Use of bi-aryl meta-pyrimidine inhibitors of kinases

1. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has a myeloproliferative disorder, comprising administering to the subject with a myeloproliferative disorder an effective amount of a compound having the structure (A):

wherein:

X is selected from a group consisting of a bond, O 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,

each R 9 is independently selected from a group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -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 and CH,

each G is independently CR 6 or C when bonded to X;

R 5 is methyl;

each of R 6 , R 7 and R 8 is independently selected from a group consisting of H, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 hydroxyalkyl or aminoalkyl, C 3 -C 6 cycloalkyl, 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 3 -C 6 cycloalkyl), SO 2 NH-heterocycle, (SO 2 N(C 3 -C 6 branched alkyl)H, NO 2 , CN, CONH 2 , CO—(C 1 -C 6 alkyl), COOH, COO—(C 1 -C 6 alkyl), and NHCO—(C 1 -C 6 alkyl), or R 6 and R 7 taken together, or R 7 and R 8 , taken together, form a moiety independently selected from the group consisting of —CH═CH—CH═CH—, and —O—(CH 2 ) n —O—;

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 being independent of every other group R 7 ; and

R 3 and R 4 are taken together with G 0 to form a heterocyclic ring system;

wherein alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycle, for each occurrence if any, are optionally substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, mercapto, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, or sulfuryl;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the compound is selected from the group consisting of compounds having the formulae:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the myeloproliferative disorder is polycythemia vera, essential thrombocythemia, or myeloid fibrosis with myeloid metaplasia.

4. The method of claim 1 , wherein the myeloproliferative disorder arises due to mutations in a kinase.

5. The method of claim 4 , wherein the kinase is a JAK2 kinase.

6. The method of claim 5 , wherein the myeloproliferative disorder arises due to gain-of-function of a JAK2 kinase pathway.

7. The method of claim 5 , wherein the myeloproliferative disorder arises as a result of gene or protein fusions due to gain-of-function of a JAK2 kinase pathway.

8. The method of claim 1 , wherein X is O.

9. The method of claim 1 , wherein G 0 is N.

10. The method of claim 8 , wherein G 0 is N.

11. The method of claim 10 , wherein Y is a bond, and R 1 and R 2 are each H.

12. The method of claim 11 , wherein R 7 is SO 2 NH—(C 3 -C 6 branched alkyl).

13. The method of claim 12 , wherein G 2 is CH, R 8 is H and R 6 is H.

14. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has a myeloproliferative disorder, comprising administering to the subject with a myeloproliferative disorder an effective amount of the compound:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the myeloproliferative disorder is polycythemia vera.

16. The method of claim 14 , wherein the myeloproliferative disorder is essential thrombocythemia.

17. The method of claim 14 , wherein the myeloproliferative disorder is myeloid fibrosis with myeloid metaplasia.

18. The method of claim 14 , wherein the disorder is a myeloproliferative myeloid-linked disorder.

19. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

24. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

25. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

26. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

27. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

28. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

29. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has a myeloproliferative disorder, comprising administering to the subject with a myeloproliferative disorder a compound selected from the group consisting of compounds having the formulae:

or a pharmaceutically acceptable salt thereof.

30. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, is in the form of a pharmaceutical composition which comprises the compound and a pharmaceutically acceptable carrier.

31. The method of claim 30 , wherein the pharmaceutical composition is administered orally.