Substituted pyrrolo[3,2-c]pyridines as TrkA kinase inhibitors

摘要

The present invention is directed to compounds of formula I and Ia: which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.;

主权项

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein ————— is a bond that when present forms a double bond with bond a or bond b; X1 is —N or —N+—O−; X2is —CH; X3is —N; Y is —CH; ——— is present at a; R is a C6-10 aryl, C5-10 heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 groups of Ra; R1 is a (CH2)nC6-10 aryl, (CH2)nC5-10 heteroaryl, and C5-10 heterocyclyl, said heterocyclyl selected from pyrrolidinyl, oxopyrrolidinyl, piperidinyl, or hydrogen, said aryl, heteroaryl, pyrrolidinyl, oxopyrrolidinyl, and piperidinyl optionally substituted with 1 to 3 groups of Rb; R2 is hydrogen, or C1-6 alkyl; A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)nO—, —CH2C(O)NH—, —O—, or —NR2—; R3 is hydrogen, CN, or C5-10 heterocyclyl, said heterocyclyl optionally substituted with 1 to 3 groups of Ra; Ra is —CN, —C1-4haloalkyl, halo, —C1-6alkyl, —OR, —NR2R2, or —NH(CH2)nOH; Rb is —CN, —C1-4haloalkyl, —OC1-4haloalkyl, —O(CH2)nhaloalkyl, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —(CH2)nC6-10 aryl, —(CH2)nC5-10 heterocyclyl, —(CH2)nO—C6-10 aryl, —(CH2)nO—C5-10 heterocyclyl, —C(O)C6-10aryl, —NHC6-10aryl, halo, —OR, —NR2R2, or SO2R2, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of Ra; and n is 0, 1, 2, 3, or 4.