Oxygen linked pyrimidine derivatives

1. A method of treating a condition in a mammal in which inhibition of one or more protein kinase(s) inhibits a pathology or a symptomology of the condition, the method comprising administration of a therapeutically effective amount of a compound of the formula (I)

wherein:

R 1 and R 2 are each independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which can be optionally substituted;

each R 3 , R 4 , and R 5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which can be optionally substituted;

each R 6 is independently selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which can be optionally substituted;

Z 2 is —N(R 7 );

each R 7 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which can be optionally substituted;

Ar 1 and Ar 2 are both phenylene, each of which can be optionally substituted;

L is a group of formula:

—X 1 —Y—X 2 —

wherein X 1 is attached to Ar 1 and X 2 is attached to Ar 2 , and wherein X 1 , X 2 and Y are selected such that the group L has between 5 and 15 atoms in the normal chain,

X 1 and X 2 are each independently a heteroalkyl group containing at least one oxygen atom in the normal chain,

Y is a group of formula —CR a ═CR b —,

wherein R a and R b are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which can be optionally substituted, or

R a and R b can be joined such that when taken together with the carbon atoms to which they are attached they form a cycloalkenyl or cycloheteroalkenyl group;

or a pharmaceutically acceptable salt or N-oxide thereof;

wherein the condition is selected from the group consisting of myelofibrosis, acute myeloid leukemia, colon cancer, glioblastoma multiforme, chronic myelomonocytic leukemia, and Hodgkin's disease.

2. The method according to claim 1 wherein the one or more protein kinase(s) is a cyclin-dependent protein kinase.

3. The method according to claim 2 wherein the cyclin-dependent kinase is a Group I CMCG kinase.

4. The method according to claim 3 wherein the Group I CMCG kinase is selected from the group consisting of CDC2Hs, CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIRE1, PCTAIRE2, PCTAIRE3, CAK/MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRK1, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, and OsC2R.

5. The method according to claim 3 wherein the Group I CMCG kinase is CDK2.

6. The method according to claim 1 wherein the one or more protein kinase(s) is a protein tyrosine kinase.

7. The method according to claim 6 wherein the protein tyrosine kinase is a Group VII protein tyrosine kinase.

8. The method according to claim 7 wherein the Group VII protein tyrosine kinase is selected from the group consisting of TYK2, JAK1, JAK2 and HOP.

9. The method according to claim 8 wherein the Group VII protein tyrosine kinase is JAK2.

10. The method according to claim 9 wherein the JAK2 includes a V to F mutation at position 617.

11. The method according to claim 6 wherein the protein tyrosine kinase is a Group XIV protein tyrosine kinase.

12. The method according to claim 11 wherein the Group XIV protein tyrosine kinase is selected from the group consisting of PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3 and FLT4.

13. The method according to claim 12 wherein the Group XIV protein tyrosine kinase is FLT3.

14. The method according to claim 13 wherein the FLT3 includes an internal tandem duplication.

15. The method according to claim 14 wherein the internal tandem duplication is a duplication of amino acids VDFREYEYDH at position 592-601.

16. The method according to claim 1 wherein the one or more protein kinase(s) include at least two kinases selected from the group consisting of CDK2, FLT3 and JAK2.

17. The method according to claim 16 wherein the one or more protein kinase(s) include all three of CDK2, FLT3 and JAK2.

18. A method of treating a proliferative disorder comprising administration of a therapeutically effective amount of a compound of formula (I)

wherein:

R 1 and R 2 are each independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl alkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonyl amino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which can be optionally substituted;

each R 3 , R 4 , and R 5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which can be optionally substituted;

each R 6 is independently selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which can be optionally substituted;

Z 2 is —N(R 7 )—;

each R 7 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which can be optionally substituted;

Ar 1 and Ar 2 are both phenylene, each of which can be optionally substituted;

L is a group of formula:

—X 1 —Y—X 2 —;

wherein X 1 is attached to Ar 1 and X 2 is attached to Ar 2 , and wherein X 1 , X 2 and Y are selected such that the group L has between 5 and 15 atoms in the normal chain,

X 1 and X 2 are each independently a heteroalkyl group containing at least one oxygen atom in the normal chain,

Y is a group of formula —CR a ═CR b —,

wherein R a and R b are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which can be optionally substituted, or

R a and R b can be joined such that when taken together with the carbon atoms to which they are attached they form a cycloalkenyl or cycloheteroalkenyl group;

or a pharmaceutically acceptable salt or N-oxide thereof;

wherein the proliferative disorder is selected from the group consisting of myelofibrosis, acute myeloid leukemia, colon cancer, glioblastoma multiforme, chronic myelomonocytic leukemia, and Hodgkin's disease.

19. The method according to claim 1 wherein in the compound of formula I Z 2 is —N(H)—.

20. The method according to claim 1 wherein in the compound of formula I Ar 1 is

wherein R 10 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, aryl alkyl, heteroaryl alkyl, aryl alkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which may be optionally substituted,

k is an integer selected from the group consisting of 0, 1, 2, 3, and 4.

21. The method according to claim 1 wherein in the compound of formula I Ar 2 is a group selected from the group consisting of:

wherein each R 11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl alkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which can be optionally substituted.

22. The method according to claim 1 wherein in the compound of formula I X 1 is selected from the group consisting of:

(a) —OCH 2 —

(b) —CH 2 O—,

(c) —OCH 2 CH 2 —,

(d) —CH 2 CH 2 O—,

(e) —CH 2 OCH 2 —, and

(f) —CH 2 CH 2 OCH 2 —.

23. The method according to claim 1 wherein in the compound of formula I X 2 is selected from the group consisting of:

(a) —OCH 2 —

(b) —CH 2 O—,

(c) —OCH 2 CH 2 —,

(d) —CH 2 CH 2 O—,

(e) —CH 2 OCH 2 —, and

(f) —CH 2 CH 2 OCH 2 —.

24. The method according to claim 1 wherein in the compound of formula I Y is selected from the group consisting of:

25. The method according to claim 1 wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

26. The method according to claim 18 wherein in the compound of formula I Z 2 is —N(H)—.

27. The method according to claim 18 wherein in the compound of formula I Ar 1 is

wherein R 10 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which can be optionally substituted,

k is an integer selected from the group consisting of 0, 1, 2, 3, and 4.

28. The method according to claim 18 wherein in the compound of formula I Ar 2 is a group selected from the group consisting of:

wherein each R 11 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, phenoxy, benzyloxy, heteroaryloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COOH, —COR 3 , —COOR 3 , —CONHR 3 , —NHCOR 3 , —NHCOOR 3 , —NHCONHR 3 , alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, —SR 3 , R 4 S(O)R 6 —, R 4 S(O) 2 R 6 —, R 4 C(O)N(R 5 )R 6 —, R 4 SO 2 N(R 5 )R 6 —, R 4 N(R 5 )C(O)R 6 —, R 4 N(R 5 )SO 2 R 6 —, R 4 N(R 5 )C(O)N(R 5 )R 6 — and acyl, each of which can be optionally substituted.

29. The method according to claim 18 wherein in the compound of formula I X 1 is selected from the group consisting of:

(a) —OCH 2 —

(b) —CH 2 O—,

(c) —OCH 2 CH 2 —,

(d) —CH 2 CH 2 O—,

(e) —CH 2 OCH 2 —, and

(f) —CH 2 CH 2 OCH 2 —.

30. The method according to claim 18 wherein in the compound of formula I X 2 is selected from the group consisting of:

(a) —OCH 2 —

(b) —CH 2 O—,

(c) —OCH 2 CH 2 —,

(d) —CH 2 CH 2 O—,

(e) —CH 2 OCH 2 —, and

(f) —CH 2 CH 2 OCH 2 —.

31. The method according to claim 18 wherein in the compound of formula I Y is selected from the group consisting of:

32. The method according to claim 18 wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

33. The method according to claim 25 wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.

34. The method according to claim 32 wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.

35. The method according to claim 33 wherein the condition is myelofibrosis.

36. The method according to claim 34 wherein the proliferative disorder is myelofibrosis.

37. The method according to claim 18 wherein the proliferative disorder is myelofibrosis.

38. The method according to claim 18 wherein the proliferative disorder is acute myeloid leukemia.

39. The method according to claim 18 wherein the proliferative disorder is colon cancer.

40. The method according to claim 18 wherein the proliferative disorder is glioblastoma multiforme.

41. The method according to claim 18 wherein the proliferative disorder is chronic myelomonocytic leukemia.

42. The method according to claim 18 wherein the proliferative disorder is Hodgkin's disease.

43. The method according to claim 1 wherein the condition is myelofibrosis.

44. The method according to claim 1 wherein the condition is acute myeloid leukemia.

45. The method according to claim 1 wherein the condition is colon cancer.

46. The method according to claim 1 wherein the condition is glioblastoma multiforme.

47. The method according to claim 1 wherein the condition is chronic myelomonocytic leukemia.

48. The method according to claim 1 wherein the condition is Hodgkin's disease.