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

1. A method of treating a disease selected from myelofibrosis, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), post polycythemia vera myelofibrosis (Post-PV MF), post essential thrombocythemia myelofibrosis (Post-ET MF), multiple myeloma, pancreatic cancer, breast cancer, lung cancer, colorectal cancer, rheumatoid arthritis, a skin disorder, lymphoma, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), graft versus host disease, cachexia, and Castleman's disease in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of 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 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 1-4 haloalkoxy, amino, C 1-4 alkylamino, and di-C 1-4 -alkylamino;

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

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 1-14 haloalkyl, C 1-14 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 method according to claim 1 , wherein said autoimmune disease is rheumatoid arthritis.

3. A method according to claim 1 , wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

4. A method according to claim 1 , wherein said disease is breast cancer, lung cancer, colorectal cancer, Castleman's disease or pancreatic cancer.

5. A method according to claim 1 , wherein said disease is lymphoma, leukemia, or multiple myeloma.

6. A method according to claim 1 , wherein said disease is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute myelogenous leukemia, acute lymphoblastic leukemia, post polycythemia vera myelofibrosis (Post-PV MF) or post essentioal thrombocythemia myelofibrosis (Post-ET MF).

7. A method according to claim 1 , wherein said disease is myelofibrosis.

8. A method according to claim 1 , wherein said disease is primary myelofibrosis (PMF).

9. A method according to claim 1 , wherein Y is N.

10. A method according to claim 1 , wherein X is cyano.

11. A method according to claim 1 , wherein Z is hydrogen.

12. A method according to claim 1 , 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.

13. A method according to claim 1 , 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, 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.

14. A method according to claim 1 , 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 .

15. A method according to claim 1 , wherein each R 1 is independently selected from fluoro, bromo, chloro, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, isopropylamino, dimethylamino, methylthio, methylsulfinyl, and methylsulfonyl.

16. A method according to claim 1 , 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.

17. A method according to claim 1 , 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 1-6 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 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 groups;

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

each R 2a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, amino, C 1-4 alkylamino, and di-C 1-4 -alkylamino;

each R a , R b , R c , R d , R e , and R f is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-7 heterocycloalkyl, C 2-7 heterocycloalkyl-C 1-4 -alkyl, phenyl, phenyl-C 1-4 -alkyl, C 1-7 heteroaryl, and C 1-7 heteroaryl-C 1-4 -alkyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R x groups; and wherein said C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 -alkyl, C 2-7 heterocycloalkyl, C 2-7 heterocycloalkyl-C 1-4 -alkyl, phenyl, phenyl-C 1-4 -alkyl, C 1-7 heteroaryl, and C 1-7 heteroaryl-C 1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R y groups;

each R x is independently selected from hydroxyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, and di-C 1-4 -alkylamino; and

each R y is independently selected from hydroxyl, halogen, cyano, nitro, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, and di-C 1-4 -alkylamino.

18. A method according to claim 1 , 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.

19. A method according to claim 1 , 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.

20. A method according to claim 1 , having formula Ia:

or a pharmaceutically acceptable salt or N-oxide thereof.

21. A method according to claim 1 , having formula Ib:

or a pharmaceutically acceptable salt or N-oxide thereof.

22. A method according to claim 1 , having formula Ic:

or a pharmaceutically acceptable salt or N-oxide thereof.

23. A method according to claim 1 , having formula Id:

or a pharmaceutically acceptable salt or N-oxide thereof.

24. A method according to claim 1 , having formula Ie:

or a pharmaceutically acceptable salt or N-oxide thereof.

25. A method according to claim 1 , having formula If:

or a pharmaceutically acceptable salt or N-oxide thereof.

26. A method 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-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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

6-(3-{2-cyano-1-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-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.

28. A method 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 thereof.

29. A method, according to claim 1 , wherein the compound 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.

30. A method, according to claim 1 , wherein the compound 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.

31. A method, according to claim 1 , wherein the compound 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.

32. A method according to claim 1 , wherein the skin disorder is psoriasis.

33. A method according to claim 1 , wherein the disease is cachexia.

34. A method according to claim 1 , wherein the disease is graft versus host disease.