Oxepan-2-yl-pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use

Patent metadata

Field	Value
Publication number	US-9963446-B2
Application number	US-201615266243-A
Country	US
Kind code	B2
Filing date	Sep 15, 2016
Priority date	Mar 18, 2014
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

Oxepan-2-yl pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

First claim

We claim:

1. A compound selected from Formula I:

and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, and —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl);
R 2 is independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 CH(CH 3 ) 2 , —CH═CH 2 , —CH═C(CH 3 ) 2 , ═CH 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 CH 2 NH 2 , —CH 2 CHCH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CN, —CO 2 H, —COCH 3 , —COCH 2 NH 2 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 CHF 2 , —NHCH 2 CF 3 , —NHCH 2 CH 2 OH, —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHC(O)OCH 2 CH 3 , —NHC(O)OCH 2 C 13 , —NHC(O)OC 6 H 5 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCH 2 CH(CH 3 ) 2 , —OC(CH 3 ) 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —CH 2 OCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, oxetan-3-ylmethylamino, (3-methyloxetan-3-yl)methylamino, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino;
n is 1, 2, 3, 4, 5, or 6;
X is selected from the structures:

where the wavy line indicates the site of attachment; and
R 3 is selected from H, Cl, Br, C 1 -C 12 alkyl, —O—(C 1 -C 12 alkyl), —(C 1 -C 12 alkylene)-(C 3 -C 12 carbocyclyl), —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), —(C 2 -C 8 alkenylene)-(C 3 -C 12 carbocyclyl), —(C 2 -C 8 alkenylene)-(C 2 -C 20 heterocyclyl), C 6 -C 20 aryl, —(C 6 -C 20 arylene)-(C 2 -C 20 heterocyclyl), —(C 6 -C 20 arylene)-(C 6 -C 20 arylene), —(C 6 -C 20 arylene)-(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), —(C 6 -C 20 arylene)-O—(C 2 -C 20 heterocyclyl), —(C 6 -C 20 arylene)-O—(C 1 -C 12 alkyl), C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, —(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl), and —(C 1 -C 20 heteroaryl)-(C 1 -C 12 alkyl); where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CHCH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH(CH 2 OH) 2 , —C(CH 2 OH) 3 , —CH(CH 3 )OH, —C(CH 3 ) 20 H, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CN, —CF 3 , —CHF 2 , —CH 2 F, —CO 2 H, —COCH 3 , —COCH(CH 3 ) 2 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —OCF 3 , —OCH(CH 3 ) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —CH 2 OCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino.

2. The compound of claim 1 wherein R 1 is H.

3. The compound of claim 1 wherein R 1 is C 1 -C 12 alkyl or C 3 -C 12 carbocyclyl.

4. The compound of claim 3 wherein R 1 is selected from —CH 3 , —CH 2 CH 3 , —CH 2 CHF 2 , and —CH 2 CF 3 .

5. The compound according to claim 1 , wherein R 2 is independently selected from F, Cl, —OH, —CH 3 , —CH 2 CH 3 , —CF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 CHF 2 , —NHCH 2 CF 3 , —CH 2 NHCH 3 , and —OCH 3 ; and n is 1, 2, or 3.

6. The compound according to claim 1 , wherein R 3 is C 6 -C 20 aryl.

7. The compound according to claim 1 , wherein R 3 is phenyl substituted with one more F.

8. The compound according to claim 1 selected from Formulas Ia, Ib, Ic, and Id:

9. The compound of according to claim 1 selected from Formula Ie:

10. The compound of according to claim 1 wherein R 2 is F or OCH 3 .

11. The compound of claim 8 selected from Formula If:

12. The compound of claim 11 wherein R 3 is C 6 -C 20 aryl.

13. The compound according to claim 1 , wherein R 3 is phenyl or pyridyl, where phenyl or pyridyl are optionally substituted with one or more groups selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CHCH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH(CH 2 OH) 2 , —C(CH 2 OH) 3 , —CH(CH 3 )OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CN, —CF 3 , —CHF 2 , —CH 2 F, —CO 2 H, —COCH 3 , —COCH(CH 3 ) 2 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —OCF 3 , —OCH(CH 3 ) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —CH 2 OCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino.

14. The compound according to claim 1 , wherein R 3 is selected from phenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2,6-difluoro-4-methylphenyl, 2,4,6-trifluorophenyl, 2,4-difluorophenyl, 2-fluoro-4-hydroxyphenyl, and 3-methylpyridin-2-yl.

15. The compound of claim 1 selected from the group consisting of:
N-(5-((2S,5R,6S)-5-amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-4-((S)-1-fluoroethyl)phenyl)thiazole-4-carboxamide;
N-[5-[(2S,5R,6S)-5-amino-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]-2-(2-fluoro-6-hydroxy-phenyl)thiazole-4-carboxamide;
N-[5-[(2R,5S,6R)-5-amino-6-fluoro-oxepan-2-yl]-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;
N-[5-[(2S,5R,6S)-5-amino-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]-2-(2,3-dihydrobenzofuran-5-yl)thiazole-4-carboxamide;
N-[5-[(2S,5R,6S)-5-amino-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]-2-pyrazin-2-yl-thiazole-4-carboxamide;
N-(5-((2S,5R,6S)-5-amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-4-((R)-1-fluoroethyl)phenyl)thiazole-4-carboxamide;
N-(5-((2R,5S,6R,7S)-5-amino-6-methoxy-7-methyloxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;
N-[5-[(2S,5R,6S)-5-amino-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]-2-(5-chloro-2-fluoro-4-methoxy-phenyl)thiazole-4-carboxamide;
N-[5-[(2S,5R,6S)-5-amino-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-y

Assignees

• Genentech Inc

Inventors

• Burch Jason
• Chen Huifen
• Wang Xiaojing

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title