Pyrimidine derivatives

• US 9,006,241 B2
• Filed: 03/23/2012
• Issued: 04/14/2015
• Est. Priority Date: 03/24/2011
• Status: Active Grant

• Current Assignee: Noviga Research AB
• Original Assignee: Noviga Research AB
• Inventors: Hgberg, Marita, Dahlstedt, Emma, Smitt, Olof, Johansson, Tommy
• Primary Examiner(s): Harward, Soren
• Assistant Examiner(s): CALVILLO, Y JEANMARIE Z
• Application Number:
  US14/005,889
• Publication Number:
  US 20140045845A1
• Time in Patent Office: 1,117 Days
• Field of Search: None
• US Class Current: 514/235.2
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

The invention provides novel pyrimidine derivatives of formula (I), methods of preparing such compounds, pharmaceutical compositions containing such compounds, and methods for using such compounds in treatment of diseases including cancer; wherein R¹-R¹¹, Z, and Y are as defined in the specification.

Claims

1. A compound of formula I or a pharmaceutically acceptable ester, solvate or salt thereof,

2. The compound according to claim 1, wherein R¹ represents hydrogen.

3. The compound according to claim 1, wherein R², R³, and R⁸ are independently selected from the group consisting of hydrogen and methyl.

4. The compound according to claim 1, wherein R², R³, and R⁸ represent hydrogen.

5. The compound according to claim 1, wherein Z represents carbon and Y represents nitrogen.

6. The compound according to claim 1, wherein R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of hydrogen, halogen, hydroxy, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, O(C₁-C₄)alkyl(C₂-C₅)heterocyclyl, and OCF₃.

7. The compound according to claim 1, wherein R⁵ represents O(C₁-C₄)alkyl.

8. The compound according to claim 1, wherein R⁵ is selected from the group consisting of methoxy, ethoxy and propoxy.

9. The compound according to claim 1, wherein R⁵ is selected from the group consisting of methoxy and methyl.

10. The compound according to claim 1, wherein each R¹⁰ is independently selected from the group consisting of hydrogen, (C₁-C₄)alkyl and NH₂ when Z or Y is carbon.

11. The compound according to claim 1, wherein each R¹⁰ is independently selected from the group consisting of hydrogen and (C₁-C₄)alkyl when Z or Y is carbon.

12. The compound according to claim 1, wherein each R¹⁰ is independently selected from the group consisting of hydrogen and methyl when Z or Y is carbon.

13. The compound according to claim 1, wherein R¹¹ is selected from the group consisting of hydrogen, (C₁-C₄)alkyl, (CO)NH₂, and (C₂-C₅)heterocyclyl(C₁-C₄)alkyl.

14. The compound according to claim 1, wherein R¹¹ is selected from the group consisting of hydrogen and methyl.

15. The compound according to claim 1, wherein R⁹ is selected from the group consisting of

16. The compound according to claim 1, wherein R⁹ is selected from the group consisting of

17. The compound according to claim 1, wherein R¹², R¹³, and R¹⁴ represent hydrogen.

18. The compound according to claim 1, wherein R¹⁵ is selected from the group consisting of hydrogen and methyl.

19. The compound according to claim 1, wherein R¹⁶ and R¹⁷ are independently selected from the group consisting of hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkyl-OH, and (CO)OH.

20. The compound according to claim 19, wherein R¹⁶ is an ester of (CO)OH, and is selected from the group consisting of (CO)OCH₃ and (CO)OC₂H₅OH.

21. The compound according to claim 1, wherein R¹⁶ and R¹⁷ are independently selected from the group consisting of hydrogen, methyl and (C₁-C₄)alkyl-OH.

22. The compound according to claim 1, wherein R¹⁶ is selected from the group consisting of hydrogen, methyl, and (C₁-C₄)alkyl-OH.

23. The compound according to claim 1, wherein R¹⁶ is selected from the group consisting of hydrogen, methyl and hydroxymethyl.

24. The compound according to claim 1, wherein R¹⁷ is selected from the group consisting of hydrogen and methyl.

25. The compound according to claim 1, wherein Y represents carbon and Z represents nitrogen.

26. The compound according to claim 1, wherein

R⁴ represents hydrogen;

R⁵ is selected from the group consisting of halogen, methyl, O(C₁-C₂)alkyl, and OCF₃;

R⁶ and R⁷ are independently selected from the group consisting of hydrogen, methyl, and methoxy;

each R¹⁰ is independently selected from the group consisting of hydrogen and methyl when Z or Y is carbon;

R¹¹ is selected from the group consisting of hydrogen, methyl, and (CO)NH₂;

R⁹ is selected from the group consisting of

27. The compound according to claim 26, wherein R¹⁶ represents methyl.

28. The compound according to claim 1, wherein

Z represents carbon and Y represents nitrogen;

R¹, R², R³, R⁸, R¹², R¹³, and R¹⁴ represent hydrogen;

R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of hydrogen, halogen, hydroxy, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, O(C₁-C₄)alkyl(C₂-C₅)heterocyclyl, and OCF₃;

each R¹⁰ is independently selected from the group consisting of hydrogen and (C₁-C₄)alkyl when Z or Y is carbon;

R¹¹ is selected from the group consisting of hydrogen, (C₁-C₄)alkyl, (CO)NH₂, and (C₂-C₅)heterocyclyl(C₁-C₄)alkyl;

R⁹ is selected from the group consisting of

29. The compound according to claim 28, wherein R¹⁶ represents methyl.

30. The compound according to claim 26, wherein R⁵ is selected from the group consisting of methoxy, methyl, and fluoro.

31. The compound according to claim 28, wherein R¹¹ is selected from the group consisting of hydrogen, methyl, and (CO)NH₂.

32. The compound according to claim 1, wherein

Z represents carbon and Y represents nitrogen;

R¹, R¹⁰, R¹², R¹³, R¹⁴, and R¹⁷ represent hydrogen;

R², R³, R⁷, R⁸, and R¹¹ are independently selected from the group consisting of hydrogen and methyl;

R⁴, R⁵, and R⁶ are independently selected from the group consisting of hydrogen, and O(C₁-C₄)alkyl;

R⁹ is selected from the group consisting of

33. The compound according to claim 1, wherein

Z represents carbon and Y represents nitrogen;

R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R¹², R¹³, and R¹⁴ represent hydrogen;

R¹⁰, R¹¹, R¹⁵, and R¹⁷ are independently selected from the group consisting of hydrogen and methyl;

R⁵ is selected from the group consisting of methoxy and ethoxy;

R⁹ is selected from the group consisting of

34. The compound according to claim 1, wherein

R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R¹², R¹⁴, and R¹⁷ represent hydrogen;

each R¹⁰ is independently selected from the group consisting of hydrogen and amino;

R¹¹ is selected from the group consisting of hydrogen, (CO)NH₂, and (C₂-C₅)heterocyclyl(C₁-C₄)alkyl;

R⁵ is selected from the group consisting of methoxy, ethoxy, and hydroxy;

R¹⁵ is selected from the group consisting of hydrogen and methyl;

R¹⁶ is selected from the group consisting of hydrogen, methyl, and hydroxymethyl; and

R⁹ is selected from the group consisting of

35. The compound according to claim 1, wherein

Z represents carbon or nitrogen;

Z represents carbon or nitrogen;

Y represents carbon or nitrogen, wherein one of Z and Y represents nitrogen;

R¹, R³, and R⁸ are independently selected from the group consisting of hydrogen and (C₁-C₄)alkyl;

R² is selected from the group consisting of hydrogen and (C₁-C₄)alkyl;

R⁴, R⁵, R⁶, and R⁷ are independently selected from the group consisting of hydrogen, halogen, hydroxy, (C₁-C₄)alkyl, and OCF₃, wherein one of R⁴, R⁵, R⁶, and R⁷ is not hydrogen;

each R¹⁰ is independently selected from the group consisting of hydrogen and amino, when Z or Y is carbon;

R¹¹ is selected from the group consisting of hydrogen, (C₁-C₄)alkyl(C₂-C₅)heterocyclyl, and (CO)NH₂;

R⁹ represents

36. The compound according to claim 1, wherein

Z represents carbon or nitrogen;

Y represents carbon or nitrogen, wherein one of Z and Y represents nitrogen;

R¹, R², R³ and R⁸ are independently selected from the group consisting of hydrogen and (C₁-C₄)alkyl;

R⁴, R⁵, R⁶ and R⁷ are independently selected from the group consisting of hydrogen, halogen, hydroxy, (C₁-C₄)alkyl, O(C₁-C₄)alkyl, O(C₁-C₄)alkyl(C₂-C₅)heterocyclyl, and OCF₃;

R⁹ represents

37. The compound according to claim 1, wherein

Z represents carbon or nitrogen;

Y represents carbon or nitrogen, wherein one of Z and Y represents nitrogen;

R¹, R², R³ and R⁸ are independently selected from the group consisting of hydrogen and methyl;

R⁴, R⁵, R⁶ and R⁷ are independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl, methoxy, ethoxy, propoxy, O(C₁-C₄)alkyl(C₂-C₅)heterocyclyl, and OCF₃;

R⁹ represents

38. The compound according to claim 1, said compound being selected from the group consisting of:

N²-[2-(1H-indol-3-yl)ethyl]-N⁴-(1H-indol-5-yl)pyrimidine-2,4-diamine;

N⁴-(1H-indol-5-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

N²-[2-(1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N⁴-(2-methyl-1H-indol-5-yl)-N²-{2-[5-(2-morpholinoethoxy)-1H-indol-3-yl]ethyl}pyrimidine-2,4-diamine;

N⁴-(2-methyl-1H-indol-5-yl)-N²-{2-[5-(trifluoromethoxy)-1H-indol-3-yl]ethyl}pyrimidine-2,4-diamine;

3-{2-[4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino]ethyl}-1H-indol-5-ol;

N²-[2-(5-methyl-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-fluoro-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(6-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(7-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N⁴-(1,2-dimethyl-1H-indol-5-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

N⁴-(2,3-dimethyl-1H-indol-5-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

(5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1H-indol-2-yl)methanol;

methyl 5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1H-indole-2-carboxylate;

2-hydroxyethyl 5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1H-indole-2-carboxylate;

N⁴-(1H-benzo[d]imidazol-5-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine;

N⁴-(1H-indol-6-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

N⁴-(1H-indol-4-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

N⁴-[2-(1H-indol-3-yl)ethyl]-N²-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N⁴-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N²-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N⁴-[2-(1H-indol-3-yl)ethyl]-N²-(1H-indol-6-yl)pyrimidine-2,4-diamine;

N⁴-[2-(1H-indol-3-yl)ethyl]-N²-(1H-indol-4-yl)pyrimidine-2,4-diamine;

N²-[2-(1H-indol-3-yl)ethyl]-6-methyl-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-6-methyl-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]-6-(2-methyl-1H-indol-5-ylamino)pyrimidine-4-carboxamide;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-5-methyl-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; and

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;

or a pharmaceutically acceptable ester, solvate or salt thereof.

39. The compound according to claim 1, said compound being selected from the group consisting of:

N²-[2-(4-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N⁴-(2-methyl-1H-indol-5-yl)-N²-[2-(5-propoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

N²-[2-(5-isopropoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5,6-dimethoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine;

N⁴-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine;

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-6-methyl-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-2-methyl-1H-indol-3-yl)ethyl]-6-methyl-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-6-methyl-N⁴-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine;

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-6-methyl-N⁴-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine;

[5-(2-{[2-(5-methoxy-1H-indol-3-yl)ethyl][methyl]amino}pyrimidin-4-ylamino)-1H-indol-2-yl]methanol;

(5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1-methyl-1H-benzo[d]imidazol-2-yl)methanol;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-methyl-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; and

N⁴-(1,2-dimethyl-1H-indol-5-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-methylpyrimidine-2,4-diamine;

or a pharmaceutically acceptable ester, solvate or salt thereof.

40. The compound according to claim 1, said compound being selected from the group consisting of:

[5-({2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-yl}amino)-1H-indol-2-yl]methanol;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-6-yl)pyrimidine-2,4-diamine;

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-6-yl)pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(1-methylindol-6-yl)pyrimidine-2,4-diamine;

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N⁴-(1-methylindol-6-yl)pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine;

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine;

3-[2-({4-[(1-methylindol-4-yl)amino]pyrimidin-2-yl}amino)ethyl]-1H-indol-5-ol;

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N⁴-(1-methylindol-4-yl)pyrimidine-2,4-diamine;

N⁴-(1,2-dimethylindol-4-yl)-N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine;

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine;

N⁴-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N²-(1-methylindol-4-yl)pyrimidine-2,4-diamine;

2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]-6-[(2-methyl-1H-indol-5-yl)amino]pyrimidine-4-carboxamide;

6-[(1,2-dimethylbenzimidazol-5-yl)amino]-2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidine-4-carboxamide;

2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]-6-[(1-methylindol-4-yl)amino]pyrimidine-4-carboxamide;

2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]-6-[(1-methylindol-4-yl)amino]pyrimidine-4-carboxamide;

N²-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N⁴-(1-methylindol-4-yl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine; and

N²-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N⁴-(2-methyl-1H-indol-5-yl)pyrimidine-2,4,5-triamine;

or a pharmaceutically acceptable ester, solvate or salt thereof.

41. A method of treating a disease wherein inhibition of tubulin polymerization is beneficial, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I, according to claim 1, or a pharmaceutically acceptable ester, solvate or salt thereof.

42. A method of treating a disease wherein induction of apoptosis is beneficial, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I, according to claim 1, or a pharmaceutically acceptable ester, solvate or salt thereof.

43. A method of treating cancer, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of formula I, according to claim 1, or a pharmaceutically acceptable ester, solvate or salt thereof.

44. The method according to claim 43, wherein said cancer is selected from the group consisting of leukemia, lymphoma, myeloma, breast cancer, ovarian cancer, prostate cancer, lung cancer, pancreatic cancer, and glioma.

45. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable ester, solvate or salt thereof, together with one or more of a pharmaceutically acceptable diluent and carrier.