Compounds, compositions, and methods

Abstract

The present disclosure relates generally to small molecule inhibitors of Sterile Alpha and TIR Motif containing 1 (SARM1) protein, 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) to U.S. Provisional Application Numbers 63 / 513,729, filed July 14, 2023, and 63 / 580,976, filed September 6, 2023, each of which is 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 dimerization 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] 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)NH2 is 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.

[0015] 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.

[0016] 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.

[0017] “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., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., C1-4 alkyl). 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).

[0018] 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.

[0019] “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., C2-20 alkenyl), 2 to 12 carbon atoms (i.e., C2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2- butadienyl and 1,3-butadienyl).

[0020] “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., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0021] “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.

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

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

[0024] “Acyl” refers to 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.

[0025] “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 be optionally 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.

[0026] “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.

[0027] “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.

[0028] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl 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.

[0029] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

[0030] “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.

[0031] “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.

[0032] “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.

[0033] “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., C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. 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 alsoincludes “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.

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

[0035] “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.

[0036] “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.

[0037] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0038] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are 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.

[0039] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0040] “Haloalkoxyalkyl” refers to an alkoxyalkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0041] “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.

[0042] “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.

[0043] “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., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl), 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, triazolyl, thiophenyl (i.e., thienyl), 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.

[0044] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.

[0045] “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 containing at least one heteroatom 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. 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., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); 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.

[0046] “Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-.”

[0047] “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.

[0048] “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.

[0049] “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.

[0050] “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.

[0051] 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 toany 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.

[0052] 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.

[0053] 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.

[0054] 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 itself substituted 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). Suchimpermissible 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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 available isotopically 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.

[0059] 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 atits natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0060] 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.

[0061] Provided are also a pharmaceutically acceptable salt, isotopically enriched analog, deuterated analog, stereoisomer, mixture of stereoisomers, and 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.

[0062] 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 organic acids. 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(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0067] 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).

[0068] “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 a compound 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 toregenerate 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

[0069] 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 R, R1, R4, R5, X1, X2, X3, and X4are each independently as defined herein.

[0070] 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: X1is N or CR6a; X2is N or CR6b; X3is N or CR6c; X4is N or CR6d; R is -NR2R3, -OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is independently optionally substituted with one to five Z1; R1is halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 each C1-6alkyl,C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; R2is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or R2and R3together form a heterocyclyl, which may further be independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -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 each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; R7is C1-6 alkyl, C2-6 alkenyl, -6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; each Z1is independently halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a;each R10is 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 Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R12is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that: a) R is not unsubstituted methyl; b) R7is not unsubstituted tert-butyl or unsubstituted benzyl; c) when X1is CR6a, X2is CR6b, X3is CR6c, and X4is CR6d; X1is N, X2is N, X3is N, and X4is CR6d; or X1is CR6a, X2is N, X3is N, and X4is N;then R isoptionally substituted with one to five Z1; d) when X1is N, X2is N, X3is CR6c, and X4is CR6d; or X1is CR6a, X2is CR6b, X3is N, and X4is N; then R is not; e) when X1is N, X2is CR6b, X3is CR6c, and X4is CR6d; or X1is CR6a, X2is CR6c, X3is CR6c, and X4is N; then: i) R is not unsubstituted cyclopropyl, substituted or unsubstituted benzyl; and ii) when R is -NR2R3, and R1is methyl, then neither of R6bor R6care substituted or unsubstituted heteroaryl; f) and the compound is not: 4-(ethylsulfonyl)-N-[2-(1H-1,2,3-triazol-1-yl)-2′-(trifluoromethoxy)[1,1′-biphenyl]-4-yl]- benzeneacetamide; 2-chloro-N-[4-[[(4-methylphenyl)sulfonyl]amino]-3-(2H-1,2,3-triazol-2-yl)phenyl]acetamide; 4-(ethylsulfonyl)-N-[2-(2H-1,2,3-triazol-2-yl)-2′-(trifluoromethoxy)[1,1′-biphenyl]-4- yl]benzeneacetamide; 2,2-dimethyl-N-[4-(2-methylbenzoyl)-3-(1H-pyrazol-1-yl)phenyl]propanamide; N-[6-[[2-amino-4-fluoro-5-(1H-pyrazol-1-yl)phenyl]amino]-6-oxohexyl]-4-methylbenzamide; N-[4-fluoro-2-nitro-5-(1H-pyrazol-1-yl)phenyl]cyclopentanecarboxamide; N-[3-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-1-yl]-4-butoxyphenyl]decanamide; N-[3-[4-[(4-bromo-2-fluorophenyl)methyl]-3-butyl-5-cyano-1H-pyrazol-1-yl]-4- chlorophenyl]propanamide; N-[2-chloro-5-[5-cyano-4-(difluoromethoxy)-3-methyl-1H-pyrazol-1-yl]-4-fluorophenyl]-2,2,2- trifluoroacetamide; 1-[5-[[3-(diethylamino)-1-oxopropyl]amino]-2-(1-methylethyl)phenyl]-5-(2,6- dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid; methyl 1-[5-[[3-(diethylamino)-1-oxopropyl]amino]-2-(1-methylethyl)phenyl]-5-(2,6- dimethoxyphenyl)-1H-pyrazole-3-carboxylate; N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-[2-chloro-5-[(2-methyl-1- oxopropyl)amino]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; N-[3-[4-[[2′-(aminosulfonyl)-3-fluoro[1,1′-biphenyl]-4-yl]methyl]-3-butyl-5-cyano-1H-pyrazol- 1-yl]-4-chlorophenyl]propanamide; N-[3-[3-butyl-5-cyano-4-[[2′-[[(1,1-dimethylethyl)amino]sulfonyl]-3-fluoro[1,1′-biphenyl]-4-yl]methyl]-1H-pyrazol-1-yl]-4-chlorophenyl]propanamide; 2-[[[1-[5-[[3-(diethylamino)-1-oxopropyl]amino]-2-(1-methylethyl)phenyl]-5-(2,6- dimethoxyphenyl)-1H-pyrazol-3-yl]carbonyl]amino]tricyclo[3.3.1.13,7]decane-2-carboxylic acid; [3-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-1-yl]-4-butoxyphenyl]-carbamic acid butyl ester; methyl N-[4-chloro-3-[5-[[[4-chloro-2-methyl-6- [(methylamino)carbonyl]phenyl]amino]carbonyl]-3-(trifluoromethyl)-1H-pyrazol-1- yl]phenyl]carbamate; 1-methylethyl N-[4-chloro-3-[5-[[[4-chloro-2-methyl-6- [(methylamino)carbonyl]phenyl]amino]carbonyl]-3-(trifluoromethyl)-1H-pyrazol-1- yl]phenyl]carbamate; 8-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]oxy]-N-[3-(1H- imidazol-1-yl)-4-[[[8-(1-methylethyl)-2-[(1-methyl-4-piperidinyl)oxy]pyrazolo[1,5-a]-1,3,5-triazin-4- yl]amino]methyl]phenyl]octanamide; N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]-γ-oxobenzenebutanamide; N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]-1-(4-morpholinylsulfonyl)-4- piperidinecarboxamide; methyl 3-[[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]amino]-3-oxopropanoate; N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]benzenebutanamide; 3,4-dihydro-N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]-3-methyl-4-oxo-1- phthalazinecarboxamide; N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]-1-(phenylsulfonyl)-2- pyrrolidinecarboxamide; 4-chloro-N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]benzeneacetamide; N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]benzenepropanamide; 3-chloro-N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]benzeneacetamide; N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]-3-(phenylsulfonyl)propanamide; 3,4-dichloro-N-[4-methoxy-3-(4-methyl-1H-imidazol-1-yl)phenyl]benzeneacetamide; 5-chloro-N-[4-chloro-3-(1H-imidazol-1-yl)phenyl]-6-oxo-4-[[(1R,2R,3R,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]amino]-1(6H)-pyridazineacetamide; N-[3-(1H-imidazol-1-yl)-4-methoxyphenyl]-9H-fluorene-1-carboxamide; N-[3-(1H-imidazol-1-yl)-4-methylphenyl]-9H-fluorene-1-carboxamide; 4-(ethylsulfonyl)-N-[2-(1H-imidazol-1-yl)-2′-(trifluoromethoxy)[1,1′-biphenyl]-4-yl]- benzeneacetamide; N-[4-methyl-3-(5′-methyl-1H,3′H-2,4′-biimidazol-1-yl)phenyl]cyclopentanecarboxamide N-[4-fluoro-3-(1′-methyl[2,2′-bi-1H-imidazol]-1-yl)phenyl]propanamide; N-[4-chloro-3-[2-(3-pyridinyl)-1H-imidazol-1-yl]phenyl]-2-methoxyacetamide; N-[4-chloro-3-[2-(3-cyclohexen-1-yl)-1H-imidazol-1-yl]phenyl]-2-methoxyacetamide;N-[4-chloro-3-(4H-1,2,4-triazol-4-yl)phenyl]propanamide; or N-[4-chloro-3-(4H-1,2,4-triazol-4-yl)phenyl]butanamide.

[0071] In certain embodiments, R is -NR2R3. 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 R1, R2, R3, R4, R5, X1, X2, X3, and X4are each independently as defined herein.

[0072] In certain embodiments, the moietywhich may optionally be fused to a C6aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NH, O, or S.

[0073] In certain embodiments, R or the moiety, wherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3. 1. In certain embodiments, the moiety; wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring A is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; and L1is a bond, C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl.

[0074] In certain embodiments, L1is a bond or C1-4 alkyl. In certain embodiments, L1is a bond or C1-2alkyl. In certain embodiments, L1is a bond or -CH2-. In certain embodiments, L1is a bond.

[0075] In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z1a. In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z1a, and L1is a bond orC1-2alkyl. In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z1a, and L1is a bond or CH2. In certain embodiments, Ring A is heteroaryl and L1is a bond. In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z1a, L1is a bond, q is 1, and Z1is C1-6 alkyl.

[0076] In certain embodiments, provided is a compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1is N or CR6a; X2is N or CR6b; X3is N or CR6c; X4is N or CR6d; R1is 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 each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; R2is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or R2and R3together form a heterocyclyl, which may further be independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -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 each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; each Z1is independently halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R10is 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 Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -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(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 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: when X1is CR6a, X2is CR6b, X3is CR6c, and X4is CR6d; X1is N, X2is N, X3is N, and X4is CR6d; or X1is CR6a, X2is N, X3is N, and X4is N; thenwherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3; and when X1is N, X2is CR6b, X3is CR6c, and X4is CR6d; or X1is CR6a, X2is CR6c, X3is CR6c, and X4is N; and R1is methyl; then neither of R6bor R6care substituted or unsubstituted heteroaryl.

[0077] In certain embodiments, provided is a compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1is N or CR6a; X2is N or CR6b; X3is N or CR6c; X4is N or CR6d; R1is 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 each C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1;R2is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or R2and R3together form a heterocyclyl, which may further be independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -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 each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; each Z1is independently halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 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 R10is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a;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 R12is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl. provided that: when X1is CR6a, X2is CR6b, X3is CR6c, and X4is CR6d; X1is N, X2is N, X3is N, and X4is CR6d; or X1is CR6a, X2is N, X3is N, and X4is N; then R is wherein q is 0, 1, 2, 3, 4, or 5;and p is 0, 1, 2, or 3; and when X1is N, X2is CR6b, X3is CR6c, and X4is CR6d; or X1is CR6a, X2is CR6c, X3is CR6c, and X4is N; and R1is methyl; then neither of R6bor R6care substituted or unsubstituted heteroaryl.

[0078] In certain embodiments, provided is a compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1is N or CR6a; X2is N or CR6b; X3is N or CR6c; X4is N or CR6d; R1is halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; R2is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1;R3is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or R2and R3together form a heterocyclyl, which may further be independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -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 each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, is 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, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R10is 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 Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -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(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 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: when X1is CR6a, X2is CR6b, X3is CR6c, and X N, X2is N, X3is N, and X4is CR6d; or X1is CR6a, X2is N, X3is N, and X4is N; thenoptionally substituted with one to five Z1and when X1is N, X2is CR6b, X3is CR6c, and X4is CR6d; or X1is CR6a, X2is CR6c, X3is CR6c, and X4is N; and R1is methyl; then neither of R6bor R6care substituted or unsubstituted heteroaryl.

[0079] In certain embodiments, R or the moiety, which is optionally substituted with one to five Z1, wherein p is 0, 1, 2, or 3.

[0080] In certain embodiments, R or the moiety, or ; wherein each is independentlyoptionally substituted with one to five Z1.

[0081] In certain embodiments, R2and R3together form a spirocyclic heterocyclyl, which may further be independently optionally substituted with one to five Z1.

[0082] In certain embodiments, R or the moietyis:

[0083] In certain embodiments, R or the moiety:,

[0084] In certain embodiments, R or the moiety

[0085] In certain embodiments, each Z1is independently halo, cyano, C1-6alkyl, C1-6haloalkyl, heteroaryl, -OR12, -C(O)R12, -C(O)OR12, or -C(O)N(R12)2; wherein each C1-6 alkyl, C1-6 haloalkyl, heteroaryl is independently optionally substituted with one to five hydroxy, methoxy, or methyl.

[0086] In certain embodiments, Z1is halo. In certain embodiments, Z1is fluoro.

[0087] In certain embodiments, R or the moiety; wherein: m is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring A is C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1aor Z1b; and L1is a bond, C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl.

[0088] In certain embodiments, the moiety; wherein: m is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring A is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1aor Z1b; and L1is a bond, C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl.

[0089] In certain embodiments, R or the moietywherein: m is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring A is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; L1is a bond, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl; and each R10is 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a.

[0090] In certain embodiments, L1is a bond or C1-4 alkyl. In certain embodiments, L1is a bond or C1-2alkyl. In certain embodiments, L1is a bond or CH2. In certain embodiments, L1is a bond.

[0091] In certain embodiments, p is 1. In certain embodiments, m is 1. In certain embodiments, R10is C1-6alkyl. In certain embodiments, m is 1 and R10is C1-6alkyl. In certain embodiments, L1is a bond, m is 1, and R10is C1-6 alkyl.

[0092] In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z1a. In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z1a, and L1is a bond or C1-2 alkyl. In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z1a, and L1is a bond or CH2. In certain embodiments, Ring A is heteroaryl and L1is a bond. In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z1a, L1is a bond, m is 1, and R10is C1-6alkyl.

[0093] In certain embodiments, provided is a compound of Formula IIA:or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; X1is N or CR6a; X2is N or CR6b; X3is N or CR6c; X4is N or CR6d; R1is halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 each 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -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 each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is 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, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R10is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R12is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0094] In certain embodiments, R is -OR7. 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 R1, R4, R5, R7, X1, X2, X3, and X4are each independently as defined herein.

[0095] In certain embodiments, R is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is independently optionally substituted with one to five Z1.

[0096] In certain embodiments, R is C1-6alkyl optionally substituted with one to five Z1. In certain embodiments, R is C1-6alkyl optionally substituted with one to five independently selected halo or C3-10cycloalkyl. In certain embodiments, R is C1-6haloalkyl.

[0097] In certain embodiments, R is C2-6alkenyl optionally substituted with one to five Z1.

[0098] In certain embodiments, R is C2-6 alkynyl optionally substituted with one to five Z1.

[0099] In certain embodiments, R is C3-10 cycloalkyl, optionally substituted with one to five Z1.

[0100] In certain embodiments, R is heterocyclyl optionally substituted with one to five Z1.

[0101] In certain embodiments, at least one of X1, X2, X3, and X4is N.

[0102] In certain embodiments, when R is -OR7, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, or heterocyclyl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, or heterocyclyl is independently optionally substituted with one to five Z1; then at least one of X1, X2, X3, and X4is N.

[0103] In certain embodiments, X1is N.

[0104] In certain embodiments, X1is CR6a.

[0105] In certain embodiments, X2is N.

[0106] In certain embodiments, X2is CR6b.

[0107] In certain embodiments, X3is N.

[0108] In certain embodiments, X3is CR6c.

[0109] In certain embodiments, X4is N.

[0110] In certain embodiments, X4is CR6d.

[0111] In certain embodiments, the moiety,

[0112] In certain embodiments, the moiety

[0113] In certain embodiments, the moietycertain embodiments, the

[0114] In certain embodiments, the moiety

[0115] In certain embodiments, the moietycertain embodiments, the

[0116] In certain embodiments, the moiety.

[0117] In certain embodiments, the moiety.

[0118] In certain embodiments, the moietycertain embodiments, the

[0119] In certain embodiments, the moiety.

[0120] In certain embodiments, R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, C1-6 alkyl, or -OR10; wherein each C1-6 alkyl is independently optionally substituted with one to five Z1.

[0121] In certain embodiments, one of R6a, R6b, R6c, and R6dis halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl. In certain embodiments, one of R6a, R6b, R6c, and R6dis halo, cyano, methyl, methoxy, trifluoromethyl, or methoxymethyl. In certain embodiments, one of R6a, R6b, R6c, and R6dis halo, cyano, methyl, methoxy, or methoxymethyl.

[0122] In certain embodiments, X1is CR6a; and R6ais halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl. In certain embodiments, X1is CR6a; and R6ais halo, cyano, methyl, methoxy, trifluoromethyl, or methoxymethyl. In certain embodiments, X1is CR6a; and R6ais halo, cyano, methyl, methoxy, or methoxymethyl.

[0123] In certain embodiments, X2is CR6b; and R6bis halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl. In certain embodiments, X2is CR6b; and R6bis halo, cyano, methyl, methoxy, trifluoromethyl, or methoxymethyl. In certain embodiments, X2is CR6b; and R6bis halo, cyano, methyl, methoxy, or methoxymethyl.

[0124] In certain embodiments, X3is CR6c; and R6cis halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl. In certain embodiments, X3is CR6c; and R6cis halo, cyano, methyl, methoxy, trifluoromethyl, or methoxymethyl. In certain embodiments, X3is CR6c; and R6cis halo, cyano, methyl, methoxy, or methoxymethyl.

[0125] In certain embodiments, X4is CR6d; and R6dis halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl. In certain embodiments, X4is CR6d; and R6dis halo, cyano, methyl, methoxy, trifluoromethyl, or methoxymethyl. In certain embodiments, X4is CR6d; and R6dis halo, cyano, methyl, methoxy, or methoxymethyl.

[0126] In certain embodiments, R4is hydrogen or halo. R4is hydrogen.

[0127] In certain embodiments, R5is hydrogen or halo. R5is hydrogen.

[0128] In certain embodiments, R4and R5are each independently hydrogen or halo.

[0129] In certain embodiments, R4and R5are hydrogen.

[0130] In certain embodiments, R1is hydrogen, halo, cyano, C1-6alkyl, or C3-10cycloalkyl; wherein the C1-6alkyl or C3-10cycloalkyl is independently optionally substituted with one to five Z1. In certain embodiments, R1is halo, cyano, C1-6 alkyl, or C3-10 cycloalkyl; wherein the C1-6 alkyl or C3-10 cycloalkyl is independently optionally substituted with one to five Z1.

[0131] In certain embodiments, R1is hydrogen, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, or C3-10 cycloalkyl. In certain embodiments, R1is halo, cyano, C1-6 alkyl, C1-6 haloalkyl, or C3-10 cycloalkyl.

[0132] In certain embodiments, R1is hydrogen, fluoro, chloro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or cyclopropyl. In certain embodiments, R1is fluoro, chloro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or cyclopropyl.

[0133] In certain embodiments, R1is halo or C1-6 alkyl optionally substituted with one to five Z1.

[0134] In certain embodiments, R1is halo or C1-6 alkyl optionally substituted with one to five independently selected halo.

[0135] In certain embodiments, R1is halo, C1-6alkyl, or C1-6haloalkyl.

[0136] In certain embodiments, R1is halo, -CH3, or -CF3.

[0137] In certain embodiments, each R10is C1-6alkyl.

[0138] In certain embodiments, each R11is independently C1-6alkyl; wherein each C1-6alkyl is independently optionally substituted with one to five Z1a. In certain embodiments, each R11is independently C1-6 alkyl; wherein each C1-6 alkyl is independently optionally substituted with one to five halo.

[0139] In certain embodiments, each Z1is independently halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, or -C(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.

[0140] In certain embodiments, each Z1is independently halo, cyano, C1-6 alkyl, C1-6 haloalkyl, -OR12, - C(O)OR12or heteroaryl; wherein each C1-6 alkyl, C1-6 haloalkyl, or heteroaryl is independently optionally substituted with one to five Z1a.

[0141] In certain embodiments, each R12is independently C1-6alkyl; wherein each C1-6alkyl is independently optionally substituted with one to five Z1b.

[0142] In certain embodiments, each Z1ais independently halo or -OR13.

[0143] In certain embodiments, each R13is independently hydrogen or C1-6 alkyl.

[0144] In certain embodiments, each R13is C1-6 alkyl, wherein each C1-6 alkyl is independently optionally substituted with one to five Z1b.

[0145] In certain embodiments, each Z1bis -L-C1-6 alkyl or -L-C1-6 haloalkyl.

[0146] In certain embodiments, L is -O- or -S(O)2.

[0147] In certain embodiments, each Z1bis independently halo.

[0148] 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

[0149] In certain embodiments, provided is a compound selected from Table 2 or a pharmaceutically acceptable salt thereof.Table 2434445ĴĶĴĸ505152535455565758593. Methods

[0150] “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.

[0151] “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.

[0152] “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.

[0153] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof means an amount sufficient to 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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).

[0158] 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 SARM1 activity (e.g., in vitro or in vivo).

[0159] 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 effectiveamount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to the subject.

[0160] 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.

[0161] 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 of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: X1is N or CR6a; X2is N or CR6b; X3is N or CR6c; X4is N or CR6d; R is -NR2R3, -OR7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, or heterocyclyl is independently optionally substituted with one to five Z1; R1is 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 each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; R2is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or R2and R3together form a heterocyclyl, which may further be independently optionally substituted with one to five Z1;R4is hydrogen, halo, cyano, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R5is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -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 each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; R7is C1-6 alkyl, C2-6 alkenyl, -6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is 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, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R10is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; 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 R12is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0162] 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.

[0163] 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.

[0164] 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 atherapeutically 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 treating comprises reducing one or more symptoms or features of neurodegeneration.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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 injurydisease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from traumatic axonal injury (TAI), a leukoencephalopathy or a leukodystrophy.

[0173] In certain embodiments, the disease or condition is an acute condition. In certain embodiments, the disease or condition is a chronic condition.

[0174] 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.

[0175] 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).

[0176] 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.

[0177] 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).

[0178] 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.

[0179] In certain embodiments, the disease or condition is glaucoma (see, e.g., Ko, K.W., et al. J. Cell Bio.2020, 219(8), e201912047).

[0180] 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.

[0181] 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.

[0182] 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.)

[0183] 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 with axonal 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.

[0184] 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 hyperexcitability, 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 (e.g. apoptosis, pyroptosis, ferroptosis, and / or necrosis) and / or inflammation.

[0185] In certain embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontinemyelinolysis, 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), Friedrich’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).

[0186] 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.

[0187] 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.

[0188] 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 peripheral neuropathies, 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.

[0189] 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.

[0190] 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 thesediseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation.

[0191] 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 by adverse drug reactions and neuropathies caused by vitamin deficiency. Ischemic optic neuropathies also include non-arteritic anterior ischemic optic neuropathy.

[0192] 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 encephalitis 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.

[0193] 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.

[0194] 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 conditioncharacterized 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.

[0195] 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 hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In certain embodiments, the subject has one or more copies of the ApoE4 allele.

[0196] 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 into 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).

[0197] 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.

[0198] 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.

[0199] 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.

[0200] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, WO2014177060, WO2015091889, WO2016142310, US20180057507, WO2018107072, WO2019241244, WO2020168111, and CN104387391A, which are hereby incorporated by reference in their entirety.

[0201] 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 a polypeptide. 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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).

[0206] 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.

[0207] 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).

[0208] 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).

[0209] 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.

[0210] 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.

[0211] 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).

[0212] 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.

[0213] 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).

[0214] 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 beappreciated that these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive.

[0215] 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).

[0216] Other embodiments include use of the presently disclosed compounds in therapy. 4. Kits

[0217] 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.

[0218] 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

[0219] 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.).

[0220] 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.

[0221] 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.

[0222] 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 active ingredient 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.

[0223] 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 propylhydroxy- benzoates; sweetening agents; and flavoring agents.

[0224] 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.

[0225] 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 thesepreformulation 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.

[0226] 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 be used 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.

[0227] 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.

[0228] 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

[0229] The following ingredients are mixed intimately and pressed into single scored tablets.Formulation Example 2 - Capsule formulation

[0230] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsuleFormulation Example 3 - Suspension formulation

[0231] The following ingredients are mixed to form a suspension for oral administration.Formulation Example 4 - Injectable formulation

[0232] The following ingredients are mixed to form an injectable formulation.Formulation Example 5 - Suppository Formulation

[0233] 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

[0234] 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. For example, 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

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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

[0240] Scheme I illustrates general methods which can be employed for the synthesis of compounds described herein (e.g., Formula I), where X1, X2, X3, X4, R, R1, R4, and R5are each independently as defined herein, and each LG is independently a leaving group (e.g., halo, alkoxy, etc.). Scheme I

[0241] In Scheme I, compounds of Formula I can be prepared by contacting compound I-1 with compound I-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required. Alternatively, compounds of Formula I can be prepared by contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required. Alternatively, compounds of Formula I can be prepared by contacting compound I-5 with compound I-6 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required. 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.

[0242] Further derivatization of the compound provided by the steps outlined in Scheme I, or any intermediate, provides additional compounds of Formula I. It should be understood that any of the compounds or intermediates shown in Scheme I 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 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 are as defined for Formula I.

[0243] In certain embodiments, compounds of Formula IA and IB can be prepared according to Scheme II, where X1, X2, X3, X4, R1, R2, R3, R4, R5, and R7are each independently as defined herein, and each LG is independently a leaving group (e.g., halo, alkoxy, etc.). Scheme II

[0244] In Scheme II, compounds of Formula IA can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide an acylated intermediate, followed by contacting the acylated intermediate with compound II-2, or a salt thereof. Compounds of Formula IB can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide the acylated intermediate, followed by contacting the acylated intermediate with compound II-3. 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.

[0245] It should be understood that any of the compounds or intermediates shown in Scheme 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 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 II are as defined for Formula I.

[0246] Certain compounds of Formula I-1 for use in Scheme I and II above can be prepared according to Scheme III, where R1, R4, R5, and R6bare each independently as defined herein, R50is an amine precursor (e.g., halo, NO2, etc.), and each LG is independently a leaving group (e.g., halo, alkoxy, etc.).Scheme III

[0247] In Scheme III, compound III-2 is prepared by contacting compound III-1 with N2H4•H2O under suitable conditions to provide a hydrazine intermediate (e.g., room temperature to about 70°C, in a suitable solvent, such as a polar aprotic solvent, e.g., dioxane, THF, dichloromethane, etc.), which upon contact with glyoxal, provides compound III-2. In certain embodiments, the glyoxal is added dropwise at 0°C in the presence of an organic acid (e.g., such as acetic acid). Contacting compound III-2 with hydroxylamine provides compound III-3. Suitable reaction conditions can comprise one or more of a protic solvent (e.g., ethanol), a base (e.g., KOAc), and an inert atmosphere. Compound III-4 is provided via cyclization of compound III-3 under suitable reaction conditions. Exemplary reaction conditions comprise an organic base (e.g., an amine base, such as pyridine). Conversion of compound III-4 to compound III-5 can proceed via a halogenated intermediate (i.e., where R6bis halo) using a halogenating reagent (e.g., POCl3), and optional functional group interconversion. Alternatively, compound III-5 where R6bis -OCH3 can be provided by contacting compound III-4 with a suitable methylating agent such as trimethyloxonium tetrafluoroborate (or alternative substituents may be provided using an alkylating agent, for example). Conversion of R50to -NH2 provides compound III-6 for use in Schemes I and II in place of compound I-1.

[0248] 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.

[0249] It should be understood that any of the compounds or intermediates shown in Scheme III 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 III can be derivatized at anystep to provide various compounds of Formula I. In certain embodiments, the various substituents of the compounds or intermediates as used in Scheme III are as defined for Formula I.

[0250] In certain embodiments, provided is a process for providing a compound of Formula I, comprising: 1) contacting a compound of Formula I-1:with a compound of Formula I-2:under conditions sufficient to provide the compound of Formula I; wherein X1, X2, X3, X4, R, R1, R4, and R5are each independently as defined herein. In certain embodiments, the conditions comprise a phosgene reagent, e.g., triphosgene. EXAMPLES

[0251] 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

[0252] 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.

[0253] 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 III 400 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 wereconsistent 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.

[0254] 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 I2 to 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)6 in 450 mL water and 50 mL concentrated H2SO4) to visualize the compound.

[0255] 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 / min with 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. General Synthesis of Anilines Intermediate 1 4-methyl-3-(4-chloro-1H-pyrazol-1-yl)aniline

[0256] Made according to the procedure for 4-methyl-3-(2H-1,2,3-triazol-2-yl)aniline using 4-chloro- 1H-pyrazole in place of 2H-triazole to give the titled compound. Intermediate 2 4-methyl-3-(3-methyl-1,2,4-triazol-1-yl)aniline

[0257] Made according to the procedure for 4-methyl-3-(2H-1,2,3-triazol-2-yl)aniline using 3-methyl- 1,2,4-triazole in place of 2H-triazole to give the titled compound. Intermediate 3 4-methyl-3-(4-fluoro-1H-pyrazol-1-yl)aniline

[0258] Made according to the procedure used for 4-methyl-3-(2H-1,2,3-triazol-2-yl)aniline using 4- fluoro-1H-pyrazole to give the titled compound. Intermediate 4 4-methyl-3-(1H-1,2,3-triazol-1-yl)aniline

[0259] 2-azido-1-methyl-4-nitrobenzene: To a solution of 2-methyl-5-nitro-aniline (2 g, 13.14 mmol) in MeCN (10 mL) at 0 °C was added t-BuONO (2.03 g, 19.72 mmol), followed by the dropwise additionof TMSN3(2.27 g, 19.72 mmol). The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction solution was concentrated under reduced pressure to give the titled compound.

[0260] 1-(2-methyl-5-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole: To a solution of 2-azido-1- methyl-4-nitro-benzene (700 mg, 3.93 mmol) and ethynyl(trimethyl)silane (463 mg, 4.72 mmol) in THF (10 mL) at 20 °C was added CuSO4•5H2O (49 mg, 0.196 mmol) in H2O (10 mL) and sodium ascorbate (156 mg, 0.786 mmol). The mixture was stirred at 20 °C for 16 h. The reaction solution was extracted with EtOAc (3 × 30 mL), the 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 = 277.1 [M+H]+.

[0261] 1-(2-methyl-5-nitrophenyl)-1H-1,2,3-triazole: To a solution of 1-(2-methyl-5-nitrophenyl)-4- (trimethylsilyl)-1H-1,2,3-triazole (800 mg, 2.89 mmol) in THF (10 mL) and MeOH (10 mL) at 25 °C was added CsF (880 mg, 5.79 mmol). The reaction solution was stirred at 25 °C for 3 h. Then the reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 205.1 [M+H]+.

[0262] 4-methyl-3-(1H-1,2,3-triazol-1-yl)aniline: To a solution of 1-(2-methyl-5-nitrophenyl)-1H- 1,2,3-triazole (400 mg, 1.96 mmol) in EtOH (5 mL) and H2O (1 mL) at 25 °C was added Fe (547 mg, 9.80 mmol) and NH4Cl (524 mg, 9.80 mmol). The reaction mixture was heated to 80 °C and stirred for 2 h. Then the reaction solution was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 175.1 [M+H]+. Intermediate 5 3-(4-(methoxymethyl)-2H-1,2,3-triazol-2-yl)-4-methylaniline

[0263] methyl 2-(2-methyl-5-nitrophenyl)-2H-1,2,3-triazole-4-carboxylate: To a solution of methyl 2H-triazole-4-carboxylate (3 g, 23.60 mmol) in toluene (100 mL) at 20 °C under O2was added (2- methyl-5-nitro-phenyl)boronic acid (5.13 g, 28.32 mmol), pyridine (5.60 g, 70.81 mmol) and Cu(OAc)2 (6.43 g, 35.40 mmol). The mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the titled compound LCMS: m / z = 263.1 [M+H]+.

[0264] (2-(2-methyl-5-nitrophenyl)-2H-1,2,3-triazol-4-yl)methanol: To a mixture of methyl 2-(2- methyl-5-nitro-phenyl)triazole-4-carboxylate (400 mg, 1.53 mmol) in EtOH (10 mL) at 0 °C was addedNaBH4(230 mg, 6.10 mmol). The mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was quenched by addition of aq. sat. NH4Cl (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 = 3:1 to 0:1) to give the titled compound. LCMS: m / z = 235.2 [M+H]+.

[0265] 4-(methoxymethyl)-2-(2-methyl-5-nitrophenyl)-2H-1,2,3-triazole: To a solution of (2-(2- methyl-5-nitrophenyl)-2H-1,2,3-triazol-4-yl)methanol (250 mg, 1.07 mmol) in THF (5 mL) at 0 °C under N2was added NaH (64 mg, 1.60 mmol, 60% purity). The mixture was stirred at 0 °C for 0.5 h, then warmed to 25 °C and MeI (227 mg, 1.60 mmol) was added. The mixture was stirred at 25 °C for 2 h before it 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 = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 249.1 [M+H]+.

[0266] 3-(4-(methoxymethyl)-2H-1,2,3-triazol-2-yl)-4-methylaniline: To a solution of 4- (methoxymethyl)-2-(2-methyl-5-nitro-phenyl)triazole (70 mg, 0.28 mmol) in EtOH (5 mL) and H2O (1 mL) at 20 °C was added NH4Cl (75 mg, 1.41 mmol) and Fe (78 mg, 1.41 mmol). The mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue 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 = 219.2 [M+H]+. Intermediate 6 3-(4-methoxy-2H-1,2,3-triazol-2-yl)-4-methylaniline

[0267] (2-methyl-5-nitrophenyl)hydrazine: To a solution of 2-methyl-5-nitroaniline (10 g, 65.72 mmol) and conc. HCl (60 mL) in H2O (60 mL) at 0 °C was added dropwise a solution of NaNO2(4.76 g,69.01 mmol) in H2O (32 mL) and the reaction mixture was stirred at 0 °C for 3 h. Then a solution of SnCl2•2H2O (29.66 g, 131.45 mmol) in conc. HCl (50 mL) was added dropwise to the mixture at 0 °C. The mixture was warmed to 25 °C and stirred for 12 h. The mixture was adjusted to pH = 7–8 with 2M NaOH solution and extracted with DCM (3 × 200 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 = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 168.1 [M+H]+.

[0268] 2-(2-(2-methyl-5-nitrophenyl)hydrazineylidene)acetaldehyde: To a solution of (2-methyl-5- nitrophenyl)hydrazine (7 g, 41.87 mmol) in conc. HCl (70 mL) and H2O (70 mL) at 25 °C under N2was added glyoxal (30.38 g, 209.37 mmol, 40% purity in H2O) and the mixture was stirred for 2 h. The reaction mixture was filtered and the filter cake was washed with H2O and dried under reduced pressure to give the titled compound. LCMS: m / z = 208.1 [M+H]+.

[0269] 2-(2-(2-methyl-5-nitrophenyl)hydrazineylidene)acetaldehyde oxime: To a solution of 2-(2-(2- methyl-5-nitrophenyl)hydrazineylidene)acetaldehyde (16 g, 77.23 mmol) in EtOH (400 mL) at 25 °C under N2 was added hydroxylamine•HCl (6.44 g, 92.67 mmol) and KOAc (18.95 g, 193.06 mmol). The mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue. The suspension was filtered, the solids were washed with H2O and dried under reduced pressure to give the titled compound. LCMS: m / z = 223.1 [M+H]+.

[0270] 2-(2-methyl-5-nitrophenyl)-2H-1,2,3-triazole 1-oxide: To a solution of CuSO4•5H2O (26.39 g, 105.69 mmol) in H2O (200 mL) at 0 °C under N2 was added dropwise a solution of 2-(2-(2-methyl-5- nitrophenyl)hydrazineylidene)acetaldehyde oxime (19.57 g, 88.07 mmol) in pyridine (400 mL). The mixture was warmed to 25 °C and stirred for 12 h. Then the mixture was adjusted to pH = 3 with 3M HCl and extracted with DCM (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) and prep-HPLC (Agela DuraShell C18250 × 70 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 10%-40%, over 20 min) to give the titled compound. LCMS: m / z = 221.1 [M+H]+.

[0271] 1-methoxy-2-(2-methyl-5-nitrophenyl)-2H-1,2,3-triazole tetrafluoroborate: To a solution of 2-(2-methyl-5-nitrophenyl)-2H-1,2,3-triazole 1-oxide (240 mg, 1.09 mmol) in DCM (5 mL) at 25 °C was added trimethyloxonium tetrafluoroborate (242 mg, 1.63 mmol). The mixture was stirred at 25 °C for 2 h and then concentrated under reduced pressure. To the crude material was added petroleum ether (5 mL) and the resulting solids were filtered and dried under reduced pressure to give the titled compound. LCMS: m / z = 235.1 [M+H]+.

[0272] 4-methoxy-2-(2-methyl-5-nitrophenyl)-2H-1,2,3-triazole: To a solution of 1-methoxy-2-(2- methyl-5-nitrophenyl)-2H-1,2,3-triazole tetrafluoroborate (180 mg, 0.56 mmol) in MeOH (3 mL) at 25 °C was added NaOMe (302 mg, 1.68 mmol, 30% purity in MeOH) and the reaction mixture was stirredfor 12 h. The reaction mixture was concentrated under reduced pressure and to the crude material was added MTBE (10 mL). The resulting solids were filtered and dried under reduced pressure to give the titled compound. LCMS: m / z = 235.1 [M+H]+.

[0273] 3-(4-methoxy-2H-1,2,3-triazol-2-yl)-4-methylaniline: To a solution of 4-methoxy-2-(2-methyl- 5-nitrophenyl)-2H-1,2,3-triazole (170 mg, 0.73 mmol) in EtOH (4 mL) and H2O (1 mL) at 25 °C was added NH4Cl (194 mg, 3.63 mmol) and Fe (203 mg, 3.63 mmol). The mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was filtered through a pad of Celite^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 titled compound. LCMS: m / z = 205.2 [M+H]+. Intermediate 7 3-(4-methyl-1H-pyrazol-1-yl)-4-(trifluoromethyl)aniline

[0274] To a mixture of 3-bromo-4-(trifluoromethyl)aniline (300 mg, 1.25 mmol) and 4-methyl-1H- pyrazole (410 mg, 5.00 mmol) in DMSO (8 mL) at 20 °C under N2 was added K2CO3 (346 mg, 2.50 mmol) and trans-N1,N2-dimethylcyclohexane-1,2-diamine (71.11 mg, 0.5 mmol) and CuI (47.61 mg, 0.25 mmol). The mixture was heated to 140 °C and stirred for 16 h. The reaction solution was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the titled compound. LCMS: m / z = 242.2 [M+H]+. Intermediate 8 3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-methylaniline

[0275] 4-chloro-2-(2-methyl-5-nitrophenyl)-2H-1,2,3-triazole: A mixture of 2-(2-methyl-5- nitrophenyl)-2H-1,2,3-triazole 1-oxide (2 g, 9.08 mmol) in POCl3(20 mL) was stirred at 110 °C for 3 h and then concentrated under reduced pressure. The crude material was diluted with H2O (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with aq. sat. NaHCO3(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 = 239.1 [M+H]+.

[0276] 3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-methylaniline: To a mixture of 4-chloro-2-(2-methyl-5- nitrophenyl)-2H-1,2,3-triazole (200 mg, 0.84 mmol) in EtOH (5 mL) and H2O (1 mL) at 20 °C was added Fe (234 mg, 4.19 mmol) and NH4Cl (224 mg, 4.19 mmol). The reaction solution was heated to 80 °C and stirred for 2 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was 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 = 209.1 [M+H]+. Intermediate 9 3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline

[0277] (5-bromo-2-(trifluoromethyl)phenyl)hydrazine: To a solution of 4-bromo-2-fluoro-1- (trifluoromethyl)benzene (20 g, 82.31 mmol) in 1,4-dioxane (500 mL) at 20 °C under N2was added N2H4•H2O (21.02 g, 411.53 mmol, 98% purity). The mixture was heated to 70 °C and stirred for 72 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 (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was slurried with MTBE (100 mL) and the solids were collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m / z = 255.0, 257.0 [M+H]+.

[0278] 2-(2-(5-bromo-2-(trifluoromethyl)phenyl)hydrazineylidene)acetaldehyde: To a solution of glyoxal (54.05 g, 372.50 mmol, 48.56 mL, 40% purity in H2O) in H2O (150 mL) at 0 °C was added dropwise a solution of (5-bromo-2-(trifluoromethyl)phenyl]hydrazine (19 g, 74.50 mmol) in AcOH (150 mL). The mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was filtered and the solids were washed with water and dried under reduced pressure to give the titled compound. LCMS: m / z = 295.0, 297.0 [M+H]+.

[0279] 2-(2-(5-bromo-2-(trifluoromethyl)phenyl)hydrazineylidene)acetaldehyde oxime: To a mixture of 2-(2-(5-bromo-2-(trifluoromethyl)phenyl)hydrazineylidene)acetaldehyde (24 g, 81.34 mmol) in EtOH (200 mL) at 20 °C under N2was added hydroxylamine•HCl (6.78 g, 97.61 mmol) and KOAc(19.96 g, 203.35 mmol). The mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 310.1, 312.1 [M+H]+.

[0280] 2-(5-bromo-2-(trifluoromethyl)phenyl)-2H-1,2,3-triazole 1-oxide: A mixture of 2-(2-(5- bromo-2-(trifluoromethyl)phenyl)hydrazineylidene)acetaldehyde oxime (20 g, 64.50 mmol) in pyridine (150 mL) at 25 °C under N2 was added CuSO4•5H2O (19.33 g, 77.40 mmol) in H2O (75 mL). The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the crude material was diluted with H2O (50 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 = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 308.0, 309.9 [M+H]+.

[0281] 2-(5-bromo-2-(trifluoromethyl)phenyl)-4-chloro-2H-1,2,3-triazole: A solution of 2-(5-bromo- 2-(trifluoromethyl)phenyl)-2H-1,2,3-triazole 1-oxide (10 g, 32.46 mmol) in POCl3 (150 mL) was stirred at 120 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was poured into H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The organic layers were combined, 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 5:1) to give the titled compound. LCMS: m / z = 325.9, 327.9 [M+H]+.

[0282] N-[3-(4-chlorotriazol-2-yl)-4-(trifluoromethyl)phenyl]-1,1-diphenyl-methanimine: To a solution of 2-(5-bromo-2-(trifluoromethyl)phenyl)-4-chloro-2H-1,2,3-triazole (4 g, 12.25 mmol) in 1,4- dioxane (80 mL) at 20 °C under N2 was added diphenylmethanimine (3.33 g, 18.38 mmol), Cs2CO3 (7.98 g, 24.50 mmol), Xantphos (1.42 g, 2.45 mmol) and Pd2(dba)3(1.12 g, 1.23 mmol). The mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 3:1) to give the titled compound.

[0283] 3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: To a solution of N-[3-(4- chlorotriazol-2-yl)-4-(trifluoromethyl)phenyl]-1,1-diphenyl-methanimine (4 g, 11.71 mmol) in THF (30 mL) at 20 °C was added 2 M HCl (10 mL) and the mixture was stirred for 2 h. The reaction mixture was adjusted to pH = 7 with aq. sat. NaHCO3 and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the titled compound. LCMS: m / z = 263.0 [M+H]+.Intermediate 10 3-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)aniline

[0284] To a solution of 3-(4-chlorotriazol-2-yl)-4-(trifluoromethyl)aniline (1.3 g, 4.95 mmol) in MeCN (30 mL) at 20 °C was added Selectfluor (2.10 g, 5.94 mmol). The mixture was heated to 50 °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 (10 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 =281.0 [M+H]+. Intermediate 11 4-chloro-3-(2H-1,2,3-triazol-2-yl)aniline

[0285] To a solution of 3-(2H-1,2,3-triazol-2-yl)aniline (500 mg, 3.12 mmol) in AcOH (10 mL) at 0 °C under N2was added NCS (459 mg, 3.43 mmol). The 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 = 1:1) to give the titled compound. LCMS: m / z = 195.1 [M+H]+. Intermediate 12 3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)aniline

[0286] 1-(5-bromo-2-(trifluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole: To a solution of 4- methyl-2H-1,2,3-triazole (1 g, 12.03 mmol) in DMF (10 mL) at 20 °C under N2was added 4-bromo-2- fluoro-1-(trifluoromethyl)benzene (3.22 g, 13.24 mmol) and K2CO3(2.00 g, 14.44 mmol). The mixturewas heated to 90 °C and stirred for 12 h. The reaction mixture was diluted by addition of 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 = 15:1 to 10:1) to give the titled compound. LCMS: m / z = 306.0, 308.0 [M+H]+.

[0287] N-(3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)-1,1-diphenylmethanimine: To a solution of 1-(5-bromo-2-(trifluoromethyl)phenyl)-4-methyl-1H-1,2,3-triazole (1.1 g, 3.59 mmol) in 1,4-dioxane (20 mL) at 20 °C under N2was added diphenylmethanimine (977 mg, 5.39 mmol), Cs2CO3(2.34 g, 7.19 mmol), Xantphos (416 mg, 0.72 mmol) and Pd2(dba)3(329 mg, 0.36 mmol). The mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compound.

[0288] 3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)aniline: To a solution of N-(3-(4- methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)-1,1-diphenylmethanimine (4.10 g, 10.09 mmol) in THF (20 mL) at 20 °C was added 2 M HCl (20 mL) and the mixture was stirred for 3 h. The reaction mixture was cooled to 0 °C before adjusting the pH = 7~8 with aq. sat. NaHCO3. After warming to room temperature, the mixture was 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 = 2:3 to 0:1) to give the titled compound. LCMS: m / z = 243.1 [M+H]+. Intermediate 13 methyl 2-(5-amino-2-methylphenyl)-2H-1,2,3-triazole-4-carboxylate and methyl 1-(5-amino-2- methylphenyl)-1H-1,2,3-triazole-4-carboxylate

[0289] To a solution of methyl 2H-triazole-4-carboxylate (3 g, 23.60 mmol) in toluene (100 mL) at 20 °C under O2 was added (5-amino-2-methyl-phenyl)boronic acid (4.28 g, 28.32 mmol), pyridine (5.60 g, 70.81 mmol) and Cu(OAc)2 (6.43 g, 35.40 mmol). The mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the titled compounds as pure separated regioisomers. LCMS: m / z = 233.2 [M+H]+.Intermediate 14 cis-3-Methyl-6-azabicyclo[3.1.1]heptane

[0290] N-(trans-3-methylcyclohexyl)picolinamide: A mixture of N-(trans-3- methylcyclohexyl)picolinamide and N-(cis-3-methylcyclohexyl)picolinamide was purified by prep- HPLC (Phenomenex Luna C18250 × 100 mm × 15 μm; mobile phase: A: 10 mM TFA in water, B: MeCN; B in A: 40%-70%, over 20 min) to provide the separated cis and trans isomers as the first and second eluting peaks respectively. The second eluting peak was concentrated under reduced pressure, adjusted to pH = 7–8 with aq. sat. NaHCO3 solution and extracted with DCM (3 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m / z = 219.2 [M+H]+.

[0291] (cis-3-Methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone To a mixture of N- (trans-3-methylcyclohexyl)picolinamide (6 g, 27.49 mmol) in 1,1,2,2-tetrachloroethane (200 mL) at 25 °C under N2was added AgOAc (13.76 g, 82.46 mmol), benzoquinone (1.49 g, 13.74 mmol), Na3PO4(13.52 g, 82.46 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (80.80 g, 274.86 mmol) and Pd(OAc)2 (1.23 g, 5.50 mmol). The mixture was heated to 145 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled compound. LCMS: m / z = 217.0 [M+H]+.

[0292] cis-3-Methyl-6-azabicyclo[3.1.1]heptane: To a mixture of (cis-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone (2.4 g, 11.1 mmol) in EtOH (30 mL) at 25 °C under N2was added NaOH (4.44 g, 111 mmol). The mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure (water pump, below 35 °C) to give a crude mixture. The mixture was stirred in DCM (20 mL) and filtered through a pad of Celite^. The filtrate was concentrated under reduce pressure (water pump, below 35 °C). The work-up procedure was repeated 2– 3 times or until the concentrated residue contained no solids to give the titled compound as the free base. The free base was converted to the TFA salt by addition of TFA and stirring for 0.5 h at 20 °C before concentrating under reduced pressure. Alternatively, a mixture of the free base in MTBE at –20 °C treated with 4M HCl / MTBE (1.2 equiv) and stirred for 10 minutes gave the HCl salt. LCMS: m / z = 112.2 [M+H]+.Intermediate 15 2-methyl-5-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazole

[0293] (5R,7R)-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione and (5S,7S)-7-methyl-1,3- diazaspiro[4.5]decane-2,4-dione: To a mixture of (R)-3-methylcyclohexan-1-one and (S)-3- methylcyclohexan-1-one (50 g, 445.76 mmol, 54.59 mL) in EtOH (250 mL) and H2O (250 mL) at 20 °C under N2 was added (NH4)2CO3 (128.49 g, 1.34 mol) and KCN (43.54 g, 669 mmol). The mixture was heated to 65 °C and stirred for 3 h. The reaction mixture was filtered, and the filter cake was washed with H2O and dried under reduced pressure. The crude product was triturated with EtOH at 20 °C for 30 min, filtered, and the solid was dried under reduced pressure to give the titled compounds. LCMS: m / z = 183.2 [M+H]+.

[0294] (1R,3R)-1-amino-3-methylcyclohexane-1-carboxylic acid and (1S,3S)-1-amino-3- methylcyclohexane-1-carboxylic acid: To a solution of (5R,7R)-7-methyl-1,3-diazaspiro[4.5]decane- 2,4-dione and (5S,7S)-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione (78.5 g, 430.80 mmol) in H2O (1000 mL) at 25 °C was added Ba(OH)2 (738 g, 4.31 mol). The mixture was heated to 140 °C and stirred for 12 h in a 5 L autoclave. The reaction was cooled to 0 °C and the pH was adjusted to pH = 3 with 3 M H2SO4. The mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compounds. LCMS: m / z = 158.2 [M+H]+.

[0295] methyl (1R,3R)-1-amino-3-methylcyclohexane-1-carboxylate hydrochloride and methyl (1S,3S)-1-amino-3-methylcyclohexane-1-carboxylate hydrochloride: To a mixture of (1R,3R)-1- amino-3-methylcyclohexane-1-carboxylic acid and (1S,3S)-1-amino-3-methylcyclohexane-1-carboxylic acid (60 g, 382 mmol) in MeOH (600 mL) at 0 °C under N2 was added SOCl2 (227 g, 1.91 mol, 138.43 mL). The mixture was heated to 75 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compounds. LCMS: m / z = 172.2 [M+H]+.

[0296] methyl (1R,3R)-3-methyl-1-(picolinamido)cyclohexane-1-carboxylate and methyl (1S,3S)-3- methyl-1-(picolinamido)cyclohexane-1-carboxylate: To a solution of methyl (1R,3R)-1-amino-3- methylcyclohexane-1-carboxylate hydrochloride and methyl (1S,3S)-1-amino-3-methylcyclohexane-1- carboxylate hydrochloride (24 g, 140 mmol) and picolinic acid (25.88 g, 210 mmol) in DCM (300 mL) at 0 °C under N2 was added DIEA (54.34 g, 420 mmol, 73.24 mL), DMAP (1.71 g, 14 mmol) and EDCI (40.30 g, 210 mmol). The mixture was warmed to 25 °C and stirred for 16 h. The reaction mixture was diluted with H2O (200 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compounds. LCMS: m / z = 277.2 [M+H]+.

[0297] methyl (1R,3R) 2-(3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptan-1-yl)-2-oxoacetate and methyl (1S,3S) 2-(3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptan-1-yl)-2-oxoacetate: To a solution of methyl (1R,3R)-3-methyl-1-(picolinamido)cyclohexane-1-carboxylate and methyl (1S,3S)-3-methyl-1- (picolinamido)cyclohexane-1-carboxylate (19 g, 68.76 mmol) in 1,1,2,2-tetrachloroethane (900 mL) at 25 °C under N2 was added Na3PO4 (33.82 g, 206 mmol, 33.82 mL), 1,2,3,4,5-pentafluoro-6-iodo-benzene (202.12 g, 688 mmol), AgOAc (34.43 g, 206 mmol, 10.56 mL), benzoquinone (3.72 g, 34 mmol, 7.74 mL) and Pd(OAc)2(3.09 g, 13.75 mmol). The mixture was heated to 145 °C and stirred for 16 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compounds. LCMS: m / z = 275.2 [M+H]+.

[0298] cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of methyl cis-3- methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxylate (10 g, 36.45 mmol) in EtOH at 25 °C under N2 (150 mL) was added NaOH (14.58 g, 364.55 mmol). The mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with H2O (100 mL) and cooled to 0 °C before the solution was acidified to pH = 4 with conc. HCl. The solution was lyophilized to give the titled compound. LCMS: m / z = 156.1 [M+H]+.

[0299] methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a solution of 3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (25 g, 35.44 mmol) in MeOH (300 mL) at 0 °C under N2was added dropwise SOCl2 (8.4 g, 70.88 mmol). The mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 170.2 [M+H]+.

[0300] 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate: To a mixture of methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (26 g, 35.34 mmol) in DCM (300 mL) and MeOH (30 mL) at 0°C under N2 was added Boc2O (15.43 g, 70.68 mmol), TEA (7.15 g, 70.68 mmol) and DMAP (431 mg, 3.53 mmol). The mixture was warmed to 20 °C and stirred for 12 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 (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 5:1) to give the titled compound. LCMS: m / z = 270.2 [M+H]+.

[0301] cis-6-(tert-butoxycarbonyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate (6.3 g, 23.39 mmol) in MeOH (60 mL) at 20 °C was added a solution of NaOH (1.92 g, 48 mmol) in H2O (12 mL) and the reaction mixture was stirred for 2 h. Then the reaction mixture was acidified to pH = 4 by addition of 4 M HCl and the resulting aqueous mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m / z = 200.1 [M-tBu+H]+.

[0302] tert-butyl cis-1-(2-acetylhydrazine-1-carbonyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a solution of cis-6-(tert-butoxycarbonyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1- carboxylic acid (4 g, 15.67 mmol) in DMF (60 mL) at 0 °C under N2was added acetylhydrazine (2.32 g, 31.33 mmol), HATU (11.91 g, 31.33 mmol) and DIEA (6.07 g, 47.00 mmol). The mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 50 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 = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 212.2 [M–Boc+H]+.

[0303] tert-butyl cis-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a solution of cis-1-(2-acetylhydrazine-1-carbonyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxylate (2.3 g, 7.39 mmol) in MeCN (50 mL) at 20 °C under N2 was added Cs2CO3 (9.63 g, 29.55 mmol) and p-TsCl (2.11 g, 11.08 mmol). The 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 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled compound. LCMS: m / z = 294.2 [M+H]+.

[0304] 2-methyl-5-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazole: To a solution of cis-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (300 mg, 1.02 mmol) and 2,6-lutidine (821 mg, 7.67 mmol) in DCM (10 mL) at 0 °C was added TMSOTf (681 mg, 3.07 mmol). The mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture wasquenched by the addition of MeOH (1 mL) and concentrated under reduced pressure to give the titled compound. LCMS: m / z = 194.2 [M+H]+. Intermediate 16 4-methyl-3-(5-methyl-2H-tetrazol-2-yl)aniline

[0305] To a solution of 5-methyl-1H-tetrazole (1.08 g, 12.87 mmol) in MeOH (20 mL) was added 4- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3 g, 12.87 mmol) and Cu(OAc)2 (2.34 g, 12.87 mmol) and TMEDA (3 g, 25.74 mmol) at 20 °C under N2. The reaction solution was stirred at 50 °C for 72 h. The reaction solution was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to remove MeOH. The resulting residue was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Welch Xtimate C18250 × 70 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 15%-40%, 20 min) to give the titled compound. LCMS: m / z = 190.2 [M+H]+. Intermediate 17 4-methyl-3-(4-methyl-1H-pyrazol-1-yl)aniline I

[0306] tert-butyl cis-1-carbamoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 3-iodo-4-methyl-aniline (2 g, 8.58 mmol, 1 eq) in 1,4-dioxane (10 mL) and H2O (10 mL) at 0 °C was added Boc2O (2.25 g, 10.30 mmol) and NaOH (1.37 g, 34.33 mmol). The mixture was warmed to 25 °C and stirred for 4 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 = 10:1 to 0:1) to give the titled compound. LCMS: m / z = 278.0 [M–t- Bu+H]+.

[0307] 4-methyl-3-(4-methyl-1H-pyrazol-1-yl)aniline: To a mixture of tert-butyl (3-iodo-4- methylphenyl)carbamate (200 mg, 0.60 mmol) and 4-methyl-1H-pyrazole (197 mg, 2.40 mmol) in DMSO (6 mL) at 25 °C under N2was added K2CO3(166 mg, 1.20 mmol), trans-N1,N2- dimethylcyclohexane-1,2-diamine (34 mg, 0.24 mmol) and CuI (23 mg, 0.12 mmol). The reaction mixture was heated to 140 °C and stirred for 16 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were concentrated under reducedpressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 0:1) to give the titled compound. LCMS: m / z = 188.2 [M+H]+. Intermediate 18 4-methyl-3-(4-methyl-1H-pyrazol-1-yl)aniline I

[0308] To a mixture of tert-butyl (3-iodo-4-methylphenyl)carbamate (200 mg, 0.6 mmol) and 4-methyl- 1H-pyrazole (197 mg, 2.40 mmol) in DMSO (6 mL) was added K2CO3 (166 mg, 1.20 mmol), trans- N1,N2-dimethylcyclohexane-1,2-diamine (34.16 mg, 0.24 mmol) and CuI (23 mg, 0.12 mmol) at 25 °C under N2. The reaction mixture was heated to 140 °C and stirred for 16 h. The mixture was diluted with H2O (20 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 crude product was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 0:1) to give the titled compound. LCMS: m / z = 188.2 [M+H]+. Intermediate 19 4-methyl-3-(4-methyl-2H-1,2,3-triazol-2-yl)aniline

[0309] To a mixture of 3-iodo-4-methyl-aniline (200 mg, 0.86 mmol) and 4-methyl-2H-triazole (214 mg, 2.57 mmol) in DMF (5 mL) at 20 °C under N2in a sealed tube was added K2CO3(237 mg, 1.72 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (244 mg, 1.72 mmol) and CuI (66 mg, 0.34 mmol). The sealed tube was heated to 150 °C for 2 h under microwave irradiation. Then the mixture was filtered through a pad of Celite^, the filtrate 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 = 5:1 to 1:1) to give the titled compound. LCMS: m / z = 189.1 [M+H]+. Intermediate 20 4-chloro-3-(4-methyl-1H-pyrazol-1-yl)aniline

[0310] To a solution of 4-chloro-3-iodo-aniline (300 mg, 1.18 mmol) and 4-methyl-1H-pyrazole (389 mg, 4.73 mmol) in DMSO (8 mL) at 20 °C under N2was added K2CO3(327 mg, 2.37 mmol), trans- N1,N2-dimethylcyclohexane-1,2-diamine (68 mg, 0.47 mmol) and CuI (45 mg, 0.24 mmol). The mixture was heated to 140 °C and stirred for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (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 0:1) to give the titled compound. LCMS: m / z = 207.9 [M+H]+. Intermediate 21 4-methyl-3-(2H-tetrazol-2-yl)aniline

[0311] 2-methyl-5-nitrobenzenediazonium tetrafluoroborate: A mixture of 2-methyl-5-nitro-aniline (5 g, 32.86 mmol) in EtOH (50 mL) and HBF4(14.43 g, 65.72 mmol, 40% purity in H2O) was cooled to 0 °C. Then tert-butyl nitrite (6.78 g, 65.72 mmol) was added slowly and the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was diluted with MTBE (20 mL), warmed to 25 °C and stirred for 10 min. The solution was filtered and the filter cake was dried under reduced pressure to give the titled compound.

[0312] 2-(2-methyl-5-nitrophenyl)-5-(trimethylsilyl)-2H-tetrazole: 2-methyl-5-nitro- benzenediazonium tetrafluoroborate (1.98 g, 12.04 mmol) and silver trifluoroacetate (3.19 g, 14.44 mmol) were suspended in anhydrous THF (60 mL) under N2 and cooled to –78 °C. Then TEA (1.83 g, 18.06 mmol) was added dropwise and after stirring for 10 min, TMSCHN2(1.37 g, 12.04 mmol) was added dropwise. The mixture was stirred at –78 °C for 1 h and then slowly warmed to 0 °C. The reaction solution was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 3:1) to give the titled compound.

[0313] 2-(2-methyl-5-nitrophenyl)-2H-tetrazole: To a solution of trimethyl-[2-(2-methyl-5-nitro- phenyl)tetrazol-5-yl]silane (1.3 g, 4.69 mmol) in THF (15 mL) and MeOH (7 mL) at 25 °C was added CsF (712 mg, 4.69 mmol) and the reaction solution was stirred for 12 h. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 3:1) to give the titled compound.

[0314] 4-methyl-3-(2H-tetrazol-2-yl)aniline: To a solution of 2-(2-methyl-5-nitro-phenyl)tetrazole (460 mg, 2.24 mmol) in EtOH (5 mL) and H2O (1 mL) at 20 °C was added Fe (626 mg, 11.21 mmol) and NH4Cl (600 mg, 11.21 mmol). The reaction mixture was heated to 80 °C and stirred for 2 h. The reaction solution was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 176.1 [M+H]+. Intermediate 22 4-methyl-3-(1H-1,2,4-triazol-1-yl)aniline

[0315] 1-(2-methyl-5-nitrophenyl)-1H-1,2,4-triazole: To a solution of 2-fluoro-1-methyl-4-nitro- benzene (3 g, 19.34 mmol) in DMF (40 mL) at 25 °C under N2was added K2CO3(8.02 g, 58.02 mmol) and 1H-1,2,4-triazole (2 g, 29.01 mmol). The mixture was heated to 130 °C and stirred for 12 h. The reaction mixture was diluted with H2O (120 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.

[0316] 4-methyl-3-(1H-1,2,4-triazol-1-yl)aniline: To a solution of 1-(2-methyl-5-nitrophenyl)-1H- 1,2,4-triazole (400 mg, 1.96 mmol) in EtOH (5 mL) and H2O (1 mL) was added Fe (547 mg, 9.80 mmol) and NH4Cl (524 mg, 9.80 mmol). The mixture was heated to 80 °C and stirred for 2 h. The reaction solution was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (10 mL) and extracted with EtOAc (4 × 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 = 175.2 [M+H]+. Intermediate 23 4-methyl-3-(2H-1,2,3-triazol-2-yl)aniline

[0317] 2-(2-methyl-5-nitro-phenyl)triazole: To a solution of 2-fluoro-1-methyl-4-nitro-benzene (1 g, 6.45 mmol) in DMF (15 mL) was added 2H-triazole (534.26 mg, 7.74 mmol) and K2CO3(1.78 g, 12.89 mmol) at 25 °C under N2. The mixture was stirred at 120 °C 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 (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 1:1) to give the titled compound.

[0318] 4-methyl-3-(2H-1,2,3-triazol-2-yl)aniline: To a solution of 2-(2-methyl-5-nitro-phenyl)triazole (100 mg, 0.49 mmol) in EtOH (2 mL) and H2O (0.4 mL) at 20 °C was added NH4Cl (52 mg, 0.98 mmol) and Fe (137 mg, 2.45 mmol). The reaction mixture was heated to 70 °C and stirred for 1 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was 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 = 175.4 [M+H]+. Intermediates 24 and 25 Methyl-(1R,3S,5S)-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate and methyl hyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate

[0319] The mixture of enantiomers was separated by SFC (DAICEL CHIRALPAK 250 mm × 50 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in i-PrOH MeOH; B% in A: 20%-20%, 3 min; Flow rate: 200 g / min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give methyl cis-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (peak 1 in SFC) Intermediate 24. LCMS: m / z = 275.2 [M+H]+and methyl cis-3-methyl-6-picolinoyl-6- azabicyclo[3.1.1]heptane-1-carboxylate (peak 2 in SFC) Intermediate 25. LCMS: m / z = 275.2 [M+H]+. Intermediate 26 cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid

[0320] To a solution of methyl cis-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (Intermediate 24) (3 g, 11 mmol) in EtOH (30 mL) was added NaOH (4.37 g, 109 mmol) at 25 °C under N2. The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure, adjusted to pH = 5 with 12 M HCl at 0 °C and lyophilized to give the titled compound as a single unknown enantiomer. LCMS: m / z = 156.1 [M+H]+.Intermediates 27 and 28 tert-butyl cis-1-((S)-1-hydroxypropyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate and tert- butyl cis-1-((R)-1-hydroxypropyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate

[0321] cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of methyl cis-3- methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (Intermediate 24) (10 g, 36.45 mmol) in EtOH (100 mL) was added NaOH (14.58 g, 364.55 mmol) at 25 °C under N2. The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was adjusted pH = 4 by 6 M HCl and lyophilized to give the titled compound. LCMS: m / z = 156.1 [M+H]+.

[0322] methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a solution of cis-3-methyl- 6-azabicyclo[3.1.1]heptane-1-carboxylic acid (26 g, 36.86 mmol, 22% purity) in MeOH (300 mL) was added dropwise SOCl2 (8.77 g, 73.71 mmol, 5.35 mL) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 170.2 [M+H]+.

[0323] 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate: To a solution of methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (31 g, 36.64 mmol) in DCM (300 mL) and MeOH (30 mL) was added Boc2O (15.99 g, 73.28 mmol), TEA (7.4 g, 73.28 mmol) and DMAP (447 mg, 3.66 mmol) at 0 °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 DCM (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound.

[0324] tert-butyl cis-1-carbamoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: A solution of 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate (1 g, 3.71 mmol) in NH3.H2O (20 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 199.2 [M-Boc+H]+.

[0325] tert-butyl cis-1-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl cis-1-carbamoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (750 mg, 2.95 mmol) in THF (10 mL) was added Burgess reagent (2.11 g, 8.85 mmol) at 20 °C under N2. The mixturewas stirred at 65 °C for 3 h. The reaction mixture was diluted with H2O (10 mL) and extracted with MTBE (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over 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.

[0326] tert-butyl cis-3-methyl-1-propionyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl cis-1-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (600 mg, 2.54 mmol) in THF (10 mL) was added EtMgBr (2.12 mL, 3 M in THF) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with sat. aq. NH4Cl (5 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-TLC (SiO2, PE:EtOAc = 5:1) to give the titled compound. LCMS m / z = 212.2 [M-tBu+H]+.

[0327] tert-butyl cis-1-((S)-1-hydroxypropyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate and tert-butyl cis-1-((R)-1-hydroxypropyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl cis-3-methyl-1-propionyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (450 mg, 1.68 mmol) in MeOH (10 mL) was added NaBH4 (127 mg, 3.37 mmol) at -30 °C. The mixture was stirred at 0 °C for 3 h. The mixture was diluted with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give tert-butyl cis-1-(1-hydroxypropyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxylate Intermediate 27, the first eluting isomer as a single unknown enantiomer. LCMS m / z = 214.2 [M-tBu+H]+. Further elution provided tert-butyl cis-1-(1- hydroxypropyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate Intermediate 28, the second eluting isomer as a single unknown enantiomer. LCMS m / z = 214.2 [M-tBu+H]+. Intermediates 29 and 30 (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone and (cis- 1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone

[0328] cis-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of racemic methyl cis-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (2 g, 7.29 mmol) in MeOH (20 mL) at 20 °C was added a solution of NaOH (437 mg, 10.94 mmol) in H2O (4 mL) and thereaction mixture was stirred for 3 h. The reaction mixture was adjusted to pH = 3 by addition of 2 M HCl. The resulting mixture was 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 = 261.2 [M+H]+.

[0329] cis-N-methoxy-N,3-dimethyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxamide: To a solution of cis-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (1.7 g, 6.53 mmol) in DMF (20 mL) was added N,O-dimethylhydroxylamine hydrochloride (701 mg, 7.18 mmol), HATU (2.73 g, 7.18 mmol) and DIEA (2.53 g, 19.59 mmol) at 20 °C under N2and the mixture was stirred for 3 h. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The organic layers were combined, 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 = 304.2 [M+H]+.

[0330] 1-(cis-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptan-1-yl)ethan-1-one: To a solution of cis- N-methoxy-N,3-dimethyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxamide (1.7 g, 5.60 mmol) in THF (20 mL) at –78 °C under N2 was added MeLi (2.7 M in THF, 2.70 mL). The reaction mixture was stirred at –78 °C for 2 h. The mixture was quenched by addition of aq. sat. NH4Cl (20 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 = 5:1 to 1:1) to give the titled compound. LCMS: m / z = 259.2 [M+H]+.

[0331] (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone and (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone: To a solution of 1-(cis-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptan-1-yl)ethan-1-one (5.5 g, 21.29 mmol) in MeOH (100 mL) was added NaBH4(1.61 g, 42.58 mmol) in portions at -30 °C. The mixture was stirred at 0 °C for 2 h before quenching by the addition of sat. NH4Cl (100 mL). The mixture was concentrated under reduced pressure to remove MeOH and the remaining aqueous phase was 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 1:1) to give (cis-1-(1-hydroxyethyl)-3-methyl- 6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone Intermediate 29 as the first eluting mixture of enantiomers. LCMS: m / z = 261.3 [M+ H]+and (cis-1-(1-hydroxyethyl)-3-methyl-6- azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone Intermediate 30 as the second eluting mixture of enantiomers. LCMS: m / z = 261.3 [M+H]+.Intermediate 31 cis-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-3-methyl-1-(1-(2-(methylsulfonyl)ethoxy)ethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide

[0332] 1-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)ethan-1-ol: To a solution of cis-1-(1- hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone (Intermediate 30) (500 mg, 1.92 mmol) in EtOH (15 mL) was added NaOH (768 mg, 19.21 mmol) at 20 °C under N2. The mixture was stirred at 90 °C for 12 h. The mixture was adjusted to pH = 7 by 6 M HCl at 0 °C, then lyophilized to give the titled compound. LCMS: m / z = 156.2 [M+H]+.

[0333] tert-butyl cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 1-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)ethan-1-ol (1.5 g, 1.84 mmol) in DCM (15 mL) and MeOH (1.5 mL) was added Boc2O (801 mg, 3.67 mmol), DMAP (22 mg, 0.18 mmol) and TEA (372 mg, 3.67 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 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the title compound. LCMS: m / z = 200.2 [M-tBu+H]+.

[0334] tert-butyl cis-3-methyl-1-(1-(2-(methylsulfonyl)ethoxy)ethyl)-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a solution of tert-butyl c-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (150 mg, 0.59 mmol) and 1-methylsulfonylethylene (187 mg, 1.76 mmol) in THF (3 mL) was added NaH (2 mg, 0.06 mol, 60% in mineral oil) at 0 °C under N2. The mixture was stirred at 20 °C for 4 h. The reaction mixture was diluted with sat. aq. NH4Cl (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 0:1) to give the titled compound.

[0335] cis-3-methyl-1-(1-(2-(methylsulfonyl)ethoxy)ethyl)-6-azabicyclo[3.1.1]heptane: To a solution of tert-butyl cis-3-methyl-1-(1-(2-(methylsulfonyl)ethoxy)ethyl)-6-azabicyclo[3.1.1]heptane-6- carboxylate (200 mg, 0.55 mmol) in DCM (5 mL) was added 2,6-dimethylpyridine (296 mg, 2.77 mmol) and TMSOTf (246 mg, 1.11 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added MeOH (2 mL) and the mixture was concentrated under reduced pressure to give the titled compound as a mixture of enantiomers.Intermediates 32 and 33 tert-butyl cis-1-((1S)-1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate and tert- butyl cis-1-((1R)-1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate

[0336] cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of methyl cis-3- methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (Intermediate 24) (10 g, 36.45 mmol) in EtOH (100 mL) was added NaOH (14.58 g, 364.55 mmol) at 25 °C under N2. The mixture was stirred at 90 °C for 12 h and then concentrated under reduced pressure. The resulting mixture was adjusted to pH = 4 by 6 M HCl and lyophilized to give the crude titled compound. LCMS: m / z = 156.1 [M+H]+.

[0337] methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a solution of cis-3-methyl- 6-azabicyclo[3.1.1]heptane-1-carboxylic acid (26 g crude, 36.86 mmol, 22% purity) in MeOH (300 mL) was added dropwise SOCl2(8.77 g, 73.71 mmol, 5.35 mL) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h and concentrated under reduced pressure to give the titled compound. LCMS: m / z = 170.2 [M+H]+.

[0338] 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate: To a solution of methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (31 g crude, 36.64 mmol) in DCM (300 mL) and MeOH (30 mL) was added Boc2O (15.99 g, 73.28 mmol), TEA (7.4 g, 73.28 mmol) and DMAP (447 mg, 3.66 mmol) at 0 °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 DCM (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound.

[0339] tert-butyl cis-1-carbamoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: A solution of 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate (1 g, 3.71 mmol) in NH3.H2O (20 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 199.2

[0340] tert-butyl cis-1-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl cis-1-carbamoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (750 mg, 2.95 mmol) in THF (10 mL) was added Burgess reagent (2.11 g, 8.85 mmol) at 20 °C under N2. The mixturewas stirred at 65 °C for 3 h. The reaction mixture was diluted with H2O (10 mL) and extracted with MTBE (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over 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.

[0341] tert-butyl cis-1-acetyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl cis-1-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (600 mg, 2.54 mmol) in THF (10 mL) was added MeMgBr (6.35 mmol, 3 M in Et2O) at 0 °C under N2. The mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into sat. aq. NH4Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the titled compound.

[0342] tert-butyl cis-1-((1S)-1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate and tert-butyl cis-1-((1R)-1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl cis-1-acetyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (500 mg, 1.97 mmol) in MeOH (10 mL) was added NaBH4 (164 mg, 4.34 mmol) at -30 °C under N2. The mixture was stirred at 0 °C for 3 h, diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to provide tert-butyl cis-1-(1-hydroxyethyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxylate (Intermediate 32), the first eluting isomer as a single unknown enantiomer and tert-butyl cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (Intermediate 33) the second eluting isomer as a single unknown enantiomer. Intermediate 34 cis-3-methyl-1-(1-(2-(methylsulfonyl)ethoxy)ethyl)-6-azabicyclo[3.1.1]heptane

[0343] tert-butyl cis-3-methyl-1-(1-(2-(methylsulfonyl)ethoxy)ethyl)-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a solution of tert-butyl cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (Intermediate 32) (100 mg, 0.392 mmol) and 1-methylsulfonylethylene (125 mg, 1.17 mmol) in THF (3 mL) was added NaH (1.57 mg, 0.039 mmol, 60% in mineral oil) at 0 °C under N2. The mixture was stirred at 20 °C for 4 h. The reaction mixture was diluted with sat. aq. NH4Cl (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to provide the titled compound. LCMS m / z = 306.1 [M-t-Bu+H]+.

[0344] cis-3-methyl-1-(1-(2-(methylsulfonyl)ethoxy)ethyl)-6-azabicyclo[3.1.1]heptane: To a solution of tert-butyl cis-3-methyl-1-(1-(2-(methylsulfonyl)ethoxy)ethyl)-6-azabicyclo[3.1.1]heptane-6- carboxylate (80 mg, 0.221 mmol) in DCM (2 mL) was added 2,6-dimethylpyridine (166 mg, 1.55 mmol) and TMSOTf (123 mg, 0.553 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added MeOH (2 mL) and the mixture was concentrated under reduced pressure to provide the titled compound as a single unknown enantiomer. Intermediate 35 3-(4-fluoro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline

[0345] 1-(4-methoxybenzyl)-1H-1,2,3-triazole: To a solution of 2H-1,2,3-triazole (20 g, 289.58 mmol) in DMF (200 mL) was added K2CO3(52 g, 376.46 mmol) and 1-(chloromethyl)-4-methoxybenzene (58.96 g, 376.46 mmol) at 25 °C under N2. The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with H2O (400 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 = 5:1 to 3:1) to give the titled compound. LCMS: m / z = 190.1 [M+H]+.

[0346] 5-iodo-1-(4-methoxybenzyl)-1H-1,2,3-triazole: To a mixture of 1-(4-methoxybenzyl)-1H-1,2,3- triazole (20 g, 105.70 mmol) in THF (400 mL) at –78 °C under N2was added dropwise n-BuLi (42.28 mL, 2.5 M in hexane) and the mixture was stirred at –78 °C for 0.5 h. A solution of I2(29.51 g, 116.27 mmol) in THF (150 mL) was added dropwise to the above mixture at –78 °C and the reaction mixture was stirred at –78 °C for 2 h. The mixture was poured into aq. sat. NH4Cl (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with aq. sat. Na2SO3 (2 × 100 mL) and 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 2:1) to give the titled compound. LCMS: m / z = 316.0 [M+H]+.

[0347] 5-fluoro-1-(4-methoxybenzyl)-1H-1,2,3-triazole: To a solution of 5-iodo-1-(4-methoxybenzyl)- 1H-1,2,3-triazole (28.50 g, 90.44 mmol) in toluene (400 mL) at 25 °C under N2was added TMEDA (5.26 g, 45.22 mmol) and AgF (34.42 g, 271.33 mmol). The reaction mixture was heated to 120 °C and stirredfor 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 4:1) to give the titled compound.

[0348] 4-fluoro-2H-1,2,3-triazole: A solution of 5-fluoro-1-(4-methoxybenzyl)-1H-1,2,3-triazole (2 g, 9.65 mmol) in TFA (20 mL) was heated to 65 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compound.

[0349] 4-fluoro-2-(5-nitro-2-(trifluoromethyl)phenyl)-2H-1,2,3-triazole and 4-fluoro-1-(5-nitro-2- (trifluoromethyl)phenyl)-1H-1,2,3-triazole: To a solution of 4-fluoro-2H-1,2,3-triazole (2.85 g, 6.52 mmol) in DMF (20 mL) at 25 °C under N2was added K2CO3(2.70 g, 19.56 mmol) and 2-fluoro-4-nitro- 1-(trifluoromethyl)benzene (1.50 g, 7.17 mmol). The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 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 = 277.0 [M+H]+.

[0350] 3-(4-fluoro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: To a solution of 4-fluoro-2-(5- nitro-2-(trifluoromethyl)phenyl)-2H-1,2,3-triazole (1.10 g, 3.98 mmol) in EtOH (15 mL) and H2O (3 mL) at 25 °C was added Fe (1.11 g, 19.92 mmol) and NH4Cl (426 mg, 7.97 mmol). The mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 4:1) to give the titled compound. LCMS: m / z = 247.0 [M+H]+. Intermediate 36 5-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)aniline

[0351] To a solution of 3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline (2 g, 7.62 mmol) in MeCN (20 mL) at 20 °C under N2was added Selectfluor (3.24 g, 9.14 mmol). The reaction mixture was heated to 50 °C and stirred for 2 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 = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 281.0 [M+H]+.Intermediate 37

[0352] 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 dropwise n-BuLi (42 mL, 2.5 M in n-hexane) and the reaction mixture was stirred at –78 °C for 0.5 h. A solution of perchloroethane (30 g, 126.84 mmol) in THF (100 mL) was added dropwise to the mixture at –78 °C and the reaction mixture was stirred for 2 h. The reaction mixture was warmed to 0 °C and quenched with aq. sat. NH4Cl (1000 mL) 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 flash chromatography (PE:EtOAc = 2:1 to 1:1) to give the titled compound. LCMS: m / z: 224.1 [M+H]+.

[0353] 4-chloro-2H-1,2,3-triazole trifluoroacetate: A solution of 5-chloro-1-(4-methoxybenzyl)-1H- 1,2,3-triazole (20 g, 89.42 mmol) in TFA (200 mL) was stirred at 65 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the titled compound.

[0354] 2-(5-bromo-2-chlorophenyl)-4-chloro-2H-1,2,3-triazole: To a solution of 4-bromo-1-chloro-2- fluorobenzene (5 g, 23.87 mmol) and 4-chloro-2H-1,2,3-triazole (14.83 g, 71.62 mmol) in DMF (100 mL) at 25 °C was added K2CO3(16.50 g, 119.36 mmol). The reaction mixture was heated to 100 °C and stirred for 12 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 × 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: 291.9, 293.9 [M+H]+.

[0355] 4-chloro-3-(4-chloro-2H-1,2,3-triazol-2-yl)aniline: To a solution of 2-(5-bromo-2- chlorophenyl)-4-chloro-2H-1,2,3-triazole (700 mg, 2.39 mmol) in 1,4-dioxane (20 mL) at 25 °C under N2 was added diphenylmethanimine (650 mg, 3.58 mmol), Xantphos (277 mg, 0.48 mmol), Cs2CO3(1.56 g, 4.78 mmol) and Pd2(dba)3(219 mg, 0.24 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was diluted in THF (15 mL) and 2M HCl (15 mL) wasadded at 25 °C and stirred for 2 h. The reaction mixture was adjusted to pH = 7–8 by addition of aq. sat. Na2CO3. The aqueous phase was extracted with EtOAc (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 = 3:1 to 1:1) to give the titled compound. LCMS: m / z: 229.1, 231.1 [M+H]+. Intermediate 38 4-(trifluoromethyl)-3-(4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl)aniline

[0356] 2-(5-nitro-2-(trifluoromethyl)phenyl)-4-(trifluoromethyl)-2H-1,2,3-triazole: To a solution of 4-(trifluoromethyl)-2H-1,2,3-triazole (1 g, 7.30 mmol) in DMF (20 mL) at 20 °C under N2 was added K2CO3 (2.02 g, 14.59 mmol) and 2-fluoro-4-nitro-1-(trifluoromethyl)benzene (1.68 g, 8.03 mmol). The reaction mixture was heated to 90 °C and stirred for 18 h. The reaction mixture was diluted with H2O (50 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 flash silica gel chromatography (PE:EtOAc = 1:0 to 10:1) to give the titled compound. LCMS: m / z = 327.0 [M+H]+.

[0357] 4-(trifluoromethyl)-3-(4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl)aniline: To a solution of 2- (5-nitro-2-(trifluoromethyl)phenyl)-4-(trifluoromethyl)-2H-1,2,3-triazole (510 mg, 1.56 mmol) in EtOH (10 mL) and H2O (2 mL) at 20 °C was added Fe (437 mg, 7.82 mmol) and NH4Cl (418 mg, 7.82 mmol). The reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was filtered through a pad of Celite^and the filtrate 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 (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. Intermediate 39 4-chloro-3-(4-fluoro-1H-1,2,3-triazol-1-yl)aniline

[0358] 1-(5-bromo-2-chlorophenyl)-4-fluoro-1H-1,2,3-triazole and 2-(5-bromo-2-chlorophenyl)-4- fluoro-2H-1,2,3-triazole: To a solution of 4-fluoro-2H-1,2,3-triazole (13 g, 104.53 mmol) in DMF (100 mL) at 25 °C under N2 was added K2CO3 (21.67 g, 156.8 mmol) and 4-bromo-1-chloro-2-fluorobenzene (10.95 g, 52.27 mmol). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organiclayers 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 chromatography (PE:EtOAc = 10:1 to 5:1) to give the separated titled compounds. LCMS: m / z = 275.9, 278.0 [M+H]+.

[0359] N-(4-chloro-3-(4-fluoro-1H-1,2,3-triazol-1-yl)phenyl)-1,1-diphenylmethanimine: To a solution of 1-(5-bromo-2-chlorophenyl)-4-fluoro-1H-1,2,3-triazole (2.4 g, 8.68 mmol) in 1,4-dioxane (60 mL) at 25 °C under N2 was added diphenylmethanimine (2.36 g, 13.02 mmol), Cs2CO3 (5.6 g, 17.36 mmol), Xantphos (1 g, 1.74 mmol) and Pd2(dba)3 (794 mg, 0.88 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 377.1 [M+H]+.

[0360] 4-chloro-3-(4-fluoro-1H-1,2,3-triazol-1-yl)aniline: To a solution of N-(4-chloro-3-(4-fluoro- 1H-1,2,3-triazol-1-yl)phenyl)-1,1-diphenylmethanimine (3 g, 7.96 mmol) in THF (30 mL) at 25 °C was added 2M HCl (30 mL) and the reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was adjusted to pH = 7–8 with aq. sat. NaHCO3 and extracted with EtOAc (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 silica gel column chromatography (PE:MTBE = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 213.1 [M+H]+. Intermediate 40 4-chloro-3-(3-fluoro-1H-1,2,4-triazol-1-yl)aniline

[0361] 1-(5-bromo-2-chlorophenyl)-3-fluoro-1H-1,2,4-triazole: To a solution of 3-fluoro-1H-1,2,4- triazole (500 mg, 4.02 mmol) in DMF (15 mL) at 25 °C under N2 was added K2CO3 (1.67 g, 12.06 mmol) and 4-bromo-1-chloro-2-fluorobenzene (1.68 g, 8.04 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 × 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 chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 276.0, 277.9 [M+H]+.

[0362] N-(4-chloro-3-(3-fluoro-1H-1,2,4-triazol-1-yl)phenyl)-1,1-diphenylmethanimine: To a solution of 1-(5-bromo-2-chlorophenyl)-3-fluoro-1H-1,2,4-triazole (350 mg, 1.27 mmol) in 1,4-dioxane (10 mL) at 25 °C under N2 was added diphenylmethanimine (344 mg, 1.90 mmol), Cs2CO3 (824 mg, 2.53 mmol), Xantphos (146 mg, 0.23 mmol) and Pd2(dba)3 (115 mg, 0.12 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 377.1 [M+H]+.

[0363] 4-chloro-3-(3-fluoro-1H-1,2,4-triazol-1-yl)aniline: To a solution of N-(4-chloro-3-(3-fluoro- 1H-1,2,4-triazol-1-yl)phenyl)-1,1-diphenylmethanimine (450 mg, 1.19 mmol) in THF (5 mL) at 25 °C was added 2M HCl (5 mL) and the reaction mixture was stirred for 12 h. The reaction mixture was adjusted to pH = 7–8 with aq. sat. NaHCO3, 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 = 10:1 to 5:1) to the titled compound. LCMS: m / z = 213.1 [M+H]+. Intermediate 41 4-chloro-3-(4-fluoro-2H-1,2,3-triazol-2-yl)aniline

[0364] N-(4-chloro-3-(4-fluoro-2H-1,2,3-triazol-2-yl)phenyl)-1,1-diphenylmethanimine: To a solution of 2-(5-bromo-2-chlorophenyl)-4-fluoro-2H-1,2,3-triazole (1.5 g, 5.43 mmol) in 1,4-dioxane (60 mL) at 25 °C under N2 was added diphenylmethanimine (1.47 g, 8.14 mmol), Cs2CO3(3.54 g, 10.85 mmol), Xantphos (627 mg, 1.09 mmol) and Pd2(dba)3(496 mg, 0.54 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 377.1 [M+H]+.

[0365] 4-chloro-3-(4-fluoro-2H-1,2,3-triazol-2-yl)aniline: To a solution of N-(4-chloro-3-(4-fluoro- 2H-1,2,3-triazol-2-yl)phenyl)-1,1-diphenylmethanimine (2.5 g, 6.63 mmol) in THF (25 mL) at 25 °C was added 2 M HCl (25 mL) and the reaction mixture was stirred for 12 h. The reaction mixture was adjusted to pH = 7–8 with aq. sat. NaHCO3 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 = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 213.1 [M+H]+. Intermediate 42 4-chloro-3-(4-fluoro-1H-pyrazol-1-yl)aniline1-(5-bromo-2-chlorophenyl)-4-fluoro-1H-pyrazole: To a solution of 4-fluoro-1H-pyrazole (10 g, 116.19 mmol) in DMF (80 mL) at 25 °C under N2 was added K2CO3 (48 g, 348.56 mmol) and 4-bromo- 1-chloro-2-fluorobenzene (36.50 g, 174.28 mmol). The reaction mixture was heated to 100 °C and stirred for 5 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 chromatography (PE:EtOAc = 10:1 to 8:1) to give the titled compound. LCMS: m / z = 274.8, 276.8 [M+H]+.N-(4-chloro-3-(4-fluoro-1H-pyrazol-1-yl)phenyl)-1,1-diphenylmethanimine: To a solution of 1-(5- bromo-2-chlorophenyl)-4-fluoro-1H-pyrazole (5.00 g, 18.15 mmol) in 1.4-dioxane (70 mL) at 25 °C under N2. was added diphenylmethanimine (4.93 g, 27.22 mmol), Cs2CO3 (1.83 g, 36.30 mmol), Xantphos (2.10 g, 3.63 mmol) and Pd2(dba)3(1.66 g, 1.81 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 376.2 [M+H]+.

[0366] 4-chloro-3-(4-fluoro-1H-pyrazol-1-yl)aniline: To a solution of N-(4-chloro-3-(4-fluoro-1H- pyrazol-1-yl)phenyl)-1,1-diphenylmethanimine (7 g, 18.63 mmol) in THF (70 mL) at 25 °C was added 2 M HCl (70 mL) and the reaction mixture was stirred for 12 h. The reaction mixture was cooled to 0 °C and adjusted to pH = 7–8 with aq. sat. Na2CO3 and then extracted with EtOAc (3 × 50 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 = 3:1 to 0:1) and triturated with PE:DCM (v:v = 20:1) (40 mL). The solid was collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m / z = 212.2 [M+H]+. Intermediate 43 4-chloro-3-(3-fluoro-1H-pyrazol-1-yl)aniline

[0367] 1-(5-bromo-2-chlorophenyl)-3-fluoro-1H-pyrazole: To a solution of 3-fluoro-1H-pyrazole (1 g, 8.13 mmol) in DMF (15 mL) at 25 °C under N2 was added K2CO3 (3.3 g, 24.40 mmol) and 4-bromo-1- chloro-2-fluorobenzene (3.4 g, 16.27 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× 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 (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 275.0, 277.0 [M+H]+.

[0368] N-(4-chloro-3-(3-fluoro-1H-pyrazol-1-yl)phenyl)-1,1-diphenylmethanimine: To a solution of 1-(5-bromo-2-chlorophenyl)-3-fluoro-1H-pyrazole (2.2 g, 7.99 mmol) in 1,4-dioxane (22 mL) at 25 °C under N2 was added diphenylmethanimine (2.17 g, 11.98 mmol), Cs2CO3 (5.20 g, 15.97 mmol), Xantphos (924 mg, 1.60 mmol) and Pd2(dba)3 (731 mg, 0.7 mmol). The reaction mixture was heated to110 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 376.2 [M+H]+.

[0369] 4-chloro-3-(3-fluoro-1H-pyrazol-1-yl)aniline: To a solution of N-(4-chloro-3-(3-fluoro-1H- pyrazol-1-yl)phenyl)-1,1-diphenylmethanimine (3 g, 7.98 mmol) in THF (15 mL) at 25 °C was added 2 M HCl (15 mL) and the mixture was stirred for 12 h. The reaction mixture was adjusted to pH = 7–8 with aq. sat. NaHCO3 and extracted with EtOAc (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 silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 212.1 [M+H]+. Intermediate 44 4-chloro-3-(1H-pyrazol-1-yl)aniline

[0370] 1-(5-bromo-2-chlorophenyl)-1H-pyrazole: To a solution of 4-bromo-1-chloro-2-fluorobenzene (30 g, 143.24 mmol) and 1H-pyrazole (19.5 g, 286.47 mmol) in DMF (500 mL) at 25 °C was added K2CO3(59.4 g, 429.71 mmol). The reaction mixture was heated to 100 °C and stirred for 5 h. The reaction mixture was diluted with H2O (1000 mL) and extracted with EtOAc (3 × 300 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 = 20:1 to 10:1) to give the titled compound. LCMS: m / z = 257.0, 259.0 [M+H]+.

[0371] 4-chloro-3-(1H-pyrazol-1-yl)aniline: To a solution of 1-(5-bromo-2-chlorophenyl)-1H-pyrazole (5 g, 19.42 mmol) and diphenylmethanimine (3.9 g, 21.36 mmol) in 1,4-dioxane (80 mL) at 25 °C under N2was added Cs2CO3(12.7 g, 38.83 mmol), Xantphos (2.3 g, 3.88 mmol) and Pd2(dba)3(1.8 g, 1.94 mmol). The reaction mixture was heated to 100 °C and stirred for 5 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The residue was diluted with THF (20 mL) and 2M HCl (20 mL) was added and the reaction mixture was stirred for 2 h. The reaction mixture was adjusted to pH = 8 with aq. sat. NaHCO3, diluted with H2O (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 194.1 [M+H]+.Intermediate 45 2-(3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)ethan-1-ol hydrochloride

[0372] 2-(1-amino-3-methylcyclohexyl)acetic acid: To a mixture of 3-methylcyclohexan-1-one (100 g, 891.51 mmol) in n-BuOH (1200 mL) at 20 °C under N2 was added malonic acid (92.77 g, 891.51 mmol) and NH4OAc (68.72 g, 891.51 mmol). The reaction mixture was heated to 135 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with acetone (2 L) and stirred at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 172.2 [M+H]+.

[0373] methyl 2-(1-amino-3-methylcyclohexyl)acetate hydrochloride: To a solution of 2-(1-amino-3- methylcyclohexyl)acetic acid (50 g, 291.99 mmol) in MeOH (1500 mL) at 0 °C was added dropwise SOCl2 (173.69 g, 1.46 mol). The reaction mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 186.2 [M+H]+.

[0374] methyl 2-(3-methyl-1-(picolinamido)cyclohexyl)acetate: To a mixture of methyl 2-(1-amino-3- methyl-cyclohexyl)acetate (50 g, 225.5 mmol) and pyridine-2-carboxylic acid (41.64 g, 337.5 mmol) in EtOAc (1000 mL) at 0 °C under N2was added TEA (91.28 g, 902.5 mmol) and T4P (243.72 g, 337.5 mmol, 50% purity in EtOAc). The reaction mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was diluted with H2O (2 L) and extracted with EtOAc (3 × 500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:MTBE = 10:1 to 3:1) to give the titled compound. LCMS: m / z = 291.2 [M+H]+.

[0375] methyl 2-(3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptan-1-yl)acetate: To a mixture of 2-(3- methyl-1-(picolinamido)cyclohexyl)acetate (40 g, 137.76 mmol) in 1,1,2,2-tetrachloroethane (1200 mL) at 25°C under N2was added AgOAc (68.98 g, 413.28 mmol), benzoquinone (7.45 g, 68.88 mmol), Na3PO4 (67.75 g, 413.28 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (404.96 g, 1.38 mmol) and Pd(OAc)2 (6.19 g, 27.55 mmol). The reaction mixture was heated to 145 °C and stirred for 12 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated underreduced 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 = 289.1 [M+H]+.

[0376] (1-(2-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone: To a solution of methyl 2-[3-methyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1]heptan-1-yl]acetate (10 g, 34.68 mmol) in THF (300 mL) at 0 °C under N2 was added LiAlH4 (8.32 mL, 20.81 mmol, 2.5 M in THF) and the reaction mixture was stirred for 2 h. The reaction mixture was quenched by sequential addition of H2O (2 mL), 20% NaOH (2 mL) and H2O (10 ml) at 0 °C. The reaction mixture was filtered through a pad of Celite ^ and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:2 to 0:1) to give the titled compound. LCMS: m / z = 261.1 [M+H]+.

[0377] 2-(3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)ethan-1-ol hydrochloride: To a solution of (1-(2- hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone (12 g, 46.10 mmol) in EtOH (100 mL) at 25 °C was added NaOH (18.44 g, 460.95 mmol). The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was adjusted to pH = 3 with 6M HCl and lyophilized to give the titled compound. LCMS: m / z = 156.2 [M+H]+. Intermediate 46 cis-6-((2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3- (trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid

[0378] trans-7-(trifluoromethyl)-1,3-diazaspiro[4.5]decane-2,4-dione: To a mixture of 3- (trifluoromethyl)cyclohexanone (12 g, 72.23 mmol) in EtOH (80 mL) and H2O (80 mL) at 20°C under N2 was added (NH4)2CO3(20.82 g, 216.68 mmol) and TMSCN (10.75 g, 108.34 mmol, 13.55 mL). The reaction mixture was heated to 65 °C and stirred for 3 h. The reaction mixture was filtered, the filtrate cake was washed with H2O three times and then dried under reduced pressure to give the titled compound. LCMS: m / z = 237.1 [M+H]+.

[0379] trans -1-amino-3-(trifluoromethyl)cyclohexane-1-carboxylic acid: To a solution of trans-7- (trifluoromethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (11 g, 46.57 mmol) in H2O (200 mL) at 20 °C was added Ba(OH)2 (79.80 g, 465.73 mmol). The mixture was heated to 140 °C and stirred for 12 h. Themixture was adjusted to pH = 3 by addition of 2 M H2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the titled compound.

[0380] methyl trans-1-amino-3-(trifluoromethyl)cyclohexane-1-carboxylate: To a solution of trans- 1-amino-3-(trifluoromethyl)cyclohexane-1-carboxylic acid (9.8 g, 46.41 mmol) in MeOH (200 mL) at 0 °C was added dropwise SOCl2 (27.60 g, 232.03 mmol, 16.85 mL). The mixture was heated to 75 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compound.

[0381] methyl trans-1-(picolinamido)-3-(trifluoromethyl)cyclohexane-1-carboxylate: To a solution of methyl trans-1-amino-3-(trifluoromethyl)cyclohexane-1-carboxylate (7 g, 31.08 mmol) in DCM (200 mL) at 0 °C was added pyridine-2-carboxylic acid (4.97 g, 40.41 mmol), EDCI (8.94 g, 46.62 mmol), DMAP (380 mg, 3.11 mmol) and DIEA (12.05 g, 93.25 mmol, 16.24 mL). The mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (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 = 1:1 to 0:1) to give the titled compound. LCMS: m / z = 331.1 [M+H]+.

[0382] methyl cis-6-picolinoyl-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a solution of methyl trans-1-(picolinamido)-3-(trifluoromethyl)cyclohexane-1-carboxylate (3.9 g, 11.81 mmol) in 1,1,2,2-tetrachloroethane (120 mL) at 20 °C under N2 was added AgOAc (5.91 g, 35.42 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (34.71 g, 118.07 mmol), Pd(OAc)2 (266 mg, 1.18 mmol), benzoquinone (639 mg, 5.90 mmol) and Na3PO4 (5.81 g, 35.42 mmol). The reaction mixture was heated to 145 °C and stirred for 12 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 = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 329.1 [M+H]+.

[0383] cis-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of methyl cis-6-picolinoyl-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylate (2 g, 6.09 mmol) in EtOH (30 mL) at 20 °C was added NaOH (2.44 g, 60.92 mmol). The mixture was heated to 90 °C and stirred for 12 h. The mixture was concentrated under reduced pressure and the resulting residue was adjusted to pH = 5 by the addition of 3 M HCl and lyophilized to give the titled compound as a mixture of enantiomers.Intermediate 47 2-methyl-5-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazole n

[0384] tert-butyl (cis-3-(benzyloxy)cyclohexyl)carbamate: To a solution of tert-butyl (cis-3- hydroxycyclohexyl)carbamate (30 g, 0.14 mol) in DMF (300 mL) at 0 °C under N2 was added NaH (6.13 g, 0.15 mol, 60% in mineral oil). The reaction mixture was stirred at 0 °C for 30 min and then a solution of benzyl bromide (28.60 g, 0.17 mol) in DMF (30 mL) was added to the above reaction mixture at 0 °C under N2. The reaction mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was cooled to 0 °C, quenched by addition of aq. sat. NH4Cl (900 mL) and extracted with EtOAc (3 × 150 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 5:1) to give the titled compound.

[0385] cis-3-(benzyloxy)cyclohexanamine hydrochloride: A solution of tert-butyl (cis-3- (benzyloxy)cyclohexyl)carbamate (26 g, 85 mmol) in HCl / EtOAc (4 M, 300 mL) was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 206.4 [M+H]+.

[0386] N-(cis-3-(benzyloxy)cyclohexyl)picolinamide: To a solution of cis-3- (benzyloxy)cyclohexanamine hydrochloride (19 g, 79 mmol) and picolinic acid (12 g, 94 mmol) in EtOAc (300 mL) at 0 °C under N2was added triethylamine (32 g, 314 mmol) and T4P (85 g, 118 mmol, 50% in EtOAc). The reaction mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (2 × 100 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 = 311.2 [M+H]+.

[0387] (trans-3-(benzyloxy)-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone: To a solution of N-(cis-3-(benzyloxy)cyclohexyl)picolinamide (7 g, 23 mmol) in anisole (210 mL) at 20 °C under N2was added benzoquinone (1.22 g, 11 mmol), Na3PO4 (11.09 g, 68 mmol), AgOAc (11.29 g, 68 mmol), 1,2,3,4,5-pentafluoro-6-iodobenzene (66.29 g, 226 mmol) and Pd(OAc)2 (1.01 g, 4.00 mmol). The reaction mixture was heated to 147 °C and stirred for 12 h. Then the reaction was cooled to 20 °C and Pd(OAc)2 (1.01 g, 4.00 mmol) was added to the above reaction mixture and heated to 147 °C for an additional 5 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 = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 309.1 [M+H]+.

[0388] trans-3-(benzyloxy)-6-azabicyclo[3.1.1]heptane: To a solution of (trans-3-(benzyloxy)-6- azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone (2.3 g, 7.46 mmol) in EtOH (25 mL) at 20 °C was added NaOH (2.98 g, 74.58 mmol). The reaction mixture was heated to 90 °C and stirred for 12 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 = 204.2 [M+H]+.

[0389] trans-tert-butyl 3-(benzyloxy)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of trans-3-(benzyloxy)-6-azabicyclo[3.1.1]heptane (2 g, 9.84 mmol) in DCM (30 mL) at 0 °C under N2 was added TEA (1.99 g, 19.68 mmol), Boc2O (4.29 g, 19.68 mmol) and DMAP (120 mg, 0.98 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (2 × 15 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 = 304.2 [M+H]+.

[0390] trans-tert-butyl 3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of trans- tert-butyl 3-(benzyloxy)-6-azabicyclo[3.1.1]heptane-6-carboxylate (500 mg, 1.65 mmol) in MeOH (20 mL) at 20 °C under Ar was added 10% Pd / C (500 mg, 0.47 mmol). The suspension was evacuated and back-filled with H2three times. The reaction mixture was stirred at 30 °C under H2(50 Psi) for 12 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 = 214.2 [M+H]+.

[0391] cis-tert-butyl 3-chloro-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of trans-tert- butyl 3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylate (50 mg, 0.23 mmol) in DCM (2 mL) at 0 °C was added PCl5 (63 mg, 0.30 mmol). The reaction mixture was warmed to 20 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 × 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 prep-TLC (SiO2, PE:EtOAc = 5:1) to give the titled compound. LCMS: m / z = 176.2 [M-t-Bu+H]+.

[0392] cis-3-chloro-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a solution of cis-tert-butyl 3- chloro-6-azabicyclo[3.1.1]heptane-6-carboxylate (20 mg, 0.09 mmol) in DCM (0.6 mL) at 0 °C under N2was added TFA (0.2 mL, 2.69 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 132.1 [M+H]+. Intermediate 48 1-(5-amino-2-chlorophenyl)-1H-pyrazole-5-carbonitrile

[0393] Ethyl 4-(dimethylamino)-2-oxobut-3-enoate: A solution of ethyl 2-oxopropanoate (8 g, 68.90 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (8.21 g, 68.90 mmol) was heated to 90 °C and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 172.2 [M+H]+.

[0394] Ethyl 1-(5-bromo-2-chlorophenyl)-1H-pyrazole-5-carboxylate: To a solution of (5-bromo-2- chloro-phenyl)hydrazine (5 g, 22.58 mmol) and ethyl 4-(dimethylamino)-2-oxobut-3-enoate (7.73 g, 45.15 mmol) in EtOH (100 mL) at 25 °C was added HCl (12 M, 3 mL). The reaction mixture was heated to 80 °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 (SiO2, PE:EtOAc = 1:0 to 5:1) to give the titled compound. LCMS: m / z = 331.0, 329.0 [M+H]+.

[0395] 1-(5-bromo-2-chlorophenyl)-1H-pyrazole-5-carboxylic acid: To a solution of ethyl 1-(5- bromo-2-chlorophenyl)-1H-pyrazole-5-carboxylate (3.2 g, 9.71 mmol) in THF (15 mL) and H2O (15 mL) at 25 °C was added LiOH•H2O (1.02 g, 24.27 mmol) and the reaction mixture was stirred for 12 h. To the reaction mixture was added H2O (10 mL) and the mixture was washed with MTBE (10 mL). Then the aqueous layer was adjusted to pH = 3–4 with HCl (2 M) 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 = 302.8, 300.8 [M+H]+.

[0396] 1-(5-bromo-2-chlorophenyl)-1H-pyrazole-5-carboxamide: To a solution of 1-(5-bromo-2- chlorophenyl)-1H-pyrazole-5-carboxylic acid (2.4 g, 7.96 mmol) and NH4Cl (1.28 g, 23.88 mmol) in DCM (50 mL) at 25 °C was added HOBt (1.40 g, 10.35 mmol), EDCI (2.59 g, 13.53 mmol) and TEA (2.01 g, 19.90 mmol) and the reaction mixture was stirred for 12 h. The reaction mixture was added to H2O (50 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography (SiO2, PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 301.8, 299.8 [M+H]+.

[0397] 1-(5-bromo-2-chlorophenyl)-1H-pyrazole-5-carbonitrile: To a solution of 1-(5-bromo-2- chlorophenyl)-1H-pyrazole-5-carboxamide (2.5 g, 8.32 mmol) in 1,4-dioxane (50 mL) at 25 °C under N2 was added Burgess reagent (9.91 g, 41.59 mmol). The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (SiO2, PE:EtOAc = 5:1 to 3:1) to give the titled compound. LCMS: m / z = 283.9, 281.8 [M+H]+.

[0398] 1-(5-amino-2-chlorophenyl)-1H-pyrazole-5-carbonitrile: To a solution of 1-(5-bromo-2- chlorophenyl)-1H-pyrazole-5-carbonitrile (1.7 g, 6.02 mmol) in 1,4-dioxane (30 mL) at 25 °C under N2 was added diphenylmethanimine (1.64 g, 9.03 mmol), Cs2CO3 (3.92 g, 12.03 mmol), Pd2(dba)3 (551 mg, 0.60 mmol) and Xantphos (696 mg, 1.20 mmol). The reaction mixture was heated at 90 °C and stirred for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in THF (27 mL) and 2 M HCl (27 mL) was added at 0 °C. The reaction mixture was warmed at 25 °C for 4 h. The reaction mixture was adjusted to pH = 7 by addition of aq. sat. NaHCO3 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 (SiO2, PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 218.9 [M+H]+. Intermediate 49 4-chloro-3-(5-fluoro-1H-pyrazol-1-yl)aniline

[0399] 1-(5-bromo-2-chlorophenyl)-1H-pyrazole: To a solution of 4-bromo-1-chloro-2-fluorobenzene (30 g, 143.24 mmol) in DMF (300 mL) at 25 °C was added 1H-pyrazole (19.50 g, 286.47 mmol) and K2CO3(59.39 g, 429.71 mmol). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was added to H2O (600 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, andconcentrated 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 = 259.0, 256.9 [M+H]+.

[0400] 4-chloro-N-(diphenylmethylene)-3-(1H-pyrazol-1-yl)aniline: To a solution of 1-(5-bromo-2- chlorophenyl)-1H-pyrazole (24 g, 93.20 mmol) in 1,4-dioxane (300 mL) at 25 °C under N2 was added diphenylmethanimine (25.34 g, 139.80 mmol), Cs2CO3 (60.73 g, 186.40 mmol), Xantphos (10.79 g, 18.64 mmol) and Pd2(dba)3 (8.53 g, 9.32 mmol). The mixture was heated at 90 °C and stirred for 12 h. To the reaction mixture was added H2O (500 mL) and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compound. LCMS: m / z = 358.2 [M+H]+.

[0401] 4-chloro-3-(1H-pyrazol-1-yl)aniline: To a solution of 4-chloro-N-(diphenylmethylene)-3-(1H- pyrazol-1-yl)aniline (42 g, 82.16 mmol) in THF (200 mL) at 0 °C was added 2 M HCl (200 mL). The reaction mixture was warmed to 25 °C for 12 h. The reaction mixture was adjusted to pH = 7 by addition of aq. sat. NaHCO3 and extracted with EtOAc (3 × 50 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 = 3:1 to 1:1) to give the titled compound. LCMS: m / z = 193.9 [M+H]+.

[0402] 1-(2-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-1H-pyrazole: To a solution of 4-chloro- 3-(1H-pyrazol-1-yl)aniline (15 g, 77.47 mmol) in toluene (150 mL) at 25 °C under N2 was added hexane- 2,5-dione (10.61 g, 92.96 mmol) and TsOH (4.00 g, 23.24 mmol). The reaction mixture was heated to 110 °C and stirred for 4 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 50 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 = 272.2 [M+H]+.

[0403] 1-(2-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-5-fluoro-1H-pyrazole: To a solution of 1-(2-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-1H-pyrazole (5 g, 18.40 mmol) in THF (50 mL) at – 78 °C under N2 was added LDA (12.88 mL, 2 M in THF). The reaction mixture was stirred at –78 °C for 0.5 h and then NFSI (8.70 g, 27.60 mmol) in THF (10 mL) was added to the reaction mixture at –78 °C. The mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was cooled to 0 °C and quenched by addition of aq. sat. NH4Cl (100 mL) and cooled to 0 °C. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compound. LCMS: m / z = 290.2 [M+H]+.

[0404] 4-chloro-3-(5-fluoro-1H-pyrazol-1-yl)aniline: To a solution of 1-(2-chloro-5-(2,5-dimethyl- 1H-pyrrol-1-yl)phenyl)-5-fluoro-1H-pyrazole (600 mg, 2.07 mmol) in EtOH (12 mL) at 25 °C was added NH2OH•HCl (2.88 g, 41.42 mmol) and TEA (838 mg, 8.28 mmol). The reaction mixture was heated to100 °C and stirred for 12 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 (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled compound. LCMS: m / z = 212.2 [M+H]+. Intermediate 50 trans-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid hydrochloride

[0405] cis-1-amino-3-(trifluoromethyl)cyclohexanecarboxylic acid: To a solution of cis-7- (trifluoromethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (1 g, 4.23 mmol) in H2O (20 mL) at 25 °C was added Ba(OH)2(13.36 g, 42.34 mmol). The reaction mixture was heated to 140 °C and stirred for 12 h. The reaction mixture was adjusted to pH = 3 by addition of 2 M H2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 212.1 [M+H]+.

[0406] cis-methyl 1-amino-3-(trifluoromethyl)cyclohexanecarboxylate hydrochloride: To a solution of cis-1-amino-3-(trifluoromethyl)cyclohexanecarboxylic acid (7 g, 33.15 mmol) in MeOH (100 mL) at 0 °C under N2 was added SOCl2 (19.72 g, 165.73 mmol). The reaction mixture was heated to 75 °C and stirred for 4 h. Then the reaction mixture was concentrated under reduced pressure to give the titled compound.

[0407] cis-methyl 1-(picolinamido)-3-(trifluoromethyl)cyclohexanecarboxylate: To a solution of cis- methyl 1-amino-3-(trifluoromethyl)cyclohexanecarboxylate hydrochloride (8 g, 30.57 mmol) in DCM (100 mL) at 0 °C under N2 was added picolinic acid (4.89 g, 39.74 mmol), DIEA (19.76 g, 152.87 mmol) and T4P (33.04 g, 45.86 mmol, 50% purity in EtOAc). The reaction mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was concentrated and the resulting residue was dissolved in DCM (100 mL) and washed with HCl (0.5 M, 200 mL). The organic layer was 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 = 331.1 [M+H]+.

[0408] trans-methyl 6-picolinoyl-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a solution of cis-methyl 1-(picolinamido)-3-(trifluoromethyl)cyclohexanecarboxylate (1 g, 3.03 mmol) in1,1,2,2-tetrachloroethane (30 mL) at 25 °C under N2was added AgOAc (1.52 g, 9.08 mmol), benzoquinone (164 mg, 1.51 mmol), 1,2,3,4,5-pentafluoro-6-iodobenzene (8.90 g, 30.28 mmol), Na3PO4(1.49 g, 9.08 mmol) and Pd(OAc)2 (136 mg, 0.61 mmol). The reaction mixture was heated to 145 °C and stirred for 16 h. The reaction mixture was filtered through a pad of Celite^. The filtrate was concentrated under reduced pressure and 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 = 329.1 [M+H]+.

[0409] trans-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid hydrochloride: To a solution of trans-methyl 6-picolinoyl-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylate (280 mg, 0.85 mmol) in EtOH (7 mL) at 25 °C was added NaOH (341 mg, 8.53 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and concentrated under reduced pressure to remove EtOH. The reaction mixture was adjusted to pH = 2 by addition of HCl (6 M) and lyophilized to give the titled compound. LCMS: m / z = 210.1 [M+H]+. Intermediate 51 methyl 2-(5-amino-2-chlorophenyl)-2H-1,2,3-triazole-4-carboxylate

[0410] To a solution of (5-amino-2-chlorophenyl)boronic acid (11.33 g, 66.09 mmol) in toluene (280 mL) at 20 °C under O2 atmosphere was added methyl 2H-1,2,3-triazole-4-carboxylate (7 g, 55.07 mmol), pyridine (13.07 g, 165.22 mmol) and Cu(OAc)2 (15.00 g, 82.61 mmol). The reaction mixture was heated to 80 °C and stirred for 12 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 × 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 1:1) to give the titled compound. LCMS: m / z = 253.1 [M+H]+. Example 1 2-cyclobutyl-N-(4-methyl-3-(3-methyl-1H-pyrazol-1-yl)phenyl)acetamideI

[0411] 2-cyclobutyl-N-(3-iodo-4-methylphenyl)acetamide: To a mixture of 3-iodo-4-methylaniline (10 g, 42.91 mmol) and 2-cyclobutylacetic acid (6.37 g, 55.78 mmol) in pyridine (150 mL) at 0 °C under N2was added EDCI (16.45 g, 85.82 mmol). The mixture was warmed to 25 °C and stirred for 16 h. Then the reaction mixture was concentrated under reduced pressure and the crude product was diluted with H2O (50 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried overanhydrous Na2SO4, filtered and concentrated under reduced pressure. To the crude product was added MTBE (30 mL) and the solids were collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m / z = 329.9 [M+H]+.

[0412] 2-cyclobutyl-N-(4-methyl-3-(3-methyl-1H-pyrazol-1-yl)phenyl)acetamide: To a mixture of 2- cyclobutyl-N-(3-iodo-4-methylphenyl)acetamide (400 mg, 1.22 mmol) and 3-methyl-1H-pyrazole (399 mg, 4.86 mmol) in DMF (5 mL) at 20 °C under N2 was added K2CO3 (336 mg, 2.43 mmol), trans-N1,N2- dimethylcyclohexane-1,2-diamine (69 mg, 0.49 mmol) and CuI (46 mg, 0.24 mmol). The sealed tube was heated at 150 °C for 2 h under microwave irradiation. The reaction mixture was diluted with 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. The resulting residue was purified by prep- HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 30%-60%, 10 min) to give the titled compound. LCMS: m / z = 284.2 [M+H]+. Examples 2 and 3 (1S,3R,5R)-N-(3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(2H-1,2,3-triazol-2- yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide

[0413] 2-(5-nitro-2-(trifluoromethyl)phenyl)-2H-1,2,3-triazole: To a solution of 2-fluoro-4-nitro-1- (trifluoromethyl)benzene (8 g, 38.26 mmol) in DMF (20 mL) at 20 °C was added 2H-1,2,3-triazole (3.17 g, 45.91 mmol) and K2CO3(6.87 g, 49.74 mmol). The mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was diluted with H2O (80 mL) and extracted with EtOAc (3 × 30 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 = 10:1 to 5:1) to give the titled compound. LCMS: m / z = 259.0 [M+H]+.

[0414] 3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)aniline: To a solution of 2-(5-nitro-2- (trifluoromethyl)phenyl)-2H-1,2,3-triazole (3.5 g, 13.56 mmol) in EtOH (40 mL) and H2O (10 mL) at 20 °C was added Fe (3.79 g, 67.79 mmol) and NH4Cl (3.63 g, 67.79 mmol). The mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was triturated with DCM:MeOH (V:V = 10:1), filtered, and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m / z = 229.1 [M+H]+.

[0415] cis-6-((3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of triphosgene (520 mg, 1.75 mmol) in THF (25 mL) at 0 °C under N2was added a mixture of TEA (887 mg, 8.77 mmol) and 3-(2H-1,2,3-triazol-2- yl)-4-(trifluoromethyl)aniline (1 g, 4.38 mmol) in THF (25 mL). The mixture was stirred at 0 °C for 1 h, then a solution of TEA (887 mg, 8.77 mmol) and cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid hydrochloride (4.2 g, 5.26 mmol, 24% purity) was added at 0 °C. The mixture was warmed to 20 °C and stirred for 15 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (Agela DuraShell C18250 × 70 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water, B: MeCN; B in A: 15%-45% B, 20.0 min) to give the titled compound. LCMS: m / z = 410.1 [M+H]+.

[0416] cis-N-(3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-1-(2-acetylhydrazine-1- carbonyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-6-((3-(2H-1,2,3- triazol-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (700 mg, 1.71 mmol) in DMF (7 mL) at 20 °C was added acetylhydrazine (253 mg, 3.42 mmol), DIEA (442 mg, 3.42 mmol) and HATU (975 mg, 2.56 mmol). The mixture was stirred at 20 °C for 2 h and then the mixture was diluted with H2O (30 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 to give the titled compound. LCMS: m / z = 466.1 [M+H]+.

[0417] cis-N-(3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-N-(3-(2H-1,2,3- triazol-2-yl)-4-(trifluoromethyl)phenyl)-1-(2-acetylhydrazine-1-carbonyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (600 mg, 1.29 mmol) in MeCN (10 mL) at 20 °C was added p- TsCl (369 mg, 1.93 mmol) and Cs2CO3 (1.68 g, 5.16 mmol) and the mixture was stirred for 2 h. Then the reaction mixture was diluted with H2O (20 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 = 1:1 to 0:1) to give the titled compound. LCMS: m / z = 448.2 [M+H]+.

[0418] (1S,3R,5R)-N-(3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(2H-1,2,3- triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (ChiralPak IH, 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 35%-35%, 15 min; Flow rate: 70 g / min; Wavelength: 220 & 254 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3- methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide(peak 1 in SFC) Example 2. LCMS: m / z = 448.1 [M+H]+and cis-N-(3-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)- 3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 3. LCMS: m / z = 448.1 [M+H]+. Example 4 cis-N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide

[0419] To a solution of triphosgene (35.56 mg, 0.12 mmol) in THF (1 mL) at 0 °C under N2 was added 3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-methylaniline (50 mg, 0.24 mmol, 1 eq) and TEA (72.75 mg, 0.72 mmol). The mixture was warmed to 25 °C and stirred for 2 h. Then cis-3-methyl-6- azabicyclo[3.1.1]heptane (47.38 mg, 0.426 mmol) and TEA (65 mg, 0.64 mmol) were added to the reaction solution. The mixture was stirred for an additional 2 h before 2 drops of H2O were added and the reaction mixture 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 NH4HCO3 in water; B: MeCN; B% in A: 35%-65%, 8 min) to give the titled compound. LCMS: m / z = 346.1 [M+H]+. Example 5 cis-3-methyl-N-(4-methyl-3-(2H-1,2,3-triazol-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-c- arboxamide

[0420] To a solution of triphosgene (43 mg, 0.14 mmol) in THF (1 mL) at 0 °C under N2was dropwise added a mixture of TEA (87 mg, 0.86 mmol) and 4-methyl-3-(2H-1,2,3-triazol-2-yl)aniline (50 mg, 0.29 mmol) in THF (1 mL) and the mixture was stirred at 0 °C for 1 h. Then the solution was warmed to 20 °C and cis-3-methyl-6-azabicyclo[3.1.1]heptane (77 mg, 0.69 mmol, 20% purity) was added to the above mixture followed by TEA (115 mg, 1.14 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (0.5 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex C1880 × 40 mm × 3 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 = 312.2 [M+H]+. Example 6 cis-N-(3-(4-cyano-2H-1,2,3-triazol-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide

[0421] 2-(5-amino-2-methylphenyl)-2H-1,2,3-triazole-4-carboxamide: To a solution of methyl 2-(5- amino-2-methyl-phenyl)triazole-4-carboxylate (600 mg, 2.58 mmol) in MeOH (10 mL) at 25 °C was added NH3 / MeOH (2 M, 1.29 mL). The reaction solution was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 0:1) to give the titled compound. LCMS: m / z = 218.3 [M+H]+.

[0422] cis-N-(3-(4-carbamoyl-2H-1,2,3-triazol-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (68 mg, 0.23 mmol)) in THF (3 mL) at 0 °C under N2 was added TEA (139 mg, 1.38 mmol) and 1-(5-amino-2-methyl-phenyl)triazole-4- carboxamide (100 mg, 0.46 mmol). The mixture was warmed to 25 °C and stirred for 1 h. Then cis-3- methyl-6-azabicyclo[3.1.1]heptane hydrochloride (67 mg, 0.46 mmol) was added at 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, EtOAc) to give the titled compound. LCMS: m / z = 355.2 [M+H]+.

[0423] cis-N-(3-(4-cyano-2H-1,2,3-triazol-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-N-(3-(4-carbamoyl-2H-1,2,3-triazol-2- yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (40 mg, 0.12 mmol) in 1,4- dioxane (1 mL) at 0 °C under N2 was added pyridine (44 mg, 0.56 mmol) and TFAA (47 mg, 0.22 mmol). The mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 × 3 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (Phenomenex C18100 × 30 mm × 10 μm; mobile phase A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 40%-70%, 8 min) to give the titled compound. LCMS: m / z = 337.3 [M+H]+.Example 7 cis-N-(3-(4-cyano-1H-1,2,3-triazol-1-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide

[0424] 1-(5-amino-2-methylphenyl)-1H-1,2,3-triazole-4-carboxamide: To a solution of methyl 1-(5- amino-2-methyl-phenyl)triazole-4-carboxylate (600 mg, 2.58 mmol) in MeOH (10 mL) was added NH3 / MeOH (2 M, 1.29 mL) and the reaction solution was stirred at 25 °C for 12 h. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled compound. LCMS: m / z = 218.1 [M+H]+.

[0425] cis-N-(3-(4-carbamoyl-1H-1,2,3-triazol-1-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (68 mg, 0.23 mmol) in THF (3 mL) at 0 °C under N2was added TEA (139 mg, 1.38 mmol) and 1-(5-amino-2-methyl-phenyl)triazole-4- carboxamide (100 mg, 0.46 mmol). The mixture was warmed to 25 °C and stirred for 1 h. Then cis-3- methyl-6-azabicyclo[3.1.1]heptane hydrochloride (67 mg, 0.46 mmol) was added at 25 °C and stirred for 2 h. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, EtOAc) to give the titled compound. LCMS: m / z = 355.2 [M+H]+.

[0426] cis-N-(3-(4-cyano-1H-1,2,3-triazol-1-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-N-(3-(4-carbamoyl-1H-1,2,3-triazol-1- yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (40 mg, 0.12 mmol) in 1,4- dioxane (5 mL) at 0 °C under N2was added pyridine (44 mg, 0.56 mmol) and TFAA (47 mg, 0.22 mmol). The mixture was warmed to 20 °C and stirred for 2 h. Then the reaction mixture was diluted with H2O (3 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 (Phenomenex C18100 × 30 mm × 10 μm; mobile phase A: 10 mM NH4HCO3in water, B: MeCN; B% in A: 40%-70%, 8 min) to give the titled compound. LCMS: m / z = 337.3 [M+H]+.Examples 8 and 9 (1S,3R,5R)-N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(4-chloro-2H- 1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide

[0427] cis-6-((3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of triphosgene (1.13 g, 3.81 mmol) in THF (60 mL) at 0 °C under N2was added TEA (2.31 g, 22.85 mmol) and 3-(4-chloro-2H-1,2,3-triazol-2-yl)-4- (trifluoromethyl)aniline (2 g, 7.62 mmol). The mixture was warmed to 20 °C and stirred for 1 h. Then 3- methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (6.72 g, 10.39 mmol, 20% purity) was added and the mixture was stirred for 1 h. The reaction mixture was quenched with the addition of H2O (1 mL), then concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex C18180 × 70 mm × 10 μm; mobile phase A: 10 mM TFA in water, B: MeCN; B% in A: 20%-50%, 20 min) to give the titled compound. LCMS: m / z = 444.1 [M+H]+.

[0428] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis- 6-((3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (400 mg, 0.9 mmol) in DMF (5 mL) at 0 °C under N2 was added acetylhydrazine (100 mg, 1.35 mmol), DIEA (232 mg, 1.80 mmol) and HATU (685 mg, 1.80 mmol). The mixture was warmed to 25 °C and stirred for 2 h. The reaction mixture was diluted with H2O(10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (DCM:MeOH = 20:1) to give the titled compound. LCMS: m / z = 500.2 [M+H]+.

[0429] cis-N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-1-(2- acetylhydrazine-1-carbonyl)-N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl- 6-azabicyclo[3.1.1]heptane-6-carboxamide (500 mg, 1.00 mmol) in MeCN (10 mL) at 25 °C under N2was added p-TsCl (286 mg, 1.50 mmol) and Cs2CO3(1.30 g, 4.00 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM:MeOH (V:V = 10:1) (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-TLC (SiO2, DCM:MeOH = 20:1) to give the titled compound. LCMS: m / z = 482.0 [M+H]+.

[0430] (1S,3R,5R)-N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(4- chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (ChiralPak IH, 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 27%-27%, 10 min; Flow rate: 55 g / min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give cis-N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl- 1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 8 and cis-N-(3-(4-chloro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide(peak 2 in SFC) Example 9. LCMS: m / z = 482.0 [M+H]+.Examples 10 and 11 (1S,3R,5R)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(4-methyl-1H-1,2,3-triazol-1-yl)-4- (trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)-N-(3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide

[0431] cis-3-methyl-6-((3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (306 mg, 1.03 mmol) in THF (25 mL) at 0 °C under N2was added dropwise a mixture of TEA (627 mg, 6.19 mmol) and 3-(4-methyl- 1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)aniline (500 mg, 2.06 mmol) in THF (15 mL). The mixture was stirred at 0 °C for 1 h and then cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (3.18 g, 4.10 mmol, 20% purity) was added to the above mixture followed by TEA (627 mg, 6.19 mmol). The reaction mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was diluted by the addition of H2O (0.5 mL) and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (Welch Xtimate C18180 × 70 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water; B: MeCN; B% in A: 15%-40%, over 20 min) to give the titled compound. LCMS: m / z = 424.2 [M+H]+.

[0432] cis-1-(2-acetylhydrazine-1-carbonyl)-3-methyl-N-(3-(4-methyl-1H-1,2,3-triazol-1-yl)-4- (trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-3-methyl-6- ((3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-6-azabicyclo[3.1.1]heptane- 1-carboxylic acid (200 mg, 0.47 mmol) in DMF (3 mL) at 0 °C under N2 was added acetylhydrazine (70 mg, 0.94 mmol), DIEA (121 mg, 0.94 mmol) and HATU (359 mg, 0.94 mmol). The mixture was warmed to 20 °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 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was slurried with MTBE (5 mL), the solids were collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m / z = 480.2 [M+H]+.

[0433] cis-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(4-methyl-1H-1,2,3-triazol-1-yl)-4- (trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-1-(2- acetylhydrazine-1-carbonyl)-3-methyl-N-(3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (70 mg, 0.15 mmol) in MeCN (3 mL) at 20 °C under N2was added Cs2CO3(190 mg, 0.58 mmol) and p-TsCl (42 mg, 0.22 mmol). The mixture was stirred at 20 °C 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:EtOH = 2:3:1). to give the titled compound. LCMS: m / z = 462.3 [M+H]+.

[0434] (1S,3R,5R)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(4-methyl-1H-1,2,3-triazol-1- yl)-4-(trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-3-methyl- 1-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(4-methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)- 6-azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (DAICEL CHIRALCEL IG (250 mm × 30 mm × 10 μm); Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 35%-35%, 10 min; Flow rate: 70 g / min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(4- methyl-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 10 and cis-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(4-methyl-1H- 1,2,3-triazol-1-yl)-4-(trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 11. LCMS: m / z = 462.3 [M+H]+. Example 12 and 13 (1R,3S,5S)-N-(5-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)phenyl)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-N-(5-(4- chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0435] cis-N-(5-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)phenyl)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (317 mg, 1.07 mmol) in THF (30 mL) at 0 °C under N2 was added TEA (649 mg, 6.41 mmol) and 5-(4- chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)aniline (600 mg, 2.14 mmol). The mixture waswarmed to 25 °C and stirred for 1 h. Then 2-methyl-5-(3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,3,4- oxadiazole (621 mg, 2.35 mmol) was added and the mixture was stirred for 1 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 = 3:1 to 1:2) to give the titled compound. LCMS: m / z =500.0 [M+H]+.

[0436] (1R,3S,5S)-N-(5-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)phenyl)-3- methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-N-(5-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)phenyl)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (DAICEL CHIRALPAK IC, 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 25%-25%, 12 min; Flow rate: 65 g / min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give cis-N-(5-(4-chloro-2H-1,2,3-triazol- 2-yl)-2-fluoro-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 12. LCMS: m / z = 500.0 [M+H]+. and cis-N-(5-(4-chloro-2H-1,2,3-triazol-2-yl)-2-fluoro-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 13. LCMS: m / z = 500.0 [M+H]+. Examples 14 and 15 (1R,3S,5S)-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)- 6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-N-(4-chloro-3-(2H-1,2,3-triazol-2- yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0437] cis-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)- 6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (53.37 mg, 0.178 mmol) in THF (2 mL) at 0 °C under N2 was added TEA (110 mg, 1.08 mmol), followed by 4-chloro-3-(triazol-2- yl)aniline (70 mg, 0.36 mmol). The mixture was warmed to 20 °C and stirred for 1 h. Then TEA (109 mg, 1.07 mmol) and a solution of 2-methyl-5-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazole (346 mg, 0.358 mmol, 20% purity) in THF (1 mL) were added to the reaction mixture at 20 °C and the mixture was stirred for 3 h. The reaction mixture was diluted with H2O (3 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 = 1:2) to give the titled compound.

[0438] (1R,3S,5S)-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-N-(4-chloro-3-(2H-1,2,3- triazol-2-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide: The mixture of enantiomers was separated by SFC (ChiralPak IH, 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 25%-25%, 11 min; Flow rate: 70 g / min; Wavelength: 220 nm & 254 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 14 and cis-N-(4-chloro-3-(2H-1,2,3- triazol-2-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 2 in SFC) Example 15. LCMS: m / z = 414.1 [M+H]+.

[0439] The following compounds were, or can be, made via similar procedures as those described herein.Example 47 cis-N-(3-(4-fluoro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0440] cis-6-((3-(4-fluoro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (121 mg, 0.41 mmol) in THF (4 mL) at 0 °C under N2 was added dropwise a mixture of 3-(4-fluoro-2H-1,2,3-triazol-2-yl)-4- (trifluoromethyl)aniline (200 mg, 0.81 mmol) and TEA (247 mg, 2.44 mmol) in THF (4 mL) and the reaction mixture was stirred at 0 °C for 1 h. cis-3-Methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (Intermediate 26) (775 mg, 0.97 mmol, 24% purity) was added to above mixture followed by TEA (327 mg, 3.22 mmol) and the reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (0.5 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Welch Xtimate C18250 × 70 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water; B: MeCN; B% in A: 5%-45%, over 20 min) to give the titled compound. LCMS: m / z = 428.4 [M+H]+.

[0441] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(3-(4-fluoro-2H-1,2,3-triazol-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-6-((3- (4-fluoro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane- 1-carboxylic acid (120 mg, 0.28 mmol) in DMF (2 mL) at 0 °C under N2 was added acetylhydrazine (62 mg, 0.84 mmol), HATU (214 mg, 0.56 mmol) and DIEA (73 mg, 0.56 mmol). The reaction mixture was warmed to 25 °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 (2 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. LCMS: m / z = 484.1 [M+H]+.

[0442] cis-N-(3-(4-fluoro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide : To a solution of cis-1-(2- acetylhydrazine-1-carbonyl)-N-(3-(4-fluoro-2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (140 mg, 0.29 mmol) in MeCN (3 mL) at 25 °C under N2was added p-TsCl (83 mg, 0.43 mmol) and Cs2CO3 (377 mg, 1.16 mmol). The reaction mixture was diluted with H2O (6 mL) and extracted with EtOAc (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 (column: Waters Xbridge Prep OBD C18150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3in water; B: MeCN; B% in A: 40%-70%, over 8 min) to give the titled compound as a single unknown enantiomer. LCMS: m / z = 466.2 [M+H]+.Examples 48 and 49 and 50 and 51 (1R,3R,5S)-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1-(cyanomethyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3S,5R)-N-(4-chloro-3-(2H-1,2,3-triazol-2- yl)phenyl)-1-(cyanomethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (1R,3S,5S)-N-(4- chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1-(cyanomethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and (1S,3R,5R)-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1-(cyanomethyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0443] N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-hydroxyethyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of bis(trichloromethyl) carbonate (1.52 g, 5.14 mmol) in THF (60 mL) at 0 °C under N2 was added dropwise a solution of TEA (3.12 g, 30.83 mmol) and 4- chloro-3-(2H-1,2,3-triazol-2-yl)aniline (2 g, 10.28 mmol) in THF (60 mL) and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was added dropwise into a solution of 2-(3-methyl-6- azabicyclo[3.1.1]heptan-1-yl)ethanol (15.80 g, 18.13 mmol) and TEA (2.75 g, 27.20 mmol) in THF (60 mL) at 25 °C and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 50 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 = 1:3 to 0:1) to give the titled compound.

[0444] 2-(6-((4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptan-1-yl)acetic acid: To a solution of N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1- (2-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (2.7 g, 7.18 mmol) in t-BuOH (50 mL) at 0 °C under N2was added KMnO4(11.35 g, 71.84 mmol). The reaction mixture was warmed to 30 °C and stirred for 12 h. The reaction mixture was cooled to 0 °C and it was quenched with aq. sat. Na2S2O3(150 mL) and MeOH (200 mL). The reaction mixture was filtered through a pad of Celite^and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters XbridgeBEH C18250 × 70 mm × 10 μm; mobile phase: A: 4 mM NH3H2O and 10 mM NH4HCO3in water, B: MeCN; B% in A: 5%-35%, over 17 min) to give the titled compound. LCMS: m / z = 390.0 [M+H]+.

[0445] 1-(2-amino-2-oxoethyl)-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of 2-(6-((4-chloro-3-(2H-1,2,3-triazol-2- yl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)acetic acid (370 mg, 0.95 mmol) and NH4Cl (305 mg, 5.69 mmol) in DCM (10 mL) at 25 °C was added DIEA (736 mg, 5.69 mmol), HOBt (192 mg, 1.42 mmol) and EDCI (273 mg, 1.42 mmol). The reaction mixture was stirred for 12 h and then it was diluted with 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. The resulting residue was purified by prep-TLC (SiO2, EtOAc) to give the titled compound. LCMS: m / z = 389.1 [M+H]+.

[0446] N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1-(cyanomethyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of 1-(2-amino-2-oxoethyl)-N-(4-chloro-3-(2H- 1,2,3-triazol-2-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (180 mg, 0.46 mmol) in 1,4- dioxane (10 mL) at 0 °C was added pyridine (183 mg, 2.31 mmol) and TFAA (194 mg, 0.93 mmol). The mixture was warmed to 25 °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 dried over anhydrous Na2SO4, filtered, and 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 = 371.1 [M+H]+.

[0447] (1R,3R,5S)-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1-(cyanomethyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3S,5R)-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1- (cyanomethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (1R,3S,5S)-N-(4-chloro-3-(2H- 1,2,3-triazol-2-yl)phenyl)-1-(cyanomethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1-(cyanomethyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of isomers was separated by SFC (DAICEL CHIRALCEL OD, 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in i-PrOH; B% in A: 21%-21%, 12 min; Flow rate: 51 g / min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give three peaks: N-(4-chloro-3-(2H-1,2,3-triazol-2-yl)phenyl)-1-(cyanomethyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-...

Claims

What is claimed is:

1. A compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X1is N or CR6a; X2is N or CR6b; X3is N or CR6c; X4is N or CR6d; R1is 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 each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z1; R2is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R3is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; or R2and R3together form a heterocyclyl, which may further be independently optionally substituted with one to five Z1; R4is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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)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; R5is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, - - ,C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1; R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR10, -SR10, -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 each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is 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, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R10is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R12is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -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(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 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: when X1is CR6a, X2is CR6b, X3is CR6c, and X4is CR6d; X1is N, X2is N, X3is N, and X4is CR6d; or X1is CR6a, X2is N, X3is N, and X4is N; thenwherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3; and when X1is N, X2is CR6b, X3is CR6c, and X4is CR6d; or X1is CR6a, X2is CR6c, X3is CR6c, and X4is N; and R1is methyl; then neither of R6bor R6care substituted or unsubstituted heteroaryl.

2. The compound of claim 1, wherein at least one of X1, X2, X3, and X4is N.

3. The compound of claim 1 or 2, wherein the moiety; wherein: m is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring A is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1aor Z1b; and L1is a bond, C1-4alkyl, C2-4alkenyl, or C2-4alkynyl.

4. The compound of claim 3, wherein Ring A is heteroaryl optionally substituted with one to five Z1a. 5 The compound of claim 1 or 2, wherein the moiety, which is optionally substituted with one to five Z1, wherein p is 0, 1, 2, or 3. 6 The compound of claim 1 or 2, wherein the moiety:, , , , , , , or .

7. The compound of any preceding claim, wherein the moietyis:, or.

8. The compound of any preceding claim, wherein R6a, R6b, R6c, and R6dare each independently hydrogen, halo, cyano, C1-6alkyl, or -OR10; wherein each C1-6alkyl is independently optionally substituted with one to five Z1.

9. The compound of any preceding claim, wherein X1is CR6a; and R6ais halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl.

10. The compound of any preceding claim, wherein X2is CR6b; and R6bis halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl.

11. The compound of any preceding claim, wherein X3is CR6c; and R6cis halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl.

12. The compound of any preceding claim, wherein X4is CR6d; and R6dis halo, cyano, methyl, methoxy, trifluoromethyl, hydroxymethyl, or methoxymethyl.

13. The compound of any preceding claim, wherein R4is hydrogen or halo.

14. The compound of any preceding claim, wherein R5is hydrogen or halo.

15. The compound of any preceding claim, wherein R4and R5are hydrogen.

16. The compound of any preceding claim, wherein R1is halo or C1-6 alkyl optionally substituted with one to five Z1.

17. The compound of any preceding claim, wherein R1is halo or C1-6alkyl optionally substituted with one to five independently selected halo.

18. The compound of any preceding claim, wherein R1is halo, -CH3, or -CF3.

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

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

21. A pharmaceutical composition comprising 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.

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

23. The method of claim 22, wherein the contacting is in vivo.

24. 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 1-20, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21.

25. 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 1-20, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21.

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

27. The method of claim 26, 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.

28. The method of claim 24, 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), Friedrich’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).

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

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

31. The use of claim 30, 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 axonalinjury (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 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), Friedrich’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).

32. A compound of any one of claims 1-20, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21, for use in therapy.

33. A compound of any one of claims 1-20, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21, for 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 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 supranuclear palsy (PSP), Friedrich’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).

34. The use of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 21, for the 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 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 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), Friedrich’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).

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