IP Library › Granted Patent US 8,716,303

Granted Patent B2

US 8,716,303 · App. 12/784,916 · Granted May 6, 2014

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

Inventors: James D. Rodgers (Landenberg, PA); Stacey Shepard (Wilmington, DE); Argyrios G. Arvanitis (Kennett Square, PA); Haisheng Wang (Hockessin, DE); Louis Storace (Middletown, DE); Beverly Folmer (Hockessin, DE); Lixin Shao (Newark, DE); Wenyu Zhu (Media, PA); Joseph Glenn (Mount Royal, NJ)

Assignee: Incyte Corporation

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Quick Facts

Patent No.: US 8,716,303
App. No.: 12/784,916
Granted: May 6, 2014
Kind: B2

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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 (376)

1. A compound of Formula I:

or a pharmaceutically acceptable salt or N-oxide thereof; wherein:

X is cyano or halogen;

Y is CH or N;

Z is hydrogen, C 1-4 alkyl, C 1-4 fluorinated alkyl, or fluoro;

Ar is C 6-14 aryl, C 1-14 heteroaryl, C 7-14 fused cycloalkylaryl, C 6-14 fused heterocycloalkylaryl, C 2-14 fused cycloalkylheteroaryl, or C 2-14 fused heterocycloalkylheteroaryl, each of which is optionally substituted by 1, 2, 3, 4, 5, or 6 independently selected R 1 groups;

each R 1 is independently selected from halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-4 -alkyl, C 2-14 heterocycloalkyl, C 2-14 heterocycloalkyl-C 1-4 -alkyl, C 6-14 aryl, C 6-14 aryl-C 1-4 -alkyl, C 1-13 heteroaryl, C 1-13 heteroaryl-C 1-4 -alkyl, —OR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O)NR e R f , —C(═O)R b , —C(═O)OR b , —C(═O)NR e R f , —OC(═O)R b , —OC(═O)NR e R f , —NR e R f , —NR c C(═O)R d , —NR c C(═O)OR d , NR c S(═O) 2 R d , and —NR b S(═O) 2 NR e R f ; 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; and wherein said C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-4 -alkyl, C 2-14 heterocycloalkyl, C 2-14 heterocycloalkyl-C 1-4 -alkyl, C 6-14 aryl, C 6-14 aryl-C 1-4 -alkyl, C 1-13 heteroaryl, and C 1-13 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 halogen, 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, di-C 1-4 -alkylamino, C 1-4 alkylcarbonyl, carboxy, C 1-4 alkoxycarbonyl, C 1-4 -alkylcarbonylamino, di-C 1-4 -alkylcarbonylamino, C 1-4 -alkoxycarbonylamino, C 1-4 -alkoxycarbonyl-(C 1-4 alkyl)amino, carbamyl, C 1-4 alkylcarbamyl, and di-C 1-4 -alkylcarbamyl;

each R 2a is independently selected from halogen, cyano, nitro, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, 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, di-C 1-4 -alkylamino, C 1-4 alkylcarbonyl, carboxy, C 1-4 alkoxycarbonyl, C 1-4 -alkylcarbonylamino, di-C 1-4 -alkylcarbonylamino, C 1-4 -alkoxycarbonylamino, C 1-4 -alkoxycarbonyl-(C 1-4 alkyl)amino, carbamyl, C 1-4 alkylcarbamyl, and di-C 1-4 -alkylcarbamyl;

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;

or any R c and R d , together with the moiety to which they are attached, can form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 14 haloalkoxy, amino, C 1-4 alkylamino, and di-C 1-4 -alkylamino;

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

each R x is independently selected from hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 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;

provided that the valency of each atom in the optionally substituted moieties is not exceeded.

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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 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 R 1 groups.

22. A compound according to claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R 1 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) 2 R b , —S(═O)NR e R f , —NR e R f , —C(═O)R b , —C(═O)OR b , —C(═O)NR e R f , —NR c C(═O)R d , and —NR c C(═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 R 1 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) 2 R b , —S(═O)NR e R f , —NR e R f , —C(═O)R b , —C(═O)OR b , —C(═O)NR e R f , and —NR c C(═O)R d .

24. A compound according to claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R 1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, —OR a , —SR a , —S(═O)R b , —S(═O) 2 R b , and —NR e R f .

25. A compound according to claim 1 , or a pharmaceutically acceptable salt or N-oxide thereof, wherein each R 1 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 1-7 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 R 1 groups;

each R 1 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) 2 R b , —S(═O)NR e R f , —NR e R f , —C(═O)R b , —C(═O)OR b , —C(═O)NR e R f , —NR c C(═O)R d , and —NR c C(═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 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 R 1 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 R 1 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 R 1 groups;

each R 1 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) 2 R b , —S(═O)NR e R f , —NR e R f , —C(═O)R b , —C(═O)OR b , —C(═O)NR e R f , and —NR c C(═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;

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 R 1 groups;

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 R 1 groups;

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 R 1 groups;

each R 1 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) 2 R b , —S(═O)NR e R f , —NR e R f , —C(═O)R b , —C(═O)NR e R f , and —NR c C(═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;

each R 1 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) 2 R b , and —NR e R f ; and

each R a , R b , R c , 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;

each R 1 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR a , —SR a , —S(═O)R b , —S(═O) 2 R b , and —NR e R 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;

each R 1 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR a , —SR a , —S(═O)R b , —S(═O) 2 R b , and —NR e R 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;

each R 1 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR a , —SR a , —S(═O)R b , —S(═O) 2 R b , and —NR e R 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 R 1 groups;

each R 1 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) 2 R b , and —NR e R 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;

each R 1 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR a , —SR a , —S(═O)R b , —S(═O) 2 R b , and —NR e R 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;

each R 1 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;

each R 1 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 R 1 groups; and

each R 1 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:

or a pharmaceutically acceptable salt or N-oxide thereof.

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

or a pharmaceutically acceptable salt or N-oxide thereof.

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

or a pharmaceutically acceptable salt or N-oxide thereof.

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

or a pharmaceutically acceptable salt or N-oxide thereof.

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

or a pharmaceutically acceptable salt or N-oxide thereof.

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

or a pharmaceutically acceptable salt or N-oxide thereof.

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 R 1 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 R 1 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 R 1 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-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.

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.

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.

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

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

68. A pharmaceutical composition, comprising a compound according to claim 65 , 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.

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.

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.

Assignments (3)

CORRECTIVE ASSIGNMENT TO CORRECT THE OMMISSION OF SECOND RECEIVING PARTY NAME PREVIOUSLY RECORDED AT REEL: 035292 FRAME: 0004. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Jul 2, 2015

From: INCYTE CORPORATION

To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION

Reel/Frame 036054/0696 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2015

From: INCYTE CORPORATION

To: INCYTE HOLDINGS CORPORATION AND INCYTE CORPORATION

Reel/Frame 035924/0004 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 22, 2010

From: RODGERS, JAMES D.; SHEPARD, STACEY; ARVANITIS, ARGYRIOS G.; WANG, HAISHENG; STORACE, LOUIS; FOLMER, BEVERLY; SHAO, LIXIN; ZHU, WENYU; GLENN, JOSEPH

To: INCYTE CORPORATION

Reel/Frame 024725/0213 →

Continuity (3)

Provisional Application 61180622 · May 22, 2009

Provisional Application 61225092 · Jul 13, 2009

Related Publication 20100298334A1 · Nov 25, 2010