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

摘要

A compound of formula I: or a pharmaceutically acceptable salt or N-oxide thereof; in which: X is cyano or halogen; Y is CH or N; Z is hydrogen, C1-4 alkyl, fluorinated C1-4 alkyl or fluorine; Ar is C6-14 aryl, C1-14 heteroaryl, C7-14 cycloalkyl-fused aryl, heterocycloalkyl C6-14-aryl condensed, cycloalkyl C2-14-heteroaryl fused or heterocycloalkyl C2-14-fused heteroaryl, 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, C3-14 cycloalkyl, C3-14 cycloalkyl-C1-4 alkyl, C2- heterocycloalkyl 14, C2-14 heterocycloalkyl-C1-4 alkyl, C6-14 aryl, C6-14 aryl-C1-4 alkyl, C1-13 heteroaryl, C1-13 heteroaryl-C1-4 alkyl, -ORa, -SR3, -S ( = O) Rb, -S ( = O) 2Rb, -S ( = O) NReRf, -C ( = O) Rb, -C ( = O) ORb, -C ( = O) NReRf, -OC ( = O) Rb, - OC ( = O) NReRf, -NReRf, -NRcC ( = O) Rd, -NRcC ( = O) ORd, -NRcS ( = O) 2Rd and -NRbS ( = O) 2NReRf; wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with independently selected 1, 2, 3 or 4 R1 to 30 groups; and wherein said C3-14 cycloalkyl, C3-14 cycloalkyl-C1-4 alkyl, C2-14 heterocycloalkyl, C2-14 heterocycloalkyl-C1-4 alkyl, C6-14 aryl, C6-14 aryl-C1-4 alkyl, C1-13 heteroaryl and C1-13 heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R2a groups; Each R1a is independently selected from halogen, cyano, nitro, hydroxyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkyl sulfonyl, amino, C1- alkyl 4-amino, di-C 1-4 alkyl-amino, C 1-4 alkylcarbonyl, carboxy, C 1-4 alkoxycarbonyl, C 1-4 alkylcarbonylamino, C 1-4 alkylcarbonylamino, C 1-4 alkoxy carbonylamino, C 1-4 alkoxycarbonyl- (C 1-4 alkyl) amino, carbamyl, C 1-4 alkylcarbamyl and diC 1-4 alkylcarbamyl; each R2a is independently selected from halogen, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkyl , C 1-4 alkyl sulfinyl, C 1-4 alkyl sulfonyl, amino, C 1-4 alkyl, di C 1-4 alkyl, C 1-4 alkylcarbonyl, carboxy, C 1-4 alkoxycarbonyl, alkyl C1-4- carbonylamino, di-C1-4 alkylcarbonylamino, C1-4 alkoxycarbonylamino, C1-4 alkoxycarbonyl- (C1-4 alkyl) amino, carbamyl, C1-4 alkylcarbamyl and di-C1 alkyl -4-carbamyl; Each Ra, Rb, Rc, Rd, Re and Rf are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl -4, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4 alkyl, heteroaryl C1-7 and heteroaryl C1-7-alkyl C1-4 alkyl; wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with 1, 2, 3 or 4 independently selected Rx 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 heteroaryl C1-7-C1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected Ry groups; or any Rc and Rd, together with the rest 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 independently selected groups of hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkyl and di C 1-4 alkyl; or any Re and Rf, 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 alkyl and di C 1-4 alkyl -Not me; each Rx is independently selected from hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkyl and di C 1-4 alkyl; and each Ry 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 alkyl and di C 1-4 alkyl -Not me; provided that the valence of each atom in the optionally substituted residues is not exceeded.