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US 2026/0272920 A1Published application
Nlrp3 modulators
AssigneeZomagen Biosciences Ltd
InventorsJohn NUSS, Shendong YUAN, James COLLINS
Life of this patent
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Abstract
Described herein are NLRP3 modulators and methods of utilizing NLRP3 modulators in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.
Claims85
A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
- wherein:
- X is N, N(R7a), C(R7), or C(O);
- Y is N, N(R8a), C(R8), or C(O);
- wherein one of X and Y is N, N(R7a), or N(R8a);
- Z is -L-R6,
- L is —C(H)(OH)—;
- R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, S(═O)(═NH)N(R10)(R11), —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, and —CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- or R1 and R2 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14 groups;
- or R2 and R3 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14 groups;
- or R3 and R4 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14 groups;
- or R4 and R5 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, 4-, 5-, or 6-membered heterocycloalkyl ring, 5- or 6-membered heteroaryl ring, or phenyl ring are optionally substituted with one, two, or three R14 groups;
- R6 is
- R6a is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl optionally substituted with one, two, or three R14 groups;
- or R6a and an R15 are taken together to form a bridge that is —CH2— or —CH2CH2—;
- R7 and R8 are each independently selected from hydrogen, halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- R7a and R8a are each independently selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl optionally substituted with one, two, or three R14 groups;
- each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
- each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
- each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
- each R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
- each R14 is independently selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, S(═O)(═NH)N(R10)(R11), —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, and —CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- each R15 is independently selected from halogen, oxo, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, S(═O)(═NH)N(R10)(R11), —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, and —CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- or two R15 are taken together to form a bridge that is —CH2— or —CH2CH2—;
- n is 0, 1, 2, 3, or 4;
- and
- indicates a single or double bond such that all valences are satisfied.
23 more elements
A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
- wherein:
- X is N, N(R7a), C(R7), or C(O);
- Y is N, N(R8a), C(R8), or C(O);
- Z is -L-R6,
- L is —C(H)(OH)—;
- R6 is
- R6a is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl optionally substituted with one, two, or three R14 groups;
- or R6a and an R15 are taken together to form a bridge that is —CH2— or —CH2CH2—;
- R7 and R8 are each independently selected from hydrogen, halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- R7a and R8a are each independently selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl optionally substituted with one, two, or three R14 groups;
- R9 is C1-9heteroaryl optionally substituted with one, two, or three R14 groups;
- each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
- each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
- each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
- each R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
- each R14 is independently selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, S(═O)(═NH)N(R10)(R11), —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, and —CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- each R15 is independently selected from halogen, oxo, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, S(═O)(═NH)N(R10)(R11), —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, and —CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- or two R15 are taken together to form a bridge that is —CH2— or —CH2CH2—;
- n is 0, 1, 2, 3, or 4;
- and
- indicates a single or double bond such that all valences are satisfied.
18 more elements
A compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
- wherein:
- R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, and —OR9;
- R6 is
- R6a is selected from hydrogen, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl optionally substituted with one, two, or three R14 groups;
- or R6a and an R15 are taken together to form a bridge that is —CH2— or —CH2CH2—;
- R7 and R8 are each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl, wherein is optionally substituted with one, two, or three groups selected from —OR10 and —N(R10)(R11);
- each R9 is independently C1-6haloalkyl;
- each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
- each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
- each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
- each R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
- each R14 is independently selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, S(═O)(═NH)N(R10)(R11), —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, and —CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- each R15 is independently selected from halogen, oxo, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, S(═O)(═NH)N(R10)(R11), —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, and —CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, —OR10, and —N(R10)(R11);
- or two R15 are taken together to form a bridge that is —CH2— or —CH2CH2—;
- and
- n is 0, 1, 2, 3, or 4.
13 more elements
A compound selected from:
- or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from:
- or a pharmaceutically acceptable salt or solvate thereof.
Dependencies are inferred from the claim text.