Compositions useful as inhibitors of protein kinases

• US 8,017,619 B2
• Filed: 02/26/2010
• Issued: 09/13/2011
• Est. Priority Date: 10/14/2003
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Gao, Huai, Moon, Young-Choon, Jimenez, Juan-Miguel, Green, Jeremy, Knegtel, Ronald, Pierard, Francoise, Brenchley, Guy
• Primary Examiner(s): Jarrell; Noble
• Assistant Examiner(s): LEESER, ERICH A
• Application Number:
  US12/713,811
• Publication Number:
  US 20100280026A1
• Time in Patent Office: 564 Days
• Field of Search: 514/267, 544/250
• US Class Current: 514/267
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 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 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• 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 37/02 : Immunomodulators
• 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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: C07D 239/70 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 239/84 : Nitrogen atoms
• CPC Class Codes: C07D 333/22 : Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/54 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 333/70 : attached in position 2
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/14 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

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

Claims

1. A compound of formula I:

3. The compound of claim 1 or claim 2, wherein:

when n is 0, Cy¹ is an optionally substituted phenyl, benzotriazolyl, benzothiazolyl, indolyl, or pyridyl group, and X is —

(CH₂)₂—

, optionally substituted with one or more halogen atoms or C_1-3alkyl groups, then R¹ and R², taken together with the carbon atoms to which they are bound do not form a thienyl group that is unsubstituted or is substituted with a substituent other than a 3-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

4. The compound of claim 1 or claim 2, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5-membered heteroaryl ring selected from iv-1, iv-2, and xviii:

5. The compound of claim 1 or claim 2, wherein each occurrence of WR^y, when present, is independently halogen, CN, NO₂, —

N(R′

)₂, —

-CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NRCOR′

, —

CON(R′

)₂, or —

S(O)₂N(R′

)₂, or an optionally substituted group selected from C_1-4alkyl, aryl, heteroaryl.

6. The compound of claim 1 or claim 2, wherein —

WR^y groups are each independently F, Cl, Br, I, Me, Et, —

CN, —

OMe, —

SMe, —

NMe₂, —

NEt₂, —

COOMe, —

COOH, —

OH, —

SO₂NH₂, —

CON(CH₃)₂, —

CO(optionally substituted N-piperazinyl), —

CO(N-morpholinyl), —

CO(N-piperidinyl), —

CH₂N(Me)₂, —

CH₂N(Et)₂, or an optionally substituted group selected from C_1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thiophene, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.

7. The compound of claim 1 or claim 2, wherein —

WR^y groups are each independently CF₃, F, Cl, Br, I, Me, Et, —

CN, —

OMe, —

SMc, —

NMe₂, —

NEt₂, —

COOMe, —

COOH, —

OH, —

SO₂NH₂, —

CON(CH₃)₂, —

CO(optionally substituted N-piperazinyl, —

CO(N-morpholinyl), —

CO(N-piperidinyl), —

CO(pyrrolidinyl), —

CO(N(H)pyrrolidinyl), —

CH₂N(Me)₂, —

CH₂N(Et)₂, or an optionally substituted group selected from C_1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thiophene, N-morpholinyl, N-piperidinyl, N-piperazinyl, furanyl, pyrrolidinyl, or N(H)pyrrolidinyl.

8. The compound of claim 1 or claim 2, wherein m is 1 and WR^y is an optionally substituted aryl or heteroaryl group, wherein substituents for the optionally substituted aryl or heteroaryl group are independently selected from —

VR^v;

wherein V is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of V are independently optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; and

each occurrence of R^v is independently selected from R′

, halogen, NO₂, or CN, or -QR^x is ═

O, ═

S, or ═

NR′

.

9. The compound of claim 1 or claim 2, wherein m is 1 and WR^y is —

CH₂N(R′

)₂, —

N(R′

)₂, or —

CON(R′

)₂.

10. The compound of claim 1 or claim 2, wherein T groups, when present are —

CH₂—

, —

CH₂CH₂, —

CO—

, or —

SO₂—

.

11. The compound of claim 1 or claim 2, wherein T groups, when present are —

C(H)(CH₃)—

, —

C(H)(CH₃)CH₂—

, —

CH₂C(H)(CH₃)—

, or —

CH₂CH₂CH₂—

.

12. The compound of claim 1 or claim 2, wherein n is 0 and T is absent.

13. The compound of claim 1 or claim 2, wherein T is absent (n=0) or T is —

CO—

.

14. The compound of claim 1 or claim 2, wherein Cy¹ is selected from one of the following groups:

15. The compound of claim 1 or claim 2, wherein Cy¹ is selected from:

16. The compound of claim 1 or claim 2, wherein Cy¹ is selected from:

17. The compound of claim 1 or claim 2, wherein Cy¹ is phenyl (a), and compounds have the formula I-A:

18. The compound of claim 1 or claim 2, wherein QR^X groups, when present, are each independently halogen, CN, NO₂, or an optionally substituted group selected from C_1-4alkyl, aryl, aralkyl, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NRCOR′

, —

CON(R′

)₂, —

SO₂R′

, NR′

SO₂R′

, or —

SO₂N(R′

)₂.

19. The compound of claim 1 or claim 2, wherein QR^X groups, when present, are each independently halogen, CN, NO₂, or an optionally substituted group selected from C_1-4alkyl, —

CF₃, aryl, heteroaryl, aralkyl, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NRCOR′

, —

CON(R′

)₂, —

SO₂R′

, NR′

SO₂R′

, SO₂N═

R′

, or —

SO₂N(R′

)₂.

20. The compound of claim 1 or claim 2, wherein QR^X groups are each independently Cl, Br, F, CF₃, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, NO₂, —

OH, —

SO₂NH₂, SO₂CH₃, NH₂, SO₂NHCH₃, NHSO₂CH₃, or an optionally substituted group selected from C_1-4alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.

21. The compound of claim 1 or claim 2, wherein X is —

(CH₂)₂—

, and the compounds have the structure of III;

22. The compound of claim 21 wherein Cy¹ is optionally substituted phenyl, and compounds have the formula III-A:

23. The compound of claim 21, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5-membered heteroaryl ring selected from thiophenyl.

24. The compound of claim 21, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5-membered heteroaryl ring selected from thiophenyl and compounds have one of the formulae III-G, III-H, or III-I:

25. The compound of claim 21, wherein Cy¹ is phenyl, optionally substituted with 0-3 occurrences of QR^X.

26. The compound of claim 21, wherein n is 0, or n is 1 and T is CH₂, —

CH₂CH₂—

, —

CO—

or —

SO₂—

;

k is 0-3; and

each occurrence of QR^X is independently halogen, CN, NO₂, or an optionally substituted group selected from C_1-4alkyl, aryl, aralkyl, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NRCOR′

, —

CON(R′

)₂, —

SO₂R′

, NR′

SO₂R′

, or —

SO₂N(R′

)₂.

27. The compound of claim 21, wherein m is 0-3;

and each occurrence of WR^y is independently halogen, CN, NO₂, or an optionally substituted group selected from C_1-4alkyl, aryl, heteroaryl, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NRCOR′

, —

CON(R′

)₂, or —

S(O)₂N(R′

)₂.

28. The compound of claim 27, wherein —

WR^y groups are each independently F, Cl, Br, I, Me, Et, —

CN, —

OMe, —

SMe, —

NMe₂, —

NEt₂, —

COOMe, —

COOH, —

OH, —

SO₂NH₂, —

CON(CH₃)₂, —

CO(optionally substituted N-piperazinyl), —

CO(N-morpholinyl), —

CO(N-piperidinyl), —

CH₂N(Me)², —

CH₂N(Et)₂, or an optionally substituted group selected from C_1-4alkoxy, phenyl, phcnyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thiophene, N-morpholinyl, N-piperidinyl, N-piperazinyl, or furanyl.

29. The compound claim 27, wherein —

WR^y groups arc each independently CF₃, F, Cl, Br, I, Me, Et, —

CN, —

OMc, —

SMe, —

NMe₂, —

NEt₂, —

COOMe, —

COOH, —

OH, —

SO₂NH₂, —

CON(CH₃)₂, —

CO(optionally substituted N-piperazinyl), —

CO(N-morpholinyl), —

CO(N-piperidinyl), —

CO(pyrrolidinyl), —

CO(N(H)pyrrolidinyl), —

CH₂N(Me)₂, —

CH₂N(Et)₂, or an optionally substituted group selected from C_1-4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, pyridyl, pyrimidinyl, thiophene, N-morpholinyl, N-piperidinyl, N-piperazinyl, furanyl, pyrrolidinyl, or N(H)pyrrolidinyl.

30. The compound of claim 27, wherein one occurrence of WR^y is an optionally substituted aryl or heteroaryl group, denoted by Ar¹ in formula III-H-i below, wherein m is 1-3:

31. The compound of claim 30, wherein m is 1 and Ar¹ is a phenyl, pyridyl, pyrimidinyl, thiophenyl, or furanyl group optionally substituted with one or more occurrences of —

VR^v;

wherein V is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of V are independently optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; and

each occurrence of R^v is independently selected from R′

, halogen, NO₂, or CN, or -QR^x is ═

O, ═

S, or ═

NR′

.

32. The compound of claim 27, wherein one occurrence of WR^y is —

CH₂N(R′

)₂, and compounds have the formulae III-H-ii below, wherein m is 1-3;

33. The compound of claim 27, wherein one occurrence of WR^y is —

N(R′

)₂, and compounds have the formulae III-H-iii below, wherein m is 1-3;

34. The compound of claim 27, wherein one occurrence of WR^y is —

CON(R′

)₂ and compounds have the formulae III-H-iv below, wherein m is 1-3;

35. The compound of claim 32, 33, or 34, wherein —

CH₂N(R′

)₂ is —

CH₂N(CH₂)₃, —

CH₂N(CH₂CH₃)₂, —

CH₂(optionally substituted N-piperazinyl), —

CH₂(optionally substituted N-piperidinyl), or —

CH₂(optionally substituted N-morpholinyl);

—

N(R′

)₂ is —

N(CH₂)₃, —

N(CH₂CH₃)₂, -optionally substituted N-piperazinyl, optionally substituted N-piperidinyl, or -optionally substituted N-morpholinyl; and

—

CON(R′

)₂ is —

CON(CH₂)₃, —

CON(CH₂CH₃)₂, —

CO(optionally substituted N-piperazinyl), —

CO(optionally substituted N-piperidinyl), or —

CO(optionally substituted N-morpholinyl).

36. The compound of claim 32, 33, or 34, wherein —

CH₂N(R′

)₂ is —

CH₂N(CH₂)₃, —

CH₂N(CH₂CH₃)₂, —

CH₂(optionally substituted N-piperazinyl), —

CH₂(optionally substituted N-piperidinyl), or —

CH₂(optionally substituted N-morpholinyl);

—

N(R′

)₂ is —

N(CH₂)₃, —

N(CH₂CH₃)₂, -optionally substituted N-piperazinyl, optionally substituted N-piperidinyl, or -optionally substituted N-morpholinyl; and

—

CON(R′

)₂ is —

CON(CH₂)₃, —

CON(CH₂CH₃)₂, —

CO(optionally substituted N-piperazinyl), —

CO(optionally substituted N-piperidinyl), —

CO(optionally substituted N-morpholinyl), —

CO(optionally substituted pyrrolidinyl), —

CO(N(H)optionally substituted pyrrolidinyl), optionally substituted pyrrolidinyl, or —

N(H)(optionally substituted pyrrolidinyl).

37. The compound of claim 21, wherein n is 0, or n is 1 and T is CH₂, —

CH₂CH₂—

, —

CO—

or —

SO₂.

38. The compound of claim 21, wherein wherein n is 0, or n is 1 and —

C(H)(CH₃)—

, —

C(H)(CH₃)CH₂—

, —

CH₂C(H)(CH₃)—

, or —

CH₂CH₂CH₂—

.

39. The compound of claim 21, wherein n is 0, or n is 1 and T is CH₂, —

CH₂CH₂—

, —

CO—

or —

SO₂—

;

x is 0-3; and

each occurrence of QR^X is independently halogen, CN, NO₂, or an optionally substituted group selected from C_1-4alkyl, aryl, aralkyl, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NRCOR′

, —

CON(R′

)₂, —

SO₂R′

, NR′

SO₂R′

, or —

SO₂N(R′

)₂.

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

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

2. A compound of formula I:

42. A composition comprising a compound of formula I:

43. The composition of claim 42, wherein the compound is present in a therapeutically effective amount.

44. The composition of claim 42, wherein the compound is present in an amount to detectably inhibit GSK-3, SYK, Aurora-2, CDK-2, JAK-3, LCK, SRC, and/or Tec family protein kinase activity.

45. The composition of claim 42, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.