IP Library › Granted Patent US 11,072,607
Granted Patent B2
US 11,072,607 · App. 15/839,788 · Granted Jul 27, 2021

Inhibitors of RIP1 kinase and methods of use thereof

Inventors: Snahel Patel (Foster City, CA); Gregory Hamilton (San Mateo, CA)
Assignee: Genentech, Inc.
C07D471/04A61P1/00A61P1/04A61P1/16A61P1/18A61P9/10A61P11/00A61P13/12A61P17/06A61P25/00A61P29/00C07D487/04C07D498/04C07D519/00
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Quick Facts
Patent No.
US 11,072,607
App. No.
15/839,788
Granted
Jul 27, 2021
Kind
B2
Abstract

The invention provides novel compounds having RIP1 kinase inhibitory activity, pharmaceutical compositions including the compounds and methods of using the compounds.

Claims (49)

1. A compound selected from the group consisting of:

(5R)-5 -(1, 1-difluoropropyl)-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

rac-(5R,7S)-7-fluoro-5-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

rac-(5R, 7S)-7-fluoro-5-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(5R,7R)-7-fluoro-5-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

1-(2,2-difluoropropyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[3,4-d]pyrimidine-6-carboxamide;

1-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo [3,4-d]pyrimidine-6-carboxamide;

(5R)-5-phenyl-N-[(3S)-7-methoxy-1-methyl-2-oxo-4,5-dihydro-3H-pyrido[3,4-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(5R)-5-phenyl-N-[(7S)-6-oxo-5,7,8,9-tetrahydropyrido[3,2-b]azepin-7-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

5-(1,1-difluoropropyl)-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2carboxamide;

rac-(5S,7S)-7-fluoro-5-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

rac-(5S,7S)-7-fluoro-5-phenyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(5S)-5-(2-fluorophenyl)-N-[(3S)-7-methoxy-1-methyl-2-oxo-4,5-dihydro-3H-pyrido[3,4-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(5S)-5-(2-fluorophenyl)-N-[(7S)-6-oxo-5,7,8,9-tetrahydropyrido[3,2-b]azepin-7-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(5R)-5-(2-fluorophenyl)-N-[(7S)-5-methyl-6-oxo-8,9-dihydro-7H-pyrido[3,2-b]azepin-7-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(4S)-4-phenyl-N- [(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide;

4-phenyl-N- [(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide;

1-(2,2-difluoropropyl)-N-[(3S)-5-methyl -4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]pyrazolo[4,3-c]pyridine-6-carboxamide;

1-cyclopropyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro- 1,5-benzoxazepin-3-yl]pyrazolo[4,3-c]pyridine-6-carboxamide;

(7S)-7-(2-fluorophenyl)-N-[(7S)-5-methyl-6-oxo-8,9-dihydro-7H-pyrido[3,2-b ]-azepin-7-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(7S)-7-phenyl-N-[(7S)-5-methyl-6-oxo-8,9-dihydro-7H-pyrido[3,2-b]azepin-7-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2carboxamide;

(5S)-5-phenyl-N-[(7S)-5-methyl-6-oxo-8,9-dihydro-7H-pyrido[3,2-b ]azepin-7-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2carboxamide;

(5S,7R)-7-fluoro-5-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(5S,7R)-7-fluoro-5-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(5R,7S)-7-fluoro-5-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo [1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(5R,7S)-7-fluoro-5-phenyl-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

4-phenyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide;

7,7-difluoro-5-phenyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

7,7-difluoro-5-phenyl-N-[rac-(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

7-fluoro-5-phenyl-N-[rac-(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

7-fluoro-5-phenyl-N-[rac-(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

7-fluoro-5-phenyl-N-[6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(7S)-7-(2-fluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

(7S)-7-(2-fluorophenyl)-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

1-[(2-fluorophenyl)methyl]-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[4,3-b]azepin-6-yl]-1,2,4-triazole-3-carboxamide;

1-benzyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[4,3-b]azepin-6-yl]-1,2,4-triazole-3-carboxamide;

1-[(2-fluorophenyl)methyl]-N-[6S)-1,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[4,3-b]azepin-6-yl]-1,2,4-triazole-3-carboxamide;

1-benzyl-N-[(6S)-1,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[4,3-b]azepin-6-yl]-1,2,4-triazole-3-carboxamide;

1-benzyl-N-[rac-(6S)-4-methyl-5-oxo-2-(tetrahydrofuran-3-ylmethyl)-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-1,2,4-triazole-3-carboxamide;

rac-(5S,7S)-7-fluoro-5-phenyl-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

rac-(5S,7S)-7-fluoro-5-phenyl-N-[rac-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

rac-(5S,7S)-7-fluoro-5-phenyl-N-[rac-(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

rac-(5R)-7,7-difluoro-5-phenyl-N-[rac-(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

rac-(5R)-7,7-difluoro-5-phenyl-N-[rac-(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

rac-(5R)-7,7-difluoro-5-phenyl-N-[rac-(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[1,5-a][1,3]diazepin-6-yl]-5,6-dihydropyrrolo[1,2-b][1,2,4]triazole-2-carboxamide; and

5-(1,1-difluoropropyl)-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;

or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1 , or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

3. A method for the treatment of a disease or disorder in a human, the method comprising administration to the human of an effective treatment amount of a compound of claim 1 , or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from the group consisting of irritable bowel disorder (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs, cisplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatitis, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney disease, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD).

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 29, 2018
From: PATEL, SNAHEL; HAMILTON, GREGORY
To: GENENTECH, INC,
Reel/Frame 044754/0005 →
Continuity (2)
Provisional Application 62435567 · Dec 16, 2016
Related Publication 20180170927A1 · Jun 21, 2018
Cited By (3)
US 12,281,101 US 12,338,241 US 12,344,612