CXCR3 receptor antagonists

摘要

The present invention relates to compounds of formula (I):;
and pharmaceutically acceptable salts thereof, wherein R1 to R3, A, B, X, and n are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

主权项

1. A compound of formula (I): wherein: A is —CH—; B is N; X is —CH2—, —CH2C(O)—, or —CH2CH2—; R1 is in the D- or E-position and is selected from H, —CN, halogen, —CF3, —OCF3, C1-3alkyl, C1-3alkoxy, —CH2OH, —S(O)2CH3, —S(O)2NH2, amino, mono- or dimethylamino, —NHC(O)C1-3alkyl, —NO2, —C(O)NH2, —C(O)C1-3alkyl, phenyl and pyridyl; and if R1 may also be selected from —C(O)NHC1-3alkyl, —C(O)NHC3-6cycloalkyl and —C(O)N(C1-3alkyl)2; R2 is phenyl, naphthyl, 2-pyridyl, 4-pyridyl or benzothiazolyl each optionally substituted with one to two R6, wherein R6 is not ortho to the —C(O)NH— group; R3 is heterocyclyl selected from azabicyclo[2.2.1]hept-2-yl, azepan-1-yl, 1,4-diazepan-1-yl, hexahydropyrrolo[1,2-a]pyrazin-2-yl, morpholin-4-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazepan-4-yl, piperazin-1-yl and piperidin-1-yl or —N(R4)(R5), or R3 is heteroaryl selected from benzimidazol-1-yl, imidazol-1-yl, pyrazol-1-yl imidazo[4,5-b]pyridine-3-yl and 1H-pyrrolo[2,3-b]pyridine-1-yl, with the proviso that X is —CH2CH2—, wherein each heteroaryl or heterocyclyl group is optionally and independently substituted with one to two R7; R4 is H or C1-3alkyl; R5 is selected from
(A) C2-6alkyl,(B) —(CH2)0-1C3-7cycloalkyl,(C) —CH(CH3)C3-7cycloalkyl,(D) —C(R8)(R9)phenyl,(E) —[C(R8)(R9)]0-1heteroaryl,(F) —[C(R8)(R9)]0-1heterocyclyl,(G) —C(O)NHR10, wherein R10 is selected from ethyl, benzyl and phenyl,(H) —S(O)2CH2phenyl,(I) cyclopropyl, optionally substituted with a CN,(J) —CH2CF3,(K) —CH2CF2H,(L) —NHC(O)CH(CH3)phenyl(M) —C(O)(1-methylpiperidin-3-yl),(N) —CH2C(O)NHC1-3 alkyl, and(O) indan-1-yl,(P) —CH2C(O)N(C1-3alkyl)2, wherein each C2-5alkyl, heteroaryl, heterocyclyl or phenyl is optionally and independently substituted with one to four R7; R6 is independently selected from halogen, —CF3, —OCF3, CN, —NO2, —SO2CH3, C1-3alkoxy, C1-4alkyl, phenoxy, benzoyl and phenyl; R7 is independently selected from C1-4alkyl, C3-6cycloalkyl, C1-3alkoxy, —CH2OC1-3alkyl, —OH, oxo, —CHO, —C(O)C1-3alkyl, halogen, —CF3, —CN, and —S(O)2C1-3alkyl; R8 and R9 are independently selected from H and C1-2alkyl; or R8 and R9, together with the carbon they are bonded to, may form a cyclopropyl ring; n is 1; or a pharmaceutically acceptable salt thereof.