Pyridone and aza-pyridone compounds and methods of use

Patent metadata

Field	Value
Publication number	US-10053469-B2
Application number	US-201615281923-A
Country	US
Kind code	B2
Filing date	Sep 30, 2016
Priority date	May 7, 2010
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

Pyridone and aza-pyridone compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

First claim

We claim:

1. A compound selected from Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
R 1 is H, D, F, Cl, CN, NH 2 , NHCH 3 , —N(CH 3 ) 2 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, heteroaryl selected from imidazolyl and pyrazolyl, heterocyclyl selected from oxetanyl and azetidinyl, and C 1 -C 3 alkyl;
R 2 , R 3 and R 4 are independently selected from H, D, F, Cl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, and C 1 -C 3 alkyl;
R 5 is optionally substituted C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, —(C 6 -C 20 aryl)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl), —(C 1 -C 20 heteroaryl)-(C 1 -C 6 alkyl), or —(C 1 -C 20 heteroaryl)-C(═O)—(C 2 -C 20 heterocyclyl);
R 6 is H, F, —NH 2 , —OH, or optionally substituted C 1 -C 3 alkyl;
X is S, S(═O), S(═O) 2 , N, NR 6 , O, or CR 7 ;
R 7 is independently selected from H, D, F, Cl, —CH 3 , —CH 2 CH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —NH 2 , —OH, and —OCH 3 ;
Y 1 and Y 2 are independently selected from CR 6 and N;
Z 1 , Z 2 , Z 3 , and Z 4 are independently selected from C, CR 7 , and N;
Z 5 is selected from —C(R 3 ) 2 —, —C(═O)—;
one of Z 1 and Z 2 , or X and Z 1 , where X is not S, S(═O), or S(═O) 2 , forms a five-, six-, or seven-membered aryl, carbocyclyl, heterocyclyl or heteroaryl ring;

where alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from D, F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH 2 CH(CH 3 ) 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 , —CH 2 OP(O)(OH) 2 , —CN, —CH 2 F, —CHF 2 , —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 , —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 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —CH 2 OCH 3 , —S(O) 2 CH 3 , cyclopropyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, oxetanyl, and morpholino.

2. The compound of claim 1 selected from Formulas Ia-c:

3. The compound of claim 1 selected from Formulas Id-f:

4. The compound of claim 1 selected from Formulas Ig-n:

5. The compound of claim 1 selected from Formulas Io-t:

6. The compound of claim 1 where Z 1 and Z 2 forms a five-, six-, or seven-membered aryl, carbocyclyl, heterocyclyl or heteroaryl ring, and selected from Formulas Iaa-ap:

7. The compound of claim 1 where X and Z′, and X is not S, forms a five-, six-, or seven-membered aryl, carbocyclyl, heterocyclyl or heteroaryl ring, and selected from Formulas Iaq-bf:

8. The compound of claim 1 wherein R 1 , R 2 , R 3 , and R 4 are each H.

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

10. The compound of claim 1 wherein R is —CH 2 OH.

11. The compound of claim 1 wherein R 3 is F.

12. The compound of claim 1 wherein R 1 is —CH 2 OH, R 2 and R 4 are each H, and R 3 is F.

13. The compound of claim 1 wherein R 5 is optionally substituted C 6 -C 20 aryl selected from phenyl and naphthyl.

14. The compound of claim 1 wherein R 5 is optionally substituted C 3 -C 12 carbocyclyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

15. The compound of claim 1 wherein R 5 is optionally substituted C 2 -C 20 heterocyclyl selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl.

16. The compound of claim 1 wherein R 5 is optionally substituted C 1 -C 20 heteroaryl selected from pyrazolyl, pyridinyl, pyrimidinyl, 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, 5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, and 1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-yl.

17. The compound of claim 1 wherein R 5 is substituted with one or more groups selected from F, Cl, —CH 3 , cyclopropyl, azetidinyl, oxetanyl, and morpholino.

18. The compound of claim 1 wherein R 5 is selected from the structures:

where the wavy line indicates the site of attachment.

19. The compound of claim 1 wherein R 6 is H.

20. The compound of claim 1 wherein X is S.

21. The compound of claim 1 wherein X is N.

22. The compound of claim 1 wherein X is CR 7 .

23. The compound of claim 1 wherein Y 1 is CR 6 and Y 2 is N.

24. The compound of claim 1 wherein Y 1 is N and Y 2 is CR 6 .

25. The compound of claim 1 wherein Y 1 and Y 2 are each CR 6 .

26. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

27. The pharmaceutical composition of to claim 1 , further comprising a second therapeutic agent.

Assignees

• Gilead Connecticut Inc
• Genentech Inc

Inventors

• Barbosa Antonio J M
• Blomgren Peter A
• Currie Kevin S
• Krishnamoorthy Ravi
• Kropf Jeffrey E
• Lee Seung H
• Mitchell Scott A
• ORTWINE Daniel
• Schmitt Aaron C
• Wang Xiaojing
• Xu Jianjun
• Young Wendy
• Zhang Honglu
• Zhao Zhongdong
• Zhichkin Pavel E

Classifications

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title