HETEROARYLS AND USES THEREOF

• US 20160333007A1
• Filed: 01/13/2015
• Published: 11/17/2016
• Est. Priority Date: 01/14/2014
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: BHARATHAN, INDU T., BLACKBURN, Chris, CHOUITAR, Jouhara, CILLIS, Courtney A., D'AMORE, Natalie, FLE,OMG, Paul E., GIGSTAD, Kenneth M., GIPSON, Kirsta E., GIRARD, Mario, HU, Yongbo, LEE, Janice, LI, Gang, REZAEI, Mansoureh, SINTCHAK, Michael D., STROUD, Stephen g., VOS, Tricia J., XU, He, CIAVARRI, Jeffrey P., SOUCY, Francois, YE, Yingchun
• Granted Patent: US 10,202,373 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides a compound of formula I:

• • wherein R¹, X¹, X², R², R³, R⁴, R⁵, n, and m are as described in the specification. Such compounds are inhibitors of VPS34 and thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

Claims

1. A compound of formula I

2. The compound or a pharmaceutically acceptable salt of claim 1 with formula (I) below,

3. The compound or a pharmaceutically acceptable salt of claim 1 or claim 2, wherein R¹ is -L²-R⁶.

4. The compound or a pharmaceutically acceptable salt of claim 3, wherein L¹ is —

C(O)—

or —

C(O)O—

.

5. The compound or a pharmaceutically acceptable salt of claim 3, wherein L¹ is —

C(O)—

.

6. The compound or a pharmaceutically acceptable salt of claim 3, wherein X¹ is N and X² is CH or CR⁴.

7. The compound or a pharmaceutically acceptable salt of claim 3, wherein X¹ and X² are both CH.

8. The compound or a pharmaceutically acceptable salt of claim 3, wherein L² is —

C(O)—

or —

S(O)₂—

.

9. The compound or a pharmaceutically acceptable salt of claim 3, wherein R⁶ is C_1-4 alkyl, 3-6-membered cycloaliphatic, phenyl, naphthyl, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

10. The compound or a pharmaceutically acceptable salt of claim 9, wherein R⁶ is methyl, ethyl, or phenyl optionally substituted with 1-3 groups selected from halo or C₃ alkyl.

11. The compound or a pharmaceutically acceptable salt of claim 3, wherein R² is hydrogen.

12. The compound or a pharmaceutically acceptable salt of claim 3, wherein R³ is C_1-3 alkyl.

13. The compound or a pharmaceutically acceptable salt of claim 3, wherein L¹ is a bond and R³ is optionally substituted 5-10-membered heteroaryl.

14. The compound or a pharmaceutically acceptable salt of claim 13, wherein R³ is

15. The compound or a pharmaceutically acceptable salt of claim 14, wherein R³ is

16. The compound or a pharmaceutically acceptable salt of claim 13, wherein R³ is

17. The compound or a pharmaceutically acceptable salt of claim 3, wherein R⁴ is halo or -L⁴-R⁹ wherein L⁴ is C_1-4 alkylene chain, —

O—

, or —

N(R^e)—

where R^e is hydrogen or methyl, and R⁹ is hydrogen or C_1-3 alkyl.

18. The compound or a pharmaceutically acceptable salt of claim 3, wherein R⁴ is substituted at the ring position between the ring nitrogen and the ring carbon connected to —

N(R¹)—

.

19. The compound or a pharmaceutically acceptable salt of claim 3, wherein m is 0-2.

20. The compound or a pharmaceutically acceptable salt of claim 3, wherein R⁴ is fluoro, chloro, C_1-3 alkyl, trifluoromethyl, hydroxyl, —

NH₂ or —

NH—

C_1-3 alkyl m is 0-2; and

R⁴ is substituted at the ring position between the ring nitrogen and the ring carbon connected to —

N(R¹)—

.

21. The compound or a pharmaceutically acceptable salt of claim 3, wherein R⁵ is halo, or -L⁴-R⁹ wherein L⁴ is C₄ alkylene chain, —

O—

, —

N(R^e)—

where R^e is hydrogen or methyl, and R⁹ is hydrogen or C_1-3 alkyl.

22. The compound or a pharmaceutically acceptable salt of claim 3, wherein n is 0-2.

23. The compound or a pharmaceutically acceptable salt of claim 1 or claim 2 with formula (II) below:

24. The compound or a pharmaceutically acceptable salt of claim 23, wherein R⁶ is C_1-4 alkyl, 3-6-membered cycloaliphatic, phenyl, naphthyl, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R³ is C_1-3 alkyl or optionally substituted 5-10-membered heteroaryl; and

R⁴ is halo or -L⁴-R⁹ wherein L⁴ is C_1-4 alkylene chain, —

O—

, or —

N(R^e)—

where R^e is hydrogen or methyl, and R⁹ is hydrogen or C_1-3 alkyl.

25. The compound or a pharmaceutically acceptable salt of claim 24, wherein -L¹-R³ is —

C(O)—

O—

C_1-3 alkyl.

26. The compound or a pharmaceutically acceptable salt of claim 24, wherein -L¹-R³ is —

C(O)—

C_1-3 alkyl.

27. The compound or a pharmaceutically acceptable salt of claim 24, wherein -L¹-R³ is

28. The compound or a pharmaceutically acceptable salt of claim 27 wherein X³ is N.

29. The compound or a pharmaceutically acceptable salt of claim 24, wherein -L¹-R³ is

30. The compound or a pharmaceutically acceptable salt of any of claims 25-29, wherein R⁶ is methyl, ethyl, cyclopropyl, or phenyl optionally substituted with C_1-3 alkyl, fluoro, or chloro.

31. The compound or a pharmaceutically acceptable salt of claim 1 or claim 2, wherein the compound is selected from Table 1.

32. A composition comprising a compound of claim 1, claim 2, or claim 31, and a pharmaceutically acceptable carrier.

33. The pharmaceutical composition of claim 32, further comprising a second therapeutic agent.

34. The pharmaceutical composition of claim 33, wherein the second therapeutic agent is a tyrosine kinase inhibitor.

35. A method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, claim 2, or claim 31.

36. The method of claim 35, wherein the proliferative disorder is breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, head and neck cancer, squamous cell carcinoma, or ovarian cancer.

37. A method of treating an inflammatory or cardiovascular disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, claim 2, or claim 31.

38. The method of claim 37, wherein the inflammatory or cardiovascular disorder is selected from allergies/anaphylaxis, acute and chronic inflammation, rheumatoid arthritis, autoimmunity disorders, thrombosis, hypertension, cardiac hypertrophy, and heart failure.

39. A method of inhibiting the VPS34 activity in a cell comprising administering to the cell an effective amount of a compound of claim 1, claim 2, or claim 31.

40. A method for inhibiting VPS34 activity in a patient comprising administering a composition comprising a therapeutically effective amount of a compound of claim 1, claim 2, or claim 31.