Piperazine Derivatives of oxo - and oxo diazepam, Methods for their Preparation and their use for the treatment of diseases mediated by the antagonism of receptor CCR2, CCR3 and CCR5.

摘要

These compounds are antagonistic to CCR2 receptor, CCR5 receptor and / or CCR3 receptor and can be used as drugs to treat asthma, rheumatoid arthritis and stroke. Item 1: compounds of formula (1), wherein a is arilo, heterosexual, arilmetho or heterosexual, arilo and arilmetho of arilmetho and arilmetho, and these heterosexual and heterosexual heterosexual heterosexuals, can be replaced by one to three independently selected substitutes from the halogen group, Arilo, heaterilo, C1-6 tar, C1-6 halogen tar, Alcoy C1-6 and halogen alcoxi C1-6,O these arilo and heteromorphic substitutes are C1-6, xes-n (R1) (R2) tar;R1 and R2 are independently hydrogen, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C2-6 hydroxyalkyl, (C1-6 alkoxy) -C2-6 alkyl, C3-7 cycloalkyl, (C3-7 cycloalkyl ) -C1-6alkyl, C7-10 bicycloalkyl, phenylC1-3alkyl, heteroaryl-C1-3alkyl, heterocyclyl, or heterocyclylC1-6alkyl in which the cycloalkyl of said C3-7cycloalkyl and (C3-7cycloalkyl) - C1-3alkyl, phenyl of said phenylalkyl C1-3, heteroaryl of said heteroaryl-C1-3alkyl and heterocyclyl of said heterocyclyl and heterocyclylalkylC1-6 are optionally substituted one to three times by substituents independently chosen from the group formed by Rd;O R1 and R2, together with the nitroglycerin atom attached to them, form an optional non cyclohexane substitute, the substitute is independently selected between a group consisting of one carbon atom in the non cyclohexane ring and a group consisting of R1 and R2, and the substitute is replaced by one carbon group; And / or one carbon atom in the heterocyclic ring composed of R1 and R2 may be a carbon atom in another ring, which is a c3-7 ring or heterocyclic ring, while one or two carbon atoms in the other ring are replaced by one carbon group, while the other ring is replaced by C1-6 tar;R3 and R4 are independently hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, (C3-7 cycloalkyl) -C1-6 alkyl, (C1-6 alkoxy) -carbonyl, carboxyl, carbamoyl, carbamoyl mono or substituted by C1-6 alkyl, (C1-6 alkoxy) -carbonyloxy, aminocarbonyloxy mono- or di-substituted by C1-6 alkyl, (C1-20 alkyl) -carbonyloxy-C1-6 alkyl, (C1- alkoxy 20) -carbonyloxy-C1-6alkyl, arylcarbonyloxy-C1-6alkyl, aminocarbonyloxy-C1-6alkyl mono- or substituted by C1-6alkyl, aminocarbonyloxy-C1-6alkyl substituted by aryl, hydroxyalkyl-C1-6, C1-6 alkoxy-C1-6 alkyl, halogen or halo C1-6 alkyl,Alternatives 1 to 3 were replaced with independently selected alternatives from the halide, C1-6 tar, C1-6 halo-6, Alcoy C1-6, and halogenated alcox C1-6 groups. With the addition of carbon atoms, they form one to three times C1-4, C1-4 and halogenated tar group, Y1 is C (o) or s (o) 2, Y2 is o or s, Y3 is NH u; P is 0 or 1 independently selected substitute, the substitute can replace one to three times cycloquilo c3-7 or non ring carbon atom; R5 and R6 are independent of hydrogen, C1-6 or c3-7 cyclododecane,These C1-6 and c3-7 C1-6 and cyclopentanediol may be replaced by substitutes selected independently from a group consisting of C1-6 and (alcox C1-6) - carbides, one to three times, or R5 and R6, plus the carbon atoms connected to them. A c3-7 cyclopropyl or isocyclopropyl; R7, R8, R9, and R10 are C1-6 tar independent of hydrogen, C1-6 tar, c3-7 cyclopropyl, or arilo, and may optionally be replaced one to three times by alternatives consisting of hydrogen Xi, alcox C1-6, carboxyl, and carbamoilo.carbamoyl mono- or substituted by C1-6 alkyl and (C1-6 alkoxy) -carbonyl, aryl and heteroaryl, said aryl and heteroaryl are optionally substituted one to three times by substituents independently chosen from the group consisting of halogen, C1-alkyl -6, C1-6 haloalkyl, C1-6 alkoxy and C1-6 haloalkoxy; Rd is hydroxy, cyano, NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxyalkyl C1-6, C1-6 alkoxy, (C1-6 alkoxy) -C1-6 alkyl, C3-7 cycloalkyl, (C1 alkoxy -6) -carbonyl, acyl, -c (o) NRaRb, -NRa-C (O) -Rb, -NRa-C (O) ORb, NRa-C (O) -NRb, NRa-so2-Rb, NRa -so2-NRbRc, -OC (O) NRaRb, -oc (o) oRa, C1-6alkylsulfonyl, C1-6alkylsulfinyl, C1-6alkylthio, phenyl, phenyl-C1-3alkyl,heteroaryl, heteroarylC1-3alkyl and heterocyclyl, and the phenyl of said phenyl and phenyl-C1-3alkyl, the heteroaryl of said heteroaryl and heteroaryl-C1-3alkyl, and the heterocyclyl are optionally substituted one to three times by chosen substituents independently of the group consisting of hydroxy, cyano, NRaRb, halogen, C1-6 alkyl, haloC1-6 alkyl, hydroxyalkyl C1-6, (C1-6 alkoxy) -carbonyl, acyl, -c (o) nRaRb, NRa- c (o) -Rb, -NRa-C (O) -ORb, NRa-C (O) -NRb, -NRa-so2-Rb, -NRa-so2-NRbRc, -OC (O) NRaRb, -OC ( O) ORa, C1-6 alkylsulfonyl,C1-6alkylsulfinyl and C1-6alkylthio and one or two carbon atoms of the heterocyclyl ring has optionally been replaced by a carbonyl group; Ra, Rb and Rc are independently hydrogen or C1-6 alkyl; n is an integer from 0 to 3; m is an integer from 0 to 3; m + n is an integer from 1 to 5; or the prodrugs or pharmaceutically acceptable salts thereof; wherein, unless otherwise indicated, the term "aryl" means phenyl or naphthyl; the term "heterocyclyl" means non-aromatic mono- or bicyclic moieties, from four to nine ring atoms, from one to three of said ring atoms are heteroatoms chosen from N,O and S (o) n (n) are integers from 0 to 2,The other atoms in the ring are C, called heteromorphism,Alone or combined with others, it means that the aromatic residue of single or double rings in the ring is 5 to 10 atoms, and there are 1 to 3 different atoms in the ring. These atoms are independently selected between N and S. the other atoms in the ring are C; "acid" refers to R-C (o) -.R is C1-6, C1-6 halide, c3-7 cyclopropyl or c3-7 cyclopropyl-c1-6.