AU2024255597A1 - Compounds, compositions, and methods - Google Patents

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) of United States Provisional Application Number 63/496,375, filed April 14, 2023, and United States Provisional Application Number 63/580,951, filed September 6, 2023, the contents of each of which are hereby incorporated by reference in their 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 the compounds, 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, “C_1-6 alkyl” 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., C_1-20 alkyl), 1 to 12 carbon atoms (i.e., C_1-12 alkyl), 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., C_2-20 alkynyl), 2 to 12 carbon atoms (i.e., C_2-12 alkynyl), 2 to 8 carbon atoms (i.e., C_2-8 alkynyl), 2 to 6 carbon atoms (i.e., C_2-6 alkynyl), 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)R^y, wherein R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include, 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)NR^yR^z and an “N- amido” group which refers to the group -NR^yC(O)R^z, wherein R^y and R^z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or R^y and R^z are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein. [0026] “Amino” refers to the group -NR^yR^z wherein R^y and R^z are 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(NR^y)(NR^z2), wherein R^y and R^z are 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., C_6-20 aryl), 6 to 12 carbon ring atoms (i.e., C_6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C_6-10 aryl). 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)NR^yR^z and an “N-carbamoyl” group which refers to the group -NR^yC(O)OR^z, wherein R^y and R^z are 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)R^x and -C(O)OR^x, wherein R^x is 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 sp³ carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C_3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C_3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C_3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C_3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C_3-8 cycloalkyl), 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 also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl. [0034] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”. [0035] “Imino” refers to a group -C(NR^y)R^z, wherein R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0036] “Imido” refers to a group -C(O)NR^yC(O)R^z, wherein R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [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, -NR^y-, -O-, -S-, -S(O)-, -S(O)₂-, and the like, wherein R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of 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., -CH2NR^yCH3, -CH(CH3)NR^yCH3, -CH2CH2NR^yCH3, -CH2CH2NR^yCH2CH2NR^yCH3, etc., where R^y is 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, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. [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., C_2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C_2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C_2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C_2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., 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 -CR^y(=NOH) wherein R^y is 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)₂R^y, where R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl. [0049] “Sulfinyl” refers to the group -S(O)R^y, where R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl. [0050] “Sulfonamido” refers to the groups -SO₂NR^yR^z and -NR^ySO₂R^z, where R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [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 to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. [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(R^y)3, wherein each R^y is 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, -NR^gR^h, -NR^gC(O)R^h, -NR^gC(O)NR^gR^h, -NR^gC(O)OR^h, -NR^gS(O)_1-2R^h, -C(O)R^g, -C(O)OR^g, -OC(O)OR^g, -OC(O)R^g, -C(O)NR^gR^h, -OC(O)NR^gR^h, -OR^g, -SR^g, -S(O)R^g, -S(O)₂R^g, -OS(O)_1-2R^g, -S(O)_1-2OR^g, -NR^gS(O)_1-2NR^gR^h, =NSO₂R^g, =NOR^g, -S(O)1-2NR^gR^h, -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)R^g, -C(O)OR^g, -C(O)NR^gR^h, -CH2SO2R^g, or -CH2SO2NR^gR^h. In the foregoing, R^g and R^h are 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 R^g and R^h and Rⁱ are 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). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. [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 as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ³H and ¹⁴C 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. An ¹⁸F, ³H, or ¹¹C 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 at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. [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 to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety. 2. Compounds [0069] Provided herein are compounds that are inhibitors of SARM1. In certain embodiments, provided is a compound of Formula I: I or a pharmaceutically og, stereoisomer, tautomer, mixture of stereoisomers ther eof, wherein: each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; Ring A is C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z¹; L is a bond, C_1-4 alkylene, C_2-4 alkenylene, or C_2-4 alkynylene; R¹ is hydrogen, 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R² is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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; or two R² together form a C_3-10 cycloalkyl or heterocyclyl; wherein the C_3-10 cycloalkyl or heterocyclyl is independently optionally substituted with one to five Z¹; R⁴ is 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; R⁵ is hydrogen, halo, cyano, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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; each R⁶ is independently hydrogen, halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C_3-10 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1a; each Z¹ is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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 Z^1a; each R¹² is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1b; each Z^1a is 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1b; each R¹³ is 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 Z^1b; each Z^1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L¹-C1-6 alkyl, -L¹-C2-6 alkenyl, -L¹-C_2-6 alkynyl, -L¹-C_1-6 haloalkyl, -L¹-C_3-10 cycloalkyl, -L¹-heterocyclyl, -L¹-aryl, or -L¹-heteroaryl; and each L¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O)₂-, -N(C_1-6 alkyl)-, -N(C_2-6 alkenyl)-, -N(C_2-6 alkynyl)-, -N(C_1-6 haloalkyl)-, -N(C_3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(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 Z^1b and L¹ is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH₂, -NO₂, -SF₅, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0070] In certain embodiments, provided is a compound of Formula I: or a pharmaceut g, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; Ring A is C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z¹; L is a bond, C_1-4 alkylene, C_2-4 alkenylene, or C_2-4 alkynylene; R¹ is hydrogen, 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R² is independently 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 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 two R² together form a C_3-10 cycloalkyl or heterocyclyl; wherein the C_3-10 cycloalkyl or heterocyclyl is independently optionally substituted with one to five Z¹; R⁴ is 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; R⁵ is hydrogen, halo, cyano, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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; each R⁶ is independently hydrogen, halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1a; each Z¹ is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 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 Z^1a; each R¹² is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1a; each Z^1a is independently 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. [0071] In certain embodiments, X¹ is N. [0072] In certain embodiments, X², X³, and X⁴ are CR⁶. [0073] In certain embodiments, X² is N. [0074] In certain embodiments, X¹, X³, and X⁴ are CR⁶. [0075] In certain embodiments, X³ is N. [0076] In certain embodiments, X¹, X², and X⁴ are CR⁶. [0077] In certain embodiments, X¹ is N and X² and X⁴ are CR⁶. [0078] In certain embodiments, X⁴ is N. [0079] In certain embodiments, X¹, X², and X³ are CR⁶. [0080] In certain embodiments, X¹ and X³ are N. [0081] In certain embodiments, X² and X⁴ are CR⁶. [0082] In certain embodiments, X¹ and X⁴ are N. [0083] In certain embodiments, X² and X³ are CR⁶. [0084] In certain embodiments, X² and X⁴ are N. [0085] In certain embodiments, X¹ and X³ are CR⁶. [0086] In certain embodiments, X³ and X⁴ are N. [0087] In certain embodiments, X¹ and X² are CR⁶. [0088] In certain embodiments, X¹ is N and X² and X³ are CR⁶. [0089] In certain embodiments, X² is N and X¹ and X³ are CR⁶. [0090] In certain embodiments, X³ is N and X¹ and X² are CR⁶. [0091] In certain embodiments, L is a bond or -CH2-. is: . y hydrogen or halo. [0094] In certain embodiments, each R⁶ is independently hydrogen, halo, cyano, C1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, -O-C_1-6 alkyl, or -O-C_1-6 haloalkyl. [0095] In certain embodiments, each R⁶ is independently hydrogen, halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, or -O-C_1-6 alkyl. [0096] In certain embodiments, each R⁶ is independently hydrogen, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy, 2-methoxyethoxymethyl, fluoromethoxy, or difluoromethoxy. [0097] In certain embodiments, each R⁶ is independently hydrogen, fluoro, chloro, cyano, methyl, ethyl, trifluoromethyl, cyclopropyl, or methoxy. [0098] In certain embodiments, each R⁶ is independently hydrogen, fluoro, cyano, methyl, trifluoromethyl, cyclopropyl, or methoxy. [0099] In certain embodiments, each R⁶ is independently hydrogen, halo, cyano, hydroxy, or -O-C_{1- 6} alkyl. [0100] In certain embodiments, each R⁶ is independently hydrogen, halo, cyano, hydroxy, or methoxy. [0101] In certain embodiments, each R⁶ is independently hydrogen, fluoro, chloro, cyano, hydroxy, or methoxy. [0102] In certain embodiments, each R⁶ is independently hydrogen, halo, cyano, or -O-C1-6 alkyl. [0103] In certain embodiments, no R⁶ is hydroxy. [0104] In certain embodiments, when an R⁶ is hydroxy, then the hydroxy is not alpha to a ring N, or one or two of X¹-X⁴ is N. [0105] In certain embodiments, each R⁶ is independently hydrogen, halo, cyano, hydroxy, or -O-C_1- 6 alkyl; provided that when an R⁶ is hydroxy, then the hydroxy is not alpha to a ring N, or one or two of X¹-X⁴ is N. or C_3-10 cycloalkyl, wherein each C1-6 alkyl or C3-10 cycloalkyl is independently optionally substituted with one to five Z¹. [0110] In certain embodiments, each R² is independently C1-6 alkyl. In certain embodiments, each R² is C1-6 alkyl substituted with one to three halo. In certain embodiments, each R² is C1-6 alkyl substituted with one to three fluoro. [0111] In certain embodiments, each R² is independently C3-10 cycloalkyl. [0112] In certain embodiments, m is 0 or 1. [0113] In certain embodiments, m is 0 or 1 and R² is methyl, ethyl, cyclopropyl, or trifluoromethyl. [0114] In certain embodiments, m is 0 or 1 and R² is methyl. [0115] In certain embodiments, m is 0 or 1 and R² is ethyl. [0116] In certain embodiments, m is 0 or 1 and R² is trifluoromethyl. [0117] In certain embodiments, m is 0 or 1 and R² is cyclopropyl. [0118] In certain embodiments, n is 1 or 2. [0119] In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z¹. [0120] In certain embodiments, each Z¹ is independently cyano, C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, or -N(R¹²)₂. [0121] In certain embodiments, each R¹² is hydrogen. [0122] In certain embodiments, Ring A is heteroaryl optionally substituted with one to five Z¹. [0123] In certain embodiments, Ring A is heteroaryl optionally substituted with cyano, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, or -N(R¹²)2. [0124] In certain embodiments, Ring A is heteroaryl optionally substituted with cyano, C1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, or -NH₂. [0125] In certain embodiments, Ring A is heterocyclyl optionally substituted with one to five Z¹. [0126] In certain embodiments, R⁴ is hydrogen, halo, cyano, or C_1-6 alkyl. [0127] In certain embodiments, R⁴ is hydrogen, fluoro, chloro, bromo, cyano, or methyl. [0128] In certain embodiments, R⁴ is hydrogen. [0129] In certain embodiments, R⁵ is hydrogen or halo. [0130] In certain embodiments, R⁴ is hydrogen, and R⁵ is hydrogen or halo. [0131] In certain embodiments, R⁵ is hydrogen, fluoro, or chloro. [0132] In certain embodiments, R⁵ is hydrogen or fluoro. [0133] In certain embodiments, R⁴ and R⁵ are hydrogen. [0134] In certain embodiments, L is a bond or C_1-4 alkylene. [0135] In certain embodiments, R¹ is C1-6 alkyl, optionally substituted with one to five Z¹. [0136] In certain embodiments, each Z¹ is independently halo. [0137] In certain embodiments, R¹ is C1-6 alkyl or C1-6 haloalkyl. [0138] In certain embodiments, R¹ is halo, cyano, C1-6 alkyl, C3-10 cycloalkyl, aryl, or -OR¹¹; wherein the C1-6 alkyl, C3-10 cycloalkyl, or aryl is optionally substituted with one to five Z¹. [0139] In certain embodiments, R¹ is halo, cyano, C_1-6 alkyl, C_3-10 cycloalkyl, or -OR¹¹; wherein the C_1-6 alkyl or C_3-10 cycloalkyl is optionally substituted with one to five Z¹. [0140] In certain embodiments, R¹ is fluoro, chloro, bromo, cyano, methyl, ethyl, isopropyl, -CH₂F, -CHF2, -CF3, -CH2CN, -OCF3, cyclopropyl optionally substituted with methyl, or phenyl. [0141] In certain embodiments, R¹ is fluoro, chloro, cyano, methyl, ethyl, -CF3, -CH2CN, -OCF3, or cyclopropyl. [0142] In certain embodiments, R¹ is fluoro, chloro, cyano, methyl, ethyl, isopropyl, -CHF2, -CF3, -CH2CN, -OCF3, cyclopropyl optionally substituted with methyl, or phenyl. [0143] In certain embodiments, each Z¹ is independently halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, heteroaryl, -OR¹², or -C(O)OR¹²; wherein each C_1-6 alkyl, C_1-6 haloalkyl, heteroaryl is independently optionally substituted with one to five hydroxy, methoxy, or methyl. [0144] In certain embodiments, each Z¹ is independently halo, cyano, C1-6 alkyl, C1-6 haloalkyl, heteroaryl, C1-6 alkoxy, or -C(O)O-C1-6 alkyl; wherein each C1-6 alkyl, C1-6 haloalkyl, heteroaryl is independently optionally substituted with one to five hydroxy, methoxy, or methyl. [0145] In certain embodiments, each Z¹ is independently halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, or -N(R¹²)₂. In certain embodiments, each R¹² is independently hydrogen or C_1-6 alkyl. [0146] In certain embodiments, provided is a compound of Formula I: or a pharmaceutically g, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; Ring A is C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z¹; L is a bond, C1-4 alkylene, C2-4 alkenylene, or C2-4 alkynylene; R¹ is hydrogen, 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R² is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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; or two R² together form a C_3-10 cycloalkyl or heterocyclyl; wherein the C_3-10 cycloalkyl or heterocyclyl is independently optionally substituted with one to five Z¹; R⁴ is hydrogen, halo, cyano, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z¹; R⁵ is hydrogen, halo, cyano, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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; each R⁶ is independently hydrogen, halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1a; each Z¹ is 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; and each R¹² is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0147] In certain embodiments, provided is a compound of Formula I: or a pharmaceuticall g, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0 or 1; n is 0, 1, or 2; Ring A is heterocyclyl or heteroaryl; wherein each heterocyclyl or heteroaryl is independently optionally substituted with one to five Z¹; L is a bond or C1-4 alkylene; R¹ is halo, cyano, C1-6 alkyl, or C1-6 haloalkyl; R² is C_1-6 alkyl optionally substituted with one to five Z¹; or two R² together form a C_3-10 cycloalkyl or heterocyclyl; wherein the C_3-10 cycloalkyl or heterocyclyl is independently optionally substituted with one to five Z¹; R⁴ is hydrogen; R⁵ is hydrogen or halo; each R⁶ is independently hydrogen, 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Z¹ is 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; and each R¹² is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0148] In certain embodiments, provided is a compound of Formula I: or a pharmaceutically g, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein: each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0 or 1; n is 1; Ring A is heteroaryl optionally substituted with one to five Z¹; L is a bond or C1-4 alkylene; R¹ is halo, cyano, C1-6 alkyl, or C1-6 haloalkyl; R² is C1-6 alkyl optionally substituted with one to five Z¹; R⁴ is hydrogen; R⁵ is hydrogen or halo; each R⁶ is independently hydrogen, halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Z¹ is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 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; and each R¹² is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0149] In certain embodiments, provided is a compound of Formula I: or a pharmaceutically a g, stereoisomer, tautomer, mixture of stereoisomers thereo f, wherein: each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0 or 1; n is 1; Ring A is heteroaryl optionally substituted with one to five Z¹; L is a bond or C1-4 alkylene; R¹ is halo, cyano, C_1-6 alkyl, or C_1-6 haloalkyl; R² is C_1-6 alkyl optionally substituted with one to five Z¹; R⁴ is hydrogen; R⁵ is hydrogen; each R⁶ is independently hydrogen, 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Z¹ is 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; and each R¹² is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0150] In certain embodiments, provided is a compound of Formula I: I or a pharmaceuticall log, stereoisomer, tautomer, mixture of stereoisomers ther eof, wherein: each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0 or 1; n is 1; Ring A is heteroaryl optionally substituted with one to five Z¹; L is a bond or C1-4 alkylene; R¹ is halo, cyano, C1-6 alkyl, or C1-6 haloalkyl; R² is C1-6 alkyl optionally substituted with one to five Z¹; R⁴ is hydrogen; R⁵ is halo; each R⁶ is independently hydrogen, halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; each Z¹ is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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; and each R¹² is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0151] 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 Structure Structure 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. [0154] “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. [0155] “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. [0156] 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. [0157] 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. [0158] 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. [0159] 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. [0160] 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). [0161] 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). [0162] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for inhibiting NADase activity of SARM1. In certain embodiments, provided is a method of inhibiting SARM1 NADase activity and/or treating a neurodegenerative or neurological disease or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to the subject. [0163] 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. [0164] 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. [0165] 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. [0166] In certain embodiments, provided is a method for treating degeneration of a central nervous system neuron or a portion thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0167] In certain embodiments, the treating comprises reducing one or more symptoms or features of neurodegeneration. [0168] 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. [0169] 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. [0170] 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. [0171] 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. [0172] 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. [0173] 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. [0174] In certain embodiments, the present disclosure provides use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof in the manufacture of a medicament for treating a neurodegenerative or neurological disease or disorder, such as a disease or disorder associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from traumatic axonal injury (TAI), a leukoencephalopathy or a leukodystrophy. [0175] In certain embodiments, the disease or condition is an acute condition. In certain embodiments, the disease or condition is a chronic condition. [0176] 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. [0177] 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). [0178] 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. [0179] 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). [0180] 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. [0181] In certain embodiments, the disease or condition is glaucoma (see, e.g., Ko, K.W., et al. J. Cell Bio.2020, 219(8), e201912047). [0182] 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. [0183] 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. [0184] 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.) [0185] 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. [0186] 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. [0187] In certain embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a leukodystrophy. In certain embodiments, the neurodegenerative or neurological disease or disorder is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe’s disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, Tay-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic complications of chemotherapy (e.g., chemotherapy induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, glaucoma, retinitis pigmentosa, traumatic optic injury, Leber’s hereditary optic atrophy (neuropathy), Leber congenital amaurosis (e.g., Leber congenital amaurosis type 9 (LCA9)), neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell’s palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), 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). [0188] 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. [0189] 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. [0190] 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. [0191] 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. [0192] In certain embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy which includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, a disorder of lipid/glycolipid metabolism, a nutritional/vitamin deficiency, or a mitochondrial disorder. The common hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation. [0193] 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. [0194] 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. [0195] 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. [0196] In certain embodiments, the present methods comprise administering an effective amount of a compound and/or composition as described herein (e.g., a compound of Formula I) to a subject in need thereof. In some such embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In certain embodiments, the subject has a condition characterized by axonal degeneration. In certain embodiments, the subject has been diagnosed with a condition characterized by axonal degeneration. In certain embodiments, the subject is at risk of developing a condition characterized by axonal degeneration. In certain embodiments, the subject is identified as being at risk of axonal degeneration, e.g., based on the subject’s genotype, a diagnosis of a condition associated with axonal degeneration, and/or exposure to an agent and/or a condition that induces axonal degeneration. [0197] 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. [0198] In certain embodiments, a neurodegenerative disease, disorder or condition may be or comprise a traumatic neuronal injury. In certain embodiments, a traumatic neuronal injury is blunt force trauma, a closed-head injury, an open head injury, exposure to a concussive and/or explosive force, a penetrating injury in to the brain cavity or innervated region of the body. In certain embodiments, a traumatic neuronal injury is a force which causes the axons to deform, stretch, crush or sheer. In certain embodiments, the disease or disorder is a traumatic brain injury (TBI). [0199] 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. [0200] 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. [0201] 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. [0202] 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. [0203] 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. [0204] 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. [0205] 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. [0206] 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. [0207] 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). [0208] 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. [0209] 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). [0210] 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). [0211] 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. [0212] 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. [0213] 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). [0214] 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. [0215] 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). [0216] In certain embodiments, the disease or condition may be a disease or condition of the central nervous system, and/or may be caused by or associated with a pathogen or traumatic injury. It will be appreciated that these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive. [0217] 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). [0218] Other embodiments include use of the presently disclosed compounds in therapy. 4. Kits [0219] 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. [0220] 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 [0221] 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.). [0222] 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. [0223] 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. [0224] 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. [0225] 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. [0226] 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. [0227] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. [0228] 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. [0229] 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. [0230] 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 le. Formulation Example 3 - Suspension formulation with nd has 6. Dosing [0236] 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 [0237] 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. [0238] It will be appreciated that where typical or preferred 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. [0239] 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. [0240] 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. [0241] 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 [0242] 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, n, m, L, Ring A, R¹, R², R⁴, and R⁵ are each independently as defined herein, and R^X is a functional group precursor to -L-Ring A (e.g., -C(O)OR, where R is hydrogen, C_1-6 alkyl, etc.). Scheme I compound I-2 under suitable carbamoylation reaction conditions, e.g., using a phosgene reagent, such as triphosgene, followed by optional functionalization or deprotection when required. Alternatively, compound I-4 can be prepared by contacting compound I-1 with compound I-3 under suitable carbamoylation reaction conditions, e.g., using a phosgene reagent, such as triphosgene, followed by optional functionalization or deprotection when required. Functional group interconversion of R^X to -L-Ring A (e.g., under ring forming reaction conditions) provides compounds of Formula I. 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. [0244] Scheme II illustrates an alternate general method which can be employed for the synthesis of compounds described herein (e.g., Formula I), where X¹, X², X³, X⁴, n, m, L, Ring A, R¹, R², R⁴, and R⁵ are each independently as defined herein, LG is a leaving group (e.g., halo, alkoxy, -OCCl₃, imidazolyl, 4-nitrobenzyloxy-O-, -S-C_1-6 alkyl, -Sn(C_1-6 alkyl)₃, etc.), each R⁵⁰ are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic boronic ester, and R^Y is R^X or -L-Ring A, where R^X is a functional group precursor to -L-Ring A (e.g., -C(O)OR, where R is hydrogen, C1-6 alkyl, etc.). Scheme II compound II-2 under suitable coupling reaction conditions, such as in the presence of a palladium catalyst (e.g., Pd(dppf)Cl₂) and a base, followed by optional functionalization (e.g., functional group interconversion of R^Y to -L-Ring A, e.g., under ring forming reaction conditions) and/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. [0246] Further derivatization of the compound provided by the steps outlined in Scheme I or Scheme II, or any intermediate, provides additional compounds of Formula I. It should be understood that any of the compounds or intermediates shown in Scheme I or 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 I or 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 I or Scheme II are as defined for Formula I. [0247] For example, compounds I-1 and II-5 can be prepared according to Scheme III below according to similar procedures as described in Scheme II, where X¹, X², X³, X⁴, m, n, R¹, R², R⁴, and R⁵ are each independently as defined herein, X is a leaving group (e.g., halo, Sn(C_1-6 alkyl)₃, etc.), each R⁵⁰ are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic boronic ester, and R^Y is R^X or -L-Ring A, where R^X is a functional group precursor to -L-Ring A (e.g., -C(O)OR, where R is hydrogen, C_1-6 alkyl, etc.).

[0248] I mpound II- 2 under suitable coupling reaction conditions, such as in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) and a base. Reduction of compound III-2 provides compound I-1. Alternatively, compound I-1 can be provided by contacting amine III-3 with compound II-2 under suitable coupling reaction conditions, such as in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) and a base. Compound III-4 can be provided by borylation of compound III-3. Carbamoylation of compound III-4 under suitable reaction conditions, e.g., using a phosgene reagent, such as triphosgene, forms urea II-1. 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 any step 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: a I; wherein L, Ring A, n, m, X¹, X², X³, X⁴, R, R¹, R⁴, and R⁵ are 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 5mm ¹H-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 both ¹H and ¹³C). In certain cases, ¹H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker Advance 400 instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad. [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 NH₄HCO₃ in 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 Acquity^TM system equipped with PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternated positive and negative electrospray ionization mode. The column used was a Cortecs UPLC C18, 1.6 µm, 2.1 × 50 mm. A linear gradient was applied, starting at 95% A (A: 0.1% formic acid in water) and ending at 95% B (B: 0.1% formic acid in MeCN) over 2.0 min with a total run time of 2.5 min. The column temperature was at 40 ºC with the flow rate of 0.8 mL/min. Intermediate 1 4-methyl-3-(pyrimidin-2-yl)aniline [0256] To a solution tetramethyl-1,3,2- dioxaborolan-2-yl)an iline (3.52 g, 15.10 mmol) in 1,4-dioxane (40 mL) and H2O (4 mL) was added K2CO3 (5.22 g, 37.74 mmol) and Pd(dppf)Cl2 (920 mg, 1.26 mmol) under N2 at 25 °C. The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (60 mL) and extracted with EtOAc (3 × 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 1:1) to give the titled compound. LCMS = 186.1 [M+H]⁺. Intermediate 2 [0257] To a mixt niline (1 g, 4.29 mmol) and 2-bromo-5-fluoropyrimidine (1.14 g, 6.43 mmol) in DMF (20 mL) and H₂O (2 mL) was added K₂CO₃ (1.78 g, 12.87 mmol) and Pd(PPh₃)₄ (496 mg, 0.43 mmol) at 25 °C under N₂. The 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 column chromatography (PE:EtOAc = 10:1 to 2:1) to give the titled compound. LCMS: m/z = 204.1 [M+H]⁺. Intermediate 3 H₂ [0258] (5 amino 2 methylphenyl)boronic acid: To a solution of 4 methyl 3 (4,4,5,5 tetramethyl 1,3,2- dioxaborolan-2-yl)aniline (8 g, 34.32 mmol) in DCM (80 mL) was added BCl3 (172 mL, 1 M in toluene) at –40 °C under N₂. The reaction mixture was warmed to 20 °C and stirred for 4 h. Then the reaction was cooled to 0 °C and was quenched by addition of MeOH (250 mL) and then concentrated under reduced pressure. The resulting residue was adjusted to pH = 7–8 with aq. sat. NaHCO3 and extracted with DCM (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. [0259] 4-methyl-3-(1,2,4-triazin-3-yl)aniline: To a solution of 3-(methylthio)-1,2,4-triazine (2 g, 15.73 mmol) and (5-amino-2-methylphenyl)boronic acid (4.75 g, 31.45 mmol) in 1,4-dioxane (40 mL) was added thiophene-2-carbonyloxycopper•hydrate (7.22 g, 34.60 mmol) and Pd(PPh₃)₄ (1.82 g, 1.57 mmol) at 20 °C. The reaction mixture was heated to 100 °C and stirred for 12 h. Then the reaction was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:5 to 0:1). The crude product was adjusted to pH = 3 with 1N HCl and extracted with EtOAc (3 × 15 mL). Then aqueous phase was adjusted to pH = 7–8 with aq. sat. NaHCO3 and extracted with EtOAc (3 × 15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 187.3 [M+H]⁺. Intermediate 4 3-(1,2,4-triazin-3-yl)-4-(trifluoromethyl)aniline S NH NC Br Br H₂N Br H₂N N (trifluoromethyl)benzonitrile (10 g, 40 mmol) in DMF (150 mL) at 0 °C was added MgCl₂ (3.81 g, 40 mmol). The reaction mixture was stirred for 5 min before adding NaSH (6.73 g, 120 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2h, diluted with H2O (1 L) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. To the crude material was added H2O (50 ml) and the resulting solid was filtered and the filter cake was dried under reduced pressure to give the titled compound. LCMS: m/z = 284.0, 286.0 [M+H]⁺. [0261] 5-bromo-2-(trifluoromethyl)benzimidohydrazide: To a solution of 5-bromo-2- (trifluoromethyl)benzothioamide (6 g, 21.12 mmol) in EtOH (70 mL) was added hydrazine hydrate (10.57 g, 211.20 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was then concentrated under reduced pressure to give the titled compound. LCMS: m/z = 282.0, 284.0 [M+H]⁺. [0262] 3-(5-bromo-2-(trifluoromethyl)phenyl)-1,2,4-triazine: To a solution of 5-bromo-2- (trifluoromethyl)benzimidohydrazide (6 g, 21.27 mmol) in EtOH (100 mL) was added oxalaldehyde (15.43 g, 106.36 mmol, 40% purity in H2O) at 25 °C. The mixture was heated to 80 °C and stirred for 2 h. Then the reaction mixture was concentrated under reduced pressure and 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 = 304.0, 306.0 [M+H]⁺. [0263] N-(3-(1,2,4-triazin-3-yl)-4-(trifluoromethyl)phenyl)-1,1-diphenylmethanimine: To a solution of 3-(5-bromo-2-(trifluoromethyl)phenyl)-1,2,4-triazine (2.5 g, 8.22 mmol) and diphenylmethanimine (1.64 g, 9.04 mmol) in 1,4-dioxane (50 mL) at 25 °C under N₂ was added Cs₂CO₃ (5.36 g, 16.44 mmol), Xantphos (951 mg, 1.64 mmol) and Pd₂(dba)₃ (753 mg, 0.82 mmol). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 405.1 [M+H]⁺. [0264] 3-(1,2,4-triazin-3-yl)-4-(trifluoromethyl)aniline: To a solution of N-(3-(1,2,4-triazin-3-yl)-4- (trifluoromethyl)phenyl)-1,1-diphenylmethanimine (2 g, 4.95 mmol) in THF (15 mL) at 25 °C was added HCl (1M, 15 mL) and the mixture was stirred for 2 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 15 mL). The aqueous phase was adjusted to pH = 7–8 by addition of aq. sat. NaHCO₃ and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 241.1 [M+H]⁺. Intermediate 5 2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)aniline O S NH B B H N B methylbenzamide (28 g, 120.66 mmol) in toluene (300 mL) at 25 °C under N₂ was added Lawesson’s reagent (29 g, 72.40 mmol). The reaction mixture was heated to 110 °C and stirred for 2 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the titled compound. LCMS: m/z = 248.0, 250.0 [M+H]⁺. [0266] 5-bromo-4-fluoro-2-methylbenzimidohydrazide: To a mixture of 5-bromo-4-fluoro-2- methylbenzothioamide (11 g, 44.33 mmol) in EtOH (130 mL) at 25 °C under N₂ was added N₂H₄•H₂O (11 g, 221.67 mmol, 11 mL, 98% purity). The mixture was heated to 50 °C and stirred for 8 h. Then the reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 246.1, 248.1 [M+H]⁺. [0267] 3-(5-bromo-4-fluoro-2-methylphenyl)-1,2,4-triazine: To a mixture of 5-bromo-4-fluoro-2- methylbenzimidohydrazide (10.9 g, 44.29 mmol) in EtOH (140 mL) at 25 °C was added oxalaldehyde (32 g, 221.47 mmol, 29 mL, 40% purity in H₂O). The reaction mixture was heated to 80 °C and stirred for 2 h before it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the titled compound. LCMS: m/z = 268.0, 270.0 [M+H]⁺. [0268] N-(2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)phenyl)-1,1-diphenylmethanimine: To a mixture of 3-(5-bromo-4-fluoro-2-methylphenyl)-1,2,4-triazine (2 g, 7.46 mmol) and diphenylmethanimine (1.35 g, 7.46 mmol) in 1,4-dioxane (50 mL) at 20 °C under N2 was added Pd2(dba)3 (683 mg, 0.75 mmol), Xantphos (863 mg, 1.49 mmol) and Cs2CO3 (4.86 g, 14.92 mmol). The reaction mixture was heated to 100 °C and stirred for 5 h. The reaction mixture 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 = 369.2 [M+H]⁺. [0269] 2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)aniline: To a mixture of N-(2-fluoro-4-methyl-5-(1,2,4- triazin-3-yl)phenyl)-1,1-diphenylmethanimine (400 mg, 1.09 mmol) in THF (6 mL) at 25 °C was added HCl (2 M, 3 mL) and the reaction mixture was stirred for 12 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 phases 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 = 204.9 [M+H]⁺. Intermediate 6 2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylaniline F O N [0270] To a solution of 2 fluoro 4 methyl 5 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)aniline (5 g, 15.93 mmol) and 2-bromo-5-fluoro-pyrimidine (2.35 g, 13.27 mmol) in 1,4-dioxane (80 mL) and H2O (8 mL) at 25 °C under N₂ was added K₂CO₃ (4.6 g, 33.19 mmol) and Pd(dppf)Cl₂ (970 mg, 1.33 mmol). The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compound. LCMS: m/z = 222.2 [M+H]⁺. Intermediate 7 2-fluoro-5-(pyridazin-3-yl)-4-(trifluoromethyl)aniline 3-bromo-4-(trifluoromethyl)aniline (20 g, 83.33 mmol) in DMSO (300 mL) at 25 °C under N2 was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (31.74 g, 124.99 mmol), Pd(dppf)Cl2 (6.10 g, 8.33 mmol) and KOAc (20.44 g, 208.32 mmol). The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was filtered through a celite pad and the filtrate was diluted with H₂O (200 mL) and then extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 7:3) to give the titled compound. LCMS: m/z = 288.1 [M+H]⁺. [0272] 3-(pyridazin-3-yl)-4-(trifluoromethyl)aniline: To a solution of 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (15 g, 52.25 mmol) in 1,4-dioxane (150 mL) and H2O (10 mL) at 25 °C under N2 was added 3-bromopyridazine (9.97 g, 62.70 mmol), K2CO3 (21.66 g, 156.75 mmol) and Pd(dppf)Cl₂ (3.82 g, 5.22 mmol). The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled compound. LCMS: m/z = 240.1 [M+H]⁺. [0273] 2-fluoro-5-(pyridazin-3-yl)-4-(trifluoromethyl)aniline: To a solution of 3-(pyridazin-3-yl)-4- (trifluoromethyl)aniline (3.5 g, 14.63 mmol) in MeCN (40 mL) at 25 °C under N2 was added Selectfluor (6.22 g, 17.56 mmol). The reaction mixture was heated to 50 °C and stirred for 1.5 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled compound. LCMS: m/z = 258.1 [M+H]⁺. Intermediate 8 2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)aniline F O N F N yl- 1,3,2 dioxaborolan 2 yl) 4 (trifluoromethyl)aniline (3 g, 10.45 mmol) and 2 bromo 5 fluoro pyrimidine (2.22 g, 12.54 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) was added K2CO3 (3.61 g, 26.12 mmol) and Pd(dppf)Cl₂ (765 mg, 1.04 mmol) at 25 °C under N₂. The mixture was heated to 100 °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 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 = 258.1 [M+H]⁺. [0275] 2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)aniline: To a solution of 3-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)aniline (7.49 g, 27.22 mmol) in MeCN (70 mL) at 0 °C under N₂ was added Selectfluor (9.64 g, 27.22 mmol). The mixture was warmed to 25 °C and stirred for 2 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 prep-HPLC (Phenomenex luna C18100 × 40 mm × 5 μm; mobile phase: A: 0.2% FA in water, B: MeCN; B% in A: 35%-60%, over 8 min) to give the titled compound. LCMS: m/z = 276.0 [M+H]⁺. Intermediate 9 trans-6-((2-fluoro-4-methyl-5-(pyrimidin-2-yl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid [ 0276] 2 fluoro 4 methyl 5 (4,4,5,5 tetramethyl 1,3,2 dioxaborolan 2 yl)aniline: To a solution of 5- bromo-2-fluoro-4-methylaniline (20 g, 98.02 mmol) in 1,4-dioxane (600 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (37.34 g, 147.03 mmol), KOAc (28.86 g, 29406 mmol) and Pd(dppf)Cl2 (717 g 980 mmol) at 25 °C under N2 The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 15:1 to 10:1) to give the titled compound. LCMS: m/z = 252.1 [M+H]⁺. [0277] trans-6-((2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (1.18 g, 3.98 mmol) in THF (20 mL) at 0 °C under N2 was added dropwise 2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2 g, 2.14 mmol) and TEA (2.42 g, 23.89 mmol) in THF (30 mL). The mixture was warmed to 25 °C and stirred for 1 h. Then trans-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (8.25 g, 9.57 mmol, 18% purity) was added to the mixture followed by TEA (2.42 g, 23.89 mmol). Then the reaction solution was stirred at 25 °C for 12 h. The reaction was diluted with H2O (1 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18250 × 70 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water; B: MeCN; B% in A: 20%-50%, over 20 min) to give the titled compound. LCMS: m/z = 433.2 [M+H]⁺. [0278] trans-6-((2-fluoro-4-methyl-5-(pyrimidin-2-yl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of trans-6-((2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1- carboxylic acid (1.10 g, 2.45 mmol) in 1,4-dioxane (15 mL) and H₂O (1.5 mL) was added 2- bromopyrimidine (485 mg, 3.05 mmol), K2CO3 (1.06 g, 7.63 mmol) and Pd(dppf)Cl2 (186 mg, 0.25 mmol) at 25 °C under N2. The mixture was heated at 100 °C for 12 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH 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 = 385.0 [M+H]⁺.

Intermediate 10 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 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) was added (NH4)2CO3 (128.49 g, 1.34 mol) and KCN (43.54 g, 669 mmol) at 20 °C under N2. 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]⁺. [0280] (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) was added Ba(OH)2 (738 g, 4.31 mol) at 25 °C. The mixture was heated at 140 °C 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 celite pad and the filtrate was concentrated under reduced pressure to give the titled compounds. LCMS: m/z = 158.2 [M+H]⁺. [0281] 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) was added SOCl2 (227 g, 1.91 mol, 138.43 mL) at 0 °C under N2. The mixture was heated at 75 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compounds. LCMS: m/z = 172.2 [M+H]⁺. [0282] 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) was added DIEA (54.34 g, 420 mmol, 73.24 mL), DMAP (1.71 g, 14 mmol) and EDCI (40.30 g, 210 mmol) at 0 °C under N2. 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]⁺. [0283] 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) 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) at 25 °C under N₂. The mixture was heated to 145 °C and stirred for 16 h and then the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compound. LCMS: m/z = 275.2 [M+H]⁺. Intermediate 11 trans-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid [ ] y y y y ( g, 7 mol) in TMSCN (61 g, 0.61 mol) was added diiodozinc (15 g, 0.047 mol) at 0 °C under N2. The reaction was warmed to 20 °C and stirred for 3 h. Then a –78 °C solution of NH3 in MeOH (7M, 500 mL), formed by bubbling NH3(g) into MeOH at –78 °C, was added to the reaction mixture and stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with DCM (500 mL) at 20 °C for 20 min. Then the mixture was filtered and the filtrate was concentrated under reduced pressure to give the titled compound. [0285] 1-amino-3-methylcyclohexanecarboxylic acid hydrochloride: A solution of 1-amino-3- methylcyclohexanecarbonitrile (97 g, 0.70 mol) in HCl (10 M, 970 mL) was stirred at 100 °C for 12 h. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give the titled compound. LCMS: m/z = 158.2 [M+H]⁺. [0286] methyl 1-amino-3-methylcyclohexanecarboxylate hydrochloride: To a mixture of 1-amino-3- methylcyclohexanecarboxylic acid hydrochloride (94 g, 0.49 mol) in MeOH (940 mL) was added dropwise SOCl2 (106 mL, 1.46 mol) at 0 °C under N2. The mixture was then heated to 75 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the crude product was triturated with MTBE (1500 mL) at 20 °C for 30 min. Then the solid was filtered and the filter cake was dried under reduced pressure to give the titled compound. LCMS: m/z = 172.2 [M+H]⁺. [0287] methyl 3-methyl-1-(picolinamido)cyclohexanecarboxylate: To a mixture of methyl 1-amino-3- methylcyclohexanecarboxylate hydrochloride (79 g, 0.38 mol) and picolinic acid (61 g, 0.49 mol) in DCM (1500 mL) was added DIEA (147 g, 1.14 mol), DMAP (4.7 g, 0.038 mol) and EDCI (109 g, 0.57 mol) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (700 mL) and extracted with DCM (2 × 400 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (PE:EtOAc = 1:0 to 3:1) to give the titled compound. LCMS: m/z = 277.0 [M+H]⁺. [0288] methyl trans-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a mixture of methyl 3-methyl-1-(pyridine-2-carbonylamino)cyclohexanecarboxylate (30 g, 0.11 mol) in 1,1,2,2- tetrachloroethane (900 mL) was added Na3PO4 (53.40 g, 0.32 mol), 1,4-benzoquinone (5.87 g, 0.05 mol), AgOAc (54.36 g, 0.32 mol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (319 g, 1.09 mol) and Pd(OAc)₂ (4.87 g, 0.02 mol) in one portion at 20 °C under N₂. The mixture was stirred at 140 °C for 12 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to give the titled compound. LCMS: m/z = 275.0 [M+H]⁺. [0289] trans-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of methyl trans-3- methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (2 g, 0.007 mol) in EtOH (20 mL) was added NaOH (2.92 g, 0.072 mol) in one portion at 20 °C under N2. The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the EtOH and then the crude was adjusted to pH ~ 3–4 by addition of dilute aq. HCl. The solution was then lyophilized to give the titled compound. LCMS: m/z = 156.2 [M+H]⁺. Intermediate 12 cis-3-methyl-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptan-1-yl)-2-oxoacetate (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. Then 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. LCMS: m/z = 156.1 [M+H]⁺. [0291] methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a mixture of cis-3-methyl- 6-azabicyclo[3.1.1]heptane-1-carboxylic acid (9 g, 11.31 mmol, 19% purity) in MeOH (100 mL) at 0 °C under N2 was added SOCl2 (2.69 g, 22.62 mmol, 1.64 mL). 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]⁺. [0292] 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 (9.74 g, 10.93 mmol, 19% purity) in DCM (100 mL) and MeOH (10 mL) at 0 °C under N₂ was added DMAP (134 mg, 1.09 mmol), TEA (2.21 g, 21.86 mmol, 3.04 mL), and Boc₂O (4.77 g, 21.86 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 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 = 169.2 [M-Boc+H]⁺. [0293] tert-butyl cis-1-carbamoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: A mixture of 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate (1.8 g, 6.68 mmol) and NH₃•H₂O (20 mL) was stirred at 20 °C for 12 h. The reaction mixture was diluted with H₂O (20 mL) then filtered and dried under reduced pressure to provide the titled compound. LCMS: m/z = 199.2 [M-t- Bu+1]⁺. [0294] 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 (1.6 g, 6.29 mmol) in THF (20 mL) was added Burgess reagent (4.50 g, 18.87 mmol) at 20 °C under N2. The mixture was heated to 65 °C and stirred for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled compound. [0295] tert-butyl cis-1-(imino(methoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a mixture of tert-butyl cis-1-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (800 mg, 3.39 mmol) in MeOH (10 mL) was added NaOMe (610 mg, 3.39 mmol, 30% purity) at 0 °C under N2 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 = 269.3 [M+H]⁺. [0296] tert-butyl cis-1-carbamimidoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of tert-butyl cis-1-(imino(methoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (900 mg, 3.35 mmol) in MeOH (10 mL) was added NH4Cl (215 mg, 4.02 mmol) at 20 °C under N2. The mixture was heated to 80 °C and stirred for 3 h. The reaction was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 254.4 [M+H]⁺. [0297] tert-butyl cis-3-methyl-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of tert-butyl cis-1-carbamimidoyl-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (900 mg, 3.55 mmol) and (Z)-3-(dimethylamino)prop-2-enal (528 mg, 5.33 mmol) in EtOH (20 mL) was added K2CO3 (982 mg, 7.11 mmol) at 20 °C under N2. The mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) and further 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%, 8 min) to give the titled compound. LCMS: m/z = 290.3 [M+H]⁺. [0298] cis-3-methyl-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a mixture of tert-butyl cis-3-methyl-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (120 mg, 0.42 mmol) in DCM (3 mL) was added TFA (2.31 g, 20.26 mmol, 1.5 mL) at 20 °C under N₂ and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 190.4 [M+H]⁺. Intermediate 13 2-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)pyrimidine-5-carbonitrile ca bo y ate: o a tu e o te t buty cis ca ba doy 3 et y 6 a abcyc o[3. . ] epta e 6 carboxylate (650 mg, 2.57 mmol) and (E)-2-bromo-3-(dimethylamino)prop-2-enal (914 mg, 5.13 mmol) in EtOH (10 mL) under N2 was added K2CO3 (709 mg, 5.13 mmol). The mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled compound. LCMS: m/z = 368.0, 370.1 [M+H]⁺. [0300] tert-butyl cis-1-(5-cyanopyrimidin-2-yl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of tert-butyl cis-1-(5-bromopyrimidin-2-yl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (350 mg, 0.95 mmol) in DMF (6 mL) under N2 was added Zn(CN)2 (223 mg, 1.90 mmol), Pd(PPh3)4 (220 mg, 0.19 mmol). The mixture was heated to 130 °C and stirred for 12 h. The reaction mixture was cooled to 20 °C and diluted with H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 337.2 [M+Na]⁺. [0301] 2-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)pyrimidine-5-carbonitrile: To a mixture of tert-butyl cis-1-(5-cyanopyrimidin-2-yl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (110 mg, 0.35 mmol) in DCM (4 mL) was added TFA (3 g, 26.92 mmol, 2 mL). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 215.1 [M+H]⁺. Intermediate 14 cis 3 methyl 1 (135 triazin 2 yl) 6 azabicyclo[311]heptane trifluoroacetate [030 late: To a mixture of tert-butyl cis-1-(imino(methoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (363 mg, 4.47 mmol) in EtOH (10 mL) at 20 °C was added AcOH (269 mg, 4.47 mmol). The reaction mixture was heated to 80 °C and stirred for 12 h. Then the reaction mixture was adjusted to pH = 7–8 by addition of aq. sat. NaHCO₃ 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 = 3:1 to 0:1) to give the titled compound. LCMS: m/z = 191.3 [M–Boc+H]⁺. [0303] cis-3-methyl-1-(1,3,5-triazin-2-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a mixture of tert-butyl cis-3-methyl-1-(1,3,5-triazin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (170 mg, 0.29 mmol) in DCM (3 mL) at 20 °C was added TFA (1 mL) and the mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. Intermediate 15 cis-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate carboxylate: To a solution of tert-butyl cis-1-(imino(methoxy)methyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxylate (1.00 g, 0.78 mmol) in EtOH (15 mL) at 20 °C under N₂ was added N₂H₄•H₂O (291 mg, 5.70 mmol, 98% purity). The reaction mixture was heated to 80 °C and stirred for 2 h. Then the reaction was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 269.3 [M+H]⁺. [0305] tert-butyl cis-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of cis-1-(carbamohydrazonoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (300 mg, 1.12 mmol) in EtOH (10 mL) at 20 °C was added oxalaldehyde (811 mg, 5.59 mmol, 40% purity in H₂O). The reaction mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (15 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 1:1) to give the titled compound. LCMS: m/z = 291.2 [M+H]⁺. [0306] cis-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a solution of cis-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (20 mg, 0.69 mmol) in DCM (4 mL) at 20 °C was added TFA (2 mL) and the mixture was stirred for 1 h. Then the reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 191.2 [M+H]⁺. Intermediate 16 cis-1-((1H-pyrazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate N N N N B B B B mixture of 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate (2.5 g, 9.28 mmol) in MeOH (50 mL) at 0 °C under N2 was added NaBH4 (2.11 g, 55.69 mmol) and CaCl2 (4.12 g, 37.13 mmol). The mixture was heated to 50 °C and stirred for 2 h. The reaction mixture was diluted with aq. sat. NH₄Cl (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 186.2 [M–t-Bu+H]⁺. [0308] tert-butyl cis-3-methyl-1-(((methylsulfonyl)oxy)methyl)-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a mixture of tert-butyl cis-1-(hydroxymethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (500 mg, 2.07 mmol) and TEA (419.31 mg, 4.14 mmol) in DCM (10 mL) at 0 °C was added MsCl (356 mg, 3.11 mmol) and DMAP (25 mg, 0.21 mmol). The mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with aq. sat. NH₄Cl (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compound. [0309] tert-butyl cis-1-((1H-pyrazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a mixture of tert-butyl cis-3-methyl-1-(((methylsulfonyl)oxy)methyl)-6- azabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 0.63 mmol) in DMSO (5 mL) at 20 °C under N2 was added 1H-pyrazole (64 mg, 0.94 mmol) and t-BuONa (121 mg, 1.25 mmol). The mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with aq. Sat. NH₄Cl (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 2:1) to give the titled compound. LCMS: m/z = 292.2 [M+H]⁺. [0310] cis-1-((1H-pyrazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a mixture of tert-butyl cis-1-((1H-pyrazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (100 mg, 0.34 mmol) in DCM (6 mL) at 20 °C under N₂ was added TFA (4.62 g, 40.52 mmol, 3 mL) and the reaction was stirred for 1 h. The reaction was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 192.4 [M+H]⁺. Intermediate 17 cis-1-((4H-1,2,4-triazol-4-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate N N Boc ^O N carboxylate: To a mixture of tert-butyl cis-3-methyl-1-(methylsulfonyloxymethyl)-6- azabicyclo[3.1.1]heptane-6-carboxylate (1.80 g, 5.64 mmol) in DMF (30 mL) at 20 °C under N2 was added (1,3-dioxoisoindolin-2-yl)potassium (3.13 g, 16.91 mmol). The mixture was heated to 140 °C and stirred for 12 h. Then 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 = 5:1 to 2:1) to give the titled compound. [0312] tert-butyl cis-1-(aminomethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl cis-1-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (800 mg, 2.16 mmol) in EtOH (10 mL) at 20 °C was added N2H4•H2O (270 mg, 4.32 mmol) and the mixture was 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 = 241.2 [M+H]⁺. [0313] tert-butyl cis-1-((4H-1,2,4-triazol-4-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a solution of tert-butyl cis-1-(aminomethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (430 mg, 1.79 mmol) in toluene (10 mL) was added p-TsOH (308 mg, 1.79 mmol) and N'- [(E)-dimethylaminomethyleneamino]-N,N-dimethyl-formamidine (254 mg, 1.79 mmol) at 20 °C. The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex Gemini-NX C1875 × 30 mm × 3 μm; mobile phase: A: 10 mM NH₄HCO₃ in water; B: MeCN; B% in A: 15%-45%, 9 min) to give the titled compound. LCMS m/z = 293.2 [M+H]⁺. [0314] cis-1-((4H-1,2,4-triazol-4-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a mixture of tert-butyl cis-1-((4H-1,2,4-triazol-4-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (100 mg, 0.34 mmol) in DCM (3 mL) at 20 °C was added TFA (1.92 g, 16.83 mmol, 1.25 mL) and the reaction mixture was stirred for 2 h. Then the reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS m/z = 193.3 [M+H]⁺. Intermediate 18 cis-1-((1H-1,2,4-triazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate [ ne-6- c arboxylate: To a mixture of tert-butyl cis-3-methyl-1-(methylsulfonyloxymethyl)-6- azabicyclo[3.1.1]heptane-6-carboxylate (350 mg, 1.10 mmol) in DMSO (5 mL) at 20 °C under N₂ was added 1H-1,2,4-triazole (152 mg, 2.19 mmol) and t-BuONa (211 mg, 2.19 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. Then the reaction mixture was diluted with aq. sat. NH4Cl (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 2:1) to give the titled compound. LCMS m/z = 293.2 [M+H]⁺. [0316] cis-1-((1H-1,2,4-triazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a mixture of tert-butyl cis-1-((1H-1,2,4-triazol-1-yl)methyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxylate (180 mg, 0.62 mmol) in DCM (4 mL) at 20 °C was added TFA (3 g, 26.92 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. Intermediates 19 and 20 tert-butyl cis-1-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate and tert-butyl cis -1-((2H-1,2,3-triazol-2-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate [0317] To a mixture of tert-butyl cis-3-methyl-1-(((methylsulfonyl)oxy)methyl)-6- azabicyclo[3.1.1]heptane-6-carboxylate (1.1 g, 3.44 mmol) in DMSO (8 mL) at 20 °C under N₂ was added triazole (475 mg, 6.89 mmol) and t-BuONa (660 mg, 6.89 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 20 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 = 3:1 to 1:1) to give tert-butyl cis-1-((2H-1,2,3-triazol- 2-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (first eluting) and tert-butyl cis-1-((1H- 1,2,3-triazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (second eluting). LCMS: m/z = 293.4 [M +H]⁺. Intermediate 21 cis-1-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate [0318] To a solution -6- azabicyclo[3.1.1]hepta ne-6-carboxylate (278 mg, 0.95 μmol) in DCM (6 mL) at 25 °C was added TFA (2 mL) and the reaction mixture was stirred for 2 h. Then the reaction mixture was concentrated to give the titled compound. LCMS: m/z = 193.2 [M+H]⁺. Intermediate 22 cis-1-((2H-1,2,3-triazol-2-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate [0319] To a mixture of yl-6- azabicyclo[3.1.1]heptane-6-carboxylate (290 mg, 0.99 mmol) in DCM (6 mL) at 20 °C was added TFA (2 mL) and the reaction mixture was stirred for 1h. Then the reaction mixture was concentrated under reduced pressure to give the titled compound. Intermediate 23 7-azabicyclo[4.1.1]octane-1-carboxylic acid [0320] Methyl 1-aminocycloheptanecarboxylate hydrochloride: To a solution of 1- aminocycloheptanecarboxylic acid (1 g, 6.36 mmol) in MeOH (15 mL) was added SOCl₂ (3.78 g, 31.80 mmol) at 0 °C under N2. The mixture was heated to 65 °C and stirred for 12h. The reaction mixture was cooled to rt and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 172.2 [M+H]⁺. [0321] Methyl 1-(pyridine-2-carbonylamino)cycloheptanecarboxylate: To a solution of methyl 1- aminocycloheptanecarboxylate hydrochloride (1.1 g, 5.30 mmol) in DCM (10 mL) was added pyridine-2- carboxylic acid (978 mg, 7.94 mmol), DIEA (2.05 g, 15.89 mmol), DMAP (65 mg, 0.53 mmol) and EDCI (1.52 g, 7.94 mmol) at 25 °C under N₂ and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with H₂O (10 mL) and extracted with DCM (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 the titled compound. LCMS: m/z = 277.2 [M+H]⁺. [0322] Methyl 7-(pyridine-2-carbonyl)-7-azabicyclo[4.1.1]octane-1-carboxylate: To a solution of methyl 1-(pyridine-2-carbonylamino)cycloheptanecarboxylate (1.26 g, 4.56 mmol) in 1,1,2,2- tetrachloroethane (30 mL) was added Na₃PO₄ (2.24 g, 13.68 mmol), AgOAc (2.28 g, 13.68 mmol), p- benzoquinone (246 mg, 2.28 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (13.4 g, 45.60 mmol) and Pd(OAc)₂ (205 mg, 0.91 mmol) at 25 °C under N₂. The mixture was heated to 145 °C and stirred for 12 h. The reaction 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 = 100:1 to 1:1) to give the titled compound. LCMS: m/z = 275.1 [M+H]⁺. [0323] 7-azabicyclo[4.1.1]octane-1-carboxylic acid: To a solution of methyl 7-(pyridine-2-carbonyl)- 7-azabicyclo[4.1.1]octane-1-carboxylate (910 mg, 3.32 mmol) in EtOH (10 mL) was added NaOH (1.33 g, 33.17 mmol) at 25 °C. The mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to remove the EtOH and the resulting residue was diluted with H₂O (3 mL) and adjusted to pH = 4–5 by addition of HCl (3 M). The resulting solution was lyophilized to give the titled compound. LCMS: m/z = 156.1 [M+H]⁺. Intermediates 24 and 25 methyl-(1R,3S,5S)-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate and methyl (1S,3R,5R)-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate [0324] 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-6-((2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3- (trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid [0 (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]⁺. [0326] 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. The mixture 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. [0327] 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. [0328] 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]⁺. [0329] 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]⁺. [0330] 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. Intermediate 27 cis-3-cyclopropyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid [033 cyclopropylcyclohexanone (3 g, 21.71 mmol) in EtOH (20 mL) and H₂O (20 mL) at 20 °C under N₂ was added (NH₄)₂CO₃ (6.26 g, 65.12 mmol) and KCN (2.12 g, 32.56 mmol). The mixture was heated to 65 °C and stirred for 3 h. The reaction mixture was filtered, the filter cake was washed with H₂O three times and dried under reduced pressure to give the titled compound. LCMS: m/z = 209.2 [M+H]⁺. [0332] trans-1-amino-3-cyclopropylcyclohexane-1-carboxylic acid: To a solution of trans-7- cyclopropyl-1,3-diazaspiro[4.5]decane-2,4-dione (3 g, 14.41 mmol) in H2O (40 mL) ) at 20 °C was added Ba(OH)2 (24.68 g, 144.05 mmol). The mixture was heated to 140 °C for 12 h in an autoclave. The mixture was then adjusted to pH = 3 by addition of 2 M H₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the titled compound. [0333] methyl trans-1-amino-3-cyclopropylcyclohexane-1-carboxylate hydrochloride: To a solution of trans-1-amino-3-cyclopropylcyclohexane-1-carboxylic acid (3 g, 16.37 mmol) in MeOH (50 mL) at 0 °C was added dropwise SOCl2 (9.74 g, 81.86 mmol, 5.95 mL). The mixture was heated to 75 °C and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 198.2 [M+H]⁺. [0334] methyl trans-3-cyclopropyl-1-(picolinamido)cyclohexane-1-carboxylate: To a solution of methyl trans-1-amino-3-cyclopropylcyclohexane-1-carboxylate hydrochloride (2.5 g, 10.70 mmol), pyridine-2-carboxylic acid (1.71 g, 13.90 mmol) in DCM (30 mL) at 0 °C under N₂ was added EDCI (3.08 g, 16.04 mmol), DMAP (130 mg, 1.07 mmol) and DIEA (4.15 g, 32.09 mmol, 5.59 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 = 303.2 [M+H]⁺. [0335] methyl cis-3-cyclopropyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a solution of methyl trans-3-cyclopropyl-1-(picolinamido)cyclohexane-1-carboxylate (900 mg, 2.98 mmol) in 1,1,2,2-tetracloroethane (30 mL) at 20 °C under N2 was added AgOAc (1.49 g, 8.93 mmol), 1,2,3,4,5- pentafluoro-6-iodo-benzene (8.75 g, 29.77 mmol), Pd(OAc)2 (66.83 mg, 0.30 mmol), benzoquinone (160.88 mg, 1.49 mmol) and Na3PO4 (1.46 g, 8.93 mmol). The 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 = 5: 1 to 1:1) to give the titled compound. LCMS: m/z = 301.1 [M+H]⁺. [0336] cis-3-cyclopropyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of methyl cis-3- cyclopropyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (500 mg, 1.66 mmol) in EtOH (10 mL) at 20 °C was added NaOH (666 mg, 16.65 mmol). The mixture was heated to 140 °C and stirred for 3 h in an autoclave. The mixture was concentrated under reduced pressure and the crude material was adjusted to pH = 5 by the addition of 3 M HCl and lyophilized to give the titled compound. LCMS: m/z = 182.2 [M+H]⁺.

Intermediate 28 cis-3-ethyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid [0 one (2 3 g, 182.26 mmol) in EtOH (120 mL) and H2O (120 mL) at 20 C under N2 was added (NH4)2CO3 (52.54 g, 547 mmol) and KCN (17.8 g, 273.39 mmol). The reaction mixture was heated to 65 °C and stirred for 4 h. The reaction mixture was filtered, the filter cake was washed with H₂O three times, and the filter cake was dried under reduced pressure to give the titled compound. LCMS: m/z = 197.2 [M+H]⁺. [0338] trans-1-amino-3-ethylcyclohexane-1-carboxylic acid: To a solution of trans-7-ethyl-1,3- diazaspiro[4.5]decane-2,4-dione in H2O (50 mL) at 20 °C was added Ba(OH)2 (26.19 g, 152.87 mmol). The mixture was heated to 140 °C and stirred for 12 h in an autoclave. The reaction mixture was adjusted to pH = 3 by the addition of 3 M H2SO4, filtered and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 172.2 [M+H]⁺. [0339] methyl trans-1-amino-3-ethylcyclohexane-1-carboxylate hydrochloride: To a solution of trans-1-amino-3-ethylcyclohexane-1-carboxylic acid (6 g, 35.04 mmol) in MeOH (60 mL) at 0 °C under N2 was added SOCl2 (20.84 g, 175.20 mmol). The reaction mixture was heated to 75 °C and stirred for 6 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 186.2 [M+H]⁺. [0340] methyl trans-3-ethyl-1-(picolinamido)cyclohexane-1-carboxylate: To a solution of methyl trans-1-amino-3-ethylcyclohexane-1-carboxylate hydrochloride (8 g, 36.08 mmol) in DCM (100 mL) at 0 °C was added picolinic acid (6.66 g, 54.12 mmol)，EDCI (10.38 g, 54.12 mmol), DMAP (440.79 mg, 3.61 mmol) and DIEA (13.99 g, 108.24 mmol). The mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (200 mL) and extracted with DCM (3 × 50 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 column chromatography (SiO2, PE:EtOAc = 4:1 to 1:1) to give the titled compounds. LCMS: m/z = 291.2 [M+H]⁺. [0341] methyl cis-3-ethyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate: To a solution of methyl trans-3-ethyl-1-(picolinamido)cyclohexane-1-carboxylate (4.6 g, 15.84 mmol) in 1,1,2,2- tetrachloroethane (135 mL) at 20 °C under N₂ was added AgOAc (7.93 g, 47.53 mmol), benzoquinone (856 mg, 7.92 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (46.57 g, 158.43 mmol), Na₃PO₄ (7.79 g, 47.53 mmol) and Pd(OAc)2 (711 mg, 3.17 mmol). The mixture was heated to 145 °C and stirred for 12 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc=4:1 to 1:1) to give the titled compound. LCMS: m/z = 289.1 [M+H]⁺. [0342] cis-3-ethyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of methyl cis-3-ethyl- 6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (800 mg, 2.77 mmol) in EtOH (15 mL) at 20 °C under N₂ was added NaOH (1.11 g, 27.74 mmol). The reaction mixture was heated to 90 °C and stirred for 12 h. The mixture was diluted with H₂O (10 mL) and concentrated under reduced pressure to remove EtOH. The mixture was quenched by the addition of 6 M HCl until pH = 4 and lyophilized to give the titled compound. LCMS: m/z = 170.2 [M+H]⁺. Intermediate 29 cis-1-(1-(4H-1,2,4-triazol-4-yl)ethyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate a solution of tert-butyl cis-1-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (500 mg, 2.12 mmol) in toluene (10 mL) at 0 °C was added MeMgBr (3 M in Et2O, 1.1 mL). The mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was cooled to 0 °C and MeOH (2 mL) was added and stirred for 0.2 h. NaBH₄ (88 mg, 2.33 mmol) was added to the reaction mixture and it was stirred at 0 °C for 1 h. The mixture was quenched at 0 °C by the addition of aq. sat. NH₄Cl (10 mL) and then concentrated under reduced pressure. The crude product was triturated with DCM:MeOH (v:v = 10:1, 30 mL) and the solid was collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m/z = 255.2 [M+H]⁺. [0344] tert-butyl cis-1-(1-(4H-1,2,4-triazol-4-yl)ethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate: To a solution of tert-butyl cis-1-(1-aminoethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (800 mg, 1.57 mmol) in toluene (2 mL) at 20 °C under N2 was added p-TsOH (812 mg, 4.72 mmol) and N'-((Z)-(dimethylamino)methylene)-N,N-dimethylformohydrazonamide (671 mg, 4.72 mmol). The reaction mixture was heated to 100 °C and stirred for 16 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 prep-TLC (SiO2, DCM:MeOH = 10:1) and further purified by prep- HPLC (Phenomenex Gemini-NX 75 × 30 mm × 3 μm; A: 10 mM FA in water, B: MeCN; B% in A: 20%-50%, 9 min) to give the titled compound. LCMS: m/z = 307.2 [M+H]⁺. [0345] cis-1-(1-(4H-1,2,4-triazol-4-yl)ethyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate: A solution of tert-butyl cis-1-(1-(4H-1,2,4-triazol-4-yl)ethyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxylate (70 mg, 0.23 mmol) in DCM (2 mL) at 20 °C was added TFA (0.5 mL) and the reaction mixture was stirred for 2 h and then concentrated under reduced pressure to give the titled compound. Intermediates 30 and 31 tert-butyl cis-3-methyl-1-((4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)methyl)-6- azabicyclo[3.1.1]heptane-6-carboxylate and tert-butyl cis-3-methyl-1-((4-(trifluoromethyl)-2H- 1,2,3-triazol-2-yl)methyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate [0346] To azabicyclo[ 3.1.1]heptane-6-carboxylate (200 mg, 0.63 mmol, a single unknown enantiomer prepared using the procedures described for Intermediate 16 and employing intermediate 24) and 4- (trifluoromethyl)-1H-1,2,3-triazole (172 mg, 1.25 mmol) in DMSO (10 mL) at 25 °C was added t- BuONa (120 mg, 1.25 mmol). The reaction mixture was heated to 140 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (15 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO₂, PE: EtOAc = 3:1) to give tert-butyl cis-3-methyl-1- ((4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate, Intermediate 30. LCMS: m/z = 361.0 [M+H]⁺ and tert-butyl cis-3-methyl-1-((4-(trifluoromethyl)-2H- 1,2,3-triazol-2-yl)methyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate, Intermediate 31, as single unknown enantiomers. LCMS: m/z = 361.0 [M+H]⁺. Intermediate 32 cis-3-methyl-1-((4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-azabicyclo[3.1.1]heptane trifluoroacetate [0347] To a so azol-1-yl)methyl)-6- azabicyclo[3.1.1]heptane-6-carboxylate (Intermediate 30, 30 mg, 0.08 mmol) in DCM (1 mL) at 25 °C was added TFA (0.3 mL) and the reaction mixture was stirred for 1 h before it was concentrated under reduced pressure to give the titled compound as a single unknown enantiomer. LCMS: m/z = 261.0 [M+H]⁺. Intermediate 33 cis-3-methyl-1-((4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl)methyl)-6-azabicyclo[3.1.1]heptane trifluoroacetate [0348] To a so l-2-yl)methyl)-6- azabicyclo[3.1. 1]heptane 6 carboxylate (Intermediate 31, 20 mg, 0.06 mmol) in DCM (1 mL) at 25 °C was added TFA (0.3 mL) and the reaction mixture was stirred for 1 h before it was concentrated under reduced pressure to give the titled compound as a single unknown enantiomer. LCMS: m/z = 261.0 [M+H]⁺. Intermediate 34 4-chloro-3-(1,2,4-triazin-3-yl)aniline mmol) in DMF (80 mL) at 0 °C was added MgCl2 (2.20 g, 23.10 mmol) and the reaction mixture was stirred for 0.5 h. NaSH (3.88 g, 69.30 mmol) was added to the reaction mixture at 0 °C and it was stirred for 2 h. The reaction mixture was diluted with H2O (500 mL) and the resulting solid was collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m/z = 249.9, 251.9 [M+H]⁺. [0350] 5-bromo-2-chlorobenzimidohydrazide: To a solution of 5-bromo-2-chloro- benzenecarbothioamide (2 g, 7.98 mmol) in EtOH (30 mL) at 25 °C was added N2H4•H2O (4.08 g, 79.83 mmol). The mixture was heated to 80 °C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 247.9, 249.9 [M+H]⁺. [0351] 3-(5-bromo-2-chlorophenyl)-1,2,4-triazine: To a solution of oxaldehyde (12.84 g, 88.53 mmol, 40% purity) in EtOH (50 mL) at 25 °C was added dropwise 5-bromo-2-chlorobenzimidohydrazide (4.4 g, 17.71 mmol). The reaction mixture was heated to 80 °C and stirred for 2 h before the reaction mixture was concentrated under reduce pressure. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc = 3:1 to 1:1) to give the crude product that was triturated with MTBE:PE (3:1, 30 mL) to give the titled compound. LCMS: m/z = 269.9, 271.9 [M+H]⁺. [0352] 4-chloro-3-(1,2,4-triazin-3-yl)aniline: To a solution of 3-(5-bromo-2-chlorophenyl)-1,2,4- triazine (800 mg, 2.96 mmol) and diphenylmethanimine (804 mg, 4.44 mmol) in 1,4-dioxane (15 mL) at 25 °C under N2 was added Cs2CO3 (1.93 g, 5.91 mmol), Xantphos (342 mg, 0.59 mmol) and Pd2(dba)3 (271 mg, 0.3 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 crude material was dissolved in THF (5 mL) at 25 °C and 2 M HCl (5 mL) was added and stirred for 1 h. The mixture was adjusted to pH = 7–8 by the addition of aq. sat. NaHCO₃. The aqueous phase was extracted with EtOAc (3 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 207.0 [M+H]⁺. Intermediate 35 2-methyl-5-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazole solution of 6-(tert-butyl) 1-methyl cis-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate (2 g, 7.43 mmol) (prepared from Intermediate 24 using the procedure described for Intermediate 12) in MeOH (25 mL) at 20 °C was added a solution of NaOH (594 mg, 14.85 mmol) in H₂O (5 mL). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was adjusted to pH = 4 by addition of 4 M aqueous HCl. The resulting aqueous mixture was extracted with DCM:MeOH = 10:1 (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]⁺. [0354] 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 (1.7 g, 6.67 mmol) in DMF (20 mL) at 0 °C under N₂ was added acetylhydrazine (987 mg, 13.33 mmol), HATU (4.8 g, 13.33 mmol) and DIEA (2.52 g, 19.98 mmol). The reaction 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 (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 212.2 [M-Boc+H]⁺. [0355] 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 (5.6 g, 5.30 mmol, 30% purity) in MeCN (30 mL) at 20 °C under N2 was added Cs2CO3 (6.91 g, 21.20 mmol) and p-TsCl (1.52 g, 7.95 mmol). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were 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]⁺. [0356] 2-methyl-5-(cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazole: To a solution of tert-butyl 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 under N2 was added TMSOTf (681 mg, 3.07 mmol) in DCM (3 mL). The reaction mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was quenched by addition of MeOH (0.5 mL) and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 194.2 [M+H]⁺. Examples 1 and 2 (1R,3R,5S)-N-(2-fluoro-4-methyl-5-(pyrimidin-2-yl)phenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol- 5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3S,5R)-N-(2-fluoro-4-methyl-5-(pyrimidin- 2-yl)phenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide N N H H N N N N N oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of trans-6-((2-fluoro-4- methyl-5-(pyrimidin-2-yl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (200 mg, 0.52 mmol) in DMF (3 mL) at 25 °C under N₂ was added (Z)-N'-hydroxyacetimidamide (57 mg, 0.78 mmol) and T3P (993 mg, 1.56 mmol, 50% purity in EtOAc). The mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 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-HPLC (Phenomenex C1880 × 40 mm × 3 μm; mobile phase: A: 10 mM NH4HCO3 in water; B: MeCN; B% in A: 30%-70%, over 8 min) to give the titled compound as a mixture of enantiomers. LCMS: m/z = 423.0 [M+H]⁺. [0358] (1R,3R,5S)-N-(2-fluoro-4-methyl-5-pyrimidin-2-ylphenyl)-3-methyl-1-(3-methyl-1,2,4- oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3S,5R)-N-(2-fluoro-4-methyl-5- pyrimidin-2-ylphenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide: The mixture of enantiomers was purified by SFC (DAICEL CHIRALPAK IG (250 mm × 30 mm × 10 μm); Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 45%-45%, 8 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give trans-N-(2-fluoro-4-methyl-5-(pyrimidin-2-yl)phenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 1. LCMS: m/z = 423.2 [M+H]⁺ and trans-N-(2-fluoro-4-methyl-5-(pyrimidin-2-yl)phenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 2. LCMS: m/z = 423.2 [M+H]⁺ Examples 3 and 4 (1S,3R,5R)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide F F N N H NH N N [ ] (( ( py y) y p y) y ) y azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (335 mg, 1.13 mmol) in THF (7 mL) at 0 °C under N2 was added dropwise a mixture of TEA (457 mg, 4.52 mmol) and 2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-methylaniline (500 mg, 2.26 mmol) in THF (7 mL). The mixture was stirred at 0 °C for 1 h. Then cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid hydrochloride (2.09 g, 2.55 mmol, 23.4% purity) and TEA (344 mg, 3.40 mmol) were added to the above mixture and then the reaction mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was diluted with H₂O (0.5 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Welch Xtimate C18250 × 70 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water; B: MeCN; B% in A: 5%-35%, over 20 min) to give the titled compound. LCMS: m/z = 403.2 [M+H]⁺. [0360] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-6-((2- fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1- carboxylic acid (380 mg, 0.99 mmol) and acetylhydrazide (110 mg, 1.48 mmol) in DMF (8 mL) at 0 °C under N₂ was added DIEA (255 mg, 1.98 mmol) and HATU (255 mg, 1.98 mmol). The mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 459.2 [M+H]⁺. [0361] cis-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-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-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (250 mg, 0.5 mmol) in MeCN (4 mL) at 25 °C under N2 was added p-TsCl (146 mg, 0.76 mmol) and Cs2CO3 (665 mg, 2.05 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO₂, PE:EE (EtOAc:EtOH = 3:1) = 1:1) to give the titled compound.¹H NMR (400 MHz, CDCl₃): d 8.66 (s, 2H), 8.59 (d, J = 8.4 Hz, 1H), 8.02 (br s, 1H), 7.00 (d, J = 11.6 Hz, 1H), 4.33 (t, J = 6 Hz, 1H), 3.01-2.90 (m, 2H), 2.83-2.70 (m, 1H), 2.58 (s, 3H), 2.46 (s, 3H), 2.30-2.17 (m, 1H), 1.79-1.73 (m, 1H), 1.55 (d, J = 8.4 Hz, 1H), 1.41-1.35 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H). LCMS: m/z = 441.2 [M+H]⁺. [0362] (1S,3R,5R)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was purified by SFC (ChiralPak IH, 250 mm × 30 mm × 10 μm; Mobile phase: A: CO₂, B: 0.1% NH₃H₂O in EtOH; B% in A: 33%-33%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give cis-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 3. LCMS: m/z = 441.2 [M+H]⁺ and cis-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 4. LCMS: m/z = 441.2 [M+H]⁺. Example 5 and 6 (1S,3R,5R)-N-(3-(5-fluoropyrimidin-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-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide F F N N H NH₂ N N azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (288 mg, 0.97 mmol) in THF (10 mL) at 0 °C under N2 was added a solution of 3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)aniline (500 mg, 1.94 mmol) and TEA (590 mg, 5.83 mmol) in THF (10 mL). The mixture was stirred at 0 °C for 1 h. Then to the reaction mixture was added cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (2.06 g, 2.65 mmol) and TEA (893 mg, 8.83 mmol) at 25 °C under N₂ and the reaction was stirred for an additional 1 h before concentrating under reduced pressure. The resulting residue was purified by prep-HPLC (Agela DuraShell C18250 × 70 mm×10 μm; mobile phase: A: 10 mM NH₄HCO₃ in water, B: MeCN; B% in A: 22%-52%, 17.0 min) to give the titled compound. LCMS: m/z = 439.1 [M+H]⁺. [0364] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(3-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis- 6-[[3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl]carbamoyl]-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (300 mg, 0.68 mmol) and acetylhydrazide (76 mg, 1.03 mmol) in DMF (10 mL) was added DIEA (177 mg, 1.37 mmol) and HATU (520 mg, 1.37 mmol) at 0 °C under N₂. The mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 495.1 [M+H]⁺. [0365] cis-N-(3-(5-fluoropyrimidin-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-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (200 mg, 0.40 mmol) in MeCN (12 mL) was added TsCl (116 mg, 0.60 mmol) and Cs₂CO₃ (527 mg, 1.62 mmol) at 25 °C under N₂. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-TLC (EtOAc) to give the titled compound. LCMS: m/z = 477.3 [M+H]⁺. [0366] (1S,3R,5R)-N-(3-(5-fluoropyrimidin-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-(5- fluoropyrimidin-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 IPA; %B in A: 50%-50%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give crude peak 1, which was further purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 5 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 27%-57%, 8 min) to give cis-N-[3-(5-fluoropyrimidin-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 5. LCMS: m/z = 477.2 [M+H]⁺ and cis-N-[3-(5-fluoropyrimidin-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 6. LCMS: m/z = 477.2 [M+H]⁺.

Examples 7 and 8 (1S,3R,5R)-N-(2-fluoro-5-(5-fluoropyrimidin-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-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide F F N N H NH₂ N N N N thyl- 6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (135 mg, 0.45 mmol) in THF (5 mL) was added dropwise a solution of 2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)aniline (250 mg, 0.91 mmol) and TEA (276 mg, 2.73 mmol) in THF (5 mL) at 0 °C under N₂.The mixture was stirred at 0 °C for 1 h. Then cis-3-methyl-6-azabicyclo[3.1.1]heptane-1- carboxylic acid (966 mg, 1.25 mmol) and TEA (252 mg, 2.49 mmol) were added to the mixture at 25 °C. The mixture was stirred at 25 °C for 1 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 NH4HCO3 in water, B: MeCN; B% in A: 15%-45%, over 20 min) to give the titled compound. LCMS: m/z = 457.1 [M+H]⁺. [0368] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis- 6-((2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (180 mg, 0.39 mmol) and acetylhydrazide (44 mg, 0.59 mmol) in DMF (2 mL) at 0 °C under N2 was added DIEA (102 mg, 0.79 mmol) and HATU (300 mg, 0.79 mmol). The mixture was warmed to 25 °C and stirred for 2 h. The reaction mixture was diluted with H₂O (15 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, EtOAc) to give the titled compound. LCMS: m/z = 513.4 [M+H]⁺. [0369] cis-N-(2-fluoro-5-(5-fluoropyrimidin-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- (acetamidocarbamoyl)-N-[2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl]-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (100 mg, 0.2 mmol) in MeCN (5 mL) at 25 °C was added Cs₂CO₃ (254 mg, 0.78 mmol) and TsCl (56 mg, 0.29 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, DCM:MeOH = 10:1) to give the titled compound. LCMS: m/z = 495.3 [M+H]⁺. [0370] (1S,3R,5R)-N-(2-fluoro-5-(5-fluoropyrimidin-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-(2- fluoro-5-(5-fluoropyrimidin-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 (DAICEL CHIRALPAK IG, 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 40%-40%, 8 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(2-fluoro-5-(5-fluoropyrimidin-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 7. LCMS: m/z = 495.2 [M+H]⁺ and cis-N-(2-fluoro-5-(5- fluoropyrimidin-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 8. LCMS: m/z = 495.1 [M+H]⁺.

Examples 9 and 10 (1S,3R,5R)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(pyrimidin-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide F N F NH₂ N H [03 aza bicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (110 mg, 0.40 mmol) in THF (3 mL) at 0 °C under N2 was added 3-(5-fluoropyrimidin-2-yl)-4-methylaniline (150 mg, 0.74 mmol) and TEA (299 mg, 2.95 mmol). The reaction mixture was warmed to 20 °C and stirred for 1 h. Then a solution of cis-3-methyl-1-pyrimidin-2-yl-6-azabicyclo[3.1.1]heptane trifluoroacetate (120 mg, 0.40 mmol) and TEA (141.27 mg, 1.40 mmol) in THF (2 mL) was added to the above mixture and stirred for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were 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 = 419.2 [M+H]⁺. [0372] (1S,3R,5R)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(pyrimidin-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (DAICEL CHIRALPAK OZ (250 mm × 25 mm × 10 μm); Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 50%-50%, 13 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(3-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 1 in SFC) Example 9. LCMS: m/z = 419.2 [M+H]⁺ and cis-N-(3-(5-fluoropyrimidin- 2-yl)-4-methylphenyl)-3-methyl-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 10. LCMS: m/z = 419.2 [M+H]⁺. Examples 11 and 12 (1S,3R,5R)-1-(5-cyanopyrimidin-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1-(5-cyanopyrimidin-2-yl)-N-(3-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide 6- azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (109.52 mg, 0.40 mmol) in THF (3 mL) at 0°C under N₂ was added 3-(5-fluoropyrimidin-2-yl)-4-methyl-aniline (150 mg, 0.74 mmol) and TEA (298.77 mg, 2.95 mmol). The reaction mixture was warmed to 20 °C and stirred for 1 h. Then a solution of 2-[cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl]pyrimidine-5-carbonitrile (172 mg, 0.52 mmol) and TEA (177 mg, 1.75 mmol) in THF (2 mL) was added and the reaction mixture was stirred for an additional 1 h. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give the titled compound. LCMS: m/z = 444.1 [M+H]⁺. [0374] (1S,3R,5R)-1-(5-cyanopyrimidin-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1-(5-cyanopyrimidin-2-yl)-N-(3- (5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: The racemic mixture of cis-1-(5-cyanopyrimidin-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide was separated by SFC (DAICEL CHIRALCEL OD (250 mm × 30 mm × 10 μm); mobile phase: A: CO₂, B: 0.1% NH₃H₂O in IPA; B% in A: 50%-50%, 13 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-1-(5-cyanopyrimidin-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 11. LCMS: m/z = 444.2 [M+H]⁺ and cis-1-(5-cyanopyrimidin-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 12. LCMS: m/z = 444.2 [M+H]⁺. Example 13 cis-1-(3-amino-1,2,4-oxadiazol-5-yl)-N-(2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of triphosgene (73 mg, 0.25 mmol) in THF (3 mL) at 0 °C under N₂ was added dropwise a solution of 2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)aniline (100 mg, 0.49 mmol) and TEA (149 mg, 1.47 mmol) in THF (3 mL). The reaction mixture was stirred at 0 °C for 1 h and then cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (300 mg crude, 50% purity) was added to the reaction mixture. The mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep- HPLC (column: Welch Xtimate C18250 × 70mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 1%-30%, 20 min) to give the titled compound. LCMS: m/z = 386.2 [M+H]⁺. [0376] cis-N¹-cyano-N⁶-(2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1,6-dicarboxamide: To a mixture of cis-6-((2-fluoro-4-methyl-5-(1,2,4- triazin-3-yl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (250 mg, 0.65 mmol) in DMF (7 mL) at 0 °C under N₂ was added (cyanoamino)sodium (207 mg, 3.25 mmol), DIEA (419 mg, 3.24 mmol) and HATU (740 mg, 1.95 mmol). The mixture was warmed to 25 °C and stirred for 24 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by p-HPLC (Waters Xbridge Prep OBD C18150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 20%-50%, 8 min) to give the titled compound. LCMS: m/z = 410.2 [M+H]⁺. [0377] cis-1-(3-amino-1,2,4-oxadiazol-5-yl)-N-(2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)phenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-N¹-cyano-N⁶-(2-fluoro-4- methyl-5-(1,2,4-triazin-3-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1,6-dicarboxamide (110 mg, 0.27 mmol) in EtOH (5 mL) was added NH2OH•HCl (93 mg, 1.34 mmol) and pyridine (128 mg, 1.61 mmol) at 25 °C. The reaction mixture was warmed to 35 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM:i-PrOH (v:v=3:1) (3 × 15 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 Attorney Docket No.: 95BK-350635-WO NCO-029-09-WO phase: A: 10 mM NH₄HCO₃ in water, B: MeCN; B% in A: 25%-55%, 8 min) to give the titled compound. LCMS: m/z = 425.2 [M+H]⁺. Examples 14 and 15 (1S,6R)-N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)- 7-azabicyclo[4.1.1]octane-7-carboxamide and (1R,6S)-N-(3-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-7-azabicyclo[4.1.1]octane-7- carboxamide azabicyclo[4.1.1]octane-1-carboxylic acid: To a solution of triphosgene (288 mg, 0.972 mmol) in THF (15 mL) at 0 °C under N2 was added dropwise a solution of TEA (590 mg, 5.83 mmol) and 3-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)aniline (500 mg, 1.94 mmol) in THF (15 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was warmed to 25 °C and a solution of 7- azabicyclo[4.1.1]octane-1-carboxylic acid (548 mg, 3.53 mmol) in THF (30 mL) was added, followed by TEA (357 mg, 3.53 mmol). The reaction mixture was stirred for 12 h. The reaction was quenched by addition of H₂O (1 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 NH₄HCO₃ in water, B: MeCN; B% in A: 10%-40% over 20 min) to give the titled compound. LCMS: m/z = 439.2 [M+H]⁺. [0379] 1-(acetamidocarbamoyl)-N-[3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl]-7- azabicyclo[4.1.1]octane-7-carboxamide: To a solution of 7-[[3-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl]carbamoyl]-7-azabicyclo[4.1.1]octane-1-carboxylic acid (250 mg, 0.57 mmol) in DMF (2 mL) at 25 °C under N₂ was added acetylhydrazine (63 mg, 0.855 mmol), HATU (434 mg, 1.14 mmol) and DIEA (221 mg, 1.71 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (SiO2, PE:EtOAc = 3:1 to 0:1) to provide the titled compound. LCMS: m/z = 495.1 [M+H]⁺. [0380] N-[3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl]-1-(5-methyl-1,3,4-oxadiazol-2-yl)- 7-azabicyclo[4.1.1]octane-7-carboxamide: To a solution of 1-(acetamidocarbamoyl)-N-[3-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl]-7-azabicyclo[4.1.1]octane-7-carboxamide (120 mg, 0.243 mmol) in MeCN (2 mL) at 25 °C was added Cs₂CO₃ (316 mg, 0.97 mmol) and TsCl (69 mg, 0.364 mmol). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EE (EtOAc:EtOH = 3:1) = 1:1) to give the titled compound. LCMS: m/z = 477.1 [M+H]⁺. [0381] (1S,6R)-N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)-7-azabicyclo[4.1.1]octane-7-carboxamide and (1R,6S)-N-(3-(5-fluoropyrimidin-2- yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-7-azabicyclo[4.1.1]octane-7- carboxamide: The mixture of enantiomers was separated by SFC (REGIS (s,s) WHELK-O1, 250 mm × 30 mm, 5 μm; mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 45%-45%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give N- (3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-7- azabicyclo[4.1.1]octane-7-carboxamide (peak 1 in SFC) Example 14. LCMS: m/z = 477.0 [M+H]⁺ and N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-7- azabicyclo[4.1.1]octane-7-carboxamide (peak 2 in SFC) Example 15. LCMS: m/z = 477.0 [M+H]⁺. Examples 16 and 17 (1S,3R,5R)-1-((2H-1,2,3-triazol-2-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1-((2H-1,2,3-triazol-2-yl)methyl)- N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide F F N N H methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (110 mg, 0.37 mmol) in THF (8 mL) at 0 °C was added TEA (149 mg, 1.48 mmol) and 3-(5-fluoropyrimidin-2-yl)-4- methylaniline (150 mg, 0.74 mmol). The reaction mixture was stirred at 0 °C for 1 h. Then cis-1-((2H- 1,2,3-triazol-2-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate (301 mg, 0.98 mmol) and TEA (199 mg, 1.96 mmol) in THF (2 mL) were added to the reaction mixture. The reaction mixture was warmed to 20 °C and stirred for 1 h. To the reaction mixture was added three drops of water, then the mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge Prep OBD, C18, 150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH₄HCO₃ in water, B: MeCN; B% in A: 35%-65%, over 8.0 min) to give the titled compound. LCMS: m/z = 422.3 [M+H]⁺. [0383] (1S,3R,5R)-1-((2H-1,2,3-triazol-2-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1-((2H-1,2,3- triazol-2-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALCEL OZ 250 × 25 mm I.D.10 μm; mobile phase: A: CO₂, B: 0.1% NH₃H₂O in MeOH; B% in A: 45%, Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give the first eluting isomer that was further purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; gradient: 35%-65% B over 8.0 min to provide cis-1-((2H-1,2,3-triazol-2-yl)methyl)-N-(3-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 16. LCMS: m/z = 422.1 [M+H]⁺ and cis-1-((2H-1,2,3-triazol-2-yl)methyl)-N-(3-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 17. LCMS: m/z = 422.1 [M+H]⁺. Examples 18 and 19 (1S,3R,5R)-1-((1H-1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1- ((1H-1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl- 6-azabicyclo[3.1.1]heptane-6-carboxamide F F N N H (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (57.69 mg, 0.19 mmol) in THF (3 mL) at 0 °C was added 3-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)aniline (100 mg, 0.39 mmol) and TEA (118 mg, 1.17 mmol) in THF (2 mL). The reaction mixture was stirred at 0 °C for 1 h. Then cis-1-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-6- azabicyclo[3.1.1]heptane trifluoroacetate (81 mg, 0.26 mmol) and TEA (54 mg, 0.53 mmol) were added to the solution at 20 °C and stirred for 1 h. The reaction mixture was quenched by addition of three drops of water before concentrating under reduced pressure. The resulting residue was purified by prep-TLC (SiO₂, DCM:MeOH = 10:1) to give the titled compound. LCMS: m/z = 476.4 [M+H]⁺. [0385] (1S,3R,5R)-1-((1H-1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1- ((1H-1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl- 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: 25%-25%, 4 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 125 bar) to give cis-1-((1H-1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 18. LCMS: m/z = 476.4 [M+H]⁺ and cis-1-((1H-1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2- yl)-4-(trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 19. LCMS: m/z = 476.4 [M+H]⁺. Examples 20 and 21 (1S,3R,5R)-N-(3-(1,2,4-triazin-3-yl)-4-(trifluoromethyl)phenyl)-1-((1H-1,2,3-triazol-1-yl)methyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(1,2,4-triazin-3-yl)-4- (trifluoromethyl)phenyl)-1-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide N ^N _H N NH₂ N N N methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (74 mg, 0.25 mmol) in THF (3 ml) at 0 °C under N2 was added TEA (150 mg, 1.50 mmol) and (1,2,4-triazin-3-yl)-4- (trifluoromethyl)aniline (120 mg, 0.5 mmol) and the reaction mixture was stirred for 1 h. Then cis-1- ((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate (180 mg, 0.94 mmol) was added to the solution at 25 °C and stirred for 2 h. The reaction mixture was quenched by addition of three drops of water and then concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO₂, EtOAc) to give the titled compound. LCMS: m/z = 459.2 [M +H]⁺. [0387] (1S,3R,5R)-N-(3-(1,2,4-triazin-3-yl)-4-(trifluoromethyl)phenyl)-1-((1H-1,2,3-triazol-1- yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(1,2,4-triazin- 3-yl)-4-(trifluoromethyl)phenyl)-1-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (Column: REGIS (s,s) WHELK-O1 (250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 50%-50%, 10 min; Flow rate: 80 g/min; Wavelength:220 nm; Column temperature: 40 °C; System back pressure: 100 bar)) to give cis-3-methyl-N-[3-(1,2,4-triazin-3-yl)-4- (trifluoromethyl)phenyl]-1-(triazol-1-ylmethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 20. and cis-3-methyl-N-[3-(1,2,4-triazin-3-yl)-4-(trifluoromethyl)phenyl]-1-(triazol-1- ylmethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 21. LCMS: m/z = 459.2 [M+H]⁺. Examples 22 and 23 (1S,3R,5R)-1-((4H-1,2,4-triazol-4-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1-((4H-1,2,4-triazol-4-yl)methyl)- N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide F F N N H NH N N [0 3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (65 mg, 0.22 mmol) in THF (2 mL) at 0 °C under N2 was added 3-(5-fluoropyrimidin-2-yl)-4-methyl-aniline (100 mg, 0.49 mmol) and TEA (199 mg, 1.97 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h, then cis-1-((4H-1,2,4-triazol-4-yl)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane (100 mg, 0.33 mmol) and TEA (141.27 mg, 1.40 mmol) was added to the reaction and stirred for an additional 1 h. The reaction was quenched by the addition of two drops of water and then concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO₂, EtOAc) to give the titled compound. LCMS: m/z = 422.2 [M+H]⁺. [0389] (1S,3R,5R)-1-((4H-1,2,4-triazol-4-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1-((4H-1,2,4- triazol-4-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (Column: REGIS (s,s) WHELK-O1, 250 mm × 30 mm, 5 μm; Mobile phase: A: CO₂, B: 0.1% NH₃H₂O in MeOH; B% in A: 50%-50%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar)) to give cis-1-((4H-1,2,4-triazol-4-yl)methyl)-N-(3-(5-fluoropyrimidin-2- yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 22. LCMS m/z = 422.2 [M+H]⁺ and cis-1-((4H-1,2,4-triazol-4-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 23. LCMS m/z = 422.2 [M+H]⁺. Examples 24 and 25 (1S,3S,5R)-N-(3-(5-fluoropyrimidin-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,3R,5S)-N-(3-(5-fluoropyrimidin- 2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide F F N N H NH₂ N N azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of triphosgene (288 mg, 0.97 mmol) in THF (15 mL) at 0 °C was added dropwise a solution of 3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)aniline (500 mg, 1.94 mmol) and TEA (393 mg, 3.89 mmol) in THF (15 mL). The reaction mixture was warmed to 20 °C and stirred for 1 h. Then trans-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (400 mg, 1.41 mmol) and TEA (286 mg, 2.83 mmol) were added at 20 °C and stirred for an additional 1 h. The reaction mixture was quenched by the addition of H₂O (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: 0.05% NH₃H₂O+10 mM NH₄HCO₃ in water, B: MeCN; B% in A: 20%-45% B over 20.0 min) to give the titled compound. LCMS: m/z = 439.2 [M+H]⁺. [0391] trans-1-(2-acetylhydrazine-1-carbonyl)-N-(3-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of trans-6-((3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (210 mg, 0.48 mmol) and acetylhydrazine (53 mg, 0.72 mmol) in DMF (5 mL) at 0 °C was added DIEA (124 mg, 0.96 mmol) and HATU (364 mg, 0.96 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. Then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), 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 = 495.3 [M+H]⁺. [0392] trans-N-(3-(5-fluoropyrimidin-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 mixture of trans-1-(2- acetylhydrazine-1-carbonyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (100 mg, 0.20 mmol) in MeCN (4 mL) at 20 °C was added Cs2CO3 (263.59 mg, 0.81 mmol) and TsCl (58 mg, 0.30 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 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 = 477.0 [M+H]⁺. [0393] (1S,3S,5R)-N-(3-(5-fluoropyrimidin-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,3R,5S)-N-(3-(5- fluoropyrimidin-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-3, 50 × 4.6 mm I.D, 3 μm); mobile phase: A: CO₂, B: 0.1% NH₃H₂O in EtOH; B% in A: 50%-50%, Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give trans-N-(3-(5-fluoropyrimidin-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 24. and trans-N-(3-(5-fluoropyrimidin-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 25.

Examples 26 and 27 (1S,3R,5R)-N-(2-fluoro-5-(pyridazin-3-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-(2-fluoro-5- (pyridazin-3-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide H N _N ^NH ₂ N N N N azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (375 mg, 1.26 mmol) in THF (20 mL) was added a solution of TEA (767 mg, 7.58 mmol) and 2-fluoro-5-(pyridazin-3-yl)-4- (trifluoromethyl)aniline (650 mg, 2.53 mmol) in THF (20 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (2.35 g, 3.03 mmol) and TEA (767 mg, 7.58 mmol) were added to the above mixture at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of H₂O (0.5 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Welch Xtimate C18250 × 100 mm × 10 μm; mobile phase: A: 10 mM NH₄HCO₃ in water, B: MeCN; B% in A: 5%-40%, 20 min) to give the titled compound. LCMS: m/z = 439.1 [M+H]⁺. [0395] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(2-fluoro-5-(pyridazin-3-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis- 6-((2-fluoro-5-(pyridazin-3-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (780 mg, 1.78 mmol) in DMF (6 mL) was added acetylhydrazine (198 mg, 2.67 mmol)，DIEA (690 mg, 5.34 mmol) and HATU (1.35 g, 3.56 mmol) at 25 °C and the mixture was 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 (10 mL), dried over anhydrous Na₂SO₄ filtered and concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (EtOAc) to give the titled compound. LCMS: m/z = 495.1 [M+H]⁺. [0396] cis-N-(2-fluoro-5-(pyridazin-3-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-(2-fluoro-5-(pyridazin-3-yl)-4-(trifluoromethyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (50 mg, 0.10 mmol) in MeCN (2 mL) was added p-TsCl (29 mg, 0.15 mmol) and Cs2CO3 (132 mg, 0.40 mmol) at 25 °C and the mixture was stirred for 12 h. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO₂, DCM:MeOH = 10:1) to give the titled compound. LCMS: m/z = 477.1 [M+H]⁺. [0397] (1S,3R,5R)-N-(2-fluoro-5-(pyridazin-3-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-(2-fluoro-5- (pyridazin-3-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 (DAICEL CHIRALCEL OZ, 250 mm × 25 mm × 10 μm; mobile phase: A: CO₂, B: 0.1% NH₃H₂O in MeOH; B% in A: 38%-38%, 12 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-N-(2-fluoro-5-(pyridazin-3-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 26. LCMS: m/z = 477.0 [M+H]⁺ and cis-N-(2-fluoro-5-(pyridazine-3-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 27. LCMS: m/z = 477.0 [M+H]⁺. Examples 28 and 29 (1S,3R,5R)-N-(3-(5-chloropyridazin-3-yl)-4-methylphenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (1R,3S,5S)-N-(3-(5-chloropyridazin-3-yl)-4-methylphenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide Cl O O H [ ] y (( y ( , , , y , , yl)phenyl)carbamoyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (637 mg, 2.14 mmol) in THF (10 mL) at 0°C under N₂ was added a solution of TEA (1.74 g, 17.16 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.29 mmol) in THF (10 mL) and the reaction mixture was stirred at 0 °C for 1 h. Then a solution of cis-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (4.31 g, 5.14 mmol) in THF (5 mL) and TEA (867 mg, 8.57 mmol) was added to the reaction solution and the mixture was warmed to 25 °C and stirred for 2 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (Welch Xtimate C18250 × 100 mm × 10 μm; mobile phase A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 10%-45%, 22 min) to give the titled compound. LCMS: m/z = 415.1 [M+H]⁺. [0399] cis-6-((3-(5-chloropyridazin-3-yl)-4-methylphenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of 3-methyl-6-[[4-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl]-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (370 mg, 0.89 mmol) and 3,5-dichloropyridazine (160 mg, 1.07 mmol) in 1,4-dioxane (15 mL) and H2O (1.5 mL) at 25 °C under N2 was added Pd(dppf)Cl2 (65 mg, 0.08 mmol) and K2CO3 (370 mg, 2.68 mmol). The reaction mixture was heated to 100 °C and stirred for 3 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 prep-HPLC (Phenomenex luna C18100 × 40 mm × 5 μm; mobile phase A: FA in water; B:MeCN; B% in A: 20%-60%, 8 min) to give the titled compound. LCMS: m/z = 401.1 [M+H]⁺. [0400] cis-N-(3-(5-chloropyridazin-3-yl)-4-methylphenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of 6-[[3-(5-chloropyridazin-3-yl)-4- methyl-phenyl]carbamoyl]-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (140 mg, 0.35 mmol) and N'-hydroxyacetamidine (39 mg, 0.52 mmol) in DMF (3 mL) at 25 °C under N₂ was added TEA (106 mg, 1.05 mmol) and T3P (667 mg, 1.05 mmol, 50% purity in EtOAc). The reaction mixture was heated to 90 °C and stirred for 12 h. Then the reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep- TLC (SiO2, EtOAc) to give the titled compound. LCMS: m/z = 439.2 [M+H]⁺. [0401] (1S,3R,5R)-N-(3-(5-chloropyridazin-3-yl)-4-methylphenyl)-3-methyl-1-(3-methyl-1,2,4- oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(5-chloropyridazin- 3-yl)-4-methylphenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide: The mixture of enantiomers was separated by SFC (DAICEL CHIRALCEL OD, 250 mm × 30 mm, 10 μm; mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 35%-35%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give N-(3-(5-chloropyridazin-3-yl)-4-methylphenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 28. and N-(3-(5-chloropyridazin-3- yl)-4-methylphenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide (Peak 2 in SFC) Example 29 which was further 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%, 8 min). The following compounds were made as described above or using similar procedures Examples 30 and 31 (1S,3R,5R)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-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-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide [0402] The mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 27%-27%, 13 min; Flow rate: 70 g/min; Wavelength:220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(3-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 30. LCMS: m/z = 423.1 [M+H]⁺ and cis-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 31. LCMS: m/z = 423.1 [M+H]⁺. Examples 32 and 33 (1S,3R,5R)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(4-methyl-3-(1,2,4-triazin-3-yl)phenyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5- yl)-N-(4-methyl-3-(1,2,4-triazin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide [0403] The mix p y ( 0 mm × 10 μm; Mobile phase: A: CO2, B: 0.1% NH3.H2O in MeOH; B% in A: 40%-40%, 11 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-3-methyl- 1-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(4-methyl-3-(1,2,4-triazin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane- 6-carboxamide (peak 1 in SFC) Example 32. LCMS: m/z = 406.1 [M+H]⁺ and cis-3-methyl-1-(3-methyl- 1,2,4-oxadiazol-5-yl)-N-(4-methyl-3-(1,2,4-triazin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 2 in SFC) Example 33. LCMS: m/z = 406.1 [M+H]⁺. Examples 34 and 35 (1S,3R,5R)-1-((1H-1,2,4-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1-((1H-1,2,4-triazol-1-yl)methyl)- N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide [0404] Th 0 mm × 30 mm × 5 μm ; mobile phase: A: CO2, B: 0.1% NH3H2O in IPA; B% in A: 45%-45%, 13 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-1- ((1H-1,2,4-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 34. LCMS: m/z = 422.2 [M+H]⁺ and cis-1-((1H-1,2,4-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 35.¹H NMR (400 MHz, CDCl3): δ 8.70 (s, 2H), 8.32 (s, 1H), 8.02 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 2.4, 8.4 Hz, 1H), 7.26-7.23 (m, 1H), 6.38-6.10 (m, 1H), 4.91-4.21 (m, 2H), 4.00 (t, J = 5.6 Hz, 1H), 2.55 (s, 3H), 2.59-2.42 (m, 2H), 2.24-2.12 (m, 2H), 1.44-1.32 (m, 2H), 1.16 (d, J = 8.4 Hz, 1H), 1.07 (d, J = 6.4 Hz, 3H). LCMS: m/z = 422.2 [M+H]⁺. Examples 36 and 37 (1S,3R,5R)-1-((1H-1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1-((1H-1,2,3-triazol-1-yl)methyl)- N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide [0405] T p y ( ( , ) , mm × 30 mm, 5 μm; mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 50%-50%, Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-1-((1H- 1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 36. LCMS: m/z = 422.2 [M+H]⁺ and cis-1-((1H-1,2,3-triazol-1-yl)methyl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 37.¹H NMR (400 MHz, MeOD): δ 8.83 (s, 2H), 7.90 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.45 (dd, J = 2.0, 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.89-4.87 (m, 1H), 4.62 (d, J = 14.8 Hz, 1H), 4.17-4.12 (m, 1H), 2.59-2.47 (m, 2H), 2.44 (s, 3H), 2.12-1.99 (m, 2H), 1.50-1.31 (m, 2H), 1.16 (d, J = 8.8 Hz, 1H), 1.09 (d, J = 6.4 Hz, 3H). LCMS: m/z = 422.1 [M+H]⁺. Examples 38 and 39 (1R,3S,5S)-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-1-(5-cyclopropyl-1,3,4- oxadiazol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide [0406] Th mm, 10 μm; Mobile phase: A: CO₂, B: 0.1% NH₃H₂O in EtOH; B% in A: 25%-25%, 4 min; Flow rate: 3.4 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 125 bar) to give cis-1-(5- cyclopropyl-1,3,4-oxadiazol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 38. LCMS: m/z = 449.4 [M+H]⁺ and cis-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 39. LCMS: m/z = 449.4 [M+H]⁺. Examples 40 and 41 (1R,3S,5S)-1-(5-ethyl-1,3,4-oxadiazol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-1-(5-ethyl-1,3,4-oxadiazol-2-yl)- N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide [0407] The m mm, 10 μm, Mobile phase: A: CO2, B: 0.1% NH3H2O in IPA; B% in A: 50%-50%, 8 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-1-(5-ethyl- 1,3,4-oxadiazol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 40. LCMS: m/z = 437.2 [M+H]⁺ and cis-1-(5-ethyl-1,3,4-oxadiazol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 41. LCMS: m/z = 437.2 [M+H]⁺. Examples 42 and 43 (1S,3S,5R)-N-[3-(5-fluoropyrimidin-2-yl)-4-methylphenyl]-3-methyl-1-[5-(trifluoromethyl)-1,3,4- oxadiazol-2-yl]-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3R,5S)-N-[3-(5-fluoropyrimidin- 2-yl)-4-methylphenyl]-3-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-6- azabicyclo[3.1.1]heptane-6-carboxamide [0408] The mm × 5 μm; Mobile phas e: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 45%-45%, 8 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give trans-N-(3-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 42. LCMS: m/z = 477.2 [M+H]⁺ and trans-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 43. LCMS: m/z = 477.2 [M+H]⁺. Examples 44 and 45 (1R,3S,5S)-N-[2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)phenyl]-3-methyl-1-(3-methyl-1,2,4-oxadiazol- 5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-N-[2-fluoro-4-methyl-5-(1,2,4- triazin-3-yl)phenyl]-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide [0409] The mix 0 mm, 10 μm; Mobile phase: A: CO₂, B: 0.1% NH₃H₂O in MeOH; B% in A: 22%-22%, 15 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(2- fluoro-4-methyl-5-(1,2,4-triazin-3-yl)phenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 44. LCMS: m/z = 424.1 [M+H]⁺ and cis-N-(2-fluoro-4-methyl-5-(1,2,4-triazin-3-yl)phenyl)-3-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 45. LCMS: m/z = 424.1 [M+H]⁺. Examples 46 and 47 (1R,3S,5S)-N-[3-(5-fluoropyrimidin-2-yl)-4-methylphenyl]-3-methyl-1-(pyrazol-1-ylmethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3R,5R)-N-[3-(5-fluoropyrimidin-2-yl)-4- methylphenyl]-3-methyl-1-(pyrazol-1-ylmethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide [0410] The 50 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 50%-50%, 13 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis- N-[3-(5-fluoropyrimidin-2-yl)-4-methylphenyl]-3-methyl-1-(pyrazol-1-ylmethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 46. LCMS: m/z = 421.2 [M+H]⁺ and cis-N-[3-(5-fluoropyrimidin-2-yl)-4-methylphenyl]-3-methyl-1-(pyrazol-1-ylmethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 47. LCMS: m/z = 421.2 [M+H]⁺. Examples 48 and 49 (1R,3R,5S)-N-[2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl]-3-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1S,3S,5R)-N-[2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-methylphenyl]-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide F F N H N H [0411] The m , 250 mm × 30 mm, 10 μm; mobile phase: A: CO₂, B: 0.1% NH₃H₂O in IPA; B% in A: 43%-43%, 12 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give trans- N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 48. LCMS: m/z = 441.2 [M+H]⁺ and trans-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 49. LCMS: m/z = 441.2 [M+H]⁺. Examples 50 and 51 (1S,3R,5R)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(1,3,5-triazin-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-1-(1,3,5-triazin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide F F N H N H N N N N N N N [0412] Th mm × 30 mm, 10 μm; mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 50%-50%, Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(3-(5- fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(1,3,5-triazin-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide (Peak 1 in SFC) Example 50. LCMS: m/z = 420.2 [M+H]⁺ and cis-N-(3-(5-fluoropyrimidin- 2-yl)-4-methylphenyl)-3-methyl-1-(1,3,5-triazin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 51. LCMS: m/z = 420.2 [M+H]⁺. Examples 52 and 53 (1S,3R,5R)-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(1,2,4-triazin-3-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(5-fluoropyrimidin-2-yl)-4- methylphenyl)-3-methyl-1-(1,2,4-triazin-3-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide F F N H N H [0413] Th 250 mm × 30 mm × 10 μm; Mobile phase: A: CO₂, B: 0.1% NH₃H₂O in MeOH; B% in A: 40%-40%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(1,2,4-triazin-3-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 52. LCMS: m/z = 420.1 [M+H]⁺ and cis-N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-3-methyl-1-(1,2,4-triazin-3-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 53. LCMS: m/z = 420.1 [M+H]⁺. Examples 54 and 55 (1S,3R,5R)-N-(3-(1,2,4-triazin-3-yl)-4-(trifluoromethyl)phenyl)-1-(5-ethyl-1,3,4-oxadiazol-2-yl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(3-(1,2,4-triazin-3-yl)-4- (trifluoromethyl)phenyl)-1-(5-ethyl-1,3,4-oxadiazol-2-yl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide N H N H N N N N N N N N [0414] The m, 10 μm; Mobile phas e: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 50%-50%, 7 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give cis-N-(3- (1,2,4-triazin-3-yl)-4-(trifluoromethyl)phenyl)-1-(5-ethyl-1,3,4-oxadiazol-2-yl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 54. LCMS: m/z = 474.0 [M+H]⁺ and cis-N-(3-(1,2,4-triazin-3-yl)-4-(trifluoromethyl)phenyl)-1-(5-ethyl-1,3,4-oxadiazol-2-yl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 55. LCMS: m/z = 474.0 [M+H]⁺. Examples 56 and 57 (1S,3R,5R)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(2- fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-3- (trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide [0415] cis-6-((2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3- (trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of triphosgene (291 mg, 0.98 mmol) in THF (15 mL) at 0 °C under N2 was added 2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)aniline (600 mg, 2.18 mmol) and TEA (883 mg, 8.72 mmol) in THF (15 mL). The mixture was warmed to 20 °C and stirred for 2 h. cis-3-(Trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1- carboxylic acid (3.84 g, 2.19 mmol) and TEA (739 mg, 7.30 mmol) was added and stirred for an additional 2 h. The reaction mixture was quenched by the addition of H2O (1 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Welch Xtimate C18250 × 70 mm × 15 μm; mobile phase: A: 10 mM FA in water; B: MeCN; B% in A: 50%-80%, over 20 min) to give the titled compound. LCMS: m/z = 511.2 [M+H]⁺. [0416] cis-6-((2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3- (trifluoromethyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of cis-6-((2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (250 mg, 0.49 mmol) and acetylhydrazine (54 mg, 0.74 mmol) in DMF (5 mL) at 20 °C was added HATU (373 mg, 0.98 mmol) and DIEA (127 mg, 0.98 mmol). The mixture was stirred for 2 h before it was diluted with H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled compound. LCMS: m/z = 567.2 [M+H]⁺. [0417] cis-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis- 6-((2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)carbamoyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (150 mg, 0.27 mmol) in MeCN (3 mL) at 20 °C was added p- TsCl (76 mg, 0.40 mmol), Cs₂CO₃ (345 mg, 1.06 mmol). The mixture was stirred for 2 h before it was diluted with H₂O (5 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 = 549.1 [M+H]⁺. [0418] (1S,3R,5R)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (DAICEL CHIRALPAK IG 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 50%-50%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-N-(2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)- 6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 56. LCMS: m/z = 549.0 [M+H]⁺ and cis-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol- 2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 57. LCMS: m/z = 549.0 [M+H]⁺. Examples 58 and 59 (1S,3R,5R)-3-cyclopropyl-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-3- cyclopropyl-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide [0419] Pr ntiomers was separ ated by SFC (DAICEL CHIRALPAK IG 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 50%-50%, 10 min; Flow rate: 70 g/min; Wavelength:220 nm; Column temperature: 40 °C; System back pressure: 100 bar)) to give cis-3-cyclopropyl-N-(2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 58. LCMS: m/z = 521.0 [M+H]⁺ and cis-3-cyclopropyl-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide) (Peak 2 in SFC) Example 59. LCMS: m/z = 521.0 [M+H] ⁺. Examples 60 and 61 (1S,3R,5R)-3-ethyl-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl- 1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-3-ethyl-N-(2- fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide [0420] Pre p p g nantiomers was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 µm), mobile phase: A: CO2 and B: IPA (0.1%NH₃H₂O), gradient: B%=50% isocratic elution mode, flow rate: 70 g/min, monitor wavelength: 220 & 254 nm, column temperature: 40 ℃, system back pressure: 100 bar) to give cis-3-ethyl-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 60. LCMS: m/z = 509.1 [M+H]⁺ and cis-3-ethyl-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 61. LCMS: m/z = 509.2 [M+H]⁺. Examples 62 and 63 (1S,3R,5R)-N-(4-chloro-3-(1,2,4-triazin-3-yl)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-(4-chloro-3-(1,2,4-triazin-3-yl)phenyl)- 3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide [0421] The mi mm, 10 μm; Mobile phase: A : CO₂, B: 0.1% NH₃H₂O in EtOH; B% in A: 40%-40%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-N-(4- chloro-3-(1,2,4-triazin-3-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 62. LCMS: m/z = 426.0 [M+H]⁺ and cis-N-(4-chloro-3-(1,2,4-triazin-3-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 63. LCMS: m/z = 426.0 [M+H]⁺. Examples 64 and 65 (1S,3R,5R)-1-((S)-1-(4H-1,2,4-triazol-4-yl)ethyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1- ((R)-1-(4H-1,2,4-triazol-4-yl)ethyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide F F F N N H [0422] ci (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (97 mg, 0.33 mmol) in THF (6 mL) at 0 °C under N₂ was added 2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)aniline (200 mg, 0.77 mmol) and TEA (294 mg, 2.91 mmol) in THF (6 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was used directly in next step. Then a mixture of TEA (34 mg, 0.33 mmol) and 3-methyl-1-[1-(1,2,4-triazol-4-yl)ethyl]-6- azabicyclo[3.1.1]heptane trifluoroacetate (69 mg, 0.22 mmol) in THF (3 mL) was added to the above solution. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM:MeOH = 10:1) to give the titled compound. LCMS: m/z = 508.2 [M+H]⁺. [0423] (1S,3R,5R)-1-((S)-1-(4H-1,2,4-triazol-4-yl)ethyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-1- ((R)-1-(4H-1,2,4-triazol-4-yl)ethyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (DAICEL CHIRALPAK IG 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 50%-50%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give 1-(1-(4H-1,2,4-triazol-4- yl)ethyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (Peak 1 in SFC) Example 64. LCMS: m/z = 508.1 [M+H]⁺ and 1-(1-(4H-1,2,4-triazol-4-yl)ethyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (Peak 2 in SFC) Example 65. LCMS: m/z = 508.1 [M+H]⁺. Example 66 1-(-1-(4H-1,2,4-triazol-4-yl)ethyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4- (trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide [0424] The title compound from a mixture of diastereomers which was prepared using the procedures described for Intermediates 12 and 29 employing intermediate 24. The separation was performed by SFC (DAICEL CHIRALPAK IG 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 40%-40%, 10 min; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to provide the titled compound (Peak 1 in SFC). LCMS: m/z = 508.2 [M+H]⁺. Example 67 and 68 (1S,3R,5R)-3-ethyl-N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-3-ethyl-N-(3-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide [0425] Th 50 mm × 30 mm, 10 μm ; Mobile phase: A: CO₂, B: 0.1% NH₃.H₂O in EtOH; B% in A: 30% 30%; Flow rate: 70 g/min; Wavelength:220 nm; Column temperature: 35 °C; System back pressure: 120 bar)) to give cis-3- ethyl-N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 67. LCMS: m/z = 491.1 [M+H]⁺ and cis-3-ethyl-N-(3-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)- 6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 68. LCMS: m/z = 491.1 [M+H]⁺. Examples 69 and 70 (1S,3R,5R)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(1,2,4- triazol-4-ylmethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(2-fluoro-5-(5- fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-1-(1,2,4-triazol-4-ylmethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide [0426] T p y ( ( ) ( 0 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3.H2O in i-PrOH; B% in A: 45%-45%; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-1-((4H-1,2,4-triazol-4-yl)methyl)-N-(2-fluoro-5-(5-fluoropyrimidin-2-yl)-4-(trifluorometh yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 69. LCMS: m/z = 494.1 [M+H]⁺ and cis-1-((4H-1,2,4-triazol-4-yl)methyl)-N-(2-fluoro-5- (5-fluoropyrimidin-2-yl)-4-(trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 70. LCMS: m/z = 494.1 [M+H]+. [0427] The following compounds were, or can be, made via similar procedures as those described herein. Ex. Structure LCMS Ex. Structure LCMS Example 81 N-(4-chloro-3-(5-methoxypyrimidin-2-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide O H OH O N O N H N N B ^NO ₂ ^{B NH} ₂ ^NH ₂ N HO HO N C_l ^O - chloro-5-nitro-phenyl)boronic acid (10.8 g, 53.63 mmol) in MeOH (210 mL). The fixed bed (1/4 SS, volume 5 mL) was completely packed with granular catalyst 1% Pt/C(WXC1043). The H2 back pressure regulator was adjusted to 1.0 MPa, and the flow rate of H2 was 30 mL/min. Then the solution S1 was pumped by Pump 1 {S1, P1, 0.3 mL/min} to fixed bed {FLR1, SS, fixed bed, 6.350(1/4'') mm, 5 mL, 40 °C}. The solution S1 was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 172.0 [M+H]⁺. [0429] 4-chloro-3-(5-methoxypyrimidin-2-yl)aniline: To a solution of 2-chloro-5-methoxypyrimidine (506 mg, 3.50 mmol) and (5-amino-2-chlorophenyl)boronic acid (500 mg, 2.92 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) at 25 °C under N2 was added K2CO3 (1.01 g, 7.29 mmol) and Pd(dppf)Cl2 (213 mg, 0.29 mmol). The mixture was heated to 100 °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 = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 236.1 [M+H]⁺. [0430] N-(4-chloro-3-(5-methoxypyrimidin-2-yl)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 (13 mg, 0.04 mmol) in THF (1 mL) at 0 °C under N₂ was added TEA (32 mg, 0.32 mmol) and 4-chloro-3-(5-methoxypyrimidin- 2-yl)aniline (25 mg, 0.11 mmol). The reaction mixture was stirred at 0 °C for 1 h and then 2-methyl-5- (cis-3-methyl-6-azabicyclo[3.1.1]heptan-1-yl)-1,3,4-oxadiazole (intermediate 34, 117 mg, 0.11 mmol, single unknown enantiomer prepared from intermediate 24) in THF (1 mL) was added to the above reaction mixture. The mixture was warmed to 25 °C and stirred for 3 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 (3 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: WePure Biotech XP C18150 × 40 × 70 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 25%-55% over 8.0 min) and further prep-TLC (SiO2, DCM:MeOH = 10:1) to give the titled compound as a single unknown enantiomer. LCMS: m/z = 455.2 [M+H]⁺. [0431] The following compounds were made via similar procedures as those described herein. Ex. Structure LCMS Biochemical Assay of the Compounds [0432] Preparation of full-length SARM1 (FL-SARM1) lysate: HEK293T cells (ATCC: CRL-3216) were grown on 150 mm TC-treated dishes to 80-90% confluency in complete DMEM (DMEM (Thermo Fisher: 11965175) supplemented with 10% HI-FBS (VWR: 10802-772), 1x Pen/Strep (Thermo Fisher: 15140122), 1x NEAA (Thermo Fisher: 1140050), 1x glutamax (Thermo Fisher: 35050061), and 1 mM sodium pyruvate (Thermo Fisher: 11360070)) at 37 °C and 5% CO₂. One hour prior to transfection, the media was replaced with fresh, 37 °C complete DMEM (20 mL per one 150 mm dish) supplemented with additional 10mM glucose (Alfa Aesar AAJ60067EQE). Per one 150 mm dish, 30 mg FL-SARM1 (SEQ. ID.1; cloned in-house) plasmid was dissolved in 1 mL DMEM at ambient temperature and were mixed by inverting the tube 8-10 times.90 µL of GenJet™ in vitro DNA transfection reagent (Ver2) was dissolved in 1 mL DMEM at ambient temperature and were mixed by inverting the tube 8-10 times. The plasmid and transfection agent solutions were combined, mixed by 8-10 inversions and incubated for 10 minutes at ambient temperature.2 mL of this transfection mixture was added to each dish containing HEK293T cells as prepared above followed by a gentle mixing of 4-5 horizontal rotations. The dishes were incubated at 37^°C and 5% CO₂ for 24 h. The dishes were removed from the incubator, the medium was aspirated and the cells were scraped off using cell scrapers in ice-cold 1x PBS (5 mL/dish, Thermo Fisher Scientific 10010023). The collected cells were centrifuged at 300 g for 5 minutes at 4 °C. The supernatant was aspirated and the pellet was frozen at -80 °C until needed. The cell pellet from 30 dishes was dissolved in 30 mL 1x PBS supplemented with 4 tablets of Complete, Mini EDTA-free protease inhibitor cocktail at 4 °C. This mixture was sonicated on ice for 10 minutes at 50% amplitude with a 1 second on/1 second off interval using a Model 120 sonicator (Thermo Fisher Scientific, FB120110). The lysate was centrifuged at 16000 g for 10 minutes at 4 °C. Batches with supernatant possessing NMN- dependent SARM1 activity were selected, pooled, and stored at -80 °C until used in the FL-SARM1 cellular lysate assay described below. [0433] To a white 384-well Proxiplate (PerkinElmer, PE-6008280) was added 50 nL/well of a DMSO solution containing test compounds followed by 7.5 mL/well of a 0.067 mg/mL solution of SARM1 cellular lysate in reaction buffer (DPBS containing CHAPSO (0.1%) and fatty acid free BSA (0.032%)). The plate was centrifuged for 1 minute at 1000 RPM and then placed in an incubator at 23 °C for 15 minutes. To the wells were added 2.5 mL/well of a solution containing 40 mM NAD⁺ and 4 mM nicotinamide mononucleotide (NMN) in reaction buffer. The plate was centrifuged for 1 min at 1000 RPM, the plate was sealed and placed in an incubator at 23 °C for 3.5 hours before adding 3.5 mL/well of NAD/NADH-Glo™ solution (preparation as described by Promega using the extended detection protocol). The plate was centrifuged for 1 minute at 1000 RPM and then incubated at 23 °C for 20 minutes.1 mL/well of a 3.625 mM solution of menadione in DMSO was added and the plate was centrifuged for 1 minute at 1000 RPM. Relative light units (RLU) were recorded using an Envision plate reader at a height of 6.5 mm. Percent inhibition was calculated as follows: % inhibition = (sample - low control) / (high control - low control) x 100. [0434] IC₅₀ values were calculated from an 11 point curve using ½ log dilutions using a four-parameter logistic regression curve fit. Activity of the tested compounds is provided in Table 3 below as follows: +++ = 0.0001 µM < IC50 < 1 µM; ++ = IC501-10 µM; + = IC50 > 10 µM. Table 3 tagtaggaggcttggtaggtttaagaatagtttttgctgtactttctatagtgaatagagttaggcaggg a t c a t c t g g g a c c t c c t c c g g g t C G G G G G G G T G G T C AAGGAGGTGGAGCGCGAGGTGGAGCGCTCGGGCACGCTGGCGCTCGTGGAGCCGCTTGTGGCCTCGCTGG ACCCTGGCCGCTTCGCCCGCTGTCTGGTGGACGCCAGCGACACAAGCCAGGGCCGCGGGCCCGACGACCT atcaacctctggattacaaaatttgtgaaagattgactggtattcttaactatgttgctccttttacgct atgtggatacgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctcc cgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaat Toll/interleukin-1 receptor motif-containing 1 (SARM1) by a candidate compound, said method comprising: providing a solution comprising a SARM1 protein and the candidate compound; adding to the solution nicotinamide mononucleotide (NMN) and nicotinamide adenine dinucleotide (NAD⁺); and measuring the amount of NAD⁺ remaining in solution to determine modulation of SARM1 by the candidate compound. [0437] In certain embodiments, the measuring comprises a fluorescent detection step. [0438] In certain embodiments, the SARM1 protein is a protein comprising at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 97%, or at least about 99% sequence homology to native SARM1 protein. [0439] In certain embodiments, the SARM1 protein comprises a fluorescent tag. [0440] In certain embodiments, the SARM1 protein is provided using SEQ. ID.1, or a derivative thereof. In certain embodiments, the derivative comprises at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 97%, or at least about 99% sequence homology to SEQ. ID.1. In certain embodiments, the SARM1 protein is provided using SEQ. ID.1. [0441] In certain embodiments, the candidate compound is an inhibitor of SARM1. [0442] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [0443] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claims. [0444] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. [0445] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

What is claimed is: 1. A compound of Formula I: or a pharmaceutica g, stereoisomer, tautomer, mixture of stereoisomers th e eo , w e e : each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; 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; L is a bond, C_1-4 alkylene, C_2-4 alkenylene, or C_2-4 alkynylene; R¹ is hydrogen, halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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; each R² is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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; or two R² together form a C3-10 cycloalkyl or heterocyclyl; wherein the C3-10 cycloalkyl or heterocyclyl is independently optionally substituted with one to five Z¹; R⁴ is hydrogen, halo, cyano, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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; R⁵ is hydrogen, halo, cyano, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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; each R⁶ is independently hydrogen, halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C_3-10 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is 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 Z^1a; each Z¹ is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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 Z^1a; each R¹² is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1b; each Z^1a is independently halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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 Z^1b; each R¹³ is independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1b; each Z^1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L¹-C1-6 alkyl, -L¹-C2-6 alkenyl, -L¹-C2-6 alkynyl, -L¹-C1-6 haloalkyl, -L¹-C3-10 cycloalkyl, -L¹-heterocyclyl, -L¹-aryl, or -L¹-heteroaryl; and each L¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O)₂-, -N(C_1-6 alkyl)-, -N(C_2-6 alkenyl)-, -N(C_2-6 alkynyl)-, -N(C_1-6 haloalkyl)-, -N(C_3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(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 Z^1b and L¹ is further independently optionally substituted with one to five halo, cyano, -OH, -SH, -NH₂, -NO₂, -SF₅, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. 2. The compound of claim 1, wherein X¹ is N. 3. The compound of claim 1 or 2, wherein X², X³, and X⁴ are CR⁶. 4. The compound of claim 1, wherein X² is N. 5. The compound of claim 1 or 4, wherein X¹, X³, and X⁴ are CR⁶. 6. The compound of claim 1, wherein X³ is N. 7. The compound of claim 1 or 6, wherein X¹, X², and X⁴ are CR⁶. 8. The compound of claim 1, 6, or 7, wherein X¹ is N and X² and X⁴ are CR⁶. 9. The compound of claim 1, wherein X⁴ is N. 10. The compound of claim 1 or 9, wherein X¹, X², and X³ are CR⁶. 11. The compound of claim 1 or 9, wherein X¹ is N and X² and X³ are CR⁶. 12. The compound of claim 1 or 9, wherein X² is N and X¹ and X³ are CR⁶. 13. The compound of claim 1 or 9, wherein X³ is N and X¹ and X² are CR⁶. 14. The compound of any preceding claim, wherein L is a bond or -CH₂-. 15. The compound of claim 1, wherein the mo s: . 16. n each R⁶ is independently hydrogen, halo, cyano, hydroxy, or -O-C_1-6 alkyl. 17. The compound of claim 1, wherein the moie s: C_3-10 cycloalkyl, wherein each C1-6 alkyl or C3-10 cycloalkyl is independently optionally substituted with one to five Z¹. 19. The compound of any preceding claim, wherein m is 0 or 1. 20. The compound of any preceding claims, wherein m is 0 or 1 and R² is methyl, ethyl, cyclopropyl, or trifluoromethyl. 21. The compound of any preceding claim, wherein m is 0 or 1 and R² is methyl. 22. The compound of any preceding claim, wherein n is 1 or 2. 23. The compound of any preceding claim, wherein Ring A is heteroaryl optionally substituted with one to five Z¹. 24. The compound of any one of claims 1-22, wherein Ring A is heterocyclyl optionally substituted with one to five Z¹. 25. The compound of any preceding claim, wherein each Z¹ is independently cyano, C1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, or -N(R¹²)₂. 26. The compound of any preceding claim, wherein each R¹² is hydrogen. 27. The compound of any preceding claim, wherein R⁴ is hydrogen. 28. The compound of any preceding claim, wherein R⁵ is hydrogen or halo. 30. The compound of claim 1, wherein the compound of Formula I is represented by Formula II: 31. The compound of cla s represented by Formula III: I. 32 The compound of an y p g C alkylene

33. The compound of any preceding claim, wherein R¹ is C_1-6 alkyl, optionally substituted with one to five Z¹. 34. The compound of any preceding claim, wherein each Z¹ is independently halo. 35. The compound of any preceding claim, wherein R¹ is C1-6 alkyl or C1-6 haloalkyl. 36. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof. 37. A compound selected from Table 2, or a pharmaceutically acceptable salt thereof. 38. 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. 39. A method for inhibiting SARM1 activity, the method comprising contacting a cell with an effective amount of a compound of any one of claims 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, the pharmaceutical composition of claim 38. 40. The method of claim 36, wherein the contacting is in vivo. 41. 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 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 38. 42. 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 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 38. 43. 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 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 38, to a subject in need thereof. 44. The method of claim 40, 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. 45. The method of claim 38, wherein the disease or condition is a spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe’s disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, Tay-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic complications of chemotherapy (chemotherapy induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, 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). 46. 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 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 38. 47. Use of a compound of any one of claims 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 38, for treating a disease or condition mediated, at least in part, by SARM1. 48. The use of claim 44, wherein the disease or condition is a spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe’s disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, Tay-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic complications of chemotherapy (chemotherapy induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic injury, Leber’s hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell’s palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T-lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motoneuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), 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). 49. A compound of any one of claims 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 38, for use in therapy. 50. A compound of any one of claims 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 38, 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 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). 51. The use of a compound of any one of claims 1-37, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 38, for the manufacture of a medicament for treating a spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital hypomyelination, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelolysis, osmotic hyponatremia, hypoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe’s disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, Tay-Sacks disease, Gaucher’s disease, Hurler Syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post radiation injury, neurologic complications of chemotherapy (chemotherapy induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic injury, Leber’s hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell’s palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, tropical spastic paraparesis human T- lymphotropic virus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motoneuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP), 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). 52. A process for providing a compound of Formula I, comprising contacting a compound of Formula I-1: with a compound of Formu under conditions sufficient to pro vide the compound of Formula I; wherein: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof wherein: each of X¹, X², X³, and X⁴ are independently N or CR⁶; provided no more than two of X¹, X², X³, and X⁴ are N; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; 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; L is a bond, C1-4 alkylene, C2-4 alkenylene, or C2-4 alkynylene; R¹ is hydrogen, halo, cyano, -NO₂, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(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; each R² is independently 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 the C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z¹; or two R² together form a C3-10 cycloalkyl or heterocyclyl; wherein the C3-10 cycloalkyl or heterocyclyl is independently optionally substituted with one to five Z¹; R⁴ is hydrogen, halo, cyano, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 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 C_1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z¹; R⁵ is 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z¹; each R⁶ is independently hydrogen, 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, is independently optionally substituted with one to five Z¹; each R¹¹ is 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 Z^1a; each Z¹ is 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 C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1a; each R¹² is 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 Z^1b; each Z^1a is 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1b; each R¹³ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z^1b; each Z^1b is independently halo, cyano, -OH, -SH, -NH₂, -NO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L¹-C_1-6 alkyl, -L¹-C_2-6 alkenyl, -L¹-C2-6 alkynyl, -L¹-C1-6 haloalkyl, -L¹-C3-10 cycloalkyl, -L¹-heterocyclyl, -L¹-aryl, or -L¹-heteroaryl; and each L¹ 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(C_1-6 haloalkyl)-, -C(O)N(C_3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)₂NH-; wherein each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z^1b and L¹ 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. 53. The process of claim 52, wherein the conditions comprise triphosgene.