Pyridinones/pyrazinones, method of making, and method of use thereof
Pyridone and pyrazinone compounds of Formula I 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.
1. A compound selected from Formula I:
and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from:
where the wavy line indicates the site of attachment;
R 4 is selected from OH, CN, NR b R c , piperidinyl, C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 6 alkyl or C 1 -C 4 haloalkyl, and C 1 -C 6 alkyl optionally substituted with OH or OC 1 -C 4 alkyl;
R 2 is H, CH 3 or CF 3 ;
ring B is selected from phenyl, 5-6 membered heteroaryl having at least one nitrogen ring atom, and 8-11 membered heterocyclyl having at least one nitrogen ring atom;
R 3 is independently selected from H, —R a , —OR b , —SR b , —NR b R c , halo, cyano, nitro, —COR b , —CO 2 R b , —CONR b R c , —OCOR b , —OCO 2 R a , —OCONR b R c , —NR c COR b , —NR c CO 2 R a , —NR c CONR b R c , —CO 2 R b , —CONR b R c , —NR c COR b , —SOR a , —SO 2 R a , —SO 2 NR b R c , and —NR c SO 2 R a ; or two adjacent R 3 groups are optionally taken together to form a 5-6 membered ring having 0-2 heteroatoms selected from O, S or N, wherein said 5-6 membered ring is fused to ring B;
R a is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each member of R a is optionally substituted with one to three R 11 groups;
R b is H, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each member of R b except H is optionally substituted with one to three R 11 groups;
R c is H or C 1 -C 4 alkyl optionally substituted with one or three R 11 groups; or R b and R c , and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group;
each R 11 is independently selected from C 1 -C 4 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, cycloalkyl-C 1 -C 4 alkyl-, heterocycloalkyl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl-, —OC 1 -C 4 alkyl, —O-heterocycloalkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH(C 1 -C 4 alkylphenyl), cyano, nitro, oxo, —CO 2 H, —C(O)OC 1 -C 4 alkyl, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —NHC(O)(C 1 -C 4 alkyl), —NHC(O)(phenyl), —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)C(O)(phenyl), —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 phenyl, —C(O)C 1 -C 4 haloalkyl, —OC(O)C 1 -C 4 alkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (phenyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —SO 2 NH(phenyl), —NHSO 2 (C 1 -C 4 alkyl), —NHSO 2 (phenyl), and —NHSO 2 (C 1 -C 4 haloalkyl);
R 5 is H or F;
R 6 is H, CH 3 , F, Cl, CN, OCH 3 , OH, or methyl substituted with OH, OCH 3 or one or more halo groups;
R 7 is H, CH 3 , F, Cl, CN or OCH 3 ;
R 8 is H, CH 3 , CF 3 , F, Cl, CN or OCH 3 ;
V is CH or N;
each R 9 is independently C 1 -C 3 alkyl; and
each R 10 is independently H or CH 3 .
2. The compound of claim 1 wherein R 2 is H or CH 3 .
3. The compound of claim 1 wherein R 3 is H, —R a , —NR b R c or —C(O)R b .
4. The compound of claim 1 wherein R 3 is selected from cyclopropyl, azetidinyl, morpholinyl, piperidinyl, oxopiperidinyl, piperazinyl, and oxopiperazinyl, optionally substituted with F, OH, CH 3 , or COCH 3 .
5. The compound of claim 1 wherein R 3 is:
where the wavy line indicates the site of attachment.
6. The compound of claim 1 wherein R 4 is H, t-butyl, N-pyrrolidinyl, N-piperidinyl, N-azepanyl, 2-hydroxy-2-methylpropyl, prop-1-en-2-yl, —N(CH 3 )Et, i-propyl, cyclopentyl, cyclohexyl, 3-methylbutan-2-yl, —N(CH 3 )(i-Pr), or —NH(cyclopropyl).
7. The compound of claim 1 wherein R 5 is H or F.
8. The compound of claim 1 wherein R 6 is H, CH 3 , F, or CH 2 OH.
9. The compound of claim 1 wherein R 7 is H or F.
10. The compound of claim 1 wherein B is pyrazolo[1,5-a]pyrazin-2-yl, pyrazol-3-yl, pyrimidin-4-yl, or pyridin-2-yl.
11. The compound of claim 1 wherein:
is selected from the structures:
where the wavy line indicates the site of attachment.
12. The compound of claim 1 having the structure of Formula Ia:
13. The compound of claim 1 having the structure of Formula Ib:
14. The compound of claim 1 having the structure of Formula Ic:
15. The compound of claim 1 chosen from Table 1.
16. The compound of claim 1 chosen from Table 2.
17. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
18. The pharmaceutical composition according to claim 17 , further comprising a second therapeutic agent.
19. A kit for treating a condition mediated by Bruton's tyrosine kinase, comprising:
a) a first pharmaceutical composition comprising a compound of claim 1 ; and
b) instructions for use.