Heteroaryls and uses thereof

• US 9,802,960 B2
• Filed: 01/13/2015
• Issued: 10/31/2017
• 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, Ciavarri, Jeffrey P., Chouitar, Jouhara, Cullis, Courtney A., D'Amore, Natalie, Fleming, Paul E., Gigstad, Kenneth M., Gipson, Krista E., Girard, Mario, Hu, Yongbo, Lee, Janice, Li, Gang, Rezaei, Mansoureh, Sintchak, Michael D., Soucy, Francois, Stroud, Stephen G., Vos, Tricia J., Wong, Tzu-Tshin, Xu, He, Xu, Tianlin, Ye, Yingchun
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US14/596,052
• Publication Number:
  US 20150225422A1
• Time in Patent Office: 1,022 Days
• 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 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/549 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The present invention provides a compound of formula I:

and pharmaceutically acceptable salts thereof, wherein X, R¹, R², R³, R⁴, R⁵, L¹, L², m, and n, 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 of claim 1, having a structure according to formula I,

3. The compound or a pharmaceutically acceptable salt of claim 1, wherein L¹ is —

N(R⁸)C(O)—

, —

N(R¹⁰)S(O)₂—

, —

C(O)—

, or —

S(O)₂—

.

4. The compound or a pharmaceutically acceptable salt of claim 3, wherein each of R⁸ and R¹⁰, independently, is hydrogen, methyl or ethyl.

5. The compound or a pharmaceutically acceptable salt of claim 1, wherein R¹ is C_1-4 aliphatic, 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.

7. The compound or a pharmaceutically acceptable salt of claim 1, wherein X is a bond, methylene, or ethylene.

8. The compound or a pharmaceutically acceptable salt of claim 1, wherein R² is hydrogen.

9. The compound or a pharmaceutically acceptable salt of claim 1, wherein L² is a bond, —

C(O)—

or —

C(O)—

O—

.

10. The compound or a pharmaceutically acceptable salt of claim 1, wherein R³ is methyl, cyclopropyl, or 6-membered heteroaryl that is optionally substituted with 1-2 R⁶.

11. The compound or a pharmaceutically acceptable salt of claim 1, wherein:

R⁴ is fluoro, chloro, unsubstituted C_1-3 aliphatic, trifluoromethyl, hydroxyl, methoxy, —

NH₂ or —

NH—

C_1-3 aliphatic;

m is 0-2;

wherein one R⁴, if present, is located at the ring carbon between the ring nitrogen and the ring carbon to which —

X-L¹-R¹ is substituted.

12. The compound or a pharmaceutically acceptable salt of claim 1,

wherein:

X is a bond;

L¹ is —

N(R⁸)C(O)—

, —

N(R¹⁰)S(O)₂—

, —

C(O)—

, or —

S(O)₂—

;

R² is hydrogen, methyl, ethyl, or cyclopropylmethyl;

L² is a bond, —

C(O)—

or —

C(O)—

O—

;

R³ is C_1-3 alkyl, cyclopropyl, or 6-membered heteroaryl, each of which being optionally substituted with 1-2 R⁶;

R⁴ is fluoro, chloro, C_1-3 alkyl, trifluoromethyl, hydroxyl, methoxy, —

NH₂ or —

NH—

C_1-3 aliphatic;

m is 0-2;

wherein one R⁴, if present, is located at the ring carbon between the ring nitrogen and the ring carbon to which —

X-L¹-R¹ is substituted;

n is 0 or 1; and

R¹ is

13. The compound of claim 1 with formula (II) below:

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

L¹ is —

N(R⁸)C(O)—

or —

N(R¹⁰)S(O)₂—

;

each of R⁸ and R¹⁰, independently, is hydrogen, methyl, or ethyl;

R¹ is C_1-4 aliphatic, phenyl, naphthyl, 3-6-membered cycloaliphatic, 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 cyclopropyl, each of which being optionally substituted with 1-2 R⁶;

each R⁶ is C_1-4 alkyl or halo; and

R⁴ is halo or -L⁴-R¹⁷ wherein;

L⁴ is C_1-4 alkylene, —

O—

, or —

N(R^z)—

;

R^z is hydrogen or methyl; and

R¹⁷ is hydrogen or C_1-3 aliphatic.

15. The compound or a pharmaceutically acceptable salt of claim 14, wherein R⁴ is methyl, ethyl, fluoro, chloro, —

NH₂, methoxy, or ethoxy.

16. The compound or a pharmaceutically acceptable salt of claim 14, wherein (m-1) is 0.

17. The compound of claim 1 with formula (VIII) below:

19. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, further comprising a second therapeutic agent.

21. The pharmaceutical composition of claim 20, wherein the second therapeutic agent is a tyrosine kinase inhibitor.

22. The compound or a pharmaceutically acceptable salt of claim 17, wherein:

L¹ is —

N(R¹¹)S(O)₂—

; and

R¹⁰ optionally joins with R⁴ to form an optionally substituted 5-membered heterocyclyl or an optionally substituted 5-membered heteroaryl.

23. The compound or a pharmaceutically acceptable salt of claim 22, wherein:

R⁴ is halo or -L⁴-R¹⁷;

wherein

L⁴ is C_1-4 alkylene, —

O—

, or —

N(R^z)—

;

R^z is hydrogen or methyl,

R¹⁷ is hydrogen or C_1-3 aliphatic; and

R⁶ is cyano, fluoro, chloro, C_1-6 alkyl, 3-6-membered cycloalkyl, or phenyl.

24. The compound or a pharmaceutically acceptable salt of claim 23, wherein R⁴ is methyl, ethyl, fluoro, chloro, —

NH₂, methoxy, or ethoxy.

25. The compound or a pharmaceutically acceptable salt of claim 24, wherein (m-1) is 0.

26. The compound or a pharmaceutically acceptable salt of claim 24, wherein:

the compound is represented by formula VIII-B

27. The compound of claim 1, wherein the compound is selected from:

28. The compound of claim 27, wherein the compound is:

29. The compound of claim 27, wherein the compound is:

6. A compound of formula I:

18. A compound or a pharmaceutically acceptable salt thereof selected from