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 20100298334A1
• Filed: 05/21/2010
• Published: 11/25/2010
• Est. Priority Date: 05/22/2009
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Glenn, Joseph, Folmer, Beverly, Wang, Haisheng, Shepard, Stacey, Rodgers, James D., Shao, Lixin, Storace, Louis, Arvanitis, Argyrios G., Zhu, Wenyu
• Granted Patent: US 8,716,303 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• 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 hetereoaryl, 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 hetereoaryl, 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 hetereoaryl, 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, a pyridimine 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 pyridimine 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 pyridimine 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, pyridimin-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, pyridimin-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, pyridimin-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.

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, —

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.

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_2-7 heterocycloalkyl-C_1-4-alkyl, phenyl, phenyl-C_1-4-alkyl, C_1-7heteroaryl, and C_1-7heteroaryl-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_1-7heteroaryl.

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, C₂ alkynyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-4 alkylthio, C_1-4 alkylsulfinyl, C_1-4 alkylsulfonyl, amino, C_1-4alkylamino, 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 hetereoaryl, 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 groups;

each R^1a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C_1-4 alkoxy, C_1-4haloalkoxy, 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 hetereoaryl, 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_1-4haloalkoxy, 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 hetereoaryl, 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, C₂ 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 hetereoaryl, 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;

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 hetereoaryl, 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;

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 pyridimine 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_1-6 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 pyridimine 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, a pyridimine 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)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.

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

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, pyridimin-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_1-6 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.

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, pyridimin-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_1-6 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.

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, pyridimin-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_1-6 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 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, pyridimin-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, pyridimin-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, pyridimin-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 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, pyridimin-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;

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, pyridimin-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;

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-yl]-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, 3-1)]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-cyano ethyl)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-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 salt selected from a trifluoroacetic acid salt and a phosphoric acid salt of the compound according to any one of claims 57-59.

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

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

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

64. A method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory 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 or N-oxide thereof.

65. A method according to claim 64, 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.

66. A method according to claim 64, wherein said autoimmune disease is rheumatoid arthritis.

67. A method according to claim 64, wherein said autoimmune diseases is a skin disorder.

68. A method according to claim 67, wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

69. A method according to claim 64, wherein said cancer is a solid tumor.

70. A method according to claim 64, 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.

71. A method according to claim 64, wherein said cancer is lymphoma, leukemia, or multiple myeloma.

72. A method according to claim 64, 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).

73. A method according to claim 64, wherein said myeloproliferative disorder is myelofibrosis.

74. A method according to claim 64, wherein said myeloproliferative disorder is primary myelofibrosis (PMF).

75. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, for use in a method of modulating a JAK1.

76. A compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, for use in a method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, or organ transplant rejection.