Bicyclic ketone compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11098058-B2
Application number	US-201816034207-A
Country	US
Kind code	B2
Filing date	Jul 12, 2018
Priority date	Jul 14, 2017
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The invention provides novel compounds having the general formula I:wherein R1, the A ring and the B ring are as described herein, pharmaceutical compositions including the compounds, and methods of using the compounds.

First claim

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-N(R N ) 2 , phenyl, benzyl, 4 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl; wherein R 1 is bound to the adjacent carbonyl by a carbon atom, and wherein R 1 is optionally substituted by one or two substituents selected from the group consisting of F, Cl, Br, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl-N(R N ) 2 , hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O)C 1 -C 6 alkyl, phenyl, benzyl, CH 2 —(C 3 -C 6 cycloalkyl), 5 to 6 membered heteroaryl, and CH 2 -(5 to 6 membered heteroaryl);
each R N is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkyl; or two R N may together with the adjacent N form a 4-6 membered ring; and
the A ring and the B ring together are selected from the group consisting of:

wherein:
R 2 is selected from the group consisting of C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, phenyl, benzyl, CH 2 -(C 3 -C 6 cycloalkyl), CH 2 CH 2 —(C 3 -C 6 cycloalkyl), CH 2 -(4 to 6 membered heterocyclyl), CH 2 CH 2 -(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl, and CH 2 -(5 to 6 membered heteroaryl); wherein when a phenyl ring or 5 to 6 membered heteroaryl ring is present it may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyclopropyl, and cyano; and
R 3a and R 3b are selected as follows:
(i) one of R 3a and R 3b is H, and the other is selected from the group consisting of D, halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, and C 1 -C 6 alkyl-N(R N ) 2 ;
(ii) each of R 3a and R 3b is selected from the group consisting of D, F, Cl, OH, CN and methyl, provided that R 3a and R 3b cannot both be OH or CN; or
(iii) R 3a and R 3b together form cyclopropyl.

2. The compound of claim 1 , wherein R 1 is C 3 -C 6 cycloalkyl or phenyl, and R 1 is optionally substituted by one substituent selected from the group consisting of F, Cl and C 1 -C 6 alkyl.

3. The compound of claim 2 , wherein R 1 is cyclopropyl, and R 1 is optionally substituted by F or methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of phenyl, monofluorophenyl, difluorophenyl, monochlorophenyl, dichlorophenyl, pyridinyl, chloro substituted pyridinyl, fluoro substituted pyridinyl, pyrazolyl, 1-methyl-1H-pyrazol-4-yl and 4-chloro-1-methyl-1H-pyrazol-3-yl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are selected from the group consisting of:

wherein:
R 3a and R 3b are selected as follows:
(i) one of R 3a and R 3b is H, and the other is selected from the group consisting of D, F, Cl, OH, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyclopropyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy;
(ii) each of R 3a and R 3b is selected from the group consisting of D, F, Cl, OH, CN and methyl, provided that R 3a and R 3b cannot both be OH or CN; or
(iii) R 3a and R 3b together form cyclopropyl;

each R 5 is selected from the group consisting of H, F, Cl, C 1 -C 6 alkyl C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 6 haloalkoxy; and
m is 1, 2 or 3.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the A ring and the B ring together are:

wherein:
each R 5 is selected from the group consisting of F, Cl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 6 haloalkoxy; and
m is 1, 2 or 3.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having a RIP1 kinase inhibitory activity K i of less than 100 nM.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)((1R,2R)-2-fluorocyclopropyl)methanone;
phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone;
(rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl)methanone;
cyclopropyl((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone;
[(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone;
cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone;
cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone;
cyclopropyl-[(5S,7S)-7-chloro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone; and
cyclopropyl((5S,7S)-7-fluoro-5-(3-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is ((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)(1R,2R)-2-fluorocyclopropyl)methanone.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is phenyl-[rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is (rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-(1-methylcyclopropyl)methanone.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanone.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is [(1R,2S)-2-fluorocyclopropyl]-[(5S,7S)-7-fluoro-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl-[(5S,7S)-5-(2,6-difluorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl-[(5S,7S)-5-(2-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]methanone.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is cyclo

Assignees

• Genentech Inc

Inventors

• Patel Snahel
• Hamilton Gregory
• Zhao Guiling
• Chen Huifen
• Daniels Blake
• Stivala Craig

Classifications

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07B2200/07

  Optical isomers · CPC title

• A61P17/06

  Antipsoriatics · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title