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WO2025054369A1 - Compounds, compositions, and methods - Google Patents

Compounds, compositions, and methods Download PDF

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Publication number
WO2025054369A1
WO2025054369A1 PCT/US2024/045444 US2024045444W WO2025054369A1 WO 2025054369 A1 WO2025054369 A1 WO 2025054369A1 US 2024045444 W US2024045444 W US 2024045444W WO 2025054369 A1 WO2025054369 A1 WO 2025054369A1
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Prior art keywords
alkyl
heterocyclyl
cycloalkyl
alkenyl
alkynyl
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French (fr)
Inventor
Alex L. BAGDASARIAN
Cyril Bucher
Javier De Vicente Fidalgo
Anthony A. ESTRADA
Brian M. Fox
Benjamin J. HUFFMAN
Takashi Miyamoto
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Tenvie Therapeutics Inc
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Nico Therapeutics Inc
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Publication of WO2025054369A1 publication Critical patent/WO2025054369A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/08—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/38—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing five carbon atoms

Definitions

  • 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 + .
  • SARM1 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]
  • SARM1 compounds that inhibit SARM1.
  • 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.
  • 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.
  • 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.
  • SARM1 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.
  • alkynyl also includes those groups having one triple bond and one double bond.
  • 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.
  • Alkoxyalkyl refers to the group “alkyl-O-alkyl”.
  • 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.
  • 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.
  • Amino refers to the group -NR y 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.
  • Amino refers to -C(NR y )(NR z 2), 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.
  • 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.
  • 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 does not encompass or overlap in any way with heteroaryl defined below.
  • 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-”.
  • Carbamoyl refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NR y R z and an “N-carbamoyl” group which refers to the group -NR y C(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.
  • 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.
  • 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.
  • 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 sp 3 carbon atom (i.e., at least one non-aromatic ring).
  • 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.
  • 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.
  • 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.
  • spirocycloalkyl refers to the group “cycloalkyl-alkyl-”.
  • haloalkyl examples include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • 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.
  • 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.
  • Hydroalkyl 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.
  • 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.
  • heteroalkyl groups include, e.g., ethers (e.g., -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , etc.), thioethers (e.g., -CH 2 SCH 3 , -CH(CH 3 )SCH 3 , -CH 2 CH 2 SCH 3 ,-CH 2 CH 2 SCH 2 CH 2 SCH 3 , etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 , -CH(CH 3 )S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 , etc.), and amines (e.g., -CH 2 NR y CH 3 , -CH(CH 3 )NR y CH 3 , amine
  • 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.
  • 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.
  • “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.
  • 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.
  • 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).
  • 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.
  • 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., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 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.
  • ring carbon atoms i.e., C 2-20 heterocyclyl
  • 2 to 12 ring carbon atoms i
  • 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-ox
  • heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
  • 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.
  • 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.
  • Heterocyclylalkyl refers to the group “heterocyclyl-alkyl-.”
  • “Sulfonyl” refers to the group -S(O) 2 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.
  • 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.
  • “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.
  • 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.
  • “Sulfonamido” refers to the groups -SO 2 NR y R z and -NR y SO 2 R 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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 g R h , -NR g C(O)R h , -NR g C(O)NR g R h , -NR g C(O)OR h , -NR g S(O) 1-2 R h , -C(O)R g , -C(O)OR g , -OC(O)OR g ,
  • 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 g R h , -CH 2 SO2R g , or -CH 2 SO2NR g R h .
  • 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.
  • 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 R i 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.
  • 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.
  • substituted may describe other chemical groups defined 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.
  • Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • 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).
  • ADME drug metabolism and pharmacokinetics
  • the free base can be obtained by basifying a solution of the acid salt.
  • 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.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids.
  • each Z 1 is independently heteroaryl, oxo, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, or - OR 12 wherein each R 12 is independently hydrogen or C 1-6 alkyl optionally substituted with -OH or -NH 2 (e.g., -OR 12 is -OH, -OCH 2 CH 2 OH, or -OCH 2 CH 2 NH 2 ).
  • A is or wherein each is optionally substituted with one to five Z 1 .
  • each Z 1 is independently halo, cyano, C 1-6 alkyl, or C 1-6 haloalkyl.
  • R 1 is halo, -CH 2 NH 2 , -CH 3 , or -CF 3 .
  • R 1 is halo, -CH 3 , or -CF3.
  • each Z 1 is C 1-6 alkyl.
  • each R 11 is independently C 1-6 alkyl; wherein each C 1-6 alkyl is independently optionally substituted with one to five Z 1a .
  • each R 11 is independently C 1-6 alkyl; wherein each C 1-6 alkyl is independently optionally substituted with one to five halo.
  • each Z 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -OR 12 , -C(O)OR 12 or heteroaryl; wherein each C 1-6 alkyl, C 1-6 haloalkyl, or heteroaryl is independently optionally substituted with one to five Z 1a .
  • each R 12 is independently hydrogen or C 1-6 alkyl; wherein each C 1-6 alkyl is independently optionally substituted with one to five Z 1b .
  • each R 12 is independently C 1-6 alkyl; wherein each C 1-6 alkyl is independently optionally substituted with one to five Z 1b .
  • each Z 1a is independently halo or -OR 13 .
  • each R 13 is independently hydrogen or C 1-6 alkyl.
  • each Z 1b is independently halo.
  • each Z 1b is independently -OH or -NH 2 .
  • 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 Ex.
  • terapéuticaally 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.
  • 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.
  • the compounds provided herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof inhibits SARM1.
  • the compound is a compound of Formula I: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, or heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z 1 ; R is C 1-6 alkyl, -NR 2 R 3 , -OR 7 , C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z 1 ;
  • the compound is a compound of Formula I: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, or heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z 1 ; R is C 1-6 alkyl, -NR 2 R 3 , -OR 7 , C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z 1 ;
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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+.
  • 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.
  • 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.
  • the treating comprises reducing one or more symptoms or features of neurodegeneration.
  • a method for inhibiting axon degeneration 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.
  • a method for treating a neurodegenerative or neurological disease or disorder 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • the disease or condition is an acute condition. In certain embodiments, the disease or condition is a chronic condition. [0174] In certain embodiments, the disease or condition is characterized by axonal degeneration in the central nervous system, the peripheral nervous system, the optic nerve, the cranial nerves, or a combination thereof. [0175] In certain embodiments, the disease or condition is or comprises acute injury to the central nervous system, such as, but not limited to, injury to the spinal cord and/or traumatic brain injury (TBI). In certain embodiments, the disease or condition is or comprises a chronic injury to the central nervous system, such as, but not limited to, injury to the spinal cord, traumatic brain injury (TBI), and/or traumatic axonal injury (TAI).
  • TBI traumatic brain injury
  • TAI traumatic axonal injury
  • the disease or condition is or comprises chronic traumatic encephalopathy (CTE).
  • CTE chronic traumatic encephalopathy
  • 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.
  • the disease or condition is an acute peripheral neuropathy.
  • the disease or condition is chemotherapy-induced peripheral neuropathy (CIPN).
  • CIPN chemotherapy-induced peripheral neuropathy
  • Chemotherapy-induced 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).
  • 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., bor
  • 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.
  • the disease or condition is glaucoma (see, e.g., Ko, K.W., et al. J. Cell Bio.2020, 219(8), e201912047).
  • 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.
  • 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.
  • the disease or condition is associated with retinal degeneration.
  • the disease or condition is Leber congenital amaurosis, such as Leber congenital amaurosis type 9 (LCA9) (see, e.g., Sasaki, Y., et al.
  • 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.
  • one or more compounds and/or compositions as described herein are useful, for example to treat a neuropathy or axonopathy associated with axonal degeneration.
  • a neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy.
  • a neuropathy associated with axonal degeneration results from a de novo or somatic mutation.
  • a neuropathy associated with axonal degeneration is selected from a list contained herein.
  • 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.
  • 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.
  • a relevant symptom or feature may be selected from the group consisting of extent, rate, and/or timing of neuronal disruption.
  • 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.
  • neuronal disruption is characterized by an inability to maintain an appropriate resting neuronal membrane potential.
  • neuronal disruption is characterized by the appearance of inclusion bodies, plaques, and/or neurofibrillary tangles.
  • neuronal disruption is characterized by the appearance of stress granules.
  • neuronal disruption is characterized by the intracellular activation of one or more members of the cysteine-aspartic protease (Caspase) family.
  • neuronal disruption is characterized by a neuron undergoing programed cell death (e.g.
  • 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.
  • 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 brain injury (TB
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a neurodegenerative disease, disorder or condition may be or comprise a traumatic neuronal injury.
  • a traumatic neuronal injury is blunt force trauma, a closed-head injury, an open head injury, exposure to a concussive and/or explosive force, a penetrating injury into the brain cavity or innervated region of the body.
  • 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.
  • the DLK inhibitor is a small molecule.
  • the DLK inhibitor is a siRNA.
  • the DLK inhibitor is an antisense oligonucleotide.
  • the DLK inhibitor is a polypeptide.
  • a DLK inhibitor is a peptide fragment.
  • a DLK inhibitor is a nucleic acid. In certain embodiments, a DLK inhibitor is an antisense oligonucleotide.
  • 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.
  • 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.
  • the NAMPT inhibitor is a small molecule.
  • the NAMPT inhibitor is a siRNA.
  • the NAMPT inhibitor is an antisense oligonucleotide.
  • the NAMPT inhibitor is a polypeptide.
  • a NAMPT inhibitor is a peptide fragment.
  • 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).
  • SARM1 inhibition as described herein may be utilized in combination with one or more other therapies to treat a relevant disease, disorder, or condition.
  • 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.
  • compositions which comprise an additional therapeutic agent, that additional therapeutic agent and a provided compound may act synergistically.
  • 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.
  • 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).
  • a NAD + or a NAD + precursor e.g., nicotinamide riboside (NR), nicotinic acid (NA), nicotinic acid riboside (NaR), nicotinamide (NAM
  • SARM1 sterile alpha and TIR motif-containing protein 1
  • 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.
  • SARM1 sterile alpha and TIR motif-containing protein 1
  • 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.
  • 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 B 3 ).
  • NAD + or a NAD + precursor e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B 3 .
  • 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 B 3 ), in the manufacture of a medicament for treating or preventing a neurodegenerative disease in a subject in need thereof.
  • NAD + or a NAD + precursor e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B 3
  • 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).
  • NAD + or a NAD + precursor e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3
  • 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.
  • 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).
  • NAD + or a NAD + precursor e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3
  • Other embodiments include use of the presently disclosed compounds in therapy. 4.
  • 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.
  • a kit further includes instructions for use.
  • 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.
  • compositions and modes of Administration [0219] Compounds provided herein are usually administered in the form of pharmaceutical compositions.
  • 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.1 7t h Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3r d Ed. (G.S. Banker & C.T. Rhodes, Eds.).
  • 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.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • intra-arterial injection intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • parenteral for example, by injection.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • 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.
  • a carrier that can be in the form of a capsule, sachet, paper or other container.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • 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.
  • the amount of the compound in a pharmaceutical composition or formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below.
  • Formulation Example 1 - Tablet formulation [0229] The following ingredients are mixed intimately and pressed into single scored tablets.
  • Formulation Example 2 Capsule formulation [0230] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule
  • Formulation Example 3 Suspension formulation [0231] The following ingredients are mixed to form a suspension for oral administration.
  • Formulation Example 4 Injectable formulation [0232] The following ingredients are mixed to form an injectable formulation.
  • Formulation Example 5 Suppository Formulation [0233] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: 6.
  • 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.
  • a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate.
  • Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. 7. Synthesis of the Compounds [0235]
  • the compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art.
  • 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.
  • protecting groups for alcohols 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.
  • TMS trimethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TOM tri-iso- propylsilyloxymethyl
  • TIPS triisopropylsilyl
  • 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.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • 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).
  • Scheme I illustrates general methods which can be employed for the synthesis of compounds described herein (e.g., Formula I), where A, R, R 1 , R 4 , and R 5 are each independently as defined herein, and each LG is independently a leaving group (e.g., halo, alkoxy, etc.).
  • compounds of Formula I can be prepared by contacting compound I-1 with compound I-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required.
  • compounds of Formula I can be prepared by contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required.
  • compounds of Formula I can be prepared by contacting compound I-5 with a suitable functionalized precursor to the moiety A, under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required.
  • 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.
  • compounds of Formula I wherein R is -OR 7 can be prepared according to Scheme II, where A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are each independently as defined herein, and each LG is independently a leaving group (e.g., halo, alkoxy, etc.).
  • compounds of Formula IA can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide an acylated intermediate, followed by contacting the acylated intermediate with compound II-2, or a salt thereof.
  • Compounds of Formula I wherein R is -OR 7 can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide the acylated intermediate, followed by contacting the acylated intermediate with compound II-3. Upon each reaction completion, each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. [0245] It should be understood that any of the compounds or intermediates shown in Scheme II may be prepared using traditional methods or purchased from commercial sources. In addition, any of the intermediates or any product obtained by the process outlined in Scheme II can be derivatized at any step to provide various compounds of Formula I or IA.
  • 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.
  • a process for providing a compound of Formula I comprising: contacting a compound of Formula I-1: with a compound of Formula I-2: under conditions sufficient to provide the compound of Formula I; wherein A, R, R 1 , R 4 , and R 5 are each independently as defined herein.
  • a process for providing a compound of Formula I comprising: contacting a compound of Formula I-1: with a compound of Formula IA-2: under conditions sufficient to provide the compound of Formula IA; wherein A, R 1 , R 2 , R 3 , R 4 , and R 5 are each independently as defined herein.
  • the conditions comprise a phosgene reagent, e.g., triphosgene.
  • NMR Spectroscopy 1 H 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 1 H- 13 C 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.
  • NMR nuclear magnetic resonance
  • TLC Thin Layer Chromatography
  • TLC thin layer chromatography
  • 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.
  • the TLC plate was developed with iodine (generated by adding approximately 1 g of I 2 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) 2 Ce(IV)(NO3)6 in 450 mL water and 50 mL concentrated H2SO4) to visualize the compound.
  • iodine generated by adding approximately 1 g of I 2 to 10 g silica gel and thoroughly mixing
  • ninhydrin available commercially from Aldrich
  • Magic Stain generated by thoroughly mixing 25 g (NH4)6Mo7O24.4H2O, 5 g (NH4) 2 Ce(IV)(NO3)6 in 450 mL
  • LCMS was detected under 220 and 254 nm or used evaporative light scattering (ELSD) detection as well as positive electrospray ionization (MS).
  • Neutral Waters Xbridge 150 ⁇ 25, 5 ⁇ m; MPA: 10 mM NH4HCO3 in H2O; MPB: ACN.
  • 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 ⁇ m, 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.
  • LCMS: m/z 158.2 [M+H] + .
  • methyl trans-1-amino-3-methylcyclohexane-1-carboxylate hydrochloride To a mixture of trans-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 compound.
  • LCMS: m/z 172.2 [M+H] + .
  • methyl trans-3-methyl-1-(picolinamido)cyclohexane-1-carboxylate To a solution of methyl trans-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 irradiated with two 34 W blue LEDs (vials approximately 6 cm away from the light source) with a fan placed above for cooling for 16 h at 25 °C.
  • LCMS: m/z 182.0 [M+H] + .
  • tert-butyl (cis-2-(3-nitrophenyl)cyclobutane-1-carbonyl)(quinolin-8-yl)carbamate To a solution of cis-2-(3-nitrophenyl)-N-(quinolin-8-yl)cyclobutane-1-carboxamide (10 g, 28.79 mmol) in MeCN (100 mL) was added Boc2O (12.6 g, 57.58 mmol), DMAP (351.70 mg, 2.88 mmol) and TEA (5.9 g, 57.58 mmol) at 25 °C under N2. The mixture was stirred at 50 °C for 12 h.
  • cis-2-(3-nitrophenyl)cyclobutane-1-carboxamide To a solution of cis-2-(3- nitrophenyl)cyclobutane-1-carboxylic acid (3.2 g, 14.47 mmol) in DCM (30 mL) was added NH4Cl (1.6 g, 28.93 mmol), DIEA (5.7 g, 43.40 mmol), HOBt (3 g, 21.70 mmol) and EDCI (4.2 g, 21.70 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 12 h.
  • cis-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxamide To a mixture of cis-2-(2-methyl- 5-nitrophenyl)cyclobutane-1-carboxylic acid (300 mg, 1.28 mmol) and NH4Cl (81.86 mg, 1.53 mmol) in DMF (5 mL) was added DIEA (659 mg, 5.10 mmol), HOBt (207 mg, 1.53 mmol) and EDCI (293 mg, 1.53 mmol) at 20 °C under N2. The reaction mixture was stirred at 20 °C for 2 h.
  • ethyl cis-2-(5-((tert-butoxycarbonyl)amino)-2-chlorophenyl)cyclopropane-1-carboxylate To a solution of ethyl cis-2-(5-amino-2-chloro-phenyl)cyclopropanecarboxylate (1 g, 4.17 mmol) in MeCN (15 mL) was added Boc2O (1.8 g, 8.34 mmol), TEA (1.3 g, 12.52 mmol) and DMAP (51 mg, 0.41 mmol). The mixture was stirred at 25 °C for 12 h.
  • tert-butyl (4-chloro-3-(cis-2-cyanocyclopropyl)phenyl)carbamate To a solution of cis-2-(5- ((tert-butoxycarbonyl)amino)-2-chlorophenyl)cyclopropane-1-carboxylic acid (310 mg, 0.99 mmol) in THF (5 mL) was added Burgess reagent (475 mg, 2.00 mmol).
  • reaction mixture was heated to 70 °C and stirred for 4 h. Then the reaction mixture was filtered, washed with toluene (40 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene (100 mL) and triethyl phosphite (13.38 g, 80.54 mmol) was added at 25 °C. The reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 ⁇ 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • diethyl (2-(3-nitrophenyl)cyclobut-1-en-1-yl) phosphate To a solution of 2-bromocyclobut-1- en-1-yl diethyl phosphate (13.40 g, 47.01 mmol) in toluene (200 mL) at 25 °C under N2 was added (3- nitrophenyl)boronic acid (11.77 g, 70.51 mmol), K3PO4 (29.93 g, 141.02 mmol), RuPhos (4.39 g, 9.40 mmol) and Pd(OAc) 2 (1.06 g, 4.70 mmol).
  • the reaction mixture was heated to 60 °C and stirred for 12 h.
  • the reaction mixture was filtered through a Celite ⁇ pad and the filtrate was concentrated under reduced pressure.
  • the fixed bed (named FLR1, volume 5 mL) was packed with granular catalyst 1% Pt/C (3 g, 0.81 mmol).
  • the H 2 backpressure regulator was adjusted to 1.5 MPa, and the flow rate of H 2 was 30 mL/min.
  • 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, 50 °C) and the reaction mixture was collected from the reactor output. The reaction mixture was concentrated under reduced pressure.
  • reaction mixture was heated to 110 °C and stirred for 12 h.
  • the reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (3 ⁇ 10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • N-(3-(trifluoromethyl)cyclohexyl)picolinamide To a solution of (3- (trifluoromethyl)cyclohexanamine hydrochloride (210 mg, 1.03 mmol) in DCM (5 mL) at 0 °C under N 2 was added pyridine-2-carboxylic acid (165 mg, 1.34 mmol), DIEA (666 mg, 5.16 mmol) and T4P (1.11 g, 1.55 mmol, 50% w/w in EtOAc).
  • the reaction mixture was heated to 145 °C and stirred for 16 h.
  • the reaction mixture was cooled to 25 °C under N 2 and Pd(OAc) 2 (99 mg, 0.44 mmol) was added to the mixture.
  • the reaction mixture was warmed to 145 °C and stirred for 16 h.
  • the reaction mixture was filtered through a Celite ⁇ pad and the filtrate was concentrated under reduced pressure.
  • LCMS: m/z 271.1 [M+H] + .
  • the reaction mixture was heated to110 °C and stirred for 1 h.
  • the reaction mixture was diluted with H 2 O (100 mL) and extracted with MTBE (50 mL).
  • the combined organic layers were washed brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound.
  • benzyl cyclobut-1-enecarboxylate To a solution of cyclobut-1-enecarboxylic acid (4.8 g, 48.93 mmol) and TEA (14.85 g, 146.79 mmol) in THF (100 mL) at 0 °C was dropwise added methyl carbonochloridate (9.25 g, 97.86 mmol). The reaction mixture was warmed to 20 °C and stirred for 1 h. Benzyl alcohol (15.87 g, 146.79 mmol) was added and the reaction mixture was stirred at 20 °C for 1 h.
  • benzyl 2-(3-nitrophenyl)cyclobutanecarboxylate To a solution of benzyl cyclobut-1- enecarboxylate (5 g, 26.56 mmol) and (3-nitrophenyl)boronic acid (8.87 g, 53.13 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) at 25 °C under N2 was added TEA (8.06 g, 79.69 mmol) and [Rh(cod)Cl]2 (655 mg, 1.33 mmol). The reaction mixture was heated to 100 °C and stirred for 16 h.
  • Example 1 cis-N-(4-chloro-3-cyclobutyl-phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide [0330] cis-6-[(4-chloro-3-cyclobutyl-phenyl)carbamoyl]-3-methyl-6-azabicyclo[3.1.1]heptane-1- carboxylic acid: To a solution of bis(trichloromethyl) carbonate (163 mg, 0.55 mmol) in THF (3 mL) was added a solution of 4-chloro-3-cyclobutyl-aniline (200 mg, 1.10 mmol) and TEA (334 mg, 3.30 mmol) in THF (3 mL) at 0 °C under N2.
  • reaction mixture was stirred for 16 h at 25 °C and irradiated with two 34 W blue LEDs (vials approximately 6 cm away from the light source) with a fan placed above for cooling.
  • LCMS: m/z 216.1 [M+H] + .
  • the aqueous phase was extracted with EtOAc (3 ⁇ 50 mL).
  • the combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the titled compound.
  • benzyl cyclobut-1-ene-1-carboxylate To a solution of cyclobut-1-ene-1-carboxylic acid (9.5 g, 96.84 mmol) and TEA (29.40 g, 290.52 mmol) in THF (100 mL) was added dropwise methyl chloroformate (19.77 g, 209.17 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 1 h. Benzyl alcohol (31.42 g, 290.52 mmol) was added to above mixture at 0 °C under N 2 . The reaction mixture was stirred at 20 °C for 1 h.
  • benzyl 2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxylate To a solution of (2-methyl-5- nitrophenyl)boronic acid (7.69 g, 42.50 mmol) in 1,4-dioxane (60 mL) and H2O (6 mL) was added benzyl cyclobut-1-ene-1-carboxylate (4 g, 21.25 mmol), TEA (6.45 g, 63.75 mmol) and [RuCl(COD)]2 (1.05 g, 2.13 mmol) at 25 °C under N2. The mixture was stirred at 100 °C for 12 h.
  • trans-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxylic acid To a solution of benzyl 2-(2- methyl-5-nitrophenyl)cyclobutane-1-carboxylate (500 mg, 1.54 mmol) in 1,4-dioxane (10 mL) was added HCl (2M, 10 mL) at 20 °C. The mixture was stirred at 80 °C for 12 h.
  • trans-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxamide To a solution of trans-2-(2- methyl-5-nitrophenyl)cyclobutane-1-carboxylic acid (300 mg, 1.28 mmol) in DCM (4 mL) was added NH 4 Cl (82 mg, 1.53 mmol), DIEA (659 mg, 5.10 mmol), HOBt (207 mg, 1.53 mmol) and EDCI (293 mg, 1.53 mmol) at 0 °C under N 2 . The mixture was stirred at 20 °C for 16 h.
  • trans-2-(5-amino-2-methylphenyl)cyclobutane-1-carbonitrile To a mixture of trans-2-(2- methyl-5-nitrophenyl)cyclobutane-1-carbonitrile (150 mg, 0.69 mmol) and NH4Cl (186 mg, 3.47 mmol) in H2O (1 mL) and EtOH (5 mL) was added Fe (194 mg, 3.47 mmol) at 20 °C under N2. The mixture was stirred at 80 °C for 2 h and then filtered through a pad of Celite ⁇ .
  • Example 11 2-cyclobutyl-N-(3-cyclobutyl-4-methylphenyl)acetamide
  • N-(3-bromo-4-methylphenyl)-2-cyclobutylacetamide To a mixture of 3-bromo-4-methyl- aniline (4.89 g, 26.28 mmol) in DMF (50 mL) was added 2-cyclobutylacetic acid (3 g, 26.28 mmol), HATU (11.99 g, 31.54 mmol) and DIEA (13.59 g, 105.13 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h.
  • the reaction mixture was stirred for 16 h under 34 W blue LEDs (vials approximately 6 cm away from the light source) with a fan placed above for cooling.
  • 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 Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the resulting residue was purified by prep-HPLC (column: Phenomenex C1880 ⁇ 40 mm ⁇ 3 ⁇ m; mobile phase: A: NH 4 HCO 3 in water, B: MeCN; B% in A: 35%-65%, 8 min) to give the titled compound.
  • tert-butyl (3-cyclobutyl-4-methylphenyl)carbamate To a solution of tert-butyl (3-bromo-4- methylphenyl)carbamate (300 mg, 1.05 mmol) in DME (2 mL) was added bromocyclobutane (707 mg, 5.24 mmol), Na2CO3 (222 mg, 2.10 mmol) and NiCl2.glyme (1 mg, 0.01 mmol), 4,4-di-tert-butyl-2,2- dipyridyl (14 mg, 0.05 mmol), tris(trimethylsilyl)silane (260 mg, 1.05 mmol) and Ir[dF(CF3)ppy]2(dtbpy)(PF6) (11 mg, 0.01 mmol) at 20 °C under N2.
  • the reaction mixture was stirred for 16 h and irradiated with two 34 W blue LEDs (vials approximately 6 cm away from the light source) with a fan placed above for cooling.
  • LCMS: m/z 206.2 [M-t-Bu+H] + .
  • N-(3-cyclobutyl-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide To a mixture of CDI (59 mg, 0.36 mmol) in DCM (1 mL) was added a solution of 3-cyclobutyl-4-methylaniline hydrochloride (60 mg, 0.30 mmol) and TEA (30 mg, 0.30 mmol) in DCM (1 mL) at -20 °C under N2. The mixture was stirred at 20 °C for 1 h before TEA (31 mg, 0.31 mmol) and 6-azabicyclo[3.1.1]heptane (61 mg, 0.62 mmol) were added at 20 °C.
  • N-(3-(cyclopropylmethyl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide To a mixture of triphosgene (46 mg, 0.15 mmol) in THF (2 mL) was added TEA (94 mg, 0.93 mmol) and 3- (cyclopropylmethyl)-4-methylaniline (50 mg, 0.31 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h before 6-azabicyclo[3.1.1]heptane hydrochloride (53 mg, 0.41 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 12 h.
  • Example 14 N-(4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide [0368] To a mixture of CDI (48 mg, 0.3 mmol) in THF (3 mL) was added TEA (54 mg, 0.53 mmol) and 4-(5-amino-2-methylphenyl)-1-methylpyrrolidin-2-one (50 mg, 0.24 mmol) at 0 °C under N 2 .
  • Example 15 N-(4-methyl-3-(1-methylazetidin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide [0369] To a solution of CDI (88 mg, 0.54 mmol) in DCM (2 mL) was added dropwise a mixture of 4- methyl-3-(1-methylazetidin-3-yl)aniline (80 mg, 0.45 mmol) in DCM (2 mL) at -20 °C under N2. The mixture was stirred at 20 °C for 1 h.
  • Example 18 cis-N-(4-chloro-3-cyclobutylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide [0374] To a mixture of triphosgene (163 mg, 0.55 mmol) in THF (6 mL) was added TEA (334 mg, 3.3 mmol) and 4-chloro-3-cyclobutylaniline (200 mg, 1.10 mmol) at 0 °C under N2.
  • TEA 29 mg, 0.29 mmol
  • cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride 84 mg, 0.13 mmol
  • the reaction mixture was warmed to 25 °C and stirred for 0.5 h.
  • the reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 ⁇ 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • reaction mixture was stirred at 0 °C for 10 min. Then TEA (29 mg, 0.29 mmol) and cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (84 mg, 0.13 mmol) was added to the above mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 ⁇ 1 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the fixed bed (named FLR1, volume 5 mL) was packed with granular catalyst 1%Pt/C (0.79 mmol).
  • the H2 back pressure regulator was adjusted to 1.5 MPa, and the flow rate of H2 was 30 mL/min.
  • 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, 50 °C).
  • reaction was warmed to 25 °C and TEA (29 mg, 0.29 mmol) and cis-3-methyl-6- azabicyclo[3.1.1]heptane hydrochloride (70 mg, 0.10 mmol) were added and the reaction mixture was stirred for 0.5 h.
  • the reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 ⁇ 1 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the fixed bed (named FLR1, volume 5 mL) was packed with granular catalyst 1%Pt/C (0.46 mmol).
  • the H2 back pressure regulator was adjusted to 1.5 MPa, and the flow rate of H2 was 30 mL/min.
  • 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, 50 °C).
  • reaction mixture was warmed to 25 °C and TEA (15 mg, 0.14 mmol) and cis-3-methyl-6- azabicyclo[3.1.1]heptane hydrochloride (42 mg, 0.06 mmol) were added.
  • the reaction mixture was stirred at 25 °C for 0.5 h.
  • the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3 ⁇ 1 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • reaction mixture was stirred at 0 °C for 0.5 h. Then TEA (65.24 mg, 0.64 mmol) and cis-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane hydrochloride (56 mg, 0.27 mmol) were added at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 ⁇ 2 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • the mixture was stirred at 0 °C for 0.5 h.
  • the reaction mixture was warmed to 20 °C and cis-3-methyl-6- azabicyclo[3.1.1]heptane hydrochloride (82 mg, 0.55 mmol) and TEA (153 mg, 1.52 mmol) were added and the reaction mixture was stirred at 20 °C for 12 h.
  • the reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 ⁇ 1 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • reaction mixture was warmed to 25 °C and stirred for 2 h.
  • the reaction mixture was diluted with aq. sat. NH4Cl (10 mL) and extracted with EtOAc (3 ⁇ 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • reaction mixture was stirred at 0 °C for 10 min. Then TEA (72 mg, 0.70 mmol) and 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane (51 mg, 0.28 mmol) were added to the above mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 0.5 h. The reaction mixture was diluted with H 2 O (3 mL) and extracted with EtOAc (3 ⁇ 5 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • reaction mixture was stirred at 0 °C for 10 min and then TEA (72 mg, 0.70 mmol) and 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane (51 mg, 0.28 mmol) were added to above mixture.
  • TEA 72 mg, 0.70 mmol
  • 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane 51 mg, 0.28 mmol
  • the reaction mixture was warmed to 25 °C and stirred for 0.5 h.
  • the reaction mixture was diluted with H 2 O (3 mL) and extracted with EtOAc (3 ⁇ 5 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Example 70 (1R,3S,5S)-N-(4-chloro-3-(3-hydroxyazetidin-1-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
  • 1-(5-bromo-2-chlorophenyl)azetidin-3-ol To a solution of 4-bromo-1-chloro-2-fluorobenzene (80 g, 381.96 mmol) in DMSO (600 mL) was added azetidin-3-ol hydrochloride (50.22 g, 458.36 mmol) and K 2 CO 3 (211.16 g, 1530 mmol) at 20 °C under N 2 .
  • reaction mixture was filtered through a Celite ⁇ pad and the filtrate was concentrated under reduced pressure.
  • the resulting residue was dissolved in MeOH (10 mL) and NaOAc (276 mg, 3.36 mmol) and NH 2 OH.HCl (187 mg, 2.69 mmol) were added to the reaction mixture at 25 °C.
  • the mixture was stirred at 25 °C for 12 h.
  • the reaction mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (3 ⁇ 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • 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% CO 2 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.
  • 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 ⁇ L/well of NAD/NADH-GloTM 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 ⁇ L/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.
  • % inhibition (sample - low control) / (high control - low control) x 100.
  • Table 3 [0442] FL-SARM1 plasmid sequence (SEQ.
  • the measuring comprises a fluorescent detection step.
  • 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.
  • the SARM1 protein comprises a fluorescent tag.
  • the SARM1 protein is provided using SEQ. ID.1, or a derivative thereof.
  • 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.
  • the SARM1 protein is provided using SEQ. ID.1.
  • the candidate compound is an inhibitor of SARM1.

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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 of U.S. Provisional Patent Application No.63/580,958, filed September 6, 2023, the content of which is incorporated herein by reference in its entirety. FIELD [0002] The present disclosure relates generally to small molecule modulators of Sterile Alpha and TIR Motif containing 1 (SARM1) protein, and their use as therapeutic agents. BACKGROUND [0003] Neurodegenerative diseases are a class of progressive neurological disorders, in which nerve cells malfunction and ultimately die. The degradation of neurons in those suffering from a neurodegenerative disease can present as a wide variety of symptoms, including changes in mood and behavior, agitation, sensory disturbances, motor and cognitive difficulties, and memory loss, which can progress to inability to move or speak, dementia, and ultimately death. [0004] Axonal degeneration has been identified as an important pathology in most neurodegenerative diseases. Axons are vulnerable to both mechanical injury (Wallerian degeneration) and disease (Wallerian-like degeneration). [0005] In healthy axons, SARM1’s N-terminus interacts with the TIR domain, preventing TIR dimerization and subsequent enzymatic cleavage of NAD+. However, under neuronal injury or disease conditions, SARM1’s N-terminus-TIR domain interaction is disrupted, allowing TIR multimerization to occur, followed by a rapid loss of NAD+ and associated axon degeneration. DESCRIPTION [0006] Provided herein are compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, that are useful in treating and/or preventing diseases mediated, at least in part, by SARM1. [0007] In certain embodiments, provided are compounds that inhibit SARM1. [0008] In another embodiment, provided is a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier. [0009] In another embodiment, provided is a method for treating a disease or condition mediated, at least in part, by SARM1, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0010] The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, methods of using (or administering) and making 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, “C1-6 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., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 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., C2-20 alkynyl), 2 to 12 carbon atoms (i.e., C2-12 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 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)Ry, wherein Ry 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)NRyRz and an “N- amido” group which refers to the group -NRyC(O)Rz, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or Ry and Rz 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 -NRyRz wherein Ry and Rz 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(NRy)(NRz2), wherein Ry and Rz 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., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 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)NRyRz and an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ry and Rz 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)Rx and -C(O)ORx, wherein Rx 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., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 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(NRy)Rz, wherein Ry and Rz 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)NRyC(O)Rz, wherein Ry and Rz 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, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ry 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., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyCH3, etc., where Ry 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, triazolyl, thiophenyl (i.e., thienyl), tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. [0044] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”. [0045] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 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 -CRy(=NOH) wherein Ry 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)2Ry, where Ry 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)Ry, where Ry 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 -SO2NRyRz and -NRySO2Rz, where Ry and Rz 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(Ry)3, wherein each Ry 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, -NRgRh, -NRgC(O)Rh, -NRgC(O)NRgRh, -NRgC(O)ORh, -NRgS(O)1-2Rh, -C(O)Rg, -C(O)ORg, -OC(O)ORg, -OC(O)Rg, -C(O)NRgRh, -OC(O)NRgRh, -ORg, -SRg, -S(O)Rg, -S(O)2Rg, -OS(O)1-2Rg, -S(O)1-2ORg, -NRgS(O)1-2NRgRh, =NSO2Rg, =NORg, -S(O)1-2NRgRh, -SF5, -SCF3, or -OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh. In the foregoing, Rg and Rh 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 Rg and Rh 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 IA: IA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein A, R1, R2, R3, R4, and R5 are each independently as defined herein. [0070] In certain embodiments, provided is a compound of Formula IA: IA or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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, oxo, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl. [0071] In certain embodiments, provided is a compound of Formula IA: IA or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl. [0072] In certain embodiments, the moiety is , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NH, O, or S; and A is optionally substituted C3-10 cycloalkyl, optionally substituted 4-5 membered N- linked heterocyclyl, or optionally substituted C-linked heterocyclyl provided the compound is not: 1954516-21-2 1,3-dihydro-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-ethano-2H- isoindole-2-carboxamide, 1953807-30-1 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-1,3,3-trimethyl-6- azabicyclo[3.2.1]octane-6-carboxamide, 1956565-60-8 3-hydroxy-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-8- azabicyclo[3.2.1]octane-8-carboxamide, 1946370-08-6 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-3-oxo-8-azabicyclo[3.2.1]octane-8- carboxamide, 1949726-68-4 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-2-azabicyclo[2.2.1]heptane-2- carboxamide, or 1953038-00-0 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-8-azabicyclo[3.2.1]octane-8- carboxamide. [0073] In certain embodiments, the moiety is , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NR9, O, or S, wherein R9 is H or Z1; and A is optionally substituted C3-10 cycloalkyl, optionally substituted 4-5 membered N-linked heterocyclyl, or optionally substituted C-linked heterocyclyl provided the compound is not: 1954516-21-2 1,3-dihydro-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-ethano-2H- isoindole-2-carboxamide, 1953807-30-1 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-1,3,3-trimethyl-6- azabicyclo[3.2.1]octane-6-carboxamide, 1956565-60-8 3-hydroxy-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-8- azabicyclo[3.2.1]octane-8-carboxamide, 1946370-08-6 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-3-oxo-8-azabicyclo[3.2.1]octane-8- carboxamide, 1949726-68-4 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-2-azabicyclo[2.2.1]heptane-2- carboxamide, or 1953038-00-0 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-8-azabicyclo[3.2.1]octane-8- carboxamide. [0074] In certain embodiments, the moiety is , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NH, O, or S; and A is optionally substituted C3-10 cycloalkyl or optionally substituted C-linked heterocyclyl. [0075] In certain embodiments, the moiety is , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NR9, O, or S, wherein R9 is H or Z1; and A is optionally substituted C3-10 cycloalkyl or optionally substituted C-linked heterocyclyl. [0076] In certain embodiments, the moiety is , wherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3. [0077] In certain embodiments, A is optionally substituted C4-10 cycloalkyl. [0078] In certain embodiments, A is optionally substituted heterocyclyl. In certain embodiments, A is optionally substituted N-linked heterocyclyl. In certain embodiments, A is optionally substituted 4- or 5- membered N-linked heterocyclyl. [0079] In certain embodiments, A is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is substituted with at least one substituent selected from cyano, -OR12 (e.g., - OMe or -OH), and C3-10 cycloalkyl. [0080] In certain embodiments, A is ; where R12 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, or C3-10 cycloalkyl. [0081] In certain embodiments, A is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; wherein the C1-6 alkyl, C2- 6 alkenyl, or C2-6 alkynyl is substituted with at least one substituent selected from cyano and C3- 10 cycloalkyl. [0082] In certain embodiments, provided is a compound of Formula IA: IA or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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, oxo, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl; provided that: a) the moiety is: a. , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NR9, O, or S, wherein R9 is H or Z1; and A is optionally substituted C3-10 cycloalkyl, optionally substituted 4- or 5- membered N-linked heterocyclyl, or optionally substituted C-linked heterocyclyl; provided the compound is not: 1954516-21-2 1,3-dihydro-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]- 1,3-ethano-2H-isoindole-2-carboxamide, 1953807-30-1 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-1,3,3- trimethyl-6-azabicyclo[3.2.1]octane-6-carboxamide, 1956565-60-8 3-hydroxy-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-8- azabicyclo[3.2.1]octane-8-carboxamide, 1946370-08-6 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-3-oxo-8- azabicyclo[3.2.1]octane-8-carboxamide, 1949726-68-4 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-2- azabicyclo[2.2.1]heptane-2-carboxamide, or 1953038-00-0 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-8- azabicyclo[3.2.1]octane-8-carboxamide; or b. , wherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3; b) A is optionally substituted C4-10 cycloalkyl; c) A is ; where R12 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3- 10 cycloalkyl; or d) A is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is substituted with at least one substituent selected from cyano and C3-10 cycloalkyl. [0083] In certain embodiments, provided is a compound of Formula IA: IA or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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, oxo, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl; provided that: a) the moiety is: a. , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NH, O, or S; and A is optionally substituted C3-10 cycloalkyl, optionally substituted 4- or 5- membered N-linked heterocyclyl, or optionally substituted C-linked heterocyclyl; provided the compound is not: 1954516-21-2 1,3-dihydro-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]- 1,3-ethano-2H-isoindole-2-carboxamide, 1953807-30-1 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-1,3,3- trimethyl-6-azabicyclo[3.2.1]octane-6-carboxamide, 1956565-60-8 3-hydroxy-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-8- azabicyclo[3.2.1]octane-8-carboxamide, 1946370-08-6 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-3-oxo-8- azabicyclo[3.2.1]octane-8-carboxamide, 1949726-68-4 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-2- azabicyclo[2.2.1]heptane-2-carboxamide, or 1953038-00-0 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-8- azabicyclo[3.2.1]octane-8-carboxamide; or b. , wherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3; b) A is optionally substituted C4-10 cycloalkyl; c) A is ; where R12 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3- 10 cycloalkyl; or d) A is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is substituted with at least one substituent selected from cyano and C3-10 cycloalkyl. [0084] In certain embodiments, provided is a compound of Formula IA: IA or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl; provided that: a) the moiety is: a. , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NH, O, or S; and A is optionally substituted C3-10 cycloalkyl or optionally substituted C-linked heterocyclyl; or b. , wherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3; A is optionally substituted C4-10 cycloalkyl; or b) A is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is substituted with at least one substituent selected from cyano, -OR12 and C3-10 cycloalkyl. [0085] In certain embodiments, the moiety is , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NH, O, or S. [0086] In certain embodiments, the moiety is , which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NR9, O, or S, wherein R9 is H or Z1. [0087] In certain embodiments, the moiety is , wherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3. [0088] In certain embodiments, A is optionally substituted C4-10 cycloalkyl. [0089] In certain embodiments, A is optionally substituted heterocyclyl. In certain embodiments, A is optionally substituted N-linked heterocyclyl. In certain embodiments, A is optionally substituted 4- or 5- membered N-linked heterocyclyl. In certain embodiments, A is substituted 4- or 5-membered N-linked heterocyclyl. In certain embodiments, A is substituted 4- or 5-membered N-linked heterocyclyl substituted with -OH. [0090] In certain embodiments, A is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; wherein the C1-6 alkyl, C2- 6 alkenyl, or C2-6 alkynyl is substituted with at least one substituent selected from cyano, -OR12 (e.g., - OMe or -OH), and C3-10 cycloalkyl. [0091] In certain embodiments, A is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; wherein the C1-6 alkyl, C2- 6 alkenyl, or C2-6 alkynyl is substituted with at least one substituent selected from cyano and C3- 10 cycloalkyl. [0092] In certain embodiments, provided is a compound of Formula IB: IB or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein q is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, or 3; and A, R1, R4, R5, and Z1 are each independently as defined herein. [0093] In certain embodiments, provided is a compound of Formula IB: IB or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; each Z1 is independently halo, cyano, oxo, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl. [0094] In certain embodiments, provided is a compound of Formula IB: IB or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl. [0095] In certain embodiments, provided is a compound of Formula IB: IB or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; each Z1 is independently halo, cyano, oxo, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1a; each Z1a 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. [0096] In certain embodiments, provided is a compound of Formula IB: IB or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1a; each Z1a 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. [0097] In certain embodiments, R or the moiety is , , , , , , , or . [0098] In certain embodiments, R or the moiety is , , or . [0099] In certain embodiments, each Z1 is independently oxo, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, heteroaryl, -N(R12)2, -OR12, -C(O)R12, -C(O)OR12, or -C(O)N(R12)2; wherein each C1-6 alkyl, C1-6 haloalkyl, heteroaryl is independently optionally substituted with one to five substituents independently selected from hydroxy, methoxy, and methyl. [0100] In certain embodiments, each Z1 is independently halo, cyano, C1-6 alkyl, C1-6 haloalkyl, heteroaryl, -OR12, -C(O)R12, -C(O)OR12, or -C(O)N(R12)2; wherein each C1-6 alkyl, C1-6 haloalkyl, heteroaryl is independently optionally substituted with one to five substituents independently selected from hydroxy, methoxy, and methyl. [0101] In certain embodiments, Z1 is halo. In certain embodiments, Z1 is fluoro. [0102] In certain embodiments, the moiety is ; wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring B is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1a; and L1 is a bond, C1-4 alkylene, C2-4 alkenylene, or C2-4 alkynylene. [0103] In certain embodiments, L1 is a bond or C1-4 alkylene. In certain embodiments, L1 is a bond or C1-2 alkylene. In certain embodiments, L1 is a bond or -CH2-. In certain embodiments, L1 is a bond. [0104] In certain embodiments, the moiety is ; wherein: q is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; Ring B is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1b; and L1 is a bond, C1-4 alkylene, C2-4 alkenylene, or C2-4 alkynylene. [0105] In certain embodiments, Ring B is heteroaryl optionally substituted with one to five Z1a. In certain embodiments, Ring B is heteroaryl optionally substituted with one to five Z1a, and L1 is a bond or C1-2 alkylene. In certain embodiments, Ring B is heteroaryl optionally substituted with one to five Z1a, and L1 is a bond or CH2. In certain embodiments, Ring B is heteroaryl and L1 is a bond. In certain embodiments, Ring B is heteroaryl optionally substituted with one to five Z1a, L1 is a bond, q is 1, and Z1 is C1-6 alkyl. [0106] In certain embodiments, Ring B is heteroaryl optionally substituted with one to five Z1b. In certain embodiments, Ring B is heteroaryl optionally substituted with one to five Z1b, and L1 is a bond or C1-2 alkylene. In certain embodiments, Ring B is heteroaryl optionally substituted with one to five Z1b, and L1 is a bond or CH2. In certain embodiments, Ring B is heteroaryl and L1 is a bond. In certain embodiments, Ring B is heteroaryl optionally substituted with one to five Z1b, L1 is a bond, q is 1, and Z1 is C1-6 alkyl. [0107] In certain embodiments, A is C1-6 alkyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1. [0108] In certain embodiments, A is C1-6 alkyl optionally substituted with one to five Z1. [0109] In certain embodiments, A is C1-6 alkyl substituted with cyano, -OR12 (e.g., -OMe or -OH), or C3-10 cycloalkyl, and optionally further substituted with one to four Z1. [0110] In certain embodiments, A is C1-6 alkyl substituted with cyano or C3-10 cycloalkyl, and optionally further substituted with one to four Z1. [0111] In certain embodiments, A is C3-10 cycloalkyl optionally substituted with one to five Z1. [0112] In certain embodiments, A is C4-10 cycloalkyl optionally substituted with one to five Z1. [0113] In certain embodiments, A is heterocyclyl optionally substituted with one to five Z1. [0114] In certain embodiments, A is a C-linked heterocyclyl optionally substituted with one to five Z1. [0115] In certain embodiments, A is a N-linked heterocyclyl such as 4- or 5-membered N-linked heterocyclyl optionally substituted with one to five Z1. [0116] In certain embodiments, A is
Figure imgf000037_0001
Figure imgf000037_0002
, , , or O ; wherein each is optionally substituted with one to five Z1. In certain embodiments, each Z1 is independently heteroaryl, oxo, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, or - OR12 wherein each R12 is independently hydrogen or C1-6 alkyl optionally substituted with -OH or -NH2 (e.g., -OR12 is -OH, -OCH2CH2OH, or -OCH2CH2NH2). [0117] In certain embodiments, A is
Figure imgf000037_0003
or
Figure imgf000037_0004
wherein each is optionally substituted with one to five Z1. In certain embodiments, each Z1 is independently halo, cyano, C1-6 alkyl, or C1-6 haloalkyl. [0118] In certain embodiments, R4 is hydrogen or halo. [0119] In certain embodiments, R4 is hydrogen. [0120] In certain embodiments, R4 is fluoro. [0121] In certain embodiments, R5 is hydrogen or halo. R5 is hydrogen. [0122] In certain embodiments, R4 and R5 are each independently hydrogen or halo. [0123] In certain embodiments, R4 and R5 are hydrogen. [0124] In certain embodiments, R1 is hydrogen, halo, cyano, C1-6 alkyl, or C3-10 cycloalkyl; wherein the C1-6 alkyl or C3-10 cycloalkyl is independently optionally substituted with one to five Z1. In certain embodiments, R1 is halo, cyano, C1-6 alkyl, or C3-10 cycloalkyl; wherein the C1-6 alkyl or C3-10 cycloalkyl is independently optionally substituted with one to five Z1. [0125] In certain embodiments, R1 is hydrogen, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, or C3-10 cycloalkyl. In certain embodiments, R1 is halo, cyano, C1-6 alkyl, C1-6 haloalkyl, or C3-10 cycloalkyl. [0126] In certain embodiments, R1 is hydrogen, fluoro, chloro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, -CH2NH2, or cyclopropyl. In certain embodiments, R1 is fluoro, chloro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, -CH2NH2, or cyclopropyl. [0127] In certain embodiments, R1 is hydrogen, fluoro, chloro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or cyclopropyl. In certain embodiments, R1 is fluoro, chloro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, or cyclopropyl. [0128] In certain embodiments, R1 is halo or C1-6 alkyl optionally substituted with one to five Z1. [0129] In certain embodiments, R1 is halo or C1-6 alkyl optionally substituted with one to five groups independently selected from halo and -NH2. [0130] In certain embodiments, R1 is halo or C1-6 alkyl optionally substituted with one to five independently selected halo. [0131] In certain embodiments, R1 is halo, C1-6 alkyl optionally substituted with -NH2, or C1-6 haloalkyl. [0132] In certain embodiments, R1 is halo, C1-6 alkyl, or C1-6 haloalkyl. [0133] In certain embodiments, R1 is halo, -CH2NH2, -CH3, or -CF3. [0134] In certain embodiments, R1 is halo, -CH3, or -CF3. [0135] In certain embodiments, each Z1 is C1-6 alkyl. [0136] In certain embodiments, each R11 is independently C1-6 alkyl; wherein each C1-6 alkyl is independently optionally substituted with one to five Z1a. In certain embodiments, each R11 is independently C1-6 alkyl; wherein each C1-6 alkyl is independently optionally substituted with one to five halo. [0137] In certain embodiments, each Z1 is independently oxo, halo, cyano, 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, or -C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a. [0138] In certain embodiments, each Z1 is independently oxo, halo, cyano, 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, or -C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a. [0139] In certain embodiments, each Z1 is independently heteroaryl, oxo, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, -OR12, -C(O)OR12 or heteroaryl; wherein each C1-6 alkyl, C1-6 haloalkyl, or heteroaryl is independently optionally substituted with one to five Z1a. [0140] In certain embodiments, each Z1 is independently halo, cyano, C1-6 alkyl, C1-6 haloalkyl, -OR12, -C(O)OR12 or heteroaryl; wherein each C1-6 alkyl, C1-6 haloalkyl, or heteroaryl is independently optionally substituted with one to five Z1a. [0141] In certain embodiments, each R12 is independently hydrogen or C1-6 alkyl; wherein each C1-6 alkyl is independently optionally substituted with one to five Z1b. [0142] In certain embodiments, each R12 is independently C1-6 alkyl; wherein each C1-6 alkyl is independently optionally substituted with one to five Z1b. [0143] In certain embodiments, each Z1a is independently halo or -OR13. [0144] In certain embodiments, each R13 is independently hydrogen or C1-6 alkyl. [0145] In certain embodiments, each Z1b is independently halo. [0146] In certain embodiments, each Z1b is independently -OH or -NH2. [0147] 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
Figure imgf000039_0001
Ex. Structure H N N 6 NC O Mixture of enantiomers H N N 7 NC O Single unknown enantiomer, first eluting H N N 8 NC O Single unknown enantiomer, second eluting H N N 9 NC O Cl Single unknown enantiomer, first eluting H N N 10 NC O Cl Single unknown enantiomer, second eluting H N 11 O H 12 N N O H 13 N N O
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
[0148] In certain embodiments, provided is a compound selected from Table 2 or a pharmaceutically acceptable salt thereof. Table 2
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000064_0002
Figure imgf000064_0001
Figure imgf000065_0002
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000067_0002
Figure imgf000067_0001
Figure imgf000068_0002
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000070_0002
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000071_0002
Structure Structure 3. Methods [0149] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. [0150] “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. [0151] “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. [0152] 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. [0153] 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. [0154] 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. [0155] In certain methods, uses and compositions provided herein, the compound is a compound of Formula I: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R is C1-6 alkyl, -NR2R3, -OR7, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R7 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl. [0156] In certain methods, uses and compositions provided herein, the compound is a compound of Formula I: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R is C1-6 alkyl, -NR2R3, -OR7, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R7 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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, oxo, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, - S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl. [0157] 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. [0158] 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). [0159] 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). [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 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. [0161] In certain embodiments, provided is a method for treating a disease or condition mediated, at least in part, by SARM1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof to a subject in need thereof. [0162] In certain embodiments, provided is a method of treating axonal degeneration in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to the subject. In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, inhibits axonal degeneration, including axonal degeneration that results from reduction or depletion of NAD+. In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, prevents an axon distal to an axonal injury from degenerating. [0163] In certain embodiments, provided is a method for treating degradation of a peripheral nervous system neuron or a portion thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0164] In certain embodiments, provided is a method for treating degeneration of a central nervous system neuron or a portion thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0165] In certain embodiments, the treating comprises reducing one or more symptoms or features of neurodegeneration. [0166] In certain embodiments, provided is a method for inhibiting axon degeneration, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0167] In certain embodiments, provided is a method for treating a neurodegenerative or neurological disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0168] In certain embodiments, provided is a method for treating a neurodegenerative or neurological disease or disorder associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage resulting from traumatic axonal injury (TAI) (see Ziogas et al., J. Neuroscience, 2018, 38(16):4031-4032 and WO2020191257), a leukoencephalopathy or a leukodystrophy, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0169] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating a disease or condition mediated, at least in part, by SARM1 in a subject in need thereof. [0170] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting axon degeneration in a subject in need thereof. [0171] In certain embodiments, the present disclosure provides use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof in the manufacture of a medicament for inhibiting axon degeneration in a subject in need thereof. [0172] In certain embodiments, the present disclosure provides use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof in the manufacture of a medicament for treating a neurodegenerative or neurological disease or disorder, such as a disease or disorder associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central pontine myelinolysis, a nerve 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. [0173] In certain embodiments, the disease or condition is an acute condition. In certain embodiments, the disease or condition is a chronic condition. [0174] In certain embodiments, the disease or condition is characterized by axonal degeneration in the central nervous system, the peripheral nervous system, the optic nerve, the cranial nerves, or a combination thereof. [0175] In certain embodiments, the disease or condition is or comprises acute injury to the central nervous system, such as, but not limited to, injury to the spinal cord and/or traumatic brain injury (TBI). In certain embodiments, the disease or condition is or comprises a chronic injury to the central nervous system, such as, but not limited to, injury to the spinal cord, traumatic brain injury (TBI), and/or traumatic axonal injury (TAI). In certain embodiments, the disease or condition is or comprises chronic traumatic encephalopathy (CTE). [0176] In certain embodiments, the disease or condition is a chronic condition affecting the central nervous system, such as, but not limited to, Parkinson’s disease (see, e.g., Sajadi, A., et al. Curr. Biology. 2004, 14, 326-330; and Hasbani, D.M., et al. Exp. Neurology.2006, 202, 93-99), amyotrophic lateral sclerosis (see, e.g., White, M.A., et al. Acta Neuropath. Comm.2019, 7(1), 166), multiple sclerosis, Huntington disease, or Alzheimer’s disease. [0177] In certain embodiments, the disease or condition is an acute peripheral neuropathy. In certain embodiments, the disease or condition is chemotherapy-induced peripheral neuropathy (CIPN). See, e.g., Geisler, S., et al. Brain.2016, 139, 3092-3108; Turkiew, E., et al. J. Peripher. Nerv. Syst.2017, 22, 162- 171; Geisler, S., et al. JCI Insight.2019, 4(17), e129920; and Cetinkaya-Fisgin, A., et al. Sci. Rep.2020, 21889. Chemotherapy-induced peripheral neuropathy (CIPN), an example of an acute peripheral neuropathy, can be associated with various drugs, such as, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), or platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin). [0178] In certain embodiments, the disease or condition is a chronic condition affecting the peripheral nervous system, such as, but not limited to, diabetic neuropathy, HIV neuropathy, Charcot Marie Tooth disease, or amyotrophic lateral sclerosis. [0179] In certain embodiments, the disease or condition is glaucoma (see, e.g., Ko, K.W., et al. J. Cell Bio.2020, 219(8), e201912047). [0180] In certain embodiments, the disease or condition is an acute condition affecting the optic nerve, such as, but not limited to, diabetic optic neuropathy, acute optic neuropathy (AON) or acute angle closure glaucoma. [0181] In certain embodiments, the disease or condition is a chronic condition affecting the optic nerve, such as, but not limited to, diabetic optic neuropathy, Leber’s congenital amaurosis, Leber’s hereditary optic neuropathy (LHON), primary open angle glaucoma, or autosomal dominant optic atrophy. [0182] In certain embodiments, the disease or condition is associated with retinal degeneration. In certain embodiments, the disease or condition is Leber congenital amaurosis, such as Leber congenital amaurosis type 9 (LCA9) (see, e.g., Sasaki, Y., et al. eLife.2020, 9, e62027.) [0183] In certain embodiments, one or more compounds and/or compositions as described herein are useful, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from the group consisting of neuropathies or axonopathies. In certain embodiments, one or more compounds and/or compositions as described herein are useful, for example to treat a neuropathy or axonopathy associated with axonal degeneration. In certain embodiments, a neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In certain embodiments, a neuropathy associated with axonal degeneration results from a de novo or somatic mutation. In certain embodiments, a neuropathy associated with axonal degeneration is selected from a list contained herein. In certain embodiments, a neuropathy or axonopathy is associated with axonal degeneration, including, but not limited to Parkinson’s disease, Alzheimer’s disease, herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia, stroke, chemical injury, thermal injury, or AIDS. [0184] In certain embodiments, one or more compounds or compositions as described herein is characterized that, when administered to a population of subjects, reduces one or more symptoms or features of neurodegeneration. For example, in certain embodiments, a relevant symptom or feature may be selected from the group consisting of extent, rate, and/or timing of neuronal disruption. In certain embodiments, neuronal disruption may be or comprise axonal degradation, loss of synapses, loss of dendrites, loss of synaptic density, loss of dendritic arborization, loss of axonal branching, loss of neuronal density, loss of myelination, loss of neuronal cell bodies, loss of synaptic potentiation, loss of action-potential potentiation, loss of cytoskeletal stability, loss of axonal transport, loss of ion channel synthesis and turnover, loss of neurotransmitter synthesis, loss of neurotransmitter release and reuptake capabilities, loss of axon-potential propagation, neuronal hyperexcitability, and/or neuronal hypoexcitability. In certain embodiments, neuronal disruption is characterized by an inability to maintain an appropriate resting neuronal membrane potential. In certain embodiments, neuronal disruption is characterized by the appearance of inclusion bodies, plaques, and/or neurofibrillary tangles. In certain embodiments, neuronal disruption is characterized by the appearance of stress granules. In certain embodiments, neuronal disruption is characterized by the intracellular activation of one or more members of the cysteine-aspartic protease (Caspase) family. In certain embodiments, neuronal disruption is characterized by a neuron undergoing programed cell death (e.g. apoptosis, pyroptosis, ferroptosis, and/or necrosis) and/or inflammation. [0185] In certain embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, a demyelinating disease, a central 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). [0186] In certain embodiments, the present disclosure provides inhibitors of SARM1 activity for treatment of neurodegenerative or neurological diseases or disorders that involve axon degeneration or axonopathy. The present disclosure also provides methods of using inhibitors of SARM1 activity to treat, prevent or ameliorate axonal degeneration, axonopathies and neurodegenerative or neurological diseases or disorders that involve axonal degeneration. In certain embodiments, the present disclosure provides a method for inhibiting axon degeneration, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. [0187] In certain embodiments, the present disclosure provides methods of treating neurodegenerative or neurological diseases or disorders related to axonal degeneration, axonal damage, axonopathies, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a leukodystrophy. [0188] In certain embodiments, neuropathies and axonopathies include any disease or condition involving neurons and/or supporting cells, such as for example, glia, muscle cells or fibroblasts, and, in particular, those diseases or conditions involving axonal damage. Axonal damage can be caused by traumatic injury or by non-mechanical injury due to diseases, conditions, or exposure to toxic molecules or drugs. The result of such damage can be degeneration or dysfunction of the axon and loss of functional neuronal activity. Disease and conditions producing or associated with such axonal damage are among a large number of neuropathic diseases and conditions. Such neuropathies can include peripheral neuropathies, central neuropathies, or combination thereof. Furthermore, peripheral neuropathic manifestations can be produced by diseases focused primarily in the central nervous systems and central nervous system manifestations can be produced by essentially peripheral or systemic diseases. [0189] In certain embodiments, a peripheral neuropathy may involve damage to the peripheral nerves, and/or can be caused by diseases of the nerves or as the result of systemic illnesses. Some such diseases include diabetes, uremia, infectious diseases such as AIDS or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, or autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. In certain embodiments, peripheral nerve degeneration results from traumatic (mechanical) damage to nerves as well as chemical or thermal damage to nerves. Such conditions that injure peripheral nerves include compression or entrapment injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fracture or dislocated bones; pressure involving superficial nerves (ulna, radial, or peroneal) which can result from prolonged use of crutches or staying in one position for too long, or from a tumor; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain medicines or toxic substances such as herbicides or pesticides. In particular, the nerve damage can result from chemical injury due to a cytotoxic anticancer agent such as, for example, taxol, cisplatinin, a proteasome inhibitor, or a vinca alkaloid such as vincristine. Typical symptoms of such peripheral neuropathies include weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, pricking or tingling) and pain in the arms, hands, legs and/or feet. In certain embodiments, a neuropathy is associated with mitochondrial dysfunction. Such neuropathies can exhibit decreased energy levels, i.e., decreased levels of NAD and ATP. [0190] In certain embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy which includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. These diseases include, for example, diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, a disorder of lipid/glycolipid metabolism, a nutritional/vitamin deficiency, or a mitochondrial disorder. The common hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation. [0191] In certain embodiments, neuropathies include optic neuropathies such as glaucoma, retinal ganglion degeneration such as those associated with retinitis pigmentosa and outer retinal neuropathies, optic nerve neuritis and/or degeneration including that associated with multiple sclerosis, traumatic injury to the optic nerve which can include, for example, injury during tumor removal, hereditary optic neuropathies such as Kjer’s disease and Leber’s hereditary optic neuropathy (LHON), ischemic optic neuropathies, such as those secondary to giant cell arteritis, metabolic optic neuropathies such as neurodegenerative diseases including Leber’s neuropathy, nutritional deficiencies such as deficiencies in vitamins B12 or folic acid, and toxicities such as due to ethambutol or cyanide, neuropathies caused by adverse drug reactions and neuropathies caused by vitamin deficiency. Ischemic optic neuropathies also include non-arteritic anterior ischemic optic neuropathy. [0192] In certain embodiments, neurodegenerative diseases that are associated with neuropathy or axonopathy in the central nervous system include a variety of diseases. Such diseases include those involving progressive dementia such as, for example, Alzheimer’s disease, senile dementia, Pick’s disease, and Huntington’s disease, central nervous system diseases affecting muscle function such as, for example, Parkinson’s disease, motor neuron diseases and progressive ataxias such as amyotrophic lateral sclerosis, demyelinating diseases such as, for example multiple sclerosis, viral encephalitis such as, for example, those caused by enteroviruses, arboviruses, and herpes simplex virus, and prion diseases. Mechanical injuries such as glaucoma or traumatic injuries to the head and spine can also cause nerve injury and degeneration in the brain and spinal cord. In addition, ischemia and stroke as well as conditions such as nutritional deficiency and chemical toxicity such as with chemotherapeutic agents can cause central nervous system neuropathies. [0193] In certain embodiments, the present disclosure provides a method of treating a neuropathy or axonopathy associated with axonal degeneration. In certain embodiments, a neuropathy or axonopathy associated with axonal degeneration can be any of a number of neuropathies or axonopathies such as, for example, those that are hereditary or congenital or associated with Parkinson’s disease, Alzheimer’s disease, Herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS. In addition, neurodegenerative diseases not mentioned above as well as a subset of the above-mentioned diseases can also be treated with the methods of the present disclosure. Such subsets of diseases can include Parkinson’s disease or Alzheimer’s disease. [0194] In certain embodiments, the present methods comprise administering an effective amount of a compound and/or composition as described herein (e.g., a compound of Formula I, IA, or IB) 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. [0195] In certain embodiments, the subject is at risk of developing a neurodegenerative disorder. In certain embodiments, the subject is elderly. In certain embodiments, the subject is known to have a genetic risk factor for neurodegeneration. In certain embodiments, the subject has a family history of neurodegenerative disease. In certain embodiments, the subject expresses one or more copies of a known genetic risk factor for neurodegeneration. In certain embodiments, the subject is drawn from a population with a high incidence of neurodegeneration. In certain embodiments, the subject has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In certain embodiments, the subject has one or more copies of the ApoE4 allele. [0196] In certain embodiments, a neurodegenerative disease, disorder or condition may be or comprise a traumatic neuronal injury. In certain embodiments, a traumatic neuronal injury is blunt force trauma, a closed-head injury, an open head injury, exposure to a concussive and/or explosive force, a penetrating injury into the brain cavity or innervated region of the body. In certain embodiments, a traumatic neuronal injury is a force which causes the axons to deform, stretch, crush or sheer. In certain embodiments, the disease or disorder is a traumatic brain injury (TBI). [0197] In certain embodiments, the subject has engaged, or engages, in an activity identified as a risk factor for neuronal degradation, e.g., a contact sport or occupations with a high chance for traumatic neuronal injury or TBI. [0198] In certain embodiments, provided is a method of treating a neurodegenerative disease, disorder or condition comprising administering to a patient in need thereof, a compound as described herein, and one or more of a DLK inhibitor or a NAMPT inhibitor. In certain embodiments, provided is a combination therapy comprising a compound as described herein and a DLK inhibitor and/or a NAMPT inhibitor. In certain embodiments, provided is a combination therapy comprising a compound as described herein, a DLK inhibitor, and one or more additional therapeutic agents. In certain embodiments, provided is a combination therapy comprising a compound as described herein, a NAMPT inhibitor, and one or more additional therapeutic agents. In certain embodiments, provided is a combination therapy comprising a compound as described herein, a DLK inhibitor, a NAMPT inhibitor and one or more additional therapeutic agents. [0199] In certain embodiments, the DLK inhibitor is a small molecule, a polypeptide, a peptide fragment, a nucleic acid (e.g., a siRNA, an antisense oligonucleotide, a micro-RNA, or an aptamer), an antibody, a dominant-negative inhibitor, or a ribozyme. In certain embodiments, the DLK inhibitor is a small molecule. In certain embodiments, the DLK inhibitor is a siRNA. In certain embodiments, the DLK inhibitor is an antisense oligonucleotide. In certain embodiments, the DLK inhibitor is a polypeptide. In certain embodiments, a DLK inhibitor is a peptide fragment. In certain embodiments, a DLK inhibitor is a nucleic acid. In certain embodiments, a DLK inhibitor is an antisense oligonucleotide. [0200] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, WO2014177060, WO2015091889, WO2016142310, US20180057507, WO2018107072, WO2019241244, WO2020168111, and CN104387391A, which are hereby incorporated by reference in their entirety. [0201] In certain embodiments, the NAMPT inhibitor is a small molecule, a polypeptide, a peptide fragment, a nucleic acid (e.g., a siRNA, an antisense oligonucleotide, a micro-RNA, or an aptamer), an antibody, a dominant-negative inhibitor, or a ribozyme. In certain embodiments, the NAMPT inhibitor is a small molecule. In some embodiments, the NAMPT inhibitor is a siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In certain embodiments, the NAMPT inhibitor is a polypeptide. In some embodiments, a NAMPT inhibitor is a peptide fragment. In certain embodiments, a NAMPT inhibitor is a nucleic acid. In some embodiments, a NAMPT inhibitor is an antisense oligonucleotide. [0202] In certain embodiments, a NAMPT inhibitor prevents the formation of nicotinamide mononucleotide (NMN). In certain embodiments, inhibition of NAMPT inhibits the mammalian NAD+ salvage pathway. [0203] In certain embodiments, the provided is a composition comprising a compound as described herein, formulated for use in administering to a subject in combination with a DLK inhibitor and/or a NAMPT inhibitor. [0204] In certain embodiments, the provided is a composition comprising a compound as described herein, for use in combination with a DLK inhibitor and/or a NAMPT inhibitor. In certain embodiments, such compositions are pharmaceutical compositions that include at least one pharmaceutically acceptable carrier, diluent or excipient. [0205] In certain embodiments, the subject may be a subject who has received, is receiving, or has been prescribed, a chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin). [0206] In certain embodiments, SARM1 inhibition as described herein may be utilized in combination with one or more other therapies to treat a relevant disease, disorder, or condition. In certain embodiments, dosing of a SARM1 inhibitor is altered when utilized in combination therapy as compared with when administered as monotherapy; alternatively or additionally, a therapy that is administered in combination with SARM1 inhibition as described herein is administered according to a regimen or protocol that differs from its regimen or protocol when administered alone or in combination with one or more therapies other than SARM1 inhibition. In certain embodiments, compositions which comprise an additional therapeutic agent, that additional therapeutic agent and a provided compound may act synergistically. In certain embodiments, one or both therapies utilized in a combination regimen is administered at a lower level or less frequently than when it is utilized as monotherapy. [0207] In certain embodiments, a compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or composition provided herein is administered in combination with a NAD+ or a NAD+ precursor (e.g., nicotinamide riboside (NR), nicotinic acid (NA), nicotinic acid riboside (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), tryptophan (TRP), nicotinic acid adenine dinucleotide (NAAD), or vitamin B3). [0208] In certain embodiments, provided is a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting sterile alpha and TIR motif-containing protein 1 (SARM1) activity (e.g., in vitro or in vivo). [0209] In certain embodiments, the present disclosure provides use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for inhibiting sterile alpha and TIR motif-containing protein 1 (SARM1) activity (e.g., in vitro or in vivo) and supplementing axonal NAD+ levels. [0210] Axonal degeneration has been associated with various types of neurodegenerative diseases, being recognized as an important indicator of disease progression, and an interesting target for the therapeutic treatment of these diseases. Similarly, axonal degeneration is also observed in those with traumatic brain injuries and peripheral neuropathies. [0211] In certain embodiments, provided is a method for treating a disease or condition mediated, at least in part, by SARM1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in combination with NAD+ or a NAD+ precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3). [0212] In certain embodiments, the present disclosure provides use of a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in combination with NAD+ or a NAD+ precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3), in the manufacture of a medicament for treating or preventing a neurodegenerative disease in a subject in need thereof. [0213] In certain embodiments, provided is a method for treating any disease caused by SARM1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in combination with NAD+ or a NAD+ precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3). [0214] In certain embodiments, the disease or condition may be a disease or condition of the central nervous system, and/or may be caused by or associated with a pathogen or traumatic injury. It will be appreciated that these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive. [0215] In certain embodiments, provided is a method for treating a neurodegenerative disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in combination with NAD+ or a NAD+ precursor (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3). [0216] Other embodiments include use of the presently disclosed compounds in therapy. 4. Kits [0217] Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and suitable packaging. In certain embodiments, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein. [0218] Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag. 5. Pharmaceutical Compositions and Modes of Administration [0219] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.). [0220] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. [0221] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. [0222] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. [0223] Some examples of suitable excipients include, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents. [0224] The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [0225] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. When referring to 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. [0226] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [0227] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, in one embodiment, orally or nasally, from devices that deliver the formulation in an appropriate manner. [0228] The amount of the compound in a pharmaceutical composition or formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Formulation Example 1 - Tablet formulation [0229] The following ingredients are mixed intimately and pressed into single scored tablets.
Figure imgf000090_0001
Formulation Example 2 - Capsule formulation [0230] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule
Figure imgf000090_0002
Formulation Example 3 - Suspension formulation [0231] The following ingredients are mixed to form a suspension for oral administration.
Figure imgf000091_0001
Formulation Example 4 - Injectable formulation [0232] The following ingredients are mixed to form an injectable formulation.
Figure imgf000091_0002
Formulation Example 5 - Suppository Formulation [0233] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Figure imgf000091_0003
6. Dosing [0234] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In certain embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. In certain embodiments, a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. 7. Synthesis of the Compounds [0235] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. [0236] It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0237] Additionally, conventional protecting groups (“PG”) may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J., Wiley- Interscience, and references cited therein. For example, protecting groups for alcohols, such as hydroxy, include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso- propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ion, such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-nEt3. Other protecting groups for alcohols include acetyl, removed by acid or base, benzoyl, removed by acid or base, benzyl, removed by hydrogenation, methoxyethoxymethyl ether, removed by acid, dimethoxytrityl, removed by acid, methoxymethyl ether, removed by acid, tetrahydropyranyl or tetrahydrofuranyl, removed by acid, and trityl, removed by acid. Examples of protecting groups for amines include carbobenzyloxy, removed by hydrogenolysis p-methoxybenzyl carbonyl, removed by hydrogenolysis, tert-butyloxycarbonyl, removed by concentrated strong acid (such as HCl or CF3COOH), or by heating to greater than about 80 °C, 9-fluorenylmethyloxycarbonyl, removed by base, such as piperidine, acetyl, removed by treatment with a base, benzoyl, removed by treatment with a base, benzyl, removed by hydrogenolysis, carbamate group, removed by acid and mild heating, p-methoxybenzyl, removed by hydrogenolysis, 3,4- dimethoxybenzyl, removed by hydrogenolysis, p-methoxyphenyl, removed by ammonium cerium(IV) nitrate, tosyl, removed by concentrated acid (such as HBr or H2SO4) and strong reducing agents (sodium in liquid ammonia or sodium naphthalenide), troc (trichloroethyl chloroformate), removed by Zn insertion in the presence of acetic acid, and sulfonamides (Nosyl & Nps), removed by samarium iodide or tributyltin hydride. [0238] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0239] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). General Synthesis [0240] Scheme I illustrates general methods which can be employed for the synthesis of compounds described herein (e.g., Formula I), where A, R, R1, R4, and R5 are each independently as defined herein, and each LG is independently a leaving group (e.g., halo, alkoxy, etc.).
Figure imgf000094_0001
[0241] In Scheme I, compounds of Formula I can be prepared by contacting compound I-1 with compound I-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required. Alternatively, compounds of Formula I can be prepared by contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required. Alternatively, compounds of Formula I can be prepared by contacting compound I-5 with a suitable functionalized precursor to the moiety A, under suitable coupling reaction conditions, followed by optional functionalization or deprotection when required. Upon each reaction completion, each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. [0242] Further derivatization of the compound provided by the steps outlined in Scheme I, or any intermediate, provides additional compounds of Formula I. It should be understood that any of the compounds or intermediates shown in Scheme I may be prepared using traditional methods or purchased from commercial sources. In addition, any of the intermediates or any product obtained by the process outlined in Scheme I can be derivatized at any step to provide various compounds of Formula I. In certain embodiments, the various substituents of the compounds or intermediates as used in Scheme I are as defined for Formula I. [0243] In certain embodiments, compounds of Formula I wherein R is -OR7, or compounds of Formula IA or IB, can be prepared according to Scheme II, where A, R1, R2, R3, R4, R5, and R7 are each independently as defined herein, and each LG is independently a leaving group (e.g., halo, alkoxy, etc.).
Figure imgf000095_0001
[0244] In Scheme II, compounds of Formula IA can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide an acylated intermediate, followed by contacting the acylated intermediate with compound II-2, or a salt thereof. Compounds of Formula I wherein R is -OR7, i.e., compound II-4, can be prepared by contacting compound I-1 with compound II-1 under suitable coupling reaction conditions to provide the acylated intermediate, followed by contacting the acylated intermediate with compound II-3. Upon each reaction completion, each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. [0245] It should be understood that any of the compounds or intermediates shown in Scheme II may be prepared using traditional methods or purchased from commercial sources. In addition, any of the intermediates or any product obtained by the process outlined in Scheme II can be derivatized at any step to provide various compounds of Formula I or IA. In certain embodiments, the various substituents of the compounds or intermediates as used in Scheme II are as defined for Formula I or IA. [0246] 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. [0247] In certain embodiments, provided is a process for providing a compound of Formula I, comprising: contacting a compound of Formula I-1:
Figure imgf000096_0001
with a compound of Formula I-2:
Figure imgf000096_0002
under conditions sufficient to provide the compound of Formula I; wherein A, R, R1, R4, and R5 are each independently as defined herein. [0248] In certain embodiments, provided is a process for providing a compound of Formula I, comprising: contacting a compound of Formula I-1:
Figure imgf000096_0003
with a compound of Formula IA-2:
Figure imgf000096_0004
under conditions sufficient to provide the compound of Formula IA; wherein A, R1, R2, R3, R4, and R5 are each independently as defined herein. In certain embodiments, the conditions comprise a phosgene reagent, e.g., triphosgene. EXAMPLES [0249] 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 [0250] 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. [0251] 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. [0252] 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. [0253] 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 AcquityTM 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 cis-3-Methyl-6-azabicyclo[3.1.1]heptane
Figure imgf000098_0001
[0254] N-(trans-3-methylcyclohexyl)picolinamide: A mixture of N-(trans-3- methylcyclohexyl)picolinamide and N-(cis-3-methylcyclohexyl)picolinamide was purified by prep- HPLC (column: Phenomenex luna C18250 × 100 mm × 15 μm; mobile phase: A: 10 mM TFA in water, B: MeCN; B in A: 40%-70%, over 20 min) to provide the separated cis and trans isomers. The second eluting peak was concentrated under reduced pressure, adjusted to pH = 7-8 with sat. aq. NaHCO3 solution and extracted with DCM (3 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the titled compound as a colorless oil. LCMS: m/z = 219.2 [M+H]+. [0255] (cis-3-Methyl-6-azabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone To a mixture of N- (trans-3-methylcyclohexyl)picolinamide (6 g, 27.49 mmol) in 1,1,2,2-tetrachloroethane (200 mL) was added AgOAc (13.76 g, 82.46 mmol), benzoquinone (1.49 g, 13.74 mmol), Na3PO4 (13.52 g, 82.46 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (80.80 g, 274.86 mmol) and Pd(oAc)2 (1.23 g, 5.50 mmol) at 25 °C under N2. The mixture was stirred at 145 °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 = 5:1 to 1:1) to give the titled compound as a brown oil. LCMS: m/z = 217.0 [M+H]+. Intermediate 2 methyl cis-2-(3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptan-1-yl)-2-oxoacetate [0256] trans-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione: To a mixture of 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 compound. LCMS: m/z = 183.2 [M+H]+. [0257] trans-1-amino-3-methylcyclohexane-1-carboxylic acid: To a solution of trans-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 compound. LCMS: m/z = 158.2 [M+H]+. [0258] methyl trans-1-amino-3-methylcyclohexane-1-carboxylate hydrochloride: To a mixture of trans-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 compound. LCMS: m/z = 172.2 [M+H]+. [0259] methyl trans-3-methyl-1-(picolinamido)cyclohexane-1-carboxylate: To a solution of methyl trans-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 compound. LCMS: m/z = 277.2 [M+H]+. [0260] methyl cis-2-(3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptan-1-yl)-2-oxoacetate: To a solution of methyl trans-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]+. Intermediates 3 and 4 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
Figure imgf000100_0001
[0261] 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 3. 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 4. LCMS: m/z = 275.2 [M+H]+. Intermediate 5 cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid
Figure imgf000100_0002
[0262] To a solution of methyl cis-3-methyl-6-picolinoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (Intermediate 3) (3 g, 11 mmol) in EtOH (30 mL) was added NaOH (4.37 g, 109 mmol) at 25 °C under N2. The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure, adjusted to pH = 5 with 12 M HCl at 0 °C and lyophilized to give the titled compound. LCMS: m/z = 156.1 [M+H]+. Intermediate 6 4-chloro-3-cyclobutylaniline
Figure imgf000101_0001
[0263] 4-chloro-3-cyclobutylaniline： To a solution of 3-bromo-4-chloro-aniline (300 mg, 1.45 mmol) in DME (6 mL) was added bromocyclobutane (392 mg, 2.91 mmol), NiCl2.glyme (2 mg, 0.01 mmol), Na2CO3 (308 mg, 2.91 mmol), dtbbpy (2 mg, 0.01 mmol), tris(trimethylsilyl)silane (361 mg, 1.45 mmol) and (IR(dF(CF3)ppy)2(bpy))PF6 (16 mg, 0.01 mmol) at 25 °C under N2. The reaction mixture was irradiated with two 34 W blue LEDs (vials approximately 6 cm away from the light source) with a fan placed above for cooling for 16 h at 25 °C. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 5:1) to give the titled compound. LCMS: m/z = 182.0 [M+H]+. Intermediate 7 cis-2-(5-amino-2-chlorophenyl)cyclobutane-1-carbonitrile
Figure imgf000101_0002
[0264] N-(quinolin-8-yl)cyclobutanecarboxamide: To a mixture of quinolin-8-amine (3 g, 20.81 mmol) in DCM (30 mL) was added TEA (6.32 g, 62.43 mmol) and cyclobutanecarbonyl chloride (2.47 g, 20.81 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (30 mL) and 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 1:1) to give the titled compound. LCMS: m/z = 227.1 [M+1]+. [0265] cis-2-(3-nitrophenyl)-N-(quinolin-8-yl)cyclobutane-1-carboxamide: To a solution of N-(8- quinolyl)cyclobutanecarboxamide (27.2 g, 120.48 mmol) and 1-iodo-3-nitro-benzene (10 g, 40.16 mmol) in DCE (120 mL) was added AgOAc (13.5 g, 80.32 mmol), dibenzyl hydrogen phosphate (2.3 g, 8.03 mmol) and Pd(oAc)2 (1.8 g, 8.03 mmol) at 20 °C under N2. The mixture was stirred at 95 °C for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to provide the titled compound. LCMS: m/z = 348.1 [M+H]+. [0266] tert-butyl (cis-2-(3-nitrophenyl)cyclobutane-1-carbonyl)(quinolin-8-yl)carbamate: To a solution of cis-2-(3-nitrophenyl)-N-(quinolin-8-yl)cyclobutane-1-carboxamide (10 g, 28.79 mmol) in MeCN (100 mL) was added Boc2O (12.6 g, 57.58 mmol), DMAP (351.70 mg, 2.88 mmol) and TEA (5.9 g, 57.58 mmol) at 25 °C under N2. The mixture was stirred at 50 °C for 12 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (80 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 = 448.2 [M+H]+. [0267] cis-2-(3-nitrophenyl)cyclobutane-1-carboxylic acid: To a solution of tert-butyl (cis-2-(3- nitrophenyl)cyclobutane-1-carbonyl)(quinolin-8-yl)carbamate (8 g, 17.88 mmol) in THF (100 mL) and H2O (50 mL) was added LiOH.H2O (4.5 g, 107.27 mmol) and H2O2 (10.2 g, 89.39 mmol) at 0 °C under N2. The mixture was stirred at 80 °C for 12 h. The mixture was poured into sat. aq. Na2S2O3 and washed with EtOAc (50 mL). The aqueous phase was adjusted to pH = 3~4 with 1 M HCl and was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 220.1 [M-H]-. [0268] cis-2-(3-nitrophenyl)cyclobutane-1-carboxamide: To a solution of cis-2-(3- nitrophenyl)cyclobutane-1-carboxylic acid (3.2 g, 14.47 mmol) in DCM (30 mL) was added NH4Cl (1.6 g, 28.93 mmol), DIEA (5.7 g, 43.40 mmol), HOBt (3 g, 21.70 mmol) and EDCI (4.2 g, 21.70 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to provide the titled compound. LCMS: m/z = 221.1 [M+H]+. [0269] cis-2-(3-nitrophenyl)cyclobutane-1-carbonitrile: To a solution of cis-2-(3- nitrophenyl)cyclobutane-1-carboxamide (2.1 g, 9.54 mmol) and pyridine (3.8 g, 47.68 mmol) in 1,4- dioxane (5 mL) was added dropwise TFAA (4.1 g, 19.07 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (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 = 203.1 [M+H]+. [0270] cis-2-(3-aminophenyl)cyclobutane-1-carbonitrile: To a solution of cis-2-(3- nitrophenyl)cyclobutane-1-carbonitrile (1.7 g, 8.41 mmol) in EtOH (20 mL) and H2O (8 mL) was added NH4Cl (2.3 g, 42.04 mmol) and Fe (2.4 g, 42.04 mmol) at 25 °C under N2. The mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the resulting residue was added H2O (10 mL) and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 172.9 [M+H]+. [0271] cis-2-(5-amino-2-chlorophenyl)cyclobutane-1-carbonitrile: To a solution of cis-2-(3- aminophenyl)cyclobutane-1-carbonitrile (900 mg, 5.23 mmol) in MeCN (20 mL) was added NCS (697 mg, 5.23 mmol) at 20 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 207.1 [M+H]+. Intermediate 8 cis-2-(5-amino-2-methylphenyl)cyclobutane-1-carbonitrile
Figure imgf000103_0001
[0272] cis-2-(2-methyl-5-nitrophenyl)-N-(quinolin-8-yl)cyclobutane-1-carboxamide: To a solution of N-(quinolin-8-yl)cyclobutanecarboxamide (3 g, 13.26 mmol) in DCE (50 mL) was added 2-iodo-1- methyl-4-nitro-benzene (10.46 g, 39.77 mmol), dibenzyl hydrogen phosphate (738 mg, 2.65 mmol), AgOAc (4.43 g, 26.52 mmol) and Pd(oAc)2 (595 mg, 2.65 mmol) at 25 °C under N2. The mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the titled compound. LCMS: m/z = 362.1 [M+1]+ [0273] tert-butyl (cis-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carbonyl)(quinolin-8-yl)carbamate: To a mixture of cis-2-(2-methyl-5-nitrophenyl)-N-(quinolin-8-yl)cyclobutane-1-carboxamide (730 mg, 2.02 mmol) in MeCN (10 mL) was added TEA (409 mg, 4.04 mmol), Boc2O (970 mg, 4.44 mmol) and DMAP (25 mg, 0.002 mmol) at 20 °C under N2. The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to the titled compound. LCMS: m/z = 362.1 [M-Boc+H]+. [0274] cis-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxylic acid: To a mixture of tert-butyl (cis- 2-(2-methyl-5-nitrophenyl)cyclobutane-1-carbonyl)(quinolin-8-yl)carbamate (760 mg, 1.65 mmol) in THF (6 mL) and H2O (3 mL) was added H2O2 (3.73 g, 32.94 mmol, 30% purity) and LiOH.H2O (415 mg, 9.88 mmol) at 0 °C under N2. The mixture was stirred at 80 °C for 12 h. The mixture was poured into sat. aq. Na2SO3 (30 mL) and washed with EtOAc (3 × 10 mL). The aqueous phase was adjusted to pH = 3-4 with 1 M HCl 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 1:1) to provide the titled compound. LCMS: m/z = 234.1 [M-H]-. [0275] cis-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxamide: To a mixture of cis-2-(2-methyl- 5-nitrophenyl)cyclobutane-1-carboxylic acid (300 mg, 1.28 mmol) and NH4Cl (81.86 mg, 1.53 mmol) in DMF (5 mL) was added DIEA (659 mg, 5.10 mmol), HOBt (207 mg, 1.53 mmol) and EDCI (293 mg, 1.53 mmol) at 20 °C under N2. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 235.0 [M+H]+. [0276] cis-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carbonitrile: To a mixture of cis-2-(2-methyl-5- nitrophenyl)cyclobutane-1-carboxamide (200 mg, 0.85 mmol) in 1,4-dioxane (3 mL) was added pyridine (294 mg, 3.72 mmol) and TFAA (1.51 g, 7.19 mmol) at 0 °C under N2. The reaction mixture was stirred at 20 °C for 3 h. The mixture was adjusted to pH = 7-8 with sat. aq. 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 to give the titled compound. [0277] cis-2-(5-amino-2-methylphenyl)cyclobutane-1-carbonitrile: To a mixture of cis-2-(2-methyl- 5-nitrophenyl)cyclobutane-1-carbonitrile (150 mg, 0.69 mmol) in EtOH (5 mL) and H2O (1 mL) was added Fe (194 mg, 3.47 mmol) and NH4Cl (185 mg, 3.47 mmol) at 20 °C under N2. The mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through a pad of Celite ^ and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 187.2 [M+H]+. Intermediate 9 4-(5-amino-2-methylphenyl)-1-methylpyrrolidin-2-one
Figure imgf000105_0001
[0278] methyl (E)-3-(2-methyl-5-nitrophenyl)acrylate: To a mixture of 2-iodo-1-methyl-4- nitrobenzene (5 g, 19 mmol) and methyl prop-2-enoate (4.91 g, 57.03 mmol) in DMF (100 mL) was added TEA (3.85 g, 38.02 mmol) and Pd(PPh3)4 (3.29 g, 2.85 mmol) at 25 °C under N2. The mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was 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 = 222.1 [M+H]+. [0279] methyl 3-(2-methyl-5-nitrophenyl)-4-nitrobutanoate: To a mixture of methyl (E)-3-(2-methyl- 5-nitrophenyl)acrylate (500 mg, 2.26 mmol) and MeNO2 (1.38 g, 22.60 mmol) in MeCN (5 mL) was added dropwise DBU (344 mg, 2.26 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. The mixture was adjusted to pH = 1-2 by 1 M HCl and extracted with EtOAc (3 × 5 mL). The combined organic layers were combined and 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. [0280] 4-(5-amino-2-methylphenyl)pyrrolidin-2-one: To a solution of methyl 3-(2-methyl-5- nitrophenyl)-4-nitrobutanoate (390 mg, 1.38 mmol) in EtOH (10 mL) was added Raney-Ni (50 mg, 0.58 mmol) under Ar2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 Psi) at 50 °C for 12 h. The reaction mixture was filtered through a pad of Celite ^ and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 191.0 [M+H]+. [0281] 4-(5-amino-2-methylphenyl)-1-methylpyrrolidin-2-one: To a mixture of 4-(5-amino-2- methylphenyl)pyrrolidin-2-one (100 mg, 0.53 mmol) in DMF (3 mL) was added NaH (21 mg, 0.53 mmol, 60% in mineral oil) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h before MeI (75 mg, 0.53 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 12 h, quenched by addition of sat. aq. 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 = 205.3 [M+H]+. Intermediate 10 4-methyl-3-(1-methylazetidin-3-yl)aniline
Figure imgf000106_0001
[0282] tert-butyl 3-(2-methyl-5-nitrophenyl)azetidine-1-carboxylate: To a mixture of 4,4,5,5- tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborolane (10 g, 38.01 mmol) in toluene (50 mL) and H2O (50 mL) was added tert-butyl 3-iodoazetidine-1-carboxylate (21.52 g, 76.02 mmol), ethanol (50 mL), Na2CO3 (12.09 g, 114.03 mmol) and Pd(dppf)Cl2·CH2Cl2 (3.10 g, 3.80 mmol) at 25 °C under N2. The mixture was stirred at 80 °C for 8 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 5:1) to give the titled compound. LCMS: m/z = 237.0 [M-t-Bu+H]+. [0283] 3-(2-methyl-5-nitrophenyl)azetidine: To a mixture of tert-butyl 3-(2-methyl-5- nitrophenyl)azetidine-1-carboxylate (3 g, 10.26 mmol) in DCM (40 mL) was added TFA (15.40 g, 135.06 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h and then concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: YMC Triart C18250 × 50 mm × 7 μm; mobile phase: A: 20 mM FA in water; B: MeCN; B% in A: B%: 0%-25%, over 20 min) to give the titled compound. LCMS: m/z = 193.0 [M+H]+. [0284] 1-methyl-3-(2-methyl-5-nitrophenyl)azetidine: To a stirred solution of 3-(2-methyl-5- nitrophenyl)azetidine (0.27 g, 1.40 mmol) in DCM (4 mL) was added HCHO (139.18 mg, 4.64 mmol) and AcOH (168.71 mg, 2.81 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 0.5 h before adding NaBH(OAc)3 (1.19 g, 5.62 mmol). The mixture was stirred at 25 °C for 11.5 h, diluted with sat. aq. NH4Cl (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 prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 μm; mobile phase: A: 20 mM FA in water; B: MeCN; B% in A: 0%-28%, over 10 min) to give the titled compound. LCMS: m/z = 207.2 [M+H]+. [0285] 4-methyl-3-(1-methylazetidin-3-yl)aniline: To a mixture of 1-methyl-3-(2-methyl-5-nitro- phenyl)azetidine (120 mg, 0.58 mmol) and NH4Cl (156 mg, 2.91 mmol) in H2O (3 mL) and MeOH (3 mL) was added Fe (97 mg, 1.75 mmol) at 20 °C. The mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered through a pad of Celite ^ and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 177.2 [M+H]+. Intermediate 11 cis-2-(5-amino-2-chlorophenyl)cyclopropane-1-carbonitrile
Figure imgf000107_0001
[0286] ethyl cis-2-(5-amino-2-chlorophenyl)cyclopropane-1-carboxylate: To a solution of 3-bromo- 4-chloro-aniline (5 g, 24.22 mmol) and ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopropanecarboxylate (8.7 g, 36.33 mmol) in 1,4-dioxane (80 mL) and H2O (8 mL) was added K2CO3 (16.7 g, 121.08 mmol) and Pd(dppf)Cl2 (1.8 g, 2.42 mmol) at 25 °C under N2. The mixture was stirred at 120 °C for 3 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 = 240.1 [M+H]+. [0287] ethyl cis-2-(5-((tert-butoxycarbonyl)amino)-2-chlorophenyl)cyclopropane-1-carboxylate: To a solution of ethyl cis-2-(5-amino-2-chloro-phenyl)cyclopropanecarboxylate (1 g, 4.17 mmol) in MeCN (15 mL) was added Boc2O (1.8 g, 8.34 mmol), TEA (1.3 g, 12.52 mmol) and DMAP (51 mg, 0.41 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 284.1 [M-t-Bu+H]+. [0288] cis-2-(5-((tert-butoxycarbonyl)amino)-2-chlorophenyl)cyclopropane-1-carboxylic acid: To a solution of ethyl cis-2-(5-(tert-butoxycarbonylamino)-2-chloro-phenyl]cyclopropanecarboxylate (840 mg, 2.47 mmol) in EtOH (8 mL) and H2O (2 mL) was added NaOH (396 mg, 9.89 mmol) at 20 °C. The mixture was stirred at 40 °C for 12 h. The mixture was adjusted to pH = 4~5 with 1M HCl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 310.1 [M-H]-. [0289] tert-butyl (4-chloro-3-(cis-2-cyanocyclopropyl)phenyl)carbamate: To a solution of cis-2-(5- ((tert-butoxycarbonyl)amino)-2-chlorophenyl)cyclopropane-1-carboxylic acid (310 mg, 0.99 mmol) in THF (5 mL) was added Burgess reagent (475 mg, 2.00 mmol). The mixture was stirred at 65 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 237.1 [M-t-Bu+H]+. [0290] cis-2-(5-amino-2-chlorophenyl)cyclopropane-1-carbonitrile: A solution of tert-butyl (4- chloro-3-(cis-2-cyanocyclopropyl)phenyl)carbamate (200 mg, 0.68 mmol) was added 4 M HCl in EtOAc (10 mL). The mixture was stirred at 25 °C for 2 h and then concentrated under reduce pressure to give the titled compound. Intermediate 12 1,3-dioxoisoindolin-2-yl bicyclo[1.1.1]pentane-1-carboxylate
Figure imgf000108_0001
[0291] To a mixture of bicyclo[1.1.1]pentane-1-carboxylic acid (1 g, 8.92 mmol) in DCM (50 mL) was added 2-hydroxyisoindoline-1,3-dione (1.45 g, 8.92 mmol), DMAP (109 mg, 0.90 mmol) and DCC (2.02 g, 9.81 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 16 h and then filtered through a pad of Celite ^. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (PE:EtOAc = 7:1 to 5:1) to give the titled compound.
Intermediates 13-15 1-(2-(3-nitrophenyl)cyclobutyl)-1H-1,2,3-triazole, 2-(trans-2-(3-nitrophenyl)cyclobutyl)-2H-1,2,3- triazole, 2-(cis-2-(3-nitrophenyl)cyclobutyl)-2H-1,2,3-triazole
Figure imgf000109_0001
[0292] 2-bromocyclobut-1-en-1-yl diethyl phosphate: To a solution of 2-bromocyclobutan-1-one (10 g, 67.12 mmol) in CCl4 (50 mL) was added NBS (11.94 g, 67.12 mmol) and BPO (3.26 g, 13.42 mmol) at 25 °C. The reaction mixture was heated to 70 °C and stirred for 4 h. Then the reaction mixture was filtered, washed with toluene (40 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene (100 mL) and triethyl phosphite (13.38 g, 80.54 mmol) was added at 25 °C. The reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled compound. [0293] diethyl (2-(3-nitrophenyl)cyclobut-1-en-1-yl) phosphate: To a solution of 2-bromocyclobut-1- en-1-yl diethyl phosphate (13.40 g, 47.01 mmol) in toluene (200 mL) at 25 °C under N2 was added (3- nitrophenyl)boronic acid (11.77 g, 70.51 mmol), K3PO4 (29.93 g, 141.02 mmol), RuPhos (4.39 g, 9.40 mmol) and Pd(OAc)2 (1.06 g, 4.70 mmol). The reaction mixture was heated to 60 °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 = 5:1 to 2:1) to give the titled compound. LCMS: m/z = 328.1 [M+H]+.2-(3-nitrophenyl)cyclobutan-1-one: To a solution of diethyl (2-(3-nitrophenyl)cyclobut-1-en-1-yl) phosphate (13 g, 39.72 mmol) in 1,4-dioxane (200 mL) at 25 °C was added HCl (200 mL, 3 M). The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with H2O (100 mL), adjusted to pH = 7 with aq. sat. NaHCO3 at 0 °C and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. [0294] 2-(3-nitrophenyl)cyclobutan-1-ol: To a solution of 2-(3-nitrophenyl)cyclobutan-1-one (2.48 g, 12.97 mmol) in MeOH (50 mL) at 0 °C under N2 was added NaBH4 (491 mg, 12.97 mmol) in portions. The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched by addition Of aq. sat. NH4Cl (50 mL) and extracted with EtOAc (3 × 20 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 = 193.9 [M+H]+. [0295] 2-(3-nitrophenyl)cyclobutyl methanesulfonate: To a solution of 2-(3-nitrophenyl)cyclobutan- 1-ol (960 mg, 4.97 mmol) in DCM (20 mL) at 0 °C under N2 was added TEA (1.01 g, 9.94 mmol) and MsCl (854 mg, 7.45 mmol). The reaction mixture was warmed to 25 °C and stirred for 1 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 = 3:1 to 1:1) to give the titled compound. [0296] 1-(2-(3-nitrophenyl)cyclobutyl)-1H-1,2,3-triazole, 2-(cis-2-(3-nitrophenyl)cyclobutyl)-2H- 1,2,3-triazole and 2-(trans-2-(3-nitrophenyl)cyclobutyl)-2H-1,2,3-triazole: To a solution of 2-(3- nitrophenyl)cyclobutan-1-ol (1.15 g, 4.24 mmol) in DMF (16 mL) at 25 °C was added 2H-1,2,3-triazole (1.71 g, 16.96 mmol) and Cs2CO3 (4.14 g, 12.72 mmol). The reaction 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 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give 1-(2-(3-nitrophenyl)cyclobutyl)-1H-1,2,3-triazole (Rf = 0.3 on TLC) as a mixture of cis and trans isomers (Intermediate 13) LCMS: m/z = 245.0 [M+H]+, 2- (cis-2-(3-nitrophenyl)cyclobutyl)-2H-1,2,3-triazole (Rf = 0.75 on TLC) (Intermediate 14) LCMS: m/z = 245.0 [M+H]+ and 2-(trans-2-(3-nitrophenyl)cyclobutyl)-2H-1,2,3-triazole (Rf = 0.65 on TLC) (Intermediate 15). LCMS: m/z = 245.0 [M+H]+. Intermediates 16 and 17 3-(trans-2-(1H-1,2,3-triazol-1-yl)cyclobutyl)aniline and 3-(cis-2-(1H-1,2,3-triazol-1- yl)cyclobutyl)aniline
Figure imgf000110_0001
[0297] 3-(trans-2-(1H-1,2,3-triazol-1-yl)cyclobutyl)aniline and 3-(cis-2-(1H-1,2,3-triazol-1- yl)cyclobutyl)aniline: Solution 1: 1-[2-(3-nitrophenyl)cyclobutyl]triazole (200 mg, 0.81 mmol) (Intermediate 13) in (MeOH, 4 mL) and (THF, 4 mL). The fixed bed (named FLR1, volume 5 mL) was packed with granular catalyst 1% Pt/C (3 g, 0.81 mmol). The H2 backpressure regulator was adjusted to 1.5 MPa, and the flow rate of H2 was 30 mL/min. 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, 50 °C) and the reaction mixture was collected from the reactor output. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, EtOAc) to give 3-(trans-2-(1H-1,2,3-triazol-1- yl)cyclobutyl)aniline (Rf = 0.45 on TLC) Intermediate 16, LCMS: m/z = 215.0 [M+H]+ and 3-(cis-2-(1H- 1,2,3-triazol-1-yl)cyclobutyl)aniline (Rf = 0.40 on TLC) Intermediate 17. LCMS: m/z = 215.0 [M+H]+. Intermediates 18 and 19 4-(cis-2-(3-nitrophenyl)cyclobutyl)-4H-1,2,4-triazole and 4-(trans-2-(3-nitrophenyl)cyclobutyl)-4H- 1,2,4-triazole
Figure imgf000111_0001
[0298] 2-methyl-N-(2-(3-nitrophenyl)cyclobutylidene)propane-2-sulfinamide: To a solution of 2-(3- nitrophenyl)cyclobutanone (5 g, 26.15 mmol) and 2-methylpropane-2-sulfinamide (3.80 g, 31.38 mmol) in THF (50 mL) at 25 °C was added Ti(i-PrO)4 (11.93 g, 52.31 mmol). The reaction mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was adjusted to pH = 7 by addition Of aq. sat. NaHCO3, filtered and the filtrate was extracted with EtOAc (3 × 20 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 = 5:1 to 3:1) to give the titled compound. LCMS: m/z = 295.1 [M+H]+. [0299] 2-methyl-N-(2-(3-nitrophenyl)cyclobutyl)propane-2-sulfinamide: To a solution of 2-methyl- N-(2-(3-nitrophenyl)cyclobutylidene)propane-2-sulfinamide (6.9 g, 23.44 mmol) in MeOH (70 mL) at 0 °C was added NaBH4 (975 mg, 25.78 mmol) in portions. The reaction mixture was warmed to 25 °C and stirred for 3 h. The reaction mixture was quenched by H2O (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 5:1) to give the titled compound. LCMS: m/z = 297.1 [M+H]+. [0300] 2-(3-nitrophenyl)cyclobutanamine•hydrochloride: A solution of 2-methyl-N-(2-(3- nitrophenyl)cyclobutyl)propane-2-sulfinamide (800 mg, 2.70 mmol) in HCl/EtOAc (15 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 193.1 [M+H]+. [0301] 4-(cis-2-(3-nitrophenyl)cyclobutyl)-4H-1,2,4-triazole and 4-(trans-2-(3- nitrophenyl)cyclobutyl)-4H-1,2,4-triazole: To a solution of 2-(3- nitrophenyl)cyclobutanamine•hydrochloride (900 mg, 3.94 mmol) in toluene (10 mL) at 25 °C was added (1E,N'Z)-N'-((dimethylamino)methylene)-N,N-dimethylformohydrazonamide (672 mg, 4.72 mmol), DIEA (509 mg, 3.94 mmol) and p-TsOH (813 mg, 4.72 mmol). The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:(EtOAc:EtOH = 3:1) = 1:1 to 1:3, 0.1% TEA) to give 4-(cis-2-(3- nitrophenyl)cyclobutyl)-4H-1,2,4-triazole (Rf = 0.20 on TLC) Intermediate 18, LCMS: m/z = 245.2 [M+H]+ and 4-(trans-2-(3-nitrophenyl)cyclobutyl)-4H-1,2,4-triazole (Rf = 0.25 on TLC) Intermediate 19. LCMS: m/z = 245.2 [M+H]+. Intermediate 20 cis-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane
Figure imgf000112_0001
[0302] 2-methyl-N-(3-(trifluoromethyl)cyclohexylidene)propane-2-sulfinamide: To a solution of 3- (trifluoromethyl)cyclohexanone (1 g, 6.02 mmol) and 2-methylpropane-2-sulfinamide (875 mg, 7.22 mmol) in THF (25 mL) at 0 °C under N2 was added Ti(i-PrO)4 (2.05 g, 7.22 mmol). The reaction mixture was warmed to 25 °C and stirred for 16 h. The reaction mixture was quenched by addition Of aq. sat. NaHCO3 (20 mL) and filtered through a Celite ^ pad. The filtrate was diluted with H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:MTBE = 5:1 to 1:1) to give the titled compound. LCMS: m/z = 270.1 [M+H]+. [0303] 2-methyl-N-(3-(trifluoromethyl)cyclohexyl)propane-2-sulfinamide: To a solution of 2- methyl-N-(3-(trifluoromethyl)cyclohexylidene)propane-2-sulfinamide (1 g, 3.71 mmol) in THF (15 mL) at –5 °C under N2 was added L-Selectride ^ (7.43 mL, 7.43 mmol, 1 M in THF). The reaction mixture was warmed to 25 °C and stirred for 16 h. The reaction mixture was quenched by addition Of aq. sat. NH4Cl (30 mL) and extracted with EtOAc (3× 15 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 = 5:1 to 1:1) to give the titled compound. [0304] 3-(trifluoromethyl)cyclohexanamine: A solution of 2-methyl-N-(3- (trifluoromethyl)cyclohexyl)propane-2-sulfinamide (200 mg, 0.73 mmol) in HCl/EtOAc (5 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was slurried with MTBE (3 mL) and the precipitate was collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m/z = 168.2 [M+H]+. [0305] N-(3-(trifluoromethyl)cyclohexyl)picolinamide: To a solution of (3- (trifluoromethyl)cyclohexanamine hydrochloride (210 mg, 1.03 mmol) in DCM (5 mL) at 0 °C under N2 was added pyridine-2-carboxylic acid (165 mg, 1.34 mmol), DIEA (666 mg, 5.16 mmol) and T4P (1.11 g, 1.55 mmol, 50% w/w in EtOAc). The reaction mixture was warmed to 25 °C and stirred for 4 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled compound. LCMS: m/z = 273.2 [M+H]+. [0306] pyridin-2-yl((cis)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptan-6-yl)methanone: To a solution of (N-(3-(trifluoromethyl)cyclohexyl)picolinamide (1.10 mmol) in anisole (18 mL) at 25 °C under N2 was added AgOAc (1.10 g, 6.61 mmol), benzoquinone (119 mg, 1.10 mmol), Na3PO4 (1.08 g, 6.61 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (3.24 g, 11.02 mmol) and Pd(OAc)2 (99 mg, 0.44 mmol). The reaction mixture was heated to 145 °C and stirred for 16 h. The reaction mixture was cooled to 25 °C under N2 and Pd(OAc)2 (99 mg, 0.44 mmol) was added to the mixture. The reaction mixture was warmed to 145 °C and stirred for 16 h. The reaction mixture was filtered through a Celite ^ pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:MTBE = 3:1 to 1:1) to give the titled compound. LCMS: m/z = 271.1 [M+H]+. [0307] cis-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane: To a solution of pyridin-2-yl(3- (trifluoromethyl)-6-azabicyclo[3.1.1]heptan-6-yl)methanone (110 mg, 0.40 mmol) in EtOH (2 mL) at 25 °C was added NaOH (163 mg, 4.07 mmol). The reaction mixture was heated to 90 °C stirred for 16 h. Then the reaction mixture was cooled to 0 °C and adjusted to pH = 2–3 with HCl (6 M), then lyophilization to give the titled compound. Intermediate 21 cis-2-(5-amino-2-chloro-3-fluorophenyl)cyclobutane-1-carbonitrile
Figure imgf000114_0001
[0308] cis-2-(3-fluoro-5-nitrophenyl)-N-(quinolin-8-yl)cyclobutane-1-carboxamide: To a solution of 1-fluoro-3-iodo-5-nitrobenzene (10 g, 37.45 mmol) and N-(quinolin-8-yl)cyclobutanecarboxamide (22.03 g, 97.38 mmol) in DCE (100 mL) at 25 °C under N2 was added AgOAc (12.50 g, 74.91 mmol), dibenzyl hydrogen phosphate (2.08 g, 7.49 mmol) and Pd(OAc)2 (1.68 g, 7.49 mmol). The reaction mixture was heated to 110 °C and stirred for 5 h. The reaction mixture was filtered through a pad of Celite ^. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 5:1) to give the titled compound. LCMS: m/z =366.1 [M+H]+. [0309] cis-2-(3-fluoro-5-nitrophenyl)cyclobutane-1-carboxylic acid: A solution of cis-2-(3-fluoro-5- nitrophenyl)-N-(quinolin-8-yl)cyclobutane-1-carboxamide (7 g, 19.16 mmol) in H2SO4 (18 mL) and H2O (54 mL) was heated to 120 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, poured into H2O (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give titled compound. LCMS: m/z = 238.1 [M-H]-. [0310] cis-2-(3-fluoro-5-nitrophenyl)cyclobutane-1-carboxamide To a solution of cis-2-(3-fluoro-5- nitrophenyl)cyclobutane-1-carboxylic acid (3.5 g, 14.63 mmol) in DCM (35 mL) at 20 °C was added NH4Cl (3.91 g, 73.16 mmol), DIEA (11.35 g, 87.79 mmol), HOBt (2.97 g, 21.95 mmol) and EDCI (4.21 g, 21.95 mmol). The reaction mixture was stirred for 16 h, diluted with H2O (30 mL) and extracted with DCM (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 = 1:0 to 1:1) to give the titled compound. LCMS: m/z = 239.1 [M+H]+. [0311] cis-2-(3-fluoro-5-nitrophenyl)cyclobutane-1-carbonitrile: To a solution of cis-2-(3-fluoro-5- nitrophenyl)cyclobutane-1-carboxamide (2 g, 8.40 mmol) in 1,4-dioxane (40 mL) at 0 °C was added pyridine (3.32 g, 41.98 mmol) and TFAA (3.53 g, 16.79 mmol) dropwise. The reaction mixture was warmed to 20 °C and stirred for 12 h. The mixture was diluted with H2O (20 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. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to give the titled compound. [0312] cis-2-(3-amino-5-fluorophenyl)cyclobutane-1-carbonitrile: To a solution of cis-2-(3-fluoro-5- nitrophenyl)cyclobutane-1-carbonitrile (1.5 g, 6.81 mmol) in EtOH (20 mL) and H2O (5 mL) at 20 °C under N2 was added Fe (1.90 g, 34.06 mmol) and NH4Cl (1.82 g, 34.06 mmol). The reaction mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to give the titled compound. LCMS: m/z = 191.2 [M+H]+. [0313] cis-2-(5-amino-2-chloro-3-fluorophenyl)cyclobutane-1-carbonitrile: To a solution of cis-2-(3- amino-5-fluorophenyl)cyclobutane-1-carbonitrile (1 g, 5.26 mmol) in MeCN (10 mL) at 20 °C was added NCS (842 mg, 6.31 mmol) and the reaction mixture was 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 (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 1:1) to give the titled compound. LCMS: m/z = 225.1 [M+H]+. Intermediate 22 potassium (3-(benzyloxy)cyclobutyl)trifluoroborate
Figure imgf000115_0001
[0314] cis-3-(benzyloxy)cyclobutanol: To a solution of 3-(benzyloxy)cyclobutanone (30 g, 170.25 mmol) in MeOH (300 mL) at 0 °C was added NaBH4 (6.44 g, 170.25 mmol) portionwise. The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was poured into H2O (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 7:1 to 3:1) to give the titled compound. [0315] cis-3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate: To a solution of cis-3- (benzyloxy)cyclobutanol (28 g, 157.10 mmol) in DCM (500 mL) at 0 °C was added TEA (79.49 g, 785.51 mmol) and 4-methylbenzene-1-sulfonyl chloride (44.93 g, 235.65 mmol) in several portions. The reaction mixture was warmed to 25 °C and stirred for 12 h. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 0:1), concentrated under reduced pressure and triturated with PE:MTBE = 10:1. The resulting solid was collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m/z = 333.1 [M+H]+. [0316] ((trans-3-iodocyclobutoxy)methyl)benzene: To a solution of cis-3-(benzyloxy)cyclobutyl 4- methylbenzenesulfonate (15 g, 45.12 mmol) in butan-2-one (200 mL) at 25 °C under N2 was added NaI (33.82 g, 225.62 mmol). The mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (2 × 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 = 15:1 to 10:1) to give the titled compound. [0317] 2-(3-(benzyloxy)cyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of ((trans-3-iodocyclobutoxy)methyl)benzene (9.1 g, 31.58 mmol) in DMF (200 mL) at 25 °C under N2 was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (12.03 g, 47.38 mmol), lithium methoxide (2.64 g, 69.48 mmol), PPh3 (1.08 g, 4.11 mmol) and CuI (601 mg, 3.16 mmol). The reaction mixture was stirred at 35 °C for 12 h, filtered through a Celite ^ pad and the filtrate was diluted with H2O (400 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m/z = 289.2 [M+H]+. [0318] potassium (3-(benzyloxy)cyclobutyl)trifluoroborate: To a solution of 2-(3- (benzyloxy)cyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.5 g, 29.49 mmol) in MeOH (150 mL) at 25 °C was added KHF2 (16.13 g, 206.46 mmol). The reaction mixture was heated to 70 °C and stirred for 6 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added MeCN (30 mL), the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was slurried with i-PrOH (50 mL), the precipitate was collected by filtration and dried under reduced pressure to give the titled compound. Intermediate 23 3-(5-amino-2-chlorophenyl)cyclobutanol
Figure imgf000117_0001
[0319] 3-(3-(benzyloxy)cyclobutyl)-4-chloroaniline: To a solution of potassium (3- (benzyloxy)cyclobutyl)trifluoroborate (5.51 g, 20.56 mmol) and 3-bromo-4-chloroaniline (2.83 g, 13.71 mmol) in toluene (80 mL) and H2O (8 mL) at 25 °C under N2 was added K2CO3 (3.79 g, 27.41 mmol) and Pd(dppf)Cl2 (1.00 g, 1.37 mmol). The reaction mixture was heated to 120 °C and stirred for 12 h. The reaction mixture was filtered through a Celite ^ pad and the filtrate was diluted with H2O (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give the titled compound. LCMS: m/z = 288.1 [M+H]+. [0320] 3-(5-amino-2-chlorophenyl)cyclobutanol: To a solution of 3-(3-(benzyloxy)cyclobutyl)-4- chloroaniline (2 g, 6.95 mmol) in DCM (40 mL) at 0 °C under N2 was added BCl3 (2.44 g, 20.85 mmol, 1 M in DCM) and the reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was adjusted to pH = 7–8 by addition Of aq. sat. NaHCO3 (100 mL) at 0 °C and extracted with DCM (3× 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled compound. Intermediate 24 3-(trans-2-(difluoromethyl)cyclobutyl)aniline and 3-(cis-2-(difluoromethyl)cyclobutyl)aniline
Figure imgf000117_0002
[0321] cyclobut-1-enecarboxylic acid: To a solution of ethyl 1-bromocyclobutanecarboxylate (10 g, 48.29 mmol) in toluene (200 mL) at 20 °C was added KOH (10.84 g, 193.18 mmol). The reaction mixture was heated to110 °C and stirred for 1 h. The reaction mixture was diluted with H2O (100 mL) and extracted with MTBE (50 mL). The aqueous phase was adjusted to pH = 2 by addition of HCl (6M) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. [0322] benzyl cyclobut-1-enecarboxylate: To a solution of cyclobut-1-enecarboxylic acid (4.8 g, 48.93 mmol) and TEA (14.85 g, 146.79 mmol) in THF (100 mL) at 0 °C was dropwise added methyl carbonochloridate (9.25 g, 97.86 mmol). The reaction mixture was warmed to 20 °C and stirred for 1 h. Benzyl alcohol (15.87 g, 146.79 mmol) was added and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was cooled to 0 °C and diluted with H2O (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give the titled compound. [0323] benzyl 2-(3-nitrophenyl)cyclobutanecarboxylate: To a solution of benzyl cyclobut-1- enecarboxylate (5 g, 26.56 mmol) and (3-nitrophenyl)boronic acid (8.87 g, 53.13 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) at 25 °C under N2 was added TEA (8.06 g, 79.69 mmol) and [Rh(cod)Cl]2 (655 mg, 1.33 mmol). The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was filtered through a pad of Celite ^ and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. [0324] (2-(3-nitrophenyl)cyclobutyl)methanol: To a solution of benzyl 2-(3- nitrophenyl)cyclobutanecarboxylate (3.2 g, 10.28 mmol) in DCM (40 mL) at –78 °C under N2 was added DIBAL-H (19.53 mL, 19.53 mmol, 1 M in toluene). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was quenched by addition Of aq. sat. Na2S2O3 (100 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to provide the titled compound. [0325] 2-(3-nitrophenyl)cyclobutanecarbaldehyde: To a solution of (2-(3- nitrophenyl)cyclobutyl)methanol (1.1 g, 5.31 mmol) in DCM (20 mL) at 0 °C under N2 was added DMP (2.93 g, 6.90 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was quenched by addition Of aq. sat. Na2S2O3 (30 mL) at 0 °C and extracted with DCM (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 = 5:1 to 3:1) to give the titled compound. [0326] 1-(2-(difluoromethyl)cyclobutyl)-3-nitrobenzene: To a solution of 2-(3- nitrophenyl)cyclobutanecarbaldehyde (1.3 g, 6.33 mmol) in DCM (25 mL) at –78 °C under N2 was added DAST (2.55 g, 15.84 mmol). The reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was quenched by slow addition of aq. sat. NaHCO3 (20 mL) at 0 °C and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the titled compound. [0327] 3-(2-(difluoromethyl)cyclobutyl)aniline: To a solution of 1-(2-(difluoromethyl)cyclobutyl)-3- nitrobenzene (350 mg, 1.54 mmol) in EtOH (10 mL) and H2O (2 mL) at 0 °C under N2 was added Fe (430 mg, 7.70 mmol) and NH4Cl (412 mg, 7.70 mmol). The reaction mixture was heated to 70 °C and stirred for 2 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 0:1) to give the titled compound. LCMS: m/z = 198.2 [M+H]+. [0328] 3-(trans-2-(difluoromethyl)cyclobutyl)aniline and 3-(cis-2- (difluoromethyl)cyclobutyl)aniline: The mixture of diastereomers was separated by SFC (DAICEL CHIRALCEL OD Preparative SFC System (250 mm × 30 mm × 10 µm); Mobile phase: A CO2, B: 0.1% NH3H2O in MeOH; B% in A: 15%-15%; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to provide the titled compounds. LCMS: m/z = 198.2 [M+H]+. Intermediate 25 and 26 (1R,2S)-2-(5-amino-2-chlorophenyl)cyclobutanecarbonitrile and (1S,2R)-2-(5-amino-2- chlorophenyl)cyclobutanecarbonitrile
Figure imgf000119_0001
[0329] The mixture of enantiomers (1.5 g, 7.27 mmol) was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 43%-43%; Flow rate: 70.00 g/min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-2-(5-amino-2-chlorophenyl)cyclobutanecarbonitrile (peak 1 in SFC) (Intermediate 25) and cis-2-(5-amino-2-chlorophenyl)cyclobutanecarbonitrile (peak 2 in SFC) (Intermediate 26).
Example 1 cis-N-(4-chloro-3-cyclobutyl-phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000120_0001
[0330] cis-6-[(4-chloro-3-cyclobutyl-phenyl)carbamoyl]-3-methyl-6-azabicyclo[3.1.1]heptane-1- carboxylic acid: To a solution of bis(trichloromethyl) carbonate (163 mg, 0.55 mmol) in THF (3 mL) was added a solution of 4-chloro-3-cyclobutyl-aniline (200 mg, 1.10 mmol) and TEA (334 mg, 3.30 mmol) in THF (3 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h before cis-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (Intermediate 5) (662 mg, 0.79 mmol) and TEA (219 mg, 2.17 mmol) were added. The mixture was stirred at 25 °C for 1 h. Water (3 drops) was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge BEH C18180 × 70 mm × 10 µm; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A: 10%-50%, over 20 min) to give the titled compound. LCMS: m/z = 363.0 [M+H]+ . [0331] cis-1-(acetamidocarbamoyl)-N-(4-chloro-3-cyclobutyl-phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-6-[(4-chloro-3-cyclobutyl- phenyl)carbamoyl]-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (100 mg, 0.27 mmol) and acetohydrazide (61 mg, 0.82 mmol) in DMF (2 mL) was added DIEA (106 mg, 0.82 mol) and HATU (157 mg, 0.41 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 419.1 [M+H]+. [0332] cis-N-(4-chloro-3-cyclobutyl-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-(4-chloro-3- cyclobutyl-phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (70 mg, 0.16 mmol) in MeCN (4 mL) was added p-TosCl (47 mg, 0.25 mmol) and Cs2CO3 (217 mg, 0.66 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge BEH C18150 × 40 mm × 10 um; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A: 40%-75%, over 10 min) to provide the titled compound. LCMS: m/z = 401.2 [M+H]+. Example 2 cis-N-(3-cyclobutyl-4-(trifluoromethyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000121_0001
[0333] 3-cyclobutyl-4-(trifluoromethyl)aniline: To a solution of 3-bromo-4-(trifluoromethyl)aniline (300 mg, 1.45 mmol) in DME (6 mL) was added bromocyclobutane (392 mg, 2.91 mmol), NiCl2.glyme (2 mg, 0.01 mmol), Na2CO3 (308 mg, 2.91 mmol), dtbbpy (2 mg, 0.01 mmol), tris(trimethylsilyl)silane (361 mg, 1.45 mmol), (IR(dF(CF3)ppy)2(bpy))PF6 (16 mg, 0.01 mmol) at 25 °C under N2. The reaction mixture was stirred for 16 h at 25 °C and irradiated with two 34 W blue LEDs (vials approximately 6 cm away from the light source) with a fan placed above for cooling. The reaction mixture was added to H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 5:1) to give the titled compound. LCMS: m/z = 216.1 [M+H]+. [0334] cis-6-((3-cyclobutyl-4-(trifluoromethyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of bis(trichloromethyl) carbonate (163 mg, 0.55 mmol) in THF (3 mL) was added the solution of 3-cyclobutyl-4-(trifluoromethyl)aniline (200 mg, 1.10 mmol) and TEA (334 mg, 3.30 mmol) in THF (3 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h before cis-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (Intermediate 5) (662 mg, 0.79 mmol) and TEA (218 mg, 2.17 mmol) were added. The mixture was stirred at 25 °C for 1 h. Water (3 drops) was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge BEH C18180 × 70 mm × 10 µm; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A: 10%-50%, over 20 min) to give the titled compound. LCMS: m/z = 397.1 [M+H]+. [0335] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(3-cyclobutyl-4-(trifluoromethyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-6-((3-cyclobutyl-4- (trifluoromethyl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (100 mg, 0.27 mmol) and acetohydrazide (61 mg, 0.82 mmol) in DMF (2 mL) was added DIEA (106 mg, 0.82 mmol) and HATU (157 mg, 0.41 mmol) at 0 °C under N2.The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the titled compound. LCMS: m/z = 453.3 [M+H]+. [0336] cis-N-(3-cyclobutyl-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- cyclobutyl-4-(trifluoromethyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (70 mg, 0.16 mmol) in MeCN (4 mL) was added p-TosCl (48 mg, 0.25 mmol) and Cs2CO3 (217.78 mg, 0.66 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3× 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge BEH C18150 × 40 mm × 10 µm; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A: 40%-75%, over 10 min) to give the titled compound. LCMS: m/z = 435.2 [M+H]+. Examples 3 and 4 cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2- cyanocyclobutyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide
Figure imgf000122_0001
[0337] cis-6-((4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of triphosgene (144 mg, 0.48 mmol) in THF (6 mL) was added TEA (294 mg, 2.90 mmol) and cis-2-(5-amino-2-chlorophenyl)cyclobutane-1- carbonitrile (200 mg, 0.96 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. Then cis-3- methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (Intermediate 5) (755 mg, 0.94 mmol) was added at 25 °C. The mixture was stirred at 20 °C for 2 h. Water (3 drops) was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250 × 70 mm × 10 µm; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A: 20%-50%, 20 min) to give the titled compound. LCMS: m/z = 388.2 [M+H]+. [0338] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-6-((4-chloro-3-(2- cyanocyclobutyl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (80 mg, 0.21 mmol) and acetohydrazide (23 mg, 0.31 mmol) in DMF (2 mL) was added HATU (157 mg, 0.41 mmol) and DIEA (54 mg, 0.41 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (2 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 = 444.1 [M+H]+. [0339] cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)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-(4- chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (80 mg, 0.18 mmol) in MeCN (3 mL) was added p-TosCl (138 mg, 0.72 mmol) and Cs2CO3 (88 mg, 0.27 mmol) at 25 °C under N2. The 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 prep-TLC (SiO2, EtOAc) to give the titled compound. LCMS: m/z = 426.1 [M+H]+. [0340] cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2- cyanocyclobutyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide: The mixture of diastereomers 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 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 cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (3, peak 1 in SFC) Example 3. LCMS: m/z = 426.1 [M+H]+ and cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (4, peak 2 in SFC) Example 4. LCMS: m/z = 426.1 [M+H]+. Example 5 cis-N-(3-(1-cyanoethyl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000124_0001
[0341] Methyl 2-cyano-2-(2-methyl-5-nitrophenyl)acetate: To a solution of 2-iodo-1-methyl-4- nitrobenzene (3 g, 11.41 mmol) and methyl 2-cyanoacetate (2 g, 21 mmol) in DMSO (60 mL) was added K2CO3 (5.67 g, 41 mmol) and CuI (217 mg, 1.14 mmol) at 20 °C under N2. The mixture was stirred at 120 °C for 12 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (60 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 = 235.1 [M+H]+. [0342] Methyl 2-cyano-2-(2-methyl-5-nitrophenyl)propanoate: To a solution of methyl 2-cyano-2-(2- methyl-5-nitrophenyl)acetate (1.20 g, 5.12 mmol) in DMSO (20 mL) was added K2CO3 (708 mg, 5.12 mmol) and MeI (2.18 g, 15.37 mmol) at 20 °C under N2. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to provide the titled compound. LCMS: m/z = 249.1 [M+H]+. [0343] 2-(2-methyl-5-nitrophenyl)propanenitrile: To a solution of methyl 2-cyano-2-(2-methyl-5- nitrophenyl)propanoate (500 mg, 2.01 mmol) in DMSO (5 mL) was added brine (0.5 mL, 2.01 mmol) at 20 °C under N2. The mixture was stirred at 140 °C for 5 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m/z = 191.1 [M+H]+. [0344] 2-(5-amino-2-methylphenyl)propanenitrile: To a solution of 2-(2-methyl-5- nitrophenyl)propanenitrile (280 mg, 1.47 mmol) in EtOH (10 mL) and H2O (2 mL) was added Fe (411 mg, 7.36 mmol) and NH4Cl (394 mg, 7.36 mmol) at 20 °C under N2. The mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered through a pad of Celite ^ and the filtrate was concentrated under reduced pressure. The crude product was triturated with DCM:MeOH (V:V = 10:1) (20 mL) at 20 °C for 15 min, filtered, and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 161.2 [M+H]+. [0345] cis-N-(3-(1-cyanoethyl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a solution of triphosgene (37 mg, 0.12 mmol) in THF (2 mL) was added 2-(5-amino-2- methylphenyl)propanenitrile (50 mg, 0.31 mmol) and TEA (95 mg, 90.94 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 1 h. TEA (90 mg, 0.89 mmol) and cis-3-methyl-6- azabicyclo[3.1.1]heptane (66 mg, 0.59 mmol) was added at 20 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 30%-60%, 8 min) to provide the titled compound. LCMS: m/z = 298.2 [M+H]+. Example 6 cis-N-(3-((trans-2-cyanocyclobutyl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide
Figure imgf000125_0001
[0346] cyclobut-1-ene-1-carboxylic acid: To a solution of ethyl 1-bromocyclobutane-1-carboxylate (20 g, 96.59 mmol) in toluene (200 mL) was added KOH (21.68 g, 386.35 mmol) at 20 °C under N2. The reaction mixture was stirred at 110 °C for 1 h. The reaction mixture was diluted with H2O (200 mL) at 0 °C and adjusted to pH = 2 with 6 M HCl. The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the titled compound. [0347] benzyl cyclobut-1-ene-1-carboxylate: To a solution of cyclobut-1-ene-1-carboxylic acid (9.5 g, 96.84 mmol) and TEA (29.40 g, 290.52 mmol) in THF (100 mL) was added dropwise methyl chloroformate (19.77 g, 209.17 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 1 h. Benzyl alcohol (31.42 g, 290.52 mmol) was added to above mixture at 0 °C under N2. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (80 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 10:1) to give the titled compound. [0348] benzyl 2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxylate: To a solution of (2-methyl-5- nitrophenyl)boronic acid (7.69 g, 42.50 mmol) in 1,4-dioxane (60 mL) and H2O (6 mL) was added benzyl cyclobut-1-ene-1-carboxylate (4 g, 21.25 mmol), TEA (6.45 g, 63.75 mmol) and [RuCl(COD)]2 (1.05 g, 2.13 mmol) at 25 °C under N2. The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered through a pad of Celite ^ and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. [0349] trans-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxylic acid: To a solution of benzyl 2-(2- methyl-5-nitrophenyl)cyclobutane-1-carboxylate (500 mg, 1.54 mmol) in 1,4-dioxane (10 mL) was added HCl (2M, 10 mL) at 20 °C. The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 234.1 [M-H]-. [0350] trans-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carboxamide: To a solution of trans-2-(2- methyl-5-nitrophenyl)cyclobutane-1-carboxylic acid (300 mg, 1.28 mmol) in DCM (4 mL) was added NH4Cl (82 mg, 1.53 mmol), DIEA (659 mg, 5.10 mmol), HOBt (207 mg, 1.53 mmol) and EDCI (293 mg, 1.53 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (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 = 5:1 to 3:1) to provide the titled compound. LCMS: m/z = 235.2 [M+H]+. [0351] trans-2-(2-methyl-5-nitrophenyl)cyclobutane-1-carbonitrile: To a solution of trans-2-(2- methyl-5-nitrophenyl)cyclobutane-1-carboxamide (250 mg, 1.07 mmol) in 1,4-dioxane (4 mL) was added pyridine (490 mg, 6.19 mmol) and TFAA (454 mg, 2.16 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m/z = 217.3 [M+H]+. [0352] trans-2-(5-amino-2-methylphenyl)cyclobutane-1-carbonitrile: To a mixture of trans-2-(2- methyl-5-nitrophenyl)cyclobutane-1-carbonitrile (150 mg, 0.69 mmol) and NH4Cl (186 mg, 3.47 mmol) in H2O (1 mL) and EtOH (5 mL) was added Fe (194 mg, 3.47 mmol) at 20 °C under N2. The mixture was stirred at 80 °C for 2 h and then filtered through a pad of Celite ^. The filtrate was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 187.4 [M+H]+. [0353] cis-N-(3-(trans-2-cyanocyclobutyl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a solution of triphosgene (40 mg, 0.13 mmol) in THF (2 mL) was added trans-2-(5- amino-2-methylphenyl)cyclobutane-1-carbonitrile (50 mg, 0.27 mmol) and TEA (54 mg, 0.54 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h before cis-3-methyl-6-azabicyclo[3.1.1]heptane (45 mg, 0.40 mmol) was added to the above mixture followed by TEA (54 mg, 0.54 mmol) at 25 °C under N2. 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 (column: Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water; B: MeCN; B% in A: 40%-70%, over 8 min) to give the titled compound. LCMS: m/z = 324.2 [M+H]+. Examples 7 and 8 cis-N-(3-((1R,2S)-2-cyanocyclobutyl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and cis-N-(3-((1S,2R)-2-cyanocyclobutyl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000127_0001
[0354] cis)-N-(3-(cis-2-cyanocyclobutyl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a mixture of triphosgene (40 mg, 0.13 mmol) in THF (2 mL) was added TEA (54.33 mg, 0.54 mmol) and cis-2-(5-amino-2-methylphenyl)cyclobutane-1-carbonitrile (50 mg, 0.27 mmol) at 0 °C under N2. The reaction solution was stirred at 20 °C for 1 h. Then TEA (48 mg, 0.47 mmol) and cis-3- methyl-6-azabicyclo[3.1.1]heptane hydrochloride (35 mg, 0.24 mmol) was added to the reaction solution at 20 °C. The reaction mixture was stirred for 1 h and then concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex C1880 × 40 mm × 3 μm; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A: 25%-55%, over 8 min) to give the titled compound. LCMS: m/z = 324.2 [M+H]+. [0355] cis-N-(3-((1R,2S)-2-cyanocyclobutyl)-4-methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane- 6-carboxamide and cis-N-(3-((1S,2R)-2-cyanocyclobutyl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALCEL OD, (250 mm × 30 mm, 10 µm, mobile phase: A: CO2, B: 0.1% NH3H2O in i- PrOH; B% in A: 30%-30%; flow rate: 70 g/min, monitor wavelength: 220 & 254 nm, column temperature: 40 °C, system back pressure: 100 bar) to give cis-N-(3-(cis-2-cyanocyclobutyl)-4- methylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (7, peak 1 in SFC) Example 7. LCMS: m/z = 324.2 [M+H]+ and cis-N-(3-(cis-2-cyanocyclobutyl)-4-methylphenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (8, peak 2 in SFC) Example 8. LCMS: m/z = 324.2 [M+H]+. Examples 9 and 10 cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and cis-N-(4-chloro-3-((1S,2R)-2-cyanocyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000128_0001
[0356] cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a mixture of triphosgene (36 mg, 0.12 mmol) in THF (3 mL) was added TEA (74 mg, 0.72 mmol) and cis-2-(5-amino-2-chlorophenyl)cyclobutane-1-carbonitrile (50 mg, 0.24 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h before cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (29 mg, 0.19 mmol) was added to the reaction solution at 20 °C. The mixture was stirred at 20 °C for 2 h. Water (3 drops) was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100 × 30 mm × 10 µm; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A: 34%-60%, 8.0 min) to give the titled compound. LCMS: m/z = 344.1 [M+H]+. [0357] cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane- 6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2-cyanocyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: The mixture of enantiomers was separated by SFC (Column: ChiralPak IH, 250 mm × 30 mm, 10 μm; Mobile phase: A: CO2, B: 0.1% NH3H2O in EtOH; B% in A: 35%-35%, 10 min; Flow rate: 65 g/min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (9, peak 1 in SFC) Example 9. LCMS: m/z = 344.1 [M+H]+ and cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (10, peak 2 in SFC) Example 10. LCMS: m/z = 344.1 [M+H]+. Example 11 2-cyclobutyl-N-(3-cyclobutyl-4-methylphenyl)acetamide
Figure imgf000128_0002
[0358] N-(3-bromo-4-methylphenyl)-2-cyclobutylacetamide: To a mixture of 3-bromo-4-methyl- aniline (4.89 g, 26.28 mmol) in DMF (50 mL) was added 2-cyclobutylacetic acid (3 g, 26.28 mmol), HATU (11.99 g, 31.54 mmol) and DIEA (13.59 g, 105.13 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (4 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the titled compound. [0359] 2-cyclobutyl-N-(3-cyclobutyl-4-methylphenyl)acetamide: To a solution of N-(3-bromo-4- methylphenyl)-2-cyclobutylacetamide (300 mg, 1.06 mmol) in DMA (5 mL) was added potassium cyclobutyltrifluoroborate (207 mg, 1.28 mmol), Na2CO3 (225 mg, 2.13 mmol), NiCl2.glyme (12 mg, 0.053 mmol), 4,4-di-tert-butyl-2,2-dipyridyl (14 mg, 0.053 mmol) and Ir[dF(CF3)ppy]2(bpy)(PF6) (11 mg, 0.011 mmol) at 20 °C under N2. The reaction mixture was stirred for 16 h under 34 W blue LEDs (vials approximately 6 cm away from the light source) with a fan placed above for cooling. 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 (column: Phenomenex C1880 × 40 mm × 3 μm; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A: 35%-65%, 8 min) to give the titled compound. LCMS: m/z = 258.2 [M+H]+. Example 12 N-(3-cyclobutyl-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000129_0001
[0360] tert-butyl (3-bromo-4-methylphenyl)carbamate: To a solution of 3-bromo-4-methylaniline (3 g, 16.12 mmol) in H2O (10 mL) was added Boc2O (4.22 g, 19.35 mmol) and aq. NaOH (2 N, 32 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. The reaction mixture was extracted with DCM (3 × 10 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 186.0, 188.0 [M-Boc+H]+. [0361] tert-butyl (3-cyclobutyl-4-methylphenyl)carbamate: To a solution of tert-butyl (3-bromo-4- methylphenyl)carbamate (300 mg, 1.05 mmol) in DME (2 mL) was added bromocyclobutane (707 mg, 5.24 mmol), Na2CO3 (222 mg, 2.10 mmol) and NiCl2.glyme (1 mg, 0.01 mmol), 4,4-di-tert-butyl-2,2- dipyridyl (14 mg, 0.05 mmol), tris(trimethylsilyl)silane (260 mg, 1.05 mmol) and Ir[dF(CF3)ppy]2(dtbpy)(PF6) (11 mg, 0.01 mmol) at 20 °C under N2. The reaction mixture was stirred for 16 h and irradiated with two 34 W blue LEDs (vials approximately 6 cm away from the light source) with a fan placed above for cooling. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 5:1) to give the titled compound. LCMS: m/z = 206.2 [M-t-Bu+H]+. [0362] 3-cyclobutyl-4-methylaniline hydrochloride: A mixture of tert-butyl (3-cyclobutyl-4- methylphenyl)carbamate (380 mg, 1.45 mmol) in 4 M HCl in EtOAc (5 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 162.2 [M+H]+. [0363] N-(3-cyclobutyl-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of CDI (59 mg, 0.36 mmol) in DCM (1 mL) was added a solution of 3-cyclobutyl-4-methylaniline hydrochloride (60 mg, 0.30 mmol) and TEA (30 mg, 0.30 mmol) in DCM (1 mL) at -20 °C under N2. The mixture was stirred at 20 °C for 1 h before TEA (31 mg, 0.31 mmol) and 6-azabicyclo[3.1.1]heptane (61 mg, 0.62 mmol) were added at 20 °C. The mixture was stirred at 50 °C for 0.5 h and then concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Phenomenex C 1875 × 30 mm × 3 μm; mobile phase A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: B%: 35%- 55%, 8min) to give the titled compound. LCMS: m/z = 285.2 [M+H]+. Example 13 N-(3-(cyclopropylmethyl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000130_0001
[0364] cyclopropyl(2-methyl-5-nitrophenyl)methanol: To a mixture of 2-methyl-5-nitro- benzaldehyde (2 g, 12.11 mmol) in THF (20 mL) was added dropwise cyclopropylmagnesium bromide (14.53 mmol, 1 M in THF, 14.53 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 3 h. The reaction mixture was diluted with sat. aq. NH4Cl (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compound. [0365] 2-(cyclopropylmethyl)-1-methyl-4-nitrobenzene: To a mixture of cyclopropyl(2-methyl-5- nitrophenyl)methanol (589 mg, 2.84 mmol) and triethylsilane (495 mg, 4.26 mmol) in DCM (5 mL) was added TFA (648 mg, 5.68 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h and then concentrated under reduced pressure. The resulting residue was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with sat. aq. NaHCO3 (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to give the titled compound. [0366] 3-(cyclopropylmethyl)-4-methylaniline: To a mixture of 2-(cyclopropylmethyl)-1-methyl-4- nitro-benzene (409 mg, 2.14 mmol) in EtOH (10 mL) and H2O (2.5 mL) was added Fe (597 mg, 10.69 mmol) and NH4Cl (572 mg, 10.69 mmol) at 25 °C under N2. The mixture was stirred at 80 °C for 2 h, 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 = 10:1 to 1:1) to give the titled compound. LCMS: m/z = 162.2 [M+H]+. [0367] N-(3-(cyclopropylmethyl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of triphosgene (46 mg, 0.15 mmol) in THF (2 mL) was added TEA (94 mg, 0.93 mmol) and 3- (cyclopropylmethyl)-4-methylaniline (50 mg, 0.31 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h before 6-azabicyclo[3.1.1]heptane hydrochloride (53 mg, 0.41 mmol) was added at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (0.5 mL) and then concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex C 18150 × 40 mm × 10 μm; mobile phase A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 35%-65%, over 8 min) to give the titled compound. LCMS: m/z = 285.2 [M+H]+. Example 14 N-(4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000131_0001
[0368] To a mixture of CDI (48 mg, 0.3 mmol) in THF (3 mL) was added TEA (54 mg, 0.53 mmol) and 4-(5-amino-2-methylphenyl)-1-methylpyrrolidin-2-one (50 mg, 0.24 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h before 6-azabicyclo[3.1.1]heptane (17 mg, 0.17 mmol) and TEA (54 mg, 0.53 mmol) were added at 25 °C. The mixture was stirred at 25 °C for 1 h, diluted with H2O (3 mL) and extracted with DCM (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B in A: 25%-45%, 10 min) to give the titled compound. LCMS: m/z = 328.2 [M+H]+. Example 15 N-(4-methyl-3-(1-methylazetidin-3-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000131_0002
[0369] To a solution of CDI (88 mg, 0.54 mmol) in DCM (2 mL) was added dropwise a mixture of 4- methyl-3-(1-methylazetidin-3-yl)aniline (80 mg, 0.45 mmol) in DCM (2 mL) at -20 °C under N2. The mixture was stirred at 20 °C for 1 h. Then 6-azabicyclo[3.1.1]heptane (54 mg, 0.56 mmol) was added to the above mixture followed by TEA (113 mg, 1.11 mmol). The reaction solution was stirred at 20 °C for 1 h and then concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C 18150 × 40 mm × 10 μm; mobile phase A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 15%-45%, over 8 min) to give the titled compound. LCMS: m/z = 300.1 [M+H]+. Examples 16 and 17 cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclopropyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)- 6-azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2- cyanocyclopropyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide
Figure imgf000132_0001
[0370] (cis)-6-((4-chloro-3-(cis-2-cyanocyclopropyl)phenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of triphosgene (124 mg, 0.41 mmol) in THF (6 mL) was added TEA (253 mg, 2.49 mmol) and cis-2-(5-amino-2-chlorophenyl)cyclopropane-1- carbonitrile (160 mg, 0.83 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. cis-3- Methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (Intermediate 5) (544 mg, 0.81 mmol) was added at 20 °C. The mixture was stirred at 20 °C for 2 h. Water (3 drops) was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Welch Xtimate C18180 × 70 mm × 10 µm; mobile phase: A: NH4HCO3 in water, B: MeCN; B% in A:5%- 45%, 20 min) to give the titled compound. LCMS: m/z = 374.1 [M+H]+ [0371] cis-1-(2-acetylhydrazine-1-carbonyl)-N-(4-chloro-3-(cis-2-cyanocyclopropyl)phenyl)-3-methyl- 6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-6-((4-chloro-3-(cis-2- cyanocyclopropyl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (120 mg, 0.32 mmol) and acetohydrazide (36 mg, 0.48 mmol) in DMF (2 mL) was added HATU (244 mg, 0.64 mmol) and DIEA (83 mg, 0.64 mmol) at 25 °C under N2. The 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 prep-TLC (SiO2, DCM:MeOH = 10:1) to give the titled compound. LCMS: m/z = 430.1 [M+H]+. [0372] cis-N-(4-chloro-3-(cis-2-cyanocyclopropyl)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-[4-chloro-3- (2-cyanocyclopropyl)phenyl]-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (70 mg, 0.16 mmol) in MeCN (3 mL) was added p-TosCl (124 mg, 0.65 mmol) and DIEA (32 mg, 0.24 mmol) at 20 °C under N2. 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 (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 = 412.1 [M+H]+. [0373] cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclopropyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol- 2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2- cyanocyclopropyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6- carboxamide: The mixture of diastereomers was separated by SFC (Column: DAICEL CHIRALPAK IG, 250 mm × 30 mm, 10 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 cis-N-(4-chloro-3-(cis-2-cyanocyclopropyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (16, peak 1 in SFC) Example 16. LCMS: m/z = 412.1 [M+H]+ and cis-N-(4-chloro-3-(cis-2-cyanocyclopropyl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol- 2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (17, peak 2 in SFC) Example 17. LCMS: m/z = 412.1 [M+H]+. Example 18 cis-N-(4-chloro-3-cyclobutylphenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000133_0001
[0374] To a mixture of triphosgene (163 mg, 0.55 mmol) in THF (6 mL) was added TEA (334 mg, 3.3 mmol) and 4-chloro-3-cyclobutylaniline (200 mg, 1.10 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h before cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (142 mg, 0.96 mmol) and TEA (390 mg, 3.85 mmol) were added to the reaction mixture at 25 °C. The mixture was stirred at 25 °C for 12 h. Water (3 drops) was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 × 40 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 60%-85%, over 8.0 min) to give the titled compound. LCMS: m/z = 318.9 [M+H]+. Example 19 cis-N-(4-chloro-3-(1-fluorocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000134_0001
[0375] 1-(3-bromo-4-chlorophenyl)-2,5-dimethyl-1H-pyrrole: To a solution of 3-bromo-4- chloroaniline (2 g, 9.69 mmol) in toluene (20 mL) was added hexane-2,5-dione (1.33 g, 11.62 mmol) and p-TsOH (500 mg, 2.91 mmol) at 20 ℃ under N2. The mixture was stirred at 110 ℃ for 2 h, diluted with H2O (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to give the titled compound. LCMS: m/z =283.9, 286.0 [M+H]+. [0376] 1-(2-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)cyclobutan-1-ol: To a solution of 1-(3- bromo-4-chlorophenyl)-2,5-dimethyl-1H-pyrrole (3 g, 10.54 mmol) in THF (45 mL) was added n-BuLi (5.06 mL, 2.5 M in n-hexane) at -78 °C under N2. The mixture was stirred at -78 °C for 0.5 h. Cyclobutanone (2.22 g, 31.63 mmol) in THF (15 mL) was added to the mixture at -78 °C. The mixture was stirred at -78 °C for 0.5 h. The reaction mixture was quenched with sat. aq. NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 10:1) to give the titled compound. LCMS: m/z =276.1 [M+H]+. [0377] 1-(5-amino-2-chlorophenyl)cyclobutan-1-ol: To a solution of 1-(2-chloro-5-(2,5-dimethyl-1H- pyrrol-1-yl)phenyl)cyclobutan-1-ol (200 mg, 0.73 mmol) in EtOH (6 mL) and H2O (2 mL) was added NH2OH.HCl (504 mg, 7.25 mmol) and TEA (294 mg, 2.90 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The mixture was adjusted to pH = 7-8 with sat. aq. 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 to give the titled compound. LCMS: m/z =198.1 [M+H]+. [0378] 4-chloro-3-(1-fluorocyclobutyl)aniline: To a solution of 1-(5-amino-2- chlorophenyl)cyclobutan-1-ol (200 mg, 1.01 mmol) in DCM (4 mL) was added DAST (196 mg, 1.21 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h and then poured into sat. aq. NaHCO3 (5 mL) and extracted with DCM (3 × 5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc = 10:1) to give the titled compound. LCMS: m/z =200.1 [M+H]+. [0379] cis-N-(4-chloro-3-(1-fluorocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a solution of bis(trichloromethyl) carbonate (30 mg, 0.1 mmol) in THF (2 mL) was added TEA (61 mg, 0.60 mmol) and 4-chloro-3-(1-fluorocyclobutyl)aniline (40 mg, 0.2 mmol) at 0 °C under N2. The reaction solution was stirred at 0 °C for 1 h before TEA (90 mg, 0.89 mmol) and cis-3- methyl-6-azabicyclo[3.1.1]heptane hydrochloride (29 mg, 0.2 mmol) were added to the mixture at 25 °C. The mixture was stirred at 25 °C for 1 h, diluted with H2O (0.5 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 35%-65%, over 8 min) to give the titled compound. LCMS: m/z = 337.1 [M+H]+. Example 20 cis-N-(3-(bicyclo[1.1.1]pentan-1-yl)-4-chlorophenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide C
Figure imgf000135_0001
[0380] cis-N-(4-chloro-3-iodophenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (177 mg, 0.60 mmol) in THF (10 mL) was added dropwise a mixture of 4-chloro- 3-iodoaniline (300 mg, 1.18 mmol) and TEA (359 mg, 3.55 mmol) in THF (10 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h before cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (192 mg, 1.30 mmol) was added at 0 °C under N2 followed by TEA (478 mg, 4.72 mmol). The mixture was stirred at 25 °C for 1 h, diluted with H2O (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with DCM (10 mL) and the solid was collected by filtration and dried under reduced pressure to give the titled compound. LCMS: m/z = 390.9 [M+H]+. [0381] cis-N-(3-(bicyclo[1.1.1]pentan-1-yl)-4-chlorophenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a mixture of 1,3-dioxoisoindolin-2-yl bicyclo[1.1.1]pentane-1-carboxylate (79 mg, 0.31 mmol) in DMA (3 mL) was added cis-N-(4-chloro-3-iodophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (100 mg, 0.25 mmol), NaHCO3 (86 mg, 1.06 mmol), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (130 mg, 0.51 mmol), NiBr2·glyme (15.80 mg, 0.05 mmol) and dtbbpy (15.12 mg, 0.06 mmol) at 25 °C under N2. The mixture was irradiated under 390 nm purple lamp (10 W) for 12 h. The reaction mixture was diluted with H2O (6 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep- HPLC (column: Phenomenex Luna C18100 × 30 mm × 3 µm; mobile phase: A: 20 mM FA in water; B: MeCN; B% in A: 40%-70%, over 8 min) to give the titled compound. LCMS: m/z = 331.1 [M+H]+. [0382] The following compounds were, or can be, made via similar procedures as those described herein.
Figure imgf000136_0002
Example 27 cis-N-(3-(trans-2-(1H-1,2,3-triazol-1-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000136_0001
[0383] 3-(trans-2-(1H-1,2,3-triazol-1-yl)cyclobutyl)-4-chloroaniline: To a solution of 3-(trans-2-(1H- 1,2,3-triazol-1-yl)cyclobutyl)aniline (55 mg, 0.25 mmol) (Intermediate 16) in MeCN (2 mL) at 25 °C under N2 was added NCS (31 mg, 0.23 mmol) and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition Of aq. sat. NaHCO3 (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:(EtOAc:EtOH = 3:1) = 2:1) to give the titled compound. LCMS: m/z = 249.1 [M+H]+. [0384] cis-N-(3-(trans-2-(1H-1,2,3-triazol-1-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (11 mg, 0.03 mmol) in THF (2 mL) at 0 °C under N2 was added TEA (24 mg, 0.24 mmol) and 3-(trans-2-(1H-1,2,3-triazol-1- yl)cyclobutyl)-4-chloroaniline (20 mg, 0.08 mmol). The mixture was stirred at 0 °C for 10 min. Then TEA (29 mg, 0.29 mmol) and cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (84 mg, 0.13 mmol) were added to the above mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, DCM:MeOH = 20:1) and further purified by prep-HPLC (column: WePure Biotech XP tC18150 × 40 × 7 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 30%-60% over 8 min) to give the titled compound as a mixture of enantiomers. LCMS: m/z = 386.2 [M+H]+. Example 28 cis-N-(3-(cis-2-(1H-1,2,3-triazol-1-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000137_0001
[0385] 3-(cis-2-(1H-1,2,3-triazol-1-yl)cyclobutyl)-4-chloroaniline: To a solution of 3-(cis-2-(1H- 1,2,3-triazol-1-yl)cyclobutyl)aniline (50 mg, 0.23 mmol) (Intermediate 17) in MeCN (2 mL) at 25 °C under N2 was added NCS (31 mg, 0.23 mmol) and the reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched by addition Of aq. sat. NaHCO3 (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:(EtOAc:EtOH = 3:1) = 1:1) to give the titled compound. LCMS: m/z = 249.1 [M+H]+. [0386] cis-N-(3-(cis-2-(1H-1,2,3-triazol-1-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (11 mg, 0.03 mmol) in THF (2 mL) at 0 °C under N2 was added TEA (24 mg, 0.24 mmol) and 3-(cis-2-(1H-1,2,3-triazol-1- yl)cyclobutyl)-4-chloroaniline (20 mg, 0.08 mmol) in THF (1 mL). The reaction mixture was stirred at 0 °C for 10 min. Then TEA (29 mg, 0.29 mmol) and cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (84 mg, 0.13 mmol) was added to the above mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: WePure Biotech XP tC18150 × 40 × 7 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 35%-65% over 8 min) and further purified by prep-TLC (SiO2, DCM:MeOH = 20:1) to give the titled compound as a mixture of enantiomers. LCMS: m/z = 386.2 [M+H]+. Example 29 cis-N-(3-(trans-2-(2H-1,2,3-triazol-2-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000138_0001
[0387] 3-(trans-2-(2H-1,2,3-triazol-2-yl)cyclobutyl)aniline: Solution 1: (2-(trans-2-(3- nitrophenyl)cyclobutyl)-2H-1,2,3-triazole (0.17 g, 0.79 mmol) (Intermediate 15) in (MeOH, 1.5 mL) and (THF, 1.5 mL). The fixed bed (named FLR1, volume 5 mL) was packed with granular catalyst 1%Pt/C (0.79 mmol). The H2 back pressure regulator was adjusted to 1.5 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, 50 °C). The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give the titled compound. [0388] 3-(trans-2-(2H-1,2,3-triazol-2-yl)cyclobutyl)-4-chloroaniline: To a solution of 3-(trans-2-(2H- 1,2,3-triazol-2-yl)cyclobutyl)aniline (45 mg, 0.21 mmol) in MeCN (3 mL) at 25 °C under N2 was added NCS (25 mg, 0.18 mmol) and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition Of aq. sat. NaHCO3 (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give the titled compound. LCMS: m/z = 249.1 [M+H]+. [0389] cis-N-(3-(trans-2-(2H-1,2,3-triazol-2-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (11 mg, 0.03 mmol) in THF (3 mL) at 0 °C under N2 was added TEA (24 mg, 0.24 mmol) and 3-(trans-2-(2H-1,2,3-triazol-2- yl)cyclobutyl)-4-chloroaniline (20 mg, 0.08 mmol). The reaction mixture was stirred at 0 °C for 10 min. Then the reaction was warmed to 25 °C and TEA (29 mg, 0.29 mmol) and cis-3-methyl-6- azabicyclo[3.1.1]heptane hydrochloride (70 mg, 0.10 mmol) were added and the reaction mixture was stirred for 0.5 h. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 35%-65% over 8 min) to give the titled compound as a mixture of enantiomers. LCMS: m/z = 386.1 [M+H]+. Example 30 cis-N-(3-(cis-2-(2H-1,2,3-triazol-2-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000139_0001
[0390] 3-(cis-2-(2H-1,2,3-triazol-2-yl)cyclobutyl)aniline: Solution 1: 2-(cis-2-(3- nitrophenyl)cyclobutyl)-2H-1,2,3-triazole (0.1 g, 0.46 mmol) (Intermediate 14) in (MeOH, 1.5 mL) and (THF, 1.5 mL). The fixed bed (named FLR1, volume 5 mL) was packed with granular catalyst 1%Pt/C (0.46 mmol). The H2 back pressure regulator was adjusted to 1.5 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, 50 °C). The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give the titled compound. [0391] 3-(cis-2-(2H-1,2,3-triazol-2-yl)cyclobutyl)-4-chloroaniline: To a solution of 3-(cis-2-(2H- 1,2,3-triazol-2-yl)cyclobutyl)aniline (55 mg, 0.25 mmol) in MeCN (2 mL) at 25 °C under N2 was added NCS (31 mg, 0.23 mmol) and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition Of aq. sat. NaHCO3 (3 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 3:1) to give the titled compound. LCMS: m/z = 249.1 [M+H]+. [0392] cis-N-(3-(cis-2-(2H-1,2,3-triazol-2-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (5 mg, 0.02 mmol) in THF (1 mL) at 0 °C under N2 was added TEA (12 mg, 0.12 mmol) and 3-(cis-2-(2H-1,2,3-triazol-2- yl)cyclobutyl)-4-chloroaniline (10 mg, 0.04 mmol). The reaction mixture was stirred at 0 °C for 10 min. Then the reaction mixture was warmed to 25 °C and TEA (15 mg, 0.14 mmol) and cis-3-methyl-6- azabicyclo[3.1.1]heptane hydrochloride (42 mg, 0.06 mmol) were added. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3 × 1 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:EE = 2:1) to give the titled compound as a mixture of enantiomers. LCMS: m/z = 386.1 [M+H]+. Example 31 cis-N-(3-trans-2-(4H-1,2,4-triazol-4-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000140_0001
[0393] 3-(trans-2-(4H-1,2,4-triazol-4-yl)cyclobutyl)aniline: To a solution of 4-(trans-2-(3- nitrophenyl)cyclobutyl)-4H-1,2,4-triazole (320 mg, 1.31 mmol) (Intermediate 19) in EtOH (3 mL) and H2O (1 mL) at 25 °C was added Fe (364 mg, 6.55 mmol) and NH4Cl (350 mg, 6.55 mmol). The reaction mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was filtered through a pad of Celite ^. The filtrate was diluted with H2O (2 mL) and extracted with DCM:MeOH = 10:1 (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:(EtOAc:EtOH = 3:1) = 3:1 to 1:1, 0.1 % TEA) to give the titled compound. LCMS: m/z = 215.2 [M+H]+. [0394] 3-(trans-2-(4H-1,2,4-triazol-4-yl)cyclobutyl)-4-chloroaniline: To a solution of 3-(trans-2-(4H- 1,2,4-triazol-4-yl)cyclobutyl)aniline (64 mg, 0.29 mmol) in MeCN (3 mL) at 25 °C under N2 was added NCS (36 mg, 0.26 mmol) and the reaction mixture was stirred for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex Gemini C1875 × 40 mm × 5 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 5%-30% over 8 min) to give the titled compound. LCMS: m/z = 249.1 [M+H]+. [0395] cis-N-(3-(trans-2-(4H-1,2,4-triazol-4-yl)cyclobutyl)-4-chlorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of 3-(trans-2-(4H-1,2,4-triazol-4- yl)cyclobutyl)-4-chloroaniline (20 mg, 0.08 mmol) and cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (16 mg, 0.10 mmol) in THF (2 mL) at 0 °C was added TEA (41 mg, 0.40 mmol) and triphosgene (11 mg, 0.03 mmol). The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (0.2 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: WePure Biotech XP tC18150 × 40 × 7 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 20%-50% over 8 min) to give the titled compound as a mixture of enantiomers. LCMS: m/z = 386.1 [M+H]+. Examples 32 and 33 cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2- cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000141_0001
[0396] cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (32 mg, 0.10 mmol) in THF (2 mL) at 0 °C under N2 was added cis-2-(5-amino-2-chlorophenyl)cyclobutanecarbonitrile (50 mg, 0.24 mmol) and TEA (73 mg, 0.72 mmol). The reaction mixture was stirred at 0 °C for 0.5 h. Then TEA (65.24 mg, 0.64 mmol) and cis-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane hydrochloride (56 mg, 0.27 mmol) were added at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex Luna C18100 × 30 mm × 3 µm; mobile phase: A: 0.2% FA in H2O, B: MeCN; B% in A: 45%-80% over 8 min) to give the titled compound. LCMS: m/z = 398.2 [M+H]+. [0397] cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2- cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-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 i-PrOH; B% in A: 35%-35%; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(4- chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide Example 32 (peak 1 in SFC) LCMS: m/z = 398.1 [M+H]+ and cis-N-(4-chloro-3-(cis-2- cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide Example 33 (peak 2 in SFC). LCMS: m/z = 398.1 [M+H]+. Examples 34 and 35 cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)-5-fluorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2-cyanocyclobutyl)-5- fluorophenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000142_0001
[0398] cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)-5-fluorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (33 mg, 0.11 mmol) in THF (2 mL) at 0 °C under N2 was added TEA (68 mg, 0.66 mmol) and cis-2-(5-amino-2-chloro-3- fluorophenyl)cyclobutane-1-carbonitrile (50 mg, 0.223 mmol). The reaction mixture was stirred at 0 °C for 0.5 h. Then cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (39 mg, 0.26 mmol) was added at 0 °C and the reaction mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was diluted with H2O (2 mL) and concentrated under reduced pressure. The resulting residue was purified by prep- TLC (SiO2, PE:EtOAc = 1:2) to give the titled compound. LCMS: m/z = 362.0 [M+H]+. [0399] cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)-5-fluorophenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2-cyanocyclobutyl)-5- fluorophenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide : The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm × 10 µm; Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 35%-35%; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(4-chloro-3-(cis-2- cyanocyclobutyl)-5-fluorophenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 34 LCMS: m/z = 362.1 [M+H]+ and cis-N-(4-chloro-3-(cis-2-cyanocyclobutyl)-5- fluorophenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 35. LCMS: m/z = 362.1 [M+H]+. Examples 36 and 37 cis-N-(4-chloro-3-(trans-3-hydroxycyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and cis-N-(4-chloro-3-(cis-3-hydroxycyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000143_0001
[0400] cis-N-(4-chloro-3-(3-hydroxycyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a solution of triphosgene (75 mg, 0.25 mmol) in THF (3 mL) at 0 °C was added 3-(5- amino-2-chlorophenyl)cyclobutanol (100 mg, 0.50 mmol) and TEA (153 mg, 1.52 mmol). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was warmed to 20 °C and cis-3-methyl-6- azabicyclo[3.1.1]heptane hydrochloride (82 mg, 0.55 mmol) and TEA (153 mg, 1.52 mmol) were added and the reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 × 1 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 silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give the titled compound. LCMS: m/z = 335.1 [M+H]+ [0401] cis-N-(4-chloro-3-(trans-3-hydroxycyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane- 6-carboxamide and cis-N-(4-chloro-3-(cis-3-hydroxycyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide : The mixture of diastereoisomers was separated by prep- HPLC (column: Phenomenex Gemini C1875 × 40 mm × 3 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 20%-50% over 8 min) to give cis-N-(4-chloro-3-(trans-3- hydroxycyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in HPLC) Example 36 LCMS: m/z = 335.1 [M+H]+ and cis-N-(4-chloro-3-(cis-3-hydroxycyclobutyl)phenyl)-3- methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in HPLC) Example 37. LCMS: m/z = 335.1 [M+H]+. Examples 38 and 39 cis-N-(4-chloro-3-(trans-3-hydroxy-3-methylcyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-(cis-3-hydroxy-3- methylcyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000144_0001
[0402] cis-N-(4-chloro-3-(3-oxocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a solution of cis-N-(4-chloro-3-(3-hydroxycyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (200 mg, 0.59 mmol) in DCM (10 mL) at 0 °C under N2 was added DMP (506 mg, 1.19 mmol). The reaction mixture was warmed to 25 °C and stirred for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 3:1) to give the titled compound. LCMS: m/z = 333.1 [M+H]+. [0403] cis-N-(4-chloro-3-(trans-3-hydroxy-3-methylcyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-(cis-3-hydroxy-3- methylcyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide : To a solution of cis- N-(4-chloro-3-(3-oxocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (80 mg, 0.24 mmol) in THF (5 mL) at 0 °C under N2 was added MeMgBr (100 mg, 0.84 mmol, 3 M in Et2O). The reaction mixture was warmed to 25 °C and stirred for 2 h. The reaction mixture was diluted with aq. sat. NH4Cl (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 × 40 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 40%-75% over 8 min) to give cis-N-(4-chloro-3-(trans-3-hydroxy-3-methylcyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide Example 38 (peak 1 in HPLC) LCMS: m/z = 349.2 [M+H]+ and cis-N-(4-chloro-3-(cis-3- hydroxy-3-methylcyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide Example 39 (peak 2 in HPLC). LCMS: m/z = 349.2 [M+H]+. Examples 40 and 41 cis-N-(4-chloro-3-((1R,2S)-2-(difluoromethyl)cyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2- (difluoromethyl)cyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000145_0001
[0404] 4-chloro-3-(cis-2-(difluoromethyl)cyclobutyl)aniline: To a solution of 3-(cis-2- (difluoromethyl)cyclobutyl)aniline (60 mg, 0.30 mmol) in MeCN (2 mL) at 0 °C was added NCS (39 mg, 0.29 mmol). The reaction mixture was heated to 40 °C and stirred for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 3:1) to give the titled compound. LCMS: m/z = 232.0 [M+H]+. [0405] cis-N-(4-chloro-3-(cis-2-(difluoromethyl)cyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of triphosgene (35 mg, 0.12 mmol) in THF (2 mL) at 0 °C was added 4-chloro-3-(cis-2-(difluoromethyl)cyclobutyl)aniline (55 mg, 0.24 mmol) and TEA (72 mg, 0.71 mmol) and the reaction mixture was stirred at 0 °C for 0.5 h. Then the reaction was warmed to 20 °C and cis-3-methyl-6-azabicyclo[3.1.1]heptane hydrochloride (42 mg, 0.28 mmol) and TEA (112 mg, 1.18 mmol) were added and the mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (2 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (Waters xbridge 150 mm × 25 mm × 10 µm; mobile phase A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 37%-67% over 8.0 min) to give the titled compound. LCMS: m/z = 369.0 [M+H]+. [0406] cis-N-(4-chloro-3-((1R,2S)-2-(difluoromethyl)cyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,2R)-2- (difluoromethyl)cyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide : The mixture of enantiomers was separated by SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 35%-35%; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(4- chloro-3-(cis-2-(difluoromethyl)cyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide Example 40 (peak 1 in SFC) LCMS: m/z = 369.1 [M+H]+ and cis-N-(4-chloro-3-(cis-2- (difluoromethyl)cyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide Example 41 (peak 2 in SFC) . LCMS: m/z = 369.1 [M+H]+. Examples 42 and 43 cis-N-(4-chloro-3-(trans-3-hydroxycyclobutyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-(cis-3- hydroxycyclobutyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000146_0001
[0407] To a solution of triphosgene (75 mg, 0.25 mmol) in THF (3 mL) at 0 °C under N2 was added 3- (5-amino-2-chlorophenyl)cyclobutanol (100 mg, 0.50 mmol) and TEA (153 mg, 1.52 mmol) and the reaction mixture was stirred at 0 °C for 0.5 h. Then cis-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane (975 mg, 0.29 mmol) and TEA (81 mg, 0.80 mmol) were added to the reaction mixture. The reaction mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (0.5 mL) and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Phenomenex Gemini C1875 × 40 mm × 3 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B% in A: 25%-55% over 8 min) to give cis-N-(4-chloro-3-(trans-3-hydroxycyclobutyl)phenyl)-3- (trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide Example 42 (peak 1 in HPLC) LCMS: m/z = 389.1 [M+H]+ and cis-N-(4-chloro-3-(cis-3-hydroxycyclobutyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide Example 43 (peak 2 in HPLC). LCMS: m/z = 389.1 [M+H]+. Example 44 trans-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane- 8-carboxamide
Figure imgf000146_0002
[0408] To a solution of triphosgene (36 mg, 0.12 mmol) in THF (1 mL) at 0 °C under N2 was added TEA (73 mg, 0.75 mmol) and cis-2-(5-amino-2-chlorophenyl)cyclobutanecarbonitrile (Intermediate 25) (50 mg, 0.24 mmol). The reaction mixture was stirred at 0 °C for 10 min. Then TEA (72 mg, 0.70 mmol) and 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane (51 mg, 0.28 mmol) were added to the above mixture at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters xbridge 150 × 25 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B in A: 43%-73% over 8 min) to give the titled compound as a single unknown enantiomer. LCMS: m/z = 412.1 [M+H]+. Example 45 trans-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane- 8-carboxamide
Figure imgf000147_0002
[0409] To a solution of triphosgene (36 mg, 0.12 mmol) in THF (1 mL) at 0 °C under N2 was added TEA (73 mg, 0.75 mmol) and cis-2-(5-amino-2-chlorophenyl)cyclobutanecarbonitrile (Intermediate 26) (50 mg, 0.24 mmol). The reaction mixture was stirred at 0 °C for 10 min and then TEA (72 mg, 0.70 mmol) and 3-(trifluoromethyl)-8-azabicyclo[3.2.1]octane (51 mg, 0.28 mmol) were added to above mixture. The reaction mixture was warmed to 25 °C and stirred for 0.5 h. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters xbridge 150 × 25 mm × 10 µm; mobile phase: A: 10 mM NH4HCO3 in water, B: MeCN; B in A: 40%-70% over 8 min) to give the titled compound as a single unknown enantiomer. LCMS: m/z = 412.1 [M+H]+. SFC Separations Examples 46 and 47 cis-N-(4-chloro-3-((1S,2S)-2-hydroxy-2-methylcyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1R,2R)-2-hydroxy-2- methylcyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000147_0001
[0410] The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in i-PrOH; B% in A: 20%-50%, 16 min; Flow rate: 50 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(4-chloro-3-(cis-2-hydroxy-2-methylcyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 46 LCMS: m/z = 349.2 [M+H]+ and cis-N-(4-chloro-3-(cis-2-hydroxy-2-methylcyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 2 in SFC) Example 47. LCMS: m/z = 349.2 [M+H]+. Examples 48 and 49 cis-N-(4-chloro-3-(trans-3-fluorocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and cis-N-(4-chloro-3-(cis-3-fluorocyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000148_0001
[0411] The mixture of diastereomers was separated by SFC (REGIS(S,S)WHELK-O1 (250 mm × 25 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in i-PrOH; B% in A: 38%-38%, 8 min; Flow rate: 64 g/min; Wavelength: 220 nm; column temperature: 35 °C; System back pressure: 100 bar) to give cis-N-(4-chloro-3-(trans-3-fluorocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 1 in SFC) Example 48 LCMS: m/z = 337.1 [M+H]+ and cis-N-(4-chloro-3-(cis-3- fluorocyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 49. LCMS: m/z = 337.1 [M+H]+. Examples 50 and 51 cis-N-(4-chloro-3-((1S,2S)-2-(difluoromethyl)cyclobutyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1R,2R)-2- (difluoromethyl)cyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000148_0002
[0412] The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in i-PrOH; B% in A: 35%-35%; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(4-chloro-3-(trans-2-(difluoromethyl)cyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 1 in SFC) Example 50 LCMS: m/z = 369.1 [M+H]+ and cis-N-(4-chloro-3-(trans-2- (difluoromethyl)cyclobutyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 51. LCMS: m/z = 369.1 [M+H]+. Examples 52 and 53 cis-N-(3-((1R,2S)-2-cyanocyclobutyl)-4-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(3-((1S,2R)-2-cyanocyclobutyl)-4- (trifluoromethyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000148_0003
[0413] 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 i-PrOH; B% in A: 25%-25%; Flow rate: 65 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis- N-(3-(cis-2-cyanocyclobutyl)-4-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane- 6-carboxamide (peak 1 in SFC) Example 52 LCMS: m/z = 432.2 [M+H]+ and cis-N-(3-(cis-2- cyanocyclobutyl)-4-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 2 in SFC) Example 53. LCMS: m/z = 432.2 [M+H]+. Examples 54 and 55 cis-N-(3-((1S,2S)-2-cyanocyclobutyl)-4-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(3-((1R,2R)-2-cyanocyclobutyl)-4- (trifluoromethyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000149_0001
[0414] The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 20%-20%; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(3-(trans-2-cyanocyclobutyl)-4-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 54 LCMS: m/z = 432.2 [M+H]+ and cis-N-(3-(trans-2-cyanocyclobutyl)-4-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 55. LCMS: m/z = 432.2 [M+H]+. Examples 56 and 57 trans-N-(4-chloro-3-((1R,2S)-2-cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and trans-N-(4-chloro-3-((1S,2R)-2- cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000149_0002
[0415] 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 i-PrOH; B% in A: 40%-40%; Flow rate: 70.00 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give trans-N-(4-chloro-3-(cis-2-cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 1 in SFC) Example 56 LCMS: m/z = 398.1 [M+H]+ and trans-N-(4-chloro-3-(cis-2- cyanocyclobutyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 57. LCMS: m/z = 398.1 [M+H]+. Examples 58 and 59 (1S,5R)-N-(4-chloro-3-cyclobutylphenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and (1R,5S)-N-(4-chloro-3-cyclobutylphenyl)-1-(5- methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000150_0001
[0416] The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALPAK IH (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in i-PrOH; B% in A: 40%-40%; Flow rate: 70.00 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give N-(4-chloro-3-cyclobutylphenyl)-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 = 387.2 [M+H]+ and N-(4-chloro-3- cyclobutylphenyl)-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 = 387.2 [M+H]+. Examples 60 and 61 cis-N-(4-chloro-3-((1R,2S)-2-cyanocyclopentyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and cis-N-(4-chloro-3-((1S,2R)-2-cyanocyclopentyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000150_0002
[0417] 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 i-PrOH; B% in A: 40%-40%; Flow rate: 70.00 g/min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-N-(4-chloro-3-(cis-2-cyanocyclopentyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 60 LCMS: m/z = 358.2 [M+H]+ and cis-N-(4-chloro-3-(cis-2- cyanocyclopentyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 61. LCMS: m/z = 358.2 [M+H]+. Examples 62 and 63 cis-N-(4-chloro-3-((1S,2S)-2-cyanocyclopentyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and cis-N-(4-chloro-3-((1R,2R)-2-cyanocyclopentyl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000150_0003
[0418] The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; 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-(4-chloro-3-(trans-2-cyanocyclopentyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide (peak 1 in SFC) Example 62 LCMS: m/z = 358.2 [M+H]+ and cis-N-(4-chloro-3-(trans-2- cyanocyclopentyl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 63. LCMS: m/z = 358.2 [M+H]+. Examples 64 and 65 cis-N-(4-chloro-3-((1S,3S)-3-hydroxy-3-methylcyclopentyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1R,3R)-3-hydroxy-3- methylcyclopentyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000151_0001
[0419] The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALPAK IK (250 mm × 30mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in i-PrOH; B% in A: 20%-20%; Flow rate: 65 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 100 bar) to give cis-N-(4-chloro-3-(trans-3-hydroxy-3-methylcyclopentyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 64 LCMS: m/z = 417.2 [M+H]+ and cis-N-(4-chloro-3-(trans-3-hydroxy-3-methylcyclopentyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 65. LCMS: m/z = 417.2 [M+H]+. Examples 66 and 67 cis-N-(4-chloro-3-((1R,3S)-3-hydroxy-3-methylcyclopentyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide and cis-N-(4-chloro-3-((1S,3R)-3-hydroxy-3- methylcyclopentyl)phenyl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000151_0002
[0420] The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 45%-45%; Flow rate: 70.00 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(4-chloro-3-(cis-3-hydroxy-3-methylcyclopentyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 66 LCMS: m/z = 415.1 [M-H]- and cis-N-(4-chloro-3-(trans-3-hydroxy-3-methylcyclopentyl)phenyl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 67. LCMS: m/z = 415.1 [M-H]-. Examples 68 and 69 (1S,3R,5R)-N-(4-chloro-3-cyclobutylphenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)- 6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3S,5S)-N-(4-chloro-3-cyclobutylphenyl)-1- (5-methyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000152_0001
[0421] The mixture of enantiomers was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 30%-30%; Flow rate: 70.00 g/min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar) to give cis-N-(4-chloro-3-cyclobutylphenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 68 LCMS: m/z = 455.1 [M+H]+ and cis-N-(4-chloro-3-cyclobutylphenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 69. LCMS: m/z = 455.1 [M+H]+.
Example 70 (1R,3S,5S)-N-(4-chloro-3-(3-hydroxyazetidin-1-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000153_0001
[0422] 1-(5-bromo-2-chlorophenyl)azetidin-3-ol: To a solution of 4-bromo-1-chloro-2-fluorobenzene (80 g, 381.96 mmol) in DMSO (600 mL) was added azetidin-3-ol hydrochloride (50.22 g, 458.36 mmol) and K2CO3 (211.16 g, 1530 mmol) at 20 °C under N2. The mixture was stirred at 100 °C for 12 h, diluted with H2O (1 L) and extracted with MTBE (2 × 600 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 261.8, 263.8 [M+H]+. [0423] 1-(5-bromo-2-chlorophenyl)-3-((tert-butyldimethylsilyl)oxy)azetidine: To a solution of 1-(5- bromo-2-chlorophenyl)azetidin-3-ol (60 g, 228.54 mmol) in DCM (1.2 L) was added TBSCl (68.89 g, 457.09 mmol) and imidazole (18.67 g, 457.08 mmol) at 20 °C under N2. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O (1 L) and extracted with DCM (2 × 500 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 = 100:1 to 10:1) to give the titled compound. LCMS: m/z = 376.0, 378.0 [M+H]+. [0424] 3-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-4-chloro-N-(diphenylmethylene)aniline: To a solution of 1-(5-bromo-2-chlorophenyl)-3-((tert-butyldimethylsilyl)oxy)azetidine (25 g, 66.35 mmol) in 1,4-dioxane (450 mL) was added diphenylmethanimine (24.05 g, 132.70 mmol), Cs2CO3 (43.24 g, 132.70 mmol), Xantphos (7.68 g, 13.27 mmol) and Pd2(dba)3 (6.08 g, 6.63 mmol) at 20 °C under N2. The mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 477.1 [M+H]+. [0425] 3-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-4-chloroaniline: To a solution of 3-(3-((tert- butyldimethylsilyl)oxy)azetidin-1-yl)-4-chloro-N-(diphenylmethylene)aniline (70 g, 146.72 mmol) in MeOH (500 mL) was added NaOAc (30.09 g, 366.79 mmol) and NH2OH·HCl (20.39 g, 293.43 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The resulting residue was diluted with H2O (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 95:5). The crude product was slurried with PE filtered and the filtrate was concentrated under reduced pressure to give the titled compound. LCMS: m/z = 313.1 [M+H]+. [0426] cis-6-((3-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-4-chlorophenyl)carbamoyl)-3- methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (4.14 g, 13.94 mmol) in THF (300 mL) was added TEA (9.40 g, 92.90 mmol) and 3-(3-((tert- butyldimethylsilyl)oxy)azetidin-1-yl)-4-chloroaniline (11.40 g, 30.97 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. Then TEA (5.11 g, 50.46 mmol) and cis-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid hydrochloride (17.64 g, 20.18 mmol) (Intermediate 5) was added to the above mixture at 20 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with 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: 10 mM NH4HCO3 in water; B: MeCN; B% in A: 35%-65%, over 17 min) to give the titled compound. [0427] cis-1-(2-acetylhydrazinecarbonyl)-N-(3-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-4- chlorophenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of cis-6-((3-(3- ((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-4-chlorophenyl)carbamoyl)-3-methyl-6- azabicyclo[3.1.1]heptane-1-carboxylic acid (6 g, 12.14 mmol) in DMF (120 mL) was added acetohydrazide (1.80 g, 24.29 mmol), DIEA (3.14 g, 24.29 mmol) and HATU (9.23 g, 24.29 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 2 h, diluted with H2O (200 mL) and extracted with DCM:MeOH (V:V=10:1) (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the titled compound. LCMS: m/z = 550.3 [M+H]+. [0428] cis-N-(3-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-4-chlorophenyl)-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- acetylhydrazinecarbonyl)-N-(3-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-4-chlorophenyl)-3-methyl- 6-azabicyclo[3.1.1]heptane-6-carboxamide (12.60 g, 8.47 mmol) in MeCN (130 mL) was added Cs2CO3 (11.04 g, 33.90 mmol) and p-TosCl (2.42 g, 12.71 mmol) at 20 °C under N2. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 2:3 to 1:3) to give the titled compound. LCMS: m/z = 532.3 [M+H]+. [0429] cis-N-(4-chloro-3-(3-hydroxyazetidin-1-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2- yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide : To a solution of cis-N-(3-(3-((tert- butyldimethylsilyl)oxy)azetidin-1-yl)-4-chlorophenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6- azabicyclo[3.1.1]heptane-6-carboxamide (4.8 g, 7.22 mmol) in MeOH (50 mL) was added KF (2.10 g, 36.08 mmol) at 20 °C under N2. The mixture was stirred at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The resulting residue 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 = 2:3 to 1:3) to provide the titled compound as a single unknown enantiomer. LCMS: m/z = 418.2 [M+H]+.
Examples 71 and 72 cis-N-(4-chloro-3-((R)-2-cyanoazetidin-1-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and cis-N-(4-chloro-3-((S)-2-cyanoazetidin-1-yl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide
Figure imgf000156_0001
[0430] 2-((5-bromo-2-chlorophenyl)amino)ethanol: To a solution of 4-bromo-1-chloro-2- fluorobenzene (15 g, 71.62 mmol) in DMSO (200 mL) was added K2CO3 (59.39 g, 429.71 mmol) and 2- aminoethanol (21.87 g, 358.09 mmol) at 20 °C. The mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give the titled compound. LCMS: m/z = 250.0, 252.0 [M+H]+. [0431] 3-(5-bromo-2-chlorophenyl)oxazolidine: To a solution of 2-((5-bromo-2- chlorophenyl)amino)ethanol (5 g, 19.96 mmol) in DCM (60 mL) was added formaldehyde (9.72 g, 119.75 mmol, 37% purity in H2O) and 4A MS (20 g). The mixture was stirred at 25 °C 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 = 262.0, 264.0 [M+H]+. [0432] 2-((5-bromo-2-chlorophenyl)(2-hydroxyethyl)amino)acetonitrile: To a solution of 2-((5- bromo-2-chlorophenyl)amino)ethanol (4 g, 15.24 mmol) in MeCN (50 mL) was added BF3.Et2O (4.32 g, 30.47 mmol) and TMSCN (3.02 g, 30.47 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were 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 = 289.0, 291.0 [M+H]+. [0433] 2-((5-bromo-2-chlorophenyl)(cyanomethyl)amino)ethyl methanesulfonate: To a solution of 2-((5-bromo-2-chlorophenyl)(2-hydroxyethyl)amino)acetonitrile (1.7 g, 5.87 mmol) in DCM (30 mL) was added TEA (2.38 g, 23.48 mmol) and methanesulfonic anhydride (3.31 g, 11.74 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (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 = 367.0, 369.0 [M+H]+. [0434] 1-(5-bromo-2-chlorophenyl)azetidine-2-carbonitrile: To a solution of 2-((5-bromo-2- chlorophenyl)(cyanomethyl)amino)ethyl methanesulfonate (1 g, 2.72 mmol) in THF (25 mL) was added t-BuOK (458 mg, 4.08 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (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-TLC (SiO2, PE:EtOAc = 3:1) to provide the titled compound. LCMS: m/z = 271.0, 273.0 [M+H]+. [0435] 1-(5-amino-2-chlorophenyl)azetidine-2-carbonitrile: To a solution of 1-(5-bromo-2- chlorophenyl)azetidine-2-carbonitrile (400 mg, 1.47 mmol) and diphenylmethanimine (400 mg, 2.21 mmol) in 1,4-dioxane (10 mL) was added Cs2CO3 (960 mg, 2.95 mmol), Xantphos (170 mg, 0.29 mmol) and Pd2(dba)3 (135 mg, 0.14 mmol) at 25 °C under N2. The mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered through a Celite ^ pad and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in MeOH (10 mL) and NaOAc (276 mg, 3.36 mmol) and NH2OH.HCl (187 mg, 2.69 mmol) were added to the reaction mixture at 25 °C. The mixture was stirred at 25 °C 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 (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 = 208.1 [M+H]+. [0436] cis-N-(4-chloro-3-(2-cyanoazetidin-1-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide: To a solution of triphosgene (57 mg, 0.19 mmol) in THF (3 mL) was added TEA (146 mg, 1.44 mmol) and 1-(5-amino-2-chlorophenyl)azetidine-2-carbonitrile (100 mg, 0.48 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. TEA (216 mg, 2.14 mmol) and cis-3-methyl-6- azabicyclo[3.1.1]heptane hydrochloride (1.08 g, 0.51 mmol) were added at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give the titled compound. LCMS: m/z = 345.1 [M+H]+. [0437] cis-N-(4-chloro-3-((R)-2-cyanoazetidin-1-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6- carboxamide and cis-N-(4-chloro-3-((S)-2-cyanoazetidin-1-yl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide : The mixture of enantiomers was separated by SFC (column: ChiralPak IH, 250 × 30 mm × 10 µm); Mobile phase: A: CO2, B: 0.1% NH3H2O in MeOH; B% in A: 40%-40%; Flow rate: 70.00 g/min; Wavelength: 220 & 254 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give cis-N-(4-chloro-3-(2-cyanoazetidin-1-yl)phenyl)-3-methyl-6- azabicyclo[3.1.1]heptane-6-carboxamide (peak 1 in SFC) Example 72 LCMS: m/z = 345.1 [M+H]+ and cis-N-(4-chloro-3-(2-cyanoazetidin-1-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (peak 2 in SFC) Example 73. LCMS: m/z = 345.1 [M+H]+. [0438] The following compounds were, or can be, made via similar procedures as those described herein.
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
BIOLOGICAL EXAMPLE 1 Biochemical Assay of the Compounds [0439] 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 µg 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. [0440] 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 µL/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 µL/well of a solution containing 40 µM 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 µL/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 µL/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. [0441] 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
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000162_0003
Figure imgf000162_0004
Figure imgf000163_0004
Figure imgf000163_0001
Figure imgf000163_0002
Figure imgf000163_0003
[0442] FL-SARM1 plasmid sequence (SEQ. ID.1): tggaagggctaattcactcccaaagaagacaagatatccttgatctgtggatctaccacacacaaggcta cttccctgattagcagaactacacaccagggccaggggtcagatatccactgacctttggatggtgctac aagctagtaccagttgagccagataaggtagaagaggccaataaaggagagaacaccagcttgttacacc ctgtgagcctgcatgggatggatgacccggagagagaagtgttagagtggaggtttgacagccgcctagc atttcatcacgtggcccgagagctgcatccggagtacttcaagaactgctgatatcgagcttgctacaag ggactttccgctggggactttccagggaggcgtggcctgggcgggactggggagtggcgagccctcagat cctgcatataagcagctgctttttgcctgtactgggtctctctggttagaccagatctgagcctgggagc tctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagtgcttcaagtagtgtg tgcccgtctgttgtgtgactctggtaactagagatccctcagacccttttagtcagtgtggaaaatctct agcagtggcgcccgaacagggacttgaaagcgaaagggaaaccagaggagctctctcgacgcaggactcg gcttgctgaagcgcgcacggcaagaggcgaggggcggcgactggtgagtacgccaaaaattttgactagc ggaggctagaaggagagagatgggtgcgagagcgtcagtattaagcgggggagaattagatcgcgatggg aaaaaattcggttaaggccagggggaaagaaaaaatataaattaaaacatatagtatgggcaagcaggga gctagaacgattcgcagttaatcctggcctgttagaaacatcagaaggctgtagacaaatactgggacag ctacaaccatcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctctatt gtgtgcatcaaaggatagagataaaagacaccaaggaagctttagacaagatagaggaagagcaaaacaa aagtaagaccaccgcacagcaagcggccggccgctgatcttcagacctggaggaggagatatgagggaca attggagaagtgaattatataaatataaagtagtaaaaattgaaccattaggagtagcacccaccaaggc aaagagaagagtggtgcagagagaaaaaagagcagtgggaataggagctttgttccttgggttcttggga gcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagacaattattgtctggta tagtgcagcagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcaactcacagtctg gggcatcaagcagctccaggcaagaatcctggctgtggaaagatacctaaaggatcaacagctcctgggg atttggggttgctctggaaaactcatttgcaccactgctgtgccttggaatgctagttggagtaataaat ctctggaacagatttggaatcacacgacctggatggagtgggacagagaaattaacaattacacaagctt aatacactccttaattgaagaatcgcaaaaccagcaagaaaagaatgaacaagaattattggaattagat aaatgggcaagtttgtggaattggtttaacataacaaattggctgtggtatataaaattattcataatga tagtaggaggcttggtaggtttaagaatagtttttgctgtactttctatagtgaatagagttaggcaggg atattcaccattatcgtttcagacccacctcccaaccccgaggggacccgacaggcccgaaggaatagaa gaagaaggtggagagagagacagagacagatccattcgattagtgaacggatctcgacggtatcgccttt aaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatac aaactaaagaattacaaaaacaaattacaaaaattcaaaattttcgggtttattacagggacagcagaga tccagtttatcgatgagtaattcatacaaaaggactcgcccctgccttggggaatcccagggaccgtcgt taaactcccactaacgtagaacccagagatcgctgcgttcccgccccctcacccgcccgctctcgtcatc actgaggtggagaagagcatgcgtgaggctccggtgcccgtcagtgggcagagcgcacatcgcccacagt ccccgagaagttggggggaggggtcggcaattgaaccggtgcctagagaaggtggcgcggggtaaactgg gaaagtgatgtcgtgtactggctccgcctttttcccgagggtgggggagaaccgtatataagtgcagtag tcgccgtgaacgttctttttcgcaacgggtttgccgccagaacacaggtaagtgccgtgtgtggttcccg cgggcctggcctctttacgggttatggcccttgcgtgccttgaattacttccacgcccctggctgcagta cgtgattcttgatcccgagcttcgggttggaagtgggtgggagagttcgaggccttgcgcttaaggagcc ccttcgcctcgtgcttgagttgaggcctggcttgggcgctggggccgccgcgtgcgaatctggtggcacc ttcgcgcctgtctcgctgctttcgataagtctctagccatttaaaatttttgatgacctgctgcgacgct ttttttctggcaagatagtcttgtaaatgcgggccaagatctgcacactggtatttcggtttttggggcc gcgggcggcgacggggcccgtgcgtcccagcgcacatgttcggcgaggcggggcctgcgagcgcggccac cgagaatcggacgggggtagtctcaagctggccggcctgctctggtgcctggcctcgcgccgccgtgtat cgccccgccctgggcggcaaggctggcccggtcggcaccagttgcgtgagcggaaagatggccgcttccc ggccctgctgcagggagctcaaaatggaggacgcggcgctcgggagagcgggcgggtgagtcacccacac aaaggaaaagggcctttccgtcctcagccgtcgcttcatgtgactccacggagtaccgggcgccgtccag gcacctcgattagttctcgagcttttggagtacgtcgtctttaggttggggggaggggttttatgcgatg gagtttccccacactgagtgggtggagactgaagttaggccagcttggcacttgatgtaattctccttgg aatttgccctttttgagtttggatcttggttcattctcaagcctcagacagtggttcaaagtttttttct tccatttcaggtgtcgtgaggatctatttccggtgaattcgccaccATGGTCCTGACGCTGCTTCTCTCC GCCTACAAGCTGTGTCGCTTCTTCGCCATGTCGGGCCCACGGCCGGGCGCCGAGCGGGATTACAAGGACG ACGATGACAAGCTGGCGGTGCCTGGGCCAGATGGGGGCGGTGGCACGGGCCCATGGTGGGCTGCGGGTGG CCGCGGGCCCCGCGAAGTGTCGCCGGGGGCAGGCACCGAGGTGCAGGACGCCCTGGAGCGCGCGCTGCCG GAGCTGCAGCAGGCCTTGTCCGCGCTGAAGCAGGCGGGCGGCGCGCGGGCCGTGGGCGCCGGCCTGGCCG AGGTCTTCCAACTGGTGGAGGAGGCCTGGCTGCTGCCGGCCGTGGGCCGCGAGGTAGCCCAGGGTCTGTG CGACGCCATCCGCCTCGATGGCGGCCTCGACCTGCTGTTGCGGCTGCTGCAGGCGCCGGAGTTGGAGACG CGTGTGCAGGCCGCGCGCCTGCTGGAGCAGATCCTGGTGGCTGAGAACCGAGACCGCGTGGCGCGCATTG GGCTGGGCGTGATCCTGAACCTGGCGAAGGAACGCGAACCCGTAGAGCTGGCGCGGAGCGTGGCAGGCAT CTTGGAGCACATGTTCAAGCATTCGGAGGAGACATGCCAGAGGCTGGTGGCGGCCGGCGGCCTGGACGCG GTGCTGTATTGGTGCCGCCGCACGGACCCCGCGCTGCTGCGCCACTGCGCGCTGGCGCTGGGCAACTGCG CGCTGCACGGGGGCCAGGCGGTGCAGCGACGCATGGTAGAGAAGCGCGCAGCCGAGTGGCTCTTCCCGCT CGCCTTCTCCAAGGAGGACGAGCTGCTTCGGCTGCACGCCTGCCTCGCAGTAGCGGTGTTGGCGACTAAC AAGGAGGTGGAGCGCGAGGTGGAGCGCTCGGGCACGCTGGCGCTCGTGGAGCCGCTTGTGGCCTCGCTGG ACCCTGGCCGCTTCGCCCGCTGTCTGGTGGACGCCAGCGACACAAGCCAGGGCCGCGGGCCCGACGACCT GCAGCGCCTCGTGCCGTTGCTCGACTCTAACCGCTTGGAGGCGCAGTGCATCGGGGCTTTCTACCTCTGC GCCGAGGCTGCCATCAAGAGCCTGCAAGGCAAGACCAAGGTGTTCAGCGACATCGGCGCCATCCAGAGCC TGAAACGCCTGGTTTCCTACTCTACCAATGGCACTAAGTCGGCGCTGGCCAAGCGCGCGCTGCGCCTGCT GGGCGAGGAGGTGCCACGGCCCATCCTGCCCTCCGTGCCCAGCTGGAAGGAGGCCGAGGTTCAGACGTGG CTGCAGCAGATCGGTTTCTCCAAGTACTGCGAGAGCTTCCGGGAGCAGCAGGTGGATGGCGACCTGCTTC TGCGGCTCACGGAGGAGGAACTCCAGACCGACCTGGGCATGAAATCGGGCATCACCCGCAAGAGGTTCTT TAGGGAGCTCACGGAGCTCAAGACCTTCGCCAACTATTCTACGTGCGACCGCAGCAACCTGGCGGACTGG CTGGGCAGCCTGGACCCGCGCTTCCGCCAGTACACCTACGGCCTGGTCAGCTGCGGCCTGGACCGCTCCC TGCTGCACCGCGTGTCTGAGCAGCAGCTGCTGGAAGACTGCGGCATCCACCTGGGCGTGCACCGCGCCCG CATCCTCACGGCGGCCAGAGAAATGCTACACTCCCCGCTGCCCTGTACTGGTGGCAAACCCAGTGGGGAC ACTCCAGATGTCTTCATCAGCTACCGCCGGAACTCAGGTTCCCAGCTGGCCAGTCTCCTGAAGGTGCACC TGCAGCTGCATGGCTTCAGTGTCTTCATTGATGTGGAGAAGCTGGAAGCAGGCAAGTTCGAGGACAAACT CATCCAGAGTGTCATGGGTGCCCGCAACTTTGTGTTGGTGCTATCACCTGGAGCACTGGACAAGTGCATG CAAGACCATGACTGCAAGGATTGGGTGCATAAGGAGATTGTGACTGCTTTAAGCTGCGGCAAGAACATTG TGCCCATCATTGATGGCTTCGAGTGGCCTGAGCCCCAGGTCCTGCCTGAGGACATGCAGGCTGTGCTTAC TTTCAACGGTATCAAGTGGTCCCACGAATACCAGGAGGCCACCATTGAGAAGATCATCCGCTTCCTGCAG GGCCGCTCCTCCCGGGACTCATCTGCAGGCTCTGACACCAGTTTGGAGGGTGCTGCACCCATGGGTCCAA CCtacccatacgatgttccagattacgctTAAggatcccgcccctctccctcccccccccctaacgttac tggccgaagccgcttggaataaggccggtgtgcgtttgtctatatgttattttccaccatattgccgtct tttggcaatgtgagggcccggaaacctggccctgtcttcttgacgagcattcctaggggtctttcccctc tcgccaaaggaatgcaaggtctgttgaatgtcgtgaaggaagcagttcctctggaagcttcttgaagaca aacaacgtctgtagcgaccctttgcaggcagcggaaccccccacctggcgacaggtgcctctgcggccaa aagccacgtgtataagatacacctgcaaaggcggcacaaccccagtgccacgttgtgagttggatagttg tggaaagagtcaaatggctctcctcaagcgtattcaacaaggggctgaaggatgcccagaaggtacccca ttgtatgggatctgatctggggcctcggtgcacatgctttacatgtgtttagtcgaggttaaaaaaacgt ctaggccccccgaaccacggggacgtggttttcctttgaaaaacacgatgataagcttgccacaacccac aaggagacgaccttccatgaccgagtacaagcccacggtgcgcctcgccacccgcgacgacgtcccccgg gccgtacgcaccctcgccgccgcgttcgccgactaccccgccacgcgccacaccgtcgacccggaccgcc acatcgagcgggtcaccgagctgcaagaactcttcctcacgcgcgtcgggctcgacatcggcaaggtgtg ggtcgcggacgacggcgccgcggtggcggtctggaccacgccggagagcgtcgaagcgggggcggtgttc gccgagatcggcccgcgcatggccgagttgagcggttcccggctggccgcgcagcaacagatggaaggcc tcctggcgccgcaccggcccaaggagcccgcgtggttcctggccaccgtcggcgtctcgcccgaccacca gggcaagggtctgggcagcgccgtcgtgctccccggagtggaggcggccgagcgcgccggggtgcccgcc ttcctggagacctccgcgccccgcaacctccccttctacgagcggctcggcttcaccgtcaccgccgacg tcgaggtgcccgaaggaccgcgcacctggtgcatgacccgcaagcccggtgcctagacgcgtctggaaca atcaacctctggattacaaaatttgtgaaagattgactggtattcttaactatgttgctccttttacgct atgtggatacgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctcc ttgtataaatcctggttgctgtctctttatgaggagttgtggcccgttgtcaggcaacgtggcgtggtgt gcactgtgtttgctgacgcaacccccactggttggggcattgccaccacctgtcagctcctttccgggac tttcgctttccccctccctattgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggg gctcggctgttgggcactgacaattccgtggtgttgtcggggaagctgacgtcctttccatggctgctcg cctgtgttgccacctggattctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagcgga ccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtcttcgccttcgccctcagacgagt cggatctccctttgggccgcctccccgcctggaattaattctgcagtcgagacctagaaaaacatggagc aatcacaagtagcaatacagcagctaccaatgctgattgtgcctggctagaagcacaagaggaggaggag gtgggttttccagtcacacctcaggtacctttaagaccaatgacttacaaggcagctgtagatcttagcc actttttaaaagaaaagaggggactggaagggctaattcactcccaacgaagacaagatatccttgatct gtggatctaccacacacaaggctacttccctgattagcagaactacacaccagggccaggggtcagatat ccactgacctttggatggtgctacaagctagtaccagttgagccagataaggtagaagaggccaataaag gagagaacaccagcttgttacaccctgtgagcctgcatgggatggatgacccggagagagaagtgttaga gtggaggtttgacagccgcctagcatttcatcacgtggcccgagagctgcatccggagtacttcaagaac tgctgatatcgagcttgctacaagggactttccgctggggactttccagggaggcgtggcctgggcggga ctggggagtggcgagccctcagatcctgcatataagcagctgctttttgcctgtactgggtctctctggt tagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagctt gccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctggtaactagagatccctcagaccc ttttagtcagtgtggaaaatctctagcagtagtagttcatgtcatcttattattcagtatttataacttg caaagaaatgaatatcagagagtgagaggccttgacattgctagcgtttaccgtcgacctctagctagag cttggcgtaatcatggtcatagctgtttcctgtgtgaaattgttatccgctcacaattccacacaacata cgagccggaagcataaagtgtaaagcctggggtgcctaatgagtgagctaactcacattaattgcgttgc gctcactgcccgctttccagtcgggaaacctgtcgtgccagctgcattaatgaatcggccaacgcgcggg gagaggcggtttgcgtattgggcgctcttccgcttcctcgctcactgactcgctgcgctcggtcgttcgg ctgcggcgagcggtatcagctcactcaaaggcggtaatacggttatccacagaatcaggggataacgcag gaaagaacatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgttttt ccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgaca ggactataaagataccaggcgtttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgc ttaccggatacctgtccgcctttctcccttcgggaagcgtggcgctttctcatagctcacgctgtaggta tctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgaccgc tgcgccttatccggtaactatcgtcttgagtccaacccggtaagacacgacttatcgccactggcagcag ccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaa ctacggctacactagaagaacagtatttggtatctgcgctctgctgaagccagttaccttcggaaaaaga gttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttttttgtttgcaagcagcaga ttacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggggtctgacgctcagtggaa cgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaat taaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgcttaa tcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcctgactccccgtcgtgta gataactacgatacgggagggcttaccatctggccccagtgctgcaatgataccgcgagacccacgctca ccggctccagatttatcagcaataaaccagccagccggaagggccgagcgcagaagtggtcctgcaactt tatccgcctccatccagtctattaattgttgccgggaagctagagtaagtagttcgccagttaatagttt gcgcaacgttgttgccattgctacaggcatcgtggtgtcacgctcgtcgtttggtatggcttcattcagc tccggttcccaacgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggttagctccttcg gtcctccgatcgttgtcagaagtaagttggccgcagtgttatcactcatggttatggcagcactgcataa ttctcttactgtcatgccatccgtaagatgcttttctgtgactggtgagtactcaaccaagtcattctga gaatagtgtatgcggcgaccgagttgctcttgcccggcgtcaatacgggataataccgcgccacatagca gaactttaaaagtgctcatcattggaaaacgttcttcggggcgaaaactctcaaggatcttaccgctgtt gagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatcttttactttcaccagcgtt tctgggtgagcaaaaacaggaaggcaaaatgccgcaaaaaagggaataagggcgacacggaaatgttgaa tactcatactcttcctttttcaatattattgaagcatttatcagggttattgtctcatgagcggatacat atttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctgac gtcgacggatcgggagatcaacttgtttattgcagcttataatggttacaaataaagcaatagcatcaca aatttcacaaataaagcatttttttcactgcattctagttgtggtttgtccaaactcatcaatgtatctt atcatgtctggatcaactggataactcaagctaaccaaaatcatcccaaacttcccaccccataccctat taccactgccaattacctgtggtttcatttactctaaacctgtgattcctctgaattattttcattttaa agaaattgtatttgttaaatatgtactacaaacttagtagt [0443] In certain embodiments, provided is a method for determining modulation of Sterile alpha and 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. [0444] In certain embodiments, the measuring comprises a fluorescent detection step. [0445] 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. [0446] In certain embodiments, the SARM1 protein comprises a fluorescent tag. [0447] 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. [0448] In certain embodiments, the candidate compound is an inhibitor of SARM1. [0449] 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. [0450] 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. [0451] 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. [0452] 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 IA:
Figure imgf000169_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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, oxo, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl; provided that: a) the moiety
Figure imgf000171_0001
a.
Figure imgf000171_0002
, which may optionally be fused to a C6 aryl; wherein q is 0, 1, 2, or 3; r is 0 or 1; s is 0, 1, or 2; t is 1 or 2; and X is CH2, CHZ1, C(Z1)2, NR9, O, or S, wherein R9 is H or Z1; and A is optionally substituted C3-10 cycloalkyl, optionally substituted 4- or 5- membered N-linked heterocyclyl, or optionally substituted C- linked heterocyclyl; provided the compound is not: 1954516-21-2 1,3-dihydro-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]- 1,3-ethano-2H-isoindole-2-carboxamide, 1953807-30-1 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-1,3,3- trimethyl-6-azabicyclo[3.2.1]octane-6-carboxamide, 1956565-60-8 3-hydroxy-N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-8- azabicyclo[3.2.1]octane-8-carboxamide, 1946370-08-6 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-3-oxo-8- azabicyclo[3.2.1]octane-8-carboxamide, 1949726-68-4 N-[4-methoxy-3-(2-oxo-1-pyrrolidinyl)phenyl]-2- azabicyclo[2.2.1]heptane-2-carboxamide, or 1953038-00-0 N-[3-(2,5-dioxo-1-pyrrolidinyl)-4-fluorophenyl]-8- azabicyclo[3.2.1]octane-8-carboxamide; or b.
Figure imgf000171_0003
wherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3; b) A is optionally substituted C4-10 cycloalkyl; c) A is 12
Figure imgf000171_0004
where R is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-10 cycloalkyl; or d) A is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is substituted with at least one substituent selected from cyano and C3-10 cycloalkyl. 2. The compound of claim 1, wherein the moiety is ; wherein: q is 0, 1, 2, 3, or 4; p is 0, 1,
2, or 3; Ring B is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1b; and L1 is a bond, C1-4 alkylene, C2-4 alkenylene, or C2-4 alkynylene.
3. The compound of claim 2, wherein Ring B is heteroaryl optionally substituted with one to five Z1b.
4. The compound of claim 2, wherein L1 is a bond or -CH2-.
5. The compound of claim 1, wherein the moiety is , , , , , , or
6. The compound of any preceding claim, wherein A is C1-6 alkyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1.
7. The compound of any one of claims 1-6, wherein A is C1-6 alkyl optionally substituted with one to five Z1.
8. The compound of any one of claims 1-6, wherein A is C1-6 alkyl substituted with cyano, -OR12, or C3-10 cycloalkyl, and optionally further substituted with one to four Z1.
9. The compound of any one of claims 1-6, wherein A is C3-10 cycloalkyl optionally substituted with one to five Z1.
10. The compound of any one of claims 1-6, wherein A is C4-10 cycloalkyl optionally substituted with one to five Z1.
11. The compound of any one of claims 1-6, wherein A is heterocyclyl optionally substituted with one to five Z1.
12. The compound of any one of claims 1-6, wherein A is a C-linked heterocyclyl optionally substituted with one to five Z1.
13. The compound of any one of claims 1-6, wherein A is a N-linked heterocyclyl optionally substituted with one to five Z1.
14. The compound of claim 13, wherein A is a 4- or 5-membered N-linked heterocyclyl optionally substituted with one to five Z1.
15. The compound of any preceding claim, wherein R4 is hydrogen or halo.
16. The compound of any preceding claim, wherein R4 is hydrogen or fluoro.
17. The compound of any preceding claim, wherein R5 is hydrogen or halo.
18. The compound of any preceding claim, wherein R1 is halo or C1-6 alkyl optionally substituted with one to five Z1.
19. The compound of any preceding claim, wherein R1 is halo, cyano, or C1-6 alkyl optionally substituted with one to five substituents independently selected from -N(R11)2 and halo.
20. The compound of any preceding claim, wherein R1 is chloro, cyano, -CH3, -CH2NH2, or -CF3.
21. The compound of any preceding claim, wherein R1 is chloro, cyano, or -CF3.
22. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
23. A compound selected from Table 2, or a pharmaceutically acceptable salt thereof.
24. 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.
25. A method for inhibiting SARM1 activity, the method comprising contacting a cell with an effective amount of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, the pharmaceutical composition of claim 21, or a compound of Formula I: I or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or heterocyclyl is optionally substituted with one to five Z1; R is C1-6 alkyl, -NR2R3, -OR7, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R1 is 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 optionally substituted with one to five Z1; R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R3 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; or R2 and R3 together form a heterocyclyl, which may further be 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 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; R7 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z1; 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, oxo, -N(R12)2, -OR12, -SR12, -C(O)R12, -C(O)OR12, -S(O)R12, -S(O)2R12, -C(O)N(R12)2, -NR12C(O)R12, -NR12S(O)R12, -NR12S(O)2R12, -S(O)N(R12)2, -S(O)2N(R12)2, -NR12C(O)N(R12)2, -NR12S(O)N(R12)2, -NR12S(O)2N(R12)2, -OC(O)N(R12)2, or -NR12C(O)OR12; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each 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 Z1a; 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 Z1b; each Z1a 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 Z1b; 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 Z1b; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 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 Z1b and L is further independently optionally substituted with one to five substituents independently selected from 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, and heteroaryl.
26. The method of claim 25, wherein the contacting is in vivo.
27. 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 1-23, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 24.
28. 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 1-23, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 24.
29. 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 1-23, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 24, to a subject in need thereof.
30. The method of claim 29, 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.
31. The method of claim 27, 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), Fredrich’s ataxia, hereditary ataxias, noise induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathies and axonopathies, Guillain- Barre syndrome, or severe acute motor axonal neuropathy (AMAN).
32. A 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 1-23, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 24.
33. Use of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 24, for treating a disease or condition mediated, at least in part, by SARM1.
34. The use of claim 33, 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), Fredrich’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).
35. A compound of any one of claims 1-23, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 24, for use in therapy.
36. A compound of any one of claims 1-23, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 24, 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), Fredrich’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).
37. The use of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 24, 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), Fredrich’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).
PCT/US2024/045444 2023-09-06 2024-09-05 Compounds, compositions, and methods Pending WO2025054369A1 (en)

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