EZH2 inhibitors

• US 10,266,542 B2
• Filed: 03/14/2018
• Issued: 04/23/2019
• Est. Priority Date: 03/15/2017
• Status: Active Grant

• Current Assignee: Mirati Therapeutics Inc. (Bristol-Myers Squibb Company)
• Original Assignee: Mirati Therapeutics Inc. (Bristol-Myers Squibb Company)
• Inventors: Marx, Matthew Arnold, Lee, Matthew Randolph, Galemmo, Robert Anthony, Bobinski, Thomas P.
• Primary Examiner(s): Pagano, Alexander R
• Assistant Examiner(s): Sackey, Ebenezer O
• Application Number:
  US15/921,097
• Publication Number:
  US 20180265517A1
• Time in Patent Office: 405 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention relates to compounds that inhibit EZH2 activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein X is O and Y and Z are each CR⁵.

3. The compound of claim 1, wherein Z is O and X and Y are each CR⁵.

4. The compound of claim 1, wherein X and Y are each CR⁵ and Z is NR⁴.

5. The compound of claim 1, wherein X is NR⁴ and Y and Z are each CR⁵.

6. The compound of claim 1, wherein R¹ is —

OR⁶.

7. The compound of claim 6, wherein R⁶ is C1-C4 alkyl, hydroxyalkyl or heterocyclyl.

8. The compound of claim 1, wherein R¹ is heterocyclyl optionally substituted with one or more R⁶.

9. The compound of claim 8, wherein the heterocyclyl is an 8-10 membered spirocycle comprising 1-4 heteroatoms selected from O, N or S.

10. The compound of claim 1, wherein R¹ is heteroaryl optionally substituted with one or more R⁶.

11. The compound of claim 10, wherein the heteroaryl is oxazolyl, 1,4-dimethyl-oxazolyl, triazinyl or 1,4-dimethyl-1H-1,2,3-triazinyl.

12. The compound of claim 1, wherein R¹ is —

NR⁴R⁶.

13. The compound of claim 12, wherein R⁴ is C1-C3 alkyl and R⁶ is heterocyclyl optionally substituted with one or more R¹⁴.

14. The compound of claim 13, wherein the heterocyclyl is tetrahydropyranyl, piperidinyl or methylsulfonylpiperdinyl.

15. The compound of claim 12, wherein R⁴ is C1-C3 alkyl and R⁶ is cycloalkyl optionally substituted with —

NR⁴R¹⁰.

16. The compound of claim 15, wherein the cycloalkyl is substituted with —

NR⁴R¹⁰, and R¹⁰ is hydrogen, acyl, C1-C3 alkyl or C1-C4 alkoxy.

17. The compound of claim 1, wherein R¹ is —

W—

R⁷.

18. The compound of claim 17, wherein:

p and q are each zero;

R⁷ is heterocyclyl optionally substituted with acyl, or one or more oxo or C1-C3 alkyl;

R⁸ is hydrogen; and

R⁹ is C1-C4 alkoxy.

19. The compound of claim 18, wherein the heterocyclyl is azetidinyl, 1-methyl-azetidinyl, oxetanyl, thietane 1,1-dioxide, furanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperdinyl, 4-methyl-piperdinyl, 4-acyl-piperdinyl, piperazinyl, 4-methyl-piperazinyl, 4-acyl-piperazinyl, dioxidothiopyranyl, or morpholinyl.

20. The compound of claim 1, wherein R² is halogen.

21. The compound of claim 20, wherein the halogen is chlorine.

22. The compound of claim 1, wherein R³ is halogen.

23. The compound of claim 22, wherein the halogen is chlorine or bromine.

24. The compound of claim 1, wherein R³ is R¹²-L-R¹³.

25. The compound of claim 24, wherein R¹² is heteroarylene.

26. The compound of claim 25, wherein the heteroarylene is pyrazolylene, pyrimidinylene or triazolylene.

27. The compound of claim 24, wherein L is a bond and R¹³ is azetidinyl, 1-methylazetidinyl, piperidinyl, 1-methylpiperdinyl, 4-acyl-piperdinyl, piperazinyl, 4-methylpiperazinyl, 4-acyl-piperazinyl, oxetanyl or morpholinyl.

28. The compound of claim 24, wherein R¹² is arylene.

29. The compound of claim 28, wherein the aryl is phenylene.

30. The compound of claim 28, wherein L is C1 alkylene and R¹³ is morpholinyl.

31. The compound of claim 24, wherein R¹² is C2-C4 alkynylene.

32. The compound of claim 31, wherein the C2-C4 alkynylene is ethynylene.

33. The compound of claim 31, wherein L is a bond and R¹³ is morpholinyl or oxetanyl.

34. The compound of claim 1, wherein the compound is:

35. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable excipient.

36. A method for inhibiting EZH2 activity in a cell, comprising contacting the cell in which inhibition of EZH2 activity is desired with an effective amount of a compound of claim 1 pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound of claim 1 or pharmaceutically acceptable salt thereof.

37. A method for treating an EZH2-associated cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, alone or combined with a pharmaceutically acceptable carrier, exicipient or diluents.

38. The method of claim 37, wherein the therapeutically effective amount of the compound is between about 0.01 to 300 mg/kg per day.

39. The method of claim 38, wherein the therapeutically effective amount of the compound is between about 0.1 to 100 mg/kg per day.

40. The method of claim 39, wherein the cancer is selected from the group consisting of leukemia, lymphoma, breast cancer, prostate cancer, pancreatic cancer, brain cancer, bladder cancer, lung cancer, head and neck cancer, liver cancer, kidney cancer, cervical cancer, uterine cancer, ovarian cancer and bone cancer.