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US 12,180,226 B2Granted
Spirotricycle RIPK1 inhibitors and methods of uses thereof
AssigneeMerck Sharp & Dohme Corp.
InventorsAbdelghani Abe Achab, Zachary G. Brill, Jenny Lorena Rico Duque, Xavier Fradera, Joey L. Methot, Phieng Siliphaivanh, Jing Su, Brandon A. Vara, Erin F. DiMauro
Life of this patent
Estimating the term…
Abstract
Described herein are compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein A, R1, R2, R3, W, X, Y, Z, m, n and p are as defined herein. The compounds of Formula I act as RIPK1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for RIPK1-related diseases.
Claims27
A compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is aryl, heteroaryl, heterocycloalkyl or C3-C6cycloalkyl;
- each occurrence of R1 is independently selected from the group consisting of:
- —OH, C1-C6alkylOH, —CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) and C1-C6alkoxy;
- W is CH2;
- X is CH2;
- Y O;
- R2 is hydrogen, OH, C1-C6alkylOH, CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) or C1-C6alkoxy, or when X or Y is N, R2 is absent;
- R3 is hydrogen, —OH, C1-C6alkylOH, —CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) or C1-C6alkoxy;
- Z is —CN, aryl, C1-C6alkylaryl, —COaryl, —CONHaryl, —SO2aryl, C3-C10cycloalkyl, C1-C6alkylC3-C10cycloalkyl, —COC3-C10cycloalkyl, —CONHC3-C10cycloalkyl, —SO2C3-C10cycloalkyl, heteroaryl, C1-C6alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO2heteroaryl, heterocycloalkyl, C1-C6alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl, —SO2heterocycloalkyl, —COOC1-C6alkyl, or —COOC3-C6cycloalkyl, wherein the aryl, C1-C6alkylaryl, —COaryl, —CONHaryl, —SO2aryl, C3-C10cycloalkyl, C1-C6alkylC3-C10cycloalkyl, —COC3-C10cycloalkyl, —CONHC3-C10cycloalkyl, —SO2C3-C10cycloalkyl, heteroaryl, C1-C6alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO2heteroaryl, heterocycloalkyl, C1-C6alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO2heterocycloalkyl, is unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, —CN, C1-C6alkylCN, C1-C6alkyl, C2-C6 alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, —COOC1-C6alkyl, —SC1-C6alkyl, oxo, C3-C6cycloalkyl, aryl, heteroaryl and heterocycloalkyl, wherein said substituent heteroaryl, heterocycloalkyl, C3-C6cycloalkyl, C2-C6 alkynyl and C1-C6alkoxy, is unsubstituted or further substituted with one to two substituents independently selected Prom the group consisting of halogen, —CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, —OH and heterocycloalkyl;
- m is 0, 1, 2 or 3;
- n is 1 or 2;
- and
- p is 1 or 2.
11 more elements
A compound of Formula I
- or a pharmaceutically acceptable salt thereof, wherein:
- A is aryl, heteroaryl, heterocycloalkyl or C3-C6cycloalkyl;
- W is CH2;
- X is CH2;
- Y is O;
- R2 is hydrogen, OH, C1-C6alkylOH, CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) or C1-C6alkoxy, or when X or Y is N, R2 is absent;
- R3 is hydrogen, —OH, C1-C6alkylOH, —CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) or C1-C6alkoxy;
- each occurrence of R4 is independently selected from the group consisting of hydrogen, —OH, C1-C6alkylOH, —CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) and C1-C6alkoxy;
- Z is heteroaryl, wherein the heteroaryl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of —CN, —OH, phenyl, halogen, C1-C6alkylOH, C1-C6alkylCN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, —COC1-C6alkyl, —COOC1-C6alkyl, —SC1-C6alkyl, oxo, C3-C6cycloalkyl, heterocycloalkyl, CONH(C1-C6alkyl), CONH2, CON(C1-C6alkyl)2 or heteroaryl, wherein the phenyl, C1-C6alkoxy or heteroaryl is unsubstituted or substituted with halogen, C1-C6haloalkyl, heterocycloalkyl or C1-C6alkyl;
- m is 0, 1, 2 or 3;
- n is 1 or 2;
- and
- p is 1 or 2.
10 more elements
A compound of Formula I
- or a pharmaceutically acceptable salt thereof, wherein:
- A is aryl, heteroaryl, heterocycloalkyl or C3-C6cycloalkyl;
- W is CH2;
- X is CH2;
- Y is O;
- R2 is hydrogen, OH, C1-C6alkylOH, CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) or C1-C6alkoxy, or when X or Y is N, R2 is absent;
- R3 is hydrogen, —OH, C1-C6alkylOH, —CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) or C1-C6alkoxy;
- each occurrence of R4 is independently selected from the group consisting of hydrogen, —OH, C1-C6alkylOH, —CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) and C1-C6alkoxy;
- Z is aryl, C1-C6alkylaryl, —COaryl, —CONHaryl, —SO2aryl, C3-C10cycloalkyl, C1-C6alkylC3-C10cycloalkyl, —COC3-C10cycloalkyl, —CONHC3-C10cycloalkyl,
- —SO2C3-C10cycloalkyl, heteroaryl, C1-C6alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO2heteroaryl, heterocycloalkyl, C1-C6alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO2heterocycloalkyl, wherein the aryl, C1-C6alkylaryl, —COaryl, —CONHaryl, —SO2aryl, C3-C10cycloalkyl, C1-C6alkylC3-C10cycloalkyl, —COC3-C10cycloalkyl, —CONHC3-C10cycloalkyl, —SO2C3-C10cycloalkyl, heteroaryl, C1-C6alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO2heteroaryl, heterocycloalkyl, C1-C6alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO2heterocycloalkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of:
- —CN, —OH, phenyl, halogen, C1-C6alkylOH, C1-C6alkylCN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, —COC1-C6alkyl, C1-C6alkynyl, —COOC1-C6alkyl, —SC1-C6alkyl, oxo, C3-C6cycloalkyl, heterocycloalkyl, —CONH(C1-C6alkyl), —CONH2, —CON(C1-C6alkyl)2 and heteroaryl, wherein said substituent phenyl, heterocycloalkyl, C1-C6alkynyl, C3-C6cycloalkyl, C1-C6alkoxy or heteroaryl is unsubstituted or further substituted with an oxo group, —CN —OH, halogen, C1-C6haloalkyl, heterocycloalkyl or C1-C6alkyl;
- m is 0, 1, 2 or 3;
- n is 1 or 2;
- and
- p is 1 or 2.
12 more elements
A compound of Formula IV:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is aryl, heteroaryl, heterocycloalkyl or C3-C6cycloalkyl;
- each occurrence of R1 is independently selected from the group consisting of —OH, C1-C6alkylOH, —CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, —NH2, —N(C1-C6alkyl)2, —NH(C1-C6alkyl) and C1-C6alkoxy;
- Z is —CN, aryl, C1-C6alkylaryl, —COaryl, —CONHaryl, —SO2aryl, C3-C10cycloalkyl, C1-C6alkylC3-C10cycloalkyl, —COC3-C10cycloalkyl, —CONHC3-C10cycloalkyl, —SO2C3-C10cycloalkyl, heteroaryl, C1-C6alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO2heteroaryl, heterocycloalkyl, C1-C6alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl, —SO2heterocycloalkyl, —COOC1-C6alkyl or —COOC3-C6cycloalkyl, wherein the aryl, C1-C6alkylaryl, —COaryl, —CONHaryl, —SO2aryl, C3-C10cycloalkyl, C1-C6alkylC3-C10cycloalkyl, —COC3-C10cycloalkyl, —CONHC3-C10cycloalkyl, —SO2C3-C10cycloalkyl, heteroaryl, C1-C6alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO2heteroaryl, heterocycloalkyl, C1-C6alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO2heterocycloalkyl, is unsubstituted or substituted with one to four substituents independently selected from the group consisting of:
- CN, OH, halogen, C1-C6alkylCN, C1-C6alkylOH, C1-C6alkyl, C1-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, —COOC1-C6alkyl, —COC1-C6alkyl, —SC1-C6alkyl, oxo, C3-C6cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —CONH(C1-C6alkyl), —CONH2, and —CON(C1-C6alkyl)2, wherein said substituent heteroaryl, heterocycloalkyl, C3-C6cycloalkyl, C1-C6alkynyl, or C1-C6alkoxy, is unsubstituted or further substituted with one to two substituents independently selected from the group consisting of:
- halogen, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, OH and heterocycloalkyl;
- and
- m is 0, 1, 2 or 3.
5 more elements
The compound of Formula V:
- or a pharmaceutically acceptable salt thereof, wherein:
- each occurrence of R1 is independently selected from the group consisting of —OH, C1-C6alkylOH, —CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen and C1-C6alkoxy;
- Z is —CN, aryl, C1-C6alkylaryl, —COaryl, —CONHaryl, —SO2aryl, C3-C10cycloalkyl, C1-C6alkylC3-C10cycloalkyl, —COC3-C10cycloalkyl, —CONHC3-C10cycloalkyl, —SO2C3-C10cycloalkyl, heteroaryl, C1-C6alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO2heteroaryl, heterocycloalkyl, C1-C6alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl, SO2heterocycloalkyl, —COOC1-C6alkyl or COOC3-C6cycloalkyl, wherein the aryl, C1-C6alkylaryl, —COaryl, —CONHaryl, —SO2aryl, C3-C10cycloalkyl, C1-C6alkylC3-C10cycloalkyl, —COC3-C10cycloalkyl, —CONHC3-C10cycloalkyl, —SO2C3-C10cycloalkyl, heteroaryl, C1-C6alkylheteroaryl, —COheteroaryl, —CONHheteroaryl, —SO2heteroaryl, heterocycloalkyl, C1-C6alkylheterocycloalkyl, —COheterocycloalkyl, —CONHheterocycloalkyl or —SO2heterocycloalkyl, is unsubstituted or substituted with one to four substituents independently selected from the group consisting of —CN, —OH, halogen, C1-C6alkylCN, C1-C6alkylOH, C1-C6alkyl, C1-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, —COOC1-C6alkyl, —COC1-C6alkyl, —SC1-C6alkyl, oxo, C3-C6cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —CONH(C1-C6alkyl), —CONH2, CON(C1-C6alkyl)2, wherein the heteroaryl, heterocycloalkyl, C3-C6cycloalkyl, C1-C6alkynyl, or C1-C6alkoxy, is unsubstituted or substituted with one to two substituents independently selected from the group consisting of halogen, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, OH and heterocycloalkyl.
A compound selected from the following structures:
Dependencies are inferred from the claim text.