Pyrrole substituted 2-indolinone protein kinase inhibitors

• US 20020156292A1
• Filed: 02/15/2001
• Published: 10/24/2002
• Est. Priority Date: 02/15/2000
• Status: Active Grant

• Current Assignee: Pharmacia & Upjohn Company LLC (Pfizer Inc.), Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Pharmacia & Upjohn Company (Pfizer Inc.), Sugen Incorporated (Pharmacia Corp.)
• Inventors: Liang, Congxin, Li, Xiaoyuan, Tang, Peng Cho, Sun, Li, Vojkovsky, Tomas, Miller, Todd A., Hawley, Michael, Wei, Chung Chen, Nematalla, Asaad S., Shirazian, Shahrzad
• Granted Patent: US 6,573,293 B2
• Time in Patent Office: Days
• US Class Current: 548/487
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: C07D 207/33 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.

Claims

1. A compound of Formula (I):

2. The compound or salt of claim 1 wherein:

R¹is selected from the group consisting of hydrogen, halo, alkyl, cyclkoalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, —

C(O)R¹⁵, —

NR¹³R¹⁴, —

(CH₂)_rR¹⁶ and —

C(O)NR⁸R⁹;

R² is selected from the group consisting of hydrogen, halo, alkyl, trihalomethyl, hydroxy, alkoxy, —

NR¹³R¹⁴, —

NR¹³C(O)R¹⁴, —

C(O)R¹⁵, aryl, heteroaryl, and —

S(O)₂NR¹³R¹⁴;

R³ is selected from the group consisting of hydrogen, halogen, alkyl, trihalomethyl, hydroxy, alkoxy, —

(CO)R¹⁵, —

NR¹³R¹⁴, aryl, heteroaryl, —

NR¹³S(O)₂R¹⁴, —

S(O)₂NR¹³R¹⁴, —

NR¹³C(O)R¹⁴,and —

NR¹³C(O)OR¹⁴;

R⁴ is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and —

NR¹³R¹⁴;

R⁵ is selected from the group consisting of hydrogen, alkyl and —

C(O)R¹⁰;

R⁶ is selected from the group consisting of hydrogen, alkyl and —

C(O)R¹⁰;

R⁷ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, —

C(O)R¹⁷ and —

C(O)R¹⁰;

R⁶ and R⁷ may combine to form a group selected from the group consisting of —

(CH₂)₄—

, —

(CH₂)₅— and

—

(CH₂)₆—

;

with the proviso that at least one of R⁵, R⁶ or R⁷ must be —

C(O)R¹⁰;

R⁸ and R⁹ are independently selected from the group consisting of hydrogen, alkyl and aryl;

R¹⁰ is selected from the group consisting of hydroxy, alkoxy, aryloxy, —

N(R¹¹)(CH₂)_nR¹² and —

NR¹³R¹⁴;

R¹¹ is selected from the group consisting of hydrogen and alkyl;

R¹² is selected from the group consisting of —

NR¹³R¹⁴, hydroxy, —

C(O)R¹⁵, aryl and heteroaryl;

R¹³ and R¹⁴ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl;

R¹³ and R¹⁴ may combine to form a group selected from the group consisting of —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₂O(CH₂)₂—

, and —

(CH₂)₂N(CH₃)(CH₂)₂—

;

R¹⁵ is selected from the group consisting of hydrogen, hydroxy, alkoxy and aryloxy;

R¹⁶ is selected from the group consisting of hydroxy, —

C(O)R¹⁵, —

NR¹³R¹⁴ and —

C(O)NR¹³R¹⁴;

R¹⁷ is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl; and

n and r are independently 1, 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

3. The compound or salt of claim 1 wherein R⁵ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein;

R¹¹ is hydrogen or lower unsubstituted alkyl;

n is 2 or 3; and

R¹² is —

NR¹³R¹⁴ wherein R¹³ and R¹⁴ are independently unsubstituted lower alkyl.

4. The compound or salt of claim 1 wherein R⁵ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein;

R¹¹ is hydrogen or lower unsubstituted alkyl;

n is 2 or 3; and

R¹² is —

NR¹³R¹⁴ wherein R¹³ and R¹⁴ combine to form a group selected from —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₂—

O—

(CH₂)₂—

or —

(CH₂)₂N(CH₃) (CH₂)₂—

.

5. The compound of claim 1 wherein R⁵ is N-(2-dimethylamino-ethyl)aminocarbonyl, N-(2-diethylaminoethyl)-N-methyl-aminocarbonyl, N-(3-dimethylaminopropyl)aminocarbonyl, N-(2-diethylaminoethyl)aminocarbonyl, N-(3-ethylaminopropyl)-aminocarbonyl, N-(2-ethylaminoethyl)aminocarbonyl, or N-(3-diethylaminopropyl)aminocarbonyl.

6. The compound of claim 1 wherein R⁵ is N-(2-diethyl-aminoethyl)aminocarbonyl or N-(2-ethylaminoethyl)amino-carbonyl.

7. The compound of claim 1 wherein R⁵ is 3-pyrrolidin-1-ylpropylaminocarbonyl, 3-morpholin-4-ylpropylamino-carbonyl, 2-pyrrolidin-1-ylethylaminocarbonyl, 2-morpholin-4-yl-ethylaminocarbonyl, 2-(4-methylpiperazin-1-yl)ethyl-aminocarbonyl, 2-(3,5-dimethylpiperazin-1-yl)ethyl-aminocarbonyl, 3-(4-methylpiperazin-1-yl)propylamino-carbonyl or 3-(3,5-dimethylpiperazin-1-yl)propylamino-carbonyl.

8. The compound or salt of claim 1 wherein R⁶ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein;

R¹¹ is hydrogen or lower unsubstituted alkyl;

n is 2 or 3; and

R¹² is —

NR¹³R¹⁴ wherein R¹³ and R¹⁴ are independently unsubstituted lower alkyl.

9. The compound or salt of claim 1 wherein R⁶ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein;

R¹¹ is hydrogen or lower unsubstituted alkyl;

n is 2 or 3; and

R¹² is —

NR¹³R¹⁴ wherein R¹³ and R¹⁴ combine to form a group selected from —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₂—

O—

(CH₂)₂—

or —

(CH₂)₂N(CH₃)(CH₂)₂—

.

10. The compound or salt of claim 1 wherein R⁶ is N-(2-dimethylamino-ethyl)aminocarbonyl, N-(2-diethyl-aminoethyl)-N-methylaminocarbonyl, N-(3-dimethylamino-propyl)-aminocarbonyl, N-(2-diethylaminoethyl)-aminocarbonyl, N-(2-ethylaminoethyl)-aminocarbonyl, N-(3-ethylaminopropyl)-aminocarbonyl, or N-(3-diethylamino-propyl)aminocarbonyl.

11. The compound or salt of claim 1 wherein R⁶ is N-(2-diethylaminoethyl)aminocarbonyl or N-(2-ethylamino-ethyl)aminocarbonyl.

12. The compound or salt of claim 1 wherein R⁶ is 3-pyrrolidin-1-ylpropylaminocarbonyl, 3-morpholin-4-ylpropylamino-carbonyl, 2-pyrrolidin-1-ylethylamino-carbonyl, 2-morpholin-4-ylethylaminocarbonyl, 2-(4-methylpiperazin-1-yl)ethyl-aminocarbonyl, 2-(3,5-dimethylpiperazin-1-yl)ethyl-aminocarbonyl, 3-(4-methylpiperazin-1-yl)propylamino-carbonyl or 3-(3,5-dimethylpiperazin-1-yl)propylamino-carbonyl.

13. The compound or salt of claim 1 wherein R⁵ is —

COR¹⁰ wherein R¹⁰ is —

NR¹³R¹⁴wherein R¹³ is hydrogen and R¹⁴ is lower alkyl substituted with hydroxy, aryl, heteroalicyclic, heteroaryl, or carboxy.

14. The compound or salt of claim 1 wherein R⁵ is 3-triazin-1-ylpropylaminocarbonyl, 2-triazin-1-ylethylaminocarbonyl, 3-imidazol-1-ylpropylaminocarbony, pyridin-4-ylmethyl-aminocarbonyl, 2-pyridin-2-ylethylaminocarbonyl or 2-imidazol-1-yl ethylaminocarbonyl.

15. The compound or salt of claim 1 wherein R⁶ is —

COR¹⁰ wherein R¹⁰ is —

NR¹³R¹⁴wherein R¹³ is hydrogen and R¹⁴ is lower alkyl substituted with hydroxy, aryl, heteroalicyclic, heteroaryl, or carboxy.

16. The compound or salt of claim 1 wherein R⁶ is 2-triazin-1-ylpropylaminocarbonyl, 2-triazin-1-ylethylaminocarbonyl, 3-imidazol-1-ylpropylaminocarbony, pyridin-4-ylmethyl-aminocarbonyl, 2-pyridin-2-ylethylaminocarbonyl or 2-imidazol-1-yl ethylaminocarbonyl.

17. The compound or salt of claim 1 wherein R⁵ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein;

R¹¹ is hydrogen or lower unsubstituted alkyl;

n is 2 or 3; and

R¹² is —

NR¹³R¹⁴ wherein R¹³ and R¹⁴ together combine to form a heterocycle.

18. The compound or salt of claim 1 wherein R⁵ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein;

R¹¹ is hydrogen or lower unsubstituted alkyl;

n is 2 or 3; and

R¹² is —

NR¹³R¹⁴ wherein R¹³ and R¹⁴ together combine to form a 5, 6 or 7 atom heterocycle containing a carbonyl group and one or two nitrogen atoms within the ring.

19. The compound or salt of claim 1 wherein R⁵is 2-(3-oxopiperazin-1-yl)ethylaminocarbonyl, 2-(imidazolidin-1-yl-2-one)ethylaminocarbonyl, 2-(tetrahydropyrimidin-1-yl-2-one)ethylaminocarbonyl, 2-(2-oxopyrrolidin-1-yl)-ethylaminocarbonyl, 3-(3-oxopiperazin-1-yl)propylaminocarbonyl, 3-(imidazolidin-1-yl-2-one)propylaminocarbonyl, 3-(tetrahydropyrimidin-1-yl-2-one)-propylaminocarbonyl, or 3-(2-oxopyrrolidin-1-yl)propylaminocarbonyl.

20. The compound or salt of claim 1 wherein R⁶ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹ (CH₂)_nR¹² wherein;

R¹¹ is hydrogen or lower unsubstituted alkyl;

n is 2 or 3; and

R¹² is —

NR¹³R¹⁴ wherein R¹³ and R¹⁴ together combine to form a heterocycle.

21. The compound or salt of claim 1 wherein R⁶ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein;

R¹¹ is hydrogen or lower unsubstituted alkyl;

n is 2 or 3; and

R¹² is —

NR¹³R¹⁴ wherein R¹³ and R¹⁴ together combine to form a 5, 6 or 7 atom heterocycle containing a carbonyl group and one or two nitrogen atoms within the ring.

22. The compound or salt of claim 1 wherein R⁶is 2-(3-oxopiperazin-1-yl)ethylaminocarbonyl, 2-(imidazolidin-1-yl-2-one)ethylaminocarbonyl, 2-(tetrahydropyrimidin-1-yl-2-one)ethylaminocarbonyl, 2-(2-oxopyrrolidin-1-yl)-ethylaminocarbonyl, 3-(3-oxopiperazin-1-yl)propylaminocarbonyl, 3-(imidazolidin-1-yl-2-one)propyl-S(O)₂NR¹³R¹⁴ wherein R¹³ is hydrogen and R¹⁴ is hydrogen, aryl or alkyl;

R³ is selected from the group consisting of hydrogen, lower alkoxy, —

C(O)R¹⁵, —

NR¹³C(O)R¹⁴, aryl optionally substituted with one or two substitutents selected from the group consisting of lower alkyl, halo, or lower alkoxy, and heteroaryl; and

R⁴ is hydrogen.

28. The compound or salt of claim 23 wherein:

R¹ is hydrogen or phenyl;

R² is hydrogen, chloro, bromo, fluoro, methoxy, ethoxy, phenyl, cyano, dimethylaminosulfonyl, 3-chlorophenyl-aminosulfonyl, carboxy, methoxy, aminosulfonyl, methylaminosulfonyl, methylsulfonyl ethylsulfonyl, benzylsulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfonyl, dimethylaminosulfonyl, or isopropylamino-sulfonyl;

R³ is hydrogen, methoxy, carboxy, phenyl, pyridin-3-yl, 3,4-dichlorophenyl, 2-methoxy-5-isopropylphenyl, 4-n-butylphenyl, or 3-isopropylphenyl; and

R⁴ is hydrogen.

29. The compound or salt of claim 23 wherein:

R¹ is hydrogen;

R² is hydrogen, cyano, fluoro, chloro, or bromo;

R³ is hydrogen; and

R⁴ is hydrogen.

30. The compound or salt of claim 25 wherein:

R¹ is hydrogen, unsubstituted lower alkyl, —

C(O)NR⁸R⁹, unsubstituted cycloalkyl or aryl;

R² is hydrogen, halo, lower alkoxy, cyano, aryl, —

SO₂R20, or —

S(O)₂NR¹³R¹⁴ wherein R¹³ is hydrogen and R¹⁴ is hydrogen, aryl or alkyl;

R³ is selected from the group consisting of hydrogen, lower alkoxy, —

C(O)R¹⁵, —

NR¹³C(O)R¹⁴, aryl and heteroaryl;

and

R⁴ is hydrogen.

31. The compound or salt of claim 25 wherein:

R¹ is hydrogen or phenyl;

R² is hydrogen, chloro, bromo, fluoro, methoxy, ethoxy, phenyl, dimethylaminosulfonyl, cyano, methylsulfonyl, ethylsulfonyl, benzylsulfonyl, 3-chlorophenyl-aminosulfonyl, carboxy, methoxy, aminosulfonyl, methylaminosulfonyl, phenylaminosulfonyl, pyridin-3-yl-aminosulfonyl, dimethylaminosulfonyl, or isopropylamino-sulfonyl;

R³ is hydrogen, methoxy, carboxy, phenyl, pyridin-3-yl, 3,4-dichlorophenyl, 2-methoxy-5-isopropylphenyl, 4-n-butylphenyl, 3-isopropylphenyl; and

R⁴ is hydrogen.

32. The compound or salt of claim 25 wherein:

R¹ is hydrogen;

R² is hydrogen, cyano, fluoro, chloro, or bromo;

R³ is phenyl; and

R⁴ is hydrogen.

33. The compound or salt of claim 1 wherein:

R¹ is hydrogen, unsubstituted lower alkyl, —

C(O)NR⁸R⁹, unsubstituted cycloalkyl or aryl;

R² is hydrogen, halo, lower alkoxy, cyano, aryl or —

S(O)₂NR¹³R¹⁴ wherein R¹³ is hydrogen and R¹⁴ is hydrogen, aryl or alkyl;

R³ is selected from the group consisting of hydrogen, lower alkoxy, —

C(O)R¹⁵, —

NR¹³C(O)R¹⁴, aryl, and heteroaryl; and

R⁴ is hydrogen.

34. The compound or salt of claim 1 wherein:

R¹ is hydrogen, or methyl;

R² is hydrogen, cyano, chloro, fluoro, or bromo;

R³ is selected from the group consisting of hydrogen or phenyl; and

R⁴ is hydrogen.

35. The compound or salt of claim 33 or 34 wherein:

R⁵ is —

COR¹⁰;

R⁶ is selected from the group consisting of hydrogen and unsubstituted lower alkyl; and

R⁷ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and —

C(O)R¹⁷ wherein R¹⁷ is hydroxy, unsubstituted lower alkyl or aryl.

36. The compound or salt of claim 33 or 34 wherein:

R⁶ is —

COR¹⁰;

R⁵ is selected from the group consisting of hydrogen and unsubstituted lower alkyl; and

R⁷ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and —

C(O)R¹⁷ wherein R¹⁷ is hydroxy, unsubstituted lower alkyl or aryl.

37. The compound or salt of claim 1 wherein R⁵ is —

COR¹⁰ wherein R¹⁰ is —

NR¹³R¹⁴ wherein R¹³ is hydrogen and R¹⁴ is lower alkyl substituted with hydroxy, lower alkyl substituted with hydroxyalkylamino, carboxy, or —

NR¹⁸R¹⁹ wherein R¹⁸ and R¹⁹ are independently hydrogen or lower unsubstituted alkyl.

38. The compound or salt of claim 1 wherein R⁵ is 2-[(diethylamino)-2-hydroxyethyl]aminocarbonyl, 2-(N-ethyl-N-2-hydroxyethylamino)ethylaminocarbonyl, carboxymethylamino-carbonyl, or 2-hydroxyethylaminocarbonyl.

39. The compound or salt of claim 1 wherein R⁶ is —

COR¹⁰ wherein R¹⁰ is —

NR¹³R¹⁴ wherein R¹³ is hydrogen and R¹⁴ is lower alkyl substituted with hydroxy, lower alkyl substituted with hydroxyalkylamino, carboxy, or —

NR¹⁸R¹⁹ wherein R¹⁸ and R¹⁹ are independently hydrogen or lower unsubstituted alkyl.

40. The compound or salt of claim 1 wherein R⁶ is [2-(diethylamino)-2-hydroxy]ethylaminocarbonyl, 2-(N-ethyl-N-2-hydroxyethylamino)ethylaminocarbonyl, carboxymethylaminocarbonyl, or 2-hydroxyethylaminocarbonyl.

41. The compound of claim 1 wherein R⁵ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein R¹² is —

N⁺(O⁻

)NR¹³R¹⁴ or —

N(OH)R¹³ wherein R¹³ and R¹⁴ are independently selected from the group consisting of unsubstituted lower alkyl.

42. The compound of claim 1 wherein R⁵ is 2-(N-hydroxy-N-ethylamino)ethylaminocarbonyl or 2-[N⁺(O⁻

) (C₂H₅)₂]ethylaminocarbonyl

43. The compound of claim 1 wherein R⁶ is —

COR¹⁰ wherein R¹⁰ is —

NR¹¹(CH₂)_nR¹² wherein R¹² is —

N⁺(O⁻

)NR¹³R¹⁴ or —

N(OH)R¹³ wherein R¹³ and R¹⁴ are independently selected from the group consisting of unsubstituted lower alkyl.

44. The compound of claim 1 wherein R⁶ is 2-(N-hydroxy-N-ethylamino)ethylaminocarbonyl or 2-[N⁺(O⁻

) (C₂H₅)₂]ethylaminocarbonyl.

45. The compound or salt of claim 37, 38, 41 or 42 wherein:

R⁶ is selected from the group consisting of hydrogen, or methyl; and

R⁷ is selected from the group consisting of methyl, hydrogen or phenyl.

46. The compound or salt of any of the claims 39, 40, 43, 44 or 20-22 wherein:

R⁵ is selected from the group consisting of hydrogen, or methyl; and

R⁷ is selected from the group consisting of methyl, hydrogen or phenyl.

47. The compound or salt of claim 45 wherein:

R¹ is hydrogen;

R² is hydrogen, cyano, chloro, fluoro, or bromo;

R³ is hydrogen; and

R⁴ is hydrogen.

48. The compound or salt of claim 46 wherein:

R¹ is hydrogen;

R² is cyano, chloro, fluoro, or bromo;

R³ is hydrogen; and

R⁴ is hydrogen.

49. The compound or salt of claim 1, wherein the compound is selected from the group consisting of:

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

51. A pharmaceutical composition, comprising a compound or salt of claim 49 and, a pharmaceutically acceptable carrier or excipient.

52. A method for the modulation of the catalytic activity of a protein kinase comprising contacting said protein kinase with a compound or salt of claim 1 or 49.

53. The method of claim 52 wherein said protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase and a serine-threonine kinase.

54. A method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound or salt of claim 50 or claim 51 and, a pharmaceutically acceptable carrier or excipient to said organism.

55. The method of claim 54 wherein said protein kinase related disorder is selected from the group consisting of a receptor tyrosine kinase related disorder, a non-receptor tyrosine kinase related disorder and a serine-threonine kinase related disorder.

56. The method of claim 54 wherein said protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder and a flk related disorder.

57. The method of claim 54 wherein said protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi'"'"'s sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.

58. The method of claim 54 wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, von Heppel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder.

59. The method of claim 54 wherein said organism is a human.

60. An intermediate of Formula (II):