Modulators of methyl modifying enzymes, compositions and uses thereof

• US 10,689,371 B2
• Filed: 04/18/2019
• Issued: 06/23/2020
• Est. Priority Date: 04/18/2018
• Status: Active Grant

• Current Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Original Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Inventors: Cote, Alexandre, Gehling, Victor S., Khanna, Avinash, Moine, Ludivine, Stuckey, Jacob I.
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US16/387,851
• Publication Number:
  US 20190322651A1
• Time in Patent Office: 432 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

Provided are novel compounds of Formula (I):

and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions, associated with methyl modifying enzymes. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with methyl modifying enzymes.

Claims

1. A compound of the Formula I:

2. The compound of claim 1, wherein:

R¹ is halo or —

S(C₁-C₄)alkyl;

R² is halo;

R³ is (C₁-C₄)alkyl;

R⁴ is (C₃-C₇)cycloalkyl or (C₄-C₇)heterocyclyl, each of which are optionally substituted with 1 to 2 groups selected from halo(C₁-C₄)alkyl and —

NR^aR^b;

R^a is hydrogen or (C₁-C₄)alkyl;

R^b is (C₁-C₄)alkyl or (C₄-C₇)heterocyclyl, wherein said heterocyclyl is optionally substituted with halo(C₁-C₄)alkyl;

or

R^a and R^b together with the nitrogen atom to which they are attached form a 4-7 membered nitrogen containing heterocyclyl optionally substituted with 1 to 3 groups selected from halo and —

OR^c;

R^c is (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, or (C₃-C₇)cycloalkyl; and

R⁵ is halo or (C₁-C₄)alkyl.

3. The compound of claim 1, wherein the compound is of the Formula II:

4. The compound of claim 1, wherein R¹ is chloro.

5. The compound of claim 1, wherein R¹ is SCH₃.

6. The compound of claim 1, wherein R⁴ is cyclohexyl or piperidinyl, each of which are optionally substituted with 1 to 2 groups selected from halo(C₁-C₄)alkyl and —

NR^aR^b.

7. The compound of claim 1, wherein the compound is of the Formula III:

8. The compound of claim 1, wherein the compound is of the Formula IV:

9. The compound of claim 1, wherein the compound is of the Formula (V):

10. The compound of claim 1, wherein the compound is of the Formula:

11. The compound of claim 1, wherein the compound is of the Formula:

12. The compound of claim 1, wherein R^b is (C₁-C₄)alkyl or oxetanyl, wherein said oxetanyl is optionally substituted with halo(C₁-C₄)alkyl;

or R^a and R^b together with the nitrogen atom to which they are attached form an azetidinyl optionally substituted with halo or —

OR^c.

13. The compound of claim 1, wherein R^a is hydrogen or methyl;

and R^b is methyl or oxatanyl, wherein said oxetanyl is optionally substituted with —

CH₂F or —

CF₃.

14. The compound of claim 1, wherein R^a and R^b together with the nitrogen atom to which they are attached form an azetidinyl optionally substituted with 1 to 2 fluoro or —

OR^c; and

R^c is —

CH₃, —

CHF₂, or cyclopropyl.

15. The compound of claim 1, wherein the compound is of the Formula:

16. The compound of claim 1, wherein the group

17. The compound of claim 1, wherein the group

18. The compound of claim 1, wherein the stereochemical configuration of the chiral center of the 1,3-dioxolanyl is R.

19. The compound of claim 1, wherein the stereochemical configuration of the chiral center of the 1,3-dioxolanyl is S.

20. The compound of claim 1, wherein the compound is of the Formula:

21. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

22. A compound having the formula:

23. A pharmaceutically acceptable composition comprising a compound of the formula:

24. A compound having the formula:

25. A pharmaceutically acceptable composition comprising a compound of the formula:

26. A compound having the formula:

27. A pharmaceutically acceptable composition comprising a compound of the formula:

28. A compound having the formula:

29. A pharmaceutically acceptable composition comprising a compound of the formula: