Compounds, compositions and methods

Abstract

The present disclosure relates generally to small molecule inhibitors of axonal degeneration or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, methods of making and intermediates thereof, and methods of using the same.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 433,346, filed December 16, 2022, pursuant to 35 U.S. SC §119(e), the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] 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

[0004] 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.

[0005] Axonal degeneration has been identified as an important pathology in most neurodegenerative diseases. Axons are susceptible to mechanical damage (Wallerian degeneration) and disease (Wallerian-like degeneration).

[0006] In healthy axons, the N-terminus of SARM1 interacts with the TIR domain, preventing TIR polymerization and subsequent NAD. + The enzyme 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

[0007] This article provides compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, that may be used to treat and / or prevent diseases at least in part mediated by SARM1.

[0008] In some implementations, compounds that inhibit SARM1 are provided.

[0009] In another embodiment, a pharmaceutical composition is provided comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0010] In another embodiment, a method for treating a disease or condition mediated at least in part by SARM1 is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0011] The present disclosure also provides compositions, including pharmaceutical compositions; kits comprising the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; methods of using (or administering) and making the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; and intermediates.

[0012] The present disclosure further provides a compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a composition thereof, for use in a method of treating a disease, disorder, or condition mediated at least in part by SARM1.

[0013] Further, the present disclosure provides use of the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a composition thereof, in the manufacture of a medicament for treating a disease, disorder, or condition mediated at least in part by SARM1.

[0014] The summary of the invention herein sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended to limit the scope of the present disclosure, but is provided as a description of exemplary embodiments.

[0015] 1. Definitions

[0016] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0017] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for substituents. For example, -C(O)NH2is attached through the carbon atom. A dash at the beginning or end of a chemical group is for convenience purposes only; the chemical group can be depicted with or without the dash without loss of its ordinary meaning. A wavy line or a dotted line drawn through a line in a structure indicates the designated point of attachment of a group. Unless otherwise required in a chemical or structural context, the order in which chemical groups are written or named is not intended to indicate or imply directionality or stereochemistry.

[0018] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6"alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0019] The reference to “about” in this document includes (and describes) embodiments for said value or parameter itself. In some embodiments, the term “about” includes an indicated amount ±10%. In other embodiments, the term “about” includes an indicated amount ±5%. In some other embodiments, the term “about” includes an indicated amount ±1%. Furthermore, the term “about X” includes a description of “X”. Additionally, unless the context clearly specifies otherwise, the singular forms “a” and “said” include multiple indicators. Thus, for example, a reference to “compound” includes multiple such compounds, and a reference to “assay” includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0020] "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 its chemical name or identified by its 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).

[0021] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, divalent heteroaryl groups, etc., may also be referred to as "alkylene" groups or "alkylenyl" groups (e.g., methylene, ethylene, and propylene), "arylene" groups or "arylenyl" groups (e.g., phenylene or naphthylene, or quinolinyl for heteroarylene). Furthermore, unless otherwise explicitly indicated, when a combination of groups is referred to herein as a part such as arylalkyl or aralkyl, the last mentioned group contains the atoms used by which said part is attached to the remainder of the molecule.

[0022] "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).

[0023] "Alkyne" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C64-C ... 2-20 alkynyl group), 2 to 12 carbon atoms (i.e., C 2-12 acetylsyl 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 triple bond and one double bond.

[0024] "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.

[0025] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl".

[0026] "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.

[0027] "Acyl" refers to the group -C(O)R y , where R y It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0028] "Amide group" refers to both of the following: -C(O)NR (substituent group) y R z The "C-amide" group and the substituent group -NR y C(O)R z The "N-amide group", in which Ry and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein, or R y and R z are taken together to form a cycloalkyl or heterocyclyl; each of which can be optionally substituted as defined herein.

[0029] "Amino" refers to the group -NR y R z where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein.

[0030] "Carbamimidoyl" refers to the group -C(NR y )(NR z 2), where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein.

[0031] "Aryl" refers to an aromatic carbocyclic group including fused rings having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic). As used herein, aryl has from 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), from 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or from 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap with heteroaryl or heteroalkyl as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is heteroaryl regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclyl group, the resulting ring system is heterocyclyl regardless of the point of attachment. If one or more aryl groups are fused to a cycloalkyl group, the resulting ring system is cycloalkyl regardless of the point of attachment.

[0032] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0033] "Carbamoyl" refers to both the "O-carbamoyl" group referring to the group -O-C(O)NR y R z and the "N-carbamoyl" group referring to the group -NR y C(O)OR z where R y and R zindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted, as defined herein.

[0034] "Carboxyl ester" or "ester" means -OC(O)R x and -C(O)OR x , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted, as defined herein.

[0035] "Cyanoalkyl" means an alkyl group as defined above in which one or more (e.g., 1 or 2) hydrogen atoms is replaced with a cyano (-CN) group.

[0036] "Cycloalkyl" means a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings which are fused, bridged or spiro systems. The term "cycloalkyl" includes cycloalkenyl (i.e., cyclic groups having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C 3-20 ycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 ycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 ycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 ycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 ycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 ycloalkyl). Single ring groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Multiple ring groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to an aryl ring, regardless of the connectivity to the rest of the molecule. Yet further, cycloalkyl also includes "spirocycloalkyl" when there are two substitution locations on the same carbon atom, such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0037] "Cycloalkylalkyl" means the group "cycloalkyl-alkyl-".

[0038] "Imino" means the group -C(NR y )R z , wherein R y and R zeach independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein.

[0039] “Acyl” refers to the group -C(O)R y C(O)R z wherein R y and R z each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein.

[0040] “Halogen” or “halo” refers to atoms occupying Group VIIA of the Periodic Table of the Elements, for example, fluorine, chlorine, bromine, or iodine.

[0041] “Haloalkyl” refers to unbranched or branched alkyl groups as defined above in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced with a halogen. For example, where a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Di- and tri-haloalkyl refer to alkyl groups substituted with two (“di”) or three (“tri”) halo groups, which can be, but are not necessarily, the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0042] “Haloalkoxy” refers to an alkoxy group as defined above in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced with a halogen.

[0043] “Haloalkoxyalkyl” refers to an alkoxyalkyl group as defined above in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced with a halogen.

[0044] “Hydroxyalkyl” refers to an alkyl group as defined above in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced with a hydroxyl group.

[0045] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom group, with the proviso that the point of attachment to the rest of the molecule is via a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chains having carbons and heteroatoms. For example, 1, 2, or 3 carbon atoms can be independently replaced with the same or different heteroatom group. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R yhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted, as defined herein. Examples of heteroalkyl 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)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally 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.

[0046] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple condensed rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system. Any aromatic ring having a single or multiple fused rings that contains at least one heteroatom is considered a heteroaryl, regardless of the attachment to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass aryl as defined above or overlap therewith.

[0047] "Heteroaralkyl" refers to the group "heteroaryl-alkyl-".

[0048] "Heterocyclyl" refers to a saturated or partially unsaturated ring alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocyclenyl (i.e., a heterocyclyl group having at least one double bond), bridged heterocyclyl, fused heterocyclyl, and spirocyclic heterocyclyl. Heterocyclyl groups can be monocyclic or polycyclic, where the multiple rings can be fused, bridged, or spiro, and can contain one or more (e.g., 1 to 3) oxo (=0) or N-oxide (-0 -) moiety. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclyl, regardless of how connected (i.e., can be bound via a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring can be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of how connected to the rest of the molecule. For example, fused ring systems such as decahydroquinolizinyl, 1,2,3,4-tetrahydroquinolinyl, and 5,6,7,8-tetrahydroquinolinyl are heterocyclyl, regardless of how connected to the rest of the molecule. As used herein, a heterocyclyl group has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6heterocyclyl) having 1 to 5 ring heteroatoms independently selected from nitrogen, sulfur, or oxygen, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyrone, dioxolanyl, dihydropyranyl, pyranyl, thienyl[l,3]dithianyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, and l,l-dioxo-thiomorpholinyl. When two substitution positions exist on the same carbon atom, the term "heterocyclyl" also includes "spiroheterocyclyl." Examples of spiroheterocyclyl rings include, for example, bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-l-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, wherein the heterocyclyl group can be bound via either ring of the fused system.

[0049] "Heteroaralkyl" means an "heteroaryl-alkyl-" group.

[0050] "Heteroaralkyl" means an "heteroaryl-alkyl-" group. y (=NOR), wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted, as defined herein. y "Heteroaralkyl" means an "heteroaryl-alkyl-" group.

[0051] "Sulfonyl" means a group -S(O)2R y , wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted, as defined herein. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0052] "Sulfonyl" means a group -S(O)2R y , wherein R yhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and tolylsulfinyl.

[0053] "Sulfonamido" refers to the group -SO2NR y R z and -NR y SO2R z wherein R y and R z each independently is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted as defined herein.

[0054] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes situations where the event or circumstance occurs and situations where it does not. Further, the term "optionally substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group can or can not be replaced with a moiety other than hydrogen.

[0055] The term "substituted" as used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, acylamino, amino, formamidinyl, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidinyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imide, hydroxyl, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamido, thiol, thioxo, N-oxide, or -Si(R y )3, where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0056] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, 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) 1-2 R g , -S(O) 1- 2OR 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 certain 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 replaced with -C(O)R g , -C(O)OR g , -C(O)NR g R h , -CH2SO2R g , or -CH2SO2NR g R h . In the foregoing, R g and Rh These are the same or different and independently 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 in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by bonds to the following groups: amino, cyano, hydroxyl, imino, nitro, oxo, thio, halo, 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, together with the atoms they are attached to, form a heterocyclic ring optionally substituted with an oxo group or a halogen group, or an alkyl group optionally substituted with an oxo group, a halogen group, an amino group, a hydroxyl group, or an alkoxy group.

[0057] Polymers or similar infinite structures achieved by defining substituents indefinitely with other attached substituents (e.g., a substituted aryl group having a substituted alkyl group, the substituted alkyl group itself being substituted by a substituted aryl group, the substituted aryl group being further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise indicated, the maximum number of successive substitutions in the compounds described herein is three. For example, successive substitution of a substituted aryl group with two other substituted aryl groups is limited to an aryl group substituted by (an aryl group substituted by (a substituted aryl group)). Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable 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.

[0058] In some implementations, as used herein, the phrase "one or more" refers to one to five. In some implementations, as used herein, the phrase "one or more" refers to one to three.

[0059] Any compound or structure described herein is intended to represent both the unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures depicted herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. 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 C13 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. Compounds of the present disclosure that are variously labeled with isotopes, e.g., 3 H and 14 C, can incorporate radioactive isotopes into the compounds. Such isotopically labeled compounds are useful in metabolic studies, receptor binding assays, 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 used in radiotherapy.

[0060] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, wherein one or more hydrogens are replaced by deuterium (e.g., hydrogens on carbon atoms). Such compounds exhibit increased metabolic resistance, and thus can be used to increase the half-life of any compound when administered to a mammal, particularly a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized using means well known in the art, e.g., by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0061] Therapeutic compounds of the present disclosure that are deuterium labeled or substituted can have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. Therapeutic compounds of the present disclosure that are deuterium labeled or substituted can be prepared by a variety of procedures known in the art. 18 F, 3 H or 11 C. The isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or the examples and preparations described below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It will be appreciated that, in this case, deuterium is regarded as a substituent in the compounds described herein.

[0062] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of said atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0063] In many cases, the compounds of the disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0064] 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" refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing pharmaceutical compositions that are suitable for veterinary or human pharmaceutical use.

[0065] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts of inorganic acids and salts of organic acids. In addition, if the compound described herein is obtained in the form of an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, particularly a pharmaceutically acceptable addition salt, in accordance with conventional procedures. Those skilled in the art will recognize various synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable addition salts. The 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, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, glycolic acid, glyceric acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. By way of example only, salts derived from inorganic bases include 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 alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (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), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (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-cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-aryl amines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, and the like. By way of example only, specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0066] 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 the tautomers exhibited or the nature of the equilibrium between the tautomers, those skilled in the art will understand that a compound comprises both an amide and an imine tautomer. Therefore, amide-containing compounds should be understood to include their imine tautomers. Similarly, imine-containing compounds should be understood to include their amide tautomers.

[0067] The compounds disclosed herein, or their pharmaceutically acceptable salts, contain asymmetric centers and thus can produce enantiomers, diastereomers, and other stereoisomers, which, in absolute stereochemistry, can be defined as (R)- or (S)- or (D)- or (L)- of an amino acid. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic products (or racemic products of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise specified, the compounds are expected to include both E and Z geometric isomers.

[0068] "Stereoisomers" are compounds consisting of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This disclosure covers various stereoisomers or mixtures thereof and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0069] A “diastereomer” is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

[0070] The relative centers of the compounds described in this article are represented graphically using a “thick bond” style (bold or parallel lines), and absolute stereochemistry is represented using wedge bonds (bold or parallel lines).

[0071] “Prodrug” means any compound that releases an active parent drug according to the structure described herein in vivo when such 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 such a way that their effectiveness of the modification can be reversed in vivo through metabolic processes or through some other means. Prodrugs can be prepared by modifying functional groups present in the compounds described herein in such a way that their effectiveness of the modification can be reversed in vivo through common manipulations or through some other means. Prodrugs include compounds described herein wherein the hydroxyl, amino, carboxyl, or sulfhydryl groups of the compounds described herein are bonded to any group that can reversibly bind in vivo to produce the free hydroxyl, amino, or sulfhydryl group. Examples of prodrugs include, but are not limited to, ester (for example, acetate, formate, and benzoate derivatives of hydroxyl groups), amide, guanidine, carbamate (for example, N,N-dimethylaminocarbonyl) of the hydroxyl functional groups of the compounds described herein, and the like. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “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 by reference in its entirety.

[0072] 2. Compound

[0073] Provided herein are compounds that are inhibitors of SARM1. In certain embodiments, a compound of Formula I is provided:

[0074]

[0075] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein:

[0076] Y is N or CR 4 ;

[0077] Y 1 is N or CR 5 ;

[0078] X is N or CR 6 ;

[0079] R 1 is C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R 7 )2, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 substituents;

[0080] R 2 is halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, 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 said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 substituents;

[0081] R 3 is halo, cyano, -NO2, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, 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 said C 1-6 1-6 alkyl, C 2-6 2-6 alkenyl, C 2-6 2-6 alkynyl, C 3-10 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1

[0082] R 4 is hydrogen, halo, cyano, -NO2, C 1-6 1-6 alkyl, C 2-6 2-6 alkenyl, C 2-6 2-6 alkynyl, C3 -10 -6 cycloalkyl, heterocyclyl, 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 separated by one to five Z groups. 1 replace;

[0083] R 5 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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 -NR11 C(O)OR 11 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 substituents;

[0084] R 6 is hydrogen, halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -10 cycloalkyl, heterocyclyl, 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 said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 substituents;

[0085] each R 7 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 ; or

[0086] two R 7 , together with the nitrogen atom to which they are attached, form a heterocyclyl group that is independently optionally substituted with one to five Z 1 ;

[0087] each R 11 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1a ;

[0088] each Z 1 is independently halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with one to five Z 1a substituents;

[0089] each R 12 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with one to five Z 1b substituents;

[0090] each Z 1a is independently halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, 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 ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1b substituents;

[0091] each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1b substituents;

[0092] each Z 1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C 1-6 alkyl, -L-C 2-6 alkenyl, -L-C 2-6 alkynyl, -L-C 1-6 haloalkyl, -L-C 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and

[0093] 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 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 alkynyl)-, -C(O)N(C 1-6 haloalkyl)-, -C(O)N(C 3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-;

[0094] wherein Z 1b and each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0095] In certain embodiments, when X is N and R 1 is methyl; then R 2 is C 3-10 cycloalkyl, aryl, or heteroaryl, wherein the C 3-10 cycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 substituents.

[0096] In certain embodiments, the compound is not 4,5,6,7-tetrafluoro-lH-indole-2- sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-lH-benzimidazole (670248-30-3), 4-[(4,5-difluoro-lH-indol-2-yl)sulfonyl]-l-piperazinecarboxylic acid 1,1- dimethylethyl ester (1415396-05-2), 3-[7-chloro-5-fluoro-2-(methylsulfonyl)-lH-indol-4-yl]- 1-methyl-6-(trifluoromethyl)-2,4(lH,3H)-pyrimidinedione (1101495-34-4), 7-chloro-N- ethyl-5,6-dimethyl-lH-benzimidazole-2-sulfonamide (115243-16-8), or 4,7-dichloro-N- ethyl-5,6-dimethyl-lH-benzimidazole-2-sulfonamide (115243-12-4).

[0097] In certain embodiments, A) when X is N and R 1 is methyl; then R 2 is C 3-10 cycloalkyl, aryl, or heteroaryl, wherein the C 3-10 cycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 ; and B) the compound is not:

[0098] 4,5,6,7-tetrafluoro-lH-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2- (ethylsulfonyl)-lH-benzimidazole (670248-30-3), 4-[(4,5-difluoro-lH-indol-2-yl)sulfonyl]- 1-piperazinecarboxylic acid 1,1-dimethylethyl ester (1415396-05-2), 3-[7-chloro-5-fluoro- 2-(methylsulfonyl)-lH-indol-4-yl]-l-methyl-6-(trifluoromethyl)-2,4(lH,3H)-pyrimidinedione (1101495-34-4), 7-chloro-N-ethyl-5,6-dimethyl-lH-benzimidazole-2-sulfonamide (115243- 16-8), or 4,7-dichloro-N-ethyl-5,6-dimethyl-lH-benzimidazole-2-sulfonamide (115243-12-4).

[0099] In certain embodiments, a compound of Formula I is provided:

[0100]

[0101] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein:

[0102] Y is N or CR 4 ;

[0103] Y 1 is N or CR 5 ;

[0104] X is N or CR 6 ;

[0105] R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R 7 )2, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 ;

[0106] R 2 is halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, 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 said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 substituents;

[0107] R 3 is hydrogen, halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 substituents;

[0108] R 4 is hydrogen, halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; ​​​​​​​​​​​​​​​​​​​​​​​​

[0109] R 5 is hydrogen, halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, 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 said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 ;

[0110] R 6 is hydrogen, halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0111] each R 7 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 ; or

[0112] two R 7 , together with the nitrogen atom to which they are attached, form a heterocyclyl group that is independently optionally substituted with one to five Z 1 ;

[0113] each R 11 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1a ;

[0114] each Z 1 is independently halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1a ; and

[0115] each Z 1a is independently halo, cyano, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0116] with the proviso that: A) when X is N and R 1 is methyl; then R 2 is C 3-10 cycloalkyl, aryl, or heteroaryl, wherein the C 3-10 cycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1 substituted; and B) the compound is not: 4,5,6,7-Tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-Chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 4-[(4,5-Difluoro-1H-indol-2-yl)sulfonyl]-1-piperazinecarboxylic acid 1,1-dimethylethyl ester (1415396-05-2), 3-[7-Chloro-5-fluoro-2-(methylsulfonyl)-1H-indol-4-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1101495-34-4), 7-Chloro-N-ethyl-5,6-dimethyl-1H-benzimidazole-2-sulfonamide (115243-16-8), or 4,7-Dichloro-N-ethyl-5,6-dimethyl-1H-benzimidazole-2-sulfonamide (115243-12-4).

[0117] In certain embodiments, a compound of Formula I is provided:

[0118]

[0119] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein:

[0120] Y is CH;

[0121] Y 1 is N or CR 5 ;

[0122] X is CH;

[0123] R 1 is C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R 7 )2, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 ;

[0124] R 2 is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 ;

[0125] R 3 is halo, cyano, -NO2, or optionally substituted with one to five Z1 Replacement C 1-6 alkyl;

[0126] R 5 It is hydrogen, halogroup, cyanogroup, -NO2, or optionally surrounded by one to five Z groups. 1 Replacement C 1-6 alkyl;

[0127] Each R 7 Independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 Replace; or

[0128] Two Rs 7 Together with the nitrogen atoms they are attached to, they form independently, optionally, one to five Zn atoms. 1 Substituted heterocyclic groups;

[0129] Each Z 1 Independently, it can be a halogen 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, or heteroaryl; wherein 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 separated by one to five Z groups. 1a Replace; and

[0130] Each Z 1a Independently, it can be a halogen 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, or heteroaryl.

[0131] In some implementations, R 2 Let B be a ring; and let B be a ring C. 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 Replacement. In some implementations, R 2The ring is ring B; and ring B is aryl or heteroaryl, wherein each is independently and optionally divided by one to five Z. 1 replace.

[0132] In some embodiments, a compound of formula IA is provided:

[0133]

[0134] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, Y, Y 1 R 1 R 3 Both ring B and ring B are defined independently as in this paper.

[0135] In some embodiments, a compound of formula IB is provided:

[0136]

[0137] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 1 R 3 R 5 Both ring B and ring B are defined independently as in this paper.

[0138] In some implementations, R 1 C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, or -N(R) 11 )2, 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 separated by one to five Z groups. 1 replace.

[0139] In some implementations, R 1 Represented by ring A:

[0140]

[0141] Among them, ring A can be arbitrarily divided by one to five Z. 1 replace.

[0142] In some implementations, R 1 C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 2-6 alkenyl or C 2-6The alkynyl group is independently and optionally surrounded by one to five Z groups. 1 replace.

[0143] In some implementations, R 1 C 3-10 Cycloalkyl or heterocyclic groups, wherein each is independently and optionally surrounded by one to five Z groups. 1 replace.

[0144] In some implementations, R 1 To be arbitrarily selected by one to five Z 1 Replacement C 3-10 Cycloalkyl.

[0145] In some implementations, R 1 To be arbitrarily selected by one to five Z 1 Substituted heterocyclic groups.

[0146] In some implementations, R 1 To be arbitrarily selected by one to five Z 1 Substituted aryl groups.

[0147] In some implementations, R 1 To be arbitrarily selected by one to five Z 1 Substituted heteroaryl groups.

[0148] In some implementations, R 1 -N(R) 7 )2.

[0149] In some embodiments, a compound of formula II is provided:

[0150]

[0151] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0152] Y is N or CR 4 ;

[0153] Y 1 For N or CR 5 ;

[0154] X is N or CR 6 ;

[0155] Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace;

[0156] R 3It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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 separated by one to five Z groups. 1 replace;

[0157] R 4 It can be hydrogen, halogen, cyano, -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 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、-NR11 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 separated by one to five Z groups. 1 replace;

[0158] R 5 It can be hydrogen, halogen, cyano, -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 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(R11 )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 separated by one to five Z groups. 1 replace;

[0159] R 6 It can be hydrogen, halogen, cyano, -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 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 separated by one to five Z groups. 1 replace;

[0160] Each R 7 Independently for C 1-6 Alkyl, C 2-6alkenyl, 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 separated by one to five Z groups. 1 Replace; or

[0161] Two Rs 7 Together with the nitrogen atoms they are attached to, they form independently, optionally, one to five Zn atoms. 1 Substituted heterocyclic groups;

[0162] 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 separated by one to five Z groups. 1a replace;

[0163] Each Z 1 Independently, it can be a halogen 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、-NR12 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 separated by one to five Z groups. 1a replace;

[0164] 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 separated by one to five Z groups. 1 b substitution;

[0165] Each Z 1a Independently, it can be a halogen 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、-NR13 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 separated by one to five Z groups. 1b replace;

[0166] 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 separated by one to five Z groups. 1 b substitution;

[0167] Each Z 1b Independently, it can be a halogen group, 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

[0168] 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 3-10Cycloalkyl)-, -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 ynyl group)-, -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-;

[0169] 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 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally surrounded by one to five halogen groups, cyano groups, -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, or heteroaryl substitutions.

[0170] In some implementations, each R 7 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 separated by one to five Z groups. 1 replace.

[0171] In some implementations, each R 7 Independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl or heteroaryl, wherein each C 1-6 Alkyl, C 3-10 cycloalkyl or heteroaryl groups are independently and optionally surrounded by one to five Z groups.1 replace.

[0172] In some implementations, each R 7 Independently hydrogen, methyl, cyclobutyl, bicyclo[1.1.1.]pentyl, pyridyl, or pyrimidinyl, wherein each cyclobutyl, bicyclo[1.1.1.]pentyl, pyridyl, or pyrimidinyl group is independently and optionally surrounded by one to five Z-terminal groups. 1 replace.

[0173] In some implementations, two R 7 Together with the nitrogen atoms they are attached to, they form independently, optionally, one to five Zn atoms. 1 Substituted heterocyclic groups.

[0174] In some implementations, two R 7 Together with the nitrogen atoms they are attached to, they form ring A as defined in this article.

[0175] In some implementations, R 3 It can be hydrogen, halogen, cyano, -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 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 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace.

[0176] In some implementations, R 3 Halogenated, cyano, -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 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 separated by one to five Z groups. 1 replace.

[0177] In some implementations, R 3 To be arbitrarily selected by one to five Z 1 Replacement C 1-6 Alkyl group. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is trifluoromethyl.

[0178] In some embodiments, a compound of formula IIA is provided:

[0179]

[0180] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0181] Y is N or CR 4 ;

[0182] Y 1 For N or CR 5 ;

[0183] X is N or CR 6 ;

[0184] Ring A is arbitrarily divided by one to five Zs. 1 Substituted heterocyclic groups;

[0185] Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace;

[0186] R 3 It can be hydrogen, halogen, cyano, -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 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 ; 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 separated by one to five Z groups. 1 replace;

[0187] R 4 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, C3-10 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 separated by one to five Z groups. 1 replace;

[0188] R 5 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C2-6 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 separated by one to five Z groups. 1 replace;

[0189] R 6 It can be hydrogen, halogen, cyano, -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 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 -NR11 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 separated by one to five Z groups. 1 replace;

[0190] 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 separated by one to five Z groups. 1 a replaces;

[0191] Each Z 1 Independently, it can be a halogen 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 -NR12 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 separated by one to five Z groups. 1a replace;

[0192] 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 separated by one to five Z groups. 1b replace;

[0193] Each Z 1a Independently, it can be a halogen 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 -NR13 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 separated by one to five Z groups. 1b replace;

[0194] 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 separated by one to five Z groups. 1 b substitution;

[0195] Each Z 1b Independently, it can be a halogen group, 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

[0196] 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 ynyl group)-, -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-;

[0197] 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 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally surrounded by one to five halogen groups, cyano groups, -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, or heteroaryl substitutions.

[0198] In some implementations, Y is N. In some implementations, Y is CR. 4 In some implementations, Y is CH.

[0199] In some implementations, Y 1 For N. In some implementations, Y 1 For CR 5 In some implementations, Y 1 For CR 5 And R 5 It can be hydrogen, halo, cyano, or -N(R) 11)2、-OR 11 -SR 11 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. In some embodiments, Y 1 For CR 5 And R 5 It is a halogenated group. In some embodiments, Y 1 For CF.

[0200] In some embodiments, a compound of formula IC is provided:

[0201]

[0202] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R 1 R 3 R 5 Both ring B and ring B are defined independently as in this paper.

[0203] In some embodiments, a compound of formula ID is provided:

[0204]

[0205] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R 1 R 3 R 5 Both ring B and ring B are defined independently as in this paper.

[0206] In some embodiments, an IE compound is provided:

[0207]

[0208] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 3 R 5 R 7 Both ring B and ring B are defined independently as in this paper.

[0209] In some implementations, each R 7 C 1-6 Alkyl, heterocyclic or aryl.

[0210] In some embodiments, an IF compound of formula IF is provided:

[0211]

[0212] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 3 R 5 R 7 Both ring B and ring B are defined independently as in this paper.

[0213] In some embodiments, an IG compound of formula is provided:

[0214]

[0215] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 1 R 3 Both ring B and ring B are defined independently as in this paper.

[0216] In some embodiments, a compound of formula IH is provided:

[0217]

[0218] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R 1 R 3 Both ring B and ring B are defined independently as in this paper.

[0219] In some embodiments, a compound of formula IJ is provided:

[0220]

[0221] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 3 R 7 Both ring B and ring B are defined independently as in this paper.

[0222] In some embodiments, a compound of formula IK is provided:

[0223]

[0224] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 3 Ring A and ring B are each defined independently as described in this paper.

[0225] In some implementations, R 5 It can be hydrogen, halo, cyano, or -N(R) 11 )2、-OR 11 -SR 11 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. In some embodiments, R 5 It is a halogen group. In some embodiments, R 5 It is fluorine.

[0226] In some implementations, X is CR 4 In some embodiments, X is N or CH. In some embodiments, X is CH. In some embodiments, X is N.

[0227] In some implementations, R 1 Or ring A is C 3-10 Cycloalkyl or 4- to 10-membered heterocyclic groups, wherein each is optionally surrounded by one to five Z groups. 1 Replacement. In some implementations, R 1 Or ring A is C 3-10 Cycloalkyl or 4- to 10-membered heterocyclic groups, wherein each is optionally composed of one to five independently selected from halogen, cyano, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Substitution of alkoxy and aryl groups.

[0228] In some implementations, R 1 Or ring A can be arbitrarily divided by one to five Z. 1 Replacement of 4- to 10-membered heterocyclic groups. In some embodiments, R 1 Alternatively, ring A may be optionally surrounded by one to five independently selected groups: halogenated, cyano, -S(O)2-C. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and aryl substituents substituted with 4- to 10-membered heterocyclic groups.

[0229] In some implementations, R 1 Or ring A is:

[0230] Each of them can be chosen by one to five Z. 1 replace.

[0231] In some implementations, R 1 Or ring A is:

[0232]

[0233] Each of them can be chosen by one to five Z. 1 replace.

[0234] In some implementations, R 2 Alternatively, ring B may be aryl or heteroaryl, wherein each is optionally bounded by one to five Zn groups. 1 Replacement. In some implementations, R 2 Alternatively, ring B may be phenyl or 5 to 9-membered heteroaryl, wherein each is optionally surrounded by one to five Z-rings. 1 replace.

[0235] In some implementations, R 2 Or ring B can be arbitrarily divided by one to five Z. 1 Substituted heteroaryl groups. In some embodiments, R 2 Or ring B can be arbitrarily divided by one to five Z. 1 Substituted 5- to 9-membered heteroaryl groups. In some embodiments, R 2 Or ring B can be arbitrarily divided by one to five Z. 1 Replacement of 5- or 6-membered heteroaryl groups.

[0236] In some implementations, R 2 Alternatively, ring B may be cyclobutyl, tetrahydropyranyl, phenyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, or oxazolo[4,5-b]pyridyl, wherein each is optionally surrounded by one to five Z-rings. 1 replace.

[0237] In some implementations, R 2 Alternatively, ring B may be cyclobutyl, tetrahydropyranyl, phenyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridyl, wherein each is optionally surrounded by one to five Z-rings. 1 Replacement. In some implementations, R 2 Alternatively, ring B may be tetrahydropyranyl, phenyl, pyrazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridyl, wherein each is optionally surrounded by one to five Z-rings. 1 replace.

[0238] In some implementations, R 2 Or ring B may be optionally selected from one to three independent groups selected from halogen groups, C 1-6 Alkyl and C 1-6 Alkyl substituents, wherein each C 1-6 Alkyl groups are optionally surrounded by one to five Z. 1a replace.

[0239] In some implementations, R 2 Or ring B may be optionally selected from one to three independent groups selected from halogen groups, C 1-6 Alkyl and C 1-6 Alkyl substituents, wherein each C 1-6 Alkyl groups are optionally surrounded by one to three Cs 3-10 Cycloalkyl or halogenated substitutions.

[0240] In some implementations, R 2 Or ring B may be optionally selected from one to three independent groups selected from halogen groups, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups.

[0241] In some implementations, R 2 Alternatively, ring B may be cyclobutyl, tetrahydropyranyl, phenyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridyl, wherein each may optionally be composed of one to three independently selected from a halogen group, C 1-6 Alkyl and C 1-6 Alkyl group substitution. In some embodiments, R 2 Alternatively, ring B may be tetrahydropyranyl, phenyl, pyrazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridyl, wherein each may optionally be composed of one to three independently selected halogen groups, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups.

[0242] In some implementations, R 3 C 1-6 Alkyl group. In some embodiments, R 3 It is methyl. In some embodiments, R 2 It is a halogen group and R 3 C 1-6 Alkyl group. In some embodiments, R 2 It is fluorine and R 3 It is a methyl group.

[0243] In some implementations, each Z 1Independently selected from halogen, cyano, -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, or heteroaryl. In some embodiments, each Z 1 Independently for Z 1b .

[0244] In some embodiments, a compound of formula I is provided:

[0245]

[0246] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0247] Y is N or CR 4 ;

[0248] Y 1 For N or CR 5 ;

[0249] X is N or CR 6 ;

[0250] R 1 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, or -N(R) 7 )2, 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 separated by one to five Z groups. 1b replace;

[0251] R 2 Halogenated, cyano, -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 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 ; 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 separated by one to five Z groups. 1b replace;

[0252] R 3 Halogenated, cyano, -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 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 ;

[0253] R 4 It can be hydrogen, halogen, cyano, -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 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 ;

[0254] R 5 It can be hydrogen, halogen, cyano, -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 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 ;

[0255] R 6 It can be hydrogen, halogen, cyano, -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 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 ;

[0256] Each R 7 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 separated by one to five Z groups. 1 Replace; or

[0257] Two Rs 7 Together with the nitrogen atoms they are attached to, they form independently, optionally, one to five Zn atoms. 1b Substituted heterocyclic groups;

[0258] 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 groups;

[0259] Each Z 1b Independently, it can be a halogen group, 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

[0260] 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 3-10Cycloalkyl)-, -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 ynyl group)-, -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-;

[0261] 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 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally surrounded by one to five halogen groups, cyano groups, -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, or heteroaryl substitutions; conditions are:

[0262] A) When X is N and R 1 When it is methyl; then R 2 C 3-10 cycloalkyl, aryl or heteroaryl, wherein the C 3-10 cycloalkyl, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 Replace; and

[0263] B) The compound is not:

[0264] 4,5,6,7-Tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 4-[(4,5-difluoro-1H-indole-2-yl)sulfonyl]-1-piperazincarboxylic acid 1,1-dimethylethyl ester (1415396-05-2), 3-[7-chloro-5-fluoro-2-(methyl [Sulfoyl]-1H-indol-4-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinidone (1101495-34-4), 7-chloro-N-ethyl-5,6-dimethyl-1H-benzimidazole-2-sulfonamide (115243-16-8) or 4,7-dichloro-N-ethyl-5,6-dimethyl-1H-benzimidazole-2-sulfonamide (115243-12-4).

[0265] In some embodiments, a compound of formula II is provided:

[0266]

[0267] Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0268] Y is N or CR 4 ;

[0269] Y 1 For N or CR 5 ;

[0270] X is N or CR 6 ;

[0271] Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1b replace;

[0272] R 3 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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 ;

[0273] R 4 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, C3-10 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 ;

[0274] R 5 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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 ;

[0275] R 6 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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)2R11 -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 ;

[0276] Each R 7 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 separated by one to five Z groups. 1b Replace; or

[0277] Two Rs 7 Together with the nitrogen atoms they are attached to, they form independently, optionally, one to five Zn atoms. 1b Substituted heterocyclic groups;

[0278] 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 groups;

[0279] Each Z 1b Independently, it can be a halogen group, 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

[0280] 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-;

[0281] 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 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally surrounded by one to five halogen groups, cyano groups, -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, or heteroaryl substitutions.

[0282] In some embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided:

[0283] Table 1

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300] In some embodiments, a compound selected from Table 2, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided:

[0301] Table 2

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] 3. Methods

[0317] "Treatment / treating" is a means of achieving a favorable or desired outcome (including clinical outcomes). A favorable 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 said disease or disorder, enhancing the effect of another drug therapy, delaying the progression of the disease, improving quality of life and / or prolonging survival).

[0318] "Prevention / preventing" means the treatment of any disease or ailment that prevents the development of clinical symptoms of the stated disease or ailment. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of the stated disease or ailment or who have a family history of the stated disease or ailment.

[0319] "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.

[0320] The term "therapeutic effective amount" or "effective amount" for a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, 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 being 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 those skilled in the art.

[0321] The methods described herein can be applied to in vivo or ex vivo cell populations. “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. “Ex vivo” means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained 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 ex vivo to determine the optimal timing and / or dose of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental or clinical purposes to establish in vivo treatment regimens. Other ex vivo 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.

[0322] 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 SARM1 proteins containing sterile α and TIR motifs. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, inhibit SARM1.

[0323] In some embodiments, a method for inhibiting SARM1 activity is provided, the method comprising 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 in vitro or in vivo.

[0324] 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 SARM1 activity (e.g., in vitro or in vivo).

[0325] 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).

[0326] 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 NAD enzyme activity of SARM1. In some embodiments, a method is provided for inhibiting SARM1 NAD enzyme activity in a subject of need and / or treating neurodegeneration or neurological diseases or conditions, the method comprising administering to a subject of 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.

[0327] In some embodiments, 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0328] In some embodiments, a method of treating axonal degeneration in a subject of need is provided, the method comprising administering to the subject of 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. In some embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, inhibits axonal degeneration, including axonal degeneration caused by reduction or depletion of NAD+. In some embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, prevents axonal degeneration distal to axonal injury.

[0329] In some embodiments, a method for treating degeneration of neurons or a portion thereof in the peripheral nervous system 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0330] In some embodiments, a method for treating degeneration of neurons or a portion thereof in the central nervous system 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0331] In some implementations, the treatment includes reducing one or more symptoms or characteristics of neurodegeneration.

[0332] 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0333] 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0334] In some embodiments, a method is 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 method 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.

[0335] 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 treating a subject in need of a disease or disorder at least partially mediated by SARM1.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] In some embodiments, the disease or ailment is an acute illness. In some embodiments, the disease or ailment is a chronic illness.

[0340] In some embodiments, 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.

[0341] 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).

[0342] In some embodiments, 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.

[0343] In some embodiments, the disease or ailment is acute peripheral neuropathy. In some embodiments, 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), vinblastine alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), or platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0344] In some implementations, the disease or ailment is a chronic disease affecting the peripheral nervous system, such as, but not limited to, diabetic neuropathy, HIV neuropathy, Charcot Marie Tooth disease, or amyotrophic lateral sclerosis.

[0345] In some implementations, the disease or ailment is glaucoma (see, for example, Ko, KW et al., J. Cell Bio. 2020, 219(8), e201912047).

[0346] 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.

[0347] In some embodiments, 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.

[0348] In some embodiments, the disease or disorder is associated with retinal degeneration. In some embodiments, 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).

[0349] In some embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat 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 de novo or somatic mutations. 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.

[0350] 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 duration 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 enhancement, 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, pyroptosis, ferroptosis, and / or necrosis) and / or inflammation.

[0351] In some embodiments, 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 leukodystrophy, or leukodystrophy. In some embodiments, the neurodegeneration or neurological disease or condition is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukodystrophy, congenital myelin insufficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin melting, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, spherical leukodystrophy (Krabbe's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS), 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, human T-lymphovirus 1 (HTLV-1)-associated myelopathy with tropical spastic hemiparesis, West Nile virus encephalopathy, La Crosse virus encephalitis, and Bunyavirus encephalitis. encephalitis, viral encephalitis in children, essential tremor, peroneal muscular atrophy, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive supranuclear palsy (PSP), Friedreich's 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 spongiform encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic hemiplegia, familial spastic paraplegia, French settlement. Diseases such as Strumpell-Lorrain disease or non-alcoholic steatohepatitis (NASH) are also mentioned.

[0352] 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 a method for inhibiting axonal degeneration, the method 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.

[0353] In some embodiments, this disclosure provides methods for treating neurodegeneration or nervous system diseases or conditions associated with axonal degeneration, axonal injury, 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.

[0354] 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 injury. 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 neurological diseases and disorders. Such neuropathy can include peripheral neuropathy, central neuropathy, or a combination thereof. Furthermore, peripheral manifestations can arise from diseases primarily affecting the central nervous system, while central nervous system manifestations can arise from diseases that are essentially peripheral or systemic.

[0355] 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, vascular or collagen diseases such as 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 due to prolonged use of crutches or prolonged stay in one position 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 can be caused by chemical damage resulting from cytotoxic anticancer agents such as paclitaxel, cisplatin, 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 prickling), and pain in the arms, hands, legs, and / or feet. In some implementations, the neuropathy is associated with mitochondrial dysfunction. This type of neuropathy can manifest as decreased energy levels, specifically decreased NAD and ATP levels.

[0356] In some implementations, peripheral neuropathy is a metabolic and endocrine neuropathy, encompassing a wide range of peripheral neuropathy symptoms associated with systemic metabolic diseases. 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 disorders. A common hallmark of these diseases is the involvement of peripheral nerves due to structural or functional alterations in the myelin sheath and axons resulting from metabolic pathway dysregulation.

[0357] In some embodiments, neuropathy includes optic neuropathy such as glaucoma, retinal ganglion degeneration such as those associated with retinitis pigmentosa and extraretinal 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), 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 toxicity such as ethambutol or cyanide, neuropathy caused by adverse drug reactions, and neuropathy caused by vitamin deficiencies. Ischemic optic neuropathy also includes non-arterial anterior ischemic optic neuropathy.

[0358] 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; demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as those caused by enteroviruses, arboviruses, and herpes simplex viruses; and prion diseases. Mechanical injuries such as glaucoma or traumatic injuries to the head and spine can also lead to nerve damage and degeneration in the brain and spinal cord. Additionally, localized ischemia and stroke, as well as conditions such as nutritional deficiencies and chemical toxicity (e.g., chemotherapeutic agents), can cause central nervous system neuropathy.

[0359] In some embodiments, this disclosure provides a method 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 or stroke, chemical injuries, thermal injuries, and AIDS. Additionally, 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.

[0360] In some embodiments, the method includes administering an effective amount of a compound and / or composition (e.g., a compound of formula I) as described herein 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 conditions that induce axonal degeneration.

[0361] 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 expresses 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.

[0362] 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).

[0363] 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.

[0364] In some embodiments, a method of treating a neurodegenerative disease, condition, or disorder is provided, the method comprising administering to a subject in need one or more of a compound as described herein and a DLK inhibitor or a NAMPT inhibitor. In some embodiments, a combination therapy is provided comprising a compound as described herein and a DLK inhibitor and / or a NAMPT inhibitor. In some embodiments, a combination therapy is provided comprising a compound as described herein, a DLK inhibitor, and one or more additional therapeutic agents. In some embodiments, a combination therapy is provided comprising a compound as described herein, a NAMPT inhibitor, and one or more additional therapeutic agents. In some embodiments, a combination therapy is provided comprising a compound as described herein, a DLK inhibitor, a NAMPT inhibitor, and one or more additional therapeutic agents.

[0365] 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.

[0366] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, WO2014177060, WO2015091889, WO2016142310, US20180057507, WO2018107072, WO2019241244, WO2020168111 and CN104387391A, which are hereby incorporated in their entirety by reference.

[0367] 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.

[0368] In some embodiments, NAMPT inhibitors prevent the formation of nicotinamide mononucleotide (NMN). In some embodiments, NAMPT inhibition inhibits the mammalian NAD+ rescue pathway.

[0369] In some embodiments, the provided composition comprises compounds as described herein, formulated for administration to a subject in combination with a DLK inhibitor and / or a NAMPT inhibitor.

[0370] In some embodiments, the provided compositions comprise compounds as described herein for use in combination with DLK inhibitors and / or NAMPT inhibitors. In some embodiments, such compositions are pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0371] 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).

[0372] In some embodiments, SARM1 inhibition as described herein may be used in combination with one or more other therapies to treat the associated disease, condition, or disorder. In some embodiments, the administration of the SARM1 inhibitor is altered when used in combination therapy compared to when 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 draft than when administered alone or in combination with one or more therapies other than SARM1 inhibition. In some embodiments, an additional therapeutic agent is included, and the composition of said additional therapeutic agent with the provided compound may act synergistically. In some embodiments, one or both therapies used in the combination regimen are administered at a lower level or less frequently than when used as monotherapy.

[0373] In some embodiments, the compound provided herein, or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or composition thereof, is combined with NAD. + or NAD + Precursors (e.g., nicotinamide ribose (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.

[0374] 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 activity of protein 1 (SARM1) containing sterile α and TIR motifs (e.g., in vitro or in vivo).

[0375] In some embodiments, this disclosure provides for the manufacture of compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof for the production of activities (e.g., in vitro or in vivo) for inhibiting the activity of protein 1 (SARM1) containing sterile α and TIR motifs and for supplementing axonal NAD. + Uses in horizontal pharmaceutical preparations.

[0376] Axonal degeneration is associated with various types of neurodegenerative diseases and is considered an important indicator of disease progression and an interesting target for therapeutic treatment of these diseases. Similarly, axonal degeneration has also been observed in subjects with traumatic brain injury and peripheral neuropathy.

[0377] In some embodiments, 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, 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).

[0378] 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.

[0379] In some embodiments, a method is provided for treating any disease caused by SARM1 activity, 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, 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).

[0380] In some embodiments, the disease or ailment may be a disease or ailment of the central nervous system, and / or may be caused by or related to pathogens or traumatic injury. It should be understood that these general embodiments, defined according to broad categories of diseases, symptoms, and ailments, are not mutually exclusive.

[0381] In some embodiments, a method for treating neurodegenerative diseases 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, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug with NAD. + or NAD + A combination of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0382] Other embodiments include the use of the compounds disclosed in this invention in therapeutic applications.

[0383] 4. Medicine box

[0384] 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 thereof, or a prodrug, and suitable packaging. In some embodiments, the kit also includes instructions for use. In one aspect, the kit includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug, and a label and / or instructions for use of said compound in a therapeutic indication (including the diseases or ailments described herein).

[0385] This document also provides articles comprising, in a suitable container, the compound described herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analogue, a stereoisomer, a mixture of stereoisomers, or a prodrug. The container may be a vial, jar, ampoule, pre-loaded syringe, or intravenous bag.

[0386] 5. Drug composition and administration method

[0387] The compounds described herein are typically administered in the form of 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 the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by G.S. Banker & C.T. Rhodes).

[0388] The pharmaceutical composition may be administered in a single dose or in multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectal, oral, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition may be administered via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0389] One mode of administration is parenteral administration, such as by injection. The pharmaceutical compositions described herein may be incorporated into forms for injection administration, including, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, glucose, or sterile aqueous solutions, and similar pharmaceutical carriers.

[0390] Oral administration may be another route of administration for the compounds described herein. Administration may be via, for example, 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 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 substance, acting as a medium, carrier, or mediator of the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, sachets, granules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0391] Some examples of suitable excipients include, for example, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, astragalus 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.

[0392] Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof may 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 for use with the methods disclosed herein uses a transdermal delivery device (“patch”). Such transdermal patches can be used to deliver the compounds described herein in controlled amounts via continuous or discontinuous infusion. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0393] To prepare solid compositions such as tablets, a major active ingredient may be mixed with a pharmaceutical excipient to form a homogeneous solid preformed composition containing the compound described herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug. When these preformed compositions are referred to as homogeneous, the active ingredient is uniformly dispersed throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0394] The tablets or pills containing the compounds described herein may be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action or to protect them from the acidic conditions of the stomach. For example, tablets or pills may comprise an inner dose component and an outer dose component, the latter being an encapsulation of the former. These two components may be separated by an enteric coating that resists disintegration in the stomach and allows the inner component to enter the duodenum intact or with delayed release. A variety of substances may 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.

[0395] Compositions for inhalation or inhalation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered via oral or nasal inhalation 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 nebulizing device, or the nebulizing device may be connected to a face mask inhaler or intermittent positive pressure inhaler. In one embodiment, the solution, suspension, or powder composition may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0396] The amount of compounds in a pharmaceutical composition or formulation can vary within the full range used 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.

[0397] Formulation Example 1 - Tablet Formulation

[0398] Mix the following ingredients thoroughly and compress them into single-stripe tablets.

[0399] Ingredient Amount / capsule, mg Compound of the disclosure 400 Corn starch 50 Croscarmellose sodium 25 Lactose 120 Magnesium stearate 5

[0400] Formulation Example 2 - Capsule Formulation

[0401] Mix the following ingredients thoroughly and fill them into hard-shell gelatin capsules.

[0402] Ingredient Amount / capsule, mg Compound of the disclosure 200 Spray-dried lactose 148 Magnesium stearate 2

[0403] Formulation Example 3 - Suspension Formulation

[0404] Mix the following ingredients to form a suspension for oral administration.

[0405]

[0406]

[0407] Formulation Example 4 - Injectable Formulation

[0408] Mix the following ingredients to form an injectable formulation.

[0409] Ingredient Amount Compound of the disclosure 0.2 mg - 20 mg Sodium acetate buffer solution, 0.4 M 2.0 mL HCI (1 N) or NaOH (1 N) q.s. to appropriate pH Water (distilled, sterile) q.s. to 20 mL

[0410] Formulation Example 5 - Suppository Formulation

[0411] By combining the compounds disclosed herein with H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) was mixed to prepare a suppository with a total weight of 2.5g, and it has the following composition:

[0412]

[0413] 6. Administration

[0414] The specific dose 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, age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, combination of drugs, and the severity of the subject's specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of the subject's body weight. A dose 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, a dose between 0.5 and 60 mg / kg may be appropriate. In some embodiments, a dose 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 body weight is particularly useful when adjusting doses between subjects of significantly different sizes, for example, when using the drug in children and adults, or when converting an effective dose for a non-human subject, such as a dog, to a dose suitable for a human subject.

[0415] 7. Synthesis of Compounds

[0416] The compounds described herein can be prepared using the methods disclosed herein and their conventional modifications (which will be apparent given the disclosure herein and methods well known in the art). In addition to the teachings herein, conventional and well-known synthetic methods may 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, for example, Sigma Aldrich or other chemical suppliers.

[0417] It should be understood that, unless otherwise specified, other process conditions may be used when typical 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.

[0418] Furthermore, conventional protecting groups (“PG”) may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting specific functional groups and deprotecting them, 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. For example, protecting groups of alcohols, such as hydroxyl groups, include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsiloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), 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 for alcohols include acetyl groups removed by acid or base, benzoyl groups removed by acid or base, benzyl groups removed by hydrogenation, methoxyethoxymethyl ethers removed by acid, dimethoxytriphenylmethyl groups removed by acid, methoxymethyl ethers removed by acid, tetrahydropyranyl or tetrahydrofuranyl groups removed by acid, and triphenylmethyl groups removed by acid. Examples of protecting groups for amines include carbonylbenzyloxy groups removed by hydrogenolysis, p-methoxybenzylcarbonyl groups removed by hydrogenolysis, tert-butoxycarbonyl groups removed by concentrated strong acids (e.g., HCl or CF3COOH) or by heating to above about 80°C, 9-fluorenylmethoxycarbonyl groups removed by bases such as piperidine, acetyl groups removed by base treatment, benzoyl groups removed by base treatment, benzyl groups removed by hydrogenolysis, carbamate groups removed by acid and mild heating, and protecting groups removed by hydrogenolysis. p-Methoxybenzyl group removed by hydrolysis, 3,4-dimethoxybenzyl group removed by hydrogenolysis, p-methoxyphenyl group removed by cerium(IV)ammonium nitrate, p-toluenesulfonyl group removed by concentrated acid (e.g., HBr or H2SO4) and strong reducing agent (sodium or sodium naphthalene in liquid ammonia), troc (trichloroethyl chloroformate) removed by Zn insertion in the presence of acetic acid, and sulfonamides (nitrobenzenesulfonyl and o-nitrobenzenesulfonyl) removed by samarium iodide or tributyltin hydrogenation.

[0419] Furthermore, the compounds disclosed herein may contain one or more chiral centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures rich in 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, chiral column chromatography, chiral resolving agents, etc.

[0420] The starting materials used in the following reactions are typically known compounds, or can be prepared by known procedures or obvious modifications thereof. 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 by procedures or obvious modifications thereof, as described in the following standard references: 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).

[0421] General Synthesis

[0422] Scheme I illustrates a general method that can be used to synthesize the compounds described herein, wherein X, Y, Y 1 R 1 R 2 and R 3 Each is independently defined as described herein; LG is independently a leaving group (e.g., halogen, -OTf, etc.); and each R50 They can be -OH, -O-alkyl independently, or together with the boron atoms to which they are attached, to form cyclic borate esters.

[0423] Option I

[0424]

[0425] 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, such as in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) and a base, followed by optional functionalization or deprotection if desired. Alternatively, the compound of formula I can be prepared by borylating compound I-1 to provide compound I-3 and contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, such as in the presence of a palladium catalyst (e.g., XPhos reagent, Pd(dppf)Cl2) and a base, followed by optional functionalization or deprotection if desired. Alternatively, the compound of formula I can be prepared by contacting compound I-5 with compound I-6 (e.g., an amine).

[0426] 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.

[0427] The reagents and starting materials used in Scheme I can be purchased from commercial sources or prepared according to methods known to those skilled in the art. For example, Scheme II shows an exemplary synthesis of compound I-1, wherein X, Y, Y 1 R 1 and R 3 Each is independently defined as described herein; each LG is independently a leaving group (e.g., halogen, -OTf, etc.).

[0428] Option II

[0429]

[0430] In scheme II, compound II-3 (e.g., where R) 1 Compounds in which sulfur is bonded via carbon atoms, such as C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Compounds of formula II-1 (e.g., cycloalkyl groups) can be prepared by contacting a compound of formula II-2 with a compound of formula II-2 under suitable conditions (e.g., nucleophilic conditions). The compound of formula II-3 can then be provided by oxidizing the compound of formula II-3, for example, with a suitable oxidant such as m-CPBA. In some embodiments of the compound of formula II-2, LG is iodine.

[0431] Further derivatization of the compound or any intermediate provided by the steps outlined in Scheme I or II provides additional Formula I compounds. It should be understood that any of the compounds or intermediates shown in Scheme I or II can be prepared using conventional methods or obtained from commercial sources. Additionally, any intermediate or product obtained by the process outlined in Scheme I or II can be derivatized at any step to provide various Formula I compounds. In some embodiments, various substituents of the compounds or intermediates used as in Scheme I or II are as defined for Formula I.

[0432] In some embodiments, a method for providing a compound of formula I is provided, the method comprising making a compound of formula I-1:

[0433]

[0434] With compound of formula I-2:

[0435]

[0436] Contact under conditions sufficient to provide compound I; wherein X, Y, Y 1 R 1 R 2 and R 3 Each is independent as defined in this paper; LG is a leaving basis; and each R 50 They can be -OH, -O-alkyl independently, or together with the boron atoms to which they are attached, to form cyclic borate esters.

[0437] In some embodiments, a method for providing a compound of formula I is provided, the method comprising making a compound of formula I-1:

[0438]

[0439] Contact with a boron reagent under boronization reaction conditions yields compound I-3:

[0440]

[0441] And make the compound of formula I-3 and the compound of formula I-4:

[0442] R 2 -LG I-4

[0443] Contact under conditions sufficient to provide compound I; wherein A 1 A 2 X 1 X 2 X 3 X 4 X 5 X 6R 1 R 2 R 4 and R 5 Each LG is independently a leaving basis, as defined in this paper, and each R... 50 Independently -OH, C 1-6 alkoxy, or two R 50 Together with the boron atoms they are attached to, they form cyclic borate esters.

[0444] In some implementations, each LG is independently a halogen group.

[0445] In some embodiments, the boron reagent is 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentanane or trimethyl borate.

[0446] In some embodiments, the method comprises a palladium catalyst (e.g., XPhos reagent or Pd(dppf)Cl2) and a base. Example

[0447] 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 to constitute a particular pattern of its practice. However, those skilled in the art will understand that, based on this disclosure, many changes can be made to the disclosed specific implementations without departing from the spirit and scope of this disclosure, and similar or analogous results can still be obtained.

[0448] General experimental methods

[0449] All solvents used were commercially available and were used without further purification. Reactions were typically carried out using anhydrous solvents under a nitrogen inert atmosphere.

[0450] NMR spectrum: 1 H-NMR spectroscopy was performed using a Bruker Avance III equipped with a BBFO 300MHz probe operating at 300MHz, or one of the following instruments operating at 400MHz: a Bruker Avance 400 instrument equipped with a DUAL 400MHz S1 probe, or an instrument equipped with a 6S1 400MHz 5mm probe. 1 H- 13The Bruker Avance 400 instrument with C ID, the Bruker Avance III 400 instrument with a nanobay equipped with a direct probe Broadband BBFO 5mm, and the Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400BBO probe. All deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal. 1 H and 13 C is set to δ0.00). In some cases, 1 1H NMR spectroscopy was performed using a Bruker Advance 400 instrument operating at 400 MHz at approximately room temperature with the solvent described, unless otherwise specified. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are expressed in parts per million (ppm) and conventional abbreviations are used to designate the main peak: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; dt, doublet of triplet; br, broad peak.

[0451] Thin-layer chromatography (TLC): In the case of thin-layer chromatography (TLC), it refers to silica gel TLC using silica gel F254 (Merck) plates. Rf is the distance the compound travels on the TLC plate divided by the distance the solvent travels. Column chromatography is performed using an automated rapid chromatography system on a silica gel cylinder, or in the case of reversed-phase chromatography on a C18 cylinder. Alternatively, thin-layer chromatography (TLC) is performed using materials from Mancherey-Nagel. The process is performed on silica gel 60F254, and UV is typically used to develop the spots. In some cases, additional development methods are employed. In these cases, the TLC plate is prepared with iodine (by adding approximately 1g of I2 to 10g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (by thoroughly mixing 25g of (NH4)6Mo7O in 450mL of water and 50mL of concentrated H2SO4). 24 Imaging is produced by reacting 4H2O and 5g(NH4)2Ce(IV)(NO3)6 to develop the compound.

[0452] Liquid chromatography-mass spectrometry (LC-MS) 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, wherein the 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). LC-MS was performed at 220 and 254 nm or by evaporative light scattering (ELSD) and positive electrospray ionization (MS). Semi-preparative HPLC was performed under acidic or neutral conditions. Acidic: Luna C18 100×30mm, 5μm; MPA: HCl / H2O = 0.04%, or formic acid / H2O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150×25, 5μm; MPA: 10mM NH4HCO3 in H2O solution; MPB: ACN. Gradients under two conditions: 10% MPB to 80% MPB over 12 min at a flow rate of 20 mL / min, then 100% MPB over 2 min, and 10% MPB over 2 min, with a UV detector. SFC analysis was performed on the Thar SFC system using a UV / Vis detector and a series of chiral 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. The 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; 3.5-5 min, 10% MPB). SFC preparation was performed on a Thar 80 preparative SFC system using a UV / Vis detector and a series of chiral 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. The 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 obtained using an UPLC-MS Acquity equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer. TMThe system was collected using a mass spectrometer operating in alternating positive and negative electrospray ionization modes. A Cortecs UPLC C18 column, 1.6 μm, 2.1 × 50 mm, was used. A linear gradient was applied, starting with 95% A (A: 0.1% formic acid aqueous solution) and ending with 95% B (B: MeCN containing 0.1% formic acid) over 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.

[0453] Intermediate 1

[0454] 4-Bromo-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole

[0455]

[0456] 3-Bromo-6-fluoro-2-iodo-4-methylaniline: NIS (36.39 g, 161.73 mmol) was added to a solution of 5-bromo-2-fluoro-4-methylaniline (30 g, 147.03 mmol) in CH3COOH (500 mL) at 0 °C and N2. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (30 mL) and washed with saturated NaHCO3 aqueous solution (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the title compound. LCMS: m / z = 329.9, 331.9 [M+H] + .

[0457] 3-Bromo-6-fluoro-4-methyl-2-((trimethylsilyl)ethynyl)aniline: TEA (205.18 g, 2.03 mol), CuI (2.57 g, 13.52 mmol), Pd(PPh3)2Cl2 (9.49 g, 13.52 mmol), and 3-bromo-6-fluoro-2-iodo-4-methylaniline (44.6 g, 135.18 mmol) were added to a solution of ethynyl(trimethyl)silane (15.93 g, 162.21 mmol) in DMF (700 mL) at 0 °C and N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O (1500 mL) and extracted with EtOAc (3 × 700 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the title compound. LCMS: m / z = 300.0, 302.1 [M+H] + .

[0458] 4-Bromo-7-fluoro-5-methyl-1H-indole: CuI (35.52 g, 186.52 mmol) was added to a solution of 3-bromo-6-fluoro-4-methyl-2-((trimethylsilyl)ethynyl)aniline (28 g, 93.26 mmol) in DMF (300 mL) at 25 °C and N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered through a diatomaceous earth filter. The filtrate was diluted with H2O (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the title compound.

[0459] 4-Bromo-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole: NaH (1.05 g, 26.31 mmol, 60% purity in mineral oil) was added to a solution of 4-bromo-7-fluoro-5-methyl-1H-indole (5 g, 21.92 mmol) in DMF (70 mL) at 0 °C and N2. The mixture was stirred at 0 °C for 0.5 h. Then, TsCl (6.27 g, 32.89 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the title compound. LCMS: m / z = 382.0, 384.0 [M+H] + .

[0460] Intermediate 2

[0461] 7-Fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole-2-sulfonyl chloride

[0462]

[0463] 3,3,4-Tribromo-7-fluoro-5-methylindololin-2-one: Pyridine-Br3 (21.04 g, 65.77 mmol) was added to a solution of 4-bromo-7-fluoro-5-methyl-1H-indole (5 g, 21.92 mmol) in t-BuOH (90 mL) and H2O (30 mL) at 20 °C and N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 401.8, 403.8 [M+H] + .

[0464] 4-Bromo-7-fluoro-5-methylindoline-2-one: Zn (14.81 g, 226.45 mmol) was added to a solution of 3,3,4-tribromo-7-fluoro-5-methylindoline-2-one (9.1 g, 22.65 mmol) in saturated aqueous NH4Cl (60 mL) and THF (60 mL) at 20 °C and N2. The mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered through a diatomaceous earth filter. A saturated aqueous NaHCO3 solution (100 mL) was added to the filtrate and the mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 244.0, 246.0 [M+H] + .

[0465] 4-Bromo-7-fluoro-5-methylindoline-2-thione: P2S5 (2.24 g, 10.08 mmol) and NaHCO3 (14 mg, 0.17 mmol) were added to a solution of 4-bromo-7-fluoro-5-methylindoline-2-one (4.1 g, 16.80 mmol) in THF (50 mL) at 20 °C and N2. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Ice water (40 mL) was added to the resulting residue and the mixture was stirred for 10 min. The mixture was filtered and the filter cake was dried under reduced pressure to give the title compound. LCMS: m / z = 260.0, 262.0 [M+H] + .

[0466] 4-Bromo-7-fluoro-2-((4-methoxybenzyl)thio)-5-methyl-1H-indole: K₂CO₃ (1.91 g, 13.84 mmol) and PMBCl (1.08 g, 6.92 mmol) were added to a solution of 4-bromo-7-fluoro-5-methyl-indoline-2-thione (1.8 g, 6.92 mmol) in DMF (25 mL) at 20 °C and N₂. The mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (3 × 30 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:EtOAc = 10:1 to 5:1) to give the title compound. LCMS: m / z = 380.1, 381.9 [M+H] + .

[0467] 7-Fluoro-2-((4-methoxybenzyl)thio)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole: At 20 °C and N2, KOAc (852 mg, 8.68 mmol) and Pd(dppf)Cl2 (212 mg, 0.29 mmol) were added to a mixture of 4-bromo-7-fluoro-2-((4-methoxybenzyl)thio)-5-methyl-1H-indole (1.1 g, 2.89 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentanane (1.47 g, 5.79 mmol) in DMSO (30 mL). The mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 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 = 428.2 [M+H] + .

[0468] 7-Fluoro-2-((4-methoxybenzyl)thio)-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole: 3-bromo-1-methyl-1,2,4-triazole (483 mg, 2.98 mmol), K3PO4 (633 mg, 2.98 mmol), and XPhos PdG2 (117 mg, 0.15 mmol) were added to a solution of 7-fluoro-2-((4-methoxybenzyl)thio)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole (850 mg, 1.49 mmol) in EtOH (12 mL) and H2O (3 mL) at 20 °C and N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered through a diatomaceous earth mat. The filtrate 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. LCMS: m / z = 383.1 [M+H] + .

[0469] 7-Fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole-2-sulfonyl chloride: NCS (174 mg, 1.31 mmol) was added to a solution of 7-fluoro-2-((4-methoxybenzyl)thio)-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (200 mg, 0.52 mmol) in AcOH (0.6 mL) and H₂O (0.2 mL) at 0 °C and N₂. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 329.0 [M+H] + .

[0470] Intermediate 3

[0471] 7-Fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-indole

[0472]

[0473] Lithium 4-bromo-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole-2-sulfinate: LDA (3.14 mmol, 1.57 M, 2 M in THF / n-heptane) was added to a solution of 4-bromo-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole (5 g, 13.08 mmol) in THF (70 mL) at -78 °C and N2. The mixture was then stirred at -78 °C for 0.5 h. Subsequently, SO2 (g) was bubbled into the reaction solution for 30 min, and the reaction was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound.

[0474] 4-Bromo-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole-2-sulfonyl chloride: NCS (4.08 g, 30.55 mmol) was added to a solution of lithium 4-bromo-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole-2-sulfinate (9.2 g, 20.37 mmol) in DCM (100 mL) at 20 °C and N2. The reaction mixture was then stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.

[0475] 4-Bromo-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole: Pyridine (6.2 g, 81.12 mmol) and 4-bromo-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole-2-sulfonyl chloride (7.8 g, 16.22 mmol) were added to a solution of pyrrolidine (1.27 g, 17.85 mmol) in DCM (100 mL) at 0 °C and N2. The reaction was stirred at 0 °C for 2 h, diluted with H2O (100 mL), and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the title compound. LCMS: m / z = 515.0, 517.0 [M+H] + .

[0476] 7-Fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-indole: 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentanane) (192 mg, 0.75 mmol), KOAc (148 mg, 1.51 mmol), and Pd(dppf)Cl2·CH2Cl2 (41 mg, 0.05 mmol) were added to a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole (260 mg, 0.50 mmol) in DMSO (5 mL) at 20 °C and N2. The mixture was heated to 85°C and stirred for 12 h. The reaction mixture was then 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 = 5:1 to 3:1) to give the title compound. LCMS: m / z = 409.2 [M + H] + .

[0477] Intermediate 4

[0478] Methyl-3-(tributyltinyl)-1H-1,2,4-triazole

[0479]

[0480] 1-Methyl-3-(tributyltinyl)-1H-1,2,4-triazole: Pd(PPh3)2Cl2 (433 mg, 0.62 mmol) was added to a mixture of 3-bromo-1-methyl-1H-1,2,4-triazole (1 g, 6.17 mmol) and tributyl(tributyltinyl)stanane (7.16 g, 12.35 mmol) in toluene (20 mL) at 25 °C and N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by adding saturated KF aqueous solution (10 mL) and filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 374.1 [M+H] + .

[0481] Intermediate 5

[0482] 4-Bromo-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole

[0483]

[0484] 4-Bromo-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole: TEA (189 mg, 1.87 mmol) and 4-bromo-7-fluoro-5-methyl-1-(p-toluenesulfonyl)indole-2-sulfonyl chloride (300 mg, 0.62 mmol) were added to a solution of pyrrolidine (44 mg, 0.62 mmol) in DCM (3 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was then diluted with H₂O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 0:1) to give the title compound. LCMS: m / z = 361.0, 363.0 [M+H] + .

[0485] Intermediate 6

[0486] 2-(azacyclobutane-1-ylsulfonyl)-4-bromo-7-fluoro-5-methyl-1H-indole

[0487]

[0488] 2-(azacyclobutane-1-ylsulfonyl)-4-bromo-7-fluoro-5-methyl-1H-indole: Azacyclobutane hydrochloride (38 mg, 0.41 mmol) and TEA (105 mg, 1.04 mmol) were added to a solution of 4-bromo-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole-2-sulfonyl chloride (100 mg, 0.20 mmol) in DCM (3 mL) at 20 °C and N2. The mixture was stirred at 20 °C 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 (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc = 3:1) to give the title compound. LCMS: m / z = 347.0, 349.0 [M+H] + .

[0489] Intermediate 7

[0490] Potassium (3-(benzyloxy)cyclobutyl)trifluoroborate

[0491]

[0492] At 20 °C, KHF2 (1.29 g, 16.52 mmol) was added to a solution of 2-(3-(benzyloxy)cyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (680 mg, 2.36 mmol) in MeOH (24 mL). The reaction mixture was heated to 70 °C and stirred for 6 h. The reaction mixture was concentrated under reduced pressure. MeCN (30 mL) was added to the resulting residue, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was wet-milled with diisopropyl ether (20 mL), and the solid was collected by filtration to give the title compound.

[0493] Intermediate 8

[0494] Potassium (3-((benzyloxy)methyl)cyclobutyl)trifluoroborate

[0495]

[0496] 3-((benzyloxy)methyl)cyclobut-1-ol: NaBH4 (4.18 g, 110.39 mmol) was added fractionally to a mixture of 3-((benzyloxy)methyl)cyclobut-1-one (14 g, 73.59 mmol) in MeOH (140 mL) at 0 °C and N2. The reaction mixture was heated to 20 °C and stirred for 2 h. The reaction mixture was cooled to 0 °C, quenched by adding saturated aqueous NH4Cl solution (140 mL), and the MeOH was removed under reduced pressure. The remaining aqueous phase was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.

[0497] 3-((benzyloxy)methyl)cyclobutyl 4-methylbenzenesulfonic acid: TEA (36.84 g, 364.1 mmol) and p-TsCl (10.27 g, 145.64 mmol) were added to a solution of 3-(benzyloxy)methyl)cyclobutanol (14 g, 72.82 mmol) in DCM (200 mL) at 0 °C and N2. The reaction mixture was heated to 20 °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 = 100:1 to 3:1) to give the title compound.

[0498] (((3-Iodocyclobutyl)methoxy)methyl)benzene: NaI (6.49 g, 43.30 mmol) was added to a mixture of 3-((benzyloxy)methyl)cyclobutyl 4-methylbenzenesulfonic acid (5 g, 14.43 mmol) and butan-2-one (100 mL) at 25 °C and N2. The reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with MTBE (2 × 100 mL). The combined organic layers were washed with brine (300 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.

[0499] 2-(3-((benzyloxy)methyl)cyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane: At 25 °C and N2, a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (6.93 g, 27.30 mmol) in DMF (10 mL) was supplemented with (((3-iodocyclobutyl)methoxy)methyl)benzene (5.5 g, 18.20 mmol), LiOMe (1.52 g, 40.05 mmol), PPh3 (621 mg, 2.37 mmol), and CuI (347 mg, 1.82 mmol). The reaction mixture was heated to 35 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (3 × 15 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.

[0500] Potassium (3-((benzyloxy)methyl)cyclobutyl)trifluoroborate: KHF2 (5.07 g, 64.85 mmol) was added to a mixture of 2-(3-((benzyloxy)methyl)cyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (2.8 g, 9.26 mmol) in MeOH (30 mL) and H2O (6 mL) at 25 °C and N2, and the reaction mixture was stirred for 12 h. The reaction mixture was concentrated under reduced pressure. MeCN (100 mL) was added to the resulting residue, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was wet-milled with i-Pr2O (30 mL). The solid was collected and dried under reduced pressure to give the title compound.

[0501] Intermediates 9 and 10

[0502] trans-3-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carboxaldehyde and cis-3-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carboxaldehyde

[0503]

[0504] 4-(3-((benzyloxy)methyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole: At 25 °C and N2, K2CO3 (804 mg, 5.81 mmol) and Pd(dppf)Cl2 (142 mg, 0.19 mmol) were added to a mixture of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (0.7 g, 1.94 mmol) and potassium trifluoroborate (711 mg, 2.52 mmol) in toluene (9 mL) and H2O (3 mL). The reaction mixture was heated to 140 °C and stirred for 12 h. The reaction mixture was then poured into H2O (30 mL) and extracted with EtOAc (3 × 15 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 = 5:1 to 1:1) to give the title compound. LCMS: m / z: 457.1 [M+H] + .

[0505] (3-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole-4-yl)cyclobutyl)methanol: BCl3 (0.71 mL, 1 M in toluene) was added to a mixture of 4-(3-((benzyloxy)methyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (250 mg, 0.55 mol) in DCM (2 mL) at 0 °C and N2, and the mixture was stirred for 1 h. The reaction mixture was quenched by adding saturated aqueous NaHCO3 solution (20 mL) at 0 °C and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (PE:EtOAc = 1:1) to give the title compound. LCMS:m / z:367.1[M+H] + .

[0506] trans-3-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carboxaldehyde and cis-3-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carboxaldehyde: DMP (220 mg, 0.52 mmol) was added to a mixture of (3-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indol-4-yl)cyclobutyl)methanol (95 mg, 0.26 mmol) in DCM (10 mL) at 25 °C and N2, and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc = 2:1) to give trans-3-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carboxaldehyde (first elution) and cis-3-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carboxaldehyde (second elution). LCMS: m / z: 365.1 [M+H] + .

[0507] Intermediate 11

[0508] 5-Methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

[0509]

[0510] 4-Chloro-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl chloride: LDA (11.22 mmol, 5.61 mL, 2 M in THF / n-heptane) was added to a solution of 4-chloro-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3 g, 9.35 mmol) in THF (30 mL) at -78 °C and N2. The reaction mixture was stirred for 30 min, and then added to a solution of thioyl chloride (7.57 g, 56.11 mmol) in THF (20 mL) at -50 °C, and the resulting solution was stirred at -50 °C for 30 min. The reaction mixture was quenched by adding H2O (30 mL) cooled to 0 °C and extracted with MTBE (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 419.0 [M+H] +

[0511] 4-Chloro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: At 0 °C and N2, pyridine (3.77 g, 47.70 mmol) and pyrrolidine (1.02 g, 14.31 mmol) were added to a mixture of 4-chloro-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl chloride (4 g, 9.54 mmol) in DCM (20 mL). The reaction mixture was heated to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 × 15 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:(EtOAc:THF = 1:1) = 3:1 to 1:1) to give the title compound. LCMS: m / z = 454.1 [M+H] +

[0512] 5-Methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentane) (1.45 g, 5.73 mmol) and A mixture of 4-chloro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.3 g, 2.86 mmol) in 1,4-dioxane (20 mL) was supplemented with KOAc (1.12 g, 11.45 mmol), PCy3 (80 mg, 0.28 mmol), and Pd2(dba)3 (131 mg, 0.14 mmol). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 15 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:THF = 1:1) = 3:1 to 0:1) to give the title compound. LCMS: m / z = 546.2 [M+H] + .

[0513] Intermediate 12

[0514] 2-((1H-imidazol-1-yl)sulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-

[0515] Indole

[0516]

[0517] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: 5-fluoro-2-(tributyltinyl)pyrimidine (21 g, 0.054 mol) and Pd(t-Bu3P)2 (1.45 g, 0.003 mmol) were added to a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (11 g, 0.039 mol) in DMF (300 mL) at 20 °C and N2. The reaction mixture was heated to 110 °C and stirred for 8 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 300.0 [M+H]+ .

[0518] 3,3-Dibromo-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indololin-2-one: Pyridium tribromide (64 g, 0.2 mmol) was added to a solution of 7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole (10 g, 0.033 mol) in t-BuOH (300 mL) and H2O (100 mL) at 20 °C and N2. The reaction mixture was heated to 30 °C and stirred for 12 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 471.8 [M+H] + .

[0519] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-one: Zn (8.29 g, 0.13 mol) was added to a solution of 3,3-dibromo-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-one (24 g, 0.05 mol) in THF (240 mL) and saturated NH4Cl aqueous solution (240 mL) at 0 °C and N2. The reaction mixture was heated to 20 °C and stirred for 1 h. The reaction mixture was filtered, and the filtrate was diluted with 100 mL of H₂O and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 316.0 [M + H] + .

[0520] 7-Fluoro-4-(5-Fluoropyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-thione: P2S5 (10.16 g, 0.046 mol) and NaHCO3 (320 mg, 0.004 mol) were added to a solution of 7-fluoro-4-(5-Fluoropyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-one (12 g, 0.038 mol) in THF (220 mL) at 20 °C and N2. The reaction mixture was heated to 50 °C and stirred for 8 h. The reaction mixture was used directly in the next step.

[0521] 7-Fluoro-4-(5-Fluoropyrimidin-2-yl)-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole: At 20 °C, DMF (160 mL), K₂CO₃ (10.52 g, 0.076 mol), and PMBCl (7.14 g, 0.046 mol) were added to the above solution of 7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-thione (12.6 g, 0.038 mol) in THF (220 mL). The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with H₂O (300 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 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 = 452.0 [M+H] + .

[0522] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid tert-butyl ester: At 0 °C and N2, TEA (897 mg, 0.009 mol), DMAP (54 mg, 0.44 mmol), and Boc2O (1.16 g, 0.005 mol) were added to a solution of 7-fluoro-4-(5-fluoropyrimidin-2-yl)-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole (2 g, 0.004 mol) in DCM (40 mL). The reaction mixture was heated to 20 °C and stirred for 3 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 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 = 552.2 [M+H] + .

[0523] 2-(chlorosulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid tert-butyl ester: At 0 °C, NCS (218 mg, 1.63 mmol) was added to a solution of 300 mg (0.54 mmol) of 7-fluoro-4-(5-fluoropyrimidin-2-yl)-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid tert-butyl ester in AcOH (6 mL) and H₂O (2 mL). The reaction mixture was heated to 20 °C and stirred for 3 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 497.9 [M+H] + .

[0524] 2-((1H-imidazol-1-yl)sulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: At 20 °C, tert-butyl 2-(chlorosulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid (600 mg, 1.21 mmol) in DCM (14 mL) was added to 1H-imidazolium (410 mg, 6.03 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was wet-milled with DCM (10 mL) for 10 min and collected by filtration. The filter cake was dried under reduced pressure to give the title compound. LCMS: m / z = 429.9 [M+H] + .

[0525] Intermediate 13

[0526] 6-(trifluoromethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

[0527]

[0528] 1-(6-Bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethyl-1-one: TEA (3.53 g, 34.88 mmol) and acetyl chloride (2.74 g, 34.88 mmol) were added to a solution of 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2.5 g, 11.63 mmol) in DCM (50 mL) at 0 °C and N2. The reaction mixture was heated to 25 °C and stirred for 3 h. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 257.0, 259.0 [M+H] + .

[0529] 1-(6-(trifluoromethyl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethyl-1-one: At 25 °C and N2, methyl 2,2-dihydro-2-(fluorosulfonyl)acetate (3.74 g, 19.45 mmol) and CuI (2.22 g, 11.67 mmol) were added to a solution of 1-(6-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethyl-1-one (1 g, 3.89 mmol) in DMF (10 mL). The reaction mixture was heated to 120 °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 (3 × 10 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 obtain the title compound. LCMS: m / z = 247.1 [M+H] + .

[0530] 6-(trifluoromethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine: At 25 °C, KOH (365 mg, 6.49 mmol) was added to a solution of 1-(6-(trifluoromethyl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-yl)ethyl-1-one (800 mg, 3.25 mmol) in MeOH (8 mL). The reaction mixture was heated to 60 °C and stirred for 3 h. The reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were 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 3:1) to give the title compound. LCMS: m / z = 205.1 [M+H] + .

[0531] Intermediate 14

[0532] 7-(trifluoromethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

[0533]

[0534] At 0 °C and N2, LiAlH4 (2.5 M in THF, 4.91 mL) was added to a solution of 7-(trifluoromethyl)-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one (1.34 g, 6.14 mmol) in 20 mL of THF. The reaction mixture was heated to 70 °C and stirred for 4 h. The reaction mixture was quenched by adding Na2SO4·10H2O. The mixture was filtered through a filter pad, and the filtrate was 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 = 204.9 [M+H] + .

[0535] Example 1

[0536] 2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (1)

[0537]

[0538] 4-Bromo-2-(cyclobutylthio)-7-fluoro-5-methyl-1H-indole: Iodocyclobutane (419 mg, 2.31 mmol) and K₂CO₃ (318 mg, 2.31 mmol) were added to a solution of 4-bromo-7-fluoro-5-methylindoline-2-thione (300 mg, 1.15 mmol) in DMF (10 mL) at 25 °C and N₂. The mixture was stirred at 50 °C for 3 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 residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the title compound. LCMS: m / z = 314.0, 316.0 [M+H] + .

[0539] 4-Bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-1H-indole: m-CPBA (258 mg, 1.27 mmol, 85% purity) was added to a solution of 4-bromo-2-(cyclobutylthio)-7-fluoro-5-methyl-1H-indole (200 mg, 0.63 mmol) in DCM (6 mL) at 0 °C and N2. The mixture was then stirred at 25 °C for 6 h. The reaction mixture was diluted with saturated aqueous Na2S2O3 solution (10 mL) and extracted with DCM (3 × 10 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 residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 346.0, 348.0 [M+H] + .

[0540] 2-(Cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole: 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentanane) (458 mg, 1.81 mmol), KOAc (212 mg, 2.17 mmol), and Pd(dppf)Cl2·DCM (589 mg, 0.07 mmol) were added to a solution of 4-bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-1H-indole (250 mg, 0.72 mmol) in DMSO (10 mL) at 25 °C and N2. The mixture was then stirred at 85 °C for 12 h. The reaction mixture was diluted with 20 mL of H₂O and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 394.2 [M+H] + .

[0541] 2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (1): 2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane (2 mL) and H2O (0.2 mL) were added to a solution of 3-bromo-1-methyl-1H-1,2,4-triazole (31 mg, 0.19 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) at 25 °C and N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H₂O (2 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 preparative HPLC (Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH₄HCO₃ aqueous solution, B: MeCN; B% in A: 15%–55%, 8 min) to give the title compound. 1H NMR (400MHz, CDCl3): δ8.96 (br s,1H),8.18(s,1H),7.58(t,J=2.4Hz,1H),7.05(d,J=11.6Hz,1H),4.05(s,3H),3.98-3.93(m,1 H),2.64(s,3H),2.63-2.54(m,2H),2.32-2.21(m,2H),2.06-1.96(m,2H).LCMS:m / z=349.1[M+H] + .

[0542] Example 2

[0543] 5-Methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2)

[0544]

[0545] 4-Bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: NaH (227 mg, 5.69 mmol, 60% in mineral oil) was added to a solution of 4-bromo-5-methyl-1H-pyrrolo[2,3-b]pyridine (1 g, 4.74 mmol) in DMF (20 mL) at 0 °C and N2. The mixture was stirred at 0 °C for 0.5 h. TsCl (1.35 g, 7.11 mmol) was added to the mixture at 0 °C and N2, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (60 mL) and extracted with EtOAc (3 × 20 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 = 1:1 to 0:1) to give the title compound. LCMS: m / z = 365.0, 367.0 [M+H] + .

[0546] Lithium 4-bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-sulfinate: LDA (4.11 mmol, 2.05 mL, 2 M in THF / n-heptane) was added to a solution of 4-bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1 g, 2.74 mmol) in THF (20 mL) at -78 °C and N2. The mixture was stirred at -78 °C for 0.5 h. SO2 was then bubbled into the mixture at -78 °C for 30 min. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 429.0, 431.0 [M+H] + .

[0547] 4-Bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl chloride: NCS (552 mg, 4.14 mmol) was added to a solution of lithium 4-bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-sulfinate (1.2 g, 2.76 mmol) in DCM (25 mL) at 20 °C and N2. The mixture was stirred at 20 °C for 1 h, diluted with H2O (80 mL), and extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 462.9, 464.9 [M+H] + .

[0548] 4-Bromo-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: At 0 °C and N2, a solution of 4-bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl chloride (1 g, 2.16 mmol) in DCM (20 mL) was mixed with TEA (436 mg, 4.31 mmol) and pyrrolidine (153 mg, 2.16 mmol) in DCM (2 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were 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 3:1) to give the title compound. LCMS: m / z = 498.0, 500.0 [M+H] + .

[0549] 5-Methyl-2-(pyrrolidone-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: At 20 °C and N2, 4-bromo-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (180 mg, 0.36 mmol) and A solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentane) (229 mg, 0.90 mmol) in 1,4-dioxane (5 mL) was supplemented with KOAc (142 mg, 1.44 mmol), PCy3 (10.13 mg, 0.04 mmol), and Pd2(dba)3 (16.54 mg, 0.02 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered through a diatomaceous earth filter and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc = 5:1) to give the title compound. LCMS: m / z = 546.1 [M+H] + .

[0550] 5-Methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: 5-methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl A solution of 1,4-bromo-1H-pyrrolo[2,3-b]pyridine (120 mg, 0.22 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (43 mg, 0.26 mmol) in H₂O (0.2 mL) and 1,4-dioxane (2 mL) was mixed with K₃PO₄ (140 mg, 0.66 mmol) and Pd(dtbpf)Cl₂ (14 mg, 0.02 mmol). The mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO₂, PE:EtOAc = 1:1) to give the title compound. LCMS: m / z = 501.1 [M+H] + .

[0551] 5-Methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2): NaOH (0.2 mL, 5 M in H2O) was added to a solution of 5-methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (20 mg, 0.04 mmol) in MeOH (1 mL) at 20 °C and N2. The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with H2O (3 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were washed with brine (1 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH₄HCO₃ aqueous solution, B: MeCN; B in A: 25%–55%, 8 min) to obtain the title compound. 1 H-NMR (400MHz, DMSO-d6): δ12.78(s,1H),8.72(s,1H),8.41(s,1H),7.50(s,1H),4.03(s,3H),3.29-3.28(m,4H),2.67(s,3H),1.66-1.60(m,4H). LCMS: m / z=347.1[M+H] + .

[0552] Example 3

[0553] 7-Fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-benzo[d]imidazolium(3)

[0554]

[0555] N-(5-Bromo-2-fluoro-4-methylphenyl)acetamide: Ac₂O (6.00 g, 58.81 mmol) and TEA (5.95 g, 58.81 mmol) were added to a mixture of 5-bromo-2-fluoro-4-methylaniline (10 g, 49.01 mmol) in DCM (100 mL) at 25 °C and N₂. The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with H₂O (30 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 246.1, 248.1 [M+H] + .

[0556] N-(3-Bromo-6-fluoro-4-methyl-2-nitrophenyl)acetamide: HNO3 (6.27 g, 97.53 mmol, 98% purity) was added dropwise to a mixture of N-(5-bromo-2-fluoro-4-methylphenyl)acetamide (8 g, 32.51 mmol) in concentrated H2SO4 (80 mL) at 0 °C and N2. The mixture was stirred at 0 °C for 1 h. The mixture was poured into ice water (100 mL), filtered, and the filter cake was dried under reduced pressure to give the title compound. LCMS: m / z = 291.0, 293.0 [M+H] + .

[0557] 3-Bromo-6-fluoro-4-methyl-2-nitroaniline: HCl (4 M, 20 mL) was added to a mixture of N-(3-bromo-6-fluoro-4-methyl-2-nitrophenyl)acetamide (5 g, 17.18 mmol) in MeOH (20 mL). The mixture was stirred at 80 °C for 6 h. The reaction was concentrated under reduced pressure to give the title compound. LCMS: m / z = 249.0, 251.0 [M+H] + .

[0558] 3-Bromo-6-fluoro-4-methylphenyl-1,2-diamine: Fe (4.48 g, 80.31 mmol) and NH4Cl (4.30 g, 80.31 mmol) were added to a mixture of 3-bromo-6-fluoro-4-methyl-2-nitroaniline (4 g, 16.06 mmol) in EtOH (50 mL) and H2O (5 mL) at 25 °C and N2. The mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 219.1, 221.1 [M+H] + .

[0559] 4-Bromo-7-fluoro-5-methyl-1H-benzo[d]imidazol-2-thiol: K2CO3 (2.52 g, 18.26 mmol) and CS2 (1.39 g, 18.26 mmol) were added to a mixture of 3-bromo-6-fluoro-4-methylphenyl-1,2-diamine (2 g, 9.13 mmol) in EtOH (20 mL) and H2O (1 mL). The reaction mixture was stirred at 80 °C for 5 h, then poured into water (10 mL), filtered, and the filter cake was dried under reduced pressure to give the title compound. LCMS: m / z = 261.0, 263.0 [M+H] + .

[0560] Perfluorophenyl 4-bromo-7-fluoro-5-methyl-1H-benzo[d]imidazolium-2-sulfonic acid: First, a mixture of HCl (0.57 mL, 2 M in H₂O) and DCM (3 mL) was stirred at -5 °C. NaOCl (0.82 mL, 1.55 M, 10% purity) was added dropwise to this solution, maintaining the temperature below 0 °C. The reaction mixture was cooled to -10 °C, and 4-bromo-7-fluoro-5-methyl-1H-benzo[d]imidazolium-2-thiol (100 mg, 0.38 mmol) was added and stirred at -10 °C for 20 min. At -10 °C, the mixture was quenched with a saturated aqueous solution of Na₂S₂O₃ until the yellow color disappeared. The mixture was then rapidly extracted with DCM (maintaining the temperature below 0 °C), and the organic layer was cooled to -30 °C. TEA (39 mg, 0.38 mmol) and 2,3,4,5,6-pentafluorophenol (70 mg, 0.38 mmol) were added, and the reaction mixture was heated to -8 °C and stirred for 1 h. The reaction mixture was then diluted with H₂O (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with saturated NaHCO₃ aqueous solution (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 474.9, 476.9 [M+H] + .

[0561] 4-Bromo-7-fluoro-5-methyl-2-(piperidin-1-ylsulfonyl)-1H-benzo[d]imidazole: Piperidine (93 mg, 1.09 mmol) was added to a mixture of perfluorophenyl 4-bromo-7-fluoro-5-methyl-1H-benzo[d]imidazole-2-sulfonic acid (100 mg, 0.22 mmol) in MeCN (10 mL) at 25 °C and N2. The mixture was stirred at 25 °C 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 (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 376.0, 378.0 [M+H] + .

[0562] 7-Fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-benzo[d]imidazole (3): Pd(t-Bu3P)2 (14 mg, 0.03 mmol) was added to a mixture of 4-bromo-7-fluoro-5-methyl-2-(piperidin-1-ylsulfonyl)-1H-benzo[d]imidazole (100 mg, 0.27 mmol) and 1-methyl-3-(tributyltinyl)-1H-1,2,4-triazole (198 mg, 0.53 mmol) in DMF (2 mL) at 20 °C and N2. The mixture was stirred at 120 °C for 8 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 preparative HPLC (Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: A: aqueous NH₄HCO₃, B: MeCN; B% in A: 40%–70%, 8 min) to obtain the title compound. 1 H NMR (400MHz, CDCl3): δ12.06 (s, 1H), 8.18 (s, 1H), 7.01 (d, J = 11.2Hz, 1H), 4.06 (s,3H),3.53-3.33(m,4H),2.89(s,3H),1.74-1.66(m,4H),1.62-1.51(m,2H). LCMS: m / z=379.1[M+H] + .

[0563] Example 4

[0564] 7-Fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (4)

[0565]

[0566] 7-Fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole: Pd(PPh3)4 (22 mg, 0.019 mmol) and tributyl(pyrimidin-2-yl)stanane (86 mg, 0.23 mmol) were added to a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole (100 mg, 0.19 mmol) in DMF (2 mL) at 20 °C and N2. The mixture was stirred at 110 °C for 6 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 to give the title compound. LCMS: m / z = 515.3 [M+H] + .

[0567] 7-Fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (4): NaOH (1 mL, 5 M) was added to a solution of 100 mg, 0.19 mmol of 7-fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole (2 mL) at 20 °C and N2. The mixture was stirred at 30 °C for 2 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 preparative HPLC (Waters Xbridge BEHC18 150×40mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN: B% in A: 20%-50%, 8min) to obtain the title compound. 1 H NMR (400MHz, CDCl3): δ8.94(d,J=5.2Hz,2H),8.86(brs,1H),7.32(t,J=4.8Hz,1H),7.17-7.13(m, 1H), 7.05 (d, J = 11.6Hz, 1H), 3.37-3.25 (t, J = 6.8Hz, 4H), 2.53 (s, 3H), 1.80 (td, J = 3.6, 6.8Hz, 4H). LCMS:m / z=361.1[M+H]+ .

[0568] Example 5

[0569] 4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (5)

[0570]

[0571] 4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (5): 3-bromo-1,5-dimethyl-1H-1,2,4-triazole (95 mg, 0.54 mmol), K2CO3 (75 mg, 0.54 mmol) and Pd(dtbpf)Cl2 (18 mg, 0.027 mmol) were added to a solution of 7-fluoro-5-methyl-2-pyrrolidine-1-ylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole (110 mg, 0.27 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) at 20 °C and N2. The mixture was stirred at 100 °C for 1 h. The reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters XbridgePrep OBD C18 150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 20%–50%, 8 min) to give the title compound. 1 H NMR (400MHz, CDCl3): δ9.10 (br s,1H),7.39(t,J=2.8Hz,1H),6.99(d,J=11.6Hz,1H),3.93(s,3H),3.38-3. 27(m,4H),2.59(s,3H),2.56(s,3H),1.78-1.77(m,2H),1.76-1.75(m,2H). LCMS: m / z=378.1[M+H] +

[0572] Example 6

[0573] 2-((6-azaspiro[2.5]oct-6-yl)sulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (6)

[0574]

[0575] 2-((6-azaspiro[2.5]oct-6-yl)sulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (6): TEA (154 mg, 1.52 mmol) and 6-azaspiro[2.5]octane·HCl (90 mg, 0.61 mmol) were added to a solution of 7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole-2-sulfonyl chloride (100 mg, 0.30 mmol) in DCM (3 mL) at 0 °C and N2. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 3 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 preparative HPLC (Phenomenex Luna C18 80×40mm×3μm; mobile phase: A: 20mM FA aqueous solution, B: MeCN; B% in A: 35%-70%, 8min) to obtain the title compound. 1 H NMR (400MHz, CDCl3): δ8.78(s,1H),8.19(s,1H),7.41(t,J=2.8Hz,1H),7.03(d,J=11.6Hz ,1H),4.05(s,3H),3.22(t,J=5.6Hz,4H),2.63(s,3H),1.49(t,J=5.2Hz,4H),0.26(s,4H). LCMS: m / z=404.1[M+H] + .

[0576] The following compounds are or can be prepared by a procedure similar to that described herein.

[0577]

[0578]

[0579]

[0580]

[0581]

[0582] Example 49

[0583] 4-(6-Chlorpyridazin-3-yl)-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (50)

[0584]

[0585] 4-Bromo-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole: NaOH (5M in H2O, 9.70 mL) was added to a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole (1 g, 1.94 mmol) in MeOH (5 mL) and THF (5 mL). The mixture was stirred at 60 °C for 2 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 residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 361.0, 363.0 [M+H] + .

[0586] 7-Fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1-toluenesulfonyl-1H-indole: 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentanane) (1.58 g, 6.23 mmol), KOAc (733 mg, 7.47 mmol), and Pd(dppf)Cl2.CH2Cl2 (203 mg, 0.2 mmol) were added to a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (900 mg, 2.49 mmol) in DMSO (20 mL) at 20 °C and N2. The mixture was stirred at 105 °C for 12 h. The reaction mixture was diluted with 10 mL of H₂O and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 409.1 [M + H] + .

[0587] 4-(6-Chloropyridazin-3-yl)-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (50): 3,6-Dichloropyridazine (72 mg, 0.4 mmol), K₂CO₃ (101 mg, 0.7 mmol), and Pd(dtbpf)Cl₂ (15 mg, 0.02 mmol) were added to a solution of 7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole (100 mg, 0.2 mmol) in 1,4-dioxane (1 mL) and H₂O (0.1 mL) at 20 °C and N₂. The mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C 18 75×30mm×3μm; mobile phase: A: 43mM FA aqueous solution, B: MeCN; B% in A: 15%-55%, duration 8 min) to obtain the title compound. 1 H NMR (400MHz, CDCl3): δ9.03 (br s,1H),7.70-7.58(m,2H),7.08(d,J=11.6Hz,1H),6.79-6.77(m,1H),3.34-3.27(m,4H),2.40(s,3H),1.84-1.77(m,4H). LCMS: m / z=395.0[M+H] +

[0588] The following compounds are or can be prepared by a procedure similar to that described herein.

[0589]

[0590] Example 55

[0591] 2-(azacyclobutane-1-ylsulfonyl)-7-fluoro-5-methyl-4-(pyrimidin-2-yl)-1H-indole (60)

[0592]

[0593] 2-(azacyclobutane-1-ylsulfonyl)-7-fluoro-5-methyl-4-(pyrimidin-2-yl)-1H-indole (60): Tributyl(pyrimidin-2-yl)stanane (53 mg, 0.14 mmol) and Pd(t-Bu3P)2 (6 mg, 0.01 mmol) were added to a solution of 2-(azacyclobutane-1-ylsulfonyl)-4-bromo-7-fluoro-5-methyl-1H-indole (60 mg, 0.11 mmol) in DMF (1.5 mL) at 25 °C and N2. The mixture was stirred at 110 °C for 5 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 residue was purified by preparative HPLC (Phenomenex C 18 80×40mm×3μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: B%: 20%-50%, 8min) to obtain the title compound. 1 H NMR (400MHz, CDCl3): δ8.95(d,J=4.8Hz,2H),7.33(t,J=5.2Hz,1H),7.24(t,J=3.2Hz ,1H),7.09(d,J=11.6Hz,1H),3.87(t,J=7.6Hz,4H),2.55(s,3H),2.14-2.05(m,2H). LCMS:m / z=347.0[M+H] + .

[0594] The following compounds are or can be prepared by a procedure similar to that described herein.

[0595]

[0596] Example 62

[0597] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole

[0598]

[0599] 4-(3-(benzyloxy)cyclobutyl)-7-fluoro-5-methyl-1H-indole: At 25 °C and N2, K2CO3 (848 mg, 6.14 mmol) and Pd(dppf)Cl2 (225 mg, 0.31 mmol) were added to a solution of 4-bromo-7-fluoro-5-methyl-1H-indole (700 mg, 3.07 mmol) and potassium (3-(benzyloxy)cyclobutyl)trifluoroborate (1.23 g, 4.60 mmol) in toluene (20 mL) and H2O (3 mL). The reaction mixture was heated to 120 °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 = 10:1 to 5:1) to give the title compound. LCMS: m / z = 310.2 [M+H] + .

[0600] 4-(3-(benzyloxy)cyclobutyl)-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole: NaH (34 mg, 0.85 mmol, 60% in mineral oil) was added to a mixture of 4-(3-(benzyloxy)cyclobutyl)-7-fluoro-5-methyl-1H-indole (200 mg, 0.65 mmol) in DMF (5 mL) at 0 °C and N2, and the reaction mixture was stirred for 0.5 h. p-TsCl (185 mg, 0.97 mmol) in DMF (1 mL) was added to the reaction mixture, and the mixture was heated to 25 °C and stirred for 2 h. 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 = 10:1 to 3:1) to give the title compound. LCMS: m / z = 464.2 [M+H] + .

[0601] 3-(7-fluoro-5-methyl-1-toluenesulfonyl-1H-indol-4-yl)cyclobut-1-ol: BCl3 (3.37 mL, 1 M in toluene) was added to a solution of 4-(3-(benzyloxy)cyclobutyl)-7-fluoro-5-methyl-1-toluenesulfonyl-1H-indol (520 mg, 1.12 mmol) in DCM (15 mL) at 0 °C and N2, and the mixture was stirred for 0.5 h. The reaction mixture was adjusted to pH 7–8 by adding a saturated aqueous solution of NaHCO3 at 0 °C, and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 374.2 [M+H] + .

[0602] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-1-toluenesulfonyl-1H-indole: NaH (80 mg, 2.01 mmol, 60% in mineral oil) was added to a mixture of 3-(7-fluoro-5-methyl-1-toluenesulfonyl-1H-indole-4-yl)cyclobut-1-ol (500 mg, 1.34 mmol) in DMF (15 mL) at 0 °C and N2, and the reaction mixture was stirred for 0.5 h. MeI (380 mg, 2.68 mmol) was added to the mixture at 0 °C, and the reaction mixture was heated to 25 °C and stirred for 12 h. 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 = 5:1 to 1:1) to obtain the title compound. LCMS: m / z = 388.1 [M+H] + .

[0603] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-1-toluenesulfonyl-1H-indole-2-sulfonyl chloride: LDA (0.31 mL, 2 M in THF / n-heptane) was added to a mixture of 7-fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-1-toluenesulfonyl-1H-indole (200 mg, 0.52 mmol) in THF (5 mL) at -78 °C and N2, and the reaction mixture was stirred for 0.5 h. At -50 °C, the reaction mixture was poured into a solution of thioyl chloride (418 mg, 3.10 mmol) in THF (3 mL), and the mixture was stirred for 0.5 h. The reaction mixture was quenched by adding ice-H2O (10 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.

[0604] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole: At 0 °C, pyridine (163 mg, 2.06 mmol) and pyrrolidine (44 mg, 0.62 mmol) were added to a solution of 7-fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-1-toluenesulfonyl-1H-indole-2-sulfonyl chloride (200 mg, 0.41 mmol) in DCM (5 mL). The reaction mixture was heated to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the title compound. LCMS: m / z = 521.0 [M+H] + .

[0605] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole: At 20 °C, 4 M NaOH (1 mL) was added to a mixture of 60 mg, 0.12 mmol, of 7-fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole in THF (1 mL) and MeOH (1 mL). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture 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 HPLC (Waters Xbridge Prep BEH C18 100×30mm×5μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 33%-61%, time 8 min) to obtain the title compound. LCMS: m / z = 367.0 [M+H] + .

[0606] Example 63

[0607] 4-(trans-3-(difluoromethyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole

[0608]

[0609] DAST (27 mg, 0.16 mmol) was added to a mixture of trans-3-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carboxaldehyde (20 mg, 0.05 mmol) in DCM (5 mL) at 0 °C and N2, and the reaction mixture was stirred for 0.5 h. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (5 mL) and extracted with DCM (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 preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in H2O, B: MeCN; B% in A: 35%–65%, duration 8.0 min) to give the title compound. LCMS:m / z:387.0[M+H] + .

[0610] Example 64

[0611] 4-(cis-3-(difluoromethyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indole

[0612]

[0613] DAST (26.5 mg, 0.16 mmol) was added to a mixture of cis-3-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carboxaldehyde (20 mg, 0.05 mmol) in DCM (5 mL) at 0 °C and N2, and the mixture was stirred for 0.5 h. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (5 mL) and extracted with DCM (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 preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in H2O, B: MeCN; B% in A: 35%–65%, duration 8.0 min) to give the title compound. LCMS:m / z:387.0[M+H] + .

[0614] Example 65

[0615] 2-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole

[0616]

[0617] 2-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole-4-carbonyl)hydrazide-1-carboxylate tert-butyl ester: N-aminocarbamate tert-butyl ester (94 mg, 0.71 mmol) and AlMe3 (2 M in toluene, 0.2 mL) were added to a solution of methyl 7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole-4-carboxylate (50 mg, 0.10 mmol) in DCE (2 mL) at 20 °C and N2. The reaction mixture was heated to 60 °C and stirred for 16 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 = 2:1) to obtain the title compound. LCMS: m / z = 595.3 [M+H] + .

[0618] 7-Fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole-4-carbonylhydrazine hydrochloride: A solution of tert-butyl 2-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole-4-carbonyl)hydrazine-1-carboxylic acid (200 mg, 0.37 mmol) 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 = 495.1 [M+H] + .

[0619] 2-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indol-4-yl)-1,3,4-oxadiazole: p-TsOH (2 mg, 0.01 mol) was added to a solution of 7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indol-4-carbonylhydrazine hydrochloride (100 mg, 0.20 mmol) in trimethyl orthoformate (2 mL) at 20 °C. The reaction mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 505.1 [M+H] +

[0620] 2-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole: At 20 °C, 0.5 mL of 5 M NaOH was added to a solution of 2-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indol-4-yl)-1,3,4-oxadiazole (200 mg, 0.12 mmol) in MeOH (1 mL) and THF (1 mL). The reaction mixture was heated to 30 °C and stirred for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH 80 × 40 mm × 3 μm; mobile phase: A: 10 mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 15%–45%, 8.0 min) to give the title compound. LCMS: m / z = 351.1 [M+H] + .

[0621] Example 66

[0622] 2-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole

[0623]

[0624] Methyl 7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole-4-carboxylate: Pd(OAc)₂ (44 mg, 0.19 mmol), dppf (108 mg, 0.19 mmol), and TEA (589 mg, 5.82 mmol) were added to a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole (1 g, 1.94 mmol) in DMF (10 mL) and MeOH (10 mL). The reaction mixture was degassed under vacuum and purged several times with CO. The reaction mixture was heated to 80 °C under CO (50 psi) and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with H₂O (30 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 = 3:1) to give the title compound. LCMS: m / z = 495.3 [M+H] + .

[0625] N'-Acetyl-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole-4-carbamate: Acetylhydrazine (52 mg, 0.71 mmol) and AlMe3 (2 M in toluene, 0.15 mL) were added to a solution of methyl 7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole-4-carboxylate (50 mg, 0.10 mmol) in toluene (2 mL) at 20 °C and N2. The reaction mixture was heated to 60 °C and stirred for 6 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 preparative TLC (SiO2, EtOAc) to give the title compound. LCMS: m / z = 537.2 [M+H] + .

[0626] 2-(7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole: p-TsCl (32 mg, 0.17 mmol) and Cs₂CO₃ (146 mg, 0.45 mmol) were added to a solution of N'-acetyl-7-fluoro-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indol-4-carbazide (60 mg, 0.11 mmol) in MeCN (6 mL) at 20 °C and N₂. The reaction mixture was heated to 60 °C and stirred for 6 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 to give the title compound. LCMS: m / z = 519.0 [M+H] + .

[0627] 2-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole: At 20 °C, NaOH (116 mg, 2.89 mmol) was added to a solution of 2-(7-fluoro-5-methyl-2-(pyrrolidone-1-ylsulfonyl)-1-toluenesulfonyl-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole (60 mg, 0.12 mmol) in MeOH (3 mL). The reaction mixture was heated to 30 °C and stirred for 3 h. 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 100×30mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 25%-55%, 8.0 min) to obtain the title compound. LCMS: m / z = 365.1 [M+H] + .

[0628] Example 67

[0629] 5-Methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridine

[0630]

[0631] 4-Bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine: NaH (417 mg, 10.42 mmol, 60% in mineral oil) was added to a solution of 4-bromo-5-methyl-1H-pyrrolo[2,3-c]pyridine (2 g, 9.48 mmol) in DMF (20 mL) at 0 °C and N2, and the reaction mixture was stirred for 1 h. p-TsCl (2.71 g, 14.21 mmol) was added fractionally to the mixture, and the mixture was heated to 20 °C and stirred for 2 h. The reaction mixture was diluted with a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was wet-milled with MTBE (20 mL), and the solid was filtered to give the title compound. LCMS: m / z = 364.9, 366.9 [M+H] + .

[0632] 4-Bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine-2-sulfonyl chloride: LDA (3.56 mmol, 1.78 mL, 2 M in THF / n-heptane) was added to a solution of 4-bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine (1 g, 2.74 mmol) in THF (10 mL) at -78 °C and N2, and the reaction mixture was stirred for 0.5 h. The mixture was then added to a solution of thioyl chloride (2.40 g, 17.80 mmol) in THF (10 mL) at -78 °C, and the reaction mixture was stirred for 10 min. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 464.8 [M+H] + .

[0633] 4-Bromo-5-methyl-2-(piperidin-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine: At 0 °C and N2, pyridine (1.28 g, 16.17 mmol) and piperidine (496 mg, 5.82 mmol) were added to a solution of 4-bromo-5-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine-2-sulfonyl chloride (1.5 g, 3.23 mmol) in DCM (10 mL). The reaction mixture was heated to 20 °C and stirred for 10 min. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:THF = 3:1 to 0:1) to give the title compound. LCMS: m / z = 511.9, 513.9 [M+H] + .

[0634] 5-Methyl-2-(piperidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine: 3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)aniline (150 mg, 0.30 mmol) was reacted with 1,4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)aniline at 20 °C and N2. 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentane) (186 mg, 0.73 mmol), KOAc (115 mg, 1.17 mmol), PCy3 (8 mg, 0.03 mmol), and Pd2(dba)3 (13 mg, 0.02 mmol) were added to a solution of dioxane (5 mL). The reaction mixture was heated to 110 °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 (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 478.0 [M–C6H 10 +H] + .

[0635] 5-Methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine: at 20 °C and N2, to 5-methyl-2-(piperidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-pyrrolo A solution of [2,3-c]pyridine (250 mg, 0.45 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) was supplemented with 3-bromo-1-methyl-1H-1,2,4-triazole (109 mg, 0.67 mmol), K₃PO₄ (237 mg, 1.12 mmol), Xphos (43 mg, 0.09 mmol), and Catacxium A Pd G₃ (33 mg, 0.05 mmol). The reaction mixture was heated to 90 °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 (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO₂, PE:(EtOAc:EtOH = 3:1) = 1:1) to give the title compound. LCMS: m / z = 515.0 [M+H] + .

[0636] 5-Methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridine: At 20 °C and N2, 4 M NaOH (1 mL) and MeOH (1 mL) were added to a solution of 5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine (80 mg, 0.15 mmol) in THF (1 mL). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was diluted with H2O (6 mL) and adjusted to pH 6 by adding 4 M HCl. The aqueous phase was 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 preparative HPLC (Waters Xbridge BEH C18 100×30mm×5μm; mobile phase: A: 10mM NH4HCO3 aqueous solution; B: MeCN; B% in A: 12%-40%; duration: 8 min) to obtain the title compound. LCMS: m / z = 361.0 [M+H] + .

[0637] Example 68

[0638] 7-Fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole

[0639]

[0640] 5-Bromo-2-fluoro-4-(trifluoromethyl)aniline: SelectFluor was added to a solution of 25 g (104.16 mmol) of 3-bromo-4-(trifluoromethyl)aniline in 300 mL of MeCN at 20 °C and N2. TM (44.28 g, 124.99 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (1 L) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to give the title compound. LCMS: m / z = 258.0, 260.0 [M+H] + .

[0641] 3-Bromo-6-fluoro-2-iodo-4-(trifluoromethyl)aniline: NIS (15.54 g, 69.07 mmol) was added to a solution of 5-bromo-2-fluoro-4-(trifluoromethyl)aniline (8.10 g, 31.39 mmol) in AcOH (100 mL) at 25 °C and N2, and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (3 × 80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to give the title compound. LCMS: m / z = 381.8, 383.8 [MH] - .

[0642] 3-Bromo-6-fluoro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline: TEA (25.57 g, 252.67 mmol), CuI (962.40 mg, 5.05 mmol), and Pd(PPh3)2Cl2 (1.77 g, 2.53 mmol) were added to a solution of 3-bromo-6-fluoro-2-iodo-4-(trifluoromethyl)aniline (9.7 g, 25.27 mmol) and trimethylsilyl ethynyl (7.44 g, 75.80 mmol) in DMF (100 mL) at 20 °C and N2. The reaction mixture was heated at 60 °C for 12 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 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 10:1) to give the title compound. LCMS: m / z = 354.0, 356.0 [M+H] +

[0643] 4-Bromo-7-fluoro-5-(trifluoromethyl)-1H-indole: t-BuOK (4.91 g, 43.76 mmol) was added to a solution of 3-bromo-6-fluoro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (6.2 g, 17.50 mmol) in NMP (60 mL) at 20 °C and N2, and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 × 60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to give the title compound. LCMS: m / z = 279.9, 281.9 [MH] - .

[0644] 4-Bromo-7-fluoro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole: NaH (561 mg, 14.04 mmol, 60% in mineral oil) was added to a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (3.30 g, 11.70 mmol) in DMF (35 mL) at 0 °C and N2, and the reaction mixture was stirred for 0.5 h. p-TsCl (3.35 g, 17.55 mmol) was added, and the mixture was heated to 20 °C and stirred for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 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 10:1) to give the crude product. The material was wet-milled with PE (10 mL) and the solid was collected to obtain the title compound.

[0645] 4-Bromo-7-fluoro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: LDA (2.79 mmol, 1.38 mL, 2 M in THF / n-heptane) was added to a mixture of 4-bromo-7-fluoro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole (1 g, 2.29 mmol) in THF (16 mL) at -78 °C and N2, and the reaction mixture was stirred for 0.5 h. The mixture was then added to a solution of thioyl chloride (1.86 g, 13.75 mmol) in THF (10 mL) at -50 °C, and the reaction mixture was heated to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with saturated NH4Cl aqueous solution (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0646] 4-Bromo-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole: At 0 °C and N2, pyridine (888 mg, 11.22 mmol) and pyrrolidine (239 mg, 3.37 mmol) were added to a solution of 4-bromo-7-fluoro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (1.2 g, 2.24 mmol) in DCM (12 mL). The reaction mixture was heated to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with 1 M HCl (2 × 10 mL) and 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 = 20:1 to 10:1) to obtain the title compound.

[0647] 4-Bromo-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: 4M NaOH (1.5 mL) was added to a solution of 4-bromo-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole (220 mg, 0.39 mmol) in THF (1.5 mL) and MeOH (1.5 mL) at 20 °C and N₂. The reaction mixture was heated to 30 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (6 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (6 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was wet-milled with PE (5 mL), and the solid was collected to give the title compound.

[0648] 7-Fluoro-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole: At 20 °C and N2, KOAc (113 mg, 1.16 mmol) and Pd(dppf)Cl2 (28 mg, 0.04 mmol) were added to a solution of 4-bromo-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole (160 mg, 0.39 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentanane) (196 mg, 0.77 mmol) in DMSO (4 mL). The reaction 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 = 3:1) to give the title compound. LCMS: m / z = 463.1 [M + H] + .

[0649] 7-Fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: At 20 °C and N2, K2CO3 (30 mg, 0.11 mmol) and Pd(dtbpf)Cl2 (7 mg, 0.01 mmol) were added to a solution of 7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole (50 mg, 0.11 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (35 mg, 0.22 mmol) in 1,4-dioxane (1.6 mL) and H2O (0.4 mL). The reaction mixture was heated to 100°C and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B in A: 30%-60%, time 8.0 min) to give the title compound. LCMS: m / z = 418.1 [M+H] + .

[0650] Example 69

[0651] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole

[0652]

[0653] 4-Chloro-5-iodo-1-toluenesulfonyl-1H-indole: NaH (1.38 g, 34.60 mmol, 60% in mineral oil) was added to a solution of 4-chloro-5-iodo-1H-indole (8 g, 28.83 mmol) in DMF (100 mL) at 0 °C, and the reaction mixture was stirred for 0.5 h. p-TsCl (8.24 g, 43.24 mmol) was added to the mixture at 0 °C, and the reaction mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was then poured into a saturated aqueous solution of NH4Cl (100 mL) at 0 °C, and the mixture was stirred for 10 min. The solid was collected by filtration, washed with PE, and dried under reduced pressure to give the title compound. LCMS: m / z = 431.9 [M+H] + .

[0654] 4-Chloro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole: 2,2-Difluoro-2-fluorosulfonyl-methyl acetate (14.46 g, 75.29 mmol) and CuI (8.60 g, 45.17 mmol) were added to a solution of 4-chloro-5-iodo-1-toluenesulfonyl-1H-indole (6.5 g, 15.06 mmol) in DMF (70 mL) at 20 °C and N2. The reaction mixture was heated to 120 °C and stirred for 12 h. The reaction mixture was filtered, and the filtrate was diluted with H₂O (50 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:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 374.0 [M+H] + .

[0655] 4-Chloro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: LDA (6.42 mmol, 3.21 mL, 2 M in THF / n-heptane) was added to a solution of 4-chloro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole (2 g, 5.35 mmol) in THF (20 mL) at -78 °C and N2, and the reaction mixture was stirred for 0.5 h. The above mixture was then added to a solution of thioyl chloride (4.33 g, 32.10 mmol) in THF (10 mL) at -78 °C and N2, and the combined mixture was stirred for 10 min. The reaction mixture was poured into ice-water (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.

[0656] 4-Chloro-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: At 0 °C, pyridine (2.12 g, 26.78 mmol) and pyrrolidine (1.90 g, 26.78 mmol) were added to a solution of 4-chloro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (2.53 g, 5.36 mmol) in DCM (20 mL), and the reaction mixture was stirred for 0.5 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO₂, PE:EtOAc = 10:1) to give the title compound. LCMS: m / z = 353.0 [M+H] + .

[0657] 2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole: 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentanane) (324 mg, 1.28 mmol), KOAc (83 mg, 0.85 mmol), and P(t-Bu)3Pd G4 (25 mg, 0.04 mmol) were added to a solution of 4-chloro-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole (150 mg, 0.43 mmol) in cyclopentyl methyl ether (2 mL) at 25 °C and N2. The reaction mixture was heated to 80 °C and stirred for 5 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 preparative TLC (SiO₂, PE:EtOAc = 2:1) to give the title compound. LCMS: m / z = 443.10 [MH] - .

[0658] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: 3-bromo-1-methyl-1H-1,2,4-triazole (66 mg, 0.40 mmol), K3PO4 (86 mg, 0.41 mmol), and Pd(dtbpf)Cl2 (13 mg, 0.02 mmol) were added to a solution of 2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole (90 mg, 0.20 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) at 25 °C and N2. The reaction mixture was heated to 80 °C and stirred for 6 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 preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH₄HCO₃ aqueous solution, B: MeCN; B% in A: 20%–50%, duration 8 min) to give the title compound. LCMS: m / z = 400.0 [M + H] + .

[0659] Example 70

[0660] 5-Chloro-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-1H-

[0661] Indole

[0662]

[0663] 3-Bromo-4-chloro-6-fluoro-2-iodoaniline: NIS (36 g, 160 mmol) was added to a solution of 5-bromo-4-chloro-2-fluoroaniline (24 g, 106 mmol) in AcOH (250 mL) at 0 °C and N2. The reaction mixture was heated to 25 °C and stirred for 2 h. The reaction mixture was diluted with H2O (1 L) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 351.8 [M+H] +

[0664] 3-Bromo-4-chloro-6-fluoro-2-((trimethylsilyl)ethynyl)aniline: Trimethylsilylacetylene (8.83 g, 89 mmol), TEA (60 g, 599.40 mmol), CuI (2 g, 11.99 mmol), and Pd(PPh3)2Cl2 (4.2 g, 5.99 mmol) were added to a solution of 3-bromo-4-chloro-6-fluoro-2-iodoaniline (21 g, 59.94 mmol) in DMF (400 mL) at 25 °C and N2. The reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was diluted with H2O (1 L) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 100 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 5:1) to give the title compound. LCMS: m / z = 321.9 [M+H] + .

[0665] 4-Bromo-5-chloro-7-fluoro-1H-indole: t-BuOK (7 g, 70 mmol) was added to a solution of 3-bromo-4-chloro-6-fluoro-2-((trimethylsilyl)ethynyl)aniline (9 g, 28 mmol) in NMP (250 mL) at 25 °C and N2, and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (5 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 249.9 [M+H] +

[0666] 4-Bromo-5-chloro-7-fluoro-1-toluenesulfonyl-1H-indole: NaH (637 mg, 15 mmol, 60% in mineral oil) was added to a solution of 4-bromo-5-chloro-7-fluoro-1H-indole (3.3 g, 13 mmol) in DMF (35 mL) at 0 °C and N2, and the reaction mixture was stirred for 0.5 h. p-TsCl (3.8 g, 19.92 mmol) was added fractionally to the mixture at 0 °C, and the reaction mixture was heated to 20 °C and stirred for 1 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the crude product. This substance was further wet-milled with MTBE (30 mL) and the solid was collected to give the title compound. LCMS: m / z = 403.9 [M+H] +

[0667] 4-Bromo-5-chloro-7-fluoro-1-toluenesulfonyl-1H-indole-2-sulfonyl chloride: LDA (2.98 mL, 2 M in THF / n-heptane) was added to a mixture of 4-bromo-5-chloro-7-fluoro-1-toluenesulfonyl-1H-indole (2 g, 4.97 mmol) in THF (40 mL) at -78 °C and N2, and the reaction mixture was stirred for 0.5 h. The reaction mixture was then added to a solution of thioyl chloride (4.02 g, 29.80 mmol) in THF (10 mL) at -78 °C, and the mixture was stirred for 0.5 h. The reaction mixture was poured into ice-H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 523.8 [M + Na] + .

[0668] 4-Bromo-5-chloro-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole: At 0 °C, pyridine (1.58 g, 19.95 mmol) and pyrrolidine (425 mg, 5.99 mmol) were added to a solution of 4-bromo-5-chloro-7-fluoro-1-toluenesulfonyl-1H-indole-2-sulfonyl chloride (2 g, 3.99 mmol) in DCM (25 mL). The reaction mixture was heated to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the title compound. LCMS: m / z = 536.8 [M+H] +

[0669] 4-Bromo-5-chloro-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-1H-indole: At 20 °C, 4 M NaOH (1.92 mL) was added to a mixture of 200 mg (0.37 mmol) of 4-bromo-5-chloro-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-indole in THF (2 mL) and MeOH (2 mL). The reaction mixture was heated to 60 °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 (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 382.9 [M+H] +

[0670] 5-Chloro-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indole: At 20 °C and N2, KOAc (77 mg, 0.26 mmol) and Pd(dppf)Cl2 (19 mg, 0.02 mmol) were added to a solution of 4-bromo-5-chloro-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-1H-indole (100 mg, 0.26 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentanane) (133 mg, 0.52 mmol) in DMSO (2 mL). The reaction 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 (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 = 10:1 to 5:1) to give the title compound. LCMS: m / z = 429.1 [M + H] + .

[0671] 5-Chloro-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-1H-indole: 3-bromo-1-methyl-1H-1,2,4-triazole (34 mg, 0.21 mmol), K3PO4 (44.56 mg, 0.2 mmol), and Pd(dtbpf)Cl2 (4.56 mg, 0.07 mmol) were added to a solution of 5-chloro-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole (30 mg, 0.06 mmol) in EtOH (1 mL) and H2O (0.1 mL) at 20 °C and N2. The reaction mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30mm×5μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 12%-42%, duration 8.0 min) to give the title compound. LCMS: m / z = 384.0 [M+H] +

[0672] Example 71

[0673] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine

[0674]

[0675] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentanane) (28.8 g, 113.34 mmol), KOAc (11.12 g, 113.34 mmol), and P(Cy)3PdG3 (1.67 g, 2.27 mmol) were added to a solution of 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (5 g, 22.67 mmol) in 1,4-dioxane (200 mL) at 20 °C and N2. The reaction mixture was heated to 120 °C and stirred for 16 h. 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 = 1:0 to 3:1) to give the title compound. LCMS: m / z = 313.1 [M+H] +

[0676] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: At 20 °C and N2, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (8 g, 25.63 mmol) in 1,4-dioxane (200 mL) and H2O (20 mL) was prepared by adding 3-bromo-1-methyl-1H-1,2,4-triazole (12.46 g, 76.90 mmol), K3PO4 (16.32 g, 76.90 mmol), and... A Pd-G3 (1.87 g, 2.56 mmol). The reaction mixture was heated to 100 °C and stirred for 16 h. 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 = 268.1 [M+H] + .

[0677] 3,3-Dibromo-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one: Pyridium tribromide (7.18 g, 22.45 mmol) was added to a solution of 4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 3.74 mmol) in 2-methylprop-2-ol (20 mL) and H2O (7 mL) at 20 °C and N2. The reaction mixture was heated to 35 °C and stirred for 16 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 (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 441.8 [M+H] + .

[0678] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one: Zn (2.37 g, 36.28 mmol) was added to a solution of 3,3-dibromo-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.6 g, 3.63 mmol) in THF (15 mL) and saturated NH4Cl (15 mL) at 20 °C and N2, and the reaction mixture was stirred for 2 h. The reaction mixture was filtered through a filter pad, and the filtrate was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 284.1 [M + H] +

[0679] 2-Chloro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: A solution of 4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.2 g, 4.24 mmol) in POCl3 (6 mL) was heated to 110 °C and stirred for 4 h. The reaction mixture was cooled to 0 °C, adjusted to pH 7 by adding saturated aqueous NaHCO3 solution, and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 302.0 [M+H] +

[0680] 2-((4-methoxybenzyl)thio)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: At 20 °C, Cs₂CO₃ (2.92 g, 8.95 mmol) and (4-methoxyphenyl)methanethiol (4.60 g, 29.84 mmol) were added to a solution of 2-chloro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (900 mg, 2.98 mmol) in THF (50 mL). The reaction mixture was heated to 50 °C and stirred for 16 h. 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 5:1) and further purified by preparative HPLC (Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: A: 10 mM 0.2% FA aqueous solution, B: MeCN; B% in A: 35%–65%, 8.0 min) to give the title compound. LCMS: m / z = 420.0 [M+H] +

[0681] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl: At 0 °C and N2, NCS (64 mg, 0.48 mmol) was added to a solution of 2-((4-methoxybenzyl)thio)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.24 mmol) in AcOH (3 mL) and H2O (1 mL), and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 365.9 [M+H] + .

[0682] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: TEA (277 mg, 2.73 mmol) and pyrrolidine (97 mg, 1.37 mmol) were added to a solution of 4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl (200 mg, 0.55 mmol) in DCM (2 mL) at 20 °C and N2, and the reaction mixture was stirred for 2 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 preparative HPLC (Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 15%-45%, time: 8.0 min) to obtain the title compound. LCMS: m / z = 401.1 [M+H] +

[0683] Example 72

[0684] 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0685]

[0686] 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: 5-methyl-2-(pyrrolidine-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H- A solution of pyrrolo[2,3-b]pyridine (100 mg, 0.18 mmol) and 3-bromo-1-(cyclopropylmethyl)-1H-1,2,4-triazole (148 mg, 0.73 mmol) in 1,4-dioxane (2 mL) and H₂O (0.4 mL) was supplemented with K₃PO₄ (117 mg, 0.55 mmol) and Pd(dtbpf)Cl₂ (12 mg, 0.02 mmol). The reaction mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (SiO₂, PE:EtOAc = 0:1) to give the title compound. LCMS: m / z = 541.2 [M+H] +

[0687] 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine: At 25 °C, 4 M NaOH (2 mL) was added to a solution of 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidine-1-ylsulfonyl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.09 mmol) in MeOH (2 mL) and THF (2 mL). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture 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 = 0:1) to obtain the title compound. LCMS: m / z = 387.0 [M+H] +

[0688] Example 73

[0689] 2-(cyclobutylsulfonyl)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine

[0690]

[0691] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-thiol: A solution of 2-((4-methoxybenzyl)thio)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.12 mmol) in TFA (2 mL) was heated to 80 °C and stirred for 8 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 300.1 [M+H] +

[0692] 2-(cyclobutylthio)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: At 20 °C and N2, K2CO3 (46 mg, 0.33 mmol) and bromocyclobutane (45 mg, 0.33 mmol) were added to a solution of 4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-thiol (50 mg, 0.17 mmol) in DMF (2 mL). The reaction mixture was heated to 50 °C and stirred for 5 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 (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex Luna C18 100×40mm×3μm; mobile phase: A: 0.2% FA aqueous solution, B: MeCN; B% in A: 30%-60%, time: 8.0 min) to obtain the title compound. LCMS: m / z = 354.0 [M+H] +

[0693] 2-(cyclobutylsulfonyl)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: At 0 °C and N2, m-CPBA (7 mg, 0.04 mmol, 85% w / w) was added to a solution of 2-(cyclobutylthio)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (5 mg, 0.01 mmol) in DCM (0.5 mL). The reaction mixture was heated to 20 °C and stirred for 1 h. The reaction mixture was quenched by adding saturated Na2S2O3 aqueous solution (1 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 30%-60%, time 8.0 min) to obtain the title compound. LCMS: m / z = 386.1 [M+H] +

[0694] Example 74

[0695] 7-Fluoro-4-(1-Methyl-1H-1,2,4-triazol-3-yl)-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1H-indole

[0696]

[0697] 4-Bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole: NaH (150 mg, 3.75 mmol, 60% in mineral oil) was added to a solution of 4-bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1H-indole (1 g, 2.50 mmol) in DMF (15 mL) at 0 °C and N2, and the reaction mixture was stirred for 0.5 h. SEMCl (833 mg, 5.00 mmol) was added to the mixture at 0 °C, and the reaction mixture was heated to 25 °C and stirred for 1 h. The reaction mixture was diluted with saturated NH4Cl aqueous solution (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 = 10:1 to 3:1) to give the title compound. LCMS: m / z = 552.0, 554.0 [M + Na] +

[0698] 4-Bromo-7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole: At -78 °C and N2, LDA (1.2 mmol, 2 M in THF / n-heptane) was added to a solution of 4-bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (450 mg, 0.85 mmol) in THF (10 mL), and the reaction mixture was stirred for 0.5 h. A solution of MeI (361 mg, 2.55 mmol) in THF (2 mL) was added to the mixture at -78 °C, and the reaction mixture was stirred for 1 h. 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 to obtain the title compound. LCMS: m / z = 565.9, 568.0 [M + Na] + .

[0699] 4-Bromo-7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1H-indole: At 25 °C, TFA (1 mL) was added to a solution of 500 mg (0.92 mmol) of 4-bromo-7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (2 mL) in DCM, and the reaction mixture was stirred for 1 h. The pH of the reaction mixture was adjusted to 7–8 by adding saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 43%-73%, time 8 min) to obtain the title compound. LCMS: m / z = 412.0, 414.0 [MH] - .

[0700] 7-Fluoro-2-((1-methylcyclobutyl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole: At 25 °C and N2, KOAc (64 mg, 0.65 mmol) and Pd(dppf)Cl2 (16 mg, 0.02 mmol) were added to a solution of 4-bromo-7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1H-indole (90 mg, 0.22 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentanane) (110 mg, 0.43 mmol) in DMSO (2 mL). The reaction mixture was heated to 100 °C and stirred for 6 h. The reaction mixture 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 = 3:1) to give the title compound. LCMS: m / z = 460.2 [MH] - .

[0701] 7-Fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1H-indole: At 25 °C and N2, K3PO4 (58 mg, 0.27 mmol) and Pd(dtbpf)Cl2 (7 mg, 0.01 mmol) were added to a solution of 7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole (50 mg, 0.11 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (26 mg, 0.16 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL). The reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture 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 HPLC (Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH₄HCO₃ aqueous solution, B: MeCN; B% in A: 35%–65%, duration 8 min) to give the title compound. LCMS: m / z = 417.1 [M + H] +

[0702] Example 75

[0703] 7-Fluoro-N,4-Di(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide

[0704]

[0705] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: Pd(t-Bu3P)2 (1.81 g, 3.55 mmol) was added to a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (10 g, 35.46 mmol) and 2-(tributyltinyl)pyrimidine (19.63 g, 53.19 mmol) in DMF (100 mL) at 25 °C and N2. The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give the title compound. LCMS: m / z = 282.0 [M+H] +

[0706] 3,3-Dibromo-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indololin-2-one: Pyridium tribromide (34.12 g, 106.68 mmol) was added to a solution of 7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole (5 g, 17.78 mmol) in t-BuOH (150 mL) and H2O (50 mL) at 20 °C and N2. The reaction mixture was heated to 30 °C and stirred for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 455.9 [M+H] + .

[0707] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indololin-2-one: Zn (5.75 g, 87.91 mmol) was added to a solution of 3,3-dibromo-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indololin-2-one (8 g, 17.58 mmol) in THF (80 mL) and saturated NH4Cl aqueous solution (80 mL) at 0 °C and N2. The reaction mixture was heated to 20 °C and stirred for 1 h. The reaction mixture was filtered through a filter pad, and the filtrate was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 298.1 [M + H] + .

[0708] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-thione: P2S5 (5.12 g, 23.01 mmol) and NaHCO3 (161.11 mg, 1.92 mmol) were added to a solution of 7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-one (5.7 g, 19.18 mmol) in THF (100 mL) at 20 °C and N2. The reaction mixture was heated to 50 °C and stirred for 10 h. The reaction mixture was used directly in the next step. LCMS: m / z = 314.1 [M+H] + .

[0709] 7-Fluoro-2-((4-methoxybenzyl)thio)-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: At 20 °C, DMF (50 mL), K₂CO₃ (5.29 g, 38.31 mmol), and PMBCl (3.60 g, 22.98 mmol) were added to the above solution of 7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-thione (6 g, 19.15 mmol) in THF (100 mL). The reaction mixture was heated to 50 °C and stirred for 4 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 (2 × 50 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 obtain the title compound. LCMS: m / z = 434.2 [M+H] +

[0710] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: NCS (277 mg, 2.08 mmol) was added to a solution of 7-fluoro-2-((4-methoxybenzyl)thio)-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole (300 mg, 0.69 mmol) in AcOH (6 mL) and H₂O (2 mL) at 0 °C and N₂. The reaction mixture was heated to 20 °C and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 380.0 [M+H] + .

[0711] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide: NH3·H2O (1.39 mL, 9.01 mmol) was added to a solution of 7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (570 mg, 1.50 mmol) in DCM (12 mL) at 0 °C and N2. The reaction mixture was heated to 20 °C and stirred for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM:i-PrOH (3 × 10 mL) (v:v = 3:1). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 16%-46%, duration 8.0 min) to obtain the title compound. LCMS: m / z = 361.1 [M+H] +

[0712] 7-Fluoro-N,4-Di(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide: At 20 °C, Cs₂CO₃ (81.39 mg, 0.25 mmol) and 2-fluoropyrimidine (16 mg, 0.16 mmol) were added to a solution of 7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide (30 mg, 0.08 mmol) in DMF (1 mL). The reaction mixture was heated to 100 °C and stirred for 3 h. The resulting residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH₄HCO₃ aqueous solution, B: MeCN; B% in A: 10%–50%, duration 8.0 min) to give the title compound. LCMS: m / z = 439.0 [M+H] + .

[0713] Example 76

[0714] (S)-7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole

[0715]

[0716] 2-(benzylthio)-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: Pd(t-Bu3P)2 (76 mg, 0.15 mmol) was added to a solution of 2-(benzylthio)-4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (400 mg, 0.99 mmol) and 2-(tributyltinyl)pyrimidine (475 mg, 1.29 mmol) in DMF (8 mL) at 20 °C and N2. The reaction mixture was heated to 110 °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 washed with brine (3 × 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 3:1) to give the title compound. LCMS: m / z = 403.9 [M+H] +

[0717] 3-Chloro-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: NCS (42 mg, 0.31 mmol) was added to a solution of 2-(benzylthio)-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole (55 mg, 0.14 mmol) in AcOH (0.9 mL) and H₂O (0.3 mL) at 0 °C and N₂. The reaction mixture was heated to 20 °C and stirred for 2 h. Another portion of NCS (24 mg, 0.18 mmol) was added and the reaction mixture was stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 413.9 [M+H] + .

[0718] (S)-3-chloro-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine-1-yl)sulfonyl)-1H-indole: TEA (39 mg, 0.39 mmol) and (S)-2-(trifluoromethyl)pyrrolidine (40 mg, 0.29 mmol) were added to a solution of 3-chloro-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (40 mg, 0.10 mmol) in DCM (2 mL) at 20 °C and N2, and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 517.1 [M+H] + .

[0719] (S)-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine-1-yl)sulfonyl)-1H-indole: 10% Pd / C (30 mg) was added to a solution of (S)-3-chloro-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine-1-yl)sulfonyl)-1H-indole (30 mg, 0.06 mmol) in MeOH (1 mL) at 20 °C and N2. The suspension was degassed under vacuum and purged three times with H2, and the reaction mixture was then stirred at 20 °C for 1 h under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex Luna C18 75×30mm×3μm; mobile phase: 0.2% FA aqueous solution, B: MeCN; B% in A: 20%–50%, duration 8.0 min) and further purified by TLC (PE:EtOAc = 1:1) to give the title compound. LCMS: m / z = 483.0 [M+H] + .

[0720] Example 77

[0721] (S)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine)

[0722] -1-yl)sulfonyl)-1H-indole

[0723]

[0724] 2-(5-Bromo-2-(trifluoromethyl)phenyl)-2H-1,2,3-triazole: 2H-1,2,3-triazole (81.21 g, 0.82 mol) and K₂CO₃ (170.63 g, 1.23 mol) were added to a solution of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (100 g, 0.41 mol) in DMF (1.4 L) at 25 °C. The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (2.8 L) and extracted with EtOAc (3 × 1 L). The combined organic layers were washed with brine (3 × 300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the title compound. LCMS: m / z = 292.0, 294.0 [M+H] + .

[0725] 3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: Diphenylmethylamine (22.34 g, 123.26 mmol), Cs₂CO₃ (53.55 g, 164.35 mmol), Xantphos (9.51 g, 16.44 mmol), and Pd₂(dba)₃ (7.53 g, 8.22 mmol) were added to a solution of 2-(5-bromo-2-(trifluoromethyl)phenyl)-2H-1,2,3-triazole (24 g, 82.18 mmol) in 1,4-dioxane (600 mL) at 20 °C and N₂. The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in THF (600 mL) and cooled to 0 °C under N2, then 2 M HCl (600 mL) was added. The reaction mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was adjusted to pH 7–8 by adding saturated NaHCO3 aqueous solution and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 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 5:1) to give the title compound. LCMS: m / z = 229.2 [M+H] + .

[0726] 2-Fluoro-5-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: At 0 °C, Selectfluor was added to a solution of 3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline (10.8 g, 47.33 mmol) in MeCN (100 mL). TM (18.4 g, 52.07 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (60 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 = 247.1 [M+H] + .

[0727] 6-Fluoro-2-iodo-3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: NIS (10.25 g, 45.54 mmol) was added to a solution of 2-fluoro-5-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline (4.55 g, 18.22 mmol) in AcOH (90 mL) at 0 °C and N2. The reaction mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 10:1) to give the title compound. LCMS: m / z = 373.0 [M+H] + .

[0728] 6-Fluoro-3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline: Trimethylsilyl ethynylene (6.20 g, 63.16 mmol), CuI (481 mg, 2.53 mmol), and Pd(PPh3)2Cl2 (886 mg, 1.26 mmol) were added to a solution of 6-fluoro-2-iodo-3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline (4.7 g, 12.63 mmol) in TEA (60 mL) at 20 °C and N2. The reaction mixture was heated to 80 °C and stirred for 7 h. The reaction mixture was filtered, and the filtrate was diluted with H₂O (60 mL) and extracted with EtOAc (3 × 20 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 = 343.0 [M+H] + .

[0729] 7-Fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole: t-BuOK (1.64 g, 14.6 mmol) was added to a solution of 6-fluoro-3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (2 g, 5.84 mmol) in NMP (30 mL) at 0 °C. The reaction mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the title compound. LCMS: m / z = 271.1 [M+H] + .

[0730] 3,3-Dibromo-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)indololin-2-one: Pyridium tribromide (7.10 g, 22.21 mmol) was added to a solution of 7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole (1 g, 3.70 mmol) in t-BuOH (12 mL) and H2O (4 mL) at 20 °C and N2. The reaction mixture was heated to 30 °C and stirred for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 444.8 [M+H] + .

[0731] 7-Fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)indoline-2-one: Zn (1.47 g, 22.52 mmol) was added to a solution of 3,3-dibromo-7-fluoro-4-(triazol-2-yl)-5-(trifluoromethyl)indoline-2-one (2 g, 4.50 mmol) in THF (20 mL) and saturated NH4Cl aqueous solution (20 mL) at 0 °C and N2. The reaction mixture was heated to 20 °C and stirred for 1 h. The reaction mixture was filtered through a filter pad. The filtrate was diluted with 30 mL of H₂O and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 287.0 [M + H] + .

[0732] 7-Fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)indoline-2-thione: At 20 °C, P2S5 (932 mg, 4.19 mmol) and NaHCO3 (29 mg, 0.35 mmol) were added to a solution of 7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)indoline-2-one (1 g, 3.49 mmol) in THF (8 mL). The reaction mixture was heated to 75 °C and stirred for 12 h. The reaction mixture was used directly in the next step. LCMS: m / z = 303.0 [M+H] + .

[0733] 7-Fluoro-2-((4-methoxybenzyl)thio)-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole: At 20 °C, DMF (20 mL), K₂CO₃ (1.83 g, 13.24 mmol), and PMBCl (1.55 g, 9.92 mmol) were added to the above solution of 7-fluoro-4-(triazol-2-yl)-5-(trifluoromethyl)indoline-2-thione (2 g, 6.62 mmol) in THF (8 mL). The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with H₂O (40 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 423.0 [M+H] + .

[0734] 7-Fluoro-2-((4-methoxybenzyl)thio)-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid tert-butyl ester: At 0 °C, TEA (143 mg, 1.42 mmol), DMAP (8 mg, 0.07 mmol), and Boc₂O (232 mg, 1.07 mmol) were added to a solution of 7-fluoro-2-((4-methoxybenzyl)thio)-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole (300 mg, 0.71 mmol) in DCM (5 mL). The reaction mixture was heated to 25 °C and stirred for 1 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with DCM (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 = 10:1 to 5:1) to give the title compound. LCMS: m / z = 523.0 [M+H] + .

[0735] 2-(chlorosulfonyl)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid tert-butyl ester: At 0 °C, NCS (38 mg, 0.28 mmol) was added to a solution of 7-fluoro-2-((4-methoxybenzyl)thio)-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) in AcOH (0.6 mL) and H₂O (0.2 mL). The reaction mixture was heated to 25 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 469.0 [M+H] + .

[0736] (S)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine-1-yl)sulfonyl)-1H-indole-1-carboxylic acid tert-butyl ester: At 20 °C, TEA (54 mg, 0.53 mmol) and (S)-2-(trifluoromethyl)pyrrolidine (45 mg, 0.32 mmol) were added to a solution of 2-(chlorosulfonyl)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol) in DCM (2 mL), and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine (3 × 2 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 471.9 [M-Boc+H] + .

[0737] (S)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine-1-yl)sulfonyl)-1H-indole: At 20 °C, 0.2 mL of TFA was added to a solution of (S)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine-1-yl)sulfonyl)-1H-indole-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol) in DCM (1 mL), and the reaction mixture was stirred for 1 h. The reaction mixture was adjusted to pH 7–8 with saturated NaHCO3 aqueous solution and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEHC18 100×30mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B in A: 32%-58%, duration 8.0 min) and further purified by preparative TLC (SiO2, PE:EtOAc = 3:1) to obtain the title compound. LCMS: m / z = 472.1 [M+H] + .

[0738] Example 78

[0739] (S)-7-Fluoro-4-(5-Fluorpyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine-1-

[0740] (Sulfo)-1H-indole

[0741]

[0742] 2-(benzylthio)-4-bromo-7-fluoro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole: LDA (11.00 mL, 2 M in THF / n-heptane) was added dropwise to a solution of 4-bromo-7-fluoro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole (8 g, 18.34 mmol) in THF (80 mL) at -78 °C under N2, and the reaction mixture was stirred for 0.5 h. A solution of 1,2-dibenzyldithion (6.78 g, 27.51 mmol) in THF (70 mL) was added dropwise to the above solution at -78 °C, and the reaction mixture was heated to 20 °C and stirred for 2 h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (150 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 wet-milled with PE (20 mL) at -40 °C for 20 min, and the solid was collected to give the title compound.

[0743] 2-(benzylthio)-4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole: TBAF (23 mL, 1 M in THF) was added to a solution of 2-(benzylthio)-4-bromo-7-fluoro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole (2.6 g, 4.66 mmol) in 25 mL of THF at 0 °C and N2. The reaction mixture was heated to 20 °C and stirred for 12 h. The reaction mixture was diluted with 20 mL of H2O and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give the title compound.

[0744] 4-Bromo-7-fluoro-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: NCS (644 mg, 4.82 mmol) was added to a solution of 2-(benzylthio)-4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (500 mg, 1.24 mmol) in AcOH (9 mL) and H2O (3 mL) at 0 °C and N2. The reaction mixture was heated to 20 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 379.9 [MH] - .

[0745] (S)-4-bromo-7-fluoro-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidine-1-yl)sulfonyl)-1H-indole: At 20 °C and N2, a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (1 equivalent) in DCM (0.27 M) was mixed with TEA (5 equivalents) and (S)-2-(trifluoromethyl)pyrrolidine (4 equivalents), and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc = 5:1) to give the title compound. LCMS: m / z = 480.8, 482.8 [MH] - .

[0746] (S)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: Pd(t-Bu3P)2 (8 mg, 0.016 mmol) was added to a solution of (S)-4-bromo-7-fluoro-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole (80 mg, 0.17 mmol) and 5-fluoro-2-(tributyltinyl)pyrimidine (128 mg, 0.33 mmol) in DMF (2 mL) at 20 °C and N2. The reaction mixture was heated to 110 °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 (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: A: 0.2% FA aqueous solution, B: MeCN; B% in A: 40%–70%, duration 8.0 min) to give the title compound. LCMS: m / z = 501.0 [M + H] + .

[0747] Example 79

[0748] (S)-7-Fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole

[0749]

[0750] (S)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: At 20 °C and N2, the (S)-4-bromo-7-fluoro-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole... A solution of dole (100 mg, 0.21 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentane) (158 mg, 0.62 mmol) in DMSO (3 mL) was supplemented with Pd(dppf)Cl2 (15 mg, 0.02 mmol) and KOAc (41 mg, 0.41 mmol). The reaction mixture was heated to 100 °C and stirred for 8 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 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc = 5:1) to give the title compound. LCMS: m / z = 531.1 [M+H] + .

[0751] (S)-7-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: At 20 °C and N2, the indole is converted to (S)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole. A solution of 1,4-dioxane (50 mg, 0.09 mmol) and 4-bromo-2-methyl-2H-1,2,3-triazole (23 mg, 0.14 mmol) in 1,4-dioxane (2 mL) and H₂O (0.2 mL) was supplemented with K₃PO₄ (50 mg, 0.24 mmol) and Pd(dtbpf)Cl₂ (6 mg, 0.009 mmol). The reaction mixture was heated to 100 °C and stirred for 1 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 preparative HPLC (Phenomenex Luna C18 100×30mm×3μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 40%-75%, time: 8.0 min) to obtain the title compound. LCMS: m / z = 486.0 [M+H] + .

[0752] Example 80

[0753] 2-(cyclobutylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole

[0754]

[0755] 3,3,4-Tribromo-7-fluoro-5-(trifluoromethyl)indololin-2-one: Pyridium tribromide (68.04 g, 212.74 mmol) was added to a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (10 g, 35.46 mmol) in t-BuOH (200 mL) and H2O (70 mL) at 20 °C and N2. The reaction mixture was heated to 40 °C and stirred for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was wet-milled with EtOAc:THF (50 mL) (v:v = 1:1), filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (SiO2, PE:THF = 3:1 to 0:1) to give the title compound. LCMS: m / z = 453.6, 455.6 [MH] - .

[0756] 4-Bromo-7-fluoro-5-(trifluoromethyl)indololin-2-one: Zn (5.67 g, 86.66 mmol) was added to a solution of 3,3,4-tribromo-7-fluoro-5-(trifluoromethyl)indololin-2-one (7.9 g, 17.33 mmol) in THF (80 mL) and saturated NH4Cl aqueous solution (80 mL) at 0 °C and N2. The reaction mixture was heated to 25 °C and stirred for 2 h. The reaction mixture was filtered, and the filtrate was diluted with 50 mL of H₂O and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with 100 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (SiO₂, PE:EtOAc = 6:1 to 1:1) to give the title compound. LCMS: m / z = 296.0, 298.0 [MH] - .

[0757] 4-Bromo-7-fluoro-5-(trifluoromethyl)indoline-2-thione: P2S5 (373 mg, 1.68 mmol) and NaHCO3 (14 mg, 0.17 mmol) were added to a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)indoline-2-one (500 mg, 1.68 mmol) in THF (10 mL) at 25 °C and N2. The reaction mixture was heated to 50 °C and stirred for 6 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 313.9, 315.9 [M+H] + .

[0758] 4-Bromo-2-(cyclobutylthio)-7-fluoro-5-(trifluoromethyl)-1H-indole: K₂CO₃ (158 mg, 1.15 mmol) was added to a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)indoline-2-thione (600 mg, 0.57 mmol) and bromocyclobutane (309 mg, 2.29 mmol) in DMF (9 mL) at 25 °C and N₂. The reaction mixture was heated to 65 °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 washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 9:1 to 3:1) to give the title compound. LCMS: m / z = 368.0, 369.9 [M+H] + .

[0759] 4-Bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1H-indole: At 0 °C and N₂, m-CPBA (220 mg, 1.09 mmol, 85% w / w) was added to a solution of 4-bromo-2-(cyclobutylthio)-7-fluoro-5-(trifluoromethyl)-1H-indole (160 mg, 0.43 mmol) in DCM (4 mL). The reaction mixture was heated to 20 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with DCM (3 × 5 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 wet-milled with MTBE (10 mL), and the solid was collected to give the desired compound. LCMS: m / z = 399.9, 401.9 [M+H] + .

[0760] 2-(Cyclobutylsulfonyl)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole: At 25 °C and N2, KOAc (132 mg, 1.35 mmol) and Pd(dppf)Cl2 (33 mg, 0.04 mmol) were added to a solution of 4-bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1H-indole (180 mg, 0.45 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhecyclopentanane) (228 mg, 0.90 mmol) in DMSO (4 mL). The reaction mixture was heated to 100 °C and stirred for 6 h. The reaction mixture was diluted with 10 mL of H₂O and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 6:1 to 1:1) to give the title compound. LCMS: m / z = 446.1 [MH] - .

[0761] 2-(Cyclobutylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole: At 25 °C and N2, K3PO4 (47 mg, 0.11 mmol) and Pd(dtbpf)Cl2 (7 mg, 0.01 mmol) were added to a solution of 2-(cyclobutylsulfonyl)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole (50 mg, 0.11 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (54 mg, 0.34 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL). The reaction mixture was heated to 100 °C and stirred for 5 h. The reaction mixture was diluted with 10 mL of H₂O and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH₄HCO₃ aqueous solution, B: MeCN; B in A: 20%–50%, time 8.0 min) to give the title compound. LCMS: m / z = 403.1 [M + H] + .

[0762] Example 81

[0763] 2-(cyclopropylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole

[0764]

[0765] 4-Bromo-7-fluoro-2-iodo-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole: LDA (1.49 mL, 2 M in THF / n-heptane) was added to a solution of 4-bromo-7-fluoro-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole (1 g, 2.30 mmol) in THF (15 mL), and the reaction mixture was stirred for 1 h at -78 °C and N2. I2 (698 mg, 2.75 mmol) in THF (10 mL) was added to the above reaction mixture, and the reaction mixture was heated to 20 °C and stirred for 1 h. The reaction was quenched by adding saturated aqueous NH4Cl solution (15 mL), diluted with H2O (10 mL), and extracted with EtOAc (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 = 10:1 to 5:1) to give the title compound. LCMS: m / z = 559.6, 561.6 [MH] - .

[0766] 4-Bromo-2-(cyclopropylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1H-indole: CuI (372 mg, 1.96 mmol) was added to a solution of 4-bromo-7-fluoro-2-iodo-1-toluenesulfonyl-5-(trifluoromethyl)-1H-indole (550 mg, 0.95 mmol) and sodium cyclopropylsulfinyloxy (250 mg, 1.9 mmol) in DMSO (10 mL) at 25 °C and N2. The reaction mixture was heated to 90 °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 washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: A: 10mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 30%-60%, time: 8 min) to obtain the title compound. LCMS: m / z = 383.9, 385.9 [MH] - .

[0767] 2-(Cyclopropylsulfonyl)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)-1H-indole: Pd(dppf)Cl2 (13 mg, 0.02 mmol) and KOAc (53 mg, 0.54 mmol) were added to a solution of 4-bromo-2-(cyclopropylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1H-indole (70 mg, 0.18 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentane (138 mg, 0.54 mmol) in DMSO (2 mL) at 25 °C and N2. The reaction mixture was heated to 100 °C and stirred for 6 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 res...

Claims

1. A compound of formula I: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 ; Y 1 For N or CR 5 ; X is N or CR 6 ; R 1 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, or -N(R) 7 )2, 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 separated by one to five Z groups. 1 replace; R 2 Halogenated, cyano, -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 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 separated by one to five Z groups. 1 replace; R 3 Halogenated, cyano, -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 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 separated by one to five Z groups. 1 replace; R 4 It can be hydrogen, halogen, cyano, -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 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 separated by one to five Z groups. 1 replace; R 5 It can be hydrogen, halogen, cyano, -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 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 separated by one to five Z groups. 1 replace; R 6 It can be hydrogen, halogen, cyano, -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 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 separated by one to five Z groups. 1 replace; Each R 7 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 separated by one to five Z groups. 1 Replace; or Two Rs 7 Together with the nitrogen atoms they are attached to, they form independently, optionally, one to five Zn atoms. 1 Substituted heterocyclic groups; 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 separated by one to five Z groups. 1 a replaces; Each Z 1 Independently, it can be a halogen 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 separated by one to five Z groups. 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 separated by one to five Z groups. 1 b substitution; Each Z 1a Independently, it can be a halogen 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 separated by one to five Z groups. 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 separated by one to five Z groups. 1 b substitution; Each Z 1b Independently, it can be a halogen group, 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 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally surrounded by one to five halogen groups, cyano groups, -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, or heteroaryl substitutions; The conditions are: A) When X is N and R 1 When it is methyl; then R 2 C 3-10 cycloalkyl, aryl or heteroaryl, wherein the C 3-10 cycloalkyl, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 Replace; and B) The compound is not: 4,5,6,7-Tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 4-[(4,5-difluoro-1H-indole-2-yl)sulfonyl]-1-piperazincarboxylic acid 1,1-dimethylethyl ester (1415396-05-2), 3-[7-chloro-5-fluoro-2-(methyl [Sulfoyl]-1H-indol-4-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinidone (1101495-34-4), 7-chloro-N-ethyl-5,6-dimethyl-1H-benzimidazole-2-sulfonamide (115243-16-8) or 4,7-dichloro-N-ethyl-5,6-dimethyl-1H-benzimidazole-2-sulfonamide (115243-12-4).

2. A compound of formula IA: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace.

3. The compound of claim 2, wherein the compound is represented by formula IB: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof.

4. The compound of claim 2, wherein the compound is represented by the formula IG: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof.

5. The compound of claim 1 or 2, wherein R 1 C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, or -N(R) 11 )2, 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 separated by one to five Z groups. 1 replace.

6. The compound of claim 1 or 2, wherein R 1 C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently and optionally surrounded by one to five Z groups. 1 replace.

7. The compound of claim 1 or 2, wherein R 1 To be arbitrarily selected by one to five Z 1 Replacement C 3-10 Cycloalkyl.

8. The compound of claim 1 or 2, wherein R 1 To be arbitrarily selected by one to five Z 1 Substituted heterocyclic groups.

9. The compound of claim 1 or 2, wherein R 1 To be arbitrarily selected by one to five Z 1 Substituted aryl groups.

10. The compound of claim 1 or 2, wherein R 1 To be arbitrarily selected by one to five Z 1 Substituted heteroaryl groups.

11. The compound of claim 1 or 2, wherein R 1 -N(R) 7 )2.

12. A compound of formula II: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 ; Y 1 For N or CR 5 ; X is N or CR 6 ; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace; R 3 It can be hydrogen, halogen, cyano, -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 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 separated by one to five Z groups. 1 replace; R 4 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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 separated by one to five Z groups. 1 replace; R 5 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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 separated by one to five Z groups. 1 replace; R 6 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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 separated by one to five Z groups. 1 replace; Each R 7 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 separated by one to five Z groups. 1 Replace; or Two Rs 7 Together with the nitrogen atoms they are attached to, they form independently, optionally, one to five Zn atoms. 1 Substituted heterocyclic groups; 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 separated by one to five Z groups. 1a replace; Each Z 1 Independently, it can be a halogen 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 separated by one to five Z groups. 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 separated by one to five Z groups. 1b replace; Each Z 1a Independently, it can be a halogen 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 separated by one to five Z groups. 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 separated by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, 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 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally surrounded by one to five halogen groups, cyano groups, -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, or heteroaryl substitutions.

13. A compound of formula IIA: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 ; Y 1 For N or CR 5 ; X is N or CR 6 ; Ring A is arbitrarily divided by one to five Zs. 1 Substituted heterocyclic groups; Ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace; R 3 It can be hydrogen, halogen, cyano, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3 -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 separated by one to five Z groups. 1 replace; R 4 It can be hydrogen, halogen, cyano, -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 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 separated by one to five Z groups. 1 replace; R 5 It can be hydrogen, halogen, cyano, -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 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 separated by one to five Z groups. 1 replace; R 6 It can be hydrogen, halogen, cyano, -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 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 separated by one to five Z groups. 1 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 separated by one to five Z groups. 1 a replaces; Each Z 1 Independently, it can be a halogen 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 separated by one to five Z groups. 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 separated by one to five Z groups. 1b replace; Each Z 1a Independently, it can be a halogen 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 separated by one to five Z groups. 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 separated by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, 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 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally surrounded by one to five halogen groups, cyano groups, -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, or heteroaryl substitutions.

14. The compound according to any one of claims 1-2 or 5-13, wherein Y is CR 4 .

15. The compound according to any one of claims 1-2 or 5-14, wherein Y is CH.

16. The compound according to any one of claims 1-2 or 5-15, wherein Y 1 For CR 5 .

17. The compound according to any one of claims 1-2 or 5-15, wherein Y 1 Let N be the number of elements in the array.

18. The compound of claim 1 or 12, wherein the compound is represented by formula IE: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof; wherein ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace.

19. The compound of claim 1 or 13, wherein the compound is represented by the formula IF: Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture thereof; wherein ring A is optionally surrounded by one to five Zn groups. 1 Substituted heterocyclic group; ring B is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1 replace.

20. The compound according to any one of claims 1-3, 5-16 or 18-19, wherein R 5 It is a halogen group.

21. The compound according to any one of claims 1-20, wherein X is CR 4 .

22. The compound according to any one of claims 1-21, wherein X is CH.

23. The compound according to any one of claims 1-20, wherein X is N.

24. The compound according to any one of claims 1-23, wherein R 1 Or ring A can be arbitrarily divided by one to five Z. 1 Replacement of 4- to 10-membered heterocyclic groups.

25. The compound according to any one of claims 1-24, wherein R 1 Or ring A is: Each of them can be chosen by one to five Z. 1 replace.

26. The compound according to any one of claims 1-25, wherein R 2 Or ring B can be arbitrarily divided by one to five Z. 1 Substituted heteroaryl groups.

27. The compound according to any one of claims 1-26, wherein R 2 Or ring B can be arbitrarily divided by one to five Z. 1 Replacement of 5- or 6-membered heteroaryl groups.

28. The compound according to any one of claims 1-27, wherein R 3 C 1-6 alkyl.

29. The compound according to any one of claims 1-28, wherein each Z 1 Independently selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, -S(O)2-C 1-6 Alkyl, 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.

30. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof.

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

32. A method for inhibiting SARM1 activity, the method comprising contacting cells with an effective amount of the following: the compound of any one of claims 1-30 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 31.

33. The method of claim 32, wherein the contact is within the body.

34. 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 1-30, a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture of stereoisomers, or the pharmaceutical composition of claim 31.

35. A method for inhibiting axonal degeneration, the method comprising administering to a subject in need an effective amount of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers, or the pharmaceutical composition of claim 31.

36. 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 1-30, 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 31.

37. The method of claim 36, 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.

38. The method of claim 37, wherein the disease or ailment is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin insufficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin melting, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Peyrenia, periventricular leukomalacia, spherical cell leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lugrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher disease, Holler 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 B12. 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kenzweig 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, human T-lymphovirus 1 (HTLV-1)-associated myelopathy with tropical spastic paresis, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus disease Toxic encephalitis, pediatric viral encephalitis, essential tremor, peroneal muscular atrophy, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive supranuclear 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).

39. Use of the compound of any one of claims 1-30 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers, or the pharmaceutical composition of claim 31 for the treatment of a disease or ailment at least in part mediated by SARM1.

40. The use as described in claim 39, wherein the disease or ailment is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin insufficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin melting, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Peyrenia, periventricular leukomalacia, globular leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lugrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty Sachs disease, Gaucher disease, Holler 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 B12. 12 Vitamin deficiency syndrome, isolated vitamin E deficiency syndrome, Basen-Kenzweig 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, human T-lymphovirus 1 (HTLV-1)-associated myelopathy with tropical spastic paralysis, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalitis Viral encephalitis in children, essential tremor, peroneal muscular atrophy, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive supranuclear 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).

41. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 31, used in a therapeutic manner.

42. The compound of any one of claims 1-30 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 31, for the treatment of spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin insufficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin sheath melting, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Piece disease. Clare disease, Peyrenia, periventricular leukomalacia, globular leukodystrophy (Clare disease), Waller's disease, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lugrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty-Sachs disease, Gaucher disease, Holler 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-Kenzweig 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, human T-lymphovirus 1 (HTLV-1)-associated myelopathy with tropical spastic paralysis, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalitis Viral encephalitis in children, essential tremor, peroneal muscular atrophy, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive supranuclear 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).

43. The use of any compound of claims 1-30 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers, or the pharmaceutical composition of claim 31, in the manufacture of an agent for the treatment of the following diseases: spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin insufficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin sheathing, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexandria. Major diseases, Niemann-Pick disease, Peyrenia, periventricular leukomalacia, globular leukodystrophy (Clapey's disease), Waller's degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lugrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Ty-Sachs disease, Gaucher disease, Holler 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-Kenzweig 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, human T-lymphovirus 1 (HTLV-1)-associated myelopathy with tropical spastic paralysis, West Nile virus encephalopathy, Lacrosse virus encephalitis, Bunyavirus encephalitis Viral encephalitis in children, essential tremor, peroneal muscular atrophy, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal medullary neuropathy, progressive supranuclear 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).

44. A method for providing a compound of formula I according to claim 1, the method comprising causing the compound of formula I-1 to: With compound of formula I-2: Contact is performed under conditions sufficient to provide a compound of formula I; where LG is a leaving group; and each R 50 They can be -OH, -O-alkyl independently, or together with the boron atoms to which they are attached, to form cyclic borate esters.

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