Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors

摘要

The present invention provides heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines of Formula I:;
wherein X, Y, Z, L, A, R5, n, m, and r are defined above, as well as their compositions and methods of use, that modulate the activity of Janus kinases (JAKs) and are useful in the treatment of diseases related to the activity of JAKs 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 CH or N; Y is H, cyano, halo, C1-3 alkyl, or C1-3 haloalkyl; Z is N; L is O or S; R1, R2, and R3 are each independently H, hydroxy, halo, C1-3 alkyl, or C1-3 haloalkyl; each R5 is independently hydroxy, C1-4 alkoxy, fluorine, C1-4 alkyl, hydroxy-C1-4-alkyl, C1-4 alkoxy-C1-4-alkyl, or C1-4 fluoroalkyl; A is C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C6-10 aryl, or C1-10 heteroaryl; each optionally substituted with p independently selected R7 substituents; wherein p is 1, 2, 3, 4, or 5; each R7 is independently selected from halo, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocycloalkyl, C2-10 heterocycloalkyl-C1-4-alkyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-10 heteroaryl, C1-10 heteroaryl-C1-4-alkyl, —ORa, —SRa, —S(═O)Rb, —S(═O)2b, —S(═O)2NReRf, —C(═O)Rb, —C(═O)ORa, —C(═O)NReRf, —OC(═O)Rb,—OC(═O)NReRf, —NReRf, —NRcC(═O)Rd, —NRcC(═O)ORd, —NRcC(═O)ORd, —NRcS(═O)2Rd, and —NRcS(═O)2NReRf; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocycloalkyl, C2-10 heterocycloalkyl-C1-4-alkyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-10 heteroaryl, and C1-10 heteroaryl-C1-4 -alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rg groups; each Ra, Rc, Rd, Re, and Rf is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocycloalkyl, C2-10 heterocycloalkyl-C1-4-alkyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-10 heteroaryl, and C1-10 heteroaryl-C1-4-alkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocycloalkyl, C2-10 heterocycloalkyl-C1-4-alkyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-10 heteroaryl, and C1-10 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rg groups; each Rb is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocycloalkyl, C2-10 heterocycloalkyl-C1-4-alkyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-10 heteroaryl, and C1-10 heteroaryl-C1-4-alkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4-alkyl, C2-10 heterocycloalkyl, C2-10 heterocycloalkyl-C1-4-alkyl, C6-10 aryl, C6-10 aryl-C1-4-alkyl, C1-10 heteroaryl, and C1-10 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rg groups; each Rg is independently selected from halo, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-3-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, C1-7 heteroaryl, C1-7 heteroaryl-C1-3-alkyl, —ORa1, —SRa1, —S(═O)Rb1, —S(═O)2Rb1, —S(═O)2NRe1Rf1, —C(═O)Rb1, —C(═O)ORa1, —C(═O)NRe1Rf1, —OC(═O)Rb1, —OC(═O)NRe1Rf1, —NRe1Rf1, —NRc1C(═O)Rd1, —NRc1C(═O)ORd1, —NRc1C(═O)NRd1, —NRc1S(═O)2Rd1, and —NRc1S(═O)2NRe1Rf1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-3-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-3-alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected Rh groups; each Ra1, Rc1, Rd1, Re1, and Rf1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-3-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-3-alkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-3-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-3-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rh groups; each Rb1 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-3-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-3-alkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-3-alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-3-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rh groups; each Rh is independently selected from cyano, halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, di-C1-4-alkylamino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6- alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and r is 1, 2, or 3.