WO2024249929A2 - Composés, compositions et procédés - Google Patents

Composés, compositions et procédés Download PDF

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Publication number
WO2024249929A2
WO2024249929A2 PCT/US2024/032100 US2024032100W WO2024249929A2 WO 2024249929 A2 WO2024249929 A2 WO 2024249929A2 US 2024032100 W US2024032100 W US 2024032100W WO 2024249929 A2 WO2024249929 A2 WO 2024249929A2
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Prior art keywords
cycloalkyl
heterocyclyl
alkyl
heteroaryl
alkenyl
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WO2024249929A3 (fr
Inventor
Alex L. BAGDASARIAN
II Robert A. CRAIG
Javier De Vicente Fidalgo
Brian M. Fox
Benjamin J. HUFFMAN
Katrina W. Lexa
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Tenvie Therapeutics Inc
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Nico Therapeutics Inc
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Publication of WO2024249929A3 publication Critical patent/WO2024249929A3/fr
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    • 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
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • NLRP3 Modulators of NLRP3, inhibitors in particular, have broad therapeutic potential in a wide array of auto-inflammatory and chronic inflammatory diseases that either require better treatment options or for which no adequate therapies exist.
  • Therapies targeting NLRP3-dependent cytokines are already approved for therapeutic use; however, they have notable disadvantages relative to direct NLRP3 antagonists.
  • DESCRIPTION [0004] 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 NLRP3.
  • 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 TNF- ⁇ the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • the administration is to a subject resistant to treatment with an anti-TNF- ⁇ agent.
  • the Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO disease is a gut disease or condition.
  • the disease or condition is inflammatory bowel disease, Crohn’s disease, or ulcerative colitis.
  • 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.
  • 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 NLRP3.
  • 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 NLRP3.
  • NLRP3 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 NLRP3.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -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.
  • alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl).
  • 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.
  • butyl includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ), and tert-butyl (i.e., -C(CH 3 ) 3 ), and “propyl” includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ), and isopropyl (i.e., -CH(CH 3 ) 2 ).
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc.
  • 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
  • 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).
  • alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl, and 1,3-butadienyl).
  • 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).
  • 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.
  • 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. Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO [0023] “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.
  • acyl examples include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR y R z and an “N-amido” group which refers to the group -NR y C(O)R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or R y and R z are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.
  • “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.
  • “Amidino” 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. [0028] “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., C 3-6 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. [0033] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.
  • Imino refers to a group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Imido” refers to a group -C(O)NR y C(O)R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.
  • 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.
  • 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.
  • 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.
  • “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.
  • “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.
  • 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 ,
  • 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.
  • “Heteroaryl” refers to an aromatic group having a single ring or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • 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.
  • ring carbon atoms i.e., C1-20 heteroaryl
  • 3 to 12 ring carbon atoms i.e., C3-12 heteroaryl
  • 3 to 8 carbon ring atoms i.e., C3-8 heteroaryl
  • 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.
  • 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.
  • 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-oxido
  • 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 Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO can be bound via either ring of the fused system.
  • 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.
  • 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).
  • 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., 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.
  • 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)1-2R 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 Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO 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 SO 2 R g , or -CH 2 SO 2 NR 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.
  • isotopically enriched analogs 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 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H and 14 C 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.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • 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. [0056] 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
  • 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 18 F, 3 H, 11 C 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.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • 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.
  • “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.
  • 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.
  • physiologically acceptable salts include, for example, salts with inorganic acids, and salts with an organic acid.
  • 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.
  • 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.
  • 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., NH 2 (substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl) 2 ), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl
  • alkyl amines i.e., NH2(
  • 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.
  • tautomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers.
  • the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers.
  • the amide containing compounds are understood to include their imidic acid tautomers.
  • the imidic acid containing compounds are understood to include their amide tautomers.
  • 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.
  • 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).
  • 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.
  • “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • 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.
  • 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.
  • esters e.g., acetate, formate, and benzoate derivatives
  • amides e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylaminocarbonyl
  • 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.
  • a compound of Formula I I or a pharmaceutically analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, q is 0, 1, 2, 3, 4, 5, or 6;
  • X is C(X 1 ), NR 16 , or S(O)2;
  • Y is C(Y 1 ), O, NR 17 , or S(O)2;
  • X 1 is O, NR 18 , or S;
  • Y 1 is O, NR 19 , or S;
  • Q 1 is a bond, C1-3 alkylene or C1-3 heteroalkylene; wherein each C1-3 alkylene or C1-3 heteroalkylene is independently optionally substituted with one to four Z 1 ;
  • a 1 , A 2 , A 3 and A 4 are each independently N, CH, or CR 1 ; provided at least one of A 1 , A 2 , A 3 , and A 4 is CR 1 ;
  • each R 1 is independently halo, cyano, -NO2, -SF5, C1-6
  • X is C(X 1 ). In certain embodiments, X is NR 16 . In certain embodiments, X is S(O) 2 .
  • Y is C(X 1 ). In certain embodiments, Y is O. In certain embodiments, Y is NR 16 . In certain embodiments, Y is S(O) 2 .
  • a 2 , A 3 , and A 4 are each independently N, CH, or CR 1 ; and A 1 is CR 1 .
  • a 1 , A 3 , and A 4 are each independently N, CH, or CR 1 ; and A 2 is CR 1 .
  • a 1 , A 2 , and A 4 are each independently N, CH, or CR 1 ; and A 3 is CR 1 .
  • a 1 , A 2 , and A 3 are each independently N, CH, or CR 1 ; and A 4 is CR 1 .
  • at least one of A 1 , A 2 , A 3 , and A 4 is N.
  • a 1 , A 2 , A 3 , and A 4 are each independently CH or CR 1 .
  • a 2 , A 3 , and A 4 are each independently CH or CR 1 ; and A 1 is CR 1 .
  • a 1 , A 3 , and A 4 are each independently CH or CR 1 ; and A 2 is CR 1 .
  • a 1 , A 2 , and A 4 are each independently CH or CR 1 ; and A 3 is CR 1 .
  • a 1 , A 2 , and A 3 are each independently CH or CR 1 ; and A 4 is CR 1 .
  • X 1 is O.
  • Y 1 is O.
  • X 1 and Y 1 are O.
  • a 1 is CH or CR 1 .
  • a 2 is CH or CR 1 .
  • a 3 is CH or CR 1 .
  • a 4 is CH or CR 1 .
  • IB IB wherein Q 1 , A 1 , A 2 , A 3 , A 4 , as defined herein.
  • a by Formula IC IC wherein Q 1 , A 1 , R 1 , A 3 , A 4 , as defined herein.
  • R 5 is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 .
  • R 5 is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 .
  • each Z 1 is independently halo or cyano.
  • R 5 is (1-(2,2-difluoroethyl)cyclobutyl)methyl, (1-methyl-1H-imidazol-2- yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, (1-methyl-1H-pyrazol-5-yl)methyl, (1R,2R,4S)-7- oxabicyclo[2.2.1]heptan-2-yl, (1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl, (2-(trifluoromethyl)pyridin-3- yl)methyl, [1,2,4]triazolo[1,5-a]pyridin-2-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, [1,2,4]triazolo[1,5-a]pyrazin- 2-yl, 7-chloro-[1,2,4]triazolo[1,5-a]pyridin
  • R 4 and R 5 together form a heterocyclyl or heteroaryl ring optionally substituted with one to eight Z 1 .
  • ring A is R 5 .
  • R 4 is hydrogen or C1-6 alkyl.
  • R 4 is hydrogen or methyl.
  • R 6 is hydrogen.
  • R 7 is hydrogen.
  • Q 1 is a bond, C1-3 alkylene, or C1-3 heteroalkylene.
  • Q 1 is a bond.
  • Q 1 is C 1-3 alkylene. In certain embodiments, Q 1 is C 1-3 heteroalkylene. [0105] In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 1 or 2. In certain embodiments, p is 3. In certain embodiments, p is 4.
  • each R 1 is independently halo, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-10 cycloalkyl, or heterocyclyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 3-10 cycloalkyl are independently optionally substituted with one to eight Z 1 ; or any two adjacent R 1 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring.
  • each R 1 is independently fluoro, bromo, chloro, iodo, cyano, ethyl, vinyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, oxetan-3-yl, 2,2-difluorocycloprop-1-yl, 1-cyanocyclopropyl, 1- methylcyclopropyl, 1-fluoro-2-(trifluoromethyl)cyclopropyl, ethynyl, 1-fluorovinyl, 1-fluorocyclopropyl, 2- Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO fluorocyclopropyl, or 1,2-difluorocyclopropyl; or two
  • each R 1 is independently halo, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 3-10 cycloalkyl, wherein the C 2-6 alkenyl or C 3- 10 cycloalkyl is independently optionally substituted with one to eight Z 1 .
  • each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is independently optionally substituted with one to eight Z 1 .
  • each R 1 is independently halo, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 3-10 cycloalkyl, wherein the C 2-6 alkenyl or C 3-10 cycloalkyl is independently optionally substituted with one to eight Z 1 , wherein each is independently selected from halo, cyano and C 1-6 alkyl.
  • each R 1 is independently halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, or C 3-10 cycloalkyl. In certain embodiments, each R 1 is independently halo, cyano, C 1-6 haloalkoxy, C 1-6 haloalkyl, or C 3-10 cycloalkyl. In certain embodiments, each R 1 is independently halo, cyano, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkyl. In certain embodiments, each R 1 is independently halo or C 1-6 alkyl.
  • each R 1 is independently fluoro, bromo, chloro, iodo, cyano, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, 2,2- difluorocycloprop-1-yl, 1-cyanocyclopropyl, and 1-methylcyclopropyl, ethynyl, 1-fluorovinyl, 1- fluorocyclopropyl, or 1,2-difluorocyclopropyl.
  • each R 1 is independently fluoro, bromo, chloro, iodo, cyano, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxy, fluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, 2,2-difluorocycloprop-1-yl, 1-cyanocyclopropyl, and 1- methylcyclopropyl.
  • each R 1 is independently fluoro, bromo, -CH3, -OCHF2, -CF3, or cyclopropyl.
  • each R 1 is independently fluoro, bromo, or -CH3.
  • each R 1 is independently halo. In certain embodiments, each R 1 is independently bromo. In certain embodiments, each R 1 is independently halo or -CF3. [0111] In certain embodiments, p is 1; and each R 1 is independently halo, cyano, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkyl. In certain embodiments, p is 2; and each R 1 is independently halo, cyano, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkyl. In certain embodiments, p is 1 or 2; and each R 1 is independently halo, cyano, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkyl.
  • R 2 and R 3 together form a C3-10 cycloalkyl or heterocyclyl ring; wherein the C3-10 cycloalkyl or heterocyclyl is independently optionally substituted with one to eight Z 1 .
  • R 2 and R 3 together form a C3-10 cycloalkyl ring optionally substituted with one to eight Z 1 .
  • R 2 and R 3 together form a C3-10 cycloalkyl optionally substituted with halo, cyano, Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO C 1-6 alkyl or C 1-6 haloalkyl.
  • R 2 and R 3 together form a C 3-10 cycloalkyl optionally substituted with halo, C 1-6 alkyl or C 1-6 haloalkyl. In certain embodiments, R 2 and R 3 together form a C 3-10 cycloalkyl optionally substituted with fluoro, methyl or trifluoromethyl. In certain embodiments, R 2 and R 3 together form a C 3-10 cycloalkyl ring optionally substituted with C 1-6 alkyl. In certain embodiments, R 2 and R 3 together form a C 3-10 cycloalkyl ring optionally substituted with methyl. In certain embodiments, R 2 and R 3 together form a heterocyclyl ring optionally substituted with one to eight Z 1 .
  • R 2 and R 3 together form a C 3-10 cycloalkyl or heterocyclyl ring. In certain embodiments, R 2 and R 3 together form an unsubstituted C 3-10 cycloalkyl ring. In certain embodiments, R 2 and R 3 together form an unsubstituted cyclopropyl ring. In certain embodiments, R 2 and R 3 together form an unsubstituted heterocyclyl ring. [0113] In certain embodiments, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, or -OR 11 , wherein R 11 is C 1-6 alkyl optionally substituted with one to five Z 1a .
  • R 2 is C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 is hydrogen or C 1-6 alkyl.
  • R 2 is C 1-6 alkyl or C 1-6 haloalkyl.
  • R 2 is C 1- 6 alkyl.
  • R 2 is methyl or ethyl.
  • R 2 is -C(R 24 )2R 25 ; each R 24 and R 25 are independently hydrogen, halo, C1- 4 alkyl, or C 1-4 haloalkyl.
  • R 2 is -C(R 24 ) 2 R 25 ; each R 24 is independently hydrogen, halo, C 1-4 alkyl, or C 1-4 haloalkyl, and R 25 is hydrogen.
  • R 3 is hydrogen, C1-6 alkyl or C1-6 haloalkyl. In certain embodiments, R 3 is hydrogen or C1-6 alkyl. In certain embodiments, R 3 is C1-6 alkyl. In certain embodiments, R 3 is hydrogen or methyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is methyl.
  • R 2 is C1-6 alkyl
  • R 3 is hydrogen, or C1-6 alkyl
  • R 2 and R 3 together form a C3-10 cycloalkyl ring optionally substituted with C1-6 alkyl.
  • R 2 and R 3 are C1-6 alkyl.
  • each R 1 is independently halo, C1-6 haloalkyl, or C3-6 cycloalkyl; wherein the C3-10 cycloalkyl is independently optionally substituted with one to eight Z 1 ;
  • R 4 is hydrogen; and
  • R 5 is C3- 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 .
  • a 2 is CR 1 ; where R 1 is halo, C1-6 haloalkyl, or C3-6 cycloalkyl; wherein the C3-10 cycloalkyl is independently optionally substituted with one to eight Z 1 ; R 4 is hydrogen; and R 5 is C3- 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z 1 .
  • a 2 is CR 1 ; where R 1 is halo, C1-6 haloalkyl, or C3-6 cycloalkyl; wherein the C3-10 cycloalkyl is independently optionally substituted with halo; R 4 is hydrogen; and R 5 is heteroaryl optionally substituted with one to five halo.
  • R 1 is halo, C1-6 haloalkyl, or C3-6 cycloalkyl; wherein the C3-10 cycloalkyl is independently optionally substituted with halo;
  • R 4 is hydrogen; and R 5 is heteroaryl optionally substituted with one to five halo.
  • each Z 1a is independently halo.
  • each Z 1 is independently halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or -C(O)OR 11 .
  • each R 11 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • each R 11 is independently hydrogen or C 1-6 alkyl. In certain embodiments, each R 11 is hydrogen.
  • each R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, each R 13 is independently hydrogen or C 1-6 alkyl. [0125] 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 No. Structure Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO No. Structure
  • prov e s a compoun seece rom ale 2 or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or a mixture of stereoisomers thereof: Table 2
  • 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.
  • 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
  • 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 some embodiments, be Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • 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.
  • the subject is a mammal.
  • the subject is a human.
  • 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 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.
  • 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.
  • NLR Family Pyrin Domain Containing 3 NLRP3
  • NLR proteins are involved in the immune system, helping to start and regulate the immune system’s response to injury, toxins, or invasion by microorganisms.
  • NLRP3 also known as cryopyrin, NALP3, LRR and PYD domains-containing protein 3
  • IL interleukin
  • IL-18 active proinflammatory cytokines
  • IL-1 ⁇ and IL ⁇ 18 are known mediators of inflammation, e.g., artery wall inflammation, atherosclerosis and the aging process.
  • inflammasome e.g., the NLRP3 inflammasome
  • a method of inhibiting inflammasome 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.
  • inflammasome e.g., the NLRP3 inflammasome
  • prodrug thereof for use in inhibiting inflammasome activity (e.g., 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 inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo).
  • inflammasome e.g., the NLRP3 inflammasome
  • prodrug thereof e.g., chronic inflammation responses have been associated with various types of cancer.
  • IL- ⁇ expression is elevated in a variety of cancers (e.g., breast, prostate, colon, lung, head and neck cancers, melanomas, etc.), where patients with IL- ⁇ producing tumors generally have a worse prognosis.
  • a method for treating a disease or condition mediated, at least in part, by NLRP3, comprising administering an 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 for treating a disease or condition selected from an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO 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 an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer 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 or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a subject in need thereof.
  • the disease or condition may be a disease or condition of the immune system, the cardiovascular system, the endocrine system, the gastrointestinal tract, the renal system, the hepatic system, the metabolic system, the respiratory system, the central nervous system, may be a cancer or other malignancy, and/or may be caused by or associated with a pathogen. It will be appreciated that these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive.
  • the disease or condition includes, inflammation, including inflammation occurring as a result of an inflammatory disorder, e.g.
  • an autoinflammatory disease inflammation occurring as a symptom of a non-inflammatory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma, injury or autoimmunity
  • auto-immune diseases such as acute disseminated encephalitis, Addison’s disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn’s disease, type 1 diabetes (T1D), Goodpasture’s syndrome, Graves’ disease, Guillain-Barré syndrome (GBS), Hashimoto’s disease, idiopathic thrombocytopenic purpura, Kawasaki’s disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) including primary progressive
  • influenza virus human immunodeficiency virus (HIV), alphavirus (such as Chikungunya and Ross River virus), flaviviruses (such as Dengue virus and Zika virus), herpes viruses (such as Epstein Barr Virus, cytomegalovirus, Varicella-zoster virus, and KSHV), poxviruses (such as vaccinia virus (Modified vaccinia virus Ankara) and Myxoma virus), adenoviruses (such as Adenovirus 5), or papillomavirus), bacterial infections (e.g.
  • HAV human immunodeficiency virus
  • alphavirus such as Chikungunya and Ross River virus
  • flaviviruses such as Dengue virus and Zika virus
  • herpes viruses such as Epstein Barr Virus, cytomegalovirus, Varicella-zoster virus, and KSHV
  • poxviruses such as vaccinia virus (Modified vaccinia virus Ankara) and Myxo
  • helminth infections e.g. from Candida or Aspergillus species
  • protozoan infections e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes
  • helminth infections e.g.
  • central nervous system diseases such as Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, and amyotrophic lateral sclerosis; metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudo-gout; cardiovascular diseases such as hypertension, ischemia, reperfusion injury including post-MI ischemic reperfusion injury, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysms including abdominal aortic aneurysm, and pericarditis including Dressler’s syndrome; respiratory diseases including chronic obstructive pulmonary disorder (COPD
  • the disease, disorder or condition is an autoinflammatory disease such as cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor antagonist (DIRA), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still's disease (AOSD), haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO PLCG2- associated autoinflammatory, antibody deficiency and immune dysregulation
  • CAPS cryopyrin
  • cryopyrin-associated periodic syndromes CRS
  • Muckle-Wells syndrome FCAS
  • familial cold autoinflammatory syndrome FCAS
  • NOMID neonatal onset multisystem inflammatory disease
  • FMF familial Mediterranean fever
  • PAPA hyperimmunoglobulinemia D and periodic fever syndrome
  • HIDS hyperimmunoglobulinemia D and periodic fever syndrome
  • TNF Tumor Necrosis Factor
  • TRAPS Receptor- Associated Periodic Syndrome
  • systemic juvenile idiopathic arthritis adult-onset Still’s disease (AOSD)
  • AOSD relapsing polychondritis
  • Schnitzler’s syndrome Sweet’s syndrome
  • Behcet’s disease anti- synthetase syndrome
  • deficiency of interleukin 1 receptor antagonist DIRA
  • haploinsufficiency of A20 HA20
  • a method for treating a disease or condition that is mediated, at least in part, by TNF- ⁇ is resistant to treatment with an anti-TNF- ⁇ agent.
  • the disease is a gut disease or condition.
  • the disease or condition is inflammatory bowel disease, Crohn’s disease, or ulcerative colitis.
  • a compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered in combination with an anti-TNF- ⁇ agent.
  • the anti-TNF- ⁇ agent is infliximab, etanercept, certolizumab pegol, golimumab, or adalimumab.
  • the disease or condition is an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.
  • the disease or condition is an autoinflammatory disorder and/or an autoimmune disorder.
  • the disease or condition is a neurodegenerative disease.
  • the disease or condition is Parkinson’s disease or Alzheimer’s disease.
  • a method for treating cancer comprising administering an 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.
  • the cancer is metastasizing cancer, gastrointestinal cancer, skin cancer, non- small-cell lung carcinoma, or colorectal adenocarcinoma.
  • a neurodegenerative disease e.g., Parkinson's disease or Alzheimer's disease
  • a compound as disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof may be administered alone as a sole therapy or can be administered in addition with one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced).
  • 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.
  • kits 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.
  • 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.
  • compositions and Modes of Administration Compounds provided herein are usually administered in the form of pharmaceutical compositions.
  • 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.
  • 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.
  • 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, Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO 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.
  • 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, orally or nasally, from devices that deliver the formulation in an appropriate manner. 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 some 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.
  • body weight 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.
  • 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. [0174] 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.
  • process conditions i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.
  • 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.
  • conventional protecting groups (“PG”) may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • PG protecting groups
  • 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.
  • 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
  • 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.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • 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).
  • Scheme I illustrates a general methods which can be employed for the synthesis of compounds described herein, where each of q, X, Y, A 1 , A 2 , A 3 , A 4 , Q 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently as defined herein, R is hydrogen or C1-6 alkyl, and each LG is independently a leaving group (e.g., hydroxy, alkkoxy, halo, etc.). It should be understood that derivatization of any one or more of compounds I-1, I-2, I- 3, I-4, and I-5, or any product obtained by the process outlined in Scheme I, can be performed to provide various compounds of Formula I.
  • Scheme III illustrates a general method which can be employed for the synthesis of compounds as described herein where each of A 1 , A 2 , A 3 , A 4 , R 4 , and R 5 are each independently as defined herein.
  • Scheme III of skill in the art.
  • 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.
  • the various substituents of compounds I-1, I-2, I-3, I-4, and I-5 as used in Scheme I are as defined for Formula I.
  • 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 Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO spectrometer equipped with a Bruker 400 BBO probe operating at 400 MHz.
  • TLC Thin Layer Chromatography
  • TLC thin layer chromatography
  • 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.
  • 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.
  • Example 1 2-(cis-8-bromo-5-oxo-2,3,3a,9b-tetrahydro-1H-cyclopenta[c]isoquinolin-4-yl)-N-(5-fluoropyrimidin-2- yl)acetamide mmol) in THF (250 mL) at -10 °C was added i-PrMgCl (2 M in THF, 76 mL).
  • reaction mixture was stirred for 1 h at -10 °C followed by the addition of CuI (1.42 g, 7.43 mmol) as a solution in THF (40 mL) and then 6-oxabicyclo [3.1.0] hexane (12.5 g, 148.6 mmol) as a solution in THF (40 mL).
  • the reaction mixture was stirred at 20 °C for 2 h.
  • the reaction mixture was diluted with aq. sat. NH4Cl (100 mL) and extracted with EtOAc (3 ⁇ 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.
  • reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (3 ⁇ 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.
  • reaction mixture was filtered and the filtrate was washed with aq. sat Na2CO3 (3 ⁇ 200 mL), brine (2 ⁇ 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography.
  • tert-butyl 4-bromo-2-(3,3,3-trifluoroprop-1-en-2-yl)benzoate To a solution of 1- (trifluoromethyl)vinylboronic acid hexylene glycol ester (11.5 g, 51.7 mmol), tert-butyl 4-bromo-2- iodobenzoate (22.0 g, 57.4 mmol) in 1,4-dioxane (500 mL) were added CsF (26.2 g, 172.3 mmol) and Pd(dppf)Cl2 (4.20 g, 5.74 mmol). The reaction mixture was stirred at 90 °C for 3 h.
  • reaction mixture was poured into H2O (800 mL) and extracted with EtOAc (4 ⁇ 100 mL). The combined organic layers were washed with brine (2 ⁇ 50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by gel silica chromatography.
  • tert-butyl 4-bromo-2-(trans-2-(ethoxycarbonyl)-1-(trifluoromethyl)cyclopropyl)benzoate To a solution of tert-butyl 4-bromo-2-(3,3,3-trifluoroprop-1-en-2-yl)benzoate (800 mg, 2.28 mmol) in toluene (3.0 mL) was added ethyl 2-diazoacetate (260 mg, 2.28 mmol). The reaction mixture was stirred at 120 °C for 12 h.
  • trans-2-(5-bromo-2-(tert-butoxycarbonyl)phenyl)-2-(trifluoromethyl)cyclopropanecarboxylic acid To a solution of tert-butyl 4-bromo-2-(trans-2-(ethoxycarbonyl)-1- (trifluoromethyl)cyclopropyl)benzoate (7.2 g, 16.5 mmol) in THF (70 mL) and H 2 O (20 mL) was added Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO LiOH•H 2 O (1.73 g, 41.2 mmol). The reaction mixture was stirred at 25 °C for 12 h.
  • the reaction mixture was diluted with H 2 O (50 mL) and washed with MTBE (3 ⁇ 20 mL).
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography.
  • tert-butyl 2-(trans-2-(azidocarbonyl)-1-(trifluoromethyl)cyclopropyl)-4-bromobenzoate To a solution of trans-2-(5-bromo-2-(tert-butoxycarbonyl)phenyl)-2-(trifluoromethyl)cyclopropanecarboxylic acid (2.50 g, 6.11 mmol) in toluene (25 mL) at 0 °C were added DPPA (1.85 g, 6.72 mmol) and Et 3 N (1.24 g, 12.2 mmol). The reaction mixture was stirred at 25 °C for 5 h.
  • reaction mixture was poured into H 2 O (50 mL) and extracted with EtOAc (3 ⁇ 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to provide a residue that was used directly.
  • tert-butyl 4-bromo-2-(trans-2-((tert-butoxycarbonyl)amino)-1- (trifluoromethyl)cyclopropyl)benzoate A solution of tert-butyl 2-(trans-2-(azidocarbonyl)-1- (trifluoromethyl)cyclopropyl)-4-bromobenzoate (2.0 g, 4.61 mmol) in t-BuOH (80 mL) was stirred at 90 °C for 12h. The reaction mixture was poured into H 2 O (100 mL) and extracted with EtOAc (3 ⁇ 50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • trans-6-bromo-7b-(trifluoromethyl)-1a,2-dihydro-1H-cyclopropa[c]isoquinolin-3(7bH)-one A solution of tert-butyl 4-bromo-2-(trans-2-((tert-butoxycarbonyl)amino)-1- (trifluoromethyl)cyclopropyl)benzoate (1.20 g, 2.50 mmol) in HCl (4 M in MeOH, 20 mL) was stirred at 25 °C for 24 h. The reaction mixture was poured into H2O (20 mL) neutralized by the addition of aq. sat. NaHCO3.
  • reaction mixture was stirred at 90 °C for 2 h.
  • the reaction mixture was diluted with H 2 O (30 mL) and extracted with DCM (3 ⁇ 10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Example 4 2-(cis-7-bromo-4-oxo-1,2,2a,8b-tetrahydrocyclobuta[c]isoquinolin-3-yl)-N-(5-fluoropyrimidin-2- yl)acetamide [0208] 96.6 mmol) in toluene (200 mL) was added KOH (21.7 g, 386 mmol). The reaction mixture was stirred at 110 °C for 1 h. The reaction mixture was cooled to 0 °C, diluted with H 2 O (40 mL), and washed with MTBE (30 Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO mL).
  • benzyl cyclobut-1-enecarboxylate To a solution of cyclobut-1-enecarboxylic acid (9.0 g, 91.7 mmol) and Et 3 N (27.8 g, 275 mmol) in THF (100 mL) at 0 °C was added methyl carbonochloridate (18.7 g, 198.2 mmol).
  • the reaction mixture was stirred at 20 °C for 1 h followed by the addition of phenylmethanol (29.8 g, 275 mmol). The reaction mixture was stirred at 20 °C for a further 1 h.
  • the reaction mixture was diluted with H 2 O (100 mL) and 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. The residue was purified by silica gel column chromatography.
  • benzyl cis-2-(3-bromophenyl)cyclobutanecarboxylate To a solution of benzyl cyclobut-1- enecarboxylate (5.0 g, 26.6 mmol) and 2-(3-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.7 g, 53.1 mmol) in 1,4-dioxane (5.0 mL) and H 2 O (0.5 mL) were added [RuCl(COD)] 2 (1.31 g, 2.66 mmol) and Et 3 N (8.06 g, 79.7 mmol).
  • the reaction mixture was stirred at 23 °C for 2 h followed by the addition of 3-[3-(2-carboxy-2-methyl-propyl)phenyl]-2,2-dimethyl-propanoic acid;rhodiorhodium (158 mg, 0.21 mmol), PhI(OAc) 2 (1.34 g, 4.15 mmol), CH 3 NO 2 (7.60 g, 124.4 mmol,) and K 2 CO 3 (1.26 g, 9.13 mmol). The reaction mixture was stirred at 23 °C for a further 16 h. The reaction mixture was poured into H 2 O (50 mL) and extracted with EtOAc (3 ⁇ 75 mL).
  • BIOLOGICAL EXAMPLE 1 Biochemical Assay of the Compounds Procedure for culturing THP-1 cells Compounds as provided herein were tested in the following assay.
  • Cell culture medium employed contained RPMI 1640 medium (89%), FBS (10%), Pen/Strep (1%), and 2-mercaptoethanol (0.05 mM). Freezing medium was made up of 90% FBS and 10% DMSO.
  • THP-1 cells were removed from the liquid nitrogen and placed into a 37 o C water bath to thaw, until signs of ice dissipated. The cells were then added to 9 mL of warm cell culture medium and centrifuged for 5 minutes at 1000 rpm.
  • Serum- free media contains RPMI 1640 medium (99%), Pen/Strep (1%), and 2-mercaptoethanol (0.05 mM).
  • Day 1 Differentiation with PMA [0226] THP-1 cells were diluted to provide a suspension at a concentration of 1.0x10 6 cells/mL with the total volume of suspension required to enable the desired number of assay plates.
  • the growth media was supplemented with PMA (5 ng/mL final concentration) and the cells were incubated at 37 °C under a humidified atmosphere of 5% CO2 for 40 h.
  • Day 3 Plating with sequential LPS and nigericin stimulation Attorney Docket No.: 95BK-374860-WO NCO-028-20-WO [0227] All media was carefully aspirated from each culture flask. The cells were washed carefully with 1x DPBS. The cells were then briefly digested with trypsin LE for 5 minutes at 23 °C and immediately resuspended in cell growth media. After resuspension, the cells were centrifuged at 1000 rpm for 3 minutes and the supernatant was discarded.
  • the cells were resuspended in DPBS and once again centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded and the cell pellet was resuspended in serum-free media supplemented with LPS (25 ng/mL final concentration) to enable the distribution of 30K THP-1 cells within 45 ⁇ L of media into each well of 384-well PDL-coated plates. The 384-well plates were then incubated at 37 °C under a humidified atmosphere of 5% CO 2 for 2 h. Following this period, test compounds were dispensed by Tecan across the desired concentration range with all wells normalized to a final 0.5 % DMSO concentration.
  • the plates were then then incubated at 37 °C under a humidified atmosphere of 5% CO 2 for 1 h. Following this period, 5 ⁇ L of the 5 mg/mL nigericin stock solution was added to each of the appropriate wells and plates were centrifuged at 1000 rpm for 30 seconds. The plates were the immediately reintroduced to the incubator at 37 °C under a humidified atmosphere of 5% CO 2 for 2 h. After this time, 35 ⁇ L/well of supernatant was collected and transferred into v-bottom plate and centrifuged at 1000 rpm for 1 minute. These supernatant aliquots were analyzed using an IL-I ⁇ detection kit as described below.
  • test samples could be snap frozen and stored at -80 °C until analyzed.
  • IL-1 ⁇ detection To prepare each ELISA plate, capture antibody (mAb Mt175) was diluted with PBS to a final concentration of 2 ⁇ g/mL and then 20 ⁇ L of this solution was added to each well of the ELISA plate. Each plate was allowed to incubate overnight at 4 °C. The next day, the capture antibody solution was removed and discarded. Each ELISA plate was washed 4 times with PBST followed by the addition of 25 ⁇ L/well of blocking buffer (Licor-927-40010) supplemented with 0.1% Tween 20. Each ELISA plate was then allowed to incubate for 1 hour at 23 °C.
  • blocking buffer Lior-927-400
  • each ELISA plate was washed 4 times with PBST. During this time, the v-bottomed plates containing the supernatant aliquots from the assay run were centrifuged at 300 g for 5 minutes before transferring 15 ⁇ L/well of the supernatant sample to each ELISA plate. Each ELISA plate was then allowed to incubate for 2 h at 23 °C. After this time, the supernatant samples were removed and discarded. Each ELISA plate was washed 4 times with PBST. To each ELISA plate was added 15 ⁇ L/well of mAb7P10-biotin at 0.5 ⁇ g/mL (1:1000 diluted in blocking buffer).
  • Each ELISA plate was then allowed to incubate for 1 h at 23 °C. After this time, the antibody solution was removed and discarded. Each ELISA plate was washed 4 times with PBST. To each ELISA plate was added 20 ⁇ L/well of streptavidin-HRP (1:2000 diluted in blocking buffer). Each ELISA plate was then allowed to incubate for 1 h at 23 °C. After this time, the buffer was removed and discarded. Each ELISA plate was washed 4 times with PBST. To each ELISA plate was added 20 ⁇ L/well of HRP substrate. Each ELISA plate was then allowed to incubate for 2 minutes at 23 °C.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne de manière générale des modulateurs à petites molécules de NLRP3 (NLR Family Pyrin Domain Containing 3), 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 procédés d'utilisation de ceux-ci.
PCT/US2024/032100 2023-06-01 2024-05-31 Composés, compositions et procédés Ceased WO2024249929A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6754772B2 (ja) * 2015-10-23 2020-09-16 武田薬品工業株式会社 複素環化合物
US10807994B2 (en) * 2017-10-09 2020-10-20 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
IL302906A (en) * 2020-11-20 2023-07-01 Denali Therapeutics Inc Compounds, compositions, and methods

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1

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