THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

• US 20190023737A1
• Filed: 03/08/2018
• Published: 01/24/2019
• Est. Priority Date: 07/25/2013
• Status: Active Grant

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Lemieux, Rene M., Popovici-Muller, Janeta, Travins, Jeremy, Cai, Zhenwei, Cui, Dawei, Zhou, Ding
• Granted Patent: US 10,689,414 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.

Claims

1-18. -18. (canceled)

19. A method for treating Maffucci syndrome comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof, wherein:

21. The method of claim 19, wherein:

R¹ is C₄-C₆ carbocyclyl optionally substituted with one to three R⁷ groups;

each R² and R³ is independently selected from aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R⁷ groups;

R⁴ is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and heteroaralkyl are each independently optionally substituted with one to three R⁷ groups;

ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms selected from N, O or S, wherein ring A is optionally substituted with one or two R⁵ groups;

each R⁵ and R⁷ is independently halo;

—

CF₃;

—

CN;

—

OR⁶;

—

N(R⁶)₂;

—

C(O)C₁-C₄ alkyl;

C₁-C₄ haloalkyl;

C₁-C₄ alkyl optionally substituted with —

OR⁶ or —

N(R⁶)₂;

—

O—

C₁-C₄ alkyl optionally substituted with halo, —

OR⁶ or —

N(R⁶)₂;

—

SO₂N(R⁶)₂;

—

S(O)—

C_1-4 alkyl;

—

SO₂(C₁-C₄ alkyl);

—

NR⁶SO₂R⁶;

C₃-C₅ carbocyclyl optionally substituted with one or two R⁶ groups;

—

O—

(C₃-C₆ carbocyclyl optionally substituted with one or two R⁶ groups);

5-6 membered heteroaryl;

—

C₁-C₄ alkyl-C(O)O—

C₁-C₄ alkyl;

or —

C(O)O—

C₁-C₄ alkyl;

or

each R⁶ is independently H or C₁-C₄ alkyl.

22. The method of claim 19 wherein each R² and R³ is independently aryl optionally substituted with one to three R⁷ groups.

23. The method of claim 19 wherein the compound or pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof is a compound of formula II-a,

24. The method of claim 19, wherein R¹ is C₄ or C₆ cycloalkyl optionally substituted with one to two R⁷ groups and R⁷ associated with R¹ is halo.

25. The method of claim 24, wherein R¹ is

26. The method of claim 24, wherein ring A is:

27. The method of claim 26, wherein ring A is:

28. The method of claim 26, wherein R⁴ is aryl or heteroaryl, each aryl or heteroaryl is optionally substituted with one to three R⁷ groups.

29. The method of claim 28, wherein R⁴ is:

30. The method of claim 29, wherein R⁴ is:

31. The method of claim 19, wherein the compound or pharmaceutically acceptable salt, tautomer, isotopologue or hydrate is selected from:

38. The method of claim 26, wherein ring A is:

20. A method for treating Ollier disease comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof, wherein:

32. The method of claim 20, wherein:

R¹ is C₄-C₆ carbocyclyl optionally substituted with one to three R⁷ groups;

each R² and R³ is independently selected from aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R⁷ groups;

R⁴ is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and heteroaralkyl are each independently optionally substituted with one to three R⁷ groups;

ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms selected from N, O or S, wherein ring A is optionally substituted with one or two R⁵ groups;

each R⁵ and R⁷ is independently halo;

—

CF₃;

—

CN;

—

OR⁶;

—

N(R⁶)₂;

—

C(O)C₁-C₄ alkyl;

C₁-C₄ haloalkyl;

C₁-C₄ alkyl optionally substituted with —

OR⁶ or —

N(R⁶)₂;

—

O—

C₁-C₄ alkyl optionally substituted with halo, —

OR⁶ or —

N(R⁶)₂;

—

SO₂N(R⁶)₂;

—

S(O)—

C_1-4 alkyl;

—

SO₂(C₁-C₄ alkyl);

—

NR⁶SO₂R⁶;

C₃-C₅ carbocyclyl optionally substituted with one or two R⁶ groups;

—

O—

(C₃-C₆ carbocyclyl optionally substituted with one or two R⁶ groups);

5-6 membered heteroaryl;

—

C₁-C₄ alkyl-C(O)O—

C₁-C₄ alkyl;

or —

C(O)O—

C₁-C₄ alkyl;

or

each R⁶ is independently H or C₁-C₄ alkyl.

33. The method of claim 20, wherein each R² and R³ is independently aryl optionally substituted with one to three R⁷ groups.

34. The method of claim 20, wherein the compound or pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof is a compound of formula II-a,

35. The method of claim 20, wherein R¹ is C₄ or C₆ cycloalkyl optionally substituted with one to two R⁷ groups and R⁷ associated with R¹ is halo.

36. The method of claim 35, wherein R¹ is

37. The method of claim 35, wherein ring A is:

39. The method of claim 37, wherein R⁴ is aryl or heteroaryl, each aryl or heteroaryl is optionally substituted with one to three R⁷ groups.

40. The method of claim 39, wherein R⁴ is:

41. The method of claim 40, wherein R⁴ is:

42. The method of claim 20, wherein the compound or pharmaceutically acceptable salt, tautomer, isotopologue or hydrate is selected from: