Derivatives of piperidine antagonists of CXCR3 Receptors, Preparation Method, Pharmaceutical compositions containing them and uses for treating Diseases mediated by CXCR3 receptor activation.

摘要

Item 1: a formula compound (1)a. N-oxidizes the compound, a pharmaceutically acceptable salt of the compound, a stereoisomerized isomer or solution of the compound, wherein X represents n or CH; y and Z independently represent C (= O) or CH2, provided that at least one of Y and Z represents C (= O);R1 represents CH (R4) -aryl or CH (R4) -heteroaryl; R2 represents aryl2 or heteroaryl; R3 represents H, C1-4 alkylcarbonyl, C1-6 alkyl optionally substituted with C1-6 alkyloxy, C1-6 alkylthio, C1-6 alkyloxycarbonyl or aryl1; R4 represents H or C1-4 alkyl; R5 and R6 independently represent H or C1-6 alkyl optionally substituted with hydroxyl; or R5 and R6 together with the N to which they are attached form a monocyclic heterocycle selected from piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, where each of said rings is optionally substituted with C1-4 alkyl; R7 represents H or C1-4 alkyl; aryl represents unsubstituted naphthyl; or phenyl or naphthyl,wherein each of said phenyl or naphthyl is substituted with at least one substituent, where each substituent is independently selected from halo, hydroxyl, C1-6 alkyloxy, C1-6 alkyloxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylthio , polyhalo-C1-6 alkyl, polyhalo-C1-6 alkyloxy, cyano, nitro, carboxyl, HO-SO2-,A c1-4-so2R6R5N-C (3DO) -1. Amino, mono-o di (C1-4 tar) amino, C1-4 C1-4 asphalt, arilo1, arilo1-c1-4 asphalt, arilo1oxi, O arilo1c (= O) -;aryl1 represents phenyl or phenyl substituted with 1; 2 or 3 substituents, where each substituent is independently selected from halo, hydroxyl, C1-6 alkyl, C1-6 alkyloxy, C1-6 alkyloxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylthio, polyhalo-C1-6 alkyl, polyhalo-C 1-6 alkyloxy, cyano, nitro, carboxyl, aminocarbonyl, mono- or di (C 1-4 alkyl) aminocarbonyl, amino, or mono- or di (C 1-4 alkyl) amino; aryl2 represents phenyl or naphthyl, where each of said rings is optionally substituted with at least one substituent, where each substituent is independently selected from halo, hydroxyl, C1-6 alkyl, C1-6 alkyloxy, C1-6 alkyloxycarbonyl,C1-6 alkylcarbonyloxy, C1-6 alkylthio, C1-6 polyhalo-alkyl, C1-6 polyhalo-alkyloxy, cyano, nitro, carboxyl, HO-SO2-,A c1-4-so2R6R5N-C (3DO) -1. Amino, mono-o di (C1-4 tar) amino, C1-4 C1-4 asphalt, arilo1, arilo1-c1-4 asphalt, arilo1oxi, O arilo1c (= O) -;heteroaryl represents a selected monocyclic heterocycle pyrrolinyl, imidazolinyl, pyrazolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl thiomorpholinyl; or bicyclic heterocycle selected from indolyl, indolizinyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, benzoxadiazolyl, benzoxazolyl,benzthiazolyl, wherein each of said monocyclic or bicyclic heterocycles is optionally substituted with at least one substituent, where each substituent is independently selected from halo, hydroxyl, C1-6 alkyl, C1-6 alkyloxy, C1-6 alkyloxycarbonyl, alkylcarbonyloxy C1-6, C1-6 alkylthio, C1-6 polyhalo-alkyl, C1-6 polyhalo-alkyloxy, cyano, nitro, carboxyl, HO-SO2-,A c1-4-so2R6R5N-C (3DO) -1. Amino, mono-o di (C1-4 tar) amine, O lcarbonilamino C1-4, provided that y and Z independently represent C (= O),X represents ch, R3 represents hydrogen, R4 represents hydrogen, R2 represents unreplaced pyridine, or substituted pyridine, or pyridine substituted with halogen or C1-4 tar or one or two C1-4 tar, so in the definition of R1, arilo is not a phenyl substituted with halogen or one or two C1-4 tar; and the condition is that it represents y and Z Independent, independentX stands for CH, R3 stands for hydrogen, R2 stands for pyridine that is not replaced, or pyridine that is replaced by halogen or C1-4 tar or one or two C1-4 tar alternatively. Therefore, in the definition of R1, non-n-octanol is not an unreplaced or unreplaced pyridine.