SUBSTITUTED HETEROCYCLES AS JANUS KINASE INHIBITORS

• US 20080188500A1
• Filed: 12/20/2007
• Published: 08/07/2008
• Est. Priority Date: 12/22/2006
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Rodgers, James D., Storace, Louis, Arvanitis, Argyrios G., Folmer, Beverly
• Granted Patent: US 8,513,270 B2
• Time in Patent Office: Days
• US Class Current: 514/267
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• 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 37/06 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 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07D 471/14 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/14 : Ortho-condensed systems

Abstract

The present invention provides substituted tricyclic heteroaryl compounds, including, for example, pyridoindoles, pyrimidinoindoles and triazinoindoles that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases such as immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

Claims

1. A compound of Formula I:

2. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y¹ is N and Y² is CR⁴.

3. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y² is N and Y¹ is CR³.

4. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y² is N.

5. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y² is CR⁴.

6. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y³ is N.

7. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y³ is CR⁵.

8. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z¹ is N.

9. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z¹ is CR⁶.

10. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z² is N.

11. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z² is CR⁷.

12. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is H, C_1-6 alkyl, or C(O)C_1-6 alkyl.

13. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R¹ is H

14. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R² is H

15. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^a is arylene or heteroarylene, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

wherein said C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

16. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^a is arylene optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

wherein said C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^a1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

17. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^a is arylene optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^b1, SR^b1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b, NR^c1S(O)₂R^b1, S(O)R^b1 S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

18. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^a is arylene optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, CN, NO₂, OR^a1, SR^a1, and NR^c1R^d1.

19. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^a is arylene optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyland OR^a1.

20. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^a is a substituted aryl or substituted heteroaryl ring according to Formula IA:

21. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^a is a substituted aryl or substituted heteroaryl ring according to Formula IB:

22. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein R is selected from H, halo, CN, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, and OR^a1;

wherein said C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

23. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein R is selected from halosulfanyl, NO₂, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═

NRⁱ)NR^c1R^d1, NR^c1C(═

NRⁱ)NR^c1R^d1, NR^c1R^d, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1.

24. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein R is selected from H, halo, CN, C_1-6 alkyl and OR^a1.

25. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein Q¹ is CR^Q.

26. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein Q² is CR^Q.

27. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein Q³ is CR^Q.

28. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein Q³ is N.

29. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein R^Q is H.

30. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^b is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR², OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NRⁱ)NR^c2R^d2, NR^c2C(═

NRⁱ)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, S(O)_b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

wherein said C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NRⁱ)NR^c2R^d2, NR^c2C(═

NRⁱ)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

31. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^b is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NRⁱ)NR^c2R^d2, NR^c2C(═

NRⁱ)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂, S(O)_b2 S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

32. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^b is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a2, and NR^c2R^d2.

33. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^b is aryl, optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NRⁱ)NR^c2R^d2, NR^c2C(═

NRⁱ)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)R^b2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

wherein said C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NRⁱ)NR^c2R^d2, NR^c2C(═

NRⁱ)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

34. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy^b is heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NRⁱ)NR^c2R^d2, NR^c2C(═

NRⁱ)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, S(O)R_b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

wherein said C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Cy, C_1-6 haloalkyl, halosulfanyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═

NRⁱ)NR^c2R^d2, NR^c2C(═

NRⁱ)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2.

35. A compound of claim 1, wherein Cy^b is a substituted aryl or substituted heteroaryl ring according to Formula IF:

36. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein W¹ is CR^W.

37. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein W¹ is N.

38. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein W² is CR^W.

39. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein W² is N.

40. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein A¹ is CR^W.

41. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein A¹ is N.

42. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein A² is CR^W.

43. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein A² is N.

44. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from C_1-6 alkylene, (C_1-6 alkylene)_p-O—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-S—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-NR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-C(O)—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-OC(O)—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-C(O)NR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-OC(O)NR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-SO—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-SO₂—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-SONR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-SO₂NR^c3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-NR^c3CONR^d3—

(C_1-6 alkylene)_q, (C_1-6 alkylene)_p-NR^c3SONR^d3—

(C_1-6 alkylene)_q, and (C_1-6 alkylene)_p-NR^c3SO₂NR^d3—

(C_1-6 alkylene)_q, wherein the C_1-6 alkylene is optionally substituted by 1, 2 or 3 substituents independently selected from C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 hydroxyalkyl, C_1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, CN, NO₂, SCN, OH, C_1-4 haloalkyl, halosulfanyl, C_1-4 alkoxy-C_1-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and C_2-8 dialkylamino.

45. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from (C_1-6 alkylene)_p-C(O)NR^c3—

(C_1-6 alkylene)_q and (C_1-6 alkylene)_p-NR^c3CONR^d3—

(C_1-6 alkylene)_q, wherein the C_1-6 alkylene is optionally substituted by 1, 2 or 3 substituents independently selected from C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 hydroxyalkyl, C_1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, CN, NO₂, SCN, OH, C_1-4 haloalkyl, halosulfanyl, C_1-4 alkoxy-C_1-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and C_2-8 dialkylamino.

46. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from (C_1-6 alkylene)_p-C(O)NR^c3—

(C_1-6 alkylene)_q and (C_1-6 alkylene)_p-NR^c3CONR^d3—

(C_1-6 alkylene)_q.

47. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from C(O)NH, C(O)NH—

(C_1-6 alkylene) and NHCONH.

48. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is C(O)NH.

49. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is C(O)NH—

(C_1-6 alkylene).

50. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is NHCONH.

51. A compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula II:

52. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula III:

53. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula IIIK:

54. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula IVA or IVB:

55. The compound of claim 1, selected from:

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

3-(4-Methyl-1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(tri-fluoromethyl)benzamide;

3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide;

3-(4-formyl-1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-[4-(hydroxymethyl)-1H-imidazol-1-yl]-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-phenyl]-5-(trifluoromethyl)benzamide;

3-4-[(methylamino)methyl]-1H-imidazol-1-yl-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-(4-methylpiperazin-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)benzamide;

4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)-benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-N′

-[3-(trifluoromethyl)phenyl]urea;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-N′

-[3-(trifluoromethyl)phenyl]urea;

4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-cyano-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)-benzamide;

4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)-benzamide;

2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide;

3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-2,5-bis(trifluoromethyl)benzamide;

3-chloro-2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3,5-bis(trifluoromethyl)benzamide;

4-methoxy-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)-benzamide;

3-methoxy-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-2-(trifluoromethyl)benzamide;

N-[4-fluoro-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

N-[3-(9H-pyrimido[4,5-b]-indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

3-chloro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(pentafluoro-λ

(6)-sulfanyl)-benzamide;

N-[4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide;

3-(1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoro-methyl)benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(1H-1,2,4-triazol-1-yl)-5-(trifluoro-methyl)benzamide;

3-{4-[(dimethylamino)methyl]-1H-imidazol-1-yl}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-morpholin-4-yl-5-(trifluoromethyl)-benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-piperazin-1-yl-5-(trifluoromethyl)-benzamide;

3-(4-hydroxypiperidin-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-(3-hydroxypiperidin-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-[(2-morpholin-4-ylethyl)amino]-5-(trifluoromethyl)benzamide;

3-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-{[3-(dimethylamino)propyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-(3-hydroxypyrrolidin-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

3-{[3-(1H-imidazol-1-yl)-propyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-phenyl]-5-(trifluoromethyl)benzamide;

3-(dimethylamino)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoro-methyl)benzamide;

3-[3-(dimethylamino)-pyrrolidin-1-yl]-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-phenyl]-5-(trifluoromethyl)benzamide;

3-{[2-(dimethylamino)ethyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide;

4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)-benzamide;

3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-5-(trifluoromethyl)-benzamide;

3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]benzamide;

N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-2,5-bis(trifluoromethyl)benzamide;

3-chloro-2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-5-(trifluoromethyl)-benzamide;

4-methyl-3-(9H-pyrimido-[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-methyl-N-(3-methyl-phenyl)-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethoxy)phenyl]benzamide;

N-(2,5-difluorobenzyl)-4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)benzyl]benzamide;

4-methyl-N-(5-methyl-1,3-thiazol-2-yl)-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-methoxy-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-benzamide;

4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-N-[(1R)-1-phenylethyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-N-[(1S)-1-phenylethyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide;

4-methyl-N-[3-(pentafluoro-λ

(6)-sulfanyl)phenyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)-benzamide;

4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[5-(trifluoromethyl)pyridin-3-yl]benzamide;

N-[3-(2-amino-9H-pyrimido[4,5-b]indol-7-yl)-4-methylphenyl]-3-(trifluoromethyl)-benzamide;

4-methyl-3-(9H-pyrido[2,3-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide;

4-methyl-3-(9H-pyrido[3′

,2′

;

4,5]pyrrolo[2,3-d]pyrimidin-7-yl)-N-[3-(trifluoromethyl)phenyl]-benzamide;

N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-3-(trifluoromethyl)benzamide;

3-fluoro-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

3-(1H-imidazol-1-yl)-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-3-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)benzamide;

3-(4-formyl-1H-imidazol-1-yl)-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

3-[4-(hydroxymethyl)-1H-imidazol-1-yl]-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

3-[2-(dimethylamino)ethyl]amino-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide;

3-[3-(dimethylamino)propyl]amino-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide; and

pharmaceutically acceptable salts thereof.

56. A composition comprising a compound according to claim 1, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

57. The composition of claim 56 which is suitable for topical administration.

58. A method of treating a disease in a patient, wherein said disease is associated with abnormal activities of one or more kinases, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

59. The method of claim 58 wherein the disease is characterized by the abnormal activity of ABL.

60. The method of claim 58 wherein the disease is characterized by the abnormal activity of JAK.

61. The method of claim 58 wherein the disease is characterized by the abnormal activity of ABL and JAK.

62. The method of claim 58 wherein more than one compound of Formula I is administered

63. The method of claim 58 wherein the compound is administered in combination with another kinase inhibitor.

64. The method of claim 58 wherein said disease is allograft rejection or graft versus host disease.

65. The method of claim 58 wherein said disease is an autoimmune disease.

66. The method of claim 65 wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.

67. The method of claim 65 wherein said autoimmune disease is bullous skin disorder.

68. The method of claim 67 wherein said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).

69. The method of claim 65 wherein said disease is a skin disorder.

70. The method of claim 69 wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

71. The method of claim 65 wherein said disease is a viral disease.

72. The method of claim 71 wherein said viral disease is Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicell-Zoster Virus (VZV) or Human Papilloma Virus (HPV).

73. The method of claim 65 wherein said disease is cancer.

74. The method of claim 73 wherein said cancer is a solid tumor.

75. The method of claim 73 wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease or pancreatic cancer.

76. The method of claim 73 wherein said cancer is prostate cancer.

77. The method of claim 73 wherein said cancer is hematological.

78. The method of claim 73 wherein said cancer is lymphoma, leukemia, or multiple myeloma.

79. The method of claim 73 wherein said cancer is acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), atypical CML or CMML.

80. The method of claim 73 wherein said cancer is a skin cancer.

81. The method of claim 80 wherein said skin cancer is cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.

82. The method of claim 73 wherein said cancer is multiple myeloma.

83. The method of claim 65 said disease is characterized by a mutant JAK2.

84. The method of claim 83 wherein at least one mutation of said mutant JAK2 resides in the pseudo-kinase domain of said JAK2.

85. The method of claim 58 wherein said disease is characterized by a mutant ABL.

86. The method of claim 85 wherein at least one mutation of said mutant ABL resides in the kinase domain of said mutant ABL.

87. The method of claim 65 wherein said disease is a myeloproliferative disorder.

88. The method of claim 87 wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

89. The method of claim 65 wherein said disease is an inflammatory disease.

90. The method of claim 89 wherein said disease is an inflammatory disease of the eye.

91. The method of claim 90 wherein said disease is iritis, uveitis, scleritis, or conjunctivitis.

92. The method of claim 89 wherein said disease is an inflammatory disease of the respiratory tract.

93. The method of claim 92 wherein said inflammatory disease concerns the upper respiratory tract.

94. The method of claim 92 wherein said inflammatory disease concerns the lower respiratory tract.

95. The method of claim 89 wherein said inflammatory disease is an inflammatory myopathy.

96. The method of claim 89 wherein said inflammatory disease is myocarditis.

97. The method of claim 65 wherein said disease is ischemia reperfusion or related to an ischemic event.

98. The method of claim 65 wherein said disease is anorexia or cachexia resulting from or associated with cancer.

99. The method of claim 65 wherein said disease is fatigue resulting from or associated with cancer.

100. A method of treating autoimmune disease, skin disorder, viral disease, cancer, or myeloproliferative disorder in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I: