Pyrazolo[3,4-c]pyridine compounds and methods of use

Patent metadata

Field	Value
Publication number	US-9260425-B2
Application number	US-201213571595-A
Country	US
Kind code	B2
Filing date	Aug 10, 2012
Priority date	Aug 12, 2011
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

Pyrazolo[3,4-c]pyridine compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are as defined herein, 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 C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), —(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-O—(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-O—(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-NR 3 —(C 2 -C 20 heterocyclyl), and —(C 1 -C 20 heteroaryl)-NR 3 —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl);
R 2 is selected from C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, C 6 -C 20 aryl, —(C 6 -C 20 aryl)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl), —(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-NR 3 —(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-NR 3 —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), and —(C 1 -C 20 heteroaryl)-NR 3 —(C 1 -C 12 alkylene)-(C 1 -C 20 heteroaryl);
R 3 is independently selected from H and C 1 -C 12 alkyl optionally substituted with F, Cl, CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —NHCH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 CH 2 NH 2 , —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 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 NH 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , and —S(O) 2 CH 3 ;
where alkyl, alkylene, 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 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NH 2 , —CH 2 CHCH 2 NH 2 , —CH 2 CHCH 2 CH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 CONH 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 C(CH 3 ) 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CN, —CF 3 , —CO 2 H, —COCH 3 , —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 , —NHCH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 CH 2 NH 2 , —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 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 NH 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, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino.

2. The compound of claim 1 wherein R 1 is C 1 -C 20 heteroaryl.

3. The compound of claim 1 wherein R 1 is selected from the structures:

where the wavy line indicates the site of attachment.

4. The compound of claim 1 wherein R 2 is C 1 -C 20 heteroaryl.

5. The compound of claim 1 wherein R 2 is —(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl).

6. The compound of claim 1 wherein R 2 is selected from the structures:

where the wavy line indicates the site of attachment; and
R 4 is 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 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NH 2 , —CH 2 CHCH 2 NH 2 , —CH 2 CHCH 2 CH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 CONH 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 C(CH 3 ) 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CN, —CF 3 , —CO 2 H, —COCH 3 , —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 , —NHCH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 CH 2 NH 2 , —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 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 NH 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, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and
n is 0, 1, or 2.

7. The compound of claim 1 having the structure of Formula Ia:

where R 4 is 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 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NH 2 , —CH 2 CHCH 2 NH 2 , —CH 2 CHCH 2 CH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 CONH 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 C(CH 3 ) 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CN, —CF 3 , —CO 2 H, —COCH 3 , —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 , —NHCH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 CH 2 NH 2 , —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 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 NH 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, pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and
n is 0, 1, or 2.

8. The compound of claim 1 having the structure of Formula Ib:

where R 3 is selected from H, and C 1 -C 12 alkyl where alkyl is optionally substituted with F, Cl, CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —NHCH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 CH 2 NH 2 , —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 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 NH 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , and —S(O) 2 CH 3 .

9. The compound of claim 1 having the structure of Formula Ic:

where R 4 is 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 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NH 2 , —CH 2 CHCH 2 NH 2 , —CH 2 CHCH 2 CH 2 NH 2 , —CH 2 CH(CH 3 )NH 2 , —CH 2 CONH 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 C(CH 3 ) 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CN, —CF 3 , —CO 2 H, —COCH 3 , —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 , —NHCH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 NH 2 , —NHCH 2 CH 2 CH 2 CH 2 NH 2 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 ,

Assignees

• Do Steven
• Hu Huiyong
• Kolesnikov Aleksandr
• Lee Wendy
• Tsui Vickie H
• Wang Xiaojing
• Wen Zhaoyang
• Genentech Inc

Inventors

• Do Steven
• Hu Huiyong
• Kolesnikov Aleksandr
• Lee Wendy
• Tsui Vickie H
• Wang Xiaojing
• Wen Zhaoyang

Classifications

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title