Compositions useful as inhibitors of protein kinases

• US 20050148603A1
• Filed: 10/14/2004
• Published: 07/07/2005
• Est. Priority Date: 10/14/2003
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Moon, Young-Choon, Jimenez, Juan-Miguel, Gao, Huai, Green, Jeremy, Knegtel, Ronald, Pierard, Francoise, Brenchley, Guy
• Granted Patent: US 7,700,609 B2
• Time in Patent Office: Days
• US Class Current: 514/260.100
• 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:

a. when n is 0, Cy¹ is an optionally substituted phenyl, benzotriazolyl, benzothiazolyl, indolyl, or pyridyl group, and X is a C_1-2alkylene group 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 pyridyl, or thienyl group, when the pyridyl or thienyl group 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;

b. when n is 0, Cy¹ is an optionally substituted C₆-C₁₂ mono- or bicyclic aromatic group, and X is a C_1-2alkylene group 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 phenyl group, when the phenyl group 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;

c. when n is 0;

Cy¹ is an aryl or heteroaryl group substituted with at least one optionally substituted cycloaliphatic or heterocycloaliphatic group, wherein the cycloaliphatic or heterocycloaliphatic groups are attached directly to Cy¹ or are attached to Cy¹ through an alkylidene chain; and

X is an optionally substituted C_1-2alkylene group;

then R¹ and R², taken together with the carbon atoms to which they are bound do not form an optionally substituted phenyl group.

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 or 6-membered aryl or heteroaryl ring selected from one of the following groups:

5. 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- or 6-membered aryl or heteroaryl ring selected from phenyl (i), pyridyl (ii-1, ii-2, ii-3, ii-4), pyrazolyl (xiii-1, xiii-2, xiii-3, and xiii-4), oxadiazolyl (xiv), thiophenyl (iv-1, iv-2, and xviii), or thiazolyl (viii-1 and viii-2).

6. 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.

7. 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.

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

WR^y groups are each independently CF₃, 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), —

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.

9. The compound of claim 1 or claim 2, wherein y 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′

.

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

CH₂N(R′

)₂, —

N(R′

)₂, or —

CON(R′

)₂.

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

CH₂—

, —

CH₂CH₂, —

CO—

, or —

SO₂—

.

12. 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—

.

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

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

CO—

.

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

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 selected from:

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

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, aryl, aralkyl, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NRCOR′

, —

CON(R′

)₂, —

SO₂R′

, NR′

SO₂R′

, or —

SO₂N(R′

)₂.

20. 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.

21. 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.

22. The compound of claim 1 or claim 2, wherein X is an optionally substituted methylene group and compounds have the general formula II:

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

24. The compound of claim 22 wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5 or 6-membered aryl or heteroaryl ring selected from phenyl (i), pyridyl (ii-1, ii-2, ii-3, ii-4), pyrazolyl (xiii-2), oxadiazolyl (xiv), thiophenyl (iv-1, iv-2, and xviii), or thiazolyl (viii-1 and viii-2), and compounds have one of the structures II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, or II-M:

25. The compound of claim 24, wherein Cy¹ is phenyl, optionally substituted with 0-3 occurrences of QR^X.

26. The compound of claim 24, 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.

27. The compound of claim 24, wherein 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.

28. The compound of claim 24, wherein y 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.

29. The compound of claim 24, wherein y is 1 and WR^y is an optionally substituted aryl or heteroaryl group.

30. The compound of claim 24, wherein y is 1 and WR^y is a substituted phenyl, pyridyl, pyrimidinyl, thiophenyl, or furanyl group, optionally substituted with one of 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′

.

31. The compound of claim 24, wherein one occurrence of WR^y is an optionally substituted aryl or heteroaryl group, denoted by Ar¹ in formula II-H-i below:

32. The compound of claim 31, wherein Ar¹ is a substituted phenyl, pyridyl, pyrimidinyl, thiophenyl, or furanyl group, optionally substituted by 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′

.

33. The compound of one of claims 22-24, wherein n is 0, or n is 1 and T is CH₂, —

CH₂CH₂—

, —

CO—

, or —

SO₂.

34. The compound of one of claims 22-24, wherein n is 0, or n is 1 and T is —

C(H)(CH₃)—

C(H)(CH₃)CH₂—

, —

CH₂C(H)(CH₃) —

, or —

CH₂CH₂CH₂—

.

35. The compound of one of claims 22-24, 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.

36. The compound of one of claims 22-24, wherein n is 0, or n is 1 and T is —

C(H)(CH₃)—

C(H)(CH₃)CH₂—

, —

CH₂C(H)(CH₃) —

, or —

CH₂CH₂CH₂—

;

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.

37. The compound of claim 1 or claim 2, wherein X is an optionally substituted C₂-alkylidene chain wherein zero, one or two methylene units are optionally replaced by S, O, or —

SO₂N(R′

)—

, and the compounds have one of the structures III, IV, V, VI, VII, VIII, or IX;

38. The compound of claim 35 or 36, wherein Cy¹ is selected from any one of a through mm depicted above (including certain subsets b-i, c-i, b-ii, b-iii, c-ii, c-iii, g-i, II, o-i or mm).

39. The compound of claim 37 wherein Cy¹ is optionally substituted phenyl, and compounds have one of formulae III-A through IX-A:

40. The compound of claim 37, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5 or 6-membered aryl or heteroaryl ring selected from phenyl (i), pyridyl (ii-1, ii-2, ii-3, ii-4), pyrazolyl (xiii-2), oxadiazolyl (xiv) and thiophenyl (iv-1, iv-2, and xviii), or thiazolyl (viii-1 and viii-2).

41. The compound of claim 37, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5 or 6-membered aryl or heteroaryl ring selected from phenyl (i), pyridyl (ii-1, ii-2, ii-3, ii-4), pyrazolyl (xiii-2), oxadiazolyl (xiv), thiophenyl (iv-1, iv-2, and xviii), or thiazolyl (viii-1 and viii-2), and compounds have one of the formulas III-B, III-C, III-D, III-E, III-F, III-G, III-H, III-I, III-J, III-K, III-L, or III-M:

42. The compound of claim 37, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5 or 6-membered aryl or heteroaryl ring selected from phenyl (i), pyridyl (ii-1, ii-2, ii-3, ii-4), pyrazolyl (xiii-2), oxadiazolyl (xiv), thiophenyl (iv-1, iv-2, and xviii), or thiazolyl (viii-1 and viii-2), and compounds have one of the formulas IV-B, IV-C, IV-D, IV-E, IV-F, IV-G, IV-H, IV-I, IV-J, IV-K, IV-L, or IV-M:

43. The compound of claim 37, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5 or 6-membered aryl or heteroaryl ring selected from phenyl (i), pyridyl (ii-1, ii-2, ii-3, ii-4), pyrazolyl (xiii-2), oxadiazolyl (xiv), thiophenyl (iv-1, iv-2, and xviii), or thiazolyl (viii-1 and viii-2), and compounds have one of the formulas V-B, V-C, V-D, V-E, V-F, V-G, V-H, V-I, V-J, V-K, V-L, or V-M:

44. The compound of claim 37, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5 or 6-membered aryl or heteroaryl ring selected from phenyl (i), pyridyl (ii-1, ii-2, ii-3, ii-4), pyrazolyl (xiii-2), oxadiazolyl (xiv), thiophenyl (iv-1, iv-2, and xviii), or thiazolyl (viii-1 and viii-2), and compounds have one of the formulas IX-B, IX-C, IX-D, IX-E, IX-F, IX-G, IX-H, IX-I, IX-J, IX-K, IX-L, or IX-M:

45. The compound of one of claims 37-44, wherein Cy¹ is phenyl, optionally substituted with 0-3 occurrences of QR^X.

46. The compound of one of claims 37-45, 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.

47. The compound of one of claims 37-46, wherein y 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.

48. The compound of one of claims 37-46, 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.

49. The compound of one of claims 37-46, wherein —

WR^y groups are each independently CF₃, 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), —

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.

50. The compound of claim 47, wherein one occurrence of WR^y is an optionally substituted aryl or heteroaryl group, denoted by Ar¹ in one of formulae III-H-i, III-L-i, III-M-i, IV-H-i, IV-L-i, IV-M-i, V-H-i, V-L-i, V-M-i, IX-H-i, IX-L-i, or IX-M-i below:

51. The compound of claim 50, wherein y 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′

.

52. The compound of claim 47, wherein one occurrence of WR^y is —

CH₂N(R′

)₂, and compounds have one of formulae III-H-ii, III-L-ii, III-M-ii, IV-H-ii, IV-L-ii, IV-M-ii, V-H-ii, V-L-ii, V-M-ii, IX-H-ii, IX-L-ii, or IX-M-ii below;

53. The compound of claim 47, wherein one occurrence of WR^y is —

N(R′

)₂, and compounds have one of formulae III-H-iii, III-L-iii, III-M-iii, IV-H-iii, IV-L-iii, IV-M-iii, V-H-iii, V-L-iii, V-M-iii, IX-H-iii, IX-L-iii, or IX-M-iii below;

54. The compound of claim 47, wherein one occurrence of WR^y is —

CON(R′

)₂ and compounds have one of the formulae III-H-iv, III-L-iv, III-M-iv, IV-H-iv, IV-L-iv, IV-M-iv, V-H-iv, V-L-iv, V-M-iv, IX-H-iv, IX-L-iv, or IX-M-iv below;

55. The compound of claim 52, 53, or 54, 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).

56. The compound of claim 52, 53, or 54, 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).

57. The compound of one of claims 37-45, wherein n is 0, or n is 1 and T is CH₂, —

CH₂CH₂—

, —

CO—

or —

SO₂.

58. The compound of any one of claims 37-45, wherein wherein n is 0, or n is 1 and —

C(H)(CH₃)—

, —

C(H)(CH₃)CH₂—

, —

CH₂C(H)(CH₃)—

, or —

CH₂CH₂CH₂—

.

59. The compound of one of claims 37-45, 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.

60. The compound of claim 1 or claim 2, wherein X is an optionally substituted C₃ alkylidene moiety and compounds have the general formula VII:

61. The compound of claim 60, wherein Cy¹ is selected from any one of a through mm depicted above (including certain subsets b-i, c-i, b-ii, b-iii, c-ii, c-iii, g-i, II, o-i or mm).

62. The compound of claim 60, wherein Cy¹ is optionally substituted phenyl, and compounds have formula VII-A:

63. The compound of claim 60, wherein R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5 or 6-membered aryl or heteroaryl ring selected from phenyl (i), pyridyl (ii-1, ii-2, ii-3, ii-4), pyrazolyl (xiii-2), oxadiazolyl (xiv), thiophenyl (iv-1, iv-2, and xviii), or thiazolyl (viii-1 and viii-2), and compounds have one of the formulae X-B, X-C, X-D, X-E, X-F, X-G, X-H, X-I, X-J, X-K, X-L, or X-M:

64. The compound of claim 63, wherein Cy¹ is phenyl, optionally substituted with 0-3 occurrences of QR^X.

65. The compound of claim 63, 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.

66. The compound of claim 63, wherein y 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.

67. The compound of claim 63, wherein y is 1 and WR^y is an aryl or heteroaryl 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′

.

68. The compound of claim 63, wherein y is 1 and WR^y 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′

.

69. The compound of claim 63, wherein y is 1, W is —

CH₂—

, a bond, or —

CO— and

R^y is —

N(R′

)₂ and compounds have one of the formulae X-H-ii and X-L-ii below;

70. The compound of claim 63, wherein one occurrence of WR^y is an optionally substituted aryl or heteroaryl group, denoted by Ar¹ in formula X-H-i and X-L-i below:

71. The compound of claim 70, wherein 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′

.

72. The compound of claim 63, wherein n is 0, or n is 1 and T is CH₂, —

CH₂CH₂—

, —

CO—

or —

SO₂.

73. The compound of claim 63, 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.

74. The compound of any one of claims 1, 23-17, 31, 32, 34, 39-41, or 49, wherein X is —

CH═

CH—

.

76. The compound of claim 74 wherein R¹ and R², taken together with the carbon atoms to which they are bound, form an optionally substituted thiazolyl ring.

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

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

2. A compound of formula I:

75. The compound of 74 wherein R¹ and R², taken together with the carbon atoms to which they are bound, form an optionally substituted thieno ring.

79. A composition comprising a compound of formula I:

80. The composition of claim 79, wherein the compound is present in a therapeutically effective amount.

81. The composition of claim 79, 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 (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase activity.

82. The composition of claim 79, 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.

87. A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient a composition according to claim 79.

88. The method of claim 87, comprising the further step of administering to said patient 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, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

89. A method of inhibiting the phosphorylation of Tau protein in a patient, said method comprising a step of administering to said patient an effective amount of a composition according to claim 79.

90. The method of claim 88, wherein the disease is selected from cancer, Alzheimer'"'"'s disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

91. The method of claim 90, wherein the cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin'"'"'s, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, and leukemia.

92. The method of claim 91, wherein the cancer is selected from colon, breast, stomach, and ovarian cancer.

93. The method of claim 88, wherein the disease is selected from hematopoietic disorders.

94. The method of claim 88, wherein the disease is selected from acute-myelogenous leukemia (AML), acute-promyelocytic leukemia (APL), and acute lymphocytic leukemia (ALL).

95. The method of claim 88 wherein the disease is selected from autoimmune diseases, inflammatory diseases, metabolic, neurological and neurodegenerative diseases, cardiovascular diseases, allergy, asthma, diabetes, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig'"'"'s disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, and baldness.

96. The method of claim 88, wherein the disease is selected from immune responses such as allergic or type I hypersensitivity reactions, asthma, autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative disorders such as Familial amyotrophic lateral sclerosis (FALS), and solid and hematologic malignancies such as leukemias and lymphomass.

97. The method of claim 96, wherein the disease is selected from autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, and leukemia.

98. The method of claim 88, wherein the disease is selected from stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer'"'"'s disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders, and hormone-related diseases.

99. The method of claim 88, wherein the disease is selected from hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget'"'"'s disease.

100. The method of claim 88, wherein the disease is selected from allergic disorders.

101. The method of claim 100, wherein the allergic disorder is asthma.

102. The method of claim 88, wherein the disease is selected from diseases of the respiratory tract, inflammation of the nasal mucus membrane, bone and joint diseases, skin diseases and disorders, diseases and disorders of the gastrointestinal tract, other tissues and systemic diseases.

83. A method of inhibiting GSK-3, SYK, Aurora-2, CDK-2, JAK-3, LCK, SRC, and/or Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity in:

(a) a patient;

or

(b) a biological sample;

which method comprises administering to said patient, or contacting said biological sample with a compound of formula I;

or a pharmaceutically acceptable salt thereof, wherein;

X is an optionally substituted C₁-C₃ alkylidene chain wherein one or two non-adjacent methylene units are independently optionally replaced by CO, CONR′

, NR′

CO, SO, SO₂, NR′

SO₂, SO₂NR′

, O, S, or NR′

;

R¹ and R², taken together with the carbon atoms to which they are bound form an optionally substituted 5- or 6-membered aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

wherein the ring formed by R¹ and R² taken together, and the C₁-C₃ alkylidene chain of X, are each optionally and independently substituted at one or more carbon atoms with y occurrences of —

WR^y, wherein y is 0-5; and

wherein one or more substitutable nitrogen atoms of the ring formed by R¹ and R² taken together are optionally substituted with —

R³;

each occurrence of W is independently a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of W 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^y is independently selected from R′

, halogen, NO₂, or CN, or —

WR^y is ═

O, ═

S, or ═

NR′

;

T is CHR′

, CH₂CH(R′

), —

S(═

O)₂, or C(═

O);

n is 0 or 1;

Cy¹ is 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, wherein Cy¹ is optionally substituted at one or more carbon atoms with x independent occurrences of -QR^X;

wherein x is 0-5; and

at one or more substitutable nitrogen atoms with —

R⁴;

wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q 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^X is independently selected from R′

, halogen, NO₂, or CN, or QR^X is ═

O, ═

S, or ═

NR′

;

each occurrence of R³ and R⁴ is independently R′

, —

COR′

, —

CO₂(C_1-6 aliphatic), —

CON(R′

)₂, or —

SO₂R′

;

each occurrence of R is independently selected from hydrogen or an optionally substituted C_1-6 aliphatic group; and

each occurrence of R′

is independently selected from hydrogen or an optionally substituted group selected from C_1-8 aliphatic, C_6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R and R′

taken together with the atom(s) to which they are bound, or two occurrences of R′

taken together with the atom(s) to which they are bound, form an optionally substituted 3-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

the dashed bond represents a single or double bond, as valency permits;

and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

84. The method of claim 83, wherein the method comprises inhibiting Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity.

85. The method of claim 83, wherein the method comprises inhibiting Itk activity.

86. The method of claim 83, wherein the method comprises inhibiting Btk activity.