Compounds, compositions and methods

Patent metadata

Field	Value
Publication number	US-11174262-B2
Application number	US-201916683970-A
Country	US
Kind code	B2
Filing date	Nov 14, 2019
Priority date	May 17, 2017
Publication date	Nov 16, 2021
Grant date	Nov 16, 2021

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 of Formula I:

or a pharmaceutically acceptable salt, deuterated analog, stereoisomer, mixture of stereoisomers, tautomer, or prodrug thereof, wherein:
X is N;
Cy is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
Y 1 , Y 2 , and Y 3 are independently CR 5 R 6 ;
R 1 is cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, —SR 8 , —SOR 8 , —SO 2 R 8 , optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
or R 1 and Y 3 together form an optionally substituted heterocyclyl;
R 2 is cyano, hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 1 and R 2 together form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
each R 3 is independently halo, cyano, or optionally substituted alkyl; or two R 3 together form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
R 5 and R 6 are independently cyano, halo, hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, —SH, —SR 8 , —SOR 8 , —SO 2 R 8 , optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 together with the carbon atom to which they are both attached form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, or oxo; or any two R 5 groups attached to adjacent carbon atoms together form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
R 7 is hydrogen or optionally substituted alkyl;
R 8 is optionally substituted alkyl; and
n is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1 , wherein Y 3 are CF 2 .

3. The compound of claim 1 , wherein Y 1 , Y 2 , and Y 3 are CH 2 .

4. The compound of claim 1 , wherein Cy is optionally substituted aryl or optionally substituted heteroaryl.

5. The compound of claim 1 , wherein Cy is optionally substituted phenyl, optionally substituted pyridyl, or optionally substituted pyrazine.

6. The compound of claim 1 , wherein Cy is independently optionally substituted with one or more R 10 , wherein
R 10 is independently cyano, halo, nitro, oxo, —OR 11 , —SR 11 , —SF 5 , —NR 11 R 12 , —C(═O)R 13 , —C(═O)OR 11 , —OC(═O)OR 11 , —OC(═o)R 13 , OC(═O)NR 11 R 12 , NR 11 C(═O)NR 11 R 12 , —S(═O) 1-2 R 13 , —S(═O) 1-2 NR 11 R 12 , —NR 11 S(═O) 1-2 R 13 , —NR 11 S(═O) 1-2 NR 11 R 12 , —NR 11 C(═O)R 13 , —NR 11 C(═O)OR 12 , —C═NOR 11 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C 1-12 alkyl, C 2-12 alkenyl and C 2-12 alkynyl are optionally substituted with one or more halo; the C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl are independently optionally substituted with one or more cyano, halo, nitro, oxo, —OR 14 , —SR 14 , —SF 5 , —NR 14 R 15 , —S(═O) 1-2 R 16 , —S(═O) 1-2 NR 14 R 15 , —NR 14 S(═O) 1-2 R 16 , or R 16 ;
R 11 , R 12 , R 14 , and R 15 are independently H or C 1-12 alkyl optionally substituted with one or more halo, or two of R 11 and R 12 or two of R 14 and R 15 together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more halo or C 1-12 alkyl optionally substituted with one or more halo; and
R 13 and R 16 are independently C 1-12 alkyl optionally substituted with one or more halo.

7. The compound of claim 1 , wherein Cy is 5-cyano-pyrid-3-yl, 5-fluoro-pyrid-3-yl, 3-fluorophenyl, 3-cyanophenyl, 3-cyano-5-fluorophenyl, 5-methylpyrazin-2-yl, 3,4-difluorophenyl, or 3,5-difluorophenyl.

8. The compound of claim 1 , wherein n is 0.

9. The compound of claim 1 , wherein R 1 and R 2 are optionally substituted alkyl.

10. The compound of claim 1 , wherein R 1 and R 2 together form a cyclopropyl ring.

11. The compound of claim 1 , wherein R 1 is difluoromethyl, cyanomethyl, methyl, or ethyl.

12. The compound of claim 1 , wherein R 2 is methyl.

13. A compound that is:
3-(5-fluoro-3-pyridyl)-6,6-dimethyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a[diazepin-5-one;
4-(6,6-dimethyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a[diazepin-3-yl)benzonitrile;
3-(3-fluorophenyl)-6,6-dimethyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a[diazepin-5-one;
3-(6,6-dimethyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-3-yl)-5-fluoro-benzonitrile;
6,6-dimethyl-3-(5-methylpyrazin-2-yl)-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
3-(3,4-difluorophenyl)-6,6-dimethyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
3-(3,5-difluorophenyl)-6,6-dimethyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
5-(6,6-dimethyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-3-yl)pyridine-3-carbonitrile;
6-(difluoromethyl)-6-methyl-3-(5-methylpyrazin-2-yl)-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
3-(5-fluoro-3-pyridyl)spiro[1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepine-6,1′-cyclopropane]-5-one;
6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
2-[6-methyl-3-(5-methylpyrazin-2-yl)-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-6-yl]acetonitrile;
2-[3-(5-fluoro-3-pyridyl)-6-methyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-6-yl]acetonitrile;
5-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-3-yl]pyridine-3-carbonitrile;
7,7-difluoro-3-(5-fluoro-3-pyridyl)-6,6-dimethyl-2,3,8,9-tetrahydro-1H-pyrazolo[1,2-a]diazepin-5-one; or
6-(difluoromethyl)-6-ethyl-3-(5-methylpyrazin-2-yl)-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
or a pharmaceutically acceptable salt, deuterated analog, stereoisomer, mixture of stereoisomers, tautomer, or prodrug thereof.

14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier.

15. A compound that is:

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

16. A compound that is:

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

Assignees

• Denali Therapeutics Inc

Inventors

• Bonanomi Giorgio
• Estrada Anthony A
• Feng Jianwen A
• Fox Brian
• Francini Cinzia Maria
• Hu Cheng
• Leslie Colin Philip
• Osipov Maksim
• Sudhakar Anantha
• Sweeney Zachary K
• De Vicente Fidalgo Javier

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title