Isoxazolidine derived inhibitors of receptor interacting protein kinase 1 (RIPK1)

Patent metadata

Field	Value
Publication number	US-10709692-B2
Application number	US-201615780620-A
Country	US
Kind code	B2
Filing date	Dec 2, 2016
Priority date	Dec 4, 2015
Publication date	Jul 14, 2020
Grant date	Jul 14, 2020

Abstract

The present disclosure relates generally to methods and compositions for preventing or arresting cell death and/or inflammation.

First claim

The invention claimed is:

1. A compound having the following structure (Xa):

or a pharmaceutically acceptable salt, prodrug, stereoisomer or a mixture of stereoisomers thereof, wherein:
A is —C(═O)—, —S(═O)—, —S(═O) 2 — or —S(═O)(═NH)—;
R 1 is —NR 5 R 6 , C 1-6 alkyl, C 3-6 alkoxy, C 3-10 cycloalkyl, heterocyclyl or heteroaryl;
R 2 is aryl or heteroaryl;
R 3 is hydrogen, deuterium, C 1-6 alkyl or C 3-10 cycloalkyl;
R 3′ is hydrogen or deuterium;
R 4 is hydrogen, halo, C 1-6 alkyl or C 3-10 cycloalkyl;
R 5 and R 6 are each independently H, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl or heterocyclyl,
wherein each C 1-6 alkyl, C 3-6 alkoxy, C 3 -C 10 cycloalkyl, heterocyclyl, heteroaryl and aryl group of R 1 , R 2 , R 3 , R 3′ , R 4 , R 5 and R 6 is optionally substituted with one, two or three R 10 ;
R 10 in each instance is independently deuterium, halo, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 11 , —S(—O)R 11 , —S(—O) 2 R 11 , —NR 11 R 11 , —NR 11 C(═O)R 11 or —NR 11 C(═O)OR 11 ;
wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl of R 10 are optionally substituted with one, two or three substituents independently selected from halo, hydroxy, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; and

R 11 in each instance is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl or aryl;
wherein the C 3-10 cycloalkyl, heterocyclyl, heteroaryl or aryl of R 11 is optionally substituted with one, two or three C 1-6 alkyl;

provided the compound is not ethyl 3-phenylisoxazolidine-2-carboxylate, benzyl 3-(4-amino-2-oxopyrimidin-1 (2H)-yl)isoxazolidine-2-carboxylate, 2-(methyl sulfonyl)-3-phenyl-isoxazolidine, tert-butyl 5-benzyl-3-phenylisoxazolidine-2-carboxylate, tert-butyl 5-(naphthalen-2-ylmethyl)-3-phenylisoxazolidine-2-carboxylate, tert-butyl 5-([1,1′-biphenyl]-4-ylmethyl)-3-phenylisoxazolidine-2-carboxylate or 2,2-dimethyl-1-(3-phenylisoxazolidin-2-yl)butan-1-one or 2,2-dimethyl-1-(3-phenylisoxazolidin-2-yl)but-3-en-1-one.

2. The compound of claim 1 , wherein R 1 is optionally substituted C 1-6 alkyl, C 3-6 alkoxy, C 3-10 cycloalkyl or heterocyclyl.

3. The compound of claim 1 , wherein R 1 is optionally substituted C 1-6 alkyl.

4. The compound of claim 2 , wherein R 1 is substituted with at least one substituent selected from deuterium, hydroxy, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, C 3-10 cycloalkyl, heterocyclyl and heteroaryl;
wherein the heterocyclyl or heteroaryl is optionally substituted with one, two or three C 1-6 alkyl.

5. The compound of claim 3 , wherein R 1 is substituted with at least one substituent selected from hydroxy, halo, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and cyano.

6. The compound of claim 1 , wherein R 1 is optionally substituted C 3-6 alkoxy.

7. The compound of claim 6 , wherein R 1 is t-butoxy.

8. The compound of claim 1 , wherein R 1 is —NR 5 R 6 and at least one of R 5 or R 6 is optionally substituted C 1-6 alkyl or optionally substituted aryl.

9. The compound of claim 8 , wherein R 1 is dimethylamino, t-butylamino or phenylamino.

10. The compound of claim 1 , wherein R 1 is optionally substituted C 3-10 cycloalkyl.

11. The compound of claim 10 , wherein the C 3-10 cycloalkyl is substituted with at least one substituent selected from hydroxy, halo, cyano, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and C 1-6 alkoxyalkyl.

12. The compound of claim 10 , wherein C 3-10 cycloalkyl is cyclopropyl, cyclobutyl, or bicyclo[1.1.1]pentyl.

13. The compound of claim 1 , wherein R 1 is optionally substituted heterocyclyl or optionally substituted heteroaryl.

14. The compound of claim 13 , wherein R 1 is oxetanyl, pyrrolidinyl, tetrahydropyranyl or azetidinyl.

15. The compound of claim 13 , wherein R 1 is pyrrolyl, pyrazolopyridinyl or benzoisoxazolyl.

16. The compound as in claim 13 , wherein R 1 is optionally substituted with a C 1-6 alkyl, cyano or both.

17. The compound as in claim 1 , wherein R 2 is aryl.

18. The compound of claim 17 , wherein R 2 is phenyl.

19. The compound as in claim 1 , wherein R 2 is heteroaryl.

20. The compound of claim 19 , wherein R 2 is pyridinyl.

21. The compound as in claim 17 , wherein R 2 is unsubstituted.

22. The compound as in claim 17 , wherein R 2 is substituted.

23. The compound of claim 22 , wherein R 2 is substituted with one or more halo.

24. A compound selected from:

or a pharmaceutically acceptable salt, prodrug, stereoisomer or a mixture of stereoisomers thereof.

25. A composition comprising

Assignees

• Denali Therapeutics Inc

Inventors

• Bonanomi Giorgio
• Estrada Anthony A
• Feng Jianwen A
• Fox Brian
• Leslie Colin Philip
• Lyssikatos Joseph P
• Napolitano Carmela
• Pozzan Alfonso
• Sudhakar Anantha
• Sweeney Zachary K
• Tonelli Federica
• De Vicente Fidalgo Javier

Classifications

• C07D261/02

  not condensed with other rings · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/422 Primary

  not condensed and containing further heterocyclic rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K2121/00

  Preparations for use in therapy · CPC title