Compounds, compositions, and methods

Abstract

The present disclosure relates generally to small molecule inhibitors of axonal degeneration, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, methods of making and intermediates thereof, and methods of using thereof.

Description

COMPOUNDS, COMPOSITIONS, AND METHODS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Serial Number 63 / 433,346 filed December 16, 2022, the contents of which are hereby incorporated by reference in its entirety FIELD

[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

[0003] Neurodegenerative diseases are a class of progressive neurological disorders, in which nerve cells malfunction and ultimately die. The degradation of neurons in those suffering from a neurodegenerative disease can present as a wide variety of symptoms, including changes in mood and behavior, agitation, sensory disturbances, motor and cognitive difficulties, and memory loss, which can progress to inability to move or speak, dementia, and ultimately death.

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

[0005] In healthy axons, SARM1’s N-terminus interacts with the TIR domain, preventing TIR multimerization and subsequent enzymatic cleavage of NAD+. However, under neuronal injury or disease conditions, SARM1’s N-terminus-TIR domain interaction is disrupted, allowing TIR multimerization to occur, followed by a rapid loss of NAD+ and associated axon degeneration. DESCRIPTION

[0006] Provided herein are compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, that are useful in treating and / or preventing diseases mediated, at least in part, by SARM1.

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

[0008] In another embodiment, provided is 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, provided is a method for treating a disease or condition mediated, at least in part, by SARM1, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0010] The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, methods of using (or administering) and making thecompounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and intermediates thereof.

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

[0012] Moreover, the disclosure provides uses of the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder, or condition that is mediated, at least in part, by SARM1.

[0013] The description herein sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. 1. Definitions

[0014] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that 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 for a substituent. For example, -C(O)NH2is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0016] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0017] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled 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., C1-20alkyl), 1 to 12 carbon atoms (i.e., C1-12alkyl), 1 to 8 carbon atoms (i.e., C1-8alkyl), 1 to 6 carbon atoms (i.e., C1-6alkyl) or 1 to 4 carbon atoms (i.e., C1-4alkyl). Examples of alkyl groups include, e.g., 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 chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; 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 be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group (for example, methylenyl, ethylenyl, and propylenyl), an “arylene” group or an “arylenyl” group (for example, phenylenyl or napthylenyl, or quinolinyl for heteroarylene), respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0020] “Alkenyl” refers to an alkyl group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20alkenyl), 2 to 12 carbon atoms (i.e., C2-12alkenyl), 2 to 8 carbon atoms (i.e., C2-8alkenyl), 2 to 6 carbon atoms (i.e., C2-6alkenyl), or 2 to 4 carbon atoms (i.e., C2-4alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2- butadienyl and 1,3-butadienyl).

[0021] “Alkynyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20alkynyl), 2 to 12 carbon atoms (i.e., C2-12alkynyl), 2 to 8 carbon atoms (i.e., C2-8alkynyl), 2 to 6 carbon atoms (i.e., C2-6alkynyl), or 2 to 4 carbon atoms (i.e., C2-4alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0022] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., 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 a group -C(O)Ry, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0026] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRzand an “N- amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0027] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0028] “Amidino” refers to -C(NRy)(NRz2), wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may 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 has 6 to 20 ring carbon atoms (i.e., C6-20aryl), 6 to 12 carbon ring atoms (i.e., C6-12aryl), or 6 to 10 carbon ring atoms (i.e., C6-10aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment.

[0030] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

[0031] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0032] “Carboxyl ester” or “ester” refer to both -OC(O)Rxand -C(O)ORx, wherein Rxis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0033] “Cyanoalkyl” refers to refers to an alkyl group as defined above, wherein one or more (e.g., 1 or 2) hydrogen atoms are replaced by a cyano (-CN) group.

[0034] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-12cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6cycloalkyl). 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.Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

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

[0036] “Imino” refers to a group -C(NRy)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0037] “Imido” refers to a group -C(O)NRyC(O)Rz, wherein Ryand Rzare 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, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where 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, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., 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, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0041] “Haloalkoxyalkyl” refers to an alkoxyalkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0042] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0043] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3,-CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3,-CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyCH3, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0044] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8heteroaryl), and 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 certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., 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, 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 the 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 can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through 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, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group 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 wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder 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 the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6heterocyclyl); having 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, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, 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 positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1- azaspiro[3.3]heptanyl. Examples of the 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 bound via either ring of the fused system.

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

[0048] “Oxime” refers to the group -CRy(=NOH) wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0049] “Sulfonyl” refers to the group -S(O)2Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0050] “Sulfinyl” refers to the group -S(O)Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0051] “Sulfonamido” refers to the groups -SO2NRyRzand -NRySO2Rz, where Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0052] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0053] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, 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, sulfonamido, thiol, thioxo, N-oxide, or -Si(Ry)3, wherein each Ryis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0054] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC(O)Rh, -NRgC(O)NRgRh, -NRgC(O)ORh, -NRgS(O)1-2Rh, -C(O)Rg, -C(O)ORg, -OC(O)ORg, -OC(O)Rg, -C(O)NRgRh, -OC(O)NRgRh, -ORg, -SRg, -S(O)Rg, -S(O)2Rg, -OS(O)1-2Rg, -S(O)1-2ORg, -NRgS(O)1-2NRgRh, =NSO2Rg, =NORg, -S(O)1-2NRgRh, -SF5, -SCF3, or -OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to an 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 two of Rgand Rhand Riare taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0055] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itselfsubstituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein.

[0056] In certain embodiments, as used herein, the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to three.

[0057] Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated. Such isotopically labelled 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 radioactive treatment of patients.

[0058] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. 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 employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0059] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic index. An18F,3H, or11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0060] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0061] In many cases, the compounds of this 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] Provided is also a pharmaceutically acceptable salt, isotopically enriched analog, deuterated analog, stereoisomer, mixture of stereoisomers, or prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0063] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are 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, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., 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-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substitutedalkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0064] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0065] The compounds of the disclosure, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0066] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable 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 the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0069] “Prodrugs” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of acompound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may 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) of hydroxy functional groups in compounds described herein, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety. 2. Compounds

[0070] Provided herein are compounds that are inhibitors of SARM1. In certain embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6; R1is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R7)2, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R2is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1;R3is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; each R7is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; whereineach C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R12is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1ais independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, -C(O)OR13, -S(O)R13, -S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, -NR13S(O)R13, -NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -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)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0071] In certain embodiments, when X is N and R1is methyl; then R2is C3-10cycloalkyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

[0072] In certain embodiments, the compound is not 4,5,6,7-tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 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) when X is N and R1is methyl; then R2is C3-10cycloalkyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; and B) the compound is not: 4,5,6,7-tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2- (ethylsulfonyl)-1H-benzimidazole (670248-30-3), 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).

[0074] In certain embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6; R1is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R7)2, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R2is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl;R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; each R7is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; and each Z1ais independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that: A) when X is N and R1is methyl; then R2is C3-10cycloalkyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; and B) the compound is not: 4,5,6,7-tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro- 6-ethoxy-2-(ethylsulfonyl)-1H-benzimidazole (670248-30-3), 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).

[0075] In certain embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is CH; Y1is N or CR5; X is CH; R1is C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R7)2, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R2is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is halo, cyano, -NO2, or C1-6alkyl optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, -NO2, or C1-6alkyl optionally substituted with one to five Z1; each R7is independently hydrogen, C1-6alkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; and each Z1ais independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0076] In certain embodiments, R2is ring B; and ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1. In certain embodiments, R2is ring B; and ring B is aryl or heteroaryl, wherein each is independently optionally substituted with one to five Z1.

[0077] In certain embodiments, provided is a compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein X, Y, Y1, R1, R3, and ring B are each independently as defined herein.

[0078] In certain embodiments, provided is a compound of Formula IB:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein X, R1, R3, R5, and ring B are each independently as defined herein.

[0079] In certain embodiments, R1is C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R11)2, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

[0080] In certain embodiments, R1is represented by ring A:wherein ring A is optionally substituted with one to five Z1.

[0081] In certain embodiments, R1is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, wherein the C1-6alkyl, C2-6alkenyl, or C2-6alkynyl is independently optionally substituted with one to five Z1.

[0082] In certain embodiments, R1is C3-10cycloalkyl or heterocyclyl, wherein each is independently optionally substituted with one to five Z1.

[0083] In certain embodiments, R1is C3-10cycloalkyl optionally substituted with one to five Z1.

[0084] In certain embodiments, R1is heterocyclyl optionally substituted with one to five Z1.

[0085] In certain embodiments, R1is aryl optionally substituted with one to five Z1.

[0086] In certain embodiments, R1is heteroaryl optionally substituted with one to five Z1.

[0087] In certain embodiments, R1is -N(R7)2.

[0088] In certain embodiments, provided is a compound of Formula II:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6;ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; each R7is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2,-NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R12is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1ais independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, -C(O)OR13, -S(O)R13, -S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, -NR13S(O)R13, -NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -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)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0089] In certain embodiments, each R7is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

[0090] In certain embodiments, each R7is independently hydrogen, C1-6alkyl, C3-10cycloalkyl, or heteroaryl, wherein each C1-6alkyl, C3-10cycloalkyl, or heteroaryl is independently optionally substituted with one to five Z1.

[0091] In certain embodiments, each R7is 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 optionally substituted with one to five Z1.

[0092] In certain embodiments, two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1.

[0093] In certain embodiments, two R7, together with the nitrogen atom to which they are attached, form a ring A as defined herein.

[0094] In certain embodiments, R3is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

[0095] In certain embodiments, R3is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

[0096] In certain embodiments, R3is C1-6alkyl optionally substituted with one to five Z1. In certain embodiments, R3is methyl. In certain embodiments, R3is trifluoromethyl.

[0097] In certain embodiments, provided is a compound of Formula IIA:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6; ring A is heterocyclyl optionally substituted with one to five Z1; ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; whereinthe C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R12is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1ais independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, -C(O)OR13, -S(O)R13, -S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, -NR13S(O)R13, -NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2, or -NR13C(O)OR13; whereineach C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -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)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0098] In certain embodiments, Y is N. In certain embodiments, Y is CR4. In certain embodiments, Y is CH.

[0099] In certain embodiments, Y1is N. In certain embodiments, Y1is CR5. In certain embodiments, Y1is CR5; and R5is hydrogen, halo, cyano, -N(R11)2, -OR11, -SR11, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, Y1is CR5; and R5is halo. In certain embodiments, Y1is CF.

[0100] In certain embodiments, provided is a compound of Formula IC:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein R1, R3, R5, and ring B are each independently as defined herein.

[0101] In certain embodiments, provided is a compound of Formula ID:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein R1, R3, R5, and ring B are each independently as defined herein.

[0102] In certain embodiments, provided is a compound of Formula IE:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein X, R3, R5, R7, and ring B are each independently as defined herein.

[0103] In certain embodiments, each R7is C1-6alkyl, heterocyclyl, or aryl.

[0104] In certain embodiments, provided is a compound of Formula IF:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein X, R3, R5, R7, and ring B are each independently as defined herein.

[0105] In certain embodiments, provided is a compound of Formula IG:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein X, R1, R3, and ring B are each independently as defined herein.

[0106] In certain embodiments, provided is a compound of Formula IH:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein R1, R3, and ring B are each independently as defined herein.

[0107] In certain embodiments, provided is a compound of Formula IJ:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein X, R3, R7, and ring B are each independently as defined herein.

[0108] In certain embodiments, provided is a compound of Formula IK:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein X, R3, ring A, and ring B are each independently as defined herein.

[0109] In certain embodiments, R5is hydrogen, halo, cyano, -N(R11)2, -OR11, -SR11, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, R5is halo. In certain embodiments, R5is fluoro.

[0110] In certain embodiments, X is CR4. In certain embodiments, X is N or CH. In certain embodiments, X is CH. In certain embodiments, X is N.

[0111] In certain embodiments, R1or ring A is C3-10cycloalkyl or a 4- to 10-membered heterocyclyl, where each is optionally with one to five Z1. In certain embodiments, R1or ring A is C3-10cycloalkyl or a 4- to 10-membered heterocyclyl, where each is optionally with one to five substituents independently selected from halo, cyano, -S(O)2-C1-6alkyl, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and aryl.

[0112] In certain embodiments, R1or ring A is a 4- to 10-membered heterocyclyl optionally with one to five Z1. In certain embodiments, R1or ring A is a 4- to 10-membered heterocyclyl optionally with one tofive substituents independently selected from halo, cyano, -S(O)2-C1-6alkyl, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and aryl.

[0113] In certain embodiments, R1or ring A is:wherein each is optionally with one to five Z1.

[0114] In certain embodiments, R1or ring A is:wherein each is optionally with one to five Z1.

[0115] In certain embodiments, R2or ring B is aryl or heteroaryl, where each is optionally substituted with one to five Z1. In certain embodiments, R2or ring B is phenyl or a 5- to 9-membered heteroaryl, where each is optionally substituted with one to five Z1.

[0116] In certain embodiments, R2or ring B is heteroaryl optionally substituted with one to five Z1. In certain embodiments, R2or ring B is a 5- to 9-membered heteroaryl optionally substituted with one to five Z1. In certain embodiments, R2or ring B is a 5- or 6-membered heteroaryl optionally substituted with one to five Z1.

[0117] In certain embodiments, R2or 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, where each is optionally substituted with one to five Z1.

[0118] In certain embodiments, R2or 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, where each is optionally substituted with one to five Z1. In certain embodiments, R2or ring B is tetrahydropyranyl, phenyl, pyrazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridinyl, where each is optionally substituted with one to five Z1.

[0119] In certain embodiments, R2or ring B is optionally substituted with one to three substituents independently selected from halo, C1-6alkyl, and C1-6alkoxy, wherein each C1-6alkyl is optionally substituted with one to five Z1a.

[0120] In certain embodiments, R2or ring B is optionally substituted with one to three substituents independently selected from halo, C1-6alkyl, and C1-6alkoxy, wherein each C1-6alkyl is optionally substituted with one to three C3-10cycloalkyl or halo.

[0121] In certain embodiments, R2or ring B is optionally substituted with one to three substituents independently selected from halo, C1-6alkyl, and C1-6alkoxy.

[0122] In certain embodiments, R2or 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, where each is optionally substituted with one to three substituents independently selected from halo, C1-6alkyl, and C1-6alkoxy. In certain embodiments, R2or ring B is tetrahydropyranyl, phenyl, pyrazolyl, 1,2,4- triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or oxazolo[4,5-b]pyridinyl, where each is optionally substituted with one to three substituents independently selected from halo, C1-6alkyl, and C1-6alkoxy.

[0123] In certain embodiments, R3is C1-6alkyl. In certain embodiments, R3is methyl. In certain embodiments, R2is halo and R3is C1-6alkyl. In certain embodiments, R2is fluoro and R3is methyl.

[0124] In certain embodiments, each Z1is independently selected from halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, each Z1is independently Z1b.

[0125] In certain embodiments, In certain embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6; R1is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R7)2, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; R2is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; R3is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11,-C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; each R7is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1b; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -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)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that: A) when X is N and R1is methyl; then R2is C3-10cycloalkyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; and B) the compound is not: 4,5,6,7-tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2- (ethylsulfonyl)-1H-benzimidazole (670248-30-3), 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).

[0126] In certain embodiments, provided is a compound of Formula II:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6; ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; R3is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; each R7is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; or two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1b; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-,-C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -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)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0127] In certain embodiments, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof: Table 1

[0128] In certain embodiments, provided is a compound selected from Table 2, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof: Table 23. Methods

[0129] “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 the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0130] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in certain embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0131] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in 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 ofstereoisomers, or prodrug thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0133] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may 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 ex vivo to determine the optimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The compounds may be further characterized to examine the safety or tolerance dosage in human or non- human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0134] In certain embodiments, provided are compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, that inhibit the activity of Sterile Alpha and TIR Motif containing 1 (SARM1) protein. In certain embodiments, the compounds provided herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, inhibits SARM1.

[0135] In certain embodiments, provided is 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. The inhibiting can be in vitro or in vivo.

[0136] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0137] In certain embodiments, the present disclosure provides use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture ofstereoisomers, 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 is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for inhibiting NADase activity of SARM1. In certain embodiments, provided is a method of inhibiting SARM1 NADase activity and / or treating a neurodegenerative or neurological disease or disorder in a subject in need 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, to the subject.

[0139] In certain embodiments, provided is a method 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 to a subject in need thereof.

[0140] In certain embodiments, provided is a method of treating axonal degeneration in a subject in need 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, to the subject. In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, inhibits axonal degeneration, including axonal degeneration that results from reduction or depletion of NAD+. In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, prevents an axon distal to an axonal injury from degenerating.

[0141] In certain embodiments, provided is a method for treating degradation of a peripheral nervous system neuron or a portion 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, provided is a method for treating degeneration of a central nervous system neuron or a portion 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, the treating comprises reducing one or more symptoms or features of neurodegeneration.

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

[0145] In certain embodiments, provided is a method for treating a neurodegenerative or neurological disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0146] In certain embodiments, provided is a method for treating a neurodegenerative or neurological disease or disorder associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from traumatic axonal injury (TAI) (see Ziogas et al., J. Neuroscience, 2018, 38(16):4031-4032 and WO2020191257), a leukoencephalopathy or a leukodystrophy, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0147] In certain embodiments, provided is 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, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting axon degeneration in a subject in need thereof.

[0149] In certain embodiments, the present disclosure provides 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 axon degeneration in a subject in need thereof.

[0150] In certain embodiments, the present disclosure provides 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 damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from traumatic axonal injury (TAI), a leukoencephalopathy or a 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 nerves, or a combination thereof.

[0153] In certain embodiments, the disease or condition is or comprises 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 comprises a 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 comprises chronic traumatic encephalopathy (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, D.M., et al. Exp. Neurology.2006, 202, 93-99), amyotrophic lateral sclerosis (see, e.g., White, M.A., et al. Acta Neuropath. Comm.2019, 7(1), 166), multiple sclerosis, Huntington disease, or Alzheimer’s disease.

[0155] In certain embodiments, the disease or condition is an acute peripheral neuropathy. In certain embodiments, the disease or condition is chemotherapy-induced peripheral neuropathy (CIPN). See, e.g., 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), an example of an acute peripheral neuropathy, can be associated with various drugs, such as, 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, K.W., 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’s congenital amaurosis, Leber’s 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, e.g., 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 example, to treat one or more neurodegenerative diseases, disorders or conditions selected from the group consisting of neuropathies or axonopathies. In certain embodiments, one or more compounds and / or compositions as described herein are useful, for example to treat a neuropathy or axonopathy associated with axonal degeneration. In certain embodiments, a neuropathy associated withaxonal degeneration is a hereditary or congenital neuropathy or axonopathy. In certain embodiments, a neuropathy associated with axonal degeneration results from a de novo or somatic mutation. In certain embodiments, a neuropathy associated with axonal degeneration is selected from a list contained herein. In certain embodiments, a 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, a demyelinating disease, ischemia, stroke, chemical injury, thermal injury, or AIDS.

[0162] In certain embodiments, one or more compounds or compositions as described herein is characterized that, when administered to a population of subjects, reduces one or more symptoms or features of neurodegeneration. For example, in certain embodiments, a relevant symptom or feature may be selected from the group consisting of extent, rate, and / or timing of neuronal disruption. In certain embodiments, neuronal disruption may be or comprise axonal degradation, loss of synapses, loss of dendrites, loss of synaptic density, loss of dendritic arborization, loss of axonal branching, loss of neuronal density, loss of myelination, loss of neuronal cell bodies, loss of synaptic potentiation, loss of action-potential potentiation, loss of cytoskeletal stability, loss of axonal transport, loss of ion channel synthesis and turnover, loss of neurotransmitter synthesis, loss of neurotransmitter release and reuptake capabilities, loss of axon-potential propagation, neuronal hyperexitability, and / or neuronal hypoexcitability. In certain embodiments, neuronal disruption is characterized by an inability to maintain an appropriate resting neuronal membrane potential. In certain embodiments, neuronal disruption is characterized by the appearance of inclusion bodies, plaques, and / or neurofibrillary tangles. In certain embodiments, neuronal disruption is characterized by the appearance of stress granules. In certain embodiments, neuronal disruption is characterized by the intracellular activation of one or more members of the cysteine-aspartic protease (Caspase) family. In certain embodiments, neuronal disruption is characterized by a neuron undergoing programed cell death (c.g. apoptosis, pyroptosis, ferroapoptosis, and / or necrosis) and / or inflammation.

[0163] In certain embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a 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 myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe’s 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-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic 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 injury, Leber’s hereditary optic atrophy (neuropathy), Leber 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, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedreich’s ataxia, hereditary ataxias, noise induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathies and axonopathies, Guillain-Barre syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxias, pre-eclampsia, hereditary spastic paraplegias, spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, or non-alcoholic steatohepatitis (NASH).

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

[0165] In certain embodiments, the present disclosure provides methods of treating neurodegenerative or neurological diseases or disorders related to axonal degeneration, axonal damage, axonopathies, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a leukodystrophy.

[0166] In certain embodiments, neuropathies and axonopathies include any disease or condition involving neurons and / or supporting cells, such as for example, glia, muscle cells or fibroblasts, and, in particular, those diseases or conditions involving axonal damage. Axonal damage can be caused by traumatic injury or by non-mechanical injury due to diseases, conditions, or exposure to toxic molecules or drugs. The result of such damage can be degeneration or dysfunction of the axon and loss of functional neuronal activity. Disease and conditions producing or associated with such axonal damage are among a large number of neuropathic diseases and conditions. Such neuropathies can include peripheralneuropathies, central neuropathies, or combination thereof. Furthermore, peripheral neuropathic manifestations can be produced by diseases focused primarily in the central nervous systems and central nervous system manifestations can be produced by essentially peripheral or systemic diseases.

[0167] In certain embodiments, a peripheral neuropathy may involve damage to the peripheral nerves, and / or can be caused by diseases of the nerves or as the result of systemic illnesses. Some such diseases include diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiencies, 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 conditions that injure peripheral nerves include compression or entrapment injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fracture or dislocated bones; pressure involving superficial nerves (ulna, radial, or peroneal) which can result from prolonged use of crutches or staying in one position for too long, or from a tumor; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain medicines or toxic substances such as herbicides or pesticides. In particular, the nerve damage can result from chemical injury due to a cytotoxic anticancer agent such as, for example, taxol, cisplatinin, a proteasome inhibitor, or a vinca alkaloid such as vincristine. Typical symptoms of such peripheral neuropathies include weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, pricking or tingling) and pain in the arms, hands, legs and / or feet. In certain embodiments, a neuropathy is associated with mitochondrial dysfunction. Such neuropathies can exhibit decreased energy levels, i.e., decreased levels of NAD and ATP.

[0168] In certain embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy which includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, a disorder of lipid / glycolipid metabolism, a nutritional / vitamin deficiency, or a mitochondrial disorder. The common hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation.

[0169] In certain embodiments, neuropathies include optic neuropathies such as glaucoma, retinal ganglion degeneration such as those associated with retinitis pigmentosa and outer retinal neuropathies, optic nerve neuritis and / or degeneration including that associated with multiple sclerosis, traumatic injury to the optic nerve which can include, for example, injury during tumor removal, hereditary optic neuropathies such as Kjer’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, nutritional deficiencies such as deficiencies in vitamins B12 or folic acid, and toxicities such as due to ethambutol or cyanide, neuropathies caused byadverse drug reactions and neuropathies caused by vitamin deficiency. Ischemic optic neuropathies also include non-arteritic anterior ischemic optic neuropathy.

[0170] In certain embodiments, neurodegenerative diseases that are associated with neuropathy or axonopathy in the central nervous system include a variety of diseases. Such diseases include those involving progressive dementia such as, for example, Alzheimer’s disease, senile dementia, Pick’s disease, and Huntington’s disease, central nervous system diseases affecting muscle function such as, for example, Parkinson’s disease, motor neuron diseases and progressive ataxias such as amyotrophic lateral sclerosis, demyelinating diseases such as, for example multiple sclerosis, viral encephalitides such as, for example, those caused by enteroviruses, arboviruses, and herpes simplex virus, and prion diseases. Mechanical injuries such as glaucoma or traumatic injuries to the head and spine can also cause nerve injury and degeneration in the brain and spinal cord. In addition, ischemia and stroke as well as conditions such as nutritional deficiency and chemical toxicity such as with chemotherapeutic agents can cause central nervous system neuropathies.

[0171] In certain embodiments, the present disclosure provides a method of treating a neuropathy or axonopathy associated with axonal degeneration. In certain embodiments, a neuropathy or axonopathy associated with axonal degeneration can be any of a number of neuropathies or axonopathies such as, for example, those that are hereditary or congenital or associated with Parkinson’s disease, Alzheimer’s disease, Herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS. In addition, neurodegenerative diseases not mentioned above as well as a subset of the above mentioned diseases can also be treated with the methods of the present disclosure. Such subsets of diseases can include Parkinson’s disease or Alzheimer’s disease.

[0172] In certain embodiments, the present 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 of axonal degeneration, e.g., based on 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 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 drawn from a population with a high incidence of neurodegeneration. In certain embodiments, the subject has a hexanucleotiderepeat expansion in chromosome 9 open reading frame 72. In certain embodiments, the subject has one or more copies of the ApoE4 allele.

[0174] In certain embodiments, a neurodegenerative disease, disorder or condition may be or comprise a traumatic neuronal injury. In certain embodiments, a traumatic neuronal injury is blunt force trauma, a closed-head injury, an open head injury, exposure to a concussive and / or explosive force, a penetrating injury in to the brain cavity or innervated region of the body. In certain embodiments, a traumatic neuronal injury is a force which causes the axons to deform, stretch, crush or sheer. In certain embodiments, the disease or disorder is a traumatic brain injury (TBI).

[0175] In certain embodiments, the subject has engaged, or engages, in an activity identified as a risk factor for neuronal degradation, e.g., a contact sport or occupations with a high chance for traumatic neuronal injury or TBI.

[0176] In certain embodiments, provided is a method of treating a neurodegenerative disease, disorder or condition 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, provided is a combination therapy comprising a compound as described herein and a DLK inhibitor and / or a NAMPT inhibitor. In certain embodiments, provided is a combination therapy comprising a compound as described herein, a DLK inhibitor, and one or more additional therapeutic agents. In certain embodiments, provided is a combination therapy comprising a compound as described herein, a NAMPT inhibitor, and one or more additional therapeutic agents. In certain embodiments, provided is a combination therapy 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., a siRNA, an antisense oligonucleotide, a micro-RNA, 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 a siRNA. In certain embodiments, the DLK inhibitor is an antisense oligonucleotide. In certain embodiments, the DLK inhibitor is a polypeptide. In certain embodiments, a DLK inhibitor is a peptide fragment. In certain embodiments, a DLK inhibitor is a nucleic acid. In certain embodiments, a DLK inhibitor is an antisense oligonucleotide.

[0178] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, W02014177060, WO2015091889, W02016142310, US20180057507, W02018107072, WO2019241244, W02020168111, and CN104387391 A, which are hereby incorporated by reference in their entirety.

[0179] In certain embodiments, the NAMPT inhibitor is a small molecule, a polypeptide, a peptide fragment, a nucleic acid (e.g., a siRNA, an antisense oligonucleotide, a micro-RNA, 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 a siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In certain embodiments, the NAMPT inhibitor is apolypeptide. In some embodiments, a NAMPT inhibitor is a peptide fragment. In certain embodiments, a NAMPT inhibitor is a nucleic acid. In some embodiments, a NAMPT inhibitor is an antisense oligonucleotide.

[0180] In certain embodiments, a 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, the provided is a composition comprising a compound as described herein, formulated for use in administering to a subject in combination with a DLK inhibitor and / or a NAMPT inhibitor.

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

[0183] In certain embodiments, the subject may be a subject who has received, is receiving, or has been prescribed, a chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, 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), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0184] In certain embodiments, SARM1 inhibition as described herein may be utilized in combination with one or more other therapies to treat a relevant disease, disorder, or condition. In certain embodiments, dosing of a SARM1 inhibitor is altered when utilized in combination therapy as compared with when administered as monotherapy; alternatively or additionally, a therapy that is administered in combination with SARM1 inhibition as described herein is administered according to a regimen or protocol that differs from its regimen or protocol when administered alone or in combination with one or more therapies other than SARM1 inhibition. In certain embodiments, compositions which comprise an additional therapeutic agent, that additional therapeutic agent and a provided compound may act synergistically. In certain embodiments, one or both therapies utilized in a combination regimen is administered at a lower level or less frequently than when it is utilized as monotherapy.

[0185] In certain embodiments, a compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or composition provided herein is administered in combination with a NAD+or a NAD+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 is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug 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 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 sterile alpha and TIR motif-containing protein 1 (SARM1) activity (e.g., in vitro or in vivo) and supplementing axonal NAD+levels.

[0188] Axonal degeneration has been associated with various types of neurodegenerative diseases, being recognized as an important indicator of disease progression, and an interesting target for the therapeutic treatment of these diseases. Similarly, axonal degeneration is also observed in those with traumatic brain injuries and peripheral neuropathies.

[0189] In certain embodiments, provided is a method 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, in combination with NAD+or a NAD+precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

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

[0191] In certain embodiments, provided is a method for treating any disease caused by SARM1 activity, 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, in combination with NAD+or a NAD+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 appreciated that these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive.

[0193] In certain embodiments, provided is a method for treating a neurodegenerative disease, 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, in combination with NAD+or a NAD+precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0194] Other embodiments include use of the presently disclosed compounds in therapy.4. Kits

[0195] Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and suitable packaging. In certain embodiments, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a label and / or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

[0196] Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag. 5. Pharmaceutical Compositions and Modes of Administration

[0197] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0198] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0199] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0200] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the activeingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0201] Some examples of suitable excipients include, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0202] The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may 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 may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0203] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation 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 referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0204] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can beused for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials 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, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the 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 facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, in one embodiment, orally or nasally, from devices that deliver the formulation in an appropriate manner.

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

[0207] The following ingredients are mixed intimately and pressed into single scored tablets.Formulation Example 2 - Capsule formulation

[0208] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.Formulation Example 3 - Suspension formulation

[0209] The following ingredients are mixed to form a suspension for oral administration.Formulation Example 4 - Injectable formulation

[0210] The following ingredients are mixed to form an injectable formulation.Formulation Example 5 - Suppository Formulation

[0211] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:6. Dosing

[0212] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In certain embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. In certain embodiments, a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. 7. Synthesis of the Compounds

[0213] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.

[0214] It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0215] Additionally, 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 particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J., 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-iso- propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ion, such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, removed by acid or base, benzoyl, removed by acid or base, benzyl, removed by hydrogenation, methoxyethoxymethyl ether, removed by acid, dimethoxytrityl, removed by acid, methoxymethyl ether, removed by acid, tetrahydropyranyl or tetrahydrofuranyl, removed by acid, and trityl, removed by acid. Examples of protecting groups for amines include carbobenzyloxy, removed by hydrogenolysis p-methoxybenzyl carbonyl, removed by hydrogenolysis, tert-butyloxycarbonyl, removed by concentrated strong acid (such as HCl or CF3COOH), or by heating to greater than about 80 °C, 9-fluorenylmethyloxycarbonyl, removed by base, such as piperidine, acetyl,removed by treatment with a base, benzoyl, removed by treatment with a base, benzyl, removed by hydrogenolysis, carbamate group, removed by acid and mild heating, p-methoxybenzyl, removed by hydrogenolysis, 3,4-dimethoxybenzyl, removed by hydrogenolysis, p-methoxyphenyl, removed by ammonium cerium(IV) nitrate, tosyl, removed by concentrated acid (such as HBr or H2SO4) and strong reducing agents (sodium in liquid ammonia or sodium naphthalenide), troc (trichloroethyl chloroformate), removed by Zn insertion in the presence of acetic acid, and sulfonamides (Nosyl & Nps), removed by samarium iodide or tributyltin hydride.

[0216] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, 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 this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[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-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, 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). General Synthesis

[0218] Scheme I illustrates general methods which can be employed for the synthesis of compounds described herein, where X, Y, Y1, R1, R2, and R3are each independently as defined herein; LG is independently a leaving group (e.g., halo, -OTf, etc.); and each R50is independently -OH, -O-alkyl, or together with the boron atom to which they are attached, form a cyclic boronate.Scheme I

[0219] 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)Cl2) and a base, followed by optional functionalization or deprotection when required. Alternatively, compounds of Formula I can be prepared by borylation of compound I-1 to provide compound I-3, and contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, such as in the presence of a palladium catalyst (e.g., an XPhos reagent, Pd(dppf)Cl2) and a base, followed by optional functionalization or deprotection when required. 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] Upon each reaction completion, each of the intermediate or final compounds 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 the skilled artisan. For example, Scheme II shows an exemplary synthesis of a compound of Formula I-1, where X, Y, Y1, R1, and R3are each independently as defined herein; each LG is independently a leaving group (e.g., halo, -OTf, etc.).Scheme II

[0222] In Scheme II, compounds of Formula II-3 (such as, for example, those where R1is bonded to the sulfur via a carbon atom, e.g., C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and the like) can be prepared by contacting a compound of Formula II-1 with a compound of Formula II-2 under suitable conditions (e.g., nucleophilic reaction conditions). Compounds of Formula I-1 can then be provided by oxidation of a compound of Formula II-3, e.g., with a suitable oxidant, such as m-CPBA. In certain embodiments of a compound of Formula II-2, LG is iodo.

[0223] Further derivatization of the compound provided 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 may be prepared using traditional methods or purchased from commercial sources. In addition, any of the intermediates or any product obtained by the process 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 for Formula I.

[0224] In certain embodiments, provided is a process for providing a compound of Formula I, comprising contacting a compound of Formula I-1:with a compound of Formula I-2:under conditions sufficient to provide a compound of Formula I; wherein X, Y, Y1, R1, R2, and R3are each independently as defined herein; LG is a leaving group; and each R50is independently -OH, -O-alkyl, or together with the boron atom to which they are attached, form a cyclic boronate.

[0225] In certain embodiments, provided is a process for providing a compound of Formula I, comprising contacting a compound of Formula I-1:with a boron reagent under borylation reaction conditions to provide a compound of Formula I-3:and contacting the compound of Formula I-3 with a compound of Formula I-4:under conditions sufficient to provide a compound of Formula I; wherein A1, A2, X1, X2, X3, X4, X5, X6, R1, R2, R4, and R5are each independently as defined herein, each LG is independently a leaving group, and each R50is independently -OH, C1-6alkoxy, or two R50together with the boron atom to which they are attached 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 comprises a palladium catalyst (e.g., an XPhos reagent or Pd(dppf)Cl2) and a base. EXAMPLES

[0229] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those skilled in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes of its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. General Experimental Methods

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

[0231] NMR Spectroscopy:1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz or one of the following instruments: a Bruker Avance 400 instrument equipped with probe DUAL 400 MHz S1, a Bruker Avance 400 instrument equipped with probe 6 S1400 MHz 5mm1H-13C ID, a Bruker Avance III400 instrument with nanobay equipped with probe Broadband BBFO 5 mm direct, a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBO probe operating at 400 MHz. All deuterated solvents contained typically 0.03% to 0.05% v / v tetramethylsilane, which was used as the reference signal (set at δ 0.00 for both1H and13C). In certain cases,1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker Advance 400 instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

[0232] Thin Layer Chromatography: Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel F254 (Merck) plates, Rf is the distance travelled by the compound divided by the distance travelled by the solvent on a TLC plate. Column chromatography was performed using an automatic flash chromatography system over silica gel cartridges or in the case of reverse phase chromatography over C18 cartridges. Alternatively, thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60 F254) from Mancherey-Nagel and UV was typically used to visualize the spots. Additional visualization methods were also employed in some cases. In these cases the TLC plate was developed with iodine (generated by adding approximately 1 g of I2to 10 g silica gel and thoroughly mixing), ninhydrin (available commercially from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g (NH4)6Mo7O24.4H2O, 5 g (NH4)2Ce(IV)(NO3)6in 450 mL water and 50 mL concentrated H2SO4) to visualize the compound.

[0233] Liquid Chromatography-Mass Spectrometry and HPLC Analysis: HPLC analysis was performed on Shimadzu 20AB HPLC system with a photodiode array detector and Luna-C18(2) 2.0×50 mm, 5 µm column at a flow rate of 1.2 mL / min with a gradient solvent Mobile phase A (MPA, H2O+0.037 % (v / v) TFA): Mobile phase B (MPB, ACN+0.018 % (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4,9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS was detected under 220 and 254 nm or used evaporative light scattering (ELSD) detection as well as positive electrospray ionization (MS). Semi-preparative HPLC was performed by either acidic or neutral conditions. Acidic: Luna C18100 × 30 mm, 5 μm; MPA: HCl / H2O=0.04%, or formic acid / H2O=0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150 × 25, 5 μm; MPA: 10 mM NH4HCO3in H2O; MPB: ACN. Gradient for both conditions: 10% of MPB to 80% of MPB over 12 min at a flow rate of 20 mL / min, then 100% MPB over 2 min, 10% MPB over 2 min, UV detector. SFC analysis was performed on Thar analytical SFC system with a UV / Vis detector and series of chiral columns including AD, AS-H, OJ, OD, AY and IC, 4.6 × 100 mm, 3 µm column at a flow rate of 4 mL / min with a gradient solvent Mobile phase A (MPA, CO2): Mobile phase B (MPB, MeOH+0.05 % (v / v) IPA) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56-5 min, 10% MPB). SFC preparative was performed on Thar 80 preparative SFC system with a UV / Vis detector and series of chiral preparative columns including AD-H, AS-H, OJ-H, OD-H, AY-H and IC-H, 30×250 mm, 5 µm column at a flow rate of 65 mL / minwith a gradient solvent Mobile phase A (MPA, CO2): Mobile phase B (MPB, MeOH+0.1 % (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1-10 min, 10% MPB). LC-MS data were also collected using an UPLC-MS AcquityTMsystem equipped with PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternated positive and negative electrospray ionization mode. The column used was a Cortecs UPLC C18, 1.6 µm, 2.1 × 50 mm. A linear gradient was applied, starting at 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 at 40 ºC with the flow rate of 0.8 mL / min. Intermediate 1 4-bromo-7-fluoro-5-methyl-1-tosyl-1H-indole

[0234] 3-bromo-6-fluoro-2-iodo-4-methylaniline: To a solution of 5-bromo-2-fluoro-4-methylaniline (30 g, 147.03 mmol) in CH3COOH (500 mL) was added NIS (36.39 g, 161.73 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc (30 mL) and washed with aq. sat. NaHCO3(3 × 10 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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(PPh3)2Cl2(9.49 g, 13.52 mmol) and 3-bromo-6-fluoro-2-iodo-4- methylaniline (44.6 g, 135.18 mmol) at 0 °C under N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O (1500 mL) and extracted with EtOAc (3 × 700 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the titled 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 N2. 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 × 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 titled 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, 26.31 mmol, 60% purity in mineral oil) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. Then TsCl (6.27 g, 32.89 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by addition of aq. sat. 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 titled compound. LCMS: m / z = 382.0, 384.0 [M+H]+. Intermediate 2 7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole-2-sulfonyl chloride

[0238] 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 H2O (30 mL) was added pyridine-Br3(21.04 g, 65.77 mmol) at 20 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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 aq. sat. 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 aq. sat. NaHCO3(100 mL) and the mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (80 mL), driedover anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added ice-water (40 ml) and the mixture was stirred for 10 min. The mixture was filtered and the filter cake was dried under reduced pressure to give the titled 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 K2CO3(1.91 g, 13.84 mmol) and PMBCl (1.08 g, 6.92 mmol) at 20 °C under N2. The mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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)Cl2(212 mg, 0.29 mmol) at 20 °C under N2. The mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 10:1) to give the titled 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 H2O (3 mL) was added 3-bromo-1-methyl- 1,2,4-triazole (483 mg, 2.98 mmol) and K3PO4(633 mg, 2.98 mmol), XPhos Pd G2(117 mg, 0.15 mmol) at 20 °C under N2. 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 give the titled 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 H2O (0.2 mL) was added NCS (174 mg, 1.31 mmol) at 0 °Cunder N2. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 329.0 [M+H]+. 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

[0245] 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 N2. The mixture was then stirred at –78°C for 0.5 h. Subsequently, SO2(g) was bubbled into the reaction solution for 30 min and then the reaction was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled 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 N2. Then the reaction was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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 N2. The reaction was stirred at 0 °C for 2 h, diluted with H2O (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the titled 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)Cl2•CH2Cl2(41 mg, 0.05 mmol) at 20 °C under N2. The mixture was heated to 85 °C and stirred for 12 h. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled compound. LCMS: m / z = 409.2 [M+H]+. Intermediate 4 1-methyl-3-(tributylstannyl)-1H-1,2,4-triazole

[0249] 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) at 25 °C under N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition of aq. sat. KF (10 mL) and filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled compound. LCMS: m / z = 374.1 [M+H]+. Intermediate 5 4-bromo-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole

[0250] 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 H2O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 0:1) to give the titled compound. LCMS: m / z = 361.0, 363.0 [M+H]+.Intermediate 6 2-(azetidin-1-ylsulfonyl)-4-bromo-7-fluoro-5-methyl-1H-indole

[0251] 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 N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep- TLC (SiO2, PE:EtOAc = 3:1) to give the titled compound. LCMS: m / z = 347.0, 349.0 [M+H]+. Intermediate 7 potassium (3-(benzyloxy)cyclobutyl)trifluoroborate

[0252] 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) at 20 °C was added KHF2 (1.29 g, 16.52 mmol). The reaction mixture was heated to 70 °C and stirred for 6 h. 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 solids were collected by filtration to give the titled compound. Intermediate 8 potassium (3-((benzyloxy)methyl)cyclobutyl)trifluoroborate

[0253] 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 N2was added NaBH4(4.18 g, 110.39 mmol)portion-wise. The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was cooled to 0 °C, quenched by the addition of aq. sat. NH4Cl (140 mL), and the MeOH was removed under reduced pressure. The remaining aqueous phase was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 N2was 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 titled compound.

[0255] (((3-iodocyclobutyl)methoxy)methyl)benzene: To a mixture of 3- ((benzyloxy)methyl)cyclobutyl 4-methylbenzenesulfonate (5 g, 14.43 mmol) in butan-2-one (100 mL) at 25 °C under N2was 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 H2O (200 mL) and extracted with MTBE (2 × 100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled 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) at 25 °C under N2was added (((3-iodocyclobutyl)methoxy)methyl)benzene (5.5 g, 18.20 mmol), LiOMe (1.52 g, 40.05 mmol), PPh3(621 mg, 2.37 mmol) and CuI (347 mg, 1.82 mmol). The reaction mixture was heated to 35 °C and stirred for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (3 × 15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled 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 H2O (6 mL) at 25 °C under N2was added KHF2(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-Pr2O (30 mL). The solids were collected and dried under reduced pressure to give the titled compound.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

[0258] 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 H2O (3 mL) at 25 °C under N2was added K2CO3(804 mg, 5.81 mmol) and Pd(dppf)Cl2(142 mg, 0.19 mmol). The reaction mixture was heated to 140 °C and stirred for 12 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled 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) at 0 °C under N2was added BCl3(0.71 mL, 1 M in toluene) and the mixture was stirred for 1 h. The reaction mixture was quenched by addition of aq. sat. NaHCO3(20 mL) at 0 °C and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 1:1) to give the titled 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) at 25 °C under N2and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with aq. sat. NaHCO3(10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washedwith brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-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 eluting) and cis-3-(7-fluoro-5-methyl-2- (pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)cyclobutane-1-carbaldehyde (second eluting). LCMS: m / z: 365.1 [M+H]+. 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

[0261] 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) at -78 °C under N2was added LDA (11.22 mmol, 5.61 mL, 2 M in THF / n-heptane). The reaction mixture was stirred for 30 min and then the mixture was added into 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 H2O (30 mL) cooled to 0 °C and extracted with MTBE (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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) at 0 °C under N2was added pyridine (3.77 g, 47.70 mmol) and pyrrolidine (1.02 g, 14.31 mmol). The reaction mixture was warmed to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:(EtOAc:THF = 1:1) = 3:1 to 1:1) to give the titled 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: To a mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.45 g, 5.73 mmol) and 4-chloro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H-pyrrolo[2,3- b]pyridine (1.3 g, 2.86 mmol) in 1,4-dioxane (20 mL) at 20 °C under N2was added KOAc (1.12 g, 11.45 mmol), PCy3(80 mg, 0.28 mmol) and Pd2(dba)3(131 mg, 0.14 mmol). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over not oanhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (PE:(EtOAc:THF = 1:1) = 3:1 to 0:1) to give the titled compound. LCMS: m / z = 546.2 [M+H]+. Intermediate 12 2-((1H-imidazol-1-yl)sulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole

[0264] 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 N2was added 5-fluoro-2-(tributylstannyl)pyrimidine (21 g, 0.054 mol) and Pd(t-Bu3P)2(1.45 g, 0.003 mmol). The reaction mixture was heated to 110 °C and stirred for 8 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled 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 H2O (100 mL) at 20 °C under N2was 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 H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 aq. sat. NH4Cl (240 mL) at 0 °C under N2was added Zn (8.29 g, 0.13 mol). 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 H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The combinedorganic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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) at 20 °C under N2was added P2S5 (10.16 g, 0.046 mol) and NaHCO3(320 mg, 0.004 mol). The reaction mixture was heated to 50 °C and stirred for 8 h. The reaction mixture was used directly in 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) at 20 °C was added DMF (160 mL), K2CO3(10.52 g, 0.076 mol) and PMBCl (7.14 g, 0.046 mol). The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled 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) at 0 °C under N2was added TEA (897 mg, 0.009 mol), DMAP (54 mg, 0.44 mmol) and Boc2O (1.16 g, 0.005 mol). The reaction mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 10:1) to give the titled 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 H2O (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 H2O (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 was added 1H-imidazole (410 mg, 6.03 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reducedpressure. 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 titled compound. LCMS: m / z = 429.9 [M+H]+. Intermediate 13 6-(trifluoromethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

[0272] 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 N2was 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 H2O (50 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled 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 N2was 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 H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled 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) at 25 °C was added KOH (365 mg, 6.49 mmol). The reaction mixture was heated to 60 °C and stirred for 3 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled compound. LCMS: m / z = 205.1 [M+H]+. Intermediate 14 7-(trifluoromethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

[0275] 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 N2was added LiAlH4(2.5 M in THF, 4.91 mL). The reaction mixture washeated to 70 °C and stirred for 4 h. The reaction mixture was quenched by addition of Na2SO4•10H2O, 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 titled compound. LCMS: m / z = 204.9 [M+H]+. Example 1 2-(cyclobutylsulfonyl)-7-fluoro-5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole (1)

[0276] 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 titled 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) at 0 °C under N2. The mixture was then stirred at 25 °C for 6 h. The reaction mixture was diluted with aq. sat. Na2S2O3(10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with aq. sat. NaHCO3(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 titled 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)Cl2•DCM (589 mg, 0.07 mmol) at 25 °C under N2. The mixture was then stirred at 85 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) andextracted 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 titled 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 H2O (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), K3PO4(81 mg, 0.38 mmol), XPhos (12 mg, 0.03 mmol) and Catacxium A Pd G3(9 mg, 0.01 mmol) at 25 °C under N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge Prep OBD C 18150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 15%-55%, 8 min) to give the titled compound.1H 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]+. Example 2 5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0280] 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 N2. The mixture was stirred at 0 °C for 0.5 h. To the mixture was added TsCl (1.35 g, 7.11 mmol) at 0 °C under N2and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into aq. sat. NH4Cl (60 mL) and extracted with EtOAc (3 × 20 mL). The combinedorganic layers were washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled 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 N2. The mixture was stirred at –78 °C for 0.5 h. Then SO2gas was bubbled into the mixture for 30 min at –78 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the titled 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 N2. The mixture was stirred at 20 °C for 1 h, diluted with H2O (80 mL) and extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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 N2. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled 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: To a solution of 4-bromo-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1-tosyl-1H- pyrrolo[2,3-b]pyridine (180 mg, 0.36 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (229 mg, 0.90 mmol) in 1,4-dioxane (5 mL) was added KOAc (142 mg, 1.44 mmol), PCy3(10.13 mg, 0.04 mmol) and Pd2(dba)3(16.54 mg, 0.02 mmol) at 20 °C under N2. 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 prep-TLC (SiO2, PE:EtOAc = 5:1) to give the titled 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: 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 (120 mg, 0.22 mmol) and 3- bromo-1-methyl-1H-1,2,4-triazole (43 mg, 0.26 mmol) in H2O (0.2 mL) and 1,4-dioxane (2 mL) was added K3PO4(140 mg, 0.66 mmol) and Pd(dtbpf)Cl2(14 mg, 0.02 mmol) at 20 °C under N2. The mixturewas 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 prep-TLC (SiO2, PE:EtOAc = 1:1) to give the titled compound. LCMS: m / z = 501.1 [M+H]+.

[0286] 5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-1H-pyrrolo[2,3- b]pyridine (2): To a solution of 5-methyl-2-(pyrrolidine-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, 5M in H2O) at 20 °C under N2. The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with H2O (3 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were washed with brine (1 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B in A: 25%-55%, 8 min) to give the titled compound.1H-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]+. 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)

[0287] 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 Ac2O (6.00 g, 58.81 mmol) and TEA (5.95 g, 58.81 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 × 50 mL). The combined organic layers werewashed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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 conc. H2SO4(80 mL) was added dropwise HNO3(6.27 g, 97.53 mmol, 98% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. The mixture was poured into ice water (100 mL), filtered and the filter cake was dried under reduced pressure to give the titled 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 h. The reaction was concentrated under reduced pressure to give the titled 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 H2O (5 mL) was added Fe (4.48 g, 80.31 mmol) and NH4Cl (4.30 g, 80.31 mmol) at 25 °C under N2. 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 titled 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 H2O (1 mL) was added K2CO3(2.52 g, 18.26 mmol) and CS2(1.39 g, 18.26 mmol). The reaction mixture was stirred at 80 °C for 5 h and then poured into water (10 mL), filtered and the filter cake was dried under reduced pressure to give the titled compound. LCMS: m / z = 261.0, 263.0 [M+H]+.

[0292] Perfluorophenyl 4-bromo-7-fluoro-5-methyl-1H-benzo[d]imidazole-2-sulfonate: First, a mixture of HCl (0.57 mL, 2 M in H2O) in DCM (3 mL) was stirred at –5 °C. To this solution was added NaOCl (0.82 mL, 1.55 M, 10% purity) dropwise, maintaining a 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 for 20 min at –10 °C. While at –10 °C the mixture was quenched by aq. sat. Na2S2O3solution, until the yellow color disappeared. Then the mixture was quickly extracted with DCM (maintaining the temperature below 0 °C) and the organic layer was cooled to –30 °C. TEA (39 mg, 0.38 mmol) and 2,3,4,5,6-pentafluorophenol (70 mg, 0.38 mmol) were added and the reaction mixture was warmed to –8 °C and stirred for 1 h. The reaction mixture was then diluted with H2O (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with aq. sat. NaHCO3(5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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 perfluorophenyl 4-bromo-7-fluoro-5-methyl-1H-benzo[d]imidazole-2-sulfonate (100 mg, 0.22 mmol) in MeCN (10 mL) was added piperidine (93 mg, 1.09 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled 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-Bu3P)2(14 mg, 0.03 mmol) at 20 °C under N2. The mixture was stirred at 120 °C for 8 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (Phenomenex C1875 × 30 mm × 3 μm; mobile phase: A: NH4HCO3in water, B: MeCN; B% in A: 40%-70%, 8 min) to give the titled compound.1H 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]+. Example 4 7-fluoro-5-methyl-4-(pyrimidin-2-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (4)

[0295] 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(PPh3)4(22 mg, 0.019 mmol) and tributyl(pyrimidin-2-yl)stannane (86 mg, 0.23 mmol) at 20 °C under N2. The mixture was stirred at 110 °C for 6 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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 N2. The mixture was stirred at 30 °C for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 20%-50%, 8 min) to give the titled 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]+. Example 5 4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (5)

[0297] 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 H2O (0.2 mL) was added 3-bromo-1,5-dimethyl-1H-1,2,4-triazole (95 mg, 0.54 mmol), K2CO3(75 mg, 0.54 mmol) and Pd(dtbpf)Cl2(18 mg, 0.027 mmol) at 20 °C under N2. The mixture was stirred at 100 °C for 1 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 20%-50%, 8 min) to give the titled 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]+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)

[0298] 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 N2. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex Luna C1880 × 40 mm × 3 μm; mobile phase: A: 20 mM FA in water, B: MeCN; B% in A: 35%-70 %, 8 min) to give the titled 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, or can be, made via similar procedures as those described herein.Example 49 4-(6-chloropyridazin-3-yl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole (50)

[0300] 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 H2O, 9.70 mL). The mixture was stirred at 60 °C for 2 h. Thereaction 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 titled 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)Cl2.CH2Cl2(203 mg, 0.2 mmol) at 20 °C under N2. The mixture was stirred at 105 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled 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 H2O (0.1 mL) was added 3,6- dichloropyridazine (72 mg, 0.4 mmol), K2CO3(101 mg, 0.7 mmol) and Pd(dtbpf)Cl2(15 mg, 0.02 mmol) at 20 °C under N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-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%, over 8 min) to give the titled 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, or can be, made via similar procedures as those described herein.Example 55 2-(azetidin-1-ylsulfonyl)-7-fluoro-5-methyl-4-(pyrimidin-2-yl)-1H-indole (60)

[0304] 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-Bu3P)2(6 mg, 0.01 mmol) at 25 °C under N2. The mixture was stirred at 110 °C for 5 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex C 1880 × 40 mm × 3μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: B%: 20%-50%, 8 min) to give the titled compound.1H 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, or can be, made via similar procedures as those described herein.Example 62 7-fluoro-4-(cis-3-methoxycyclobutyl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole

[0306] 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 H2O (3 mL) at 25 °C under N2was added K2CO3(848 mg, 6.14 mmol) and Pd(dppf)Cl2(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 waspurified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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 N2was 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 and it was warmed to 25 °C and stirred for 2 h. The reaction mixture was quenched by the addition of aq. sat. 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 titled 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 N2was added BCl3(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 the addition of aq. sat. NaHCO3at 0 °C and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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) at 0 °C under N2was added NaH (80 mg, 2.01 mmol, 60% in mineral oil) 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 the addition of aq. sat. 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 titled 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 N2was 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 the addition of ice-H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 was added pyridine (163 mg, 2.06 mmol) andpyrrolidine (44 mg, 0.62 mmol). The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled 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 was added 4M NaOH (1 mL). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (Waters Xbridge Prep BEH C18100 × 30 mm × 5 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 33%-61%, over 8 min) to give the titled compound. LCMS: m / z = 367.0 [M+H]+. Example 63 4-(trans-3-(difluoromethyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole

[0313] 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 N2was added DAST (27 mg, 0.16 mmol) and the reaction mixture was stirred for 0.5 h. The reaction mixture was diluted with aq. sat. NaHCO3(5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in H2O, B: MeCN; B% in A 30%-65%, over 8.0 min) to give the titled compound. LCMS: m / z: 387.0 [M+H]+. Example 64 4-(cis-3-(difluoromethyl)cyclobutyl)-7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indole

[0314] 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) at 0 °C under N2was added DAST (26.5 mg, 0.16 mmol) and the mixture was stirred for 0.5 h. The reaction mixture was diluted with aq. sat. NaHCO3(5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in H2O, B: MeCN; B% in A: 35%-65%, over 8.0 min) to give the titled compound. LCMS: m / z: 387.0 [M+H]+. Example 65 2-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole

[0315] 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) at 20 °C under N2was added tert-butyl N-aminocarbamate (94 mg, 0.71 mmol) and AlMe3(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 H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 2:1) to give the titled 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 h. The reaction mixture was concentrated under reduced pressure to give the titled 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 h. The reaction mixture was concentrated under reduced pressure to give the titled 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 5M NaOH (0.5 mL). The reaction mixture was heated to 30 °C and stirred for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH 80 × 40 mm × 3 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 15%-45%, 8.0 min) to give the titled compound. LCMS: m / z = 351.1 [M+H]+. Example 66 2-(7-fluoro-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H-indol-4-yl)-5-methyl-1,3,4-oxadiazole

[0319] 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)2(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 H2O (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the titled 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 N2was added acetylhydrazine (52 mg, 0.71 mmol) and AlMe3(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 H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, andconcentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, EtOAc) to give the titled 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 N2was added p-TsCl (32 mg, 0.17 mmol) and Cs2CO3(146 mg, 0.45 mmol). The reaction mixture was heated to 60 °C and stirred for 6 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 25%-55%, 8.0 min) to give the titled compound. LCMS: m / z = 365.1 [M+H]+. Example 67 5-methyl-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(piperidin-1-ylsulfonyl)-1H-pyrrolo[2,3-c]pyridine

[0323] 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 N2was added NaH (417 mg, 10.42 mmol, 60% in mineral oil) and the reaction mixture stirred for 1 h. p-TsCl (2.71 g, 14.21 mmol) was added portion-wise to the above mixture and then it was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with aq. sat. 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 solids were filtered to give the titled 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 N2was added LDA (3.56 mmol, 1.78 mL, 2 M in THF / n-heptane) and the reaction mixture was stirred for 0.5 h. The above mixture was added into 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 titled 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 N2was 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 H2O (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:THF = 3:1 to 0:1) to give the titled 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: To a solution of 3-(4-methyl-1H-1,2,3-triazol-1-yl)-4- (trifluoromethyl)aniline (150 mg, 0.30 mmol) in 1,4-dioxane (5 mL) at 20 °C under N2was added 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), PCy3(8 mg, 0.03 mmol) and Pd2(dba)3(13 mg, 0.02 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. LCMS: m / z = 478.0 [M–C6H10+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: To a solution of 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 (250 mg, 0.45 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) at 20 °C under N2was added 3-bromo-1-methyl-1H-1,2,4-triazole (109 mg, 0.67 mmol), K3PO4(237 mg, 1.12 mmol), Xphos (43 mg, 0.09 mmol) and Catacxium A Pd G3(33 mg, 0.05 mmol). The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:(EtOAc:EtOH = 3:1) = 1:1) to give the titled 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) at 20 °C under N2was added 4M NaOH (1 mL) and MeOH (1 mL). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was diluted with H2O (6 mL), adjusted to pH = 6 by addition of 4M HCl. The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (Waters Xbridge BEH C18100 × 30 mm × 5 μm; mobile phase: A: 10 mM NH4HCO3in water; B: MeCN; B% in A: 12%-40%, over 8 min) to provide the titled compound. LCMS: m / z = 361.0 [M+H]+. Example 68 7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H- indole

[0329] 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 N2. The reaction mixture was heated to 50 °C and stirred for 2 h. The reaction mixture was diluted with H2O (1 L) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel columnchromatography (PE:EtOAc = 1:0 to 5:1) to give the titled 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 N2was 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 × 80 mL). The combined organic layers were washed with aq. sat. NaHCO3(3 × 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 titled 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) at 20 °C under N2was added TEA (25.57 g, 252.67 mmol), CuI (962.40 mg, 5.05 mmol) and Pd(PPh3)2Cl2(1.77 g, 2.53 mmol). The reaction mixture was heated at 60 °C for 12 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 10:1) to give the titled 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 N2was added t-BuOK (4.91 g, 43.76 mmol) and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 × 60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to give the titled 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 N2was 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 H2O (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 10:1) to give the crude product. The material was triturated with PE (10 mL) and the solids were collected to give the titled 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 N2was added LDA (2.79 mmol, 1.38 mL, 2 M in THF / n-heptane) and the reaction mixture wasstirred for 0.5 h. The mixture was added into a solution of sulfuryl chloride (1.86 g, 13.75 mmol) in THF (10 mL) at –50 °C and the reaction mixture was warmed to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with aq. sat. NH4Cl (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound.

[0335] 4-bromo-7-fluoro-2-(pyrrolidine-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) at 0 °C under N2was added pyridine (888 mg, 11.22 mmol) and pyrrolidine (239 mg, 3.37 mmol). The reaction mixture was warmed to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with 1M HCl (2 × 10 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 10:1) to give the titled compound.

[0336] 4-bromo-7-fluoro-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole: To a solution of 4-bromo-7-fluoro-2-(pyrrolidine-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 N2was added 4M NaOH (1.5 mL). The reaction mixture was heated to 30 °C and stirred for 2 h. The reaction mixture was diluted with H2O (6 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (6 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with PE (5 mL) and the solids were collected to give the titled compound.

[0337] 7-fluoro-2-(pyrrolidine-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-(pyrrolidine-1-ylsulfonyl)-5- (trifluoromethyl)-1H-indole (160 mg, 0.39 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2- dioxaborolane) (196 mg, 0.77 mmol) in DMSO (4 mL) at 20 °C under N2was added KOAc (113 mg, 1.16 mmol) and Pd(dppf)Cl2(28 mg, 0.04 mmol). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 3:1) to give the titled compound. LCMS: m / z = 463.1 [M+H]+.

[0338] 7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidine-1-ylsulfonyl)-5-(trifluoromethyl)- 1H-indole: To a solution of 7-fluoro-2-(pyrrolidine-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 H2O (0.4 mL) at 20 °C under N2was added K2CO3(30 mg, 0.22 mmol) and Pd(dtbpf)Cl2(7 mg, 0.01 mmol). The reaction mixture was heated to 100 °C and stirred for 2 h. The mixture was filtered through a Celite®pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B in A: 30%-60%, over 8.0 min) to give the titled compound. LCMS: m / z = 418.1 [M+H]+. Example 69 4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-indole

[0339] 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) at 0 °C was added NaH (1.38 g, 34.60 mmol, 60% in mineral oil) 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 25 °C and stirred for 12 h. The reaction mixture was poured into aq. sat. 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 titled 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 N2was added methyl 2,2-difluoro-2- fluorosulfonyl-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 H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the titled 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 N2was added LDA (6.42 mmol, 3.21 mL, 2 M in THF / n-heptane) 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 N2and the combined mixture was stirred for 10 min. The reaction mixture was poured into ice- water (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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) at 0 °C was added pyridine (2.12 g, 26.78 mmol) and pyrrolidine (1.90 g, 26.78 mmol) and the reaction mixture was stirred for 0.5 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 10:1) to give the titled 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) at 25 °C under N2was 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)3Pd G4 (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 × 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 prep-TLC (SiO2, PE:EtOAc = 2:1) to give the titled 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 H2O (0.1 mL) at 25 °C under N2was added 3-bromo-1-methyl-1H-1,2,4-triazole (66 mg, 0.40 mmol), K3PO4(86 mg, 0.41 mmol) and Pd(dtbpf)Cl2(13 mg, 0.02 mmol). The reaction mixture was heated to 80 °C and stirred for 6 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 20%-50%, over 8 min) to give the titled compound. LCMS: m / z = 400.0 [M+H]+.Example 70 5-chloro-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-1H-indole

[0345] 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 N2was 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 H2O (1 L) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled 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 N2was added trimethylsilyl acetylene (8.83 g, 89 mmol), TEA (60 g, 599.40 mmol), CuI (2 g, 11.99 mmol) and Pd(PPh3)2Cl2(4.2 g, 5.99 mmol). The reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was diluted with H2O (1 L) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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 N2was added t-BuOK (7 g, 70 mmol) and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (5 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled 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) at 0 °C under N2was added NaH (637 mg, 15 mmol, 60 % in mineral oil) and the reaction mixture was stirred for 0.5 h. p-TsCl (3.8 g, 19.92 mmol) was added to the above mixture portion-wise at 0 °C and the reaction mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was poured into aq. sat. 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 solids were collected to give the titled 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) at -78 °C under N2was added LDA (2.98 mL, 2 M in THF / n-heptane) and the reaction mixture was stirred for 0.5 h. The reaction mixture was added into 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-H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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) at 0 °C was added pyridine (1.58 g, 19.95 mmol) and pyrrolidine (425 mg, 5.99 mmol). The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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 was added 4M NaOH (1.92 mL). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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) inDMSO (2 mL) at 20 °C under N2was added KOAc (77 mg, 0.79 mmol) and Pd(dppf)Cl2(19 mg, 0.02 mmol). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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 H2O (0.1 mL) at 20 °C under N2was added 3- bromo-1-methyl-1H-1,2,4-triazole (34 mg, 0.21 mmol), K3PO4(44.56 mg, 0.2 mmol) and Pd(dtbpf)Cl2(4.56 mg, 0.07mmol). The reaction mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 5 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 12%-42%, over 8.0 min) to give the titled compound. LCMS: m / z = 384.0 [M+H]+Example 71 4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridine

[0354] 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) at 20 °C under N2was 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)3Pd G3(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 gelcolumn chromatography (PE:EtOAc = 1:0 to 3:1) to give the titled 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 H2O (20 mL) at 20 °C under N2was added 3- bromo-1-methyl-1H-1,2,4-triazole (12.46 g, 76.90 mmol), K3PO4(16.32 g, 76.90 mmol) and CataCXium®A Pd-G3 (1.87 g, 2.56 mmol). The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the title compound. LCMS: m / z = 268.1 [M+H]+.

[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 H2O (7 mL) at 20 °C under N2was added pyridinium tribromide (7.18 g, 22.45 mmol). The reaction mixture was heated to 35 °C and stirred for 16 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled 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 aq. sat. NH4Cl (15 mL) at 20 °C under N2was added Zn (2.37 g, 36.28 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was filtered through a Celite®pad and the filtrate was diluted with aq. sat. 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 titled 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 POCl3(6 mL) was heated to 110 °C and stirred for 4 h. The reaction mixture was cooled to 0 °C, adjusted to pH = 7 by the addition of aq. sat. NaHCO3and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 Cs2CO3(2.92 g, 8.95 mmol) and (4-methoxyphenyl)methanethiol (4.60 g, 29.84 mmol). The reactionmixture 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 prep-HPLC (Phenomenex Luna C1875 × 30 mm × 3 μm; mobile phase; A: 10 mM 0.2% FA in water, B: MeCN; B% in A: 35%- 65%, 8.0 min) to give the titled 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 H2O (1 mL) at 0 °C under N2was added NCS (64 mg, 0.48 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the titled 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) at 20 °C under N2was added TEA (277 mg, 2.73 mmol) and pyrrolidine (97 mg, 1.37 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 15%-45%, over 8.0 min) to give the titled compound. LCMS: m / z = 401.1 [M+H]+Example 72 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1H- pyrrolo[2,3-b]pyridine

[0362] 4-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-5-methyl-2-(pyrrolidin-1-ylsulfonyl)-1- tosyl-1H-pyrrolo[2,3-b]pyridine: 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 (100 mg, 0.18 mmol) and 3- bromo-1-(cyclopropylmethyl)-1H-1,2,4-triazole (148 mg, 0.73 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) at 25 °C under N2was added K3PO4(117 mg, 0.55 mmol) and Pd(dtbpf)Cl2(12 mg, 0.02 mmol). The reaction mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 0:1) to give the titled 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 4M NaOH (2 mL). The reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 0:1) to give the titled compound. LCMS: m / z = 387.0 [M+H]+Example 73 2-(cyclobutylsulfonyl)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3- b]pyridine

[0364] 4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-thiol: A solution of 2-((4-methoxybenzyl)thio)-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H- pyrrolo[2,3-b]pyridine (50 mg, 0.12 mmol) in TFA (2 mL) was heated to 80 °C and stirred for 8 h. The reaction mixture was concentrated under reduced pressure to give the titled 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) at 20 °C under N2was added K2CO3(46 mg, 0.33 mmol) and bromocyclobutane (45 mg, 0.33 mmol). The reaction mixture was heated to 50 °C and stirred for 5 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex Luna C18100 × 40 mm × 3 μm; mobile phase: A: 0.2% FA in water, B: MeCN; B% in A: 30%-60%, over 8.0 min) to give the titled 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) at 0 °C under N2was added m-CPBA (7 mg, 0.04 mmol, 85% w / w). The reaction mixture was warmed to 20 °C and stirred for1 h. The reaction mixture was quenched by the addition of aq. sat. Na2S2O3(1 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 30%-60%, over 8.0 min) to give the titled compound. LCMS: m / z = 386.1 [M+H]+Example 74 7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-((1-methylcyclobutyl)sulfonyl)-5-(trifluoromethyl)- 1H-indole

[0367] 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 N2was 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 aq. sat. NH4Cl (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled 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 N2was 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 the addition of aq. sat. 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 titled 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 was added TFA (1 mL) and the reaction mixture was stirred for 1 h. The reaction mixture was adjusted to pH = 7–8 by addition of aq. sat. 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 prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 43%-73%, over 8 min) to give the titled 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) at 25 °C under N2was added KOAc (64 mg, 0.65 mmol) and Pd(dppf)Cl2(16 mg, 0.02 mmol). The reaction mixture was heated to 100 °C and stirred for 6 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 3:1) to give the titled 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 H2O (0.2 mL) at 25 °C under N2was added K3PO4(58 mg, 0.27 mmol) and Pd(dtbpf)Cl2(7 mg, 0.01 mmol). The reaction mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 35%-65%, over 8 min) to give the titled compound. LCMS: m / z = 417.1 [M+H]+Example 75 7-fluoro-N,4-di(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indole-2-sulfonamide

[0372] 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 N2was added Pd(t-Bu3P)2(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 H2O (200 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give the titled 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 H2O (50 mL) at 20 °C under N2was added pyridinium tribromide (34.12 g, 106.68 mmol). The reaction mixture was heated to 30 °C and stirred for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 aq. sat. NH4Cl (80 mL) at 0 °C under N2was added Zn (5.75 g, 87.91 mmol). 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 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 titled 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 N2was 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 h. 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) at 20 °C was added DMF (50 mL), K2CO3(5.29 g, 38.31 mmol), and PMBCl (3.60 g, 22.98 mmol). The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled 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 H2O (2 mL) at 0 °C under N2was added NCS (277 mg, 2.08 mmol). The reaction mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to give the titled 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 N2was added NH3•H2O (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 H2O (10 mL) and extracted with DCM:i-PrOH (3 × 10 mL) (v:v = 3:1). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 16%-46%, over 8.0 min) to give the titled 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) at 20 °C was added Cs2CO3(81.39 mg, 0.25 mmol) and 2-fluoropyrimidine (16 mg, 0.16 mmol). The reaction mixture was heated to 100 °C and stirred for 3 h. The resulting residue was purified by prep- HPLC (Waters Xbridge Prep OBD C18150 × 40 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 10%-50%, over 8.0 min) to give the titled compound. LCMS: m / z = 439.0 [M+H]+.Example 76 (S)-7-fluoro-4-(pyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1- yl)sulfonyl)-1H-indole

[0380] 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 N2was added Pd(t- Bu3P)2(76 mg, 0.15 mmol). The reaction mixture was heated to 110 °C and stirred for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled 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 H2O (0.3 mL) at 0 °C under N2was added NCS (42 mg, 0.31 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. An additional portion of NCS (24 mg, 0.18 mmol) was added and the reaction mixture was stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled 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) at 20 °C under N2was added TEA (39 mg, 0.39 mmol) and (S)-2-(trifluoromethyl)pyrrolidine (40 mg, 0.29 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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) under N2at 20 °C was added 10% Pd / C (30 mg). The suspension was degassed under vacuum and purged with H2three times and then the reaction mixture was stirred under H2(15 psi) at 20 °C for 1 h. The reaction mixture was filtered through a Celite®pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex Luna C1875 × 30 mm × 3 μm; mobile phase: 0.2% FA in water, B: MeCN; B% in A: 20%-50%, over 8.0 min) and further purified by prep- TLC (PE:EtOAc = 1:1) to give the titled compound. LCMS: m / z = 483.0 [M+H]+. Example 77 (S)-7-fluoro-4-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1- yl)sulfonyl)-1H-indole

[0384] 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 was added 2H-1,2,3-triazole (81.21 g, 0.82 mol) and K2CO3(170.63 g, 1.23 mol). 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 titled 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) at 20 °C under N2was added diphenylmethanimine (22.34 g, 123.26 mmol), Cs2CO3(53.55 g, 164.35 mmol), Xantphos (9.51 g, 16.44 mmol) and Pd2(dba)3(7.53 g, 8.22 mmol). 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 N2before 2M 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 addition of aq. sat. NaHCO3and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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) at 0 °C was added Selectfluor™ (18.4 g, 52.07 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled 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) at 0 °C under N2was added NIS (10.25 g, 45.54 mmol). 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 titled 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) at 20 °C under N2was added trimethylsilylacetylene (6.20 g, 63.16 mmol), CuI (481 mg,2.53 mmol) and Pd(PPh3)2Cl2(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 H2O (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to provide the titled 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) at 0 °C was added t-BuOK (1.64 g, 14.6 mmol). The reaction mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled 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 H2O (4 mL) at 20 °C under N2was added pyridinium tribromide (7.10 g, 22.21 mmol). The reaction mixture was heated to 30 °C and stirred for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 aq. sat. NH4Cl (20 mL) at 0 °C under N2was added Zn (1.47 g, 22.52 mmol). 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 × 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 titled 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) at 20 °C was added P2S5 (932 mg, 4.19 mmol) and NaHCO3(29 mg, 0.35 mmol). 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) at 20 °C was added DMF (20 mL), K2CO3(1.83 g, 13.24 mmol), and PMBCl (1.55 g, 9.92 mmol). The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers weredried 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 titled 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 Boc2O (232 mg, 1.07 mmol). The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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 H2O (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 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 469.0 [M+H]+.

[0396] 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: 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 was added TEA (54 mg, 0.53 mmol) and (S)-2- (trifluoromethyl)pyrrolidine (45 mg, 0.32 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine (3 × 2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 was added TFA (0.2 mL) and the reaction mixture was stirred for 1 h. The reaction mixture was adjusted to pH = 7–8 with aq. sat. NaHCO3and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B in A: 32%-58%, over 8.0 min) and further purified by prep-TLC (SiO2, PE:EtOAc = 3:1) to give the titled compound. LCMS: m / z = 472.1 [M+H]+.Example 78 (S)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1- yl)sulfonyl)-1H-indole

[0398] 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) at -78 °C under N2was added dropwise LDA (11.00 mL, 2 M in THF / n-heptane) 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 the addition of aq. sat. NH4Cl (150 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with PE (20 mL) at -40 °C for 20 min and the solids were collected to give the titled 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) at 0 °C under N2was added TBAF (23 mL, 1 M in THF). 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 titled 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 H2O (3 mL) at 0 °C under N2was 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 H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the titled 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 equiv) in DCM (0.27 M) at 20 °C under N2was added TEA (5 equiv) and (S)-2- (trifluoromethyl)pyrrolidine (4 equiv) and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 5:1) to give the titled 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 N2was added Pd(t-Bu3P)2(8 mg, 0.016 mmol). The reaction mixture was heated to 110 °C and stirred for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex Luna C1875 × 30 mm × 3 μm; mobile phase: A: 0.2% FA in water, B: MeCN; B% in A 40%-70%, over 8.0 min) to give the titled compound. LCMS: m / z = 501.0 [M+H]+. 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

[0403] (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: To a solution of (S)-4-bromo-7-fluoro-5- (trifluoromethyl)-2-((2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole (100 mg, 0.21 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (158 mg, 0.62 mmol) in DMSO (3 mL) at 20 °C under N2was added Pd(dppf)Cl2(15 mg, 0.02 mmol) and KOAc (41 mg, 0.41 mmol). The reaction mixture was heated to 100 °C and stirred for 8 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 5:1) to give the titled 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: To a solution of (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 (50 mg, 0.09 mmol) and 4-bromo-2-methyl-2H-1,2,3-triazole (23 mg, 0.14 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) at 20 °C under N2was added K3PO4(50 mg, 0.24 mmol) and Pd(dtbpf)Cl2(6 mg, 0.009 mmol). The reaction mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex Luna C18100 × 30 mm × 3 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 40%-75%, over 8.0 min) to give the titled compound. LCMS: m / z = 486.0 [M+H]+. Example 80 2-(cyclobutylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole

[0405] 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 H2O (70 mL) at 20 °C under N2was 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 H2O (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was 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 titled 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 aq. sat. NH4Cl (80 mL) at 0 °C under N2was added Zn (5.67 g, 86.66 mmol). 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 H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (100mL), 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 titled 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 N2was 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 H2O (20 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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 N2was added K2CO3(158 mg, 1.15 mmol). The reaction mixture was heated to 65 °C and stirred for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 9:1 to 3:1) to give the titled 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 N2was added m-CPBA (220 mg, 1.09 mmol, 85% w / w). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with MTBE (10 mL) and the solids were 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) at 25 °C under N2was added KOAc (132 mg, 1.35 mmol) and Pd(dppf)Cl2(33 mg, 0.04 mmol). The reaction mixture was heated to100 °C and stirred for 6 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 6:1 to 1:1) to give the titled 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 H2O (0.1 mL) at 25 °C under N2was added K3PO4(47 mg, 0.22 mmol) and Pd(dtbpf)Cl2(7 mg, 0.01 mmol). 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 × 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 prep-HPLC (Waters Xbridge Prep OBD C18150 × 40 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B in A: 20%-50%, over 8.0 min) to give the titled compound. LCMS: m / z = 403.1 [M+H]+. Example 81 2-(cyclopropylsulfonyl)-7-fluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole

[0412] 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 N2was added LDA (1.49 mL, 2 M in THF / n-heptane) and the reaction mixture was stirred for 1 h. A solution of I2 (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 the addition of aq. sat. NH4Cl (15 mL), diluted with H2O (10 mL), and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled 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 N2was 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 H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30mm × 10 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 30%-60%, over 8 min) to give the titled 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) at 25 °C under N2was added Pd(dppf)Cl2(13 mg, 0.02 mmol) and KOAc (53 mg, 0.54 mmol). The reaction mixture was heated to 100 °C and stirred for 6 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep- TLC (SiO2, PE:EtOAc = 10:1) to give the titled 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 H2O (0.2 mL) at 25 °C under N2was added K3PO4(49 mg, 0.23 mmol) and Pd(dtbpf)Cl2(6 mg, 0.01 mmol). 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 prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 20%-50%, over 8 min) to give the titled compound. LCMS: m / z = 389.1 [M+H]+. 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

[0416] 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 was added TEA (112 mg, 1.10 mmol) and 3-fluoro-N- methylbicyclo[1.1.1]pentan-1-amine (76 mg, 0.66 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled 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) at 0 °C was added TFA (0.3 mL, 4.04 mmol). The reaction mixture was warmed to 20 °C and stirred for 5 h. The reaction mixture was quenched by the addition of aq. sat. NaHCO3(5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18150 × 40 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 40%- 75%, over 8.0 min) and further purified by prep-TLC (PE:EtOAc = 3:1) to give the titled compound. LCMS: m / z = 477.0 [M+H]+. 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

[0418] 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 H2O (1.5 mL) at 0 °C under N2was 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 H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 10:1) to give the titled 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) at 20 °C under N2was added TEA (20 mg, 0.20 mmol) and N,3-dimethylbicyclo[1.1.1]pentan-1-amine hydrochloride (22 mg, 0.15 mmol) and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resultingresidue was purified by prep-HPLC (Phenomenex Luna C1875 × 30 mm × 3 µm; mobile phase: A: 0.2% FA in water, B: MeCN; B% in A: 30%-70%, over 8.0 min) to give the titled compound. LCMS: m / z = 473.0 [M+H]+. 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

[0420] 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) at 25 °C under N2was 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). 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 prep-HPLC (Waters Xbridge BEH C 18100 × 30 mm × 10 μm; mobile phase A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 45%-75%, over 8.0 min) to give the titled compound. LCMS: m / z = 516.1 [M+H]+. Example 85 4-((7-fluoro-4-(5-fluoropyrimidin-2-yl)-5-(trifluoromethyl)-1H-indol-2-yl)sulfonyl)-3- (trifluoromethyl)morpholine

[0421] To a solution of 2-((1H-imidazol-1-yl)sulfonyl)-7-fluoro-4-(5-fluoropyrimidin-2-yl)-5- (trifluoromethyl)-1H-indole (15 mg, 0.035 mmol) in toluene (2 mL) at 20 °C under N2was added pyridine (14 mg, 0.17 mmol) and 3-(trifluoromethyl)morpholine hydrochloride (20 mg, 0.10 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 prep-HPLC (Phenomenex Luna C 1880 × 30 mm × 3 μm; mobile phase A: 20 mM FA in water, B: MeCN; B% in A: 25%-60%, over 9 min) and wasfurther purified by prep-TLC (PE:EtOAc = 3:1) to give the titled compound. LCMS: m / z = 517.1 [M+H]+. Example 86 (S)-4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)-2-((2- (trifluoromethyl)pyrrolidin-1-yl)sulfonyl)-1H-indole

[0422] 1-(4-methoxybenzyl)-1H-1,2,3-triazole: To a solution of 1H-1,2,3-triazole (50 g, 723.95 mmol) in DMF (500 mL) at 20 °C under N2was added K2CO3(130 g, 941 mmol) and 1-(chloromethyl)-4- methoxybenzene (147.39 g, 941 mmol). The reaction mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was poured into H2O (2 L) and extracted with EtOAc (3 × 800 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 190.1 [M+H]+.

[0423] 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole: To a solution of 1-(4-methoxybenzyl)-1H- 1,2,3-triazole (20 g, 105.70 mmol) in THF (400 mL) at -78 °C under N2was added n-BuLi (42 mL, 105 mmol, 2.5 M in hexane) dropwise over 0.5 h. The reaction mixture was stirred for 0.5 h and then a solution of perchloroethane (30 g, 127 mmol) in THF (100 mL) was added dropwise to the above mixtureat -78 °C. The reaction mixture was stirred at -78 °C for an additional 2 h and then the reaction mixture was poured into aq. sat. NH4Cl (1 L) and extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 2:1 to 1:1) to give the titled compound.

[0424] 5-chloro-1H-1,2,3-triazole trifluoroacetate: A solution of 5-chloro-1-(4-methoxybenzyl)-1H- 1,2,3-triazole (20 g, 89 mmol) in TFA (200 mL) was heated to 65 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give the titled compound.

[0425] 2-(5-bromo-2-(trifluoromethyl)phenyl)-4-chloro-2H-1,2,3-triazole: To a solution of 4-chloro- 2H-triazole (32 g crude, 131 mmol) in DMF (500 mL) at 20 °C under N2was added K2CO3(39.81 g, 288 mmol) and 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (35 g, 144 mmol). The reaction mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was diluted with H2O (1500 mL) and extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (PE:EtOAc = 1:0 to 10:1) to give the titled compound.

[0426] 3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: To a solution of 2-(5-bromo-2- (trifluoromethyl)phenyl)-4-chloro-2H-1,2,3-triazole (9.6 g, 29 mmol) and diphenylmethanimine (7.46 g, 41 mmol) in 1,4-dioxane (150 mL) at 20 °C under N2was added Cs2CO3(19.16 g, 59 mmol), Xantphos (3.40 g, 6 mmol) and Pd2(dba)3(2.69 g, 3 mmol). The reaction mixture was heated to 110 °C and stirred for 16 h. The reaction mixture was filtered through a Celite®pad and the filtrate was concentrated under reduced pressure. To the crude mixture of N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4- (trifluoromethyl)phenyl)-1,1-diphenylmethanimine (25 g, crude) in THF (130 mL) at 0 °C was added HCl (2 M in H2O, 130 mL). The reaction mixture was warmed to 20°C and stirred for 2 h. The reaction mixture was adjusted to pH = 8 by addition of aq. sat. NaHCO3, then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled compound.

[0427] 5-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)aniline: To a solution of 3-(4- chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline (5.8 g, 22 mmol) in MeCN (60 mL) at 20 °C was added SelectFluor ™ (9.39 g, 27 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. The reaction mixture was poured into H2O (80 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. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the titled compound. LCMS: m / z = 279.1 [M-H]-.

[0428] 3-(4-chloro-2H-1,2,3-triazol-2-yl)-6-fluoro-2-iodo-4-(trifluoromethyl)aniline: To a solution of 5-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)aniline (2.6 g, 9 mmol) in AcOH (50 mL) at 10 °C was added NIS (5.21 g, 23 mmol). The reaction mixture was warmed to 20 °C and stirredfor 16 h. To the reaction mixture was added NIS (1.04 g, 5 mmol) and the mixture was stirred for an additional 16 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 406.9 [M+H]+.

[0429] 3-(4-chloro-2H-1,2,3-triazol-2-yl)-6-fluoro-4-(trifluoromethyl)-2- ((trimethylsilyl)ethynyl)aniline: To a solution of 3-(4-chloro-2H-1,2,3-triazol-2-yl)-6-fluoro-2-iodo-4- (trifluoromethyl)aniline (800 mg, 2 mmol) in TEA (10 mL) at 20 °C under N2was added CuI (75 mg, 0.40 mmol), Pd(PPh3)2Cl2(138 mg, 0.20 mmol), and Et3SiH (966 mg, 9.84 mmol). The reaction mixture was heated to 80 °C and stirred for 8 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 377.0 [M+H]+.

[0430] 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)-1H-indole: To a solution of 3- (4-chloro-2H-1,2,3-triazol-2-yl)-6-fluoro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (930 mg, 2.47 mmol) in NMP (10 mL) at 0 °C under N2was added t-BuOK (692 mg, 6.17 mmol). The reaction mixture was warmed to 20 °C and stirred for 16 h. The reaction mixture was diluted with aq. sat. NH4Cl (20 mL) and extracted with EtOAc (3 × 7 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 titled compound. LCMS: m / z = 305.0 [M+H]+.

[0431] 3,3-dibromo-4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)indolin-2-one: To a solution of 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)-1H-indole (610 mg, 2 mmol) in t-BuOH (12 mL) and H2O (4 mL) at 20 °C was added pyridinium tribromide (3.84 g, 12 mmol). The reaction mixture was heated to 30 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. LCMS: m / z = 478.7 [M+H]+.

[0432] 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)indolin-2-one: To a solution of 3,3-dibromo-4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)indolin-2-one (950 mg, 2 mmol) in THF (10 mL) and aq. sat. NH4Cl (10 mL) at 0 °C under N2was added Zn (649 mg, 9.93 mmol) and the reaction mixture was stirred for 0.5 h. The reaction mixture was filtered through a Celite®pad and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 321.0 [M+H]+.

[0433] 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)indoline-2-thione: To a solution of 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)indolin-2-one (195 mg, 0.6mmol) in THF (9 mL) at 20 °C under N2was added P2S5(162 mg,0.72 mmol) and NaHCO3(5 mg, 0.06 mmol). The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was used directly in the next step. LCMS: m / z = 337.0 [M+H]+.

[0434] 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)- 1H-indole: To a solution of 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-5-(trifluoromethyl)indoline-2- thione (210 mg, 0.63 mmol) in THF (9 mL) at 20 °C under N2was added DMF (6 mL), K2CO3(171 mg, 1.26 mmol) and PMBCl (117 mg, 0.75 mmol). The reaction mixture was heated to 50 °C and stirred for 4 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 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 titled compound. LCMS: m / z = 457.0 [M+H]+.

[0435] tert-butyl 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7-fluoro-2-((4-methoxybenzyl)thio)-5- (trifluoromethyl)-1H-indole-1-carboxylate: To a solution of 4-(4-chloro-2H-1,2,3-triazol-2-yl)-7- fluoro-2-((4-methoxybenzyl)thio)-5-(trifluoromethyl)-1H-indole (130 mg, 0.28 mmol) in DCM (2 mL) at 0 °C under N2was added TEA (58 mg, 0.57 mmol), DMAP (3 mg, 0.028 mmol) and Boc2O (75 mg, 0.34 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers ...

Claims

What is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6; R1is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R7)2, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R2is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; whereinthe C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; each R7is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R12is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1ais independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, -C(O)OR13, -S(O)R13, -S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, -NR13S(O)R13, -NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; andeach L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -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)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that: A) when X is N and R1is methyl; then R2is C3-10cycloalkyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; and B) the compound is not: 4,5,6,7-tetrafluoro-1H-indole-2-sulfonamide (1451047-95-2), 7-chloro-6-ethoxy-2- (ethylsulfonyl)-1H-benzimidazole (670248-30-3), 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).

2. A compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

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

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

5. The compound of claim 1 or 2, wherein R1is C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R11)2, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

6. The compound of claim 1 or 2, wherein R1is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, wherein the C1-6alkyl, C2-6alkenyl, or C2-6alkynyl is independently optionally substituted with one to five Z1.

7. The compound of claim 1 or 2, wherein R1is C3-10cycloalkyl optionally substituted with one to five Z1.

8. The compound of claim 1 or 2, wherein R1is heterocyclyl optionally substituted with one to five Z1.

9. The compound of claim 1 or 2, wherein R1is aryl optionally substituted with one to five Z1.

10. The compound of claim 1 or 2, wherein R1is heteroaryl optionally substituted with one to five Z1.

11. The compound of claim 1 or 2, wherein R1is -N(R7)2.

12. A compound of Formula II:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6; ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2,-NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; each R7is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or two R7, together with the nitrogen atom to which they are attached, form a heterocyclyl independently optionally substituted with one to five Z1; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a;each R12is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1ais independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, -C(O)OR13, -S(O)R13, -S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, -NR13S(O)R13, -NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -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)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

13. A compound of Formula IIA:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: Y is N or CR4; Y1is N or CR5; X is N or CR6; ring A is heterocyclyl optionally substituted with one to five Z1;ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6is hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -SR11, -C(O)R11, -C(O)OR11, -S(O)R11, -S(O)2R11, -C(O)N(R11)2, -NR11C(O)R11, -NR11S(O)R11, -NR11S(O)2R11, -S(O)N(R11)2, -S(O)2N(R11)2, -NR11C(O)N(R11)2, -NR11S(O)N(R11)2, -NR11S(O)2N(R11)2, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a;each R12is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1ais independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -SR13, -C(O)R13, -C(O)OR13, -S(O)R13, -S(O)2R13, -C(O)N(R13)2, -NR13C(O)R13, -NR13S(O)R13, -NR13S(O)2R13, -S(O)N(R13)2, -S(O)2N(R13)2, -NR13C(O)N(R13)2, -NR13S(O)N(R13)2, -NR13S(O)2N(R13)2, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -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)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

14. The compound of any one of claims 1-2 or 5-13, wherein Y is CR4.

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

16. The compound of any one of claims 1-2 or 5-15, wherein Y1is CR5.

17. The compound of any one of claims 1-2 or 5-15, wherein Y1is N.

18. The compound of claim 1 or 12, wherein the compound is represented by Formula IE:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof; wherein ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

19. The compound of claim 1 or 13, wherein the compound is represented by Formula IF:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof; wherein ring A is heterocyclyl optionally substituted with one to five Z1; ring B is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1.

20. The compound of any one of claims 1-3, 5-16, or 18-19, wherein R5is halo.

21. The compound of any one of claims 1-20, wherein X is CR4.

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

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

24. The compound of any one of claims 1-23, wherein R1or ring A is a 4- to 10-membered heterocyclyl optionally with one to five Z1.

25. The compound of any one of claims 1-24, wherein R1or ring A is:wherein each is optionally with one1to five Z .

26. The compound of any one of claims 1-25, wherein R2or ring B is heteroaryl optionally substituted with one to five Z1.

27. The compound of any one of claims 1-26, wherein R2or ring B is a 5- or 6-membered heteroaryl optionally substituted with one to five Z1.

28. The compound of any one of claims 1-27, wherein R3is C1-6alkyl.

29. The compound of any one of claims 1-28, wherein each Z1is independently selected from halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, -S(O)2-C1-6alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

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

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

32. A method for inhibiting SARM1 activity, the method 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, the pharmaceutical composition of claim 31.

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

34. A method for treating a disease or condition mediated, at least in part, by SARM1, the method 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, the pharmaceutical composition of claim 31.

35. A method for inhibiting axon degeneration, the method 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 the pharmaceutical composition of claim 31.

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

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

38. The method of claim 37, wherein the disease or condition is a spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe’s 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-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic complications of chemotherapy (chemotherapy induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, retinitis pigmentosa, traumatic optic injury, Leber’s hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell’s palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motoneuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedreich’s ataxia, hereditary ataxias, noise induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathies and axonopathies, Guillain- Barre syndrome, or severe acute motor axonal neuropathy (AMAN).

39. Use 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, the pharmaceutical composition of claim 31, for treating a disease or condition mediated, at least in part, by SARM1.

40. The use of claim 39, wherein the disease or condition is a spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy(Krabbe’s 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-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic complications of chemotherapy (chemotherapy induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic injury, Leber’s hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell’s palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motoneuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedreich’s ataxia, hereditary ataxias, noise induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathies and axonopathies, Guillain- Barre syndrome, or severe acute motor axonal neuropathy (AMAN).

41. 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, for use in therapy.

42. 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, for use in treating a spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe’s 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-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic complications of chemotherapy (chemotherapy induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic injury, Leber’s hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell’s palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nilevirus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motoneuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedreich’s ataxia, hereditary ataxias, noise induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathies and axonopathies, Guillain-Barre syndrome, or severe acute motor axonal neuropathy (AMAN).

43. The use 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, for the manufacture of a medicament for treating a spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe’s 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-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic complications of chemotherapy (chemotherapy induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic injury, Leber’s hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell’s palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T- lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motoneuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), Friedreich’s ataxia, hereditary ataxias, noise induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathies and axonopathies, Guillain-Barre syndrome, or severe acute motor axonal neuropathy (AMAN).

44. A process for providing a compound of Formula I according to claim 1, comprising contacting a compound of Formula I-1:with a compound of Formula I-2:under conditions sufficient to provide a compound of Formula I; wherein LG is a leaving group; and each R50is independently -OH, -O-alkyl, or together with the boron atom to which they are attached, form a cyclic boronate.

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