N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors

• US 8,716,303 B2
• Filed: 05/21/2010
• Issued: 05/06/2014
• Est. Priority Date: 05/22/2009
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Rodgers, James D., Shepard, Stacey, Arvanitis, Argyrios G., Wang, Haisheng, Storace, Louis, Folmer, Beverly, Shao, Lixin, Zhu, Wenyu, Glenn, Joseph
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US12/784,916
• Publication Number:
  US 20100298334A1
• Time in Patent Office: 1,446 Days
• Field of Search: None
• US Class Current: 514/265.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention relates to N-(hetero)aryl-pyrrolidine derivatives of Formula I:

which are JAK inhibitors, such as selective JAK1 inhibitors, useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.

Claims

1. A compound of Formula I:

2. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is N.

3. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is CH.

4. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is cyano.

5. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is chloro or fluoro.

6. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is fluoro.

7. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Z is hydrogen.

8. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Z is fluoro.

9. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is selected from phenyl, C_1-6 monocyclic heteroaryl, C_1-9 bicyclic heteroaryl, bicyclic C_7-14 fused cycloalkylaryl, bicyclic C_6-14 fused heterocycloalkylaryl, bicyclic C_2-14 fused cycloalkylheteroaryl, and bicyclic C_2-14 fused heterocycloalkylheteroaryl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

10. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is selected from phenyl, C_1-6 monocyclic heteroaryl, C_1-9 bicyclic heteroaryl, and bicyclic C_2-14 fused heterocycloalkylheteroaryl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

11. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is phenyl, which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

12. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is C_1-6 monocyclic heteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

13. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is C_1-9 bicyclic heteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

14. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is bicyclic C_2-14 fused heterocycloalkylheteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

15. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is bicyclic C_2-14 fused cycloalkylheteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

16. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is selected from phenyl, a thiazole ring, a pyridine ring, pyrimidine ring, a pyrazine ring, a benzo[d]oxazole ring, an oxazolo[4,5-c]pyridine ring, an oxazolo[5,4-b]pyridine ring, an oxazolo[5,4-d]pyrimidine ring, a 7H-pyrrolo[2,3-d]pyrimidine ring, a 2,3-dihydrothieno[2,3-b]pyridine ring, a S-oxo-2,3-dihydrothieno[2,3-b]pyridine ring, a S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridine ring, a quinazoline ring, a quinoline ring, and a quinoxaline ring;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

17. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is selected from phenyl, a thiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a benzo[d]oxazole ring, an oxazolo[4,5-c]pyridine ring, an oxazolo[5,4-b]pyridine ring, an oxazolo[5,4-d]pyrimidine ring, a 7H-pyrrolo[2,3-d]pyrimidine ring, a 2,3-dihydrothieno[2,3-b]pyridine ring, a S-oxo-2,3-dihydrothieno[2,3-b]pyridine ring, a S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridine ring, a quinazoline ring, a quinoline ring, a pyrrolo[2,3-b]pyridine ring, an oxazolo[4,5-b]pyridine ring, a 3-oxo-3,4-dihydropyrazine ring, and a quinoxaline ring;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

18. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is selected from phenyl, a thiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a benzo[d]oxazole ring, an oxazolo[4,5-c]pyridine ring, an oxazolo[5,4-b]pyridine ring, an oxazolo[5,4-d]pyrimidine ring, a 7H-pyrrolo[2,3-d]pyrimidine ring, a 2,3-dihydrothieno[2,3-b]pyridine ring, a S-oxo-2,3-dihydrothieno[2,3-b]pyridine ring, a S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridine ring, a quinazoline ring, a quinoline ring, a pyrrolo[2,3-b]pyridine ring, an oxazolo[4,5-b]pyridine ring, a 3-oxo-3,4-dihydropyrazine ring, a quinoxaline ring, a oxazolo[5,4-d]pyrimidine ring, a thieno[3,2-b]pyridine ring, a thieno[2,3-c]pyridine ring, a thiophene ring, a thiazolo[5,4-d]pyrimidine ring, a thieno[2,3-b]pyridine ring, a 2,3-dihydrofuro[2,3-b]pyridine ring, a 6,7-dihydro-5H-cyclopenta[b]pyridine ring, a furo[3,2-c]pyridine ring, a 2,3-dihydrothieno[3,2-c]pyridine ring, a S-oxo-2,3-dihydrothieno[3,2-c]pyridine ring, a S,S-dioxo-2,3-dihydrothieno[3,2-c]pyridine ring, a thieno[3,2-c]pyridine ring, and a 1H-pyrrolo[3,2-c]pyridine ring;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

19. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, and quinoxalin-2-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

20. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, 3-oxo-3,4-dihydropyrazin-2-yl, and quinoxalin-2-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

21. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 1,2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, 3-oxo-3,4-dihydropyrazin-2-yl, quinoxalin-2-yl, thiazol-4-yl, thiazol-5-yl, pyrimidin-5-yl, oxazolo[5,4-d]pyrimidin-2-yl, thieno[3,2-b]pyridin-5-yl, thieno[2,3-c]pyridin-5-yl, thiophen-2-yl, thiophen-3-yl, thiazolo[5,4-d]pyrimidin-5-yl, thieno[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, furo[3,2-c]pyridin-6-yl, 2,3-dihydrothieno[3,2-c]pyridin-6-yl, S-oxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, thieno[3,2-c]pyridin-6-yl, and 1H-pyrrolo[3,2-c]pyridin-6-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups.

22. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R¹ is independently selected from halogen, cyano, nitro, 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_2-6 heterocycloalkyl, C_2-6 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-6 heteroaryl, C_1-6 heteroaryl-C_1-4-alkyl, —

ORa, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, —

NR^cC(═

O)R^d, and —

NR^cC(═

O)OR^d;

wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, and C_2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^1a groups;

wherein said C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-6 heterocycloalkyl, C_2-6 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-6 heteroaryl, and C_1-6 heteroaryl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^2a groups.

23. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R¹ is independently selected from halogen, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, and —

NR^cC(═

O)R^d.

24. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R¹ is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, and —

NR^eR^f.

25. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R¹ is independently selected from fluoro, bromo, chloro, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, isopropylamino, dimethylamino, methylthio, methylsulfinyl, and methylsulfonyl.

26. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein 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_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-7 heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl.

27. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein 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_3-7 cycloalkyl, C_2-7 heterocycloalkyl, phenyl, and C_1-7 heteroaryl.

28. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R^a, R^b, R^c, R^d, R^e, and R^f is independently selected from H, C_1-6 alkyl, and C_1-6 haloalkyl.

29. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R^a, R^b, R^c, R^d, R^e, and R^f is independently selected from H and C_1-6 alkyl.

30. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R^1a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

and each R^2a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkynyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino.

31. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, C_1-6 monocyclic heteroaryl, C_1-9 bicyclic heteroaryl, bicyclic C_7-14 fused cycloalkylaryl, bicyclic C_6-14 fused heterocycloalkylaryl, bicyclic C_2-14 fused cycloalkylheteroaryl, and bicyclic C_2-14 fused heterocycloalkylheteroaryl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, 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_2-6 heterocycloalkyl, C_2-6 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-6 heteroaryl, C_1-6 heteroaryl-C_1-4-alkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, —

NR^cC(═

O)R^d, and —

NR^cC(═

O)OR^d;

wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, and C_2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^1a groups;

wherein said C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-6 heterocycloalkyl, C_2-6 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-6 heteroaryl, and C_1-6 heteroaryl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^2a a groups;

each R^1a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

each R^2a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkynyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

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, phenyl, phenyl-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, and C_2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^x groups; and

wherein said C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-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 independently selected R^y groups;

each R^x is independently selected from hydroxyl, C_1-4 alkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino; and

each R^y is independently selected from hydroxyl, halogen, 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.

32. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, C_1-6 monocyclic heteroaryl, C_1-9 bicyclic heteroaryl, bicyclic C_7-14 fused cycloalkylaryl, bicyclic C_6-14 fused heterocycloalkylaryl, bicyclic C_2-14 fused cycloalkylheteroaryl, bicyclic C_2-14 fused cycloalkylheteroaryl, and bicyclic C_2-14 fused heterocycloalkylheteroaryl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, 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_2-6 heterocycloalkyl, C_2-6 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-6 heteroaryl, C_1-6 heteroaryl-C_1-4-alkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, —

NR^cC(═

O)R^d, and —

NR^cC(═

O)OR^d;

wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, and C_2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^1a groups;

wherein said C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-6 heterocycloalkyl, C_2-6 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-6 heteroaryl, and C_1-6 heteroaryl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^2a groups;

each R^1a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

each R^2a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkynyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

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, phenyl, phenyl-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, and C_2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^x groups; and

wherein said C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-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 independently selected R^y groups;

each R^x is independently selected from hydroxyl, C_1-4 alkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino; and

each R^y is independently selected from hydroxyl, halogen, 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.

33. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, C_1-6 monocyclic heteroaryl, C_1-9 bicyclic heteroaryl, and bicyclic C_2-14 fused heterocycloalkylheteroaryl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, 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_2-6 heterocycloalkyl, C_2-6 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-6 heteroaryl, C_1-6 heteroaryl-C_1-4-alkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, —

NR^cC(═

O)R^d, and —

NR^cC(═

O)OR^d;

wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, and C_2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^1a groups;

wherein said C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-6 heterocycloalkyl, C_2-6 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-6 heteroaryl, and C_1-6 heteroaryl-C_1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^2a groups;

each R^1a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

each R^2a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkynyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino;

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, phenyl, phenyl-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, and C_2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R^x groups; and

wherein said C_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-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 independently selected R^y groups;

each R^x is independently selected from hydroxyl, C_1-4 alkoxy, amino, C_1-4 alkylamino, and di-C_1-4-alkylamino; and

each R^y is independently selected from hydroxyl, halogen, 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.

34. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, C_1-6 monocyclic heteroaryl, C_1-9 bicyclic heteroaryl, bicyclic C_2-14 fused cycloalkylheteroaryl, and bicyclic C_2-14 fused heterocycloalkylheteroaryl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, and —

NR^cC(═

O)R^d; 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_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-7 heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl.

35. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, C_1-6 monocyclic heteroaryl, C_1-9 bicyclic heteroaryl, and bicyclic C_2-14 fused heterocycloalkylheteroaryl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, and —

NR^cC(═

O)R^d; 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_3-7 cycloalkyl, C_3-7 cycloalkyl-C_1-4-alkyl, C_2-7 heterocycloalkyl, C_2-7 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-7 heteroaryl, and C_1-7 heteroaryl-C_1-4-alkyl.

36. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, a thiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a benzo[d]oxazole ring, an oxazolo[4,5-c]pyridine ring, an oxazolo[5,4-b]pyridine ring, an oxazolo[5,4-d]pyrimidine ring, a 7H-pyrrolo[2,3-d]pyrimidine ring, a 2,3-dihydrothieno[2,3-b]pyridine ring, a S-oxo-2,3-dihydrothieno[2,3-b]pyridine ring, a S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridine ring, a quinazoline ring, a quinoline ring, and a quinoxaline ring;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, and —

NR^cC(═

O)R^d; and

each R^a, R^b, R^c, R^d, R^e, and R^f is independently selected from H, C_1-5 alkyl, C_1-6 haloalkyl, C_3-7 cycloalkyl, C_2-7 heterocycloalkyl, phenyl, and C_1-7 heteroaryl.

37. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, a thiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a benzo[d]oxazole ring, an oxazolo[4,5-c]pyridine ring, an oxazolo[5,4-b]pyridine ring, an oxazolo[5,4-d]pyrimidine ring, a 7H-pyrrolo[2,3-d]pyrimidine ring, a 2,3-dihydrothieno[2,3-b]pyridine ring, a S-oxo-2,3-dihydrothieno[2,3-b]pyridine ring, a S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridine ring, a quinazoline ring, a quinoline ring, a pyrrolo[2,3-b]pyridine ring, an oxazolo[4,5-b]pyridine ring, a 3-oxo-3,4-dihydropyrazine ring, and a quinoxaline ring;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)OR^b, —

C(═

O)NR^eR^f, and —

NR^cC(═

O)R^d; 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_3-7 cycloalkyl, C_2-7 heterocycloalkyl, phenyl, and C_1-7 heteroaryl.

38. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, a thiazole ring, a pyridine ring, pyrimidine ring, a pyrazine ring, a benzo[d]oxazole ring, an oxazolo[4,5-c]pyridine ring, an oxazolo[5,4-b]pyridine ring, an oxazolo[5,4-d]pyrimidine ring, a 7H-pyrrolo[2,3-d]pyrimidine ring, a 2,3-dihydrothieno[2,3-b]pyridine ring, a S-oxo-2,3-dihydrothieno[2,3-b]pyridine ring, a S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridine ring, a quinazoline ring, a quinoline ring, a pyrrolo[2,3-b]pyridine ring, an oxazolo[4,5-b]pyridine ring, a 3-oxo-3,4-dihydropyrazine ring, a quinoxaline ring, a oxazolo[5,4-d]pyrimidine ring, a thieno[3,2-b]pyridine ring, a thieno[2,3-c]pyridine ring, a thiophene ring, a thiazolo[5,4-d]pyrimidine ring, a thieno[2,3-b]pyridine ring, a 2,3-dihydrofuro[2,3-b]pyridine ring, a 6,7-dihydro-5H-cyclopenta[b]pyridine ring, a furo[3,2-c]pyridine ring, a 2,3-dihydrothieno[3,2-c]pyridine ring, a S-oxo-2,3-dihydrothieno[3,2-c]pyridine ring, a S,S-dioxo-2,3-dihydrothieno[3,2-c]pyridine ring, a thieno[3,2-c]pyridine ring, and a 1H-pyrrolo[3,2-c]pyridine ring;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, —

S(═

O)NR^eR^f, —

NR^eR^f, —

C(═

O)R^b, —

C(═

O)NR^eR^f, and —

NR^cC(═

O)R^d; 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_3-7 cycloalkyl, C_2-7 heterocycloalkyl, phenyl, and C_1-7 heteroaryl.

39. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, and quinoxalin-2-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, and —

NR^eR^f; and

each R^a, R^b, R^c, and R^f is independently selected from H, C_1-6 alkyl, and C_1-6haloalkyl.

40. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, and quinoxalin-2-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, C_1-6 alkyl, C_1-6haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, and —

NR^eR^f; and

each R^a, R^b, R^c, and R^f is independently selected from H and C_1-6 alkyl.

41. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, 3-oxo-3,4-dihydropyrazin-2-yl, quinolin-2-yl, and quinoxalin-2-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, C_1-6 alkyl, C_1-6haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, and —

NR^eR^f; and

each R^a, R^b, R^e, and R^f is independently selected from H and C_1-6 alkyl.

42. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, and quinoxalin-2-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, C_1-6 alkyl, C_1-6haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, and —

NR^eR^f; and

each R^a, R^b, R^e, and R^f is independently selected from H and methyl.

43. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, 3-oxo-3,4-dihydropyrazin-2-yl, quinolin-2-yl, quinoxalin-2-yl, thiazol-4-yl, thiazol-5-yl, pyrimidin-5-yl, oxazolo[5,4-d]pyrimidin-2-yl, thieno[3,2-b]pyridin-5-yl, thieno[2,3-c]pyridin-5-yl, thiophen-2-yl, thiophen-3-yl, thiazolo[5,4-d]pyrimidin-5-yl, thieno[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, furo[3,2-c]pyridin-6-yl, 2,3-dihydrothieno[3,2-c]pyridin-6-yl, S-oxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, thieno[3,2-c]pyridin-6-yl, and 1H-pyrrolo[3,2-c]pyridin-6-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, cyano, nitro, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, and —

NR^eR^f; and

each R^a, R^b, R^e, and R^f is independently selected from H, C_1-6 alkyl, and C_1-6 haloalkyl.

44. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, 3-oxo-3,4-dihydropyrazin-2-yl, quinolin-2-yl, quinoxalin-2-yl, thiazol-4-yl, thiazol-5-yl, pyrimidin-5-yl, oxazolo[5,4-d]pyrimidin-2-yl, thieno[3,2-b]pyridin-5-yl, thieno[2,3-c]pyridin-5-yl, thiophen-2-yl, thiophen-3-yl, thiazolo[5,4-d]pyrimidin-5-yl, thieno[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, furo[3,2-c]pyridin-6-yl, 2,3-dihydrothieno[3,2-c]pyridin-6-yl, S-oxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, thieno[3,2-c]pyridin-6-yl, and 1H-pyrrolo[3,2-c]pyridin-6-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups;

each R¹ is independently selected from halogen, C_1-6 alkyl, C_1-6 haloalkyl, —

OR^a, —

SR^a, —

S(═

O)R^b, —

S(═

O)₂R^b, and —

NR^eR^f; and

each R^a, R^b, R^e, and R^f is independently selected from H and C_1-6 alkyl.

45. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, and quinoxalin-2-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups; and

each R¹ is independently selected from fluoro, bromo, chloro, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, isopropylamino, dimethylamino, methylthio, methylsulfinyl, and methylsulfonyl.

46. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, 3-oxo-3,4-dihydropyrazin-2-yl, and quinoxalin-2-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups; and

each R¹ is independently selected from fluoro, bromo, chloro, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, isopropylamino, dimethylamino, methylthio, methylsulfinyl, and methylsulfonyl.

47. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

X is cyano or fluoro;

Y is CH or N;

Z is hydrogen or fluoro;

Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, 3-oxo-3,4-dihydropyrazin-2-yl, quinoxalin-2-yl, thiazol-4-yl, thiazol-5-yl, pyrimidin-5-yl, oxazolo[5,4-d]pyrimidin-2-yl, thieno[3,2-b]pyridin-5-yl, thieno[2,3-c]pyridin-5-yl, thiophen-2-yl, thiophen-3-yl, thiazolo[5,4-d]pyrimidin-5-yl, thieno[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, furo[3,2-c]pyridin-6-yl, 2,3-dihydrothieno[3,2-c]pyridin-6-yl, S-oxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, thieno[3,2-c]pyridin-6-yl, and 1H-pyrrolo[3,2-c]pyridin-6-yl;

each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R¹ groups; and

each R¹ is independently selected from fluoro, bromo, chloro, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, isopropylamino, dimethylamino, methylthio, methylsulfinyl, and methylsulfonyl.

48. A compound according to claim 1, having formula Ia:

49. A compound according to claim 1, having formula Ib:

50. A compound according to claim 1, having formula Ic:

51. A compound according to claim 1, having formula Id:

52. A compound according to claim 1, having formula Ie:

53. A compound according to claim 1, having formula If:

54. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein said Ar is optionally substituted with 1, 2, 3, or 4 independently selected R¹ groups.

55. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein said Ar is optionally substituted with 1, 2, or 3 independently selected R¹ groups.

56. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein said Ar is optionally substituted with 1 or 2 independently selected R¹ groups.

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

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

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

3-[1-(2-chloropyrimidin-4-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(4-chloropyrimidin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(4-bromo-1,3-thiazol-2-yl)pyrrolidin-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-[4-(dimethylamino)pyrimidin-2-yl]pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[4-(isopropylamino)pyrimidin-2-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(5-chloro-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(1-[1,3]oxazolo[4,5-c]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(1-[1,3]oxazolo[4,5-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(6-methyl[1,3]oxazolo[5,4-b]pyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(6-fluoro[1,3]oxazolo[5,4-b]pyridin-2-yl)pyrrolidin-3-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-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-3-yl]propanenitrile;

3-[1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(1-[1,3]oxazolo[5,4-d]pyrimidin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(5-fluoro-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(4-fluoro-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(7-fluoro-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(5,7-difluoro-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[2-(methylthio)pyrimidin-4-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[2-(methylsulfinyl)pyrimidin-4-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[2-(methylsulfonyl)pyrimidin-4-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[6-(methylsulfonyl)pyridin-2-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[2-(methylsulfonyl)pyridin-4-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(1-oxido-2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(1,1-dioxido-2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(3-fluoro-1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(1-[1,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propanenitrile;

3-[1-(1,1-dioxido-2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propanenitrile;

3-[1-(1-oxido-2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propanenitrile;

3-[1-(6-chloro-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-chloro-2-(3-{2-cyano-1-{4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl}ethyl}pyrrolidin-1-yl)isonicotinonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)pyridine-3,4-dicarbonitrile;

2-(3-{2-cyano-1-{4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl}ethyl}pyrrolidin-1-yl)-6-(methylthio)benzonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-(methylsulfonyl)benzonitrile;

3-[1-(8-chloroquinolin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(3-hydroxyquinoxalin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(8-chloroquinazolin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

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

3-[1-(8-fluoroquinazolin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(5-bromo-1,3-thiazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

2-chloro-6-(3-[2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl pyrrolidin-1-yl)benzonitrile;

3-(3-{2-cyano-1,4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl}ethyl pyrrolidin-1-yl)phthalonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-4-(trifluoromethyl)nicotinonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)pyrazine-2-carbonitrile;

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

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-methylbenzonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-fluorobenzonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-methoxybenzonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-(trifluoromethyl)benzonitrile;

2-bromo-6-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl pyrrolidin-1-yl)benzonitrile;

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

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)isophthalonitrile;

6-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-2,3-difluorobenzonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-3,5,6-trifluorobenzonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)nicotinonitrile;

3-chloro-5-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)isonicotinonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-2,5,6-trifluoroisonicotinonitrile;

3-{1-[3-fluoro-4-(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-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-(3,5,6-trifluoropyridin-2-yl)pyrrolidin-3-yl]propanenitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)pyridine-2-carbonitrile;

2-chloro-6-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)nicotinonitrile;

2-(3-{2-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)[1,3]oxazolo[5,4-b]pyridine;

2-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-fluoroethyl)pyrrolidin-1-yl)oxazolo[5,4-b]pyridine; and

3-[1-(1H-pyrrolo[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile,

or a pharmaceutically acceptable salt or N-oxide thereof.

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

5-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)thieno[2,3-c]pyridine-4-carbonitrile;

5-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)thieno[3,2-b]pyridine-6-carbonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-4-hydroxythiophene-3-carbonitrile;

4-bromo-2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)thiophene-3-carbonitrile;

4-chloro-2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)thiophene-3-carbonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)thiophene-3,4-dicarbonitrile;

2-(3-(1R)-2-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)thiophene-3,4-dicarbonitrile;

2-(3-{2-cyano-1-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]ethyl}pyrrolidin-1-yl)thiophene-3,4-dicarbonitrile;

4-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-1,3-thiazole-5-carbonitrile;

5-(3-{2-fluoro-1-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]ethyl}pyrrolidin-1-yl)-1,3-thiazole-4-carbonitrile;

4-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;

4-(1-{2-fluoro-1-[1-(5-fluoro-2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]ethyl}-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

4-(1-{2-fluoro-1-[1-(5-fluoro-1,1-dioxido-2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]ethyl}-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

3-[1-(5-fluoro-2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

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

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

3-{1-[6-chloro-3-fluoro-5-(hydroxymethyl)pyridin-2-yl]pyrrolidin-3-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-(5-amino-6-chloro-3-fluoropyridin-2-yl)pyrrolidin-3-yl)propanenitrile;

N-(2-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-6-chloro-5-fluoropyridin-3-yl)formamide;

3-{1-[6-(ethylsulfonyl)-3-fluoropyridin-2-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

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

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-5-fluoro-4-(methoxymethyl)nicotinonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-4-(methoxymethyl)nicotinonitrile;

4-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-6-methoxypyrimidine-5-carbonitrile;

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

2-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-4-methylnicotinonitrile;

3-{1-[3,5-difluoro-4-(methoxymethyl)pyridin-2-yl]pyrrolidin-3-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-[1,3]thiazolo[5,4-d]pyrimidin-5-ylpyrrolidin-3-yl]propanenitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-4-(difluoromethyl)nicotinonitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(5-fluoro-2-methoxypyrimidin-4-yl)pyrrolidin-3-yl)propanenitrile;

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

4-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)pyridazine-3-carbonitrile;

6-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-5-fluoronicotinonitrile;

2-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-5-fluoronicotinonitrile;

2-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-5-methylnicotinonitrile;

4-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-6-(difluoromethyl)pyrimidine-5-carbonitrile;

2-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-6-(difluoromethyl)benzonitrile;

2-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-6-(methoxymethyl)benzonitrile;

4-(3-(1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)pyridazine-3-carbonitrile;

2-(3-(1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)nicotinonitrile;

3-(3-(1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile;

4-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-fluoroethyl)pyrrolidin-1-yl)pyridazine-3-carbonitrile;

3-(3-{2-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)pyridine-2-carbonitrile;

2-(3-{2-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)nicotinonitrile;

4-(1-{1-[1-(1,1-dioxido-2,3-dihydrothieno[2,3-b]pyridin-6-yl)pyrrolidin-3-yl]-2-fluoroethyl}-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine;

2-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-fluoroethyl)pyrrolidin-1-yl)pyridine-3,4-dicarbonitrile;

3-(3-{2-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)phthalonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-4-iodonicotinonitrile;

2-chloro-4-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)nicotinonitrile;

4-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)pyridine-2,3-dicarbonitrile;

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

5-(3-{2-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-1,3-thiazole-4-carbonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-4-(methylthio)nicotinonitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-4-(methylsulfonyl)nicotinonitrile;

3-{1-[3,5-difluoro-6-(methylthio)pyridin-2-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[3,5-difluoro-6-(methylsulfonyl)pyridin-2-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-(1-{3,5-difluoro-6-[(2,2,2-trifluoroethyl)-sulfonyl]pyridin-2-yl}pyrrolidin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

4-[1-(1-{1-[3,5-difluoro-6-(methylsulfonyl)pyridin-2-yl]pyrrolidin-3-yl}-2-fluoroethyl)-1H-pyrazol-4-yl]-7H-pyrrolo-[2,3-d]pyrimidine;

3-{1-[3-fluoro-6-(methylsulfonyl)pyridin-2-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[2,5-difluoro-6-(methylsulfonyl)pyridin-3-yl}pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-4-(1-fluoroethyl)nicotinonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-(difluoromethyl)pyrazine-2-carbonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-(2,2-difluoroethyl)pyrazine-2-carbonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-(hydroxymethyl)pyrazine-2-carbonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-(methoxymethyl)pyrazine-2-carbonitrile;

6-bromo-3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)pyrazine-2-carbonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-ethynylpyrazine-2-carbonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-ethylpyrazine-2-carbonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-methylpyrazine-2-carbonitrile;

3-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-6-methylpyrazine-2-carbonitrile;

3-fluoro-5-(3-{2-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)pyridine-2-carbonitrile;

3-{1-[2-(ethylsulfonyl)pyridin-4-yl]pyrrolidin-3-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propanenitrile;

5-(3-{2-cyano-1-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]ethyl}pyrrolidin-1-yl)-1,3-thiazole-4-carbonitrile;

3-[1-(2-mercaptopyrimidin-4-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

N-[4-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)pyrimidin-2-yl]-N,N-dimethylsulfonamide;

4-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-N-methylpyridine-2-carboxamide;

4-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-N,N-dimethylpyridine-2-carboxamide;

4-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-N-phenylpyridine-2-carboxamide;

3-[1-(2,3-dihydrofuro[2,3-b]pyridin-6-yl)pyrrolidin-3-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-thieno[2,3-b]pyridin-6-ylpyrrolidin-3-yl)propanenitrile;

3-[1-(7,7-difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(7-fluoro-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]propanenitrile;

3-[1-(7-bromo-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

2-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-1,3-benzoxazole-7-carbonitrile;

3-[1-(7-hydroxy-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-[1-(7-methoxy-1,3-benzoxazol-2-yl)pyrrolidin-3-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-(7-ethoxybenzo[d]oxazol-2-yl)pyrrolidin-3-yl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(1-(7-(difluoromethoxy)benzo[d]oxazol-2-yl)pyrrolidin-3-yl)propanenitrile;

3-[1-(4-hydroxy-1,3-benzoxazol-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

3-{1-[7-(hydroxymethyl)-1,3-benzoxazol-2-yl]pyrrolidin-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile;

6-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)furo[3,2-c]pyridine-7-carbonitrile;

6-(3-{2-cyano-1-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]ethyl}pyrrolidin-1-yl)furo[3,2-c]pyridine-7-carbonitrile;

6-(3-{2-cyano-1-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]ethyl}pyrrolidin-1-yl)-2,3-dihydrothieno[3,2-c]pyridine-7-carbonitrile 1,1-dioxide;

6-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-2,3-dihydrothieno[3,2-c]pyridine-7-carbonitrile 1,1-dioxide;

6-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-2,3-dihydrothieno[3,2-c]pyridine-7-carbonitrile;

6-(3-{2-cyano-1-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]ethyl}pyrrolidin-1-yl)-2,3-dihydrothieno[3,2-c]pyridine-7-carbonitrile;

6-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)thieno[3,2-c]pyridine-7-carbonitrile;

6-(3-{2-cyano-1-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-3-yl]ethyl}pyrrolidin-1-yl)thieno[3,2-c]pyridine-7-carbonitrile;

6-(3-{2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile; and

6-((3S)-3-{2-fluoro-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-1-yl)-2,3-dihydrothieno[3,2-c]pyridine-7-carbonitrile 1,1-dioxide,

or a pharmaceutically acceptable salt or N-oxide thereof.

59. The compound according to claim 1, wherein the compound is 6-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyanoethyl)pyrrolidin-1-yl)-2-chloro-5-fluoronicotinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

60. A pharmaceutical composition, comprising a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable carrier.

61. A method of inhibiting an activity of JAK1 comprising contacting JAK1 with a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof.

62. A method according to claim 61, wherein said compound, or pharmaceutically acceptable salt or N-oxide thereof, is selective for JAK1 over JAK2.

63. A compound, which is 3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

66. A pharmaceutical composition, comprising a compound according to claim 63, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

70. A method according to claim 69, wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.

64. A compound, which is (R)-3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl] propanenitrile, or a pharmaceutically acceptable salt thereof.

67. A pharmaceutical composition, comprising a compound according to claim 64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

71. A method of inhibiting an activity of JAK1 comprising contacting JAK1 with a compound according to claim 64, or a pharmaceutically acceptable salt thereof.

65. A compound, which is (S)-3-[1-(6-chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

68. A pharmaceutical composition, comprising a compound according to claim 65, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

72. A method according to claim 65, wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.

73. A method of inhibiting an activity of JAK1 comprising contacting JAK1 with a compound according to claim 65, or a pharmaceutically acceptable salt thereof.

74. A method according to claim 73, wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.