HETEROCYCLIC DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS

• US 20110059951A1
• Filed: 08/31/2010
• Published: 03/10/2011
• Est. Priority Date: 09/01/2009
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Holdings Corporation And Incyte Corporation
• Inventors: Wang, Haisheng, Shepard, Stacey, Rodgers, James D., Li, Yun-Long
• Granted Patent: US 9,249,145 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention provides heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines, as well as their compositions and methods of use, that modulate the activity of Janus kinases (JAKs) and are useful in the treatment of diseases related to the activity of JAKs including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Claims

1. A compound of Formula Ia:

2. The compound according to claim 1, having Formula I:

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-14 cycloalkyl, C_2-13 heterocycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-14 cycloalkyl, C_2-13 heterocycloalkyl, C_6-14 aryl, and C_1-14 heteroaryl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R⁸ substituents.

4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is H, C_1-6 alkyl, C_3-14 cycloalkyl, C_2-13 heterocycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, wherein said C_1-6 alkyl, C_3-14 cycloalkyl, C_2-13 heterocycloalkyl, C_6-14 aryl, and C_1-14 heteroaryl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R⁸ substituents.

5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is C_1-6 alkyl, C_3-14 cycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R⁸ substituents.

6. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is C_1-6 alkyl.

7. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is C_3-14 cycloalkyl.

8. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is C_6-14 aryl.

9. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is phenyl.

10. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is C_1-14 heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from C_1-6 alkyl.

11. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is C_1-6 alkyl, C_3-14 cycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R⁸ substituents.

12. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is C_1-6 alkyl, C_3-14 cycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, wherein said C_3-14 cycloalkyl, C_6-14 aryl, and C_1-14 heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from halo, cyano, C_1-6 alkyl, C_1-6haloalkyl, —

OR^a, and —

NR^eR^f.

13. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is methyl, cyclopropyl, phenyl, a pyrazole ring, a pyridine ring, an indazole ring, a thiophene ring, a furan ring, a pyrimidine ring, or an imidazole ring;

wherein said phenyl, pyrazole ring, pyridine ring, indazole ring, thiophene ring, furan ring, pyrimidine ring, and imidazole ring are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, and —

NR^eR^f.

14. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein each R⁸ is independently selected from halo, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_2-9 heterocycloalkyl, C_6-10 aryl, C_1-9 heteroaryl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, —

OC(═

O)R^b, —

OC(═

O)NR^eR^f, —

NR^eR^f, —

NR^cC(═

O)R^d, —

NR^cC(═

O)OR^d, —

NR^cC(═

O)NR^d, —

NR^cS(═

O)₂R^d, and —

NR^bS(═

O)₂NR^eR^f.

15. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein each R⁸ is independently selected from halo, cyano, nitro, C_1-6alkyl, C_1-6 haloalkyl, —

OR^a, —

S(═

O)₂R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, —

NR^eR^f, and —

NR^cC(═

O)R^d.

16. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein each R⁸ is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, and —

NR^eR^f.

17. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein L is absent.

18. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein L is C(═

O).

19. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein L is S(═

O)₂.

20. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein L is C(═

O)NH.

21. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein X is CH.

22. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein X is N.

23. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is H, cyano, or halo.

24. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is H, cyano, methyl or fluoro.

25. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Z is CR⁷.

26. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

27. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Z is N.

28. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹, R², and R³ are each H.

29. The compound according to claim 2, or a pharmaceutically acceptable salt thereof;

wherein R⁴ and R⁵ are each H.

30. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein each R⁶ is C_1-4 alkyl.

31. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein m is 1.

32. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein n is 0.

33. A compound according to claim 2, having formula II:

34. A compound according to claim 2, having formula IIa:

35. A compound according to claim 2, having formula IIb:

36. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein:

A is C_1-6 alkyl, C_3-14 cycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R⁸ substituents;

each R⁸ is independently selected from halo, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-14 cycloalkyl, C_3-14 cycloalkyl-C_1-4-alkyl, C_2-14 heterocycloalkyl, C_2-14 heterocycloalkyl-C_1-4-alkyl, C_6-14 aryl, C_6-14 aryl-C_1-4-alkyl, C_1-13 heteroaryl, C_1-13 heteroaryl-C_1-4-alkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, —

OC(═

O)R^b, —

OC(═

O)NR^eR^f, —

NR^eR^f, —

NR^cC(═

O)R^d, —

NR^cC(═

O)OR^d, —

NR^cC(═

O)NR^d, —

NR^cS(═

O)₂R^d, and —

NR^bS(═

O)₂NR^eR^f;

L is C(═

O) or S(═

O)₂;

X is N;

Y is H, cyano, or halo;

Z is CH or N;

R¹, R², R³, R⁴, and R⁵ are each H;

m is 0;

n is 0; and

each R^a, R^b, R^c, R^d, R^e, and R^f is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, C_6-14 aryl, C_6-14 aryl-C_1-4-alkyl, C_1-7 heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl;

wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, C_6-14 aryl, C_6-14 aryl-C_1-4-alkyl, C_1-7 heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from hydroxyl, halo, cyano, nitro, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

or any R^c and R^d, together with the moiety to which they are attached, can form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with 1, 2, 3, or 4 groups independently selected from hydroxyl, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

or any R^e and R^f, together with the nitrogen atom to which they are attached, can form a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl ring or heteroaryl ring, wherein said heterocycloalkyl or heteroaryl ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from hydroxyl, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino.

37. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein:

A is C_1-6 alkyl, C_3-14 cycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R⁸ substituents;

each R⁸ is independently selected from halo, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

S(═

O)₂R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, —

NR^eR^f, and —

NR^cC(═

O)R^d;

L is C(═

O) or S(═

O)₂;

X is N;

Y is H, cyano, or halo;

Z is CH or N;

R¹, R², R³, R⁴, and R⁵ are each H;

m is 0;

n is 0; and

each R^a, R^b, R^c, R^d, R^e, and R^f is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, C_6-14 aryl, C_6-14 aryl-C_1-4-alkyl, C_1-7heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl;

wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, C_6-14 aryl, C_6-14 aryl-C_1-4-alkyl, C_1-7 heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from hydroxyl, halo, cyano, nitro, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

or any R^c and R^d, together with the moiety to which they are attached, can form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with 1, 2, 3, or 4 groups independently selected from hydroxyl, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

or any R^e and R^f, together with the nitrogen atom to which they are attached, can form a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl ring or heteroaryl ring, wherein said heterocycloalkyl or heteroaryl ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from hydroxyl, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino.

38. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

A is C_1-6 alkyl, C_3-14 cycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, wherein said C_3-14 cycloalkyl, C_6-14 aryl, and C_1-14 heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R⁸ substituents;

each R⁸ is independently selected from halo, cyano, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, and —

NR^eR^f;

L is absent, C(═

O), C(═

O)NH, or S(═

O)₂;

X is N or CH;

Y is H, cyano, methyl, or fluoro;

Z is CH or N;

R¹, R², R³, R⁴, and R⁵ are each H;

each R⁶ is C_1-4 alkyl;

m is 0 or 1;

n is 0 or 1;

p is 0 or 1;

each R^a, R^b, R^c, R^d, R^e, and R^f is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, C_6-14 aryl, C_6-14 aryl-C_1-4-alkyl, C_1-7heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl;

wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, C_6-14 aryl, C_6-14 aryl-C_1-4-alkyl, C_1-7heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from hydroxyl, halo, cyano, nitro, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino.

39. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein:

A is C_1-6alkyl, C_3-14 cycloalkyl, C_6-14 aryl, or C_1-14 heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R⁸ substituents;

each R⁸ is independently selected from halo, cyano, and C_1-6 alkyl;

L is C(═

O) or S(═

O)₂;

X is N;

Y is H, cyano, or fluoro;

Z is CH or N;

R¹, R², R³, R⁴, and R⁵ are each H;

m is 0; and

n is 0.

40. A compound according to claim 2, having formula IIc, IId, IIe, or IIf:

41. A compound according to claim 2, having formula IIg or IIh:

42. A compound according to claim 2, having formula IIj or IIk:

43. A compound according to claim 1, wherein said compound is selected from:

4-[4-(methylsulfonyl)piperazin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]benzonitrile;

4-[4-(3,5-difluorobenzoyl)piperazin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[1-(cyclopropylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[1-(2,4-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[1-(4-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[1-(1-methyl-2-{4-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperazin-1-yl}ethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; and

4-(1-(1-fluoro-3-(4-(1-methyl-1H-pyrazol-3-ylsulfonyl)piperazin-1-yl)propan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

or a pharmaceutically acceptable salt thereof.

44. A compound according to claim 1, wherein said compound is selected from:

4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

4-[(4-{3-cyano-2-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propyl}piperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

4-{4-[4-(difluoromethyl)-2-fluorobenzoyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]-3,5-difluorobenzonitrile;

4-{4-[(5-chloro-3-fluoropyridin-2-yl)carbonyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

6-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]-5-fluoronicotinonitrile;

4-[4-(3-fluoro-4-methoxybenzoyl)piperazin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-(4-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

6-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)carbonyl]nicotinonitrile;

4-{4-[(5-fluoropyridin-2-yl)carbonyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(1H-indazol-5-ylsulfonyl)piperazin-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(4-fluoro-2-methylphenyl)piperazine-1-carboxamide;

4-[((3R)-4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-methylpiperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

4-[((3S)-4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-methylpiperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-chloro-2-fluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-chloro-2,6-difluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-fluoro-4-methylbenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2,4,6-trifluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2,4-difluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-fluoro-4-hydroxybenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-fluoro-5-(trifluoromethyl)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2,3-difluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2,3-difluoro-4-methoxybenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-fluoro-6-hydroxybenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-fluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-fluoro-3-methylbenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(5-chloropicolinoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-chloro-4-fluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3,5-difluoropicolinoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-fluoro-5-(trifluoromethoxy)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(thiophene-2-carbonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-fluoro-3-methoxybenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3-chloro-4-methoxybenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-fluoro-4-(trifluoromethyl)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3-chloro-5-fluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-fluoro-2-methylbenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2,3,4-trifluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-fluoro-3-(trifluoromethoxy)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3,4-difluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-fluoro-3-(trifluoromethoxy)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-methoxythiophene-3-carbonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3-chloro-5-(trifluoromethoxy)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3-chloro-4-hydroxybenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3,5-difluoro-4-methoxybenzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3-fluoro-4-(trifluoromethyl)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-fluoro-3-(trifluoromethyl)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-picolinoylpiperazin-1-yl)butanenitrile;

6-(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)piperazine-1-carbonyl)nicotinonitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(4-fluoro-2-(trifluoromethyl)benzoyl)piperazin-1-yl)butanenitrile;

2-(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)piperazin-1-ylsulfonyl)benzonitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(3,5-difluorophenylsulfonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2,5-difluorophenylsulfonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(5-methylpyridin-2-ylsulfonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(6-methylpyridin-2-ylsulfonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(pyridin-3-ylsulfonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(2-(trifluoromethyl)phenylsulfonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)butanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(4-(5-chlorothiophen-2-ylsulfonyl)piperazin-1-yl)butanenitrile;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(2,6-difluorophenyl)piperazine-1-carboxamide;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(2,6-dichlorophenyl)piperazine-1-carboxamide;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(2-chloro-6-methylphenyl)piperazine-1-carboxamide;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(2,4-difluorophenyl)piperazine-1-carboxamide;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(2-fluoro-3-(trifluoromethyl)phenyl)piperazine-1-carboxamide;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(2-(difluoromethoxy)phenyl)piperazine-1-carboxamide;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(2-(trifluoromethoxy)phenyl)piperazine-1-carboxamide;

4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)-N-(2-(trifluoromethyl)phenyl)piperazine-1-carboxamide;

4-(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropyl)piperazine-1-carbonyl)-3-hydroxybenzonitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(2-fluoro-4-(trifluoromethyl)benzoyl)piperazin-1-1yl)butanenitrile;

4-(4-(2-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-3-cyanopropyl)piperazine-1-carbonyl)-3,5-difluorobenzonitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(3,5-difluoropicolinoyl)piperazin-1-yl)butanenitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(3,5-difluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(3-fluoro-4-methoxybenzoyl)piperazin-1-yl)butanenitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(5-fluoropicolinoyl)piperazin-1-yl)butanenitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(5-chloro-3-fluoropicolinoyl)piperazin-1-yl)butanenitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(4-fluoro-3-(trifluoromethoxy)benzoyl)piperazin-1-yl)butanenitrile;

3-(4-(2-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-3-cyanopropyl)piperazine-1-carbonyl)-5-fluorobenzonitrile;

6-(4-(2-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-3-cyanopropyl)piperazine-1-carbonyl)-5-fluoronicotinonitrile;

4-(4-(2-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-3-cyanopropyl)piperazine-1-carbonyl)benzonitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(3-fluoro-5-(trifluoromethyl)picolinoyl)piperazin-1-yl)butanenitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(2,4-difluorobenzoyl)piperazin-1-yl)butanenitrile;

3-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-4-(4-(4-(difluoromethyl)-2-fluorobenzoyl)piperazin-1-yl)butanenitrile;

4-{1-[1-methyl-2-(4-{[5-methyl-2-(trifluoromethyl)-3-furyl]sulfonyl}piperazin-1-yl)ethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidine;

4-[1-(2-{4-[(5-chloro-2-thienyl)sulfonyl]piperazin-1-yl}-1-methylethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;

2-[(4-{2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazin-1-yl)sulfonyl]benzonitrile;

4-(1-{2-[4-(2,4-difluorobenzoyl)piperazin-1-yl]-1-methylethyl}-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-[1-(2-{4-[(3-fluorophenyl)sulfonyl]piperazin-1-yl}-1-methylethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine;

4-[4-(2-fluoro-4-hydroxybenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(4-fluorobenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(2,4-difluorobenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(4-chloro-2-fluorobenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(2-fluorobenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

2-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-1,4-diazepan-1-yl)sulfonyl]benzonitrile;

4-[4-(2,4-dichlorobenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(4-amino-2-fluorobenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(4-chloro-2-methylbenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(4-chloro-2-methoxybenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-[4-(4-chlorobenzoyl)-1,4-diazepan-1-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[(2-methylphenyl)sulfonyl]-1,4-diazepan-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-4-(4-{[2-(trifluoromethyl)phenyl]sulfonyl}-1,4-diazepan-1-yl)butanenitrile;

3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-4-(4-{[2-(trifluoromethoxy)phenyl]sulfonyl}-1,4-diazepan-1-yl)butanenitrile;

4-{4-[(2,5-dimethoxyphenyl)sulfonyl]-1,4-diazepan-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[(5-chloro-2-methoxyphenyl)sulfonyl]-1,4-diazepan-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[(2-phenoxyphenyl)sulfonyl]-1,4-diazepan-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{4-[(5-bromo-2-methoxyphenyl)sulfonyl]-1,4-diazepan-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile;

4-{1-[1-({4-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperazin-1-yl}methyl)propyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidine;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(4-fluorophenyl)methanone;

2-[(4-{2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butyl}piperazin-1-yl)carbonyl]phenol;

3-[1-(6-anilino-5-methylpyrimidin-4-yl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-(2-fluorophenylamino)-5-methylpyrimidin-4-yl)piperidin-4-yl)propanenitrile;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(2,4-difluorophenyl)methanone;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(2,5-difluorophenyl)methanone;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(2,3-difluorophenyl)methanone;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(3,5-difluorophenyl)methanone;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(2-chloro-4-hydroxyphenyl)methanone;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(2-fluoro-4-hydroxyphenyl)methanone;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(4-chloro-2-fluorophenyl)methanone;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(4-fluoro-2-methoxyphenyl)methanone;

(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-yl)(thiophen-2-yl)methanone;

4-(1-(1-(4-(phenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

2-(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-ylsulfonyl)benzonitrile;

4-(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-ylsulfonyl)benzonitrile;

4-(1-(1-(4-(2-(trifluoromethyl)phenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(6-methylpyridin-2-ylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(3-chlorothiophen-2-ylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(3-fluorophenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(4-fluorophenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

3-(4-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butyl)piperazin-1-ylsulfonyl)benzonitrile;

4-(1-(1-(4-(2,4-difluorophenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(2,5-difluorophenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(3,5-difluorophenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(4-fluoro-2-methylphenylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(1,2-dimethyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-(1-(4-(5-bromothiophen-2-ylsulfonyl)piperazin-1-yl)butan-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-(3-fluorophenylamino)-5-methylpyrimidin-4-yl)piperidin-4-yl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-(2,5-difluorophenylamino)-5-methylpyrimidin-4-yl)piperidin-4-yl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-(3,4-difluorophenylamino)-5-methylpyrimidin-4-yl)piperidin-4-yl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-phenoxypyrimidin-4-yl)piperidin-4-yl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-(3-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-(2,3-difluorophenylamino)-5-methylpyrimidin-4-yl)piperidin-4-yl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-(2,6-difluorophenylamino)-5-methylpyrimidin-4-yl)piperidin-4-yl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(6-(2,4-difluorophenylamino)-5-methylpyrimidin-4-yl)piperidin-4-yl)propanenitrile;

4-{[4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile;

4-{[4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(methoxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile;

4-[(4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoromethylpiperazin-1-yl)carbonyl]-3-fluorobenzonitrile;

4-{[4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(difluoromethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile;

4-{[4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-2-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile;

4-[((2R)-4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-2-methylpiperazin-1-yl)carbonyl]-3-fluorobenzonitrile; and

4-[(2S)-4-{3-cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-2-methylpiperazin-1-yl)carbonyl]-3-fluorobenzonitrile

or a pharmaceutically acceptable salt thereof.

45. The compound according to claim 2, wherein the compound is the (R)-enantiomer, or a pharmaceutically acceptable salt thereof.

46. The compound according to claim 2, wherein the compound is the (S)-enantiomer, or a pharmaceutically acceptable salt thereof.

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

48. A method of modulating an activity of JAK1 comprising contacting JAK1 with a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

49. A method according to claim 48, wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.

50. A method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

51. A method according to claim 50, wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.

52. A method according to claim 50, wherein said autoimmune disease is rheumatoid arthritis.

53. A method according to claim 50, wherein said autoimmune disease is a skin disorder.

54. A method according to claim 53, wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

55. A method according to claim 50, wherein said cancer is a solid tumor.

56. A method according to claim 50, 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.

57. A method according to claim 50, wherein said cancer is lymphoma, leukemia, or multiple myeloma.

58. A method according to claim 50, wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

59. A method according to claim 50, wherein said myeloproliferative disorder is myelofibrosis.

60. A method according to claim 50, wherein said myeloproliferative disorder is primary myelofibrosis (PMF).

61. A method according to claim 50, wherein said bone resorption disease is osteoporosis, osteoarthritis, bone resorption associated with hormonal imbalance, bone resorption associated with hormonal therapy, bone resorption associated with autoimmune disease, (e.g. osseous sarcoidosis) or bone resorption associated with cancer (e.g. myeloma).

62. A composition comprising a compound according to claim 2, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

63. A method of modulating an activity of JAK1 comprising contacting JAK1 with a compound according to claim 2, or a pharmaceutically acceptable salt thereof.

64. A method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of claim 2, or a pharmaceutically acceptable salt thereof.