Cyclohexyl azetidine derivatives as JAK inhibitors

摘要

The present invention provides cyclohexyl azetidine derivatives of Formula I:;
or pharmaceutically acceptable salts thereof, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAK) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

主权项

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:
X is CR1 or N; Y is CR2 or N; W is CR3 or N; Z is CR4 or N; V is CR5 or N; wherein the 6-membered aromatic ring formed by carbon atom, X, Y, W, Z, and V has 0, 1, or 2 nitrogen ring members; R1, R2, R3, R4, and R5 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Cy, —C1-3 alkylene-Cy, ORa, NReRf, SRb, S(═O)2Rb, S(═O)2NReRf, C(═O)Rb, C(═O)ORa, C(═O)NReRf, OC(═O)Rb, OC(═O)NReRf, NRcC(═O)Rd, NRcC(═O)ORd, NRcS(═O)2Rd, NRcS(═O)2NReRf, and CRoRpORa1, and CRoRpNRe1Rf1; wherein said C1-6 alkyl is optionally substituted by 1, 2, or 3 independently selected Rx groups; R6 is F, methyl, —OH, or —OCH3; each Cy is independently selected from 3-6-membered monocyclic cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl, which are each optionally substituted by 1, 2, or 3 independently selected Regroups; each Ra, Rc, Rd, Re, and Rf is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, Cy1, and —C1-3 alkylene-Cy1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected Rh groups; or each Re and Rf, together with the nitrogen atom to which they are attached, form a 4-6 membered monocyclic heterocycloalkyl ring; which is optionally substituted with 1, 2, or 3 independently selected Rg groups; each Rb is independently selected from C1-6 alkyl, C1-6 haloalkyl, Cy1, and —C1-3 alkylene-Cy1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected Rh groups; Ro and Rp, taken together with the carbon atom to which they are attached, form a 3-4 membered monocyclic cycloalkyl ring; each Cy1 is independently selected from 3-6-membered monocyclic cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl, which are each optionally substituted by 1, 2, or 3 independently selected Rg groups; each Rg is independently selected from halo, CN, hydroxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, hydroxyl-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, cyano-C1-4 alkyl, amino, C1-4 alkylamino, di-C1-4-alkylamino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 alkylsulfonyl, C1-4 alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di-C1-4 alkylaminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino; each Rh is independently selected from halo, CN, hydroxy, C1-4 alkoxy, C1-4 haloalkoxy, hydroxyl-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, cyano-C1-4 alkyl, amino, C1-4 alkylamino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, alkylaminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino; each RX group is independently selected from halo, CN, NO2, ORa1, NRe1Rf1, SRb1, S(═O)2Rb1, S(═O)2NRe1Rf1, C(═O)Rb1, C(═O)ORa1, C(═O)NRe1Rf1, OC(═O)Rb1, OC(═O)NRe1Rf1, NRc1C(═O)Rd1, NRc1C(═O)ORd1, NRc1S(═O)2Rd1, and NRc1S(═O)2NRe1Rf1; each Ra1, Rc1, Rd1, Re1 and Rf1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, Cy2, and —C1-3 alkylene-Cy2; wherein said C1-6 alkyl is optionally substituted by 1, 2, or 3 independently selected Rk groups; or each Re1 and Rf1, together with the nitrogen atom to which they are attached, forms a 4-6 membered monocyclic heterocycloalkyl ring; which is optionally substituted with 1, 2, or 3 independently selected Rm groups; each Rb1 is independently selected from C1-6 alkyl, C1-6 haloalkyl, Cy2, and —C1-3 alkylene-Cy2; wherein said C1-6 alkyl is optionally substituted by 1, 2, or 3 independently selected Rk groups; each Cy2 is independently selected from 3-6-membered monocyclic cycloalkyl, 4-6 membered monocyclic heterocycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryl, which are each optionally substituted by 1, 2, or 3 independently selected Rm groups; each Rk is independently selected from halo, CN, hydroxy, C1-4 alkoxy, C1-4 haloalkoxy, hydroxyl-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, cyano-C1-4 alkyl, amino, C1-4 alkylamino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 alkylcarbonylamino, C1-4 alkylsulfonyl, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, alkylaminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino; each Rm is independently selected from halo, CN, hydroxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, hydroxyl-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, cyano-C1-4 alkyl, amino, C1-4 alkylamino, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 alkylsulfonyl, C1-4 alkylcarbonylamino, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, alkylaminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, and di-C1-4 alkylaminosulfonylamino; and n is 0, 1, or 2.