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 for their preparation and intermediates, and methods of their use. Provided herein are compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, useful for treating and / or preventing diseases mediated at least in part by SARM1.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 63 / 433,346, filed December 16, 2022, the entire contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates generally to small molecule modulators of sterile alpha and TIR motif-containing 1 (SARM1) protein and their use as therapeutic agents. [Background technology]

[0003] Neurodegenerative diseases are a class of progressive neurological disorders in which nerve cells malfunction and eventually die. The degradation of neurons in patients with neurodegenerative diseases can result in a variety of symptoms, including mood and behavior changes, agitation, sensory, motor and cognitive impairment, and memory loss, which can progress to the inability to move or speak, dementia, and ultimately death.

[0004] Axonal degeneration has been identified as a key pathology in most neurodegenerative diseases: axons are vulnerable to both mechanical injury (Wallerian degeneration) and disease (Wallerian-like degeneration).

[0005] In healthy axons, the N-terminus of SARM1 interacts with the TIR domain, promoting TIR multimerization and subsequent NAD + However, under neuronal injury or disease conditions, the N-terminal-TIR domain interaction of SARM1 is disrupted, resulting in TIR multimerization and subsequent rapid loss of NAD+ and associated axonal degeneration. Summary of the Invention

[0006] Detailed Description of the Invention Provided herein are compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that are useful for treating and / or preventing diseases mediated at least in part by SARM1.

[0007] In certain embodiments, compounds that inhibit SARM1 are provided.

[0008] In another embodiment, there is provided a pharmaceutical composition 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.

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

[0010] The disclosure also provides compositions, including pharmaceutical compositions, kits, including the compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, methods of using (or administering) and making the compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, and intermediates thereof.

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

[0012] Further, the present disclosure provides the use of a compound, 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 the treatment of a disease, disorder, or condition mediated at least in part by SARM1.

[0013] The description herein describes exemplary embodiments of the present technology, but it should be appreciated that such description is not intended to limit the scope of the disclosure, but instead to provide a description of exemplary embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0014] 1.Definition As used herein, the following terms, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes at the beginning or end of chemical groups are for convenience, and chemical groups may be represented with or without one or more dashes without losing their ordinary meaning. Wavy or dashed lines drawn through lines in structures indicate particular points of attachment of groups. Unless chemically or structurally required, no directionality or stereoselectivity is indicated or implied by the order in which chemical groups are written or named.

[0016] Prefix “C” u-v " means that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" means the alkyl group has from 1 to 6 carbon atoms.

[0017] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. Also, the term "about X" includes the description of "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes one or more assays, and equivalents thereof known to those of skill in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), having 1 to 8 carbon atoms (i.e., C 1-8 alkyl), having 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or having 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] Certain commonly used alternative chemical names may also be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, and divalent heteroaryl groups may also be referred to as "alkylene" or "alkylenyl" groups (e.g., methylenyl, ethylenyl, and propylenyl), "arylene" or "arylenyl" groups (e.g., phenylenyl or naphthylenyl, or, in the case of heteroarylene, quinolinyl), respectively. Also, unless expressly stated otherwise, when a combination of groups is referred to herein as a moiety, e.g., arylalkyl or aralkyl, the last-mentioned group contains the atom through which the moiety is attached to the remainder of the molecule.

[0020] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), having 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), having 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or having 2 to 4 carbon atoms (i.e., C 2-4 Alkenyl refers to alkyl groups. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0021] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl) having 2 to 12 carbon atoms (i.e., C 2-12 alkynyl) and having 2 to 8 carbon atoms (i.e., C 2-8 alkynyl) and having 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or having 2 to 4 carbon atoms (i.e., C 2-4The term "alkynyl" also includes groups having one triple bond and one double bond.

[0022] "Alkoxy" refers to the group "alkyl-O-". Example alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0023] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl."

[0024] "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.

[0025] "Acyl" refers to the group -C(O)R y and R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyl include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0026] An "amide" is a group -C(O)NR y R z refers to the "C-amido" group and the group -NR y C(O)R z and "N-amido" groups, which refer to groups such as y and R zis independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z taken together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0027] "Amino" refers to the group -NR y R z and R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0028] "Amidino" means -C(NR y )(NR z 2) where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0029] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a group having 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), having 6 to 12 ring carbon atoms (i.e., C 6-12 aryl), or having 6 to 10 ring carbon 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 in any way with heteroaryl, as described below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl, regardless of the point of attachment. When one or more aryl groups are fused with a cycloalkyl, the resulting ring system is a cycloalkyl, regardless of the point of attachment.

[0030] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0031] "Carbamoyl" refers to the group -OC(O)NR y R z refers to the "O-carbamoyl" group and the group -NR y C(O)OR z "N-carbamoyl" refers to both R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0032] "Carboxyl ester" or "ester" means -OC(O)R x and -C(O)OR x Both R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0033] "Cyanoalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 or 2) hydrogen atoms have been replaced with a cyano (-CN) group.

[0034] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cyclic groups having at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 carbon atoms (i.e., C 3-20 cycloalkyl) and having 3 to 14 carbon atoms (i.e., C 3-12 cycloalkyl) and having 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl) and having 3 to 10 carbon atoms (i.e., C 3-10 cycloalkyl) and having 3 to 8 carbon atoms (i.e., C 3-8 cycloalkyl), or having 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7 dimethyl-bicyclo[2.2.1]heptanyl, 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 attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl," such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl, when two substitution positions are present on the same carbon atom.

[0035] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0036] "Imino" refers to the group -C(NR y )R z and Ry and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0037] "Imide" refers to the group -C(O)NR y C(O)R z and R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0038] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0039] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen. For example, if a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, although these are not necessarily the same halogens. 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.

[0040] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen.

[0041] "Haloalkoxyalkyl" refers to an alkoxyalkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen.

[0042] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced by hydroxy groups.

[0043] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms), excluding either terminal carbon atom(s), are each independently replaced with the same or different heteroatom groups, provided that the point of attachment to the remainder of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. Heteroatom groups include -NR y -, -O-, -S-, -S(O)-, -S(O)2-, 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. Examples of heteroalkyl groups include, but are not limited to, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and amines (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR yCH3, -CH2CH2NR y CH2CH2NR y CH3, etc., and 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, 2 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0044] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl) and having 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or having 3 to 8 ring carbon atoms (i.e., C 3-8Heteroaryl) and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In particular examples, heteroaryl includes 5-10, 5-7, or 5-6 membered ring systems, each 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, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and 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]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl may be attached via one of the rings of the fused system. Any aromatic ring having single or multiple fused rings containing at least one heteroatom is considered heteroaryl, regardless of attachment to the rest of the molecule (i.e., via any one of the fused rings).Heteroaryl does not encompass or overlap with aryl, as defined above.

[0045] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0046] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings, where the multiple rings may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. - ) moieties. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring, regardless of attachment (i.e., attachment may be via a carbon atom or a heteroatom), is considered heterocyclyl. Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of attachment to the rest of the molecule. For example, fused ring systems such as decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclyl, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl) and having 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl) and having 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl) and having 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl) and having 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl) and having 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl) and having 3 to 6 ring carbon atoms (i.e., C 3-6 Heterocyclyl) has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanoyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindoline, and the like.

[0023] Heterocyclyl includes aryl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two substitution positions on the same carbon atom. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic ring systems such as, for example, oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-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, where the heterocyclyl can be attached via one of the rings of the fused system.

[0047] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0048] "Oxime" is a group -CR y (=NOH) and R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0049] "Sulfonyl" refers to the group -S(O)R y and R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfonyl include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0050] "Sulfinyl" refers to the group -S(O)R y and R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfinyl include methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0051] "Sulfonamide" refers to the group -SO2NR y R z and -NR y SO2R z and R y and R zare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0052] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. Also, the term "optionally substituted" refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a specified atom or group that may or may not be replaced with a non-hydrogen moiety.

[0053] As used herein, the term "substituted" refers to 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., 1-5 or 1-3) hydrogen atom has been substituted with, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl ... carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3, wherein each R yis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0054] In certain embodiments, "substituted" refers to any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1-5 or 1-3) hydrogen atoms have been 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) 1-2 OR g , -NR g S(O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(O) 1-2 NR g R h, -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" also refers to any of the above groups in which one or more (e.g., 1-5 or 1-3) hydrogen atoms are replaced independently with -C(O)R g , -C(O)OR g , -C(O)NR g R h , -CH2SO2R g , or -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also refers to any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with a bond to amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i two of which, taken together with the atoms to which they are attached, form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl (optionally substituted with oxo, halo, amino, hydroxy, or alkoxy).

[0055] Polymers or similar amorphous structures obtained by limiting the number of further substituents to a substituent (e.g., a substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein.

[0056] In certain embodiments, the phrase "one or more" as used herein refers to 1 to 5. In certain embodiments, the phrase "one or more" as used herein refers to 1 to 3.

[0057] Any compound or structure presented herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These forms of compounds may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have the structure depicted herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphate, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Various isotopically labeled compounds of the present disclosure, such as 3 H and 14 Those incorporating a radioactive isotope such as C. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0058] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogen(s), such as hydrogen on a carbon atom, is / are replaced with deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium.

[0059] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, or 11C-labeled compounds may be useful for PET or SPECT or other imaging studies. The isotopically labeled compounds and prodrugs thereof of the present disclosure can generally be prepared by following the procedures disclosed in the schemes or examples and the preparations described below, by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents. It is understood that deuterium in this context is considered a substituent in the compounds described herein.

[0060] The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, an atom that is not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of the present disclosure, an atom specifically designated as deuterium (D) is meant to represent deuterium.

[0061] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0062] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, or prodrugs of the compounds described herein are provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0063] 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 salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if a compound described herein is obtained as 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, particularly a pharmaceutically acceptable addition salt, can be formed by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include primary, secondary, and tertiary amines, such as alkylamines (i.e., NH(alkyl), dialkylamines (i.e., HN(alkyl)), trialkylamines (i.e., N(alkyl)), substituted alkylamines (i.e., NH(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)), tri(substituted alkyl)amines (i.e., N(substituted alkyl)), alkenylamines (i.e., NH(alkenyl)), dialkenylamines (i.e., HN(alkenyl)), trialkenylamines (i.e., N(alkenyl)), substituted alkenylamines (i.e., NH(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted Examples of suitable amines include, but are not limited to, salts of arylamines such as aryl, triarylamine, tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)amines, mono-, di-, or tri-cycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)), mono-, di-, or tri-allylamine (i.e., NH(aryl), HN(aryl), N(aryl)), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0064] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide tautomer and the imidic acid tautomer. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0065] The compounds of the present disclosure, or their pharmaceutically acceptable salts, contain asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids, as (D)- or (L)-. The present disclosure is intended to encompass 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 separated using conventional techniques, such as chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0066] "Stereoisomers" refer to compounds made up of the same atoms joined by the same bonds, but having different, non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers or mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0067] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0068] Relative centers of compounds as depicted herein are indicated graphically using "thick bond" type (bold or horizontal lines), and absolute stereochemistry is indicated using wedge bonds (bold or horizontal lines).

[0069] "Prodrug" refers to any compound that releases an active parent drug in vivo according to the structures described herein when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein can be prepared by modifying functional groups present in the compounds described herein in such a way that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds described herein in such a way that the modifications can be cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like, of hydroxy functional groups in the compounds described herein. The preparation, selection, and use of prodrugs are described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0070] 2.Compound Provided herein are compounds that are inhibitors of SARM1. In certain embodiments, the compound has Formula I: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 and; Y 1 is N or CR 5 and; X is N or CR 6 and; 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, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 2 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, -NR11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 3 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 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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, heteroaryl, -N(R 11 )2, -OR 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O)2R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11 , -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 5 is hydrogen, halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 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 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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, 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)R11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11 , -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; Each R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; or The Two R's 7 together with the nitrogen atom to which they are attached, independently form one to five Z 1 forming an optionally substituted heterocyclyl; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1a optionally substituted with; each Z 1 are 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 where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z1a optionally substituted with; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; each Z 1a are 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 where each C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; each Z 1b are 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, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -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 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)NH-; where Z 1b 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, and L may further independently be one to five halo, cyano, -OH, -SH, -NH, -NO, -SF, 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 It is optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0071] In certain embodiments, X is N and R 1 is methyl, R 2 is C 3-10 cycloalkyl, aryl, or heteroaryl, where C 3-10 The cycloalkyl, aryl, or heteroaryl may independently be one to five Z 1 is optionally replaced by

[0072] In certain embodiments, the compound is 4,5,6,7-tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 1,1-dimethylethyl 4-[(4,5-difluoro-1H-indol-2-yl)sulfonyl]-1-piperazinecarboxylate (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).

[0073] In certain embodiments, A) X is N and R 1 is methyl, R 2 is C 3-10 cycloalkyl, aryl, or heteroaryl, where C 3-10 The cycloalkyl, aryl, or heteroaryl may independently be one to five Z 1 and B) the compound is 4,5,6,7-Tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 1,1-dimethylethyl 4-[(4,5-difluoro-1H-indol-2-yl)sulfonyl]-1-piperazinecarboxylate (1415396-05-2), 3-[7-chloro-5-fluoro-2-(methyl sulfonyl)-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).

[0074] In certain embodiments, the compound of formula I: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 and; Y 1 is N or CR 5 and; X is N or CR 6 and; 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, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z1 optionally substituted with; R 2 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 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 3 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 , -SR11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O)2R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11 , -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 4 is hydrogen, halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; 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)R11 , -S(O)2R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11 , -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 6 is hydrogen, halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; or The Two R's 7 together with the nitrogen atom to which they are attached, independently form one to five Z 1 forming an optionally substituted heterocyclyl; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1a optionally substituted with; each Z 1 are 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, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1a optionally substituted with; and each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; However, A) X is N and R 1 is methyl, R 2 is C 3-10 cycloalkyl, aryl, or heteroaryl, where C3-10 The cycloalkyl, aryl, or heteroaryl may independently be one to five Z 1 and B) the compound is selected from the group consisting of 4,5,6,7-tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 1,1-dimethylethyl 4-[(4,5-difluoro-1H-indol-2-yl)sulfonyl]-1-piperazinecarboxylate (1415396-05-2), 3-[7-chloro-5-fluoro-2-methyl ...

[00110] 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).

[0075] In certain embodiments, the compound of formula I: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is CH; Y 1 is N or CR 5 and; X is CH; R 1 is C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R 7 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 2 is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 3 is halo, cyano, -NO2, or C optionally substituted with 1 to 5 Z1 1-6 is alkyl; R 5 is hydrogen, halo, cyano, -NO2, or one to five Z 1 C optionally substituted with 1-6 is alkyl; Each R 7 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; or The Two R's 7 together with the nitrogen atom to which they are attached, independently form one to five Z 1 forming an optionally substituted heterocyclyl; each Z 1 are 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, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1a optionally substituted with; and each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 It is cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0076] In certain embodiments, R 2 is ring B, and ring B is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 In certain embodiments, R 2 is ring B, and ring B is aryl or heteroaryl, each independently containing 1 to 5 Z 1 is optionally replaced by

[0077] In certain embodiments, the compound of formula IA: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, Y, Y 1 , R 1 , R 3 and Ring B are each independently as defined herein.

[0078] In certain embodiments, the compound of formula IB: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 1 , R 3 , R 5 and Ring B are each independently as defined herein.

[0079] In certain embodiments, R 1 is C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R 11 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 is optionally replaced by

[0080] In certain embodiments, R 1 is represented by ring A: [ka] Here, ring A is one to five Z 1 is optionally replaced by

[0081] In certain embodiments, R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, where C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl is independently one to five Z 1 is optionally replaced by

[0082] In certain embodiments, R 1 is C 3-10 cycloalkyl, or heterocyclyl, each independently selected from 1 to 5 Z 1 is optionally replaced by

[0083] In certain embodiments, R 1 is C optionally substituted with 1 to 5 Z1 3-10 It is cycloalkyl.

[0084] In certain embodiments, R 1is 1 to 5 Z 1 is heterocyclyl optionally substituted with

[0085] In certain embodiments, R 1 is 1 to 5 Z 1 is aryl optionally substituted with

[0086] In certain embodiments, R 1 is 1 to 5 Z 1 is heteroaryl optionally substituted with

[0087] In certain embodiments, R 1 is -N(R 7 )2.

[0088] In certain embodiments, the compound of formula II: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 and; Y 1 is N or CR 5 and; X is N or CR 6 and; Ring B is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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, heteroaryl, -N(R 11 )2, -OR 11 , -SR 11, -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O)2R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11 , -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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, heteroaryl, -N(R 11 )2, -OR 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O)2R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11, -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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 11C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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, heteroaryl, -N(R 11 )2, -OR 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O)2R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11 , -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; Each R 7 independently, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; or The Two R's 7 together with the nitrogen atom to which they are attached, independently form one to five Z 1 forming an optionally substituted heterocyclyl; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1a optionally substituted with; each Z 1 are 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)R12 , -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, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1a optionally substituted with; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; each Z 1a are 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 where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -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 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 1-6 alkyl)-, -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)NH-; where Z 1b 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, and L may further independently be one to five halo, cyano, -OH, -SH, -NH, -NO, -SF, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, C 3-10 It is optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0089] In certain embodiments, each R 7 independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 is optionally replaced by

[0090] In certain embodiments, each R 7 are independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, or heteroaryl, where each C 1-6 Alkyl, C 3-10 The cycloalkyl or heteroaryl may independently have 1 to 5 Z 1 is optionally replaced by

[0091] In certain embodiments, each R 7 is independently hydrogen, methyl, cyclobutyl, bicyclo[1.1.1]pentyl, pyridinyl, or pyrimidinyl, wherein each cyclobutyl, bicyclo[1.1.1]pentyl, pyridinyl, or pyrimidinyl is independently selected from one to five Z 1 is optionally replaced by

[0092] In certain embodiments, two R 7 together with the nitrogen atom to which they are attached, independently form one to five Z 1 to form an optionally substituted heterocyclyl.

[0093] In certain embodiments, two R 7 together with the nitrogen atom to which they are attached form Ring A as defined herein.

[0094] In certain embodiments, 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, heteroaryl, -N(R 11 )2, -OR 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O)2R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11 , -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 is optionally replaced by

[0095] In certain embodiments, R 3 Halo, cyano, -NO2, C 1-6Alkyl, 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 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 is optionally replaced by

[0096] In certain embodiments, R 3 is 1 to 5 Z 1 C optionally substituted with 1-6 In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is trifluoromethyl.

[0097] In certain embodiments, the compound of formula IIA: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 and; Y 1 is N or CR 5 and; X is N or CR 6 and; Ring A is 1 to 5 Z 1 is heterocyclyl optionally substituted with; Ring B is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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, 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, -NR11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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, heteroaryl, -N(R 11 )2, -OR 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O)2R 11 , -C(O)N(R 11 )2, -NR 11 C(O)R 11 , -NR 11 S(O)R 11 , -NR 11 S(O)2R 11 , -S(O)N(R 11 )2, -S(O)2N(R 11 )2, -NR 11 C(O)N(R 11 )2, -NR 11 S(O)N(R 11 )2, -NR 11 S(O)2N(R 11 )2, -OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; 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 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; R 6 is hydrogen, halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 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 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1a optionally substituted with; each Z 1are 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 where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1a optionally substituted with; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; each Z 1a are 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 where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; each Z 1b are 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, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -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 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 1-6 alkyl)-, -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 3-10cycloalkyl)-, -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)NH-; where Z 1b 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, and L may further independently be one to five halo, cyano, -OH, -SH, -NH, -NO, -SF, 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 It is optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0098] In certain embodiments, Y is N. In certain embodiments, Y is CR 4 In certain embodiments, Y is CH.

[0099] In certain embodiments, Y 1 is N. In certain embodiments, Y 1 is CR 5 In certain embodiments, Y 1 is R 5 and R 5 is hydrogen, halo, cyano, -N(R 11 )2, -OR 11 , -SR 11 , 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 3-10In certain embodiments, Y is cycloalkyl, heterocyclyl, aryl, or heteroaryl. 1 is CR 5 and R 5 is halo. In certain embodiments, Y 1 is CF.

[0100] In certain embodiments, a compound of formula IC: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R 1 , R 3 , R 5 and Ring B are each independently as defined herein.

[0101] In certain embodiments, the compound of formula ID: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R 1 , R 3 , R 5 and Ring B are each independently as defined herein.

[0102] In certain embodiments, the compound of formula IE: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 3 , R 5 , R 7 and Ring B are each independently as defined herein.

[0103] In certain embodiments, each R 7 is C 1-6It is alkyl, heterocyclyl, or aryl.

[0104] In certain embodiments, the compound of formula IF: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 3 , R 5 , R 7 and Ring B are each independently as defined herein.

[0105] In certain embodiments, the compound of formula IG: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 1 , R 3 and Ring B are each independently as defined herein.

[0106] In certain embodiments, the compound of formula IH: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R 1 , R 3 and Ring B are each independently as defined herein.

[0107] In certain embodiments, the compound of formula IJ: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein X, R 3 , R 7and Ring B are each independently as defined herein.

[0108] In certain embodiments, the compound of formula IK: [ka] 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 independently as defined herein.

[0109] In certain embodiments, R 5 is hydrogen, halo, cyano, -N(R 11 )2, -OR 11 , -SR 11 , 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 It is cycloalkyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R 5 is halo. In certain embodiments, R 5 is fluoro.

[0110] In certain embodiments, X is CR 4 In certain embodiments, X is N or CH. In certain embodiments, X is CH. In certain embodiments, X is N.

[0111] In certain embodiments, R 1 Or ring A is C 3-10 cycloalkyl, or 4- to 10-membered heterocyclyl, each of which is selected from 1 to 5 Z 1 In certain embodiments, R 1 Or ring A is C 3-10cycloalkyl, or 4- to 10-membered heterocyclyl, each of which is halo, cyano, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 It optionally has 1 to 5 substituents independently selected from alkoxy and aryl.

[0112] In certain embodiments, R 1 Or ring A is 1 to 5 Z 1 In certain embodiments, R 1 Or ring A is halo, cyano, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 and 4- to 10-membered heterocyclyl optionally having 1 to 5 substituents independently selected from alkoxy and aryl.

[0113] In certain embodiments, R 1 Or ring A is [ka] where each is 1 to 5 Z 1 Optionally,

[0114] In certain embodiments, R 1 Or ring A is [ka] where each is 1 to 5 Z 1 Optionally,

[0115] In certain embodiments, R 2 or ring B is aryl, or heteroaryl, each of which contains 1 to 5 Z 1 In certain embodiments, R 2or ring B is phenyl, or 5- to 9-membered heteroaryl, each of which is selected from 1 to 5 Z 1 is optionally replaced by

[0116] In certain embodiments, R 2 Or ring B is 1 to 5 Z 1 In certain embodiments, R 2 Or ring B is 1 to 5 Z 1 In certain embodiments, R 2 Or ring B is 1 to 5 Z 1 is a 5- or 6-membered heteroaryl optionally substituted with

[0117] In certain embodiments, R 2 or Ring B is cyclobutyl, tetrahydropyranyl, phenyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridinyl, each of which is selected from the group consisting of 1 to 5 Z 1 is optionally replaced by

[0118] In certain embodiments, R 2 or Ring B is cyclobutyl, tetrahydropyranyl, phenyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridinyl, each of which is selected from the group consisting of 1 to 5 Z 1 In certain embodiments, R 2 or Ring B is tetrahydropyranyl, phenyl, pyrazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridinyl, each of which is selected from the group consisting of 1 to 5 Z 1 is optionally replaced by

[0119] In certain embodiments, R 2Or ring B is halo, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1 to 3 substituents independently selected from alkoxy, wherein each C 1-6 Alkyl is one to five Z 1a is optionally replaced by

[0120] In certain embodiments, R 2 Or ring B is halo, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1 to 3 substituents independently selected from alkoxy, wherein each C 1-6 Alkyl is one to three C 3-10 Optionally substituted with cycloalkyl or halo.

[0121] In certain embodiments, R 2 Or ring B is halo, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1 to 3 substituents independently selected from alkoxy.

[0122] In certain embodiments, R 2 or Ring B is cyclobutyl, tetrahydropyranyl, phenyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridinyl, each of which is selected from the group consisting of halo, C 1-6 Alkyl, and C 1-6 In certain embodiments, R is optionally substituted with 1 to 3 substituents independently selected from alkoxy. 2 or Ring B is tetrahydropyranyl, phenyl, pyrazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridinyl, each of which is selected from the group consisting of halo, C 1-6 Alkyl, and C 1-6 Optionally substituted with 1 to 3 substituents independently selected from alkoxy.

[0123] In certain embodiments, R 3is C 1-6 In certain embodiments, R 3 is methyl. In certain embodiments, R 2 is a halo and R 3 is C 1-6 In certain embodiments, R 2 is fluoro and R 3 is methyl.

[0124] In certain embodiments, each Z 1 are 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 In certain embodiments, each Z is independently selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl. 1 independently, Z 1b is.

[0125] In certain embodiments, the compound of formula I: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 and; Y 1 is N or CR 5 and; X is N or CR 6 and; 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, where C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; R 2 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 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; R 3 Halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 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 and; 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, 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 and; 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 and; R 6 is hydrogen, halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 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 and; Each R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1 optionally substituted with; or The Two R's 7 together with the nitrogen atom to which they are attached, independently form one to five Z 1b forming an optionally substituted heterocyclyl; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Z 1b are 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, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -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 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 1-6 alkyl)-, -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)NH-; where Z 1b Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl, and L may further independently be one to five halo, cyano, -OH, -SH, -NH, -NO, -SF, 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 optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl; A) X is N and R 1 is methyl, R 2 is C 3-10 cycloalkyl, aryl, or heteroaryl, where C 3-10 The cycloalkyl, aryl, or heteroaryl may independently be one to five Z 1 and B) The compound is 4,5,6,7-Tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 1,1-dimethylethyl 4-[(4,5-difluoro-1H-indol-2-yl)sulfonyl]-1-piperazinecarboxylate (1415396-05-2), 3-[7-chloro-5-fluoro-2-(methyl sulfonyl)-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).

[0126] In certain embodiments, the compound of formula II: [ka] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR 4 and; Y 1 is N or CR 5 and; X is N or CR 6 and; Ring B is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; 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, 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)OR11 and; 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, 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 and; 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 and; 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, 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 and; Each R 7 independently, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be one to five Z 1b optionally substituted with; or The Two R's 7 together with the nitrogen atom to which they are attached, independently form one to five Z 1b forming an optionally substituted heterocyclyl; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Z 1b are 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, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -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 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10cycloalkyl)-, -N(heterocyclyl)-, -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 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)NH-; where Z 1b 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, and L may further independently be one to five halo, cyano, -OH, -SH, -NH, -NO, -SF, 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 It is optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0127] In certain embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0128] In certain embodiments, a compound selected from Table 2, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided. [Table 2-1] [Table 2-2] Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14

[0129] 3. Methods "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of: a) inhibiting a disease or condition (e.g., alleviating one or more symptoms resulting from a disease or condition and / or reducing the severity of the disease or condition); b) delaying or halting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliating the disease, i.e., causing a regression of clinical symptoms (e.g., alleviating the disease state, causing partial or total remission of a disease or condition, enhancing the effect of another drug, slowing the progression of a disease, improving quality of life, and / or prolonging survival).

[0130] "Prevention" or "preventing" means any treatment of a disease or condition such that the clinical symptoms of the disease or condition do not develop. The compounds may, in certain embodiments, be administered to subjects (including humans) at risk for or who have a family history of a disease or condition.

[0131] "Subject" refers to an animal, such as a mammal, including a human, who has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful for human therapy and / or veterinary applications. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0132] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, means an amount sufficient to affect therapy and provide a therapeutic benefit, such as alleviating symptoms or slowing disease progression, when administered to a subject. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition as described herein. The therapeutically effective amount can vary depending on the subject and disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, which can be readily determined by one of ordinary skill in the art.

[0133] The methods described herein may be applied to cell populations in vivo or in vitro. "In vivo" means within a living individual, as in an animal or human. In this context, the methods described herein may be used therapeutically in an individual. "In vitro" means outside a living individual. Examples of ex vivo cell populations include ex vivo cell cultures and biological samples, including fluid or tissue samples taken from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used in vitro to determine optimal schedules and / or doses of administration of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such use may be used for experimental purposes or in the clinic to design in vivo treatment protocols. Other in vitro uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to those of skill in the art. Compounds can be further characterized to test for safety or tolerability in human or non-human subjects. Such properties can be tested using methods commonly known to those skilled in the art.

[0134] In certain embodiments, compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that inhibit the activity of sterile alpha and TIR motif-containing 1 (SARM1) protein are provided. In certain embodiments, the compounds provided herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, inhibit SARM1.

[0135] In certain embodiments, there is provided a method of inhibiting SARM1 activity, comprising contacting a cell with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Inhibition can be in vitro or in vivo.

[0136] In certain embodiments, provided are compounds disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for use in inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0137] In certain embodiments, the present disclosure provides the use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0138] In certain embodiments, provided are compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for inhibiting the NADase activity of SARM 1. In certain embodiments, provided are methods for inhibiting the NADase activity of SARM 1 and / or treating a neurodegenerative or neurological disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixtures of stereoisomers, or prodrug thereof.

[0139] In certain embodiments, methods are provided for treating a disease or condition mediated at least in part by SARM1, 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.

[0140] In certain embodiments, a method for treating axon degeneration is provided for a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, stereoisomer mixture, or prodrug thereof. In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, stereoisomer mixture, or prodrug thereof, inhibits axon degeneration, including axon degeneration resulting from a decrease or depletion of NAD+. In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, stereoisomer mixture, or prodrug thereof, prevents axons distal to axonal injury from degenerating.

[0141] In certain embodiments, provided are methods for treating degradation of peripheral nervous system neurons or portions thereof, 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.

[0142] In certain embodiments, methods are provided for treating degeneration of central nervous system neurons or portions thereof, 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.

[0143] In certain embodiments, treating comprises reducing one or more symptoms or characteristics of neurodegeneration.

[0144] In certain embodiments, methods are provided for inhibiting axonal degeneration, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a subject in need thereof.

[0145] In certain embodiments, provided are methods for treating neurodegenerative or neurological diseases or disorders, 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.

[0146] In certain embodiments, provided are methods for treating a neurodegenerative or neurological disease or disorder associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, nerve injury disease or disorder, metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal injury resulting from traumatic axonal injury (TAI) (see Ziogas et al., J. Neuroscience, 2018, 38(16):4031-4032 and WO2020191257), leukoencephalopathy, or leukodystrophy, 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.

[0147] In certain embodiments, there is provided a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating a disease or condition mediated at least in part by SARM1 in a subject in need thereof.

[0148] In certain embodiments, there is provided a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting axonal degeneration in a subject in need thereof.

[0149] In certain embodiments, the present disclosure provides for the use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for inhibiting axonal degeneration in a subject in need thereof.

[0150] In certain embodiments, the present disclosure provides the use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for treating a neurodegenerative or neurological disease or disorder, such as a disease or disorder associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, neuronal injury disease or disorder, metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal injury resulting from traumatic axonal injury (TAI), leukoencephalopathy, or leukodystrophy.

[0151] In certain embodiments, the disease or condition is an acute condition. In certain embodiments, the disease or condition is a chronic condition.

[0152] In certain embodiments, the disease or condition is characterized by axonal degeneration in the central nervous system, the peripheral nervous system, the optic nerve, the cranial nerve, or a combination thereof.

[0153] In certain embodiments, the disease or condition is or includes acute injury to the central nervous system, such as, but not limited to, injury to the spinal cord and / or traumatic brain injury (TBI). In certain embodiments, the disease or condition is or includes chronic injury to the central nervous system, such as, but not limited to, injury to the spinal cord, traumatic brain injury (TBI), and / or traumatic axonal injury (TAI). In certain embodiments, the disease or condition is or includes chronic traumatic brain injury (CTE).

[0154] In certain embodiments, the disease or condition is a chronic condition affecting the central nervous system, such as, but not limited to, Parkinson's disease (see, e.g., 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, e.g., White, MA, et al. Acta Neuropath. Comm. 2019, 7(1), 166), multiple sclerosis, Huntington's disease, or Alzheimer's disease.

[0155] In certain embodiments, the disease or condition is acute peripheral neuropathy. In certain embodiments, the disease or condition is chemotherapy-induced peripheral neuropathy (CIPN). For example, see 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), one example of acute peripheral neuropathy, can be associated with a variety of drugs, including, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), or platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0156] In certain embodiments, the disease or condition is a chronic condition affecting the peripheral nervous system, such as, but not limited to, diabetic neuropathy, HIV neuropathy, Charcot-Marie-Tooth disease, or amyotrophic lateral sclerosis.

[0157] In certain embodiments, the disease or condition is glaucoma (see, e.g., Ko, KW, et al. J. Cell Bio. 2020, 219(8), e201912047).

[0158] In certain embodiments, the disease or condition 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.

[0159] In certain embodiments, the disease or condition 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.

[0160] In certain embodiments, the disease or condition is associated with retinal degeneration. In certain embodiments, the disease or condition is Leber congenital amaurosis, such as Leber congenital amaurosis type 9 (LCA9) (see, for example, Sasaki, Y., et al. eLife. 2020, 9, e62027).

[0161] In certain embodiments, one or more compounds and / or compositions as described herein are useful for treating, for example, a disorder or condition selected from the group consisting of one or more neurodegenerative diseases, neuropathy, or axonopathy. In certain embodiments, one or more compounds and / or compositions as described herein are useful for treating, for example, a neuropathy or axonopathy associated with axonal degeneration. In certain embodiments, the neuropathy associated with axonal degeneration is a genetic or congenital neuropathy or axonopathy. In certain embodiments, the neuropathy associated with axonal degeneration results from a de novo or somatic mutation. In certain embodiments, the neuropathy associated with axonal degeneration is selected from the list contained herein. In certain embodiments, the neuropathy or axonopathy is associated with axonal degeneration, including, but not limited to, Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia, stroke, chemical injury, thermal injury, or AIDS.

[0162] In certain embodiments, one or more compounds or compositions as described herein are characterized by reducing one or more symptoms or characteristics of neurodegeneration when administered to a population of subjects. For example, in certain embodiments, the relevant symptom or characteristic may be selected from the group consisting of the extent, rate, and / or timing of neuronal destruction. In certain embodiments, neuronal destruction may be or include axonal degradation, synapse loss, dendrite loss, synaptic density loss, dendritic branching loss, axonal branching loss, neuronal density loss, myelination loss, neuronal cell body loss, synaptic potentiation loss, action potential potentiation loss, cytoskeletal stability loss, axonal transport loss, ion channel synthesis and turnover loss, neurotransmitter synthesis loss, neurotransmitter release and reuptake capacity loss, axonal potential propagation loss, neuronal hyperexcitability, and / or neuronal hypoexcitability. In certain embodiments, neuronal destruction is characterized by an inability to maintain an appropriate resting neuronal membrane potential. In certain embodiments, neuronal destruction is characterized by the appearance of inclusions, plaques, and / or neurofibrillary tangles. In certain embodiments, neuronal destruction is characterized by the appearance of stress granules. In certain embodiments, neuronal destruction is characterized by the intracellular activation of one or more members of the cysteine-aspartic acid protease (caspase) family. In certain embodiments, neuronal destruction is characterized by the neuron undergoing programmed cell death (e.g., apoptosis, pyroptosis, ferroptosis, and / or necrosis) and / or inflammation.

[0163] In certain embodiments, the neurodegeneration or neurological disease or disorder is associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, neuronal injury disease or disorder, metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal injury resulting from leukoencephalopathy, or leukodystrophy.In certain embodiments, the neurodegenerative or neurological disease or disorder is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin breakdown, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbach disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lu-Georges disease), or encephalopathy. Rick's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-irradiation 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's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis (e.g., , Leber congenital amaurosis type 9 (LCA9), neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyaviral encephalitis, childhood viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenal myeloneuropathy, Progressive supranuclear palsy (PSP), Friedreich's ataxia, hereditary ataxias, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegia, spastic paraplegia, familial spastic paraplegia, French colonization disease, Strumpel-Lauren disease, or non-alcoholic steatohepatitis (NASH).

[0164] In certain embodiments, the present disclosure provides inhibitors of SARM1 activity for the treatment of neurodegenerative or neurological diseases or disorders involving axonal degeneration or axonopathy. The present disclosure also provides methods for treating, preventing, or alleviating axonal degeneration, axonopathy, and neurodegenerative or neurological diseases or disorders involving axonal degeneration using inhibitors of SARM1 activity. In certain embodiments, the present disclosure provides a method for inhibiting axonal degeneration, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a subject in need thereof.

[0165] In certain embodiments, the present disclosure provides methods of treating neurodegeneration or neurological diseases or disorders associated with axonal degeneration, axonal injury, axonopathy, demyelinating diseases, central pontine myelinolysis, neuronal injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal injury resulting from leukoencephalopathy, or leukodystrophy.

[0166] In certain embodiments, neuropathy and axonopathy include diseases or conditions involving neurons and / or supporting cells, such as glia, muscle cells, or fibroblasts, and particularly diseases or conditions involving axonal damage. Axonal damage can occur due to traumatic injury or non-mechanical injury resulting from disease, pathology, or exposure to toxic molecules or drugs. Such damage can result in axonal degeneration or dysfunction and loss of functional neuronal activity. Diseases and conditions that result in or are associated with such axonal damage are one of many neuropathic diseases and conditions. Such neuropathy can include peripheral neuropathy, central neuropathy, or a combination thereof. Furthermore, peripheral neuropathic symptoms can be caused by diseases primarily focused on the central nervous system, and central nervous system symptoms can be caused by diseases that are peripheral or systemic in nature.

[0167] In certain embodiments, peripheral neuropathy may involve damage to peripheral nerves and / or may result from a disease of the nerve or from a systemic disease. Some such diseases include infectious diseases such as diabetes, uremia, AIDS, or leprosy, nutritional disorders, vascular or collagen disorders such as atherosclerosis, or autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. In certain embodiments, peripheral nerve degeneration results from traumatic (mechanical) damage to nerves, as well as chemical or thermal damage to nerves. Such pathological conditions that damage peripheral nerves include glaucoma, carpal tunnel syndrome, compression or constriction injuries such as direct trauma, penetrating trauma, contusion, fracture, or dislocation; pressure on superficial nerves (ulna, radius, or fibula), which may be caused by prolonged use of crutches, maintaining the same posture for a long time, or tumor compression; intraneural hemorrhage; ischemia; exposure to cold, radiation, or toxic substances such as certain drugs, herbicides, or pesticides. In particular, nerve damage may be caused by chemical damage caused by cytotoxic anticancer drugs, such as taxol, cisplatin, proteasome inhibitors, or vinca alkaloids, such as vincristine. Typical symptoms of such peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, tingling, or pricking), and pain in the arms, hands, legs, and / or feet. In certain embodiments, neuropathy is associated with mitochondrial dysfunction. Such neuroses may present with reduced energy levels, i.e., reduced levels of NAD and ATP.

[0168] In certain embodiments, the peripheral neuropathy is a metabolic and endocrine neuropathy, including a wide range of peripheral neuropathies associated with systemic diseases of metabolic origin, such as diabetes mellitus, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, disorders of lipid / glycolipid metabolism, nutritional / vitamin deficiencies, or mitochondrial disorders. A common feature of these diseases is the involvement of peripheral nerves due to alterations in myelin and axon structure and function resulting from dysregulated metabolic pathways.

[0169] In certain embodiments, neuropathies include optic neuropathies such as glaucoma, retinal ganglion degenerations such as those associated with retinitis pigmentosa and outer retinal neuropathy, optic nerve neuritis and / or degeneration including those associated with multiple sclerosis, traumatic injury to the optic nerve, which may include, for example, injury during tumor removal, hereditary optic neuropathies such as Kell's disease and Leber's hereditary optic neuropathy (LHON), ischemic optic neuropathies such as those secondary to giant cell arteritis, metabolic optic neuropathies such as neurodegenerative diseases including Leber's neuropathy, neuropathies caused by nutritional disorders such as vitamin B12 or folate deficiency, and toxicity, adverse drug reactions, such as those caused by ethambutol or cyanide, and neuropathies caused by vitamin deficiencies. Ischemic optic neuropathies also include non-arteritic ischemic optic neuropathy.

[0170] In certain embodiments, neurodegenerative diseases associated with neuropathy or axonopathy in the central nervous system include various diseases.Such diseases include progressive dementias 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 disease, and progressive ataxias 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 those involving prion diseases.Mechanical damage such as glaucoma, or traumatic damage to the head and spine, can also cause nerve damage and degeneration in the brain and spinal cord.In addition, pathological conditions such as ischemia and stroke, as well as nutritional disorders, and chemical toxicity caused by chemotherapy drugs can cause central nervous system neuropathy.

[0171] In certain embodiments, the present disclosure provides a method for treating a neuropathic or axonopathic disorder associated with axonal degeneration. In certain embodiments, the neuropathic or axonopathic disorder associated with axonal degeneration may be, for example, hereditary or congenital, or any of several neuropathies or axonopathies, such as those associated with Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating diseases, ischemia or stroke, chemical injury, thermal injury, and AIDS. In addition, neurodegenerative diseases not mentioned above, as well as subsets of the aforementioned diseases, may also be treated using the methods of the present disclosure. Such subsets of diseases may include Parkinson's disease or Alzheimer's disease.

[0172] In certain embodiments, the methods comprise administering an effective amount of a compound and / or composition as described herein (e.g., a compound of Formula I) to a subject in need thereof. In some such embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In certain embodiments, the subject has a condition characterized by axonal degeneration. In certain embodiments, the subject has been diagnosed with a condition characterized by axonal degeneration. In certain embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In certain embodiments, the subject is identified as being at risk for axonal degeneration based on, for example, the subject's genotype, a diagnosis of a condition associated with axonal degeneration, and / or exposure to an agent and / or a condition that induces axonal degeneration.

[0173] In certain embodiments, the subject is at risk of developing a neurodegenerative disorder. In certain embodiments, the subject is elderly. In certain embodiments, the subject is known to have a genetic risk factor for neurodegeneration. In certain embodiments, the subject has a family history of a neurodegenerative disease. In certain embodiments, the subject expresses one or more copies of a known genetic risk factor for neurodegeneration. In certain embodiments, the subject is selected from a population with a high incidence of neurodegeneration. In certain embodiments, the subject has a hexanucleotide repeat expansion in open reading frame 72 of chromosome 9. In certain embodiments, the subject has one or more copies of the ApoE4 allele.

[0174] In certain embodiments, the neurodegenerative disease, disorder, or condition may be or include traumatic neuronal injury. In certain embodiments, the traumatic neuronal injury is blunt force trauma, closed head injury, open head injury, exposure to concussive and / or explosive force, or penetrating trauma to the brain cavity or innervated area of ​​the body. In certain embodiments, the traumatic neuronal injury is a force that deforms, stretches, crushes, or shears axons. In certain embodiments, the disease or disorder is traumatic brain injury (TBI).

[0175] In certain embodiments, the subject has been involved in or is involved in activities identified as risk factors for neuronal degradation, e.g., contact sports or occupations that carry a high likelihood of traumatic neuronal injury or TBI.

[0176] In certain embodiments, methods of treating a neurodegenerative disease, disorder, or condition are provided, comprising administering to a patient in need thereof a compound as described herein and one or more of a DLK inhibitor or a NAMPT inhibitor. In certain embodiments, combination therapies are provided comprising a compound as described herein and a DLK inhibitor and / or a NAMPT inhibitor. In certain embodiments, combination therapies are provided comprising a compound as described herein, a DLK inhibitor, and one or more additional therapeutic agents. In certain embodiments, combination therapies are provided comprising a compound as described herein, a NAMPT inhibitor, and one or more additional therapeutic agents. In certain embodiments, combination therapies are provided comprising a compound as described herein, a DLK inhibitor, a NAMPT inhibitor, and one or more additional therapeutic agents.

[0177] In certain embodiments, the DLK inhibitor is a small molecule, a polypeptide, a peptide fragment, a nucleic acid (e.g., an siRNA, an antisense oligonucleotide, a microRNA, or an aptamer), an antibody, a dominant-negative inhibitor, or a ribozyme. In certain embodiments, the DLK inhibitor is a small molecule. In certain embodiments, the DLK inhibitor is an siRNA. In certain embodiments, the DLK inhibitor is an antisense oligonucleotide. In certain embodiments, the DLK inhibitor is a polypeptide. In certain embodiments, the DLK inhibitor is a peptide fragment. In certain embodiments, the DLK inhibitor is a nucleic acid. In certain embodiments, the DLK inhibitor is an antisense oligonucleotide.

[0178] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, WO2014177060, WO2015091889, WO2016142310, US20180057507, WO2018107072, WO2019241244, WO2020168111, and CN104387391A, which are incorporated by reference in their entireties.

[0179] In certain embodiments, the NAMPT inhibitor is a small molecule, a polypeptide, a peptide fragment, a nucleic acid (e.g., an siRNA, an antisense oligonucleotide, a microRNA, or an aptamer), an antibody, a dominant-negative inhibitor, or a ribozyme. In certain embodiments, the NAMPT inhibitor is a small molecule. In some embodiments, the NAMPT inhibitor is an siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In certain embodiments, the NAMPT inhibitor is a polypeptide. In some embodiments, the NAMPT inhibitor is a peptide fragment. In certain embodiments, the NAMPT inhibitor is a nucleic acid. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide.

[0180] In certain embodiments, the NAMPT inhibitor prevents the formation of nicotinamide mononucleotide (NMN). In certain embodiments, inhibition of NAMPT inhibits the mammalian NAD+ salvage pathway.

[0181] In certain embodiments, compositions are provided comprising a compound as described herein, formulated for administration to a subject in combination with a DLK inhibitor and / or a NAMPT inhibitor.

[0182] In certain embodiments, compositions comprising a compound as described herein are provided for use in combination with a DLK inhibitor and / or a NAMPT inhibitor. In certain embodiments, such compositions are pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0183] In certain embodiments, the subject may have received, will receive, or is currently receiving chemotherapy related to peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), and platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0184] In certain embodiments, SARM1 inhibitors as described herein may be used in combination with one or more other therapies to treat related diseases, disorders, or conditions. In certain embodiments, the administration of a SARM1 inhibitor is altered when used in a combination therapy compared to when used as a monotherapy, and alternatively or additionally, a therapy administered in combination with a SARM1 inhibitor as described herein is administered according to a different regimen or protocol than when administered alone or in combination with one or more therapies other than SARM1 inhibition. In certain embodiments, a composition comprising an additional therapeutic agent, the additional therapeutic agent, and the provided compound may act synergistically. In certain embodiments, one or both therapies utilized in a combination regimen are administered at a lower level or less frequently when used as a monotherapy.

[0185] In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or composition provided herein, inhibits NAD + or NAD +It is administered in combination with a precursor (e.g., nicotinamide riboside (NR), nicotinic acid (NA), nicotinic acid riboside (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), tryptophan (TRP), nicotinic acid adenine dinucleotide (NAAD), or vitamin B3).

[0186] In certain embodiments, provided are compounds as disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for use in inhibiting sterile alpha and TIR motif-containing protein 1 (SARM1) activity (e.g., in vitro or in vivo).

[0187] In certain embodiments, the present disclosure provides a method for inhibiting sterile alpha and TIR motif-containing protein 1 (SARM1) activity (e.g., in vitro or in vivo) and increasing axonal NAD + The present invention provides the use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for supplementing the levels of

[0188] Axonal degeneration is associated with various neurodegenerative diseases and is recognized as an important indicator of disease progression and an attractive target for the treatment of these diseases. Similarly, axonal degeneration is also observed in those associated with traumatic brain injury and peripheral neuropathy.

[0189] In certain embodiments, a method for treating a disease or condition mediated at least in part by SARM1 comprises administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient receiving NADPH. + or NAD +Methods are provided that include administering to a subject in need thereof in combination with a precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0190] In certain embodiments, the present disclosure provides a method for treating or preventing a neurodegenerative disease in a subject in need thereof, comprising administering to a subject in need thereof, a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, a NAD + or NAD + Use in combination with a precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3) is provided.

[0191] In certain embodiments, a method for treating any disease caused by SARM1 activity comprises administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient receiving NAD + or NAD + Methods are provided that include administering to a subject in need thereof in combination with a precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0192] In certain embodiments, the disease or condition may be a disease or condition of the central nervous system and / or may be caused by or associated with a pathogen or traumatic injury. It will be understood that these general embodiments, defined according to broad categories of diseases, disorders, and conditions, are not mutually exclusive.

[0193] In certain embodiments, a method for treating a neurodegenerative disease comprises administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a neurodegenerative disorder (ND)-associated neurotransmitter (NAD). + or NAD+ Methods are provided that include administering to a subject in need thereof in combination with a precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0194] Other embodiments include the use of the compounds disclosed herein in therapy.

[0195] 4. Kit Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and suitable packaging. In certain embodiments, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a label and / or instructions for using the compound in treating an indication, including a disease or condition described herein.

[0196] Also provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in a suitable container, which may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

[0197] 5. Pharmaceutical Compositions and Methods of Administration The compounds provided herein are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions containing 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 vehicles selected from carriers, adjuvants, and excipients are also provided herein. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0198] The pharmaceutical composition may be administered in either a single dose or multiple doses. The pharmaceutical composition may be administered in a variety of ways, including, for example, rectally, bucally, intranasally, and transdermally. In certain embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0199] One mode of administration is parenterally, e.g., by injection. Forms into which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0200] Oral administration may be another route for administering the compounds described herein. Administration may be, for example, via capsules or enteric-coated tablets. When preparing pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the active ingredient is typically diluted with an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0201] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate; sweeteners; and flavoring agents.

[0202] Compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein uses transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0203] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulated composition containing a homogeneous mixture of a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. When these preformulated compositions are referred to as homogeneous, the active ingredient may be uniformly dispersed throughout the composition so that the composition may be readily divided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0204] The tablets or pills of the compounds described herein can be coated or otherwise formulated to provide a dosage form that offers the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope surrounding the former. The two components can be separated by an enteric layer that functions to resist disintegration in the stomach, allowing the inner component to pass unchanged into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0205] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may, in one embodiment, be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0206] The amount of the compound in a pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain, in weight percent (wt%), about 0.01 to 99.99% by weight of the compound of the present disclosure, with the remainder being one or more suitable pharmaceutical excipients, based on the total formulation. In one embodiment, the compound is present at a level of about 1 to 80% by weight. Representative pharmaceutical formulations are described below.

[0207] [Table 4]

[0208] [Table 5]

[0209] [Table 6]

[0210] [Table 7]

[0211] [Table 8]

[0212] 6. Administration The specific dosage level of the compounds of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, timing, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject being treated. For example, dosages may be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Dosages of about 0.1 to 150 mg / kg may be appropriate. In certain embodiments, about 0.1 to 100 mg / kg may be appropriate. In other embodiments, dosages of 0.5 to 60 mg / kg may be appropriate. In certain embodiments, about 0.0001 to about 100 mg of compound per kilogram of body weight, about 0.001 to about 50 mg of compound per kilogram of body weight, or about 0.01 to about 10 mg of compound per kilogram of body weight per day may be appropriate. Normalizing according to subject weight is particularly useful when adjusting dosages across a wide range of subject sizes, such as when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0213] 7. Compound Synthesis The compounds can be prepared using the methods disclosed herein, and routine modifications thereof, as will be apparent in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may be used. Synthesis of exemplary compounds described herein can be achieved as described in the Examples below. Where available, reagents and starting materials can be purchased commercially, for example, from Sigma Aldrich or other chemical manufacturers.

[0214] Typical process conditions (i.e., reaction temperatures, times, reactant ratios, solvents, pressures, etc.) are provided; however, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by optimization procedures.

[0215] In addition, conventional protecting groups ("PG") may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and references cited therein. For example, protecting groups for alcohols such as hydroxy include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed with acid or fluoride ions such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, which is removed by acid or base, benzoyl, which is removed by acid or base, benzyl, which is removed by hydrogenation, methoxyethoxymethyl ether, which is removed by acid, dimethoxytrityl, methoxymethyl ether, which is removed by acid, tetrahydropyranyl or tetrahydrofuranyl, which is removed by acid, and trityl, which is removed by acid.Examples of protecting groups for amines include carbobenzyloxy, which is removed by hydrogenolysis; p-methoxybenzylcarbonyl, which is removed by hydrogenolysis; tert-butyloxycarbonyl, which is removed by concentrated strong acid (such as HCl or CF3COOH) or by heating to above about 80°C; 9-fluorenylmethyloxycarbonyl, which is removed by base such as piperidine; acetyl, which is removed by treatment with base; benzoyl, which is removed by treatment with base; benzyl, which is removed by hydrogenolysis; p-Methoxyphenyl, which is removed by ammonium cerium(IV) nitrate; tosyl, which is removed by concentrated acid (such as HBr or H2SO4) and strong reducing agents (sodium in liquid ammonia or sodium naphthalenide); troc (trichloroethyl chloroformate), which is removed by insertion of Zn in the presence of acetic acid; and sulfonamides (Nosyl & Nps), which are removed by samarium iodide or tributyltin hydride.

[0216] Furthermore, the compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0217] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chem or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts, such as 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 Supplementals (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), or obvious modifications thereof.

[0218] General Synthesis Scheme I illustrates a general method that can be used for the synthesis of compounds described herein, where X, Y, Y 1 , R 1 , R 2 , and R 3 are each independently as defined herein, LG is independently a leaving group (e.g., halo, -OTf, etc.), and each R 50 are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic boronate.

[0219] [ka] In Scheme I, compounds 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)Cl) and a base, followed by optional functionalization or deprotection, as needed. Alternatively, compounds of Formula I can be prepared by boronating compound I-1 to give compound I-3, and then contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, such as in the presence of a radium catalyst (e.g., XPhos reagent, Pd(dppf)Cl) and a base, followed by optional functionalization or deprotection, as needed. Alternatively, compounds of Formula I can be prepared by contacting a compound of Formula I-5 with a compound of Formula I-6 (e.g., an amine).

[0220] After completion of each reaction, the intermediate or final compound, respectively, can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like.

[0221] 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 a compound of Formula I-1, where X, Y, Y 1 , R 1 , and R 3 are each independently as defined herein, and each LG is independently a leaving group (e.g., halo, -OTf, etc.).

[0222] [ka] In Scheme II, a compound of formula II-3 (e.g., where R 1 is bonded to sulfur through a carbon atom, e.g., C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 A compound of formula II-1 (e.g., cycloalkyl) can be prepared by contacting a compound of formula II-1 with a compound of formula II-2 under appropriate conditions (e.g., nucleophilic reaction conditions). A compound of formula I-1 can then be obtained by oxidation of a compound of formula II-3 with an appropriate oxidant, such as m-CPBA. In certain embodiments of a compound of formula II-2, LG is iodo.

[0223] Further derivatization of the compounds obtained by the steps outlined in Scheme I or II, or any intermediate, provides additional compounds of Formula I. It should be understood that any of the compounds or intermediates shown in Scheme I or II can be prepared using conventional methods or purchased from commercial sources. In addition, any of the intermediates or any products obtained by the processes outlined in Scheme I or II can be derivatized at any step to provide various compounds of Formula I. In certain embodiments, the various substituents of the compounds or intermediates as used in Scheme I or II are as defined with respect to Formula I.

[0224] In certain embodiments, a process for obtaining a compound of formula I comprises reacting a compound of formula I-1: [ka] with a compound of formula I-2: [ka] under conditions sufficient to obtain a compound of formula I, wherein X, Y, Y 1 , R 1 , R 2 , and R 3 are each independently as defined herein, LG is a leaving group, and each R 50 are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic boronate.

[0225] In certain embodiments, a process for obtaining a compound of formula I comprises reacting a compound of formula I-1: [ka] with a boron reagent under boronation reaction conditions to produce a compound of formula I-3: [ka] and converting the compound of formula I-3 into a compound of formula I-4: [ka] under conditions sufficient to obtain a compound of formula I, wherein A 1 , A 2 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 4 , and R 5 are each independently as defined herein, each LG is independently a leaving group, and each R 50 are independently -OH, C 1-6 Alkoxy or two R 50 together with the boron atom to which they are attached to form a cyclic boronic ester.

[0226] In certain embodiments, each LG is independently halo.

[0227] In certain embodiments, the boron reagent is 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane or trimethyl borate.

[0228] In certain embodiments, the process includes a palladium catalyst (e.g., XPhos reagent or Pd(dppf)Cl2) and a base. [Example]

[0229] The following examples are included to demonstrate specific embodiments of the present disclosure. Those skilled in the art will appreciate that the techniques disclosed in the following examples are representative of techniques that work well in carrying out the present disclosure and, as such, can be considered to constitute specific modes of its implementation. However, those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments disclosed and still obtain like or similar results without departing from the spirit and scope of the present disclosure.

[0230] General Experimental Methods All solvents used were commercially available and were used without further purification. Reactions were typically carried out using anhydrous solvents under an inert atmosphere of nitrogen.

[0231] NMR spectroscopy: Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz, or one of the following instruments: Bruker Avance 400 instrument equipped with probe DUAL 400 MHz S1, probe 6 S1 400 MHz 5mm 1 H- 13 A Bruker Avance 400 instrument fitted with a C ID, a Bruker Avance III 400 instrument with nanobay fitted with a probe Broadband BBFO 5 mm direct, and a Bruker Mercury Plus 400 NMR spectrometer fitted with a Bruker 400 BBO probe operating at 400 MHz were used. 1 H nuclear magnetic resonance (NMR) spectroscopy was performed. All deuterated solvents typically contained 0.03%-0.05% v / v tetramethylsilane, which was used as a reference signal ( 1 H and 13C, δ set to 0.00). In some cases, a Bruker Advance 400 instrument operating at 400 MHz was used, with the solvents listed near room temperature unless otherwise noted. 1 H nuclear magnetic resonance (NMR) spectroscopy was performed. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for the designation of major peaks: e.g., s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (triplet of doublets), and br (broad).

[0232] Thin-layer chromatography: When thin-layer chromatography (TLC) is used, it refers to silica gel TLC using silica gel F254 (Merck) plates, and Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography was performed on silica gel cartridges using an automated flash chromatography system, or on C18 cartridges in the case of reverse-phase chromatography. Alternatively, thin-layer chromatography (TLC) was performed on Alugram® (Silica gel 60 F254) from Mancherey-Nagel, and spots were typically visualized using UV. In some cases, additional visualization methods were also used. In these cases, TLC plates were visualized using iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (25 g of (NH4)6Mo7O 24 The compounds were visualized by developing a color using 50 mL of concentrated H2SO4 (produced by thoroughly mixing 450 mL of water containing 5 g of (NH4)2Ce(IV)(NO3)6) in 450 mL of water.

[0233] Liquid chromatography-mass spectrometry and HPLC analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system equipped with a photodiode array detector and a Luna-C18(2) 2.0 × 50 mm, 5 μm column, using a gradient solvent mobile phase A (MPA, HO + 0.037% (v / v) TFA): mobile phase B (MPB, ACN + 0.018% (v / v) TFA) at a flow rate of 1.2 mL / min (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS was detected at 220 and 254 nm or using evaporative light scattering (ELSD) detection and positive electrospray ionization (MS). Semi-preparative HPLC was performed under either acidic or neutral conditions. Acidic: Luna C18 100 x 30 mm, 5 μm; MPA: HCl / H2O = 0.04% or formic acid / H2O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150 x 25, 5 μm; MPA: H2O with 10 mM NH4HCO3; MPB: ACN. Gradient for both conditions: 10% MPB to 80% MPB over 12 min, then 100% MPB over 2 min, 10% MPB over 2 min, at a flow rate of 20 mL / min. UV detector. SFC analysis was performed on a Thar analytical SFC system equipped with a UV / Vis detector and a series of chiral columns, including 4.6 × 100 mm, 3 μm columns: AD, AS-H, OJ, OD, AY, and IC. The gradient solvents were mobile phase A (MPA, CO2):mobile phase B (MPB, MeOH + 0.05% (v / v) IPA) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56–5 min, 10% MPB) at a flow rate of 4 mL / min.SFC preparative analysis was performed on a Thar 80 preparative SFC system equipped with a UV / Vis detector and a series of chiral preparative columns, including 30 × 250 mm, 5 μm columns: AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, at a flow rate of 65 mL / min using a gradient solvent mobile phase A (MPA, CO2):mobile phase B (MPB, MeOH + 0.1% (v / v) NH3HO) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1–10 min, 10% MPB). LC-MS data were also collected using a UPLC-MS Acquity™ system coupled to a Waters single quadrupole mass spectrometer equipped with a PDA detector and operated alternately in positive and negative electrospray ionization modes. The column used was a Cortecs UPLC C18, 1.6 μm, 2.1 × 50 mm. A linear gradient was applied starting from 95% A (A: 0.1% formic acid in water) and ending at 95% B (B: 0.1% formic acid in MeCN) over 2.0 min, with a total run time of 2.5 min. The column temperature was 40°C and the flow rate was 0.8 mL / min.

[0234] Intermediate 1 4-Bromo-7-fluoro-5-methyl-1-tosyl-1H-indole [ka] 3-Bromo-6-fluoro-2-iodo-4-methylaniline: To a solution of 5-bromo-2-fluoro-4-methylaniline (30 g, 147.03 mmol) in CHCOOH (500 mL) was added NIS (36.39 g, 161.73 mmol) at 0 °C under N. 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 aqueous NaHCO (3 × 10 mL). The organic layer was dried over anhydrous NaSO, 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] + .

[0235] 3-Bromo-6-fluoro-4-methyl-2-((trimethylsilyl)ethynyl)aniline: To a solution of ethynyl(trimethyl)silane (15.93 g, 162.21 mmol) in DMF (700 mL) was added TEA (205.18 g, 2.03 mol), CuI (2.57 g, 13.52 mmol), Pd(PPh)Cl (9.49 g, 13.52 mmol), and 3-bromo-6-fluoro-2-iodo-4-methylaniline (44.6 g, 135.18 mmol) under N at 0 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with HO (1500 mL) and extracted with EtOAc (3 × 700 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous NaSO, 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] + .

[0236] 4-Bromo-7-fluoro-5-methyl-1H-indole: To a solution of 3-bromo-6-fluoro-4-methyl-2-((trimethylsilyl)ethynyl)aniline (28 g, 93.26 mmol) in DMF (300 mL) was added CuI (35.52 g, 186.52 mmol) at 25 °C under N. The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered through a Celite pad. The filtrate was diluted with H2O (500 mL) and extracted with EtOAc (3 x 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.

[0237] 4-Bromo-7-fluoro-5-methyl-1-tosyl-1H-indole: To a solution of 4-bromo-7-fluoro-5-methyl-1H-indole (5 g, 21.92 mmol) in DMF (70 mL) was added NaH (1.05 g in mineral oil, 26.31 mmol, 60% purity) at 0° C. under N. 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 (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] + .

[0238] Intermediate 2 7-Fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole-2-sulfonyl chloride [ka] 3,3,4-Tribromo-7-fluoro-5-methylindolin-2-one: To a solution of 4-bromo-7-fluoro-5-methyl-1H-indole (5 g, 21.92 mmol) in t-BuOH (90 mL) and HO (30 mL) was added pyridine-Br (21.04 g, 65.77 mmol) at 20 °C under N. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 401.8, 403.8 [M+H] + .

[0239] 4-Bromo-7-fluoro-5-methylindolin-2-one: To a solution of 3,3,4-tribromo-7-fluoro-5-methyl-indolin-2-one (9.1 g, 22.65 mmol) in saturated aqueous NH4Cl (60 mL) and THF (60 mL) was added Zn (14.81 g, 226.45 mmol) at 20 °C under N2. The mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered through a Celite pad. To the filtrate was added saturated aqueous NaHCO3 (100 mL) and the mixture was extracted with EtOAc (3 x 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] + .

[0240] 4-Bromo-7-fluoro-5-methylindoline-2-thione: To a solution of 4-bromo-7-fluoro-5-methyl-indolin-2-one (4.1 g, 16.80 mmol) in THF (50 mL) was added P2S5 (2.24 g, 10.08 mmol) and NaHCO3 (14 mg, 0.17 mmol) at 20 °C under N2. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue, ice water (40 ml) was added and the mixture was stirred for 10 minutes. 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] + .

[0241] 4-Bromo-7-fluoro-2-((4-methoxybenzyl)thio)-5-methyl-1H-indole: To a solution of 4-bromo-7-fluoro-5-methyl-indoline-2-thione (1.8 g, 6.92 mmol) in DMF (25 mL) was added KCO (1.91 g, 13.84 mmol) and PMBCl (1.08 g, 6.92 mmol) at 20 °C under N. The mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, 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] + .

[0242] 7-Fluoro-2-((4-methoxybenzyl)thio)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole: 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-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.47 g, 5.79 mmol) in DMSO (30 mL) was added KOAc (852 mg, 8.68 mmol) and Pd(dppf)Cl (212 mg, 0.29 mmol) under N at 20 °C. The mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 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] + .

[0243] 7-Fluoro-2-((4-methoxybenzyl)thio)-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole: To a solution of 7-fluoro-2-((4-methoxybenzyl)thio)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (850 mg, 1.49 mmol) in EtOH (12 mL) and HO (3 mL) was added 3-bromo-1-methyl-1,2,4-triazole (483 mg, 2.98 mmol), KPO (633 mg, 2.98 mmol), and XPhos Pd G (117 mg, 0.15 mmol) under N at 20 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered through a Celite pad. 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 obtain the title compound. LCMS: m / z = 383.1 [M+H] + .

[0244] 7-Fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole-2-sulfonyl chloride: 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 HO (0.2 mL) was added NCS (174 mg, 1.31 mmol) at 0° C. under N. The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 329.0 [M+H] + .

[0245] Intermediate 3 7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole [ka] Lithium 4-bromo-7-fluoro-5-methyl-1-tosyl-1H-indole-2-sulfinate: To a solution of 4-bromo-7-fluoro-5-methyl-1-tosyl-1H-indole (5 g, 13.08 mmol) in THF (70 mL) was added LDA (3.14 mmol, 1.57 M, 2 M in THF / n-heptane) at −78° C. under N. The mixture was then stirred at −78° C. for 0.5 h. SO (g) was then bubbled into the reaction for 30 min, and the reaction was then stirred at 20° C. for 12 h. The reaction mixture was concentrated under reduced pressure to provide the title compound.

[0246] 4-Bromo-7-fluoro-5-methyl-1-tosyl-1H-indole-2-sulfonyl chloride: To a solution of lithium 4-bromo-7-fluoro-5-methyl-1-tosyl-1H-indole-2-sulfinate (9.2 g, 20.37 mmol) in DCM (100 mL) was added NCS (4.08 g, 30.55 mmol) at 20 °C under N. The reaction was then stirred at 20 °C for 2 hours. The reaction mixture was diluted with HO (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0247] 4-Bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole: To a solution of pyrrolidine (1.27 g, 17.85 mmol) in DCM (100 mL) was added pyridine (6.2 g, 81.12 mmol) and 4-bromo-7-fluoro-5-methyl-1-tosyl-1H-indole-2-sulfonyl chloride (7.8 g, 16.22 mmol) at 0 °C under N. The reaction was stirred at 0 °C for 2 h, diluted with HO (100 mL), and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 100:1 to 10:1) to give the title compound. LCMS: m / z = 515.0, 517.0 [M+H]+ .

[0248] 7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole: To a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole (260 mg, 0.50 mmol) in DMSO (5 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (192 mg, 0.75 mmol), KOAc (148 mg, 1.51 mmol), and Pd(dppf)Cl.CHCl (41 mg, 0.05 mmol) at 20 °C under N. The mixture was heated to 85° C. and stirred for 12 hours. Then, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 5:1 to 3:1) to give the title compound. LCMS: m / z = 409.2 [M+H] + .

[0249] Intermediate 4 1-Methyl-3-(tributylstannyl)-1H-1,2,4-triazole [ka] 1-Methyl-3-(tributylstannyl)-1H-1,2,4-triazole: To a mixture of 3-bromo-1-methyl-1H-1,2,4-triazole (1 g, 6.17 mmol) and tributyl(tributylstannyl)stannane (7.16 g, 12.35 mmol) in toluene (20 mL) was added Pd(PPh3)2Cl2 (433 mg, 0.62 mmol) under N2 at 25 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by adding saturated aqueous KF solution (10 mL) and filtered through a Celite pad. 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] + .

[0250] Intermediate 5 4-Bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole [ka] 4-Bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole: To a solution of pyrrolidine (44 mg, 0.62 mmol) in DCM (3 mL) was added TEA (189 mg, 1.87 mmol) and 4-bromo-7-fluoro-5-methyl-1-(p-tolylsulfonyl)indole-2-sulfonyl chloride (300 mg, 0.62 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was then diluted with HO (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting 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] + .

[0251] Intermediate 6 2-(azetidin-1-ylsulfonyl)-4-bromo-7-fluoro-5-methyl-1H-indole [ka] 2-(Azetidin-1-ylsulfonyl)-4-bromo-7-fluoro-5-methyl-1H-indole: To a solution of 4-bromo-7-fluoro-5-methyl-1-tosyl-1H-indole-2-sulfonyl chloride (100 mg, 0.20 mmol) in DCM (3 mL) was added azetidine hydrochloride (38 mg, 0.41 mmol) and TEA (105 mg, 1.04 mmol) at 20 °C under N. 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] + .

[0252] Intermediate 7 Potassium (3-(benzyloxy)cyclobutyl)trifluoroborate [ka] To a solution of 2-(3-(benzyloxy)cyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (680 mg, 2.36 mmol) in MeOH (24 mL) was added KHF (1.29 g, 16.52 mmol) at 20° C. The reaction mixture was heated to 70° C. and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added MeCN (30 mL), the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was triturated with diisopropyl ether (20 mL), and the solid was collected by filtration to provide the title compound.

[0253] Intermediate 8 Potassium (3-(benzyloxy)methyl)cyclobutyl)trifluoroborate [ka] 3-((benzyloxy)methyl)cyclobutan-1-ol: To a mixture of 3-((benzyloxy)methyl)cyclobutan-1-one (14 g, 73.59 mmol) in MeOH (140 mL) at 0 °C under N was added NaBH (4.18 g, 110.39 mmol) portionwise. The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was cooled to 0 °C and quenched by adding saturated aqueous NH Cl (140 mL), and 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 Na SO , filtered, and concentrated under reduced pressure to provide the title compound.

[0254] 3-((Benzyloxy)methyl)cyclobutyl 4-methylbenzenesulfonate: To a solution of 3-(benzyloxymethyl)cyclobutanol (14 g, 72.82 mmol) in DCM (200 mL) at 0 °C under N was added TEA (36.84 g, 364.1 mmol) and p-TsCl (10.27 g, 145.64 mmol). The reaction mixture was warmed 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.

[0255] To a mixture of 3-((benzyloxy)methyl)cyclobutyl 4-methylbenzenesulfonate (5 g, 14.43 mmol) in (((3-iodocyclobutyl)methoxy)methyl)benzene:butan-2-one (100 mL) at 25 °C under N was added NaI (6.49 g, 43.30 mmol). The reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was diluted with HO (200 mL) and extracted with MTBE (2 × 100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, 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.

[0256] 2-(3-((benzyloxy)methyl)cyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.93 g, 27.30 mmol) in DMF (10 mL) under N was added (((3-iodocyclobutyl)methoxy)methyl)benzene (5.5 g, 18.20 mmol), LiOMe (1.52 g, 40.05 mmol), PPh (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 HO (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (3 × 15 mL), dried over anhydrous NaSO, 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.

[0257] Potassium (3-((benzyloxy)methyl)cyclobutyl)trifluoroborate: To a mixture of 2-(3-((benzyloxy)methyl)cyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.8 g, 9.26 mmol) in MeOH (30 mL) and HO (6 mL) at 25 °C under N was added KHF (5.07 g, 64.85 mmol) and the reaction mixture was stirred for 12 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added MeCN (100 mL) and the mixture was filtered. The filtrate was concentrated under reduced pressure and the crude product was triturated with i-PrO (30 mL). The solid was collected and dried under reduced pressure to give the title compound.

[0258] Intermediates 9 and 10 trans-3-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde and cis-3-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde [ka] 4-(3-((benzyloxy)methyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole: To a mixture of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (0.7 g, 1.94 mmol) and potassium 3-(benzyloxy)methyl)cyclobutyl)trifluoroborate (711 mg, 2.52 mmol) in toluene (9 mL) and HO (3 mL) under N was added KCO (804 mg, 5.81 mmol) and Pd(dppf)Cl (142 mg, 0.19 mmol). The reaction mixture was heated to 140 °C and stirred for 12 h. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, 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] + .

[0259] (3-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutyl)methanol: To a mixture of 4-(3-((benzyloxy)methyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (250 mg, 0.55 mol) in DCM (2 mL) was added BCl (0.71 mL, 1 M in toluene) at 0 °C under N and the mixture was stirred for 1 hour. The reaction mixture was quenched at 0 °C by the addition of saturated aqueous NaHCO (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, 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] + .

[0260] trans-3-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde and cis-3-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde: To a mixture of (3-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutyl)methanol (95 mg, 0.26 mmol) in DCM (10 mL) was added DMP (220 mg, 0.52 mmol) under N at 25 °C, and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, 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-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde (first eluted) and cis-3-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde (second eluted). LCMS: m / z: 365.1 [M+H] + .

[0261] Intermediate 11 5-Methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] 4-Chloro-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl chloride: To a solution of 4-chloro-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (3 g, 9.35 mmol) in THF (30 mL) was added LDA (11.22 mmol, 5.61 mL, 2 M in THF / n-heptane) at −78° C. under N. The reaction mixture was stirred for 30 min, and then the mixture was added to a solution of sulfuryl 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 the addition of HO (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] +

[0262] 4-Chloro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine: To a mixture of 4-chloro-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl chloride (4 g, 9.54 mmol) in DCM (20 mL) was added pyridine (3.77 g, 47.70 mmol) and pyrrolidine (1.02 g, 14.31 mmol) at 0 °C under N. The reaction mixture was warmed to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, 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] +

[0263] 5-Methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine: 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.45 g, 5.73 mL) in 1,4-dioxane (20 mL) To a mixture of 4-chloro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.3 g, 2.86 mmol) and 4-chloro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.3 g, 2.86 mmol) was added KOAc (1.12 g, 11.45 mmol), PCy (80 mg, 0.28 mmol), and Pd(dba) (131 mg, 0.14 mmol) under N at 20 °C. The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous NaSO, 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] + .

[0264] Intermediate 12 2-((1H-imidazol-1-yl)sulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole [ka] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (11 g, 0.039 mol) in DMF (300 mL) at 20 °C under N was added 5-fluoro-2-(tributylstannyl)pyrimidine (21 g, 0.054 mol) and Pd(t-BuP) (1.45 g, 0.003 mol). The reaction mixture was heated to 110 °C and stirred for 8 h. The reaction mixture was diluted with HO (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous NaSO, 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 = 300.0 [M+H] + .

[0265] 3,3-Dibromo-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indolin-2-one: 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 HO (100 mL) at 20 °C under N was added pyridinium tribromide (64 g, 0.2 mmol). The reaction mixture was heated to 30 °C and stirred for 12 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 471.8 [M+H] + .

[0266] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indolin-2-one: To a solution of 3,3-dibromo-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indolin-2-one (24 g, 0.05 mol) in THF (240 mL) and saturated aqueous NH4Cl (240 mL) was added Zn (8.29 g, 0.13 mol) under N2 at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was filtered through a Celite® pad, and the filtrate was diluted with HO (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 = 316.0 [M+H] + .

[0267] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-thione: To a solution of 7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)indolin-2-one (12 g, 0.038 mol) in THF (220 mL) under N was added P2S5 (10.16 g, 0.046 mol) and NaHCO3 (320 mg, 0.004 mol) at 20 °C. The reaction mixture was heated to 50 °C and stirred for 8 h. The reaction mixture was used directly in the next step.

[0268] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole: 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) was added DMF (160 mL), KCO (10.52 g, 0.076 mol), and PMBCl (7.14 g, 0.046 mol) at 20 °C. The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with HO (300 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous NaSO, 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] + .

[0269] tert-Butyl 7-fluoro-4-(5-fluoropyrimidin-2-yl)-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole-1-carboxylate: 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) under N was added TEA (897 mg, 0.009 mol), DMAP (54 mg, 0.44 mmol), and BocO (1.16 g, 0.005 mol) at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was diluted with HO (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous NaSO, 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] + .

[0270] tert-Butyl 2-(chlorosulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate: To a solution of tert-butyl 7-fluoro-4-(5-fluoropyrimidin-2-yl)-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole-1-carboxylate (300 mg, 0.54 mmol) in AcOH (6 mL) and HO (2 mL) at 0 °C was added NCS (218 mg, 1.63 mmol). The reaction mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound. LCMS: m / z = 497.9 [M+H] + .

[0271] 2-((1H-Imidazol-1-yl)sulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: To a solution of tert-butyl 2-(chlorosulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate (600 mg, 1.21 mmol) in DCM (14 mL) at 20 °C, 1H-imidazole (410 mg, 6.03 mmol) was added and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was triturated 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] + .

[0272] Intermediate 13 6-(trifluoromethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine [ka] 1-(6-Bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethan-1-one: 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 under N was added TEA (3.53 g, 34.88 mmol) and acetyl chloride (2.74 g, 34.88 mmol). The reaction mixture was warmed to 25 °C and stirred for 3 h. The reaction mixture was diluted with HO (50 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous NaSO, 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 = 257.0, 259.0 [M+H] + .

[0273] 1-(6-(Trifluoromethyl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethan-1-one: To a solution of 1-(6-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethan-1-one (1 g, 3.89 mmol) in DMF (10 mL) at 25 °C under N was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.74 g, 19.45 mmol) and CuI (2.22 g, 11.67 mmol). The reaction mixture was heated to 120 °C and stirred for 12 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous NaSO, 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 = 247.1 [M+H] + .

[0274] 6-(Trifluoromethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine: To a solution of 1-(6-(trifluoromethyl)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethan-1-one (800 mg, 3.25 mmol) in MeOH (8 mL) was added KOH (365 mg, 6.49 mmol) at 25 °C. The reaction mixture was heated to 60 °C and stirred for 3 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, 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] + .

[0275] Intermediate 14 7-(trifluoromethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine [ka] To a solution of 7-(trifluoromethyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.34 g, 6.14 mmol) in THF (20 mL) at 0 °C under N was added LiAlH (2.5 M in THF, 4.91 mL). The reaction mixture was heated to 70 °C and stirred for 4 h. The reaction mixture was quenched by adding NaSO·10H O, filtered through a Celite® 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] + .

[0276] Example 1 2-(Cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (1) [ka] 4-Bromo-2-(cyclobutylthio)-7-fluoro-5-methyl-1H-indole: To a solution of 4-bromo-7-fluoro-5-methylindoline-2-thione (300 mg, 1.15 mmol) in DMF (10 mL) was added iodocyclobutane (419 mg, 2.31 mmol) and K2CO3 (318 mg, 2.31 mmol) at 25 °C under 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] + .

[0277] 4-Bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-1H-indole: To a solution of 4-bromo-2-(cyclobutylthio)-7-fluoro-5-methyl-1H-indole (200 mg, 0.63 mmol) in DCM (6 mL) was added m-CPBA (258 mg, 1.27 mmol, 85% purity) under N at 0 °C. The mixture was then stirred at 25 °C for 6 h. The reaction mixture was diluted with saturated aqueous NaSO (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaHCO (10 mL), dried over anhydrous NaSO, 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] + .

[0278] 2-(Cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole: To a solution of 4-bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-1H-indole (250 mg, 0.72 mmol) in DMSO (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (458 mg, 1.81 mmol), KOAc (212 mg, 2.17 mmol), and Pd(dppf)Cl·DCM (589 mg, 0.07 mmol) under N at 25 °C. The mixture was then stirred at 85 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 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 = 394.2 [M+H] + .

[0279] 2-(Cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (1): 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 HO (0.2 mL) was added 2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (50 mg, 0.13 mmol), KPO (81 mg, 0.38 mmol), XPhos (12 mg, 0.03 mmol), and Catacxium A Pd G (9 mg, 0.01 mmol) at 25 °C under N. The mixture was stirred at 100° C. for 12 hours. The reaction mixture was diluted with HO (2 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C 18 150×40 mm×10 μm; mobile phase: A: 10 mM NHHCO in water, B: MeCN; % B in A: 15%-55%, 8 min) to give the title compound. 1 H NMR (400 MHz, CDCl3): δ 8.96 (br s, 1H), 8.18 (s, 1H), 7.58 (t, J = 2.4 Hz, 1H), 7.05 (d, J = 11.6 Hz, 1H), 4.05 (s, 3H), 3.98-3.93 (m, 1H), 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] + .

[0280] Example 2 5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(2) [ka] 4-Bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-bromo-5-methyl-1H-pyrrolo[2,3-b]pyridine (1 g, 4.74 mmol) in DMF (20 mL) was added NaH (227 mg, 5.69 mmol, 60% in mineral oil) at 0 °C under N. The mixture was stirred at 0 °C for 0.5 h. To the mixture was added TsCl (1.35 g, 7.11 mmol) under N at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into saturated aqueous NH Cl (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na SO , 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] + .

[0281] Lithium 4-bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-sulfinate: To a solution of 4-bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1 g, 2.74 mmol) in THF (20 mL) was added LDA (4.11 mmol, 2.05 mL, 2 M in THF / n-heptane) at −78° C. under N. The mixture was stirred at −78° C. for 0.5 h. Then, SO gas was 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] + .

[0282] 4-Bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl chloride: To a solution of lithium 4-bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-sulfinate (1.2 g, 2.76 mmol) in DCM (25 mL) was added NCS (552 mg, 4.14 mmol) at 20 °C under N. The mixture was stirred at 20 °C for 1 h, diluted with HO (80 mL), and extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 462.9, 464.9 [M+H] + .

[0283] 4-Bromo-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl chloride (1 g, 2.16 mmol) in DCM (20 mL) was added TEA (436 mg, 4.31 mmol) and pyrrolidine (153 mg, 2.16 mmol) in DCM (2 mL) at 0 °C under N. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with HO (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, 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] + .

[0284] 5-Methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine: 4-Bromo-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (180 mg, 0 mL) in 1,4-dioxane (5 mL). To a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (229 mg, 0.90 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (229 mg, 0.90 mmol), KOAc (142 mg, 1.44 mmol), PCy (10.13 mg, 0.04 mmol), and Pd(dba) (16.54 mg, 0.02 mmol) were added under N at 20 °C. The mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO, PE:EtOAc = 5:1) to give the title compound. LCMS: m / z = 546.1 [M+H] + .

[0285] 5-Methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine: 5-Methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine in HO (0.2 mL) and 1,4-dioxane (2 mL). To a solution of (dioxaborolan-2-yl)-1-tosyl-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) was added KPO (140 mg, 0.66 mmol) and Pd(dtbpf)Cl (14 mg, 0.02 mmol) under N at 20 °C. The mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO, PE: EtOAc = 1:1) to give the title compound. LCMS: m / z = 501.1 [M+H] + .

[0286] 5-Methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2): To a solution of 5-methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (20 mg, 0.04 mmol) in MeOH (1 mL) was added NaOH (0.2 mL, 5 M in HO) at 20 °C under N. The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with HO (3 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were washed with brine (1 mL), dried over anhydrous NaSO, 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 NHHCO in water, B: MeCN; B in A: 25% to 55%, 8 min) to give the title compound. 1 H-NMR (400 MHz, DMSO-d6): δ 12.78 (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] + .

[0287] Example 3 7-Fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-benzo[d]imidazole (3) [ka] N-(5-Bromo-2-fluoro-4-methylphenyl)acetamide: To a mixture of 5-bromo-2-fluoro-4-methylaniline (10 g, 49.01 mmol) in DCM (100 mL) was added AcO (6.00 g, 58.81 mmol) and TEA (5.95 g, 58.81 mmol) at 25 °C under N. The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with H0 (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 246.1, 248.1 [M+H] + .

[0288] N-(3-Bromo-6-fluoro-4-methyl-2-nitrophenyl)acetamide: To a mixture of N-(5-bromo-2-fluoro-4-methylphenyl)acetamide (8 g, 32.51 mmol) in concentrated HSO (80 mL) was added HNO (6.27 g, 97.53 mmol, 98% purity) dropwise at 0 °C under N. 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] + .

[0289] 3-Bromo-6-fluoro-4-methyl-2-nitroaniline: To a mixture of N-(3-bromo-6-fluoro-4-methyl-2-nitrophenyl)acetamide (5 g, 17.18 mmol) in MeOH (20 mL) was added HCl (4 M, 20 mL). The mixture was stirred at 80° C. for 6 hours. The reaction was concentrated under reduced pressure to give the title compound. LCMS: m / z = 249.0, 251.0 [M+H] + .

[0290] 3-Bromo-6-fluoro-4-methylbenzene-1,2-diamine: To a mixture of 3-bromo-6-fluoro-4-methyl-2-nitroaniline (4 g, 16.06 mmol) in EtOH (50 mL) and HO (5 mL) was added Fe (4.48 g, 80.31 mmol) and NHCl (4.30 g, 80.31 mmol) at 25 °C under N. The mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 219.1, 221.1 [M+H] + .

[0291] 4-Bromo-7-fluoro-5-methyl-1H-benzo[d]imidazole-2-thiol: To a mixture of 3-bromo-6-fluoro-4-methylbenzene-1,2-diamine (2 g, 9.13 mmol) in EtOH (20 mL) and HO (1 mL) was added KCO (2.52 g, 18.26 mmol) and CS (1.39 g, 18.26 mmol). The reaction mixture was stirred at 80 °C for 5 hours, 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] + .

[0292] 4-Bromo-7-fluoro-5-methyl-1H-benzo[d]imidazole-2-perfluorophenyl sulfonate: First, a mixture of HCl (0.57 mL, 2 M in HO) in DCM (3 mL) was stirred at −5° C. To this solution, NaOCl (0.82 mL, 1.55 M, 10% purity) was added dropwise while maintaining the temperature below 0° C. The reaction mixture was cooled to −10° C., and 4-bromo-7-fluoro-5-methyl-1H-benzo[d]imidazole-2-thiol (100 mg, 0.38 mmol) was added and stirred at −10° C. for 20 minutes. At −10° C., the mixture was quenched with saturated aqueous NaSO until the yellow color disappeared. Next, the mixture was quickly extracted with DCM (while 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 warmed to -8 °C and stirred for 1 h. The reaction mixture was then diluted with HO (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with saturated aqueous NaHCO (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 474.9, 476.9 [M+H] + .

[0293] 4-Bromo-7-fluoro-5-methyl-2-(piperidin-1-ylsulfonyl)-1H-benzo[d]imidazole: To a mixture of 4-bromo-7-fluoro-5-methyl-1H-benzo[d]imidazole-2-perfluorophenylsulfonate (100 mg, 0.22 mmol) in MeCN (10 mL) was added piperidine (93 mg, 1.09 mmol) at 25 °C under N. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, 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 = 376.0, 378.0 [M+H] + .

[0294] 7-Fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-benzo[d]imidazole (3): 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-(tributylstannyl)-1H-1,2,4-triazole (198 mg, 0.53 mmol) in DMF (2 mL) was added Pd(t-BuP) (14 mg, 0.03 mmol) under N at 20 °C. The mixture was stirred at 120 °C for 8 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: A: NHHCO in water, B: MeCN; B% in A: 40% to 70%, 8 min) to give the title compound. 1 H NMR (400 MHz, CDCl3): δ 12.06 (s, 1H), 8.18 (s, 1H), 7.01 (d, J = 11.2 Hz, 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] + .

[0295] Example 4 7-Fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (4) [ka] 7-Fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole: To a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole (100 mg, 0.19 mmol) in DMF (2 mL) was added Pd(PPh) (22 mg, 0.019 mmol) and tributyl(pyrimidin-2-yl)stannane (86 mg, 0.23 mmol) at 20 °C under N. The mixture was stirred at 110 °C for 6 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound. LCMS: m / z = 515.3 [M+H] + .

[0296] 7-Fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (4): To a solution of 7-fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole (100 mg, 0.19 mmol) in MeOH (2 mL) was added NaOH (1 mL, 5 M) at 20 °C under N. The mixture was stirred at 30 °C for 2 hours. The reaction mixture was diluted with H0 (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 150×40 mm×10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 20% to 50%, 8 min) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.94 (d, J = 5.2 Hz, 2H), 8.86 (br s, 1H), 7.32 (t, J = 4.8 Hz, 1H), 7.17-7.13 (m, 1H), 7.05 (d, J = 11.6 Hz, 1H), 3.37-3.25 (t, J = 6.8 Hz, 4H), 2.53 (s, 3H), 1.80 (td, J = 3.6, 6.8 Hz, 4H). LCMS: m / z = 361.1 [M+H] + .

[0297] Example 5 4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (5) [ka] 4-(1,5-Dimethyl-1H-1,2,4-triazol-3-yl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (5): To a solution of 7-fluoro-5-methyl-2-pyrrolidin-1-ylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (110 mg, 0.27 mmol) in 1,4-dioxane (2 mL) and HO (0.2 mL) was added 3-bromo-1,5-dimethyl-1H-1,2,4-triazole (95 mg, 0.54 mmol), KCO (75 mg, 0.54 mmol), and Pd(dtbpf)Cl (18 mg, 0.027 mmol) under N at 20 °C. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was filtered through a Celite pad, and the filtrate was 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 in water, B: MeCN; B% in A: 20% to 50%, 8 min) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 9.10 (br s, 1H), 7.39 (t, J = 2.8 Hz, 1H), 6.99 (d, J = 11.6 Hz, 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] +

[0298] Example 6 2-((6-Azaspiro[2.5]octan-6-yl)sulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (6) [ka] 2-((6-Azaspiro[2.5]octan-6-yl)sulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (6): 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) was added TEA (154 mg, 1.52 mmol) and 6-azaspiro[2.5]octane·HCl (90 mg, 0.61 mmol) at 0 °C under N. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase: A: 20 mM FA in water, B: MeCN; B% in A: 35% to 70%, 8 min) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.78 (s, 1H), 8.19 (s, 1H), 7.41 (t, J = 2.8 Hz, 1H), 7.03 (d, J = 11.6 Hz, 1H), 4.05 (s, 3H), 3.22 (t, J = 5.6 Hz, 4H), 2.63 (s, 3H), 1.49 (t, J = 5.2 Hz, 4H), 0.26 (s, 4H). LCMS: m / z = 404.1 [M+H] + .

[0299] The following compounds were made or can be made via procedures similar to those described herein. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11] [Table 9-12] [Table 9-13] [Table 9-14] [Table 9-15]

[0300] Example 49 4-(6-chloropyridazin-3-yl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (50) [ka] 4-Bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole: To a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole (1 g, 1.94 mmol) in MeOH (5 mL) and THF (5 mL) was added NaOH (5 M in HO, 9.70 mL). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, 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] + .

[0301] 7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole: To a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (900 mg, 2.49 mmol) in DMSO (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.58 g, 6.23 mmol), KOAc (733 mg, 7.47 mmol), and Pd(dppf)Cl.CHCl (203 mg, 0.2 mmol) at 20 °C under N. The mixture was stirred at 105° C. for 12 hours. 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 = 409.1 [M+H] + .

[0302] 4-(6-chloropyridazin-3-yl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (50): To a solution of 7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (100 mg, 0.2 mmol) in 1,4-dioxane (1 mL) and HO (0.1 mL) was added 3,6-dichloropyridazine (72 mg, 0.4 mmol), KCO (101 mg, 0.7 mmol), and Pd(dtbpf)Cl (15 mg, 0.02 mmol) under N at 20 °C. 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 75×30 mm×3 μm; mobile phase: A: 43 mM FA in water, B: MeCN; % B in A: 15%-55%, 8 min) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 9.03 (br s, 1H), 7.70-7.58 (m, 2H), 7.08 (d, J = 11.6 Hz, 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] +

[0303] The following compounds were made or can be made via procedures similar to those described herein. [Table 10-1] [Table 10-2] [Table 10-3]

[0304] Example 55 2-(Azetidin-1-ylsulfonyl)-7-fluoro-5-methyl-4-(pyrimidin-2-yl)-1H-indole (60) [ka] 2-(Azetidin-1-ylsulfonyl)-7-fluoro-5-methyl-4-(pyrimidin-2-yl)-1H-indole (60): To a solution of 2-(azetidin-1-ylsulfonyl)-4-bromo-7-fluoro-5-methyl-1H-indole (60 mg, 0.11 mmol) in DMF (1.5 mL) was added tributyl(pyrimidin-2-yl)stannane (53 mg, 0.14 mmol) and Pd(t-BuP) (6 mg, 0.01 mmol) at 25 °C under N. The mixture was stirred at 110 °C for 5 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C 18 80×40 mm×3 μm; mobile phase: A: 10 mM NH 4 HCO 3 in water, B: MeCN; B% in A: 20% to 50%, 8 min) to give the title compound. 1 H NMR (400 MHz, CDCl3): δ 8.95 (d, J = 4.8 Hz, 2H), 7.33 (t, J = 5.2 Hz, 1H), 7.24 (t, J = 3.2 Hz, 1H), 7.09 (d, J = 11.6 Hz, 1H), 3.87 (t, J = 7.6 Hz, 4H), 2.55 (s, 3H), 2.14-2.05 (m, 2H). LCMS: m / z = 347.0 [M+H] + .

[0305] The following compounds were made or can be made via procedures similar to those described herein. [Table 11]

[0306] Example 62 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole [ka] 4-(3-((benzyloxy)cyclobutyl-7-fluoro-5-methyl-1H-indole): 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 HO (3 mL) at 25 °C under N was added KCO (848 mg, 6.14 mmol) and Pd(dppf)Cl (225 mg, 0.31 mmol). 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] + .

[0307] 4-(3-(Benzyloxy)cyclobutyl)-7-fluoro-5-methyl-1-tosyl-1H-indole: 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 under N was added NaH (34 mg, 0.85 mmol, 60% in mineral oil), 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, which was warmed to 25 °C and stirred for 2 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl (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] + .

[0308] 3-(7-Fluoro-5-methyl-1-tosyl-1H-indol-4-yl)cyclobutan-1-ol: To a solution of 4-(3-(benzyloxy)cyclobutyl)-7-fluoro-5-methyl-1-tosyl-1H-indole (520 mg, 1.12 mmol) in DCM (15 mL) at 0 °C under N was added BCl (3.37 mL, 1 M in toluene) and the mixture was stirred for 0.5 h. The reaction mixture was adjusted to pH = 7-8 by adding saturated aqueous NaHCO at 0 °C, and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 374.2 [M+H] + .

[0309] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-1-tosyl-1H-indole: To a mixture of 3-(7-fluoro-5-methyl-1-tosyl-1H-indol-4-yl)cyclobutan-1-ol (500 mg, 1.34 mmol) in DMF (15 mL) was added NaH (80 mg, 2.01 mmol, 60% in mineral oil) at 0 °C under 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 warmed to 25 °C and stirred for 12 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl (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 give the title compound. LCMS: m / z = 388.1 [M+H] + .

[0310] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-1-tosyl-1H-indole-2-sulfonyl chloride: To a mixture of 7-fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-1-tosyl-1H-indole (200 mg, 0.52 mmol) in THF (5 mL) at −78° C. under N was added LDA (0.31 mL, 2 M in THF / n-heptane), and the reaction mixture was stirred for 0.5 h. The reaction mixture was poured into a solution of sulfuryl chloride (418 mg, 3.10 mmol) in THF (3 mL) at −50° C., and the mixture was stirred for 0.5 h. The reaction mixture was quenched by adding ice HO (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound.

[0311] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole: To a solution of 7-fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-1-tosyl-1H-indole-2-sulfonyl chloride (200 mg, 0.41 mmol) in DCM (5 mL) at 0 °C, pyridine (163 mg, 2.06 mmol) and pyrrolidine (44 mg, 0.62 mmol) were added. The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 × 3 mL). The combined organic layers were dried over anhydrous NaSO, 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 = 521.0 [M+H] + .

[0312] 7-Fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole: To a mixture of 7-fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole (60 mg, 0.12 mmol) in THF (1 mL) and MeOH (1 mL) at 20 °C, 4 M NaOH (1 mL) was added. The reaction mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge Prep BEH C18 100 x 30 mm x 5 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 33% to 61%, 8 min) to give the title compound. LCMS: m / z = 367.0 [M+H] + .

[0313] Example 63 4-(trans-3-(difluoromethyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole [ka] To a mixture of trans-3-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde (20 mg, 0.05 mmol) in DCM (5 mL) at 0 °C under N was added DAST (27 mg, 0.16 mmol), and the reaction mixture was stirred for 0.5 h. The reaction mixture was diluted with saturated aqueous NaHCO (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, 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 NHHCO in HO, B: MeCN; B% in A: 30% to 65%, 8.0 min) to give the title compound. LCMS: m / z: 387.0 [M+H] + .

[0314] Example 64 4-(cis-3-(difluoromethyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole [ka] To a mixture of cis-3-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde (20 mg, 0.05 mmol) in DCM (5 mL) was added DAST (26.5 mg, 0.16 mmol) at 0 °C under N and the mixture was stirred for 0.5 h. The reaction mixture was diluted with saturated aqueous NaHCO (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, 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%, 8.0 min) to give the title compound. LCMS: m / z: 387.0 [M+H] +.

[0315] Example 65 2-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole [ka] tert-Butyl 2-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carbonyl)hydrazine-1-carboxylate: To a solution of methyl 7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carboxylate (50 mg, 0.10 mmol) in DCE (2 mL) under N at 20 °C was added tert-butyl N-aminocarboxylate (94 mg, 0.71 mmol) and AlMe (2 M in toluene, 0.2 mL). The reaction mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give the title compound. LCMS: m / z = 595.3 [M+H] + .

[0316] 7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carbohydrazide hydrochloride: A solution of tert-butyl 2-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carbonyl)hydrazine-1-carboxylate (200 mg, 0.37 mmol) in HCl / EtOAc (5 mL, 4 M) was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 495.1 [M+H] + .

[0317] 2-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indol-4-yl)-1,3,4-oxadiazole: To a solution of 7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carbohydrazide hydrochloride (100 mg, 0.20 mmol) in trimethyl orthoformate (2 mL) at 20° C. was added p-TsOH (2 mg, 0.01 mol). The reaction mixture was heated to 90° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 505.1 [M+H] +

[0318] 2-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole: To a solution of 2-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indol-4-yl)-1,3,4-oxadiazole (200 mg, 0.12 mmol) in MeOH (1 mL) and THF (1 mL) at 20° C. was added 5 M NaOH (0.5 mL). The reaction mixture was heated to 30° C. and stirred for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH 80 x 40 mm x 3 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 15% to 45%, 8.0 min) to give the title compound. LCMS: m / z = 351.1 [M+H] + .

[0319] Example 66 2-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole [ka] Methyl 7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carboxylate: To a solution of 4-bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole (1 g, 1.94 mmol) in DMF (10 mL) and MeOH (10 mL) was added Pd(OAc) (44 mg, 0.19 mmol), dppf (108 mg, 0.19 mmol), and TEA (589 mg, 5.82 mmol). The reaction mixture was degassed under vacuum and purged with CO several times. 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 HO (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, 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] + .

[0320] N'-Acetyl-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carbohydrazide: To a solution of methyl 7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carboxylate (50 mg, 0.10 mmol) in toluene (2 mL) at 20 °C under N was added acetylhydrazine (52 mg, 0.71 mmol) and AlMe (2 M in toluene, 0.15 mL). The reaction mixture was heated to 60 °C and stirred for 6 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO, EtOAc) to provide the title compound. LCMS: m / z = 537.2 [M+H] + .

[0321] 2-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole: To a solution of N'-acetyl-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole-4-carbohydrazide (60 mg, 0.11 mmol) in MeCN (6 mL) at 20 °C under N was added p-TsCl (32 mg, 0.17 mmol) and CsCO (146 mg, 0.45 mmol). The reaction mixture was heated to 60 °C and stirred for 6 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound. LCMS: m / z = 519.0 [M+H] + .

[0322] 2-(7-Fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole: To a solution of 2-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole (60 mg, 0.12 mmol) in MeOH (3 mL) at 20° C. was added NaOH (116 mg, 2.89 mmol). The reaction mixture was heated to 30° C. and stirred for 3 hours. 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 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 25% to 55%, 8.0 min) to give the title compound. LCMS: m / z = 365.1 [M+H] + .

[0323] Example 67 5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridine [ka] 4-Bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridine: 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 under N was added NaH (417 mg, 10.42 mmol, 60% in mineral oil), and the reaction mixture was stirred for 1 h. p-TsCl (2.71 g, 14.21 mmol) was added portionwise to the above mixture, which was then warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with saturated aqueous 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 triturated with MTBE (20 mL), and the solid was filtered to give the title compound. LCMS: m / z = 364.9, 366.9 [M+H] + .

[0324] 4-Bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-sulfonyl chloride: To a solution of 4-bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridine (1 g, 2.74 mmol) in THF (10 mL) at −78° C. under N2, LDA (3.56 mmol, 1.78 mL, 2 M in THF / n-heptane) was added, and the reaction mixture was stirred for 0.5 h. The above mixture was added to a solution of sulfuryl 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] + .

[0325] 4-Bromo-5-methyl-2-(piperidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridine: To a solution of 4-bromo-5-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-sulfonyl chloride (1.5 g, 3.23 mmol) in DCM (10 mL) at 0 °C under N was added pyridine (1.28 g, 16.17 mmol) and piperidine (496 mg, 5.82 mmol). The reaction mixture was warmed to 20 °C and stirred for 10 min. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting 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] + .

[0326] 5-Methyl-2-(piperidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridine: 3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)aniline (150 mg, To a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (186 mg, 0.73 mmol), KOAc (115 mg, 1.17 mmol), PCy (8 mg, 0.03 mmol), and Pd(dba) (13 mg, 0.02 mmol) were added under N at 20 °C. The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 478.0 [M-CH 10 +H] + .

[0327] 5-Methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridine: 5-methyl-2-(piperidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxane) in 1,4-dioxane (5 mL) and HO (0.5 mL). To a solution of (saborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridine (250 mg, 0.45 mmol) under N2 at 20 °C, 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) were added. The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was diluted with HO (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] + .

[0328] 5-Methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridine: To a solution of 5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridine (80 mg, 0.15 mmol) in THF (1 mL) was added 4 M NaOH (1 mL) and MeOH (1 mL) at 20 °C under N. The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was diluted with HO (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 NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30 mm×5 μm; mobile phase: A: 10 mM NHHCO in water, B: MeCN; B% in A: 12% to 40%, 8 min) to give the title compound. LCMS: m / z = 361.0 [M+H] + .

[0329] Example 68 7-Fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole [ka] 5-Bromo-2-fluoro-4-(trifluoromethyl)aniline: To a solution of 3-bromo-4-(trifluoromethyl)aniline (25 g, 104.16 mmol) in MeCN (300 mL) was added SelectFluor™ (44.28 g, 124.99 mmol) at 20° C. under N. The reaction mixture was heated to 50° C. and stirred for 2 h. The reaction mixture was diluted with HO (1 L) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 5:1) to give the title compound. LCMS: m / z = 258.0, 260.0 [M+H] + .

[0330] 3-Bromo-6-fluoro-2-iodo-4-(trifluoromethyl)aniline: To a solution of 5-bromo-2-fluoro-4-(trifluoromethyl)aniline (8.10 g, 31.39 mmol) in AcOH (100 mL) at 25 °C under N was added NIS (15.54 g, 69.07 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (3 x 80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 5:1) to give the title compound. LCMS: m / z = 381.8, 383.8 [M−H] - .

[0331] 3-Bromo-6-fluoro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline: To a solution of 3-bromo-6-fluoro-2-iodo-4-(trifluoromethyl)aniline (9.7 g, 25.27 mmol) and trimethylsilylacetylene (7.44 g, 75.80 mmol) in DMF (100 mL) under N was added TEA (25.57 g, 252.67 mmol), CuI (962.40 mg, 5.05 mmol), and Pd(PPh)Cl (1.77 g, 2.53 mmol). The reaction mixture was heated at 60 °C for 12 h. The reaction mixture was diluted with HO (300 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous NaSO, 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] +

[0332] 4-Bromo-7-fluoro-5-(trifluoromethyl)-1H-indole: 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 under N was added t-BuOK (4.91 g, 43.76 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 × 60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 5:1) to give the title compound. LCMS: m / z = 279.9, 281.9 [M−H] - .

[0333] 4-Bromo-7-fluoro-1-tosyl-5-(trifluoromethyl)-1H-indole: 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 under N was added NaH (561 mg, 14.04 mmol, 60% in mineral oil), and the reaction mixture was stirred for 0.5 h. p-TsCl (3.35 g, 17.55 mmol) was added, and the mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous NaSO, 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 triturated with PE (10 mL) and the solid was collected to give the title compound.

[0334] 4-Bromo-7-fluoro-1-tosyl-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: To a mixture of 4-bromo-7-fluoro-1-tosyl-5-(trifluoromethyl)-1H-indole (1 g, 2.29 mmol) in THF (16 mL) at −78° C. under N2, LDA (2.79 mmol, 1.38 mL, 2 M in THF / n-heptane) was added, and the reaction mixture was stirred for 0.5 h. The mixture was added to a solution of sulfuryl chloride (1.86 g, 13.75 mmol) in THF (10 mL) at −50° C. The reaction mixture was warmed to 20° C. and stirred for 0.5 h. The reaction mixture was diluted with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound.

[0335] 4-Bromo-7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-1-tosyl-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (1.2 g, 2.24 mmol) in DCM (12 mL) was added pyridine (888 mg, 11.22 mmol) and pyrrolidine (239 mg, 3.37 mmol) at 0 °C under N. The reaction mixture was warmed to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with 1 M HCl (2 × 10 mL), brine (30 mL), dried over anhydrous NaSO, 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.

[0336] 4-Bromo-7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-5-(trifluoromethyl)-1H-indole (220 mg, 0.39 mmol) in THF (1.5 mL) and MeOH (1.5 mL) at 20 °C under N was added 4 M NaOH (1.5 mL). The reaction mixture was heated to 30 °C and stirred for 2 h. The reaction mixture was diluted with HO (6 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (6 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was triturated with PE (5 mL), and the solid was collected to give the title compound.

[0337] 7-Fluoro-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-2-(pyrrolidin-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-dioxaborolane) (196 mg, 0.77 mmol) in DMSO (4 mL) was added KOAc (113 mg, 1.16 mmol) and Pd(dppf)Cl (28 mg, 0.04 mmol) under N at 20 °C. 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 x 5 mL). The combined organic layers were washed with brine (3 x 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] + .

[0338] 7-Fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: To a solution of 7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 HO (0.4 mL) was added KCO (30 mg, 0.22 mmol) and Pd(dtbpf)Cl (7 mg, 0.01 mmol) at 20 °C under N. The reaction mixture was heated to 100° C. and stirred for 2 hours. The mixture was filtered through a Celite® pad, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B in A: 30% to 60%, 8.0 min) to give the title compound. LCMS: m / z = 418.1 [M+H] + .

[0339] Example 69 4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole [ka] 4-Chloro-5-iodo-1-tosyl-1H-indole: To a solution of 4-chloro-5-iodo-1H-indole (8 g, 28.83 mmol) in DMF (100 mL) was added NaH (1.38 g, 34.60 mmol, 60% in mineral oil) 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 above mixture at 0 °C, and the reaction mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was poured into saturated aqueous 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] + .

[0340] 4-Chloro-1-tosyl-5-(trifluoromethyl)-1H-indole: To a solution of 4-chloro-5-iodo-1-tosyl-1H-indole (6.5 g, 15.06 mmol) in DMF (70 mL) at 20 °C under N was added 2,2-difluoro-2-fluorosulfonyl-methyl acetate (14.46 g, 75.29 mmol) and CuI (8.60 g, 45.17 mmol). The reaction mixture was heated to 120 °C and stirred for 12 h. The reaction mixture was filtered through a Celite® pad, and the filtrate was diluted with HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, 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] + .

[0341] 4-Chloro-1-tosyl-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: To a solution of 4-chloro-1-tosyl-5-(trifluoromethyl)-1H-indole (2 g, 5.35 mmol) in THF (20 mL) at −78° C. under N 2 , LDA (6.42 mmol, 3.21 mL, 2 M in THF / n-heptane) was added, and the reaction mixture was stirred for 0.5 h. The above mixture was added to a solution of sulfuryl chloride (4.33 g, 32.10 mmol) in THF (10 mL) at −78° C. under N 2 , 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 Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound.

[0342] 4-Chloro-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: To a solution of 4-chloro-1-tosyl-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (2.53 g, 5.36 mmol) in DCM (20 mL) was added pyridine (2.12 g, 26.78 mmol) and pyrrolidine (1.90 g, 26.78 mmol) at 0 °C, 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 NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO, PE: EtOAc = 10:1) to give the title compound. LCMS: m / z = 353.0 [M+H] + .

[0343] 2-(Pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indole: To a solution of 4-chloro-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-5-(trifluoromethyl)-1H-indole (150 mg, 0.43 mmol) in cyclopentyl methyl ether (2 mL) under N was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (324 mg, 1.28 mmol), KOAc (83 mg, 0.85 mmol), and P(t-Bu)Pd G (25 mg, 0.04 mmol). 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 x 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 [M−H] - .

[0344] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: To a solution of 2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indole (90 mg, 0.20 mmol) in 1,4-dioxane (1 mL) and HO (0.1 mL) was added 3-bromo-1-methyl-1H-1,2,4-triazole (66 mg, 0.40 mmol), KPO (86 mg, 0.41 mmol), and Pd(dtbpf)Cl (13 mg, 0.02 mmol) under N at 25 °C. 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 x 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 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 20% to 50%, 8 min) to give the title compound. LCMS: m / z = 400.0 [M+H] + .

[0345] Example 70 5-chloro-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-indole [ka] 3-Bromo-4-chloro-6-fluoro-2-iodoaniline: To a solution of 5-bromo-4-chloro-2-fluoroaniline (24 g, 106 mmol) in AcOH (250 mL) at 0 °C under N was added NIS (36 g, 160 mmol). The reaction mixture was warmed to 25 °C and stirred for 2 h. The reaction mixture was diluted with H O (1 L) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over anhydrous Na SO , 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 = 351.8 [M+H] +

[0346] 3-Bromo-4-chloro-6-fluoro-2-((trimethylsilyl)ethynyl)aniline: To a solution of 3-bromo-4-chloro-6-fluoro-2-iodoaniline (21 g, 59.94 mmol) in DMF (400 mL) at 25 °C under N was added trimethylsilylacetylene (8.83 g, 89 mmol), TEA (60 g, 599.40 mmol), CuI (2 g, 11.99 mmol), and Pd(PPh)Cl (4.2 g, 5.99 mmol). The reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was diluted with HO (1 L) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous NaSO, 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] + .

[0347] 4-Bromo-5-chloro-7-fluoro-1H-indole: 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 under N was added t-BuOK (7 g, 70 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H O (500 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (5 × 100 mL), dried over anhydrous Na SO , 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 = 249.9 [M+H] +

[0348] 4-Bromo-5-chloro-7-fluoro-1-tosyl-1H-indole: To a solution of 4-bromo-5-chloro-7-fluoro-1H-indole (3.3 g, 13 mmol) in DMF (35 mL) was added NaH (637 mg, 15 mmol, 60% in mineral oil) at 0 °C under N2, and the reaction mixture was stirred for 0.5 h. p-TsCl (3.8 g, 19.92 mmol) was added portionwise to the above mixture at 0 °C, and the reaction mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was poured into saturated aqueous 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 resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the crude product. This material was further triturated with MTBE (30 mL) and the solid was collected to give the title compound. LCMS: m / z = 403.9 [M+H] +

[0349] 4-Bromo-5-chloro-7-fluoro-1-tosyl-1H-indole-2-sulfonyl chloride: To a mixture of 4-bromo-5-chloro-7-fluoro-1-tosyl-1H-indole (2 g, 4.97 mmol) in THF (40 mL) was added LDA (2.98 mL, 2 M in THF / n-heptane) at −78° C. under N , and the reaction mixture was stirred for 0.5 h. The reaction mixture was added to a solution of sulfuryl 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 HO (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 523.8 [M+Na] + .

[0350] 4-Bromo-5-chloro-7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole: To a solution of 4-bromo-5-chloro-7-fluoro-1-tosyl-1H-indole-2-sulfonyl chloride (2 g, 3.99 mmol) in DCM (25 mL) was added pyridine (1.58 g, 19.95 mmol) and pyrrolidine (425 mg, 5.99 mmol) at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, 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 = 536.8 [M+H] +

[0351] 4-Bromo-5-chloro-7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-1H-indole: To a mixture of 4-bromo-5-chloro-7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-indole (200 mg, 0.37 mmol) in THF (2 mL) and MeOH (2 mL) at 20 °C, 4 M NaOH (1.92 mL) was added. The reaction mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was diluted with H O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 382.9 [M+H] +

[0352] 5-Chloro-7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole: To a solution of 4-bromo-5-chloro-7-fluoro-2-(pyrrolidin-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-dioxaborolane) (133 mg, 0.52 mmol) in DMSO (2 mL) was added KOAc (77 mg, 0.79 mmol) and Pd(dppf)Cl (19 mg, 0.02 mmol) under N at 20 °C. 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 x 5 mL). The combined organic layers were washed with brine (2 x 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] + .

[0353] 5-Chloro-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-indole: To a solution of 5-chloro-7-fluoro-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (30 mg, 0.06 mmol) in EtOH (1 mL) and HO (0.1 mL) at 20 °C under N was added 3-bromo-1-methyl-1H-1,2,4-triazole (34 mg, 0.21 mmol), KPO (44.56 mg, 0.2 mmol), and Pd(dtbpf)Cl (4.56 mg, 0.07 mmol). The reaction mixture was heated to 80° C. and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30 mm×5 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 12% to 42%, 8 min) to give the title compound. LCMS: m / z = 384.0 [M+H] +

[0354] Example 71 4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine [ka] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: 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) under N was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (28.8 g, 113.34 mmol), KOAc (11.12 g, 113.34 mmol), and P(Cy)Pd G (1.67 g, 2.27 mmol). 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] +

[0355] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (8 g, 25.63 mmol) in 1,4-dioxane (200 mL) and HO (20 mL) at 20 °C under N was added 3-bromo-1-methyl-1H-1,2,4-triazole (12.46 g, 76.90 mmol), KPO (16.32 g, 76.90 mmol), and CataCXium® A Pd-G (1.87 g, 2.56 mmol). The reaction mixture was heated to 100° C. and stirred for 16 hours. 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] + .

[0356] 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: 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-methylpropan-2-ol (20 mL) and HO (7 mL) under N was added pyridinium tribromide (7.18 g, 22.45 mmol) at 20 °C. The reaction mixture was heated to 35 °C and stirred for 16 h. The reaction mixture was diluted with HO (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] + .

[0357] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one: 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 aqueous NH4Cl (15 mL) was added Zn (2.37 g, 36.28 mmol) under N2 at 20 °C, and the reaction mixture was stirred for 2 h. The reaction mixture was filtered through a Celite® pad, and the filtrate was diluted with saturated aqueous NaHCO3 (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] +

[0358] 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 POCl (6 mL) was heated to 110 °C and stirred for 4 hours. The reaction mixture was cooled to 0 °C, adjusted to pH = 7 by adding saturated aqueous NaHCO and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 302.0 [M+H] +

[0359] 2-((4-Methoxybenzyl)thio)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: 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) at 20 °C was added CsCO (2.92 g, 8.95 mmol) and (4-methoxyphenyl)methanethiol (4.60 g, 29.84 mmol). The reaction mixture was heated to 50 °C and stirred for 16 h. The reaction mixture was filtered through a Celite® pad, 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: 0.2% FA in 10 mM water, B: MeCN; B% in A: 35% to 65%, 8.0 min) to give the title compound. LCMS: m / z = 420.0 [M+H] +

[0360] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfonyl: 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 HO (1 mL) at 0° C. under N was added NCS (64 mg, 0.48 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 365.9 [M+H] + .

[0361] 4-(1-Methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: 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) was added TEA (277 mg, 2.73 mmol) and pyrrolidine (97 mg, 1.37 mmol) at 20 °C under N, and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 15% to 45%, 8.0 min) to give the title compound. LCMS: m / z = 401.1 [M+H] +

[0362] Example 72 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine [ka] 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine: 5-methyl-2-(pyrrolidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa)pyridine in 1,4-dioxane (2 mL) and HO (0.4 mL). To a solution of (borolan-2-yl)-1-tosyl-1H-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) under N was added KPO (117 mg, 0.55 mmol) and Pd(dtbpf)Cl (12 mg, 0.02 mmol) at 25 °C under N. 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 (SiO, PE: EtOAc = 0:1) to give the title compound. LCMS: m / z = 541.2 [M+H] +

[0363] 4-(1-(Cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.09 mmol) in MeOH (2 mL) and THF (2 mL) at 25 °C was added 4 M NaOH (2 mL). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE: EtOAc = 0:1) to give the title compound. LCMS: m / z = 387.0 [M+H] +

[0364] Example 73 2-(Cyclobutylsulfonyl)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine [ka] 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 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 300.1 [M+H] +

[0365] 2-(Cyclobutylthio)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: 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) was added KCO (46 mg, 0.33 mmol) and bromocyclobutane (45 mg, 0.33 mmol) at 20 °C under N. The reaction mixture was heated to 50 °C and stirred for 5 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex Luna C18 100×40 mm×3 μm; mobile phase: A: 0.2% FA in water, B: MeCN; B% in A: 30%-60%, 8.0 min) to give the title compound. LCMS: m / z = 354.0 [M+H] +

[0366] 2-(Cyclobutylsulfonyl)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine: 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) was added m-CPBA (7 mg, 0.04 mmol, 85 wt%) at 0 °C under N. The reaction mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaSO (1 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 30%-60%, 8.0 min) to give the title compound. LCMS: m / z = 386.1 [M+H] +

[0367] Example 74 7-Fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1H-indole [ka] 4-Bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole: 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 under N was added NaH (150 mg, 3.75 mmol, 60% in mineral oil), 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 warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with saturated aqueous NHCl (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, 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] +

[0368] 4-Bromo-7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole: 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) at −78° C. under N was added LDA (1.2 mmol, 2 M in THF / n-heptane), 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 aqueous NH4Cl (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. LCMS: m / z = 565.9, 568.0 [M+Na] + .

[0369] 4-Bromo-7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1-((2-trimethylsilyl)ethoxy)methyl)-1H-indole (500 mg, 0.92 mmol) in DCM (2 mL) at 25 °C, TFA (1 mL) was added and the reaction mixture was stirred for 1 h. The reaction mixture was adjusted to pH = 7-8 by adding saturated aqueous NaHCO3. 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 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 43% to 73%, 8 min) to give the title compound. LCMS: m / z = 412.0, 414.0 [M−H] - .

[0370] 7-Fluoro-2-((1-methylcyclobutyl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indole: 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-dioxaborolane) (110 mg, 0.43 mmol) in DMSO (2 mL) was added KOAc (64 mg, 0.65 mmol) and Pd(dppf)Cl (16 mg, 0.02 mmol) under N at 25 °C. 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 x 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 [M−H] - .

[0371] 7-Fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)-1H-indole: To a solution of 7-fluoro-2-((1-methylcyclobutyl)sulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 HO (0.2 mL) was added KPO (58 mg, 0.27 mmol) and Pd(dtbpf)Cl (7 mg, 0.01 mmol) at 25 °C under N. The reaction mixture was heated to 100° C. and stirred for 2 hours. 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 in water, B: MeCN; B% in A: 35%-65%, 8 min) to give the title compound. LCMS: m / z = 417.1 [M+H] +

[0372] Example 75 7-Fluoro-N,4-di(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide [ka] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (10 g, 35.46 mmol) and 2-(tributylstannyl)pyrimidine (19.63 g, 53.19 mmol) in DMF (100 mL) at 25 °C under N was added Pd(t-BuP) (1.81 g, 3.55 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting 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] +

[0373] 3,3-Dibromo-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indolin-2-one: 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 HO (50 mL) at 20 °C under N was added pyridinium tribromide (34.12 g, 106.68 mmol). The reaction mixture was heated to 30 °C and stirred for 12 hours. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 455.9 [M+H] + .

[0374] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indolin-2-one: To a solution of 3,3-dibromo-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indolin-2-one (8 g, 17.58 mmol) in THF (80 mL) and saturated aqueous NH4Cl (80 mL) was added Zn (5.75 g, 87.91 mmol) at 0° C. under N2. The reaction mixture was warmed to 20° C. and stirred for 1 hour. The reaction mixture was filtered through a Celite® 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] + .

[0375] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indoline-2-thione: To a solution of 7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)indolin-2-one (5.7 g, 19.18 mmol) in THF (100 mL) at 20° C. under N was added P2S5 (5.12 g, 23.01 mmol) and NaHCO3 (161.11 mg, 1.92 mmol). The reaction mixture was heated to 50° C. and stirred for 10 hours. The reaction mixture was used directly in the next step. LCMS: m / z = 314.1 [M+H] + .

[0376] 7-Fluoro-2-((4-methoxybenzyl)thio)-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: 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) was added DMF (50 mL), KCO (5.29 g, 38.31 mmol), and PMBCl (3.60 g, 22.98 mmol) at 20 °C. The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with HO (150 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous NaSO, 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 = 434.2 [M+H] +

[0377] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: 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 HO (2 mL) at 0° C. under N was added NCS (277 mg, 2.08 mmol). The reaction mixture was warmed to 20° C. and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 380.0 [M+H] + .

[0378] 7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide: 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 under N was added NH·HO (1.39 mL, 9.01 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with DCM:i-PrOH (3 × 10 mL) (v:v = 3:1). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 16% to 46%, 8.0 min) to give the title compound. LCMS: m / z = 361.1 [M+H] +

[0379] 7-Fluoro-N,4-di(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide: 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) was added CsCO (81.39 mg, 0.25 mmol) and 2-fluoropyrimidine (16 mg, 0.16 mmol) at 20 °C. 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 NHHCO in water, B: MeCN; % B in A: 10% to 50%, 8.0 min) to give the title compound. LCMS: m / z = 439.0 [M+H] + .

[0380] Example 76 (S)-7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole [ka] 2-(Benzylthio)-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole: To a solution of 2-(benzylthio)-4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (400 mg, 0.99 mmol) and 2-(tributylstannyl)pyrimidine (475 mg, 1.29 mmol) in DMF (8 mL) at 20 °C under N was added Pd(t-BuP) (76 mg, 0.15 mmol). The reaction mixture was heated to 110 °C and stirred for 2 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous NaSO, 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] +

[0381] 3-Chloro-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: 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 HO (0.3 mL) at 0° C. under N was added NCS (42 mg, 0.31 mmol). The reaction mixture was warmed to 20° C. and stirred for 2 hours. An additional portion of NCS (24 mg, 0.18 mmol) was added and the reaction mixture was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 413.9 [M+H] + .

[0382] (S)-3-Chloro-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: 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) under N at 20 °C, TEA (39 mg, 0.39 mmol) and (S)-2-(trifluoromethyl)pyrrolidine (40 mg, 0.29 mmol) were added, and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to provide the title compound. LCMS: m / z = 517.1 [M+H] + .

[0383] (S)-7-Fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: To a solution of (S)-3-chloro-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole (30 mg, 0.06 mmol) in MeOH (1 mL) was added 10% Pd / C (30 mg) at 20° C. under N. The suspension was degassed under vacuum and purged with H three times, then the reaction mixture was stirred under H (15 psi) at 20° C. for 1 hour. The reaction mixture was filtered through a Celite® pad, and the filtrate was 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 in water, B: MeCN; B% in A: 20% to 50%, 8.0 min), and further purified by preparative TLC (PE: EtOAc = 1:1) to give the title compound. LCMS: m / z = 483.0 [M+H] + .

[0384] Example 77 (S)-7-Fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole [ka] 2-(5-Bromo-2-(trifluoromethyl)phenyl)-2H-1,2,3-triazole: To a solution of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (100 g, 0.41 mol) in DMF (1.4 L) at 25 °C, 2H-1,2,3-triazole (81.21 g, 0.82 mol) and K2CO3 (170.63 g, 1.23 mol) were added. 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 resulting 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] + .

[0385] 3-(2H-1,2,3-Triazol-2-yl)-4-(trifluoromethyl)aniline: 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) under N at 20 °C, diphenylmethanimine (22.34 g, 123.26 mmol), CsCO (53.55 g, 164.35 mmol), Xantphos (9.51 g, 16.44 mmol), and Pd(dba) (7.53 g, 8.22 mmol) were added. The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered through a Celite® pad, 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 warmed to 25° C. and stirred for 12 h. The reaction mixture was adjusted to pH=7-8 by adding saturated aqueous NaHCO3 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=10:1-5:1) to give the title compound. LCMS: m / z = 229.2 [M+H] + .

[0386] 2-Fluoro-5-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: 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) was added Selectfluor™ (18.4 g, 52.07 mmol) at 0° C. The reaction mixture was heated to 50° C. and stirred for 2 hours. 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] + .

[0387] 6-Fluoro-2-iodo-3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: 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) was added NIS (10.25 g, 45.54 mmol) at 0 °C under N. The reaction mixture was warmed 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 resulting 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] + .

[0388] 6-Fluoro-3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline: 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) under N was added trimethylsilylacetylene (6.20 g, 63.16 mmol), CuI (481 mg, 2.53 mmol), and Pd(PPh)Cl (886 mg, 1.26 mmol). The reaction mixture was heated to 80° C. and stirred for 7 h. The reaction mixture was filtered through a Celite® pad, and the filtrate was diluted with HO (60 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, 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] + .

[0389] 7-Fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole: 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) was added t-BuOK (1.64 g, 14.6 mmol) at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was diluted with HO (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous NaSO, 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 = 271.1 [M+H] + .

[0390] 3,3-Dibromo-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)indolin-2-one: 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 HO (4 mL) at 20 °C under N was added pyridinium tribromide (7.10 g, 22.21 mmol). The reaction mixture was heated to 30 °C and stirred for 12 hours. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 444.8 [M+H] + .

[0391] 7-Fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)indolin-2-one: To a solution of 3,3-dibromo-7-fluoro-4-(triazol-2-yl)-5-(trifluoromethyl)indolin-2-one (2 g, 4.50 mmol) in THF (20 mL) and saturated aqueous NH4Cl (20 mL) was added Zn (1.47 g, 22.52 mmol) under N2 at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was filtered through a Celite® pad. The filtrate was diluted with H2O (30 mL) and extracted with EtOAc (3 x 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 = 287.0 [M+H] + .

[0392] 7-Fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)indoline-2-thione: To a solution of 7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)indolin-2-one (1 g, 3.49 mmol) in THF (8 mL) was added P2S5 (932 mg, 4.19 mmol) and NaHCO3 (29 mg, 0.35 mmol) at 20 °C. 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] + .

[0393] 7-Fluoro-2-((4-methoxybenzyl)thio)-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole: 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) was added DMF (20 mL), KCO (1.83 g, 13.24 mmol), and PMBCl (1.55 g, 9.92 mmol) at 20 °C. The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with HO (40 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhydrous NaSO, 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 = 423.0 [M+H] + .

[0394] tert-Butyl 7-fluoro-2-((4-methoxybenzyl)thio)-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate: 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) at 0 °C was added TEA (143 mg, 1.42 mmol), DMAP (8 mg, 0.07 mmol), and BocO (232 mg, 1.07 mmol). The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with HO (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, 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] + .

[0395] tert-Butyl 2-(chlorosulfonyl)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate: To a solution of tert-butyl 7-fluoro-2-((4-methoxybenzyl)thio)-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate (50 mg, 0.10 mmol) in AcOH (0.6 mL) and HO (0.2 mL) at 0 °C was added NCS (38 mg, 0.28 mmol). The reaction mixture was warmed to 25 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 469.0 [M+H] + .

[0396] (S)-tert-Butyl 7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole-1-carboxylate: To a solution of tert-butyl 2-(chlorosulfonyl)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate (50 mg, 0.11 mmol) in DCM (2 mL) at 20 °C, TEA (54 mg, 0.53 mmol) and (S)-2-(trifluoromethyl)pyrrolidine (45 mg, 0.32 mmol) were added, and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine (3×2 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z = 471.9 [M-Boc+H] + .

[0397] (S)-7-Fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: To a solution of tert-butyl (S)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole-1-carboxylate (40 mg, 0.07 mmol) in DCM (1 mL) at 20 °C, TFA (0.2 mL) was added and the reaction mixture was stirred for 1 h. The reaction mixture was adjusted to pH 7-8 with saturated aqueous NaHCO and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B in A: 32% to 58%, 8.0 min) and further purified by preparative TLC (SiO2, PE: EtOAc = 3:1) to give the title compound. LCMS: m / z = 472.1 [M+H] + .

[0398] Example 78 (S)-7-Fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole [ka] 2-(Benzylthio)-4-bromo-7-fluoro-1-tosyl-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-1-tosyl-5-(trifluoromethyl)-1H-indole (8 g, 18.34 mmol) in THF (80 mL) was added dropwise LDA (11.00 mL, 2 M in THF / n-heptane) under N at −78° C., and the reaction mixture was stirred for 0.5 h. A solution of 1,2-dibenzyldisulfane (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 warmed to 20° C. and stirred for 2 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl (150 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was triturated with PE (20 mL) at −40° C. for 20 minutes, and the solid was collected to give the title compound.

[0399] 2-(Benzylthio)-4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole: To a solution of 2-(benzylthio)-4-bromo-7-fluoro-1-tosyl-5-(trifluoromethyl)-1H-indole (2.6 g, 4.66 mmol) in THF (25 mL) was added TBAF (23 mL, 1 M in THF) at 0 °C under N. The reaction mixture was warmed to 20 °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 give the title compound.

[0400] 4-Bromo-7-fluoro-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: To a solution of 2-(benzylthio)-4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (500 mg, 1.24 mmol) in AcOH (9 mL) and HO (3 mL) at 0 °C under N was added NCS (644 mg, 4.82 mmol). The reaction mixture was warmed to 20 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with HO (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 379.9 [M−H] - .

[0401] (S)-4-Bromo-7-fluoro-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: To a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (1 eq.) in DCM (0.27 M) at 20 °C under N was added TEA (5 eq.) and (S)-2-(trifluoromethyl)pyrrolidine (4 eq.), and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with HO (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO, PE: EtOAc = 5:1) to give the title compound. LCMS: m / z = 480.8, 482.8 [M−H] - .

[0402] (S)-7-Fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: 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-(tributylstannyl)pyrimidine (128 mg, 0.33 mmol) in DMF (2 mL) at 20 °C under N was added Pd(t-BuP) (8 mg, 0.016 mmol). The reaction mixture was heated to 110 °C and stirred for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, 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 in water, B: MeCN; B% in A: 40% to 70%, 8.0 min) to give the title compound. LCMS: m / z = 501.0 [M+H] + .

[0403] Example 79 (S)-7-Fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole [ka] (S)-7-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: (S)-4-Bromo-7-fluoro-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole in DMSO (3 mL) To a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (158 mg, 0.62 mmol) under N was added Pd(dppf)Cl (15 mg, 0.02 mmol) and KOAc (41 mg, 0.41 mmol) at 20 °C under N. 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] + .

[0404] (S)-7-Fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole: (S)-7-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole in 1,4-dioxane (2 mL) and HO (0.2 mL). To a solution of (trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole (50 mg, 0.09 mmol) and 4-bromo-2-methyl-2H-1,2,3-triazole (23 mg, 0.14 mmol) under N was added KPO (50 mg, 0.24 mmol) and Pd(dtbpf)Cl (6 mg, 0.009 mmol) at 20 °C under N. The reaction mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex Luna C18 100 x 30 mm x 3 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 40% to 75%, 8.0 min) to give the title compound. LCMS: m / z = 486.0 [M+H] + .

[0405] Example 80 2-(Cyclobutylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole [ka] 3,3,4-Tribromo-7-fluoro-5-(trifluoromethyl)indolin-2-one: To a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)-1H-indole (10 g, 35.46 mmol) in t-BuOH (200 mL) and HO (70 mL) at 20 °C under N was added pyridinium tribromide (68.04 g, 212.74 mmol). The reaction mixture was heated to 40 °C and stirred for 12 h. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was triturated 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 [M−H] - .

[0406] 4-Bromo-7-fluoro-5-(trifluoromethyl)indolin-2-one: To a solution of 3,3,4-tribromo-7-fluoro-5-(trifluoromethyl)indolin-2-one (7.9 g, 17.33 mmol) in THF (80 mL) and saturated aqueous NH4Cl (80 mL) was added Zn (5.67 g, 86.66 mmol) at 0 °C under N2. The reaction mixture was warmed to 25 °C and stirred for 2 h. The reaction mixture was filtered through a Celite® pad, and the filtrate was diluted with HO (50 mL) and extracted with EtOAc (3 × 20 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 (SiO2, PE:EtOAc = 6:1 to 1:1) to give the title compound. LCMS: m / z = 296.0, 298.0 [M−H] - .

[0407] 4-Bromo-7-fluoro-5-(trifluoromethyl)indoline-2-thione: To a solution of 4-bromo-7-fluoro-5-(trifluoromethyl)indolin-2-one (500 mg, 1.68 mmol) in THF (10 mL) at 25 °C under N was added P2S5 (373 mg, 1.68 mmol) and NaHCO3 (14 mg, 0.17 mmol). The reaction mixture was heated to 50 °C and stirred for 6 h. The reaction mixture was diluted with HO (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] + .

[0408] 4-Bromo-2-(cyclobutylthio)-7-fluoro-5-(trifluoromethyl)-1H-indole: 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 under N was added KCO (158 mg, 1.15 mmol). The reaction mixture was heated to 65 °C and stirred for 2 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting 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] + .

[0409] 4-Bromo-2-(cyclobutylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-2-(cyclobutylthio)-7-fluoro-5-(trifluoromethyl)-1H-indole (160 mg, 0.43 mmol) in DCM (4 mL) at 0 °C under N was added m-CPBA (220 mg, 1.09 mmol, 85 wt%). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was triturated with MTBE (10 mL), and the solid was collected to give the desired compound. LCMS: m / z = 399.9, 401.9 [M+H] + .

[0410] 2-(Cyclobutylsulfonyl)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indole: 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-dioxaborolane) (228 mg, 0.90 mmol) in DMSO (4 mL) was added KOAc (132 mg, 1.35 mmol) and Pd(dppf)Cl (33 mg, 0.04 mmol) under N at 25 °C. The reaction mixture was heated to 100 °C and stirred for 6 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 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 = 6:1 to 1:1) to give the title compound. LCMS: m / z = 446.1 [M−H] - .

[0411] 2-(Cyclobutylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole: To a solution of 2-(cyclobutylsulfonyl)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 HO (0.1 mL) was added KPO (47 mg, 0.22 mmol) and Pd(dtbpf)Cl (7 mg, 0.01 mmol) under N at 25 °C. The reaction mixture was heated to 100 °C and stirred for 5 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B in A: 20% to 50%, 8.0 min) to give the title compound. LCMS: m / z = 403.1 [M+H] + .

[0412] Example 81 2-(Cyclopropylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole [ka] 4-Bromo-7-fluoro-2-iodo-1-tosyl-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-1-tosyl-5-(trifluoromethyl)-1H-indole (1 g, 2.30 mmol) in THF (15 mL) at −78 °C under N was added LDA (1.49 mL, 2 M in THF / n-heptane), and the reaction mixture was stirred for 1 h. A solution of I (698 mg, 2.75 mmol) in THF (10 mL) was added to the above reaction mixture, and the reaction mixture was warmed to 20 °C and stirred for 1 h. The reaction was quenched by adding saturated aqueous NH Cl (15 mL), diluted with HO (10 mL), and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na SO , 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 [M−H] - .

[0413] 4-Bromo-2-(cyclopropylsulfonyl)-7-fluoro-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-2-iodo-1-tosyl-5-(trifluoromethyl)-1H-indole (550 mg, 0.95 mmol) and cyclopropylsulfinyloxysodium (250 mg, 1.9 mmol) in DMSO (10 mL) at 25 °C under N was added CuI (372 mg, 1.96 mmol). The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was diluted with HO (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 30% to 60%, 8 min) to give the title compound. LCMS: m / z = 383.9, 385.9 [M−H] - .

[0414] 2-(Cyclopropylsulfonyl)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indole: 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-dioxaborolan-2-yl)-1,3,2-dioxaborolane (138 mg, 0.54 mmol) in DMSO (2 mL) was added Pd(dppf)Cl (13 mg, 0.02 mmol) and KOAc (53 mg, 0.54 mmol) under N at 25 °C. 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 x 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 = 10:1) to give the title compound. LCMS: m / z = 432.1 [M−H] - .

[0415] 2-(Cyclopropylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole: To a solution of 2-cyclopropylsulfonyl-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indole (40 mg, 0.09 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (22 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and HO (0.2 mL) was added KPO (49 mg, 0.23 mmol) and Pd(dtbpf)Cl (6 mg, 0.01 mmol) under N at 25 °C. The reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was concentrated and the resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 20% to 50%, 8 min) to give the title compound. LCMS: m / z = 389.1 [M+H] + .

[0416] Example 82 7-Fluoro-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(5-fluoropyrimidin-2-yl)-N-methyl-5-(trifluoromethyl)-1H-indole-2-sulfonamide [ka] tert-Butyl 7-fluoro-2-(N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-methylsulfamoyl)-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate: To a solution of tert-butyl 2-(chlorosulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate (110 mg, 0.22 mmol) in DCM (2 mL) at 20 °C, TEA (112 mg, 1.10 mmol) and 3-fluoro-N-methylbicyclo[1.1.1]pentan-1-amine (76 mg, 0.66 mmol) were added, and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (3×5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z = 577.0 [M+H] + .

[0417] 7-Fluoro-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(5-fluoropyrimidin-2-yl)-N-methyl-5-(trifluoromethyl)-1H-indole-2-sulfonamide: To a solution of tert-butyl 7-fluoro-2-(N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-methylsulfamoyl)-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate (120 mg, 0.21 mmol) in DCM (1.5 mL) was added TFA (0.3 mL, 4.04 mmol) at 0° C. The reaction mixture was warmed to 20° C. and stirred for 5 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, 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 NHHCO in water, B: MeCN; B% in A: 40% to 75%, 8.0 min), and further purified by preparative TLC (PE: EtOAc = 3:1) to give the title compound. LCMS: m / z = 477.0 [M+H] + .

[0418] Example 83 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-N-methyl-N-(3-methylbicyclo[1.1.1]pentan-1-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide [ka] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride: To a solution of 7-fluoro-4-(5-fluoropyrimidin-2-yl)-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole (300 mg, 0.66 mmol) in AcOH (4.5 mL) and HO (1.5 mL) at 0 °C under N was added NCS (266 mg, 1.99 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative TLC (SiO2, PE: EtOAc = 10:1) to give the title compound. LCMS: m / z = 397.9 [M+H] + .

[0419] 7-Fluoro-4-(5-fluoropyrimidin-2-yl)-N-methyl-N-(3-methylbicyclo[1.1.1]pentan-1-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide: To a solution of 7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonyl chloride (20 mg, 0.05 mmol) in DCM (1 mL) was added TEA (20 mg, 0.20 mmol) and N,3-dimethylbicyclo[1.1.1]pentan-1-amine hydrochloride (22 mg, 0.15 mmol) under N at 20 °C, and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex Luna C18 75 x 30 mm x 3 μm; mobile phase: A: 0.2% FA in water, B: MeCN; B% in A: 30% to 70%, 8.0 min) to give the title compound. LCMS: m / z = 473.0 [M+H] +.

[0420] Example 84 7-Fluoro-4-((7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indol-2-yl)sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine [ka] To a solution of 2-((1H-imidazol-1-yl)sulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole (40 mg, 0.093 mmol) in o-xylene (2 mL) under N was added pyridine (37 mg, 0.47 mmol) and 7-fluoro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (43 mg, 0.28 mmol) at 25° C. The reaction mixture was heated to 150° C. and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by preparative HPLC (Waters Xbridge BEH C 18 100×30 mm×10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; % B in A: 45% to 75%, 8.0 min) to give the title compound. LCMS: m / z = 516.1 [M+H] + .

[0421] Example 85 4-((7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indol-2-yl)sulfonyl)-3-(trifluoromethy...

Claims

1. Compounds of Formula I: 【Chemistry 81】 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR ４ and Y １ is N or CR ５ and X is N or CR ６ and 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 where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ２ is halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ３ is halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ４ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ５ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ６ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; Each R ７ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; or Two R's ７ together with the nitrogen atom to which they are attached, independently represent one to five Z １ forming an optionally substituted heterocyclyl; Each R １１ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ａ optionally substituted with; Each Z １ are independently halo, cyano, -NO ２ , 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) ２ R １２ , -C(O)N(R １２ ) ２ , -NR １２ C(O)R １２ , -NR １２ S(O)R １２ , -NR １２ S (O) ２ R １２ , -S(O)N(R １２ ) ２ , -S(O) ２ N (R １２ ) ２ , -NR １２ C(O)N(R １２ ) ２ , -NR １２ S(O)N(R １２ ) ２ , -NR １２ S (O) ２ N (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, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ａ optionally substituted with; Each R １２ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each Z １ａ are independently halo, cyano, -NO ２ , 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) ２ R １３ , -C(O)N(R １３ ) ２ , -NR １３ C(O)R １３ , -NR １３ S(O)R １３ , -NR １３ S (O) ２ R １３ , -S(O)N(R １３ ) ２ , -S(O) ２ N (R １３ ) ２ , -NR １３ C(O)N(R １３ ) ２ , -NR １３ S(O)N(R １３ ) ２ , -NR １３ S (O) ２ N (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, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each R １３ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each Z １ｂ are independently halo, cyano, —OH, —SH, —NH ２ , -NO ２ , 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 Each L is independently —O—, —NH—, —S—, —S(O)—, or —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 １－６ alkyl)-, -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) ２ NH-; Here, Z １ｂ 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, and L may further independently represent 1 to 5 halo, cyano, —OH, —SH, —NH ２ , -NO ２ , -SF ５ , 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 optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl; however, A) X is N and R １ is methyl, R ２ is C ３－１０ cycloalkyl, aryl, or heteroaryl, where C ３－１０ The cycloalkyl, aryl, or heteroaryl may independently be one to five Z １ and B) The compound is 4,5,6,7-tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 1,1-dimethylethyl 4-[(4,5-difluoro-1H-indol-2-yl)sulfonyl]-1-piperazinecarboxylate (1415396-05-2), 3-[7-chloro-5-fluoro-2-(methylsulfonyl)-1H-indol-4-yl]-1-methyl-6-( or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, tautomer, or mixture of stereoisomers thereof.

2. Compound of Formula IA: 【Chemistry 82】 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein ring B is C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, optionally substituted with

3. The compound has formula IB: 【Chemistry 83】 3. The compound of claim 2, represented by: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof.

4. The compound has formula IG: 【Chemical 84】 3. The compound of claim 2, represented by: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof.

5. R １ is C ３－１０ cycloalkyl, heterocyclyl, aryl, heteroaryl, or —N(R １１ ) ２ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ 3. The compound of claim 1 or 2, optionally substituted with:

6. R １ is C １－６ Alkyl, C ２－６ alkenyl, or C ２－６ alkynyl, where C １－６ Alkyl, C ２－６ alkenyl, or C ２－６ Alkynyl is independently one to five Z １ 3. The compound of claim 1 or 2, optionally substituted with:

7. R １ is 1 to 5 Z １ C optionally substituted with ３－１０ 3. The compound of claim 1 or 2, which is cycloalkyl.

8. R １ is 1 to 5 Z １ 3. The compound of claim 1 or 2, wherein the heterocyclyl is optionally substituted with

9. R １ is 1 to 5 Z １ 3. The compound of claim 1 or 2, wherein R is an optionally substituted aryl.

10. R １ is 1 to 5 Z １ 3. The compound of claim 1 or 2, wherein the heteroaryl is optionally substituted with

11. R １ is -N(R ７ ) ２ 3. The compound of claim 1 or 2, wherein

12. Compound of Formula II: 【Chemical 85】 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR ４ and Y １ is N or CR ５ and X is N or CR ６ and Ring B is C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ３ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ４ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ５ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ６ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; Each R ７ are independently １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; or Two R's ７ together with the nitrogen atom to which they are attached, independently represent one to five Z １ forming an optionally substituted heterocyclyl; Each R １１ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ａ optionally substituted with; Each Z １ are independently halo, cyano, -NO ２ , 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) ２ R １２ , -C(O)N(R １２ ) ２ , -NR １２ C(O)R １２ , -NR １２ S(O)R １２ , -NR １２ S (O) ２ R １２ , -S(O)N(R １２ ) ２ , -S(O) ２ N (R １２ ) ２ , -NR １２ C(O)N(R １２ ) ２ , -NR １２ S(O)N(R １２ ) ２ , -NR １２ S (O) ２ N (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, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ａ optionally substituted with; Each R １２ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each Z １ａ are independently halo, cyano, -NO ２ , 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) ２ R １３ , -C(O)N(R １３ ) ２ , -NR １３ C(O)R １３ , -NR １３ S(O)R １３ , -NR １３ S (O) ２ R １３ , -S(O)N(R １３ ) ２ , -S(O) ２ N (R １３ ) ２ , -NR １３ C(O)N(R １３ ) ２ , -NR １３ S(O)N(R １３ ) ２ , -NR １３ S (O) ２ N (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, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each R １３ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each Z １ｂ are independently halo, cyano, —OH, —SH, —NH ２ , -NO ２ , 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 Each L is independently —O—, —NH—, —S—, —S(O)—, or —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 １－６ alkyl)-, -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) ２ NH-; Here, Z １ｂ 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, and L may further independently represent 1 to 5 halo, cyano, —OH, —SH, —NH ２ , -NO ２ , -SF ５ , 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 A compound of formula II, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

13. Compound of Formula IIA: 【Chemical 86】 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: Y is N or CR ４ and Y １ is N or CR ５ and X is N or CR ６ and Ring A is one to five Z １ heterocyclyl optionally substituted with Ring B is C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ３ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ４ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ５ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; R ６ is hydrogen, halo, cyano, -NO ２ , 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) ２ R １１ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -NR １１ S(O)R １１ , -NR １１ S (O) ２ R １１ , -S(O)N(R １１ ) ２ , -S(O) ２ N (R １１ ) ２ , -NR １１ C(O)N(R １１ ) ２ , -NR １１ S(O)N(R １１ ) ２ , -NR １１ S (O) ２ N (R １１ ) ２ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ where C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ optionally substituted with; Each R １１ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ａ optionally substituted with; Each Z １ are independently halo, cyano, -NO ２ , 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) ２ R １２ , -C(O)N(R １２ ) ２ , -NR １２ C(O)R １２ , -NR １２ S(O)R １２ , -NR １２ S (O) ２ R １２ , -S(O)N(R １２ ) ２ , -S(O) ２ N (R １２ ) ２ , -NR １２ C(O)N(R １２ ) ２ , -NR １２ S(O)N(R １２ ) ２ , -NR １２ S (O) ２ N (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, C １－６ Haloalkyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ａ optionally substituted with; Each R １２ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each Z １ａ are independently halo, cyano, -NO ２ , 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) ２ R １３ , -C(O)N(R １３ ) ２ , -NR １３ C(O)R １３ , -NR １３ S(O)R １３ , -NR １３ S (O) ２ R １３ , -S(O)N(R １３ ) ２ , -S(O) ２ N (R １３ ) ２ , -NR １３ C(O)N(R １３ ) ２ , -NR １３ S(O)N(R １３ ) ２ , -NR １３ S (O) ２ N (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, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each R １３ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ｂ optionally substituted with; Each Z １ｂ are independently halo, cyano, —OH, —SH, —NH ２ , -NO ２ , 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 Each L is independently —O—, —NH—, —S—, —S(O)—, or —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 １－６ alkyl)-, -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) ２ NH-; Here, Z １ｂ 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, and L may further independently represent 1 to 5 halo, cyano, —OH, —SH, —NH ２ , -NO ２ , -SF ５ , 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 A compound of formula IIA, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

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

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

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

17. Y １ The compound of any one of claims 1-2 or 5-15, wherein is N.

18. The compound has the formula IE: 【Chemistry 87】 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein ring B is C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ 13. The compound of claim 1 or 12, optionally substituted with:

19. The compound has formula IF: 【Chemical 88】 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein ring A is selected from the group consisting of 1 to 5 Z １ Ring B is heterocyclyl optionally substituted with C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, where C ３－１０ The cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently one to five Z １ 14. The compound of claim 1 or 13, optionally substituted with:

20. R ５ is halo.

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

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

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

24. R １ Or ring A is 1 to 5 Z １ The compound according to any one of claims 1 to 23, which is a 4- to 10-membered heterocyclyl optionally having

25. R １ Or ring A is 【Chemistry 89】 where each is 1 to 5 Z １ The compound according to any one of claims 1 to 24, optionally having

26. R ２ Or ring B is 1 to 5 Z １ 26. The compound of any one of claims 1 to 25, wherein the compound is heteroaryl optionally substituted with

27. R ２ Or ring B is 1 to 5 Z １ 27. The compound of any one of claims 1 to 26, wherein the ring is a 5- or 6-membered heteroaryl optionally substituted with:

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

29. Each Z １ is halo, cyano, -OH, -SH, -NH ２ , -NO ２ , -SF ５ , -S(O) ２ -C １－６ Alkyl, 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 The compound of any one of claims 1 to 28, independently selected from cycloalkyl, heterocyclyl, 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 a compound according to any preceding claim, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, tautomer, or mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier.

32. 32. A method of inhibiting SARM1 activity, comprising contacting a cell with an effective amount of a 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.

33. 33. The method of claim 32, wherein the contacting is performed in vivo.

34. 32. A method for treating a disease or condition mediated at least in part by SARM1, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-30, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof; or a pharmaceutical composition of claim 31.

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

36. 32. A method for treating a neurodegenerative or neurological disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition of claim 31.

37. 37. The method of claim 36, wherein the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal injury, axonopathy, demyelinating disease, central pontine myelinolysis, nerve injury disease or disorder, metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal injury resulting from traumatic axonal injury (TAI), leukoencephalopathy, or leukodystrophy.

38. The disease or condition may be spinal cord injury, stroke, multiple sclerosis, progressive multifocal alveolar myelopathy, or the like. Interstitial encephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin breakdown, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbach disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-irradiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B １２ Deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, 38. The method of claim 37, wherein the condition is childhood viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), conductive sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axonal neuropathy (AMAN).

39. 32. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition according to claim 31, for treating a disease or condition mediated at least in part by SARM1.

40. The disease or condition may be spinal cord injury, stroke, multiple sclerosis, progressive multifocal alveolar myelopathy, or the like. Interstitial encephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin breakdown, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbach disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-irradiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B １２ Deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, childhood viruses 40. The use of claim 39, wherein the condition is selected from the group consisting of: Rhode Island encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), conductive sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, and severe acute motor axonal neuropathy (AMAN).

41. 32. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition according to claim 31, for use in therapy.

42. Spinal cord injury, stroke, multiple sclerosis, progressive multifocal alveolar leukemia Interstitial encephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin breakdown, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbach disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-irradiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B １２ Deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, childhood viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA) A), a compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition of claim 31, for use in the treatment of Hemodynamic Sensory and Autonomic Neuropathy (HSAN), Myelomoneuropathy, Progressive Supranuclear Palsy (PSP), Friedreich's Ataxia, Hereditary Ataxia, Noise-Induced Hearing Loss, Congenital Hearing Loss, Dementia with Lewy Bodies, Frontotemporal Dementia, Amyloidosis, Diabetic Neuropathy, HIV Neuropathy, Enteric Neuropathy and Axonopathy, Guillain-Barre Syndrome, or Severe Acute Motor Axonal Neuropathy (AMAN).

43. Spinal cord injury, stroke, multiple sclerosis, progressive multifocal alveolar leukemia Interstitial encephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelin breakdown, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus-Merzbach disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-irradiation injury, neurological complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B １２ Deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber's hereditary optic atrophy (neuropathy), Leber's congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, childhood viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary 32. Use of a compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition of claim 31, for the manufacture of a medicament for treating sex sensory and autonomic neuropathy (HSAN), myelomoneuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axonal neuropathy (AMAN).

44. A process for obtaining a compound of formula I according to claim 1, comprising the step of: 【Chemistry 90】 with a compound of formula I-2: 【Chemistry 91】 under conditions sufficient to provide a compound of formula I, wherein LG is a leaving group and each R ５０ are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic boronate.

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