TrkA kinase inhibitors, compositions and methods thereof

摘要

The present invention is directed to benzyl urea compounds, which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence may be 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 Trk-A, Trk-B and/or Trk-C.;

主权项

1. A compound of formula (I): and pharmaceutically acceptable salts thereof, wherein: R represents hydrogen, C1-6 alkyl, or —O—; R1 is selected from C5-10 heterocycle selected from the group consisting of optionally substituted pyrrolopyridinyl, said heterocycle optionally substituted with 1 to 3 groups of Ra; R2 is selected from C6-10 aryl, C5-10 heterocycle, C3-10 cycloalkyl, said aryl, heterocycle, and cycloalkyl optionally substituted with 1 to 3 groups of Ra; R3 represents C2-6 alkyl, C2-6 alkynyl, and (CH2)nC3-10 cycloalkyl, said alkyl, alkynyl, and cycloalkyl optionally substituted with 1 to 3 groups of Ra; R4 can be hydrogen, or CH(CH3)C≡CH, Ra represents —CN, —O—, —(CH2)nC1-4haloalkyl, —C1-6alkyl, —C1-6alkenyl, —C1-6alkynyl, —(CHR)nC6-10 aryl, —(CHR)nC5-10 heterocycle, —C3-10 cycloalkyl, —O—C6-10 aryl, —O—C5-10 heterocycle, —C(O)CF3, —(CH2)nhalo, —OR, —NRR, NHC6-10aryl, —SCF3, SO2CF3, OC(F)2Cl, OC1-4 haloalkyl, C(O)NRR, SO2R, SO2NRR, OC(F)2C(F)3, S(O)2CH(F)2, OC(F)2CH(F)2, C(CH3)2C≡N, —COC6-10 aryl, or —CO2R, said cycloalkyl, alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of Rb; Rb represents, —CN, —(CH2)nC1-4haloalkyl, —OC1-4haloalkyl, —C1-6alkyl, (CH2)nOR, —(CHR)nC6-10 aryl, —(CHR)nC5-10 heterocycle, —C3-10 cycloalkyl, —(CH2)nhalo, —OR, C(O)OR, —NRR, C(O)NRR, NRC3-10 cycloalkyl, or C(O)NHC3-10cycloalkyl, said aryl and heterocycle optionally substituted with 1 to 3 groups of C1-6alkyl, or halo, and n represents 0-6.