Derivatives of N - (hetero) pyrrolidine aryl pyrazole - 4-yl pyrrolo 2,3-d pyrimidines and pyrrole - 3 - il pyrrolo 2,3-d pyrimidines as Janus Kinase Inhibitors and Pharmaceutical compositions containing them

摘要

Jak Inhibitors, such as Selective inhibitors of JAK1, useful in the treatment of diseases associated with Jak, including, for example, inflammatory and Autoimmune Disorders and cancer.Claim 1: wherein is a compound of formula (1) or a pharmaceutically acceptable Salt or n-oxide thereof; where X is halogeno, cyano or; is CH or N; Z is Hydrogen, c1-4 alkyl, c1-4 alkyl fluoride or Fluorine; ar is aryl, heteroaryl c6-14, C1 C7 - 14 - 14, cicloalquilarilo fusi Held, heterocicloalquilarilo c6-14 merged, cicloalquilheteroarilo C2 14 mergedOr heterocicloalquilheteroarilo C2 14 merged, each of which is optionally substituted with 1, 2, 3, 4, 5 or 6 groups R1 selected independently; each R1 is independently selected from alkyl halogeno, cyano, Nitro, C1 - 6 - 6, haloalquilo C1, C2 alquenilo - 6, alkyd Quot C2 - C3 - cycloalkyl 6, 13, 14 cicloalquil C3 alkyl heterocicloalquilo C1 - C2 - 14 4Heterocicloalquil C2 14 c1-4 alkyl, aryl aryl C6 C6 - 14 - 14 - c1-4 alkyl, heteroaryl heteroaryl c1-3, c1-3 alkyl c1-4, ora, - S, - (= o) - (RB, S = o) 2rb, - S nrerf (= o) - C (= o) - RB, Orb, C (= o) - C (= o) - nrerf, OC (= o) - RB, OC (= o) - nrerf, nrerf, NRCC (= o) - RD, NRCC (= OR) ord - NRCC (= o) - NRD, NRCS (= o) - 2RD, and nrbs (= o) 2nrerf; where the alkyl C1 - 6 - 6, haloalquilo C1, C2 alquenilo - 6Alquinilo C2 and 6 are each optionally replaced with 1, 2, 3 or 4 groups A1A selected independently; and where the cycloalkyl C3 C3 - 14 - 14, cicloalquil c1-4 alkyl, heterocicloalquilo C2 C2 - 14 - 14, heterocicloalquil c1-4 alkyl, aryl aryl c6-14, C6 14 c1-4 alkyl, heteroar ILO c1-3, and heteroaryl c1-3 alkyl C1 - 4 are each optionally replaced with 1, 2,3 or 4 groups 2a selected independently, each is selected independently between A1A halogeno, cyano, Nitro, hydroxyl, c1-4 alkoxy, haloalcoxi c1-4, Alquiltio c1-4, alquilsulfinilo c1-4, alquilsulfonilo c1-4, amino, alquilamino c1-4, di - alquilamino C1 - 4 alquilcarbonilo, c1-4, Alcoxicarbonilo carboxy, c1-4, alquilcarbonilamino c1-4, di - alquilcarbonilamino c1-4,Alcoxicarbonilamino c1-4, alcoxicarbonil C1 - 4 - (c1-4 alkyl) amino alquilcarbamilo Carbamyl, c1-4, and di aiquilcarbamilo c1-4; each 2a is selected independently between halogeno, cyano, Nitro, hydroxyl, c1-4 alkyl, haloalquilo alquenilo C1 - C2 - 4, 4 alquinilo c2-4, c1-4 alkoxy, haloalcox I Alquiltio c1-4, c1-4, alquilsulfinilo c1-4, alquilsulfonilo c1-4, amino, alquilamino c1-4,Di - alquilamino c1-4, alquilcarbonilo c1-4, carboxy, alcoxicarbonilo c1-4, alquilcarbonilamino c1-4, di - alquilcarbonilamino c1-4, alcoxicarbonilamino c1-4, alcoxicarbonil C1 - 4 - (c1-4 alkyl) amino alquilcarbamilo Carbamyl, c1-4, and di alquilcarbamilo C1 - 4; each ra, RB, RC, RD, re, and RF is selected Independently between h, alkyl haloalquilo C1 C1 - 6, - 6, - 6 alquinilo alquenilo C2, C2 - 6Cycloalkyl C3 C3 - 7 - 7, cicloalquil c1-4 alkyl, heterocicloalquilo C2 C2 - 7 - 7, heterocicloalquil c1-4 alkyl, phenyl, phenyl alkyl C1 - 4, 7 - heteroaryl heteroaryl C1, C1 and C1 - 4 - 7 - Rent; where the alkyl haloalquilo C1 C1 - 6 - 6, 6 - alquinilo alquenilo C2 and C2 - 6 are each optionally its Replace with 1, 2,RX 3 or 4 groups selected independently; and where the cycloalkyl C3 C3 - 7 - 7, cicloalquil c1-4 alkyl, heterocicloalquilo C2 C2 - 7 - 7, heterocicloalquil c1-4 alkyl, phenyl, phenyl alkyl C1 - 4, 7 - heteroaryl heteroaryl C1, C1 C1 alkyl - 7 - - 4 are each optionally replaced with 1, 2, 3 or 4 groups ry selected independently; or any RC and Rd,Along with the unit to which they are United, they form a ring heterocicloalquilo 3, 4, 5, 6 or 7 members, where the ring heterocicloalquilo is optionally substituted with 1, 2, 3 or 4 groups independently selected from hydroxyl, c1-4 alkyl, haloalquilo c1-4, alcox I haloalcoxi c1-4, c1-4, amino, alquilamino c1-4, and di - or any alquilamino c1-4, re and RFAlong with the nitrogen Atom to which they are United, they form a Ring heteroaryl or heterocicloalquilo 3, 4, 5, 6 or 7 members, where the heterocicloalquilo or heteroaryl ring is optionally substituted with 1, 2, 3 or 4 independently selected from hydroxyl groups C1-4 alkyl, haloalquilo c1-4 alkoxy, c1-4, haloalcoxi c1-4, amino, alquilamino c1-4,Di - and alquilamino c1-4; each RX is selected independently from hydroxyl, c1-4 alkoxy, amino, haloalcoxi c1-4, alquilamino c1-4, and di alquilamino c1-4; and every ry is selected independently from hydroxyl, halogeno, cyano, Nitro, c1-4 alkyl haloalquilo, c1-4 alkoxy, c1-4, Hal Oalcoxi c1-4, amino, alquilamino c1-4,Di - and alquilamino c1-4, provided that it does not exceed the value of each Atom in the units optionally substituted.