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
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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.
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Citations
99 Claims
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1-63. -63. (canceled)
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64. A method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, or organ transplant rejection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
- View Dependent Claims (65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99)
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65. A method according to claim 64, wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.
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66. A method according to claim 64, wherein said autoimmune disease is rheumatoid arthritis.
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67. A method according to claim 64, wherein said autoimmune diseases is a skin disorder.
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68. A method according to claim 67, wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
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69. A method according to claim 64, wherein said cancer is a solid tumor.
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70. A method according to claim 64, wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease or pancreatic cancer.
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71. A method according to claim 64, wherein said cancer is lymphoma, leukemia, or multiple myeloma.
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72. A method according to claim 64, wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).
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73. A method according to claim 64, wherein said myeloproliferative disorder is myelofibrosis.
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74. A method according to claim 64, wherein said myeloproliferative disorder is primary myelofibrosis (PMF).
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77. A method according to claim 64, wherein Y is N.
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78. A method according to claim 64, wherein X is cyano.
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79. A method according to claim 64, wherein Z is hydrogen.
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80. A method according to claim 64, wherein Ar is selected from phenyl, C1-6 monocyclic heteroaryl, C1-9 bicyclic heteroaryl, and bicyclic C2-14 fused heterocycloalkylheteroaryl;
- each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1 groups.
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81. A method according to claim 64, 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 R1 groups.
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82. A method according to claim 64, wherein each R1 is independently selected from halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, —
- ORa, —
SRa, —
S(═
O)Rb, —
S(═
O)2Rb, —
S(═
O)NReRf, —
NReRf, —
C(═
O)Rb, —
C(═
O)ORb, —
C(═
O)NReRf, and —
NRcC(═
O)Rd.
- ORa, —
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83. A method according to claim 64, wherein each R1 is independently selected from fluoro, bromo, chloro, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, isopropylamino, dimethylamino, methylthio, methylsulfinyl, and methylsulfonyl.
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84. A method according to claim 64, wherein each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl.
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85. A method according to claim 64, wherein:
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X is cyano or fluoro; Y is CH or N; Z is hydrogen or fluoro; Ar is selected from phenyl, C1-6 monocyclic heteroaryl, C1-6 bicyclic heteroaryl, and bicyclic C2-14 fused heterocycloalkylheteroaryl;
each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1 groups;each R1 is independently selected from halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, C1-6 heteroaryl, C1-6 heteroaryl-C1-4-alkyl, —
ORa, —
SRa, —
S(═
O)Rb, —
S(═
O)2Rb, —
S(═
O)NReRf, —
NReRf, —
C(═
O)Rb, —
C(═
O)ORb, —
C(═
O)NReRf, —
NRcC(═
O)Rd, and —
NRcC(═
O)ORd;
wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R1a groups;
wherein said C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, C1-6 heteroaryl, and C1-6 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R2a groups;each R1a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, and di-C1-4-alkylamino; each R2a is independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, and di-C1-4-alkylamino; each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-4-alkyl;
wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rx groups; and
wherein said C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Ry groups;each Rx is independently selected from hydroxyl, C1-4 alkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino; and each Ry is independently selected from hydroxyl, halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino.
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86. A method according to claim 64, wherein:
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X is cyano or fluoro; Y is CH or N; Z is hydrogen or fluoro; Ar is selected from phenyl, C1-6 monocyclic heteroaryl, C1-9 bicyclic heteroaryl, bicyclic C2-14 fused cycloalkylheteroaryl, and bicyclic C2-14 fused heterocycloalkylheteroaryl;
each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1 groups;each R1 is independently selected from halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, —
ORa, —
SRa, —
S(═
O)Rb, —
S(═
O)2Rb, —
S(═
O)NReRf, —
NReRf, —
C(═
O)Rb, —
C(═
O)ORb, —
C(═
O)NReRf, and —
NRcC(═
O)Rd; andeach Ra, Rb, Rc, Rd, Re, and Rf is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-4-alkyl.
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87. A method according to claim 64, wherein:
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X is cyano or fluoro; Y is CH or N; Z is hydrogen or fluoro; Ar is selected from phenyl, thiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, benzo[d]oxazol-2-yl, oxazolo[4,5-c]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, oxazolo[5,4-d]pyrimidin-2-yl, 7H-pyrrolo[2,3-d]pyrimidin-2-yl, 2,3-dihydrothieno[2,3-b]pyridin-6-yl, S-oxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[2,3-b]pyridin-6-yl, quinazolin-2-yl, quinolin-2-yl, pyrrolo[2,3-b]pyridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, 3-oxo-3,4-dihydropyrazin-2-yl, quinoxalin-2-yl, thiazol-4-yl, thiazol-5-yl, pyrimidin-5-yl, oxazolo[5,4-d]pyrimidin-2-yl, thieno[3,2-b]pyridin-5-yl, thieno[2,3-c]pyridin-5-yl, thiophen-2-yl, thiophen-3-yl, thiazolo[5,4-d]pyrimidin-5-yl, thieno[2,3-b]pyridin-6-yl, 2,3-dihydrofuro[2,3-b]pyridin-6-yl, 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl, furo[3,2-c]pyridin-6-yl, 2,3-dihydrothieno[3,2-c]pyridin-6-yl, S-oxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, S,S-dioxo-2,3-dihydrothieno[3,2-c]pyridin-6-yl, thieno[3,2-c]pyridin-6-yl, and 1H-pyrrolo[3,2-c]pyridin-6-yl;
each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R1 groups; andeach R1 is independently selected from fluoro, bromo, chloro, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, isopropylamino, dimethylamino, methylthio, methylsulfinyl, and methylsulfonyl.
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88. A method according to claim 64, having formula Ia:
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89. A method according to claim 64, having formula Ib:
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90. A method according to claim 64, having formula Ic:
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91. A method according to claim 64, having formula Id:
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92. A method according to claim 64, having formula Ie:
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93. A method according to claim 64, having formula If:
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94. A method according to claim 64, wherein said compound is selected from:
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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.
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95. A method according to claim 64, wherein said compound is selected from:
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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.
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96. A method according to claim 64, wherein the compound is 6-(3-(1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-cyano ethyl)pyrrolidin-1-yl)-2-chloro-5-fluoronicotinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.
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97. A method, according to claim 64, 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.
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98. A method, according to claim 64, 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.
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99. A method, according to claim 64, 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.
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65. A method according to claim 64, wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.
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75-76. -76. (canceled)
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Current AssigneeIncyte Holdings Corporation And Incyte Corporation
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Original AssigneeIncyte Corporation
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InventorsShepard, Stacey, Arvanitis, Argyrios G, Wang, Haisheng, Storace, Louis, Folmer, Beverly, Zhu, Wenyu, Glenn, Joseph, Shao, Lixin, Rodgers, James D
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/249
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CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/04 AntipruriticsA61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 19/08 for bone diseases, e.g. rac...A61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 37/00 Drugs for immunological or ...A61P 37/02 ImmunomodulatorsA61P 37/06 Immunosuppressants, e.g. dr...A61P 37/08 Antiallergic agents antiast...A61P 5/14 of the thyroid hormones, e....A61P 9/00 Drugs for disorders of the ...C07D 471/04 : Ortho-condensed systemsC07D 487/04 : Ortho-condensed systemsC07D 491/048 : the oxygen-containing ring ...C07D 495/04 : Ortho-condensed systemsC07D 498/04 : Ortho-condensed systemsC07D 513/04 : Ortho-condensed systemsC07D 519/00 : Heterocyclic compounds cont...