Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use

Patent metadata

Field	Value
Publication number	US-9328106-B2
Application number	US-201314036160-A
Country	US
Kind code	B2
Filing date	Sep 25, 2013
Priority date	Sep 26, 2012
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 2 is a cyclic ether and 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 1:

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 selected from the structures:

where the wavy line indicates the site of attachment;
R 3 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 Cl 3 , —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 35 —S(O) 2 CH 35 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;
or where two geminal R 3 groups form a spiro ring selected from a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl, or piperidinyl ring, where the spiro ring is optionally substituted with one or more groups independently selected from —F, —OH, ═O, —CH 3 , —NH 2 , —CH 2 F, —CH 2 OH, —CH 2 OCH 3 , —CH 2 NH 2 , and —CF 3 ;
or where two vicinal R 3 groups form a five-membered or six-membered heterocyclyl fused ring, where the heterocyclyl fused ring is optionally substituted with one or more groups independently selected from —F, —OH, ═O, —CH 3 , —NH 2 , —CH 2 F, —CH 2 OH,—CH 2 OCH 3 , —CH 2 NH 2 , and —CF 3 ;
n is 0, 1, 2, 3, 4, 5, or 6;
X is selected from the structures:

where the wavy line indicates the site of attachment;
R 4 is independently H, F, —CH 3 , or —NH 2 ; and
R 5 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 ) 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.

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 of claim 1 wherein R 1 is —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl).

6. The compound of claim 5 wherein R 1 is oxetan-3-ylmethyl.

7. The compound of claim 5 wherein R 2 has the structure:

8. The compound of claim 1 wherein R 3 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.

9. The compound of claim 1 wherein R 4 is —NH 2 .

10. The compound of claim 1 wherein R 4 is H.

11. The compound of claim 1 wherein R 5 is C 6 -C 20 aryl.

12. The compound of claim 11 wherein R 5 is phenyl substituted with one or more F.

13. The compound of claim 1 selected from Formula Ia-Id:

14. The compound of claim 1 selected from Formula Ie-Ih:

15. The compound of claim 1 selected from the group consisting of:
5-amino-2-(2,6-difluorophenyl)-N-[5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide
5-amino-2-(2,6-difluorophenyl)-N-[5-(3,4-dihydro-2H-pyran-6-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide
5-amino-2-(2,6-difluorophenyl)-N-[5-(2-methoxytetrahydropyran-2-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide
5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-tetrahydropyran-2-yl-pyrazol-4-yl)thiazole-4-carboxamide
5-amino-2-(3-fluoro-2-pyridyl)-N-[5-(2-methoxytetrahydropyran-2-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide
5-amino-2-(2,6-difluorophenyl)-N-(5-((1S,4S,5S)-4-hydroxy-8-oxabicyclo[3.2.1]octan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide
5-amino-N-[5-(2-amino-8-oxabicyclo[3.2.1]octan-5-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide
5-amino-2-(2,6-difluorophenyl)-N-(5-((2R,7R)-5-hydroxy-7-methyloxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide
5-amino-2-(2,6-difluorophenyl)-N-[5-(2-hydroxy-8-oxabicyclo[3.2.1]octan-5-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide
5-amino-2-(2,6-difluorophenyl)-N-(5-((5R,6S)-5,6-dihydroxyoxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide
5-amino-N-(5-((2R,7R)-5-amino-7-ethyloxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide
5-amino-N-(5-((2R,7R)-5-amino-7-methyloxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thi

Assignees

• Genentech Inc

Inventors

• Burch Jason
• Sun Minghua
• Wang Xiaojing
• Blackaby Wesley
• Hodges Alastair James
• Sharpe Andrew

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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