Pyridone and aza-pyridone compounds and methods of use

Patent metadata

Field	Value
Publication number	US-9505785-B2
Application number	US-201314059626-A
Country	US
Kind code	B2
Filing date	Oct 22, 2013
Priority date	May 7, 2010
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

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 of 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, imidazolyl, pyrazolyl, oxetanyl, azetidinyl, or C 1 -C 3 alkyl;
R 2 , R 3 and R 4 are independently H, D, F, Cl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, or 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 H, D, F, Cl, —CH 3 , —CH 2 CH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —NH 2 , —OH, or —OCH 3 ;
Y 1 and Y 2 are independently CR 6 or N;
Z 1 , Z 2 , Z 3 , and Z 4 are independently C, CR 7 , or N;
Z 5 is —C(R 3 ) 2 C(R 3 ) 2 —, —C(R 3 ) 2 C(═O)—, —CR 3 ═CR 3 —;
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 independently substituted with one or more of 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, or morpholino.

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

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

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

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

6. The compound of claim 1 of one of Formulas Iu-z:

7. 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 of one of Formulas Iaa-ap:

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

9. The compound of claim 1 where the group:

forms one of the structures:

where the wavy line indicates the site of attachment.

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

11. The compound of claim 1 wherein R 1 is F, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

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

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

14. 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.

15. The compound of claim 1 wherein R 5 is optionally substituted phenyl or naphthyl.

16. The compound of claim 1 wherein R 5 is optionally substituted C 3 -C 12 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

17. The compound of claim 1 wherein R 5 is optionally substituted oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, or tetrahydropyranyl.

18. The compound of claim 1 wherein R 5 is optionally substituted 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, or 1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-yl.

19. The compound of claim 18 wherein R 5 is substituted with one or more of F, Cl, —CH 3 , cyclopropyl, azetidinyl, oxetanyl, or morpholino.

20. The compound of claim 1 wherein R 5 is one of:

where the wavy line indicates the site of attachment.

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

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

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

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

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

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

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

28. The compound of claim 1 which is:
2-(2-methyl-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one;
2-(2-methyl-3-(5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one;
5-[2-(Hydroxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-8-thia-5-azatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7)-dien-6-one;
10-[2-(Hydroxymethyl)-3-[1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl]phenyl]-4,4-dimethyl-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),

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

• A61P37/02

  Immunomodulators · 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

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title