Pyrrolopyrazines and pyrazolopyrazines useful as inhibitors of protein kinases

• US 20060258662A1
• Filed: 11/22/2005
• Published: 11/16/2006
• Est. Priority Date: 11/22/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Binch, Hayley, Miller, Andrew, Fraysse, Damien, Robinson, Daniel
• Granted Patent: US 7,795,259 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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 9/10 : 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 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of Aurora protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Claims

1. A compound of formula I:

2. The compound according to claim 1 wherein X is CH.

3. The compound according to claim 1 wherein X is N.

4. The compound according to claim 2 or claim 3, wherein R¹ is a 5-6 membered aryl or heteroaryl.

5. The compound according to claim 4, wherein R¹ is a 5-6 membered heteroaryl.

6. The compound according to claim 4, represented by Formula II:

7. The compound according to claim 6 wherein one, two, or three G groups are N.

8. The compound according to claim 6 wherein at least G² is nitrogen.

9. The compound according to claim 6 wherein any two G groups selected from G², G³, G⁴, G⁵, and G⁶ are N.

10. The compound according to claim 9 wherein only one G group is N.

11. The compound according lo claim 4, wherein R¹ is phenyl optionally substituted with up to 5 J.

12. The compound according to claim 1, wherein J is —

U—

(R⁶)_n wherein

U is a bond or C_1-6 aliphatic wherein up to two methylene units are optionally replaced by Y in a chemically stable arrangement;

13. The compound according to claim 12, wherein Y is —

O—

, —

NR⁵—

, or —

S—

.

14. The compound according to claim 12, wherein Y —

NR⁵(C═

O)—

or —

(C═

O)NR⁵—

;

15. The compound according to claim 12, wherein Y is —

NR⁵—

.

16. The compound according to claim 12, wherein one methylene unit of U is replaced by Y.

17. The compound according to claim 16, wherein U is —

Y—

(C_1-5aliphatic)-.

18. The compound according to claim 6, wherein G³ is C and J is substituted in the 3-position as shown in formula III:

19. The compound according to claim 18, wherein J is —

U—

(R⁶)_n.

20. The compound according to claim 19, wherein R⁶ is optionally substituted C_3-10cycloaliphatic or C_7-12 benzofused cycloaliphatic.

21. The compound according to claim 19, wherein R⁶ is an optionally substituted 5-6 membered aryl or heteroaryl.

22. The compound according to claim 19, wherein R⁶ is optionally substituted phenyl.

23. The compound according to claim 19, wherein R⁶ is an optionally substituted 5-6 membered heterocyclyl.

24. The compound according to claim 19, wherein U is a bond.

25. The compound according to claim 19, wherein U is C_1-3 aliphatic wherein zero methylene units are replaced.

26. The compound according to claim 19, wherein U is —

NRCH(CH₃)—

wherein the methyl group is in the S conformation.

27. The compound according to claim 19, wherein R⁶ is substituted with halogen, C_1-6aliphatic, C_1-6alkoxy, CN, —

N(R⁵)₂, —

C(O)R⁵, —

NC(O)R⁵, —

C(O)NR⁵, —

C(O)OR⁵, SOR⁵, or —

SO₂R⁵.

28. The compound according to claim 1, wherein R² and R³ are each independently V—

R.

29. The compound according to claim 1, wherein R² and R³ are each independently V—

R^a.

30. The compound according to claim 1, wherein R² and R³ are each independently V—

R^b.

31. The compound according to claim 1, wherein R² and R³ are each independently hydrogen, halogen, CN, or V—

R wherein V is —

C(O)O—

, —

NH—

, —

N(CH₃)—

, —

N(CH₂CH₃)—

, —

N(CH(CH₃)₂)—

, —

O(CH₂)₂O—

, —

C(O)NH—

, —

C(O)—

, —

O—

, —

CH₂O—

, —

NHC(O)—

, —

SO₂NH—

, or —

SO₂N(CH₃)—

.

32. The compound according to claim 31, wherein V—

R is —

C(O)OH, —

C(O)OR⁵, —

O(CH₂)₂OCH₃, —

C(O)OCH₃, —

OH, —

CH₂OH, —

NHC(O)CH₃, —

SO₂NH₂, or —

SO₂N(Me)₂.

33. The compound according to claim 1, wherein R² and R³ are each independently H, halogen, CN,

V—

R^b wherein V is a bond and R^b is N(R⁴)₂, or

V—

R^a wherein V is a bond and R^a is 5-6 membered aryl or 5-6 membered heteroaryl.

34. The compound according to claim 33, wherein R² and R³ are each independently halogen.

35. The compound according to claim 34, wherein R² and R³ are each independently chlorine.

36. The compound according to any one of claims 28-33, wherein R² and R³ are each independently substituted with up to three occurrences of R⁷.

37. The compound according to claim 1, wherein at least one of R² and R³ is H.

38. The compound according to claim 37, wherein R³ is H.

40. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

39. A compound selected from the following compounds:

41. A method of inhibiting Aurora protein kinase activity in a patient comprising administering to said patient a composition of claim 40 or a compound of claim 39.

42. A method of inhibiting Aurora protein kinase activity in a biological sample comprising or contacting said biological sample with a composition of claim 40 or a compound of claim 39.

43. A method of treating or lessening the severity of a proliferative disorder in a patient, comprising the step of administering to said patient:

a) a compound of claim 39;

or

b) a composition of claim 40.

44. The method according to claim 43, wherein the proliferative disorder is cancer.

45. A method of treating, or lessening the severity of, melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous;

system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof wherein said method comprises administering to said patient a compound according to claim 39 or a composition according to claim 40.

46. A method of treating or lessening the severity of a cancer in a patient in need thereof comprising the step of disrupting mitosis of the cancer cells by inhibiting one or more of Aurora-A, Aurora-B, and Auroras with:

a) a compound according to claim 39;

or

b) a composition according to claim 40.