Bi-aryl meta-pyrimidine inhibitors of kinases
The invention provides biaryl meta-pyrimidine compounds having the general structure (A). The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Jak kinase family, and various other specific receptor and non-receptor kinases.
1. A compound having the structure (A):
wherein:
X is selected from a group consisting of a bond, O, SO 2 , and CH 2 ; Y is selected from a group consisting of a bond or NR 9 ; or X and Y taken together is a bond;
each of R 1 and R 2 is independently selected from a group consisting of H, C 1 -C 6 alkyl, cycloalkyl; or R 1 and R 2 taken together is a bond; or R 1 and R 2 taken together form a moiety selected from a group consisting of (CH 2 ) m , (CH 2 ) r —S—(CH 2 ) m , (CH 2 ) r —SO—(CH 2 ) m , (CH 2 ) r —SO 2 —(CH 2 ) m , (CH 2 ) r —NR 9 —(CH 2 ) m , and (CH 2 ) r —O—(CH 2 ) m ;
each of p, q, r, n, m is independently an integer having the value between 0 and 6,
R 9 is selected from a group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 branched alkyl, C 1 -C 6 aminoalkyl, and C 1 -C 6 hydroxyalkyl;
G 0 is selected from a group consisting of N, O, H, and CH,
G is CH or C when bonded to X;
R 5 methyl;
wherein each of R 6 and R 7 is independently selected from a group consisting of C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 hydroxyalkyl or aminoalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, a halogen, CF 3 , OCF 3 , SO 2 H, SO 2 (C 1 -C 6 alkyl), SO 2 -heterocycle, SO 2 -cycloalkyl, SO 2 N(C 1 -C 6 alkyl)H, SO 2 N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), SO 2 NH(C 1 -C 6 cycloalkyl), SO 2 NH-heterocycle, (SO 2 N(C 1 -C 6 branched alkyl)H, NO 2 , CN, OH, CONH 2 , CO—(C 1 -C 6 alkyl), COOH, COO—(C 1 -C 6 alkyl), and NHCO—(C 1 -C 6 alkyl), and
R 8 is independently selected from the group consisting of H, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 hydroxyalkyl or aminoalkyl, C 1 -C 6 cycloalkyl, halogen, CF 3 , OCF 3 , SO 2 H ,SO 2 (C 1 -C 6 alkyl), SO 2 -heterocycle, SO 2 -cycloalkyl, SO 2 N(C 1 -C 6 alkyl)H, SO 2 N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), SO 2 NH(C 1 -C 6 cycloalkyl), SO 2 NH-heterocycle, (SO 2 N(C 1 -C 6 branched alkyl)HNO 2 , CN, OH, CONH 2 , CO—(C 1 -C 6 alkyl), COOH, COO—(C 1 -C 6 alkyl), and NHCO—(C 1 -C 6 alkyl);
A is selected from a group consisting of NH, and N—(C 1 -C 6 alkyl);
G 1 is CH;
G 2 is CR 7 , with each group R 7 independent of every other group R 7 ;
and R 3 and R 4 , taken together form a heterocyclic ring system,
or a pharmaceutically acceptable salt thereof.
2. A compound represented by: a first moiety chemically connected to a second moiety, or a pharmaceutically acceptable salt thereof, wherein the first moiety is selected from the group consisting of:
and wherein the second moiety is selected from the group consisting of:
3. The compound of claim 1 , wherein the compound is
4. The compound of claim 1 , wherein the compound is
5. The compound of claim 1 , wherein the compound is
6. The compound of claim 1 , wherein the compound is selected from the group consisting of:
7. The compound of claim 1 , wherein the compound is selected from the group consisting of:
8. The compound of claim 1 , wherein the compound is selected from the group consisting of:
9. The compound of claim 1 , wherein the compound is selected from the group consisting of:
10. The compound of claim 1 , wherein the compound is selected from the group consisting of:
11. The compound of claim 1 , wherein the compound is selected from the group consisting of:
12. The compound of claim 1 , wherein the compound is
13. The compound of claim 1 , wherein the compound is selected from the group consisting of:
14. A compound represented by:
and a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is
16. The compound of claim 1 , wherein the compound is
17. The compound of claim 1 , wherein the compound is selected from the group consisting of:
18. A compound, wherein the compound is
19. The compound of claim 1 , wherein the compound is
20. A compound wherein the compound is selected from the group consisting of:
21. The compound of claim 1 , wherein the compound is selected from the group consisting of:
22. The compound of claim 1 , wherein the compound is selected from the group consisting of:
23. The compound of claim 1 , wherein the compound is selected from the group consisting of:
24. The compound of claim 1 , wherein the compound is
25. A compound wherein the compound is selected from the group consisting of:
and a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 , wherein the compound is
27. The compound of claim 1 , wherein the compound is selected from the group consisting of:
28. The compound of claim 1 , wherein the compound is
29. The compound of claim 1 , wherein the compound is selected from the group consisting of:
30. The compound of claim 1 , wherein the compound is
31. The compound of claim 1 , wherein the compound is
32. The compound of claim 1 , wherein the compound is
33. The compound of claim 1 , wherein the compound is
34. The compound of claim 1 , wherein the compound is
35. The compound of claim 1 , wherein the compound is
36. The compound of claim 1 , wherein the compound is
37. The compound of claim 1 , wherein X is O.
38. The compound of claim 1 , wherein G 0 is N.
39. The compound of claim 37 , wherein G 0 is N.
40. The compound of claim 39 , wherein Y is a bond, and R 1 and R 2 are each H.
41. The compound of claim 40 , wherein R 7 is SO 2 NH—(C 1 -C 6 branched alkyl).
42. The compound of claim 39 , wherein G 2 is CH, R 8 is H and R 5 is H.
43. A compound represented by:
or a pharmaceutically acceptable salt thereof.
44. A pharmaceutical composition comprising:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.