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

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, C1-4 alkyl, C1-4 fluorinated alkyl, or fluoro;
• Ar is C6-14 aryl, C1-14 heteroaryl, C7-14 fused cycloalkylaryl, C6-14 fused heterocycloalkylaryl, C2-14 fused cycloalkylheteroaryl, or C2-14 fused heterocycloalkylheteroaryl, each of which is optionally substituted by 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, C2-14 heterocycloalkyl, 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, —SRa, —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 by 1, 2, 3, or 4 independently selected R1a 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 by 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 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, di-C1-4-alkylamino, C1-4 alkylcarbonyl, carboxy, C1-4 alkoxycarbonyl, C1-4-alkylcarbonylamino, di-C1-4-alkylcarbonylamino, C1-4-alkoxycarbonylamino, C1-4-alkoxycarbonyl-(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, and di-C1-4-alkylcarbamyl;
• each R2a is independently selected from halogen, cyano, nitro, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, di-C1-4-alkylamino, C1-4 alkylcarbonyl, carboxy, C1-4 alkoxycarbonyl, C1-4-alkylcarbonylamino, di-C1-4-alkylcarbonylamino, C1-4-alkoxycarbonylamino, C1-4-alkoxycarbonyl-(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, and di-C1-4-alkylcarbamyl;
• 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;
• or any Rc and Rd, 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, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C14 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino;
• 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, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino;
• each Rx is independently selected from hydroxyl, C1-4 alkoxy, C1-4 haloalkoxy, 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, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino;
• provided that the valency of each atom in the optionally substituted moieties is not exceeded.