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WO2025054369A1 - Composés, compositions et procédés - Google Patents

Composés, compositions et procédés 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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alkyl
heterocyclyl
cycloalkyl
alkenyl
alkynyl
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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/fr
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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de manière générale des inhibiteurs à petites molécules de la protéine SARM1 ("Sterile Alpha and TIR Motif containing 1 protein"), ou un sel pharmaceutiquement acceptable, un analogue enrichi isotopiquement, un stéréoisomère, un mélange de stéréoisomères, ou un promédicament de ceux-ci, des procédés de fabrication et des intermédiaires de ceux-ci, et des méthodes d'utilisation de ceux-ci.
PCT/US2024/045444 2023-09-06 2024-09-05 Composés, compositions et procédés Pending WO2025054369A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022031736A1 (fr) * 2020-08-04 2022-02-10 Nura Bio, Inc. Dérivés de pyridine substitués utiles comme inhibiteurs de sarm1
US20220340546A1 (en) * 2019-06-14 2022-10-27 Disarm Therapeutics, Inc. Inhibitors of sarm1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220340546A1 (en) * 2019-06-14 2022-10-27 Disarm Therapeutics, Inc. Inhibitors of sarm1
WO2022031736A1 (fr) * 2020-08-04 2022-02-10 Nura Bio, Inc. Dérivés de pyridine substitués utiles comme inhibiteurs de sarm1

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE 31 May 2019 (2019-05-31), XP093291665, Database accession no. 107480774 *
DATABASE PUBCHEM SUBSTANCE 31 May 2019 (2019-05-31), XP093291666, Database accession no. 107495588 *

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