1,4-dioxane (150 mL) and H2O (15 mL). The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (60 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 252.3 [M+H] + .

[0300] Cis- N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: At 0 °C and under N2, TEA (483 mg, 4.78 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (400 mg, 1.59 mmol) were added to a mixture of triphosgene (236 mg, 0.80 mmol) and THF (15 mL). The reaction mixture was heated to 20 °C, and cis-3-methyl-6-azabicyclo[3.1.1]heptane (300 mg, 2.70 mmol) and TEA (292 mg, 2.89 mmol) were added to the mixture. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 389.2 [M+H] + .

[0301] Intermediate 23 2-Fluoro-5-(1-methyl-1- H -1,2,4-triazol-3-yl)-4-(trifluoromethyl)aniline 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-4-(trifluoromethyl)aniline: At 25 °C under N2, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentanane) (4.76 g, 18.75 mmol), KOAc (3.07 g, 31.25 mmol), and Pd(dppf)Cl2 (915 mg, 1.25 mmol) were added to a solution of 3-bromo-4-(trifluoromethyl)aniline (3 g, 12.50 mmol) in DMSO (40 mL). The mixture was heated to 80 °C and stirred for 12 h. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the title compound. LCMS: m / z = 288.2 [M+H] + .

[0302] 3-(1-methyl-1-yl) H -1,2,4-triazol-3-yl)-4-(trifluoromethyl)aniline: At 25 °C under N2, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-4-(trifluoromethyl)aniline (1.35 g, 4.70 mmol) and 3-bromo-1-methyl-1 H -1,2,4-triazole (914 mg, 5.64 mmol) was added to a solution of 1,4-dioxane (30 mL) and H₂O (3 mL) along with K₂CO₃ (1.95 g, 14.11 mmol) and Pd(dppf)Cl₂ (344 mg, 0.47 mmol). The mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 0:1) to give the title compound. LCMS: m / z = 243.2 [M+H] + .

[0303] 2-Fluoro-5-(1-methyl-1- H -1,2,4-triazol-3-yl)-4-(trifluoromethyl)aniline: at 25°C under N2, to 3-(1-methyl-1 H1,2,4-Triazol-3-yl)-4-(trifluoromethyl)aniline (340 mg, 1.40 mmol) was added to a solution of MeCN (5 mL) with Selectfluor. TM (597 mg, 1.68 mmol). The mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 1:1) to give the title compound. LCMS: m / z = 261.1 [M+H] + .

[0304] Intermediate 24 3-(1-methyl-1-yl) H -pyrazol-4-yl)-4-(trifluoromethyl)aniline At 25 °C under N2, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (1.73 g, 8.33 mmol), K2CO3 (2.30 g, 16.67 mmol), and Pd(dppf)Cl2 (610 mg, 0.83 mmol) were added to a solution of 3-bromo-4-(trifluoromethyl)aniline (2 g, 8.33 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL). The reaction mixture was heated to 110 °C and stirred for 12 h. (The reaction was then analyzed using Celite.) ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 1:1) to give the title compound. LCMS: m / z = 242.2 [M+H] + .

[0305] Intermediate 25 3-(2,2,2-trifluoroethyl)-3,6-diazabicyclo[3.1.1]heptane trifluoroacetate 3-(2,2,2-trifluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: At 0 °C and N2, DIEA (1.96 g, 15.13 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.40 g, 6.05 mmol) were added to a mixture of 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (1 g, 5.04 mmol) in THF (20 mL). The mixture was heated to 25 °C and stirred for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:MTBE = 5:1 to 1:1) to give the title compound. LCMS: m / z = 281.2 [M+H] + .

[0306] 3-(2,2,2-trifluoroethyl)-3,6-diazabicyclo[3.1.1]heptane trifluoroacetate: TFA (5 mL) was added to a solution of 3-bromo-4-(trifluoromethyl)aniline (1.2 g, 4.28 mmol) in DCM (15 mL) at 25 °C under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound.

[0307] Intermediate 26 4-Ethyl-3-(1-methyl-1-ethyl) H -pyrazole-3-yl)aniline At 20 °C and under N2, K2CO3 (276 mg, 2.00 mmol) and Pd(dppf)Cl2 (73 mg, 0.10 mmol) were added to a solution of 3-bromo-4-ethylaniline (200 mg, 1.00 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (312 mg, 1.50 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL). The reaction mixture was heated to 100 °C and stirred for 16 h. (The reaction was then analyzed using Celite.) ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 202.1 [M+H] + .

[0308] Intermediate 27 trans-5-methyl-2-azabicyclo[2.2.1]heptane hydrochloride 5-O-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: DMP (5.97 g, 14.07 mmol) was added to a solution of (cis)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 4.69 mmol) in DCM (15 mL) at 0 °C under N2. The mixture was heated to 20 °C and stirred for 16 h. The reaction mixture was quenched by adding saturated Na2S2O3 aqueous solution (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc = 3:1) to give the title compound.

[0309] 5-Methylene-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: At 0 °C and under N2, Tebbe reagent (0.5 M, 9.47 mL) was added to a solution of 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (500 mg, 2.37 mmol) in THF (16 mL). The mixture was heated to 25 °C and stirred for 2 h. The reaction mixture was adjusted to pH = 7 by adding saturated aqueous NaHCO3 and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the title compound.

[0310] (trans)-5-methyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: At 25 °C under N2, 10% Pd / C (250 mg) was added to a solution of 5-methylene-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (540 mg, 2.58 mmol) in MeOH (5 mL). The suspension was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 25 °C under H2 (15 psi) for 1 h. (The results were obtained via Celite.) ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound.

[0311] Trans-5-methyl-2-azabicyclo[2.2.1]heptane hydrochloride: A solution of (trans)-5-methyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (350 mg, 1.66 mmol) in HCl / EtOAc (10 mL, 4 M) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 112.2 [M+H] + .

[0312] Intermediate 28 trans-5-fluoro-2-azabicyclo[2.2.1]heptane hydrochloride (trans)-5-fluoro-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: At 0 °C and under N2, DAST (1.21 g, 7.50 mmol) was added to a mixture of (cis)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.8 g, 3.75 mmol) in DCM (10 mL). The mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give the title compound.

[0313] Trans-5-fluoro-2-azabicyclo[2.2.1]heptane hydrochloride: A solution of (trans)-5-fluoro-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (90 mg, 0.418 mmol) in HCl / EtOAc (2 mL, 4 M) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound.

[0314] Intermediate 29 cis-3-methyl-6-azabicyclo[3.1.1]heptane N-( trans-3-methylcyclohexyl)pyridinecarboxamide: N-( trans-3-methylcyclohexyl)pyridinecarboxamide and N- (A mixture of cis-3-methylcyclohexyl)pyridinecarboxamides was purified by preparative HPLC (Phenomenex Luna C18 250 × 100 mm × 15 μm; mobile phase: A: 10 mM TFA in water, B: MeCN; B in A: 40%–70%, for 20 min) to provide separated cis and trans isomers as first and second elution peaks, respectively. The second elution peak was concentrated under reduced pressure, adjusted to pH 7–8 with saturated NaHCO3 aqueous solution, and extracted with DCM (3 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 219.2 [M+H] + .

[0315] (cis-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methyl ketone at 25°C under N2, to N-( A mixture of trans-3-methylcyclohexyl)pyridinecarboxamide (6 g, 27.49 mmol) in 1,1,2,2-tetrachloroethane (200 mL) was supplemented with AgOAc (13.76 g, 82.46 mmol), benzoquinone (1.49 g, 13.74 mmol), Na3PO4 (13.52 g, 82.46 mmol), 1,2,3,4,5-pentafluoro-6-iodobenzene (80.80 g, 274.86 mmol), and Pd(OAc)2 (1.23 g, 5.50 mmol). The mixture was heated to 145 °C and stirred for 12 h. The mixture was analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 217.0 [M+H] + .

[0316] Cis-3-methyl-6-azabicyclo[3.1.1]heptane: At 25 °C under N2, NaOH (4.44 g, 111 mmol) was added to a mixture of (cis-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl) methyl ketone (2.4 g, 11.1 mmol) in EtOH (30 mL). The mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure (water pump, below 35 °C) to obtain a crude mixture. The mixture was stirred in DCM (20 mL) and passed through Celite. ®Pad filtration. Concentrate the filtrate under reduced pressure (water pump, below 35°C). Repeat the post-treatment procedure 2–3 times or until the concentrated residue is free of solids, yielding the title compound as a free base. Convert the free base to a TFA salt by adding TFA and stirring at 20°C for 0.5 h, followed by concentration under reduced pressure. Alternatively, treat the mixture of free base in MTBE at -20°C with 4M HCl / MTBE (1.2 equivalents) and stir for 10 min to obtain an HCl salt. LCMS: m / z = 112.2 [M+H] + .

[0317] Intermediate 30 cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (5 R 7 R )-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione and (5 S 7 S )-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione: at 20°C, under N2, towards ( R )-3-methylcyclohexane-1-one and ( S 5-Methylcyclohexane-1-one (50 g, 445.76 mmol, 54.59 mL) was added to a mixture of EtOH (250 mL) and H₂O (250 mL) along with (NH₄)₂CO₃ (128.49 g, 1.34 mol) and KCN (43.54 g, 669 mmol). The mixture was heated to 65 °C and stirred for 3 h. The reaction mixture was filtered, and the filter cake was washed with H₂O and dried under reduced pressure. The crude product was milled with EtOH for 30 min at 20 °C, filtered, and dried as a solid under reduced pressure to give the title compound. LCMS: m / z = 183.2 [M+H] + .

[0318] (1 R ,3 R )-1-amino-3-methylcyclohexane-1-carboxylic acid and (1 S ,3 S )-1-amino-3-methylcyclohexane-1-carboxylic acid: at 25°C, to (5 R 7 R )-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione and (5 S 7 SBa(OH)₂ (738 g, 4.31 mol) was added to a solution of 7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione (78.5 g, 430.80 mmol) in H₂O (1000 mL). The mixture was heated to 140 °C and stirred for 12 h in a 5 L autoclave. The reaction mixture was cooled to 0 °C and the pH was adjusted to pH = 3 with 3 M H₂SO₄. The reaction mixture was then analyzed by Celite. ® The mixture was filtered through a filter and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 158.2 [M+H] + .

[0319] (1 R ,3 R )-1-amino-3-methylcyclohexane-1-carboxylic acid methyl ester hydrochloride and (1 S ,3 S )-1-amino-3-methylcyclohexane-1-carboxylic acid methyl ester hydrochloride: at 0°C, under N2, to (1 R ,3 R )-1-amino-3-methylcyclohexane-1-carboxylic acid and (1 S ,3 S SOCl2 (227 g, 1.91 mol, 138.43 mL) was added to a mixture of 1-amino-3-methylcyclohexane-1-carboxylic acid (60 g, 382 mmol) in MeOH (600 mL). The mixture was heated to 75 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 172.2 [M+H] + .

[0320] (1 R ,3 R methyl 1-3-methyl-1-(pyridinecarbamate)cyclohexane-1-carboxylate (1 S ,3 S 3-Methyl-1-(pyridinecarbamate)cyclohexane-1-carboxylic acid methyl ester: at 0°C under N2, to (1 R ,3 R )-1-amino-3-methylcyclohexane-1-carboxylic acid methyl ester hydrochloride and (1 S ,3 SMethyl 1-amino-3-methylcyclohexane-1-carboxylate hydrochloride (24 g, 140 mmol) and pyridinecarboxylic acid (25.88 g, 210 mmol) were added to a solution in DCM (300 mL) along with DIEA (54.34 g, 420 mmol, 73.24 mL), DMAP (1.71 g, 14 mmol), and EDCI (40.30 g, 210 mmol). The mixture was heated to 25 °C and stirred for 16 h. The reaction mixture was diluted with H₂O (200 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 277.2 [M+H] + .

[0321] (1 R ,3 R 2-(3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]hept-1-yl)-2-oxoacetic acid methyl ester and (1 S ,3 S 2-(3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]hept-1-yl)-2-oxoacetic acid methyl ester: at 25°C, under N2, to (1 R ,3 R methyl 1-3-methyl-1-(pyridinecarbamate)cyclohexane-1-carboxylate and (1 S ,3 S A solution of methyl 1-(pyridinamide)cyclohexane-1-carboxylate (19 g, 68.76 mmol) in 1,1,2,2-tetrachloroethane (900 mL) was mixed with Na3PO4 (33.82 g, 206 mmol, 33.82 mL), 1,2,3,4,5-pentafluoro-6-iodobenzene (202.12 g, 688 mmol), AgOAc (34.43 g, 206 mmol, 10.56 mL), benzoquinone (3.72 g, 34 mmol, 7.74 mL), and Pd(OAc)2 (3.09 g, 13.75 mmol). The mixture was heated to 145 °C and stirred for 16 h. The mixture was analyzed by Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 275.2 [M+H]+ .

[0322] Cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: At 25 °C under N2, NaOH (14.58 g, 364.55 mmol) was added to a solution of methyl cis-2-(3-methyl-6-(pyridin-2-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (10 g, 36.45 mmol) in EtOH (150 mL). The mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (100 mL) and cooled to 0 °C, followed by acidification with concentrated HCl to pH = 4. The solution was lyophilized to give the title compound. LCMS: m / z = 156.1 [M+H] + .

[0323] Intermediates 31 and 32 (1 R ,3 S 5 S )-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid methyl ester and (1 S ,3 R 5 R 3-Methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid methyl ester The enantiomer mixture was passed through an SFC (DAICEL CHIRALPAK 250 mm × 50 mm, 10 μm; mobile phase: A: CO2, B: ...) i -0.1% NH3H2O ​​in PrOH MeOH; B% in A: 20%-20%, 3 min; flow rate: 200 g / min; wavelength: 220 nm; column temperature: 35℃; system back pressure: 100 bar) separation yielded methyl cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (peak 1 in SFC) intermediate 31. LCMS: m / z = 275.2 [M+H] + Intermediate 32, and methyl cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (peak 2 in SFC). LCMS: m / z = 275.2 [M+H] + .

[0324] Intermediate 33 Methyl-6-azabicyclo[3.1.1]heptane Methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methyl ketone: at 25°C, under N2, to N-( A mixture of 3-methylcyclohexyl)pyridinecarboxamide (20 g, 91.62 mmol) in 1,1,2,2-tetrachloroethane (300 mL) was supplemented with AgOAc (45.88 g, 274.86 mmol), benzoquinone (4.95 g, 45.81 mmol), Na3PO4 (45 g, 274.86 mmol), 1,2,3,4,5-pentafluoro-6-iodobenzene (269 g, 916.20 mmol), and Pd(OAc)2 (2.06 g, 9.16 mmol). The mixture was stirred at 145 °C for 12 h. The precipitate was measured using Celite. ® The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 217.10 [M+H]+.

[0325] 3-Methyl-6-azabicyclo[3.1.1]heptane: NaOH (4.99 g, 124.84 mmol) was added to a mixture of (3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl) methyl ketone (2.7 g, 12.48 mmol) in EtOH (50 mL) at 25 °C under N2. The mixture was stirred at 90 °C for 4 h. The reaction mixture was concentrated under reduced pressure (water pump, below 35 °C) to give a mixture containing the product, NaOH, and the sodium salt of the acid. The mixture was stirred in DCM (20 mL) and passed through a Celite container. ® Pad filtration. Concentrate the filtrate under reduced pressure (water pump, below 35°C). Repeat the post-treatment procedure 2–3 times or until the concentrated residue is free of solids, yielding the title compound as a mixture of approximately 10:1 cis and trans isomers. LCMS: m / z = 112.2 [M+H] + .

[0326] Intermediate 34 cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid NaOH (4.37 g, 109 mmol) was added to a solution of methyl cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (intermediate 31) (3 g, 11 mmol) in EtOH (30 mL) under N2 at 25 °C. The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure, adjusted to pH = 5 with 12 M HCl at 0 °C, and lyophilized to give the title compound. LCMS: m / z = 156.1 [M+H] + .

[0327] Intermediate 35 3-(5-fluoro-4-methyloxazol-2-yl)-4-methylaniline 1-(3-iodo-4-methylphenyl)-2,5-dimethyl-1 H -Pyrrole: Add to a mixture of 3-iodo-4-methylaniline (5 g, 21.45 mmol) and toluene (50 mL) at 25 °C under N2. p -TsOH (37 mg, 0.21 mmol) and hexane-2,5-dione (2.94 g, 25.75 mmol). The reaction mixture was heated to 110 °C and stirred for 1 h. The mixture was adjusted to pH 7–8 by adding saturated aqueous NaHCO3 solution (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 5:1) to give the title compound. LCMS: m / z = 312.0 [M+H] + .

[0328] 2-(5-(2,5-dimethyl-1-yl) H (-pyrrolo-1-yl)-2-methylphenyl)-4-methyloxazole: Add to a mixture of 4-methyloxazole (334 mg, 4.02 mmol) in THF (3 mL) at -78 °C under N2. n -BuLi (4.02 mmol, 1.61 mL, 2.5 M, in hexane). The mixture was stirred at -78 °C for 10 min, followed by the addition of ZnCl2 (9.34 mmol, 4.82 mL, 2 M, in THF) and stirring for another 15 min. The reaction mixture was heated to 20 °C under N2 and 1-(3-iodo-4-methylphenyl)-2,5-dimethyl-1 H-Pyrrole (500 mg, 1.61 mmol) and Pd(PPh3)2Cl2 (113 mg, 0.16 mmol) were dissolved in THF (5 mL). The combined reaction mixture was heated at 60 °C and stirred under microwave irradiation for 20 min. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 15:1 to 5:1) to give the title compound. LCMS: m / z = 267.1 [M+H] + .

[0329] 2-(5-(2,5-dimethyl-1-yl) H -pyrrolo-1-yl)-2-methylphenyl)-5-fluoro-4-methyloxazole: at -78°C under N2, to 2-(5-(2,5-dimethyl-1) H 1-Pyrrolo-1-yl)-2-methylphenyl)-4-methyloxazole (750 mg, 2.82 mmol) was added to a solution of THF (14 mL). n -BuLi (3.38 mmol, 1.35 mL, 2.5 M, in hexane). The mixture was stirred at -78 °C for 45 min, followed by the addition of NFSI (1.07 g, 3.38 mmol) in THF (1 mL) and stirring for 1 h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the title compound. LCMS: m / z = 285.1 [M+H] + .

[0330] 3-(5-fluoro-4-methyloxazol-2-yl)-4-methylaniline: At 25°C under N2, to 2-(5-(2,5-dimethyl-1-yl)-methylaniline H1,4-pyrrolo-1-yl)-2-methylphenyl)-5-fluoro-4-methyloxazole (140 mg, 0.5 mmol) was added to a mixture of EtOH (1.5 mL) and H2O (0.5 mL) with NH2OH•HCl (411 mg, 5.91 mmol) and TEA (299 mg, 2.95 mmol). The mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure, and the crude material was diluted with H2O (5 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc = 2:1) to give the title compound. LCMS: m / z = 207.1 [M+H] + .

[0331] Intermediate 36 4-Methyl-3-(2-methyloxazol-4-yl)aniline 2-Bromo-1-(2-methyl-5-nitrophenyl)ethyl-1-one: Br2 (446 mg, 2.79 mmol) was added to a mixture of 1-(2-methyl-5-nitrophenyl)ethyl-1-one (500 mg, 2.79 mmol) in AcOH (5 mL) at 0 °C under N2. The reaction mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure, and the crude material was diluted with H2O (15 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.

[0332] 2-Methyl-4-(2-methyl-5-nitrophenyl)oxazole: Acetamide (286 mg, 4.84 mmol) was added to a mixture of 2-bromo-1-(2-methyl-5-nitrophenyl)ethyl-1-one (500 mg, 1.94 mmol) in NMP (10 mL) at 25 °C. The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound.

[0333] 4-Methyl-3-(2-methyloxazol-4-yl)aniline: 10% Pd / C (50 mg) was added to a solution of 2-methyl-4-(2-methyl-5-nitro-phenyl)oxazole (240 mg, 1.10 mmol) in MeOH (2 mL) under Ar2 conditions. The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 25 °C under H2 (15 psi) for 0.5 h, and the solution was purified by Celite. ® The solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 189.0 [M+H] + .

[0334] Intermediate 37 4-Methyl-3-[3-(trifluoromethyl)isoxazol-5-yl]aniline Trimethyl-[2-(2-methyl-5-nitro-phenyl)ethynyl]silane: TEA (5.77 g, 57.03 mmol), CuI (181 mg, 0.95 mmol), and Pd(PPh3)2Cl2 (667 mg, 0.95 mmol) were added to a solution of 2-iodo-1-methyl-4-nitro-benzene (5 g, 19.01 mmol) and ethynyl(trimethyl)silane (4.67 g, 47.52 mmol) in THF (50 mL) at 20 °C under N2. The mixture was stirred at 20 °C for 16 h. (The results were obtained via Celite.) ® The reaction mixture was filtered through a filter pad, and the filtrate was diluted with H2O (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE:EtOAc = 1:0 to 5:1) to give the title compound.

[0335] 2-Ethynyl-1-methyl-4-nitro-benzene: K₂CO₃ (4.38 g, 31.71 mmol) was added to a solution of trimethyl-[2-(2-methyl-5-nitro-phenyl)ethynyl]silane...

Claims

1. A compound of formula I: I Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The condition is that at least one of A, B, C, D, or E occurs: A. X 1 It is N and X 2 It is NR 8b ;and a. When R is C 1-6 When alkyl; the C 1-6 Alkyl groups via halogenation or C 3-10 cycloalkyl groups and optional one to four Z 1 Replace; and / or b. R 8b Not hydrogen; and / or c. When R is -OR 7 When; then R 7 Not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9 H -fluorene-9-ylmethyl; And the compound is not: B. X 2 Is it N or NR? 8b And R is -NR 2 R 3 ;and a. R 2 and R 3 Not both methyl; and / or b. When X 1 When it is O, then R 8b R 8c R 6c Or R 6d At least one of them is not hydrogen; And the compound is not: C. X 1 Is it N or CR? 6a X 2 It is O, X 3 Is it N or CR? 6c And X 4 It is N; and a. In R is C 1-6 In the case of alkyl groups, the C 1-6 Alkyl groups with one to five Z 1 Replace; and / or b. R 6c Not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl, or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridyl]amino]-5-thiazolyl; and / or c. When R is -OR 7 When, then R 7 Not isobutyl or tert-butyl; And the compound is not: D. X 1 It is O, X 2 Is it N or CR? 6b X 3 It is CR 6c X 4 It is N, R 6c It is not hydrogen; and R is -NR. 2 R 3 , where R 2 and R 3 Together they form a heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 Replace; and at least one of the following a. through d. appears: a. X 2 It is N; b. R 1 Not methyl; c. R 2 and R 3 Forming an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; d. R 2 and R 3 Form a optionally substituted monocyclic 7-membered heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; And the compound is not: E. R is , where q is 0, 1, 2, 3, 4 or 5; and p is 0, 1, 2 or 3.

2. A compound of formula II: II Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 3 Is it N or CR? 6c ; X 4 Is it N or CR? 6d ; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl groups via halogenation or C 3-10 cycloalkyl groups and optional one to four Z 1 Replace; and where said C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 8b It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8b and R 6c 、or R 6c and R 6d Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: When R is -OR 7 When; then R 7 Not methyl, ethyl, isopropyl, tert-butyl, 2-bromoethyl, 2-methoxyethyl, 2-cyanoethyl, 2-phenylethyl, benzyl, or 9 H -fluorene-9-ylmethyl; and the compound is not: 。 3. A compound of formula III: III Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 Is it N or NR? 8b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is that it contains X 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 6a and R 8b R 8b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: R 2 and R 3 Not both methyl; When X 1 When it is O, then R 8b R 8c R 6c Or R 6d At least one of them is not hydrogen; and The compound is not: 。 4. A compound of formula IV: IV Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 Is it N or CR? 6a ; X 3 Is it N or CR? 6c ; R is -NR 2 R 3 -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl groups with one to five Z 1 Replace; and where said C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 3 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Or R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6a and R 6c Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The conditions are: R 6c Not 4-amino-2-[(3,4,5-trimethoxyphenyl)amino]-5-thiazolyl, [[4-(1-pyrrolidinylmethyl)phenyl]amino]-5-thiazolyl, or [[6-(4-methyl-1-hexahydropyrazinyl)-3-pyridyl]amino]-5-thiazolyl; and When R is -OR 7 When, then R 7 Not isobutyl or tert-butyl; and the compound is not: 。 5. A compound of formula V: V Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 2 Is it N or CR? 6b ; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are optionally cycloalkylated by one to five Z-axis groups. 1 replace; R 2 and R 3 Together they form a heterocyclic group, which can be further optionally cyclically modified by one to five Z groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1 replace; R 6b It contains hydrogen, halogen, cyano, -NO2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 6c It is a halogenated group, a cyano group, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 6b and R 6c Together they form a 5-membered heterocyclic group, which can be further independently and optionally cyclically modified by one to five Z groups. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups; The condition is that at least one of the following occurs: X 2 It is N; or R 1 Not methyl; or R 2 and R 3 Forming an optionally substituted bridging heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; or R 2 and R 3 Form a optionally substituted monocyclic 7-membered heterocyclic group, which is optionally fused to an aryl or heteroaryl ring; And the compound is not: 。 6. The compound according to any one of claims 1-5, wherein R or the said portion yes It can be optionally fused to a C6 aryl group; wherein: q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; X is CH2, CHZ 1 C(Z) 1 2. NR 9 , O or S; and R 9 Is it H or Z? 1 .

7. A compound of formula VI: WE Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 It is N, NR 8a O, S or CR 6a ; X 2 It is N, NR 8b O, S or CR 6b ; X 3 It is N, NR 8c or CR 6c ; X 4 Is it N or CR? 6d ; The condition is X 1 X 2 X 3 and X 4 At least one of them is N, and it contains X. 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; q is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl groups are independently and optionally derived from one to five Z-shaped groups. 1 replace; R 4 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 5 It is hydrogen, halogroup, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 6a R 6b R 6c and R 6d Each can be independently represented by hydrogen, halogroup, cyanogroup, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 10 -SR 10 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; R 8a R 8b and R 8c Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1 replace; Or R 8a and R 6b 、or R 8b and R 6c 、or R 6b and R 6c 、or R 8c and R 6d 、or R 6c and R 6d Together they form a 5-membered cycloalkyl or 5-membered heterocyclic group, which may further independently and optionally undergo one to five Z-axis reactions. 1 replace; Each Z 1 Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 12 )2、-OR 12 -SR 12 -C(O)R 12 -C(O)OR 12 -S(O)R 12 -S(O)2R 12 -C(O)N(R) 12 )2、-NR 12 C(O)R 12 -NR 12 S(O)R 12 -NR 12 S(O)2R 12 -S(O)N(R) 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 10 Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1a replace; Each R 12 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1a Independently, it can be a halogenated group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally derived from one to five Z-terminals. 1b replace; Each Z 1b Independently, it can be a halogenated group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b And each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally and independently substituted by one to five substituents independently selected from the following: halogroup, cyanogroup, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

8. The compound according to any one of claims 1-5 or 7, wherein R, the portion or the part described yes ;in: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally enclosed in one to five Z-terminals. 1b Replace; and L 1 It is key, C 1-4 Alkylene, C 2-4 imide or C 2-4 Alynyl group.

9. The compound of claim 7 or 8, wherein p is 1.

10. The compound of claim 6, 7 or 8, wherein q is 1 or 2.

11. The compound as claimed in any of the preceding claims, wherein R 1 It is a halogenated group, a cyano group, or a C group. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 Cycloalkyl, optionally substituted with cyano or methyl.

12. The compound as claimed in any of the preceding claims, wherein R 1 It is fluorine, chlorine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclobutyl, or cyclopropyl, optionally substituted with cyano or methyl.

13. The compound as claimed in any of the preceding claims, wherein R 1 It is chloro, cyano, or trifluoromethyl.

14. The compound as claimed in any of the preceding claims, wherein R 4 Is it hydrogen or C? 1-6 alkyl.

15. The compound as claimed in any of the preceding claims, wherein R 4 It is either hydrogen or methyl.

16. The compound as claimed in any of the preceding claims, wherein R 5 It is either hydrogen or a halogroup.

17. The compound as claimed in any of the preceding claims, wherein R 5 It is either hydrogen or fluorine.

18. The compound of claim 1 or 7, wherein the portion yes , , , , , , , , , , , , , , , , , , , , , , , or .

19. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

20. A compound selected from Table 2 or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising any of the compounds of the preceding claims or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers, and a pharmaceutically acceptable carrier.

22. A method for inhibiting SARM1 activity, the method comprising contacting cells with an effective amount of the compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a tautomer or a mixture of stereoisomers, or the pharmaceutical composition of claim 21.

23. The method of claim 22, wherein the contact is within the body.

24. A method for treating a disease or ailment at least partially mediated by SARM1, the method comprising administering to a subject in need an effective amount of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers thereof, or a pharmaceutical composition of claim 21.

25. A method for inhibiting axonal degeneration, the method comprising administering to a subject in need an effective amount of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers, or a pharmaceutical composition of claim 21.

26. A method for treating neurodegeneration or a neurological disease or condition, the method comprising administering to a subject in need an effective amount of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers, or a pharmaceutical composition of claim 21.

27. The method of claim 26, wherein the neurodegeneration or neurological disease or condition is associated with axonal degeneration, axonal damage, axonal lesions, demyelinating diseases, central pontine myelinolysis, neurological injury diseases or conditions, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukodystrophy, or leukodystrophy.

28. The method of claim 24, wherein the disease or disorder is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukodystrophy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Peyreke-Métrich disease, periventricular leukomalacia, or globular leukodystrophy. Labo's disease, Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Luke-Jaliger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B1 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, retinitis pigmentosa, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunney virus encephalitis, etc. Subviral encephalitis, pediatric viral encephalitis, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN).

29. A method for treating chemotherapy-induced peripheral neuropathy (CIPN), the method comprising administering to a subject in need an effective amount of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers thereof, or a pharmaceutical composition of claim 21.

30. Use of the compound of any one of claims 1-20 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21, for the treatment of a disease or ailment at least in part mediated by SARM1.

31. The use as described in claim 29, wherein the disease or ailment is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukodystrophy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Peyreke-Meyer's disease, periventricular leukomalacia, or globular leukodystrophy. Labo's disease, Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Luke-Jaliger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B1 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalopathy Encephalitis, viral encephalitis in children, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN).

32. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers thereof, or a pharmaceutical composition of claim 21, used in a therapeutic manner.

33. The compounds of any one of claims 1-20, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, tautomers, or mixtures of stereoisomers thereof, or the pharmaceutical composition of claim 21, for the treatment of spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, and other similar conditions. - Mellitus' disease, periventricular leukomalacia, globular leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lucas-Jaliger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalopathy Encephalitis, viral encephalitis in children, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN).

34. The use of any compound of claims 1-20 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers, or the pharmaceutical composition of claim 21, for the manufacture of an agent for the treatment of: spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, hypoxic demyelination, focal ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pygmal syndrome. Clabbe's disease, Peyrenia-Méder's disease, periventricular leukomalacia, globular leukodystrophy (Clabbe's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Luke-Jaliger's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher's disease, Heller syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B1 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paralysis, human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalopathy Encephalitis, viral encephalitis in children, essential tremor, Shamadoosan disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive hypernuclear palsy (PSP), Friedrich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy body dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axononeuropathy (AMAN).

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