Heterocyclic Cyclopamine Analogs and Methods of Use Thereof

• US 20100144775A1
• Filed: 12/02/2009
• Published: 06/10/2010
• Est. Priority Date: 03/07/2007
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Discovery, Inc. (Infinity Pharmaceuticals, Inc.)
• Inventors: Grogan, Michael J., Castro, Alfredo C., Tremblay, Martin
• Granted Patent: US 7,994,191 B2
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 491/14 Ortho-condensed systems
• CPC Class Codes: C07D 513/14 Ortho-condensed systems

Abstract

The present invention relates to steroidal alkaloids that can be used in the treatment of hedgehog pathway related disorders, particularly cancer.

Claims

1-26. -26. (canceled)

27. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1a or 1b:

or a tautomer or pharmaceutically acceptable salt thereof,

wherein;

R¹ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —

SR²⁰, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W))—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰;

each of R², R⁶ and R⁹ is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, nitrile, alkoxyl, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, alkylseleno, aralkylseleno, arylseleno, alkylthio, aralkylthio, or arylthio;

R³ is H;

or R² and R³ taken together form a bond;

each of R⁴ and R⁵ independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, aralkyl, alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl, or heteroaralkyl;

or R⁴ and R⁵ taken together form ═

O, ═

S, ═

N(R²⁰), ═

N—

OR²⁰, or ═

N(N(R²⁰)₂);

each of R⁷ and R⁸ independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl;

or R⁶ and R⁷ taken together form a bond;

or R⁸ and R⁹ taken together form a bond;

each of R¹⁰ and R¹¹ independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl;

or R⁹ and R¹⁰ taken together form a bond;

or R¹⁰ and R¹¹ taken together form a bond;

R²⁰ independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —

[C(R)₂]_q—

R²¹;

or any two occurrences of R²⁰ can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;

R²¹ independently for each occurrence is H, cycloalkyl, aryl, heteroaryl, heterocyclyl;

alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, acylamino, amido, or carbonyl-containing group;

R²² independently for each occurrence is H, halide, ester, amide, or nitrile;

R²³ independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, ═

O, —

SR²⁰, —

OR²⁰, —

N(R<sup>20), —

C(O)R20</sup>, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰), —

N(R²⁰)C(O)R²⁰, —

N(R²⁰)C(O)N(R²⁰)(R²⁰), —

S(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

N(R²⁰)S(O)₂R²⁰, or —

[C(R)₂]_q—

R²¹;

R²⁴ independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, —

SR²⁰, —

OR²⁰, —

N(R²⁰)(R²⁰), —

C(O)R²⁰, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰)(R²⁰), —

N(R²⁰)C(O)R²⁰, —

N(R²⁰)C(O)N(R²⁰)(R²⁰), —

S(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

N(R²⁰)S(O)₂R²⁰, or —

[C(R²⁰)₂]_q—

R²¹;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5, or 6;

R independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

-T¹-T²-T³- is Y-B-A, B-Y-A, or A-B-Y;

each of A and B independently is N, S or C(R²³);

W is a diradical;

X is a bond or —

C(R22)₂—

;

Y is —

O—

, —

S—

, or —

N(R²⁴)—

;

and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.

28. The method according to claim 27, wherein R¹ is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, —

[(W)—

S]_pR²⁰.

29. The method according to claim 28, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

30. The method according to claim 27, wherein R² and R³ taken together form a bond.

31. The method according to claim 27, wherein R⁴ and R⁵ are each H;

or R⁴ and R⁵ taken together form ═

O or ═

S.

32. The method according to claim 31, wherein R⁴ and R⁵ are each H.

33. The method according to claim 27, wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently H or alkyl.

34. The method according to claim 27, wherein R⁶, R⁸, R⁹, R¹⁰, and R¹¹ are each H.

35. The method according to claim 27, wherein X is a bond or —

CH₂—

.

36. The method according to claim 35, wherein X is —

CH₂—

.

37. The method according to claim 27, wherein Y is —

O—

or —

N(R²⁴)—

.

38. The method according to claim 37, wherein Y is —

N(R²⁴)—

.

39. The method according to claim 27, wherein -T¹-T²-T³- is A-B-Y, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B-Y-A, A is N, B is CR²³ and Y is NR²⁴.

40. The method according to claim 27, wherein -T¹-T²-T³- is B-Y-A, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B-Y-A, A is N, B is CR²³ and Y is O;

or -T¹-T²-T³- is Y-B-A, A is N, B is CR²³ and Y is S.

41. The method according to claim 27, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

42. The method according to claim 27, wherein the compound of Formula 1a is a compound of the Formula 6a:

or a tautomer or pharmaceutically acceptable salt thereof,

wherein;

R¹ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —

SR²⁰, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S/(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰;

each of R⁴ and R⁵ independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, aralkyl, alkoxyl, aryloxy, acyloxy, halide, sulthydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl, or heteroaralkyl;

or R⁴ and R⁵ taken together form ═

O, ═

S, ═

N(R²⁰), ═

N—

OR²⁰, or ═

N(N(R²⁰)₂);

R²⁰ independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —

[C(R)₂]_q—

R²¹;

or any two occurrences of R²⁰ can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;

R²¹ independently for each occurrence is H, cycloalkyl, aryl, heteroaryl, heterocyclyl;

alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, acylamino, amido, or carbonyl-containing group;

R²² independently for each occurrence is H, halide, ester, amide, or nitrile;

R²³ independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, ═

O, —

SR²⁰, —

OR²⁰, —

N(R²⁰)(R²⁰), —

C(O)R²⁰, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰)(R²⁰), —

N(R²⁰)C(O)R²⁰, —

N(R²⁰)C(O)N(R²⁰)(R²⁰), —

S(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R<sup>20 ), —

N(R20</sup>)S(O)₂R²⁰, or —

[C(R)₂]_q—

R²¹;

R²⁴ independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, —

SR²⁰, —

OR²⁰, —

N(R²⁰)(R²⁰), —

C(O)R²⁰, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰)(R²⁰), —

N(R²⁰)C(O)R²⁰, —

N(R²⁰)C(O)N(R²⁰)(R²⁰), —

S(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

N(R²⁰)S(O)₂R²⁰, or —

[C(R²⁰)₂]_q—

R²¹;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5, or 6;

R independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

-T¹-T²-T³- is Y-B-A, B-Y-A, or A-B-Y;

each of A and B independently is N, S or C(R²³);

W is a diradical;

X is a bond or —

C(R²²)₂—

;

Y is —

O—

, —

S—

, or —

N(R²⁴)—

;

and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.

43. The method according to claim 42, wherein R¹ is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰.

44. The method according to claim 43, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

45. The method according to claim 42, wherein R⁴ and R⁵ are each H.

46. The method according to claim 42, wherein X is a bond or —

CH₂—

.

47. The method according to claim 46, wherein X is —

CH₂—

.

48. The method according to claim 42, wherein Y is —

O—

or —

N(R²⁴)—

.

49. The method according to claim 48, wherein Y is —

N(R²⁴)—

.

50. The method according to claim 42, wherein -T¹-T²-T³- is A-B-Y, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B-Y-A, A is N, B is CR²³ and Y is NR²⁴.

51. The method according to claim 42, wherein -T¹-T²-T³- is B-Y-A, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B-Y-A, A is N, B is CR²³ and Y is 0;

or -T¹-T²-T³- is Y-B-A, A is N, B is CR²³ and Y is S.

52. The method according to claim 42, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

53. The method according to claim 27, wherein the compound of Formula lb is a compound of the Formula 11b:

or a tautomer or pharmaceutically acceptable salt thereof,

wherein;

R¹ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —

SR²⁰, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰;

each of R⁴ and R⁵ independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, aralkyl, alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl, or heteroaralkyl;

or R⁴ and R⁵ taken together form —

O, ═

S, ═

N(R²⁰), ═

N—

OR²⁰, or ═

N(N(R²⁰)₂);

R²⁰ independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —

[C(R)₂]—

R²¹;

or any two occurrences of R²⁰ can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;

R²¹ independently for each occurrence is H, cycloalkyl, aryl, heteroaryl, heterocyclyl;

alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, acylamino, amido, or carbonyl-containing group;

R²² independently for each occurrence is H, halide, ester, amide, or nitrile;

R²³ independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, ═

O, —

SR²⁰, —

OR²⁰, —

N(R²⁰)(R²⁰), —

C(O)R²⁰, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰)(R²⁰), —

N(R²⁰)C(O)R²⁰, —

N(R²⁰)C(O)N(R²⁰)(R²⁰), —

S(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

N(R²⁰)S(O)₂R²⁰, or —

[C(R)₂]_q—

R²¹;

R²⁴ independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, —

SR²⁰, —

OR²⁰, —

N(R²⁰)(R²⁰), —

C(O)R²⁰, —

CO₂R²⁰, —

OC(O)R²⁰, —

C(O)N(R²⁰)(R²⁰), —

N(R²⁰)C(O)R²⁰, —

N(R²⁰)C(O)N(R²⁰)(R²⁰), —

S(O)R²⁰, —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

N(R²⁰)S(O)₂R²⁰, or —

[C(R²⁰)₂]_q—

R²¹;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5, or 6;

R independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

-T^I-T²--T³- is Y-B-A, B-Y-A, or A-B-Y;

each of A and B independently is N, S or C(R²³);

W is a diradical;

X is a bond or —

C(R²²)₂—

;

Y is —

O—

, —

S—

, or —

N(R²⁴)—

;

and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.

54. The method according to claim 53, wherein R¹ is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, '"'"'[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰.

55. The method according to claim 54, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

56. The method according to claim 53, wherein R⁴ and R⁵ are each H.

57. The method according to claim 53, wherein X is a bond or —

CH₂—

.

58. The method according to claim 57, wherein X is —

CH₂—

.

59. The method according to claim 53, wherein Y is —

O—

or '"'"'N(R²⁴)—

.

60. The method according to claim 59, wherein Y is —

N(R²⁴)—

.

61. The method according to claim 53, wherein -T¹-T²-T³- is A-B-Y, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B-Y-A, A is N, B is CR²³ and Y is NR²⁴.

62. The method according to claim 53, wherein -T¹-T²-T³- is B-Y-A, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B-Y-A, A is N, B is CR²³ and Y is O;

or -T¹-T²-T³- is Y-B-A, A is N, B is CR²³ and Y is S.

63. The method according to claim 53, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

64. The method according to any one of claim 27, 42 or 53, wherein the cancer is selected from lung cancer, medulloblastoma, brain cancer, pancreatic cancer, basal cell carcinoma, breast cancer, prostate cancer, gastrointestinal stromal tumor, colon cancer, colorectal cancer, ovarian cancer, multiple myeloma, acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome, polycythemia Vera, Waldenstrom'"'"'s macroglobulinemia, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, melanoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, stadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, uterine cancer, testicular cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, endometrial cancer, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, esophageal cancer, head and neck cancer, small cell cancers, essential thrombocythemia, agnogenic myeloid metaplasia, hypereosinophilic syndrome, systemic mastocytosis, familiar hypereosinophilia, chronic eosinophilic leukemia, thyroid cancer, neuroendocrine cancers, and carcinoid tumors.

65. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

or a tautomer or a pharmaceutically acceptable salt thereof.

66. The method according to claim 65, wherein the cancer is selected from lung cancer, medulloblastoma, brain cancer, pancreatic cancer, basal cell carcinoma, breast cancer, prostate cancer, gastrointestinal stromal tumor, colon cancer, colorectal cancer, ovarian cancer, multiple myeloma, acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic

leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome, polycythemia Vera, Waldenstrom'"'"'s macroglobulinemia, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, melanoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland

carcinoma, papillary carcinoma, papillary adenocarcinomas, stadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, uterine cancer, testicular cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, endometrial cancer, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, esophageal cancer, head and neck cancer, small cell cancers, essential thrombocythemia, agnogenic myeloid metaplasia, hypereosinophilic syndrome, systemic mastocytosis, familiar hypereosinophilia, chronic eosinophilic leukemia, thyroid cancer, neuroendocrine cancers, and carcinoid tumors.