2,5-substituted pyrimidines

摘要

The invention relates to novel substituted condensed pyrimidine compounds of general formula (I);
in which the chemical groupings, substituents and indices are as defined in the description, and to their use as medicaments, in particular as medicaments for the treatment of conditions and diseases that can be treated by inhibition of the PDE4 enzyme.

主权项

1. A 2,5-substituted pyrimidine having the following general formula (I)wherein
A, B, C each independently of each other stands for N or CH; R1 stands for (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-haloalkyl, (C3-C6)-cycloalkyl, SOx—(C1-C6)-alkyl, CONH2, CONH—(C1-C6)-alkyl, or CON((C1-C6)-alkyl)2; x is 0, 1 or 2; G is an optionally with at least one substituent Y substituted phenyl or 5- or 6-membered heteroaryl which comprises at least one oxygen, sulfur or nitrogen atom, whereas the nitrogen atoms present in the heteroaryl can be substituted with R4; R4 is hydrogen, (C1-C6)-alkyl, (C1-C6)-haloalkyl, CO—(C1-C6)-alkyl, SO(C1-C6)-alkyl, SO2(C1-C6)-alkyl; Y is OH, CN, SH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, (C1-C6)-thioalkyl, (C1-C6)-haloalkyl, (C1-C6)-thiohaloalkyl, (C1-C6)-haloalkoxy, CO2H, CO2(C1-C6)-alkyl, CHO, CO(C1-C6)-alkyl, OCO(C1-C6)-alkyl, CONH2, CONH—(C1-C6)-alkyl, CON((C1-C6)-alkyl)2, OCO—NH(C1-C6)-alkyl, OCO—N((C1-C6)-alkyl)2, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, NH—CO—(C1-C6)alkyl, NH—CO2(C1-C6)-alkyl, N(C1-C6)-alkyl-CO2(C1-C6)-alkyl, NH—CO—NH2, NH—CO—NH(C1-C6)-alkyl, NH—CO—N(C1-C6)-alkyl)2, N(C1-C6)-alkyl-CO—NH2, N(C1-C6)alkyl-CO—NH(C1-C6)-alkyl, N(C1-C6)-alkyl-CO—N((C1-C6)-alkyl)2, NH—SO2—(C1-C6)-alkyl, N(C1-C6)alkyl-SO2—(C1-C6)-alkyl, S—(C1-C6)-alkyl, SO(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2H, SO2OH, SO2NH2, SO2NH(C1-C6)-alkyl, SO2N((C1-C6)-alkyl)2, C(═N)—NH, NHC(═N)—NH2, —N═C═O, —S—CN, wherein the aforementioned alkyl chains may be substituted with at least one of the following substituents OH, CN, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, CO2H, CO2(C1-C6)-alkyl or —NH2; R2 and R3,
independently of one another stand for hydrogen or optionally substituted (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-alkoxy(C1-C6)-alkylen, (C1-C6)-alkylen-CO2H, (C1-C6)-alkylen-CO2(C1-C6)-alkyl, (C1-C6)-alkylen-CONH2, (C1-C6)-alkylen-CONH(C1-C6)-alkyl, (C1-C6)-alkylen-CON((C1-C6)-alkyl)2, (C1-C6)-alkylen-(C3-C6)-cycloalkyl, (C1-C6)-hydroxyalkyl-(C3-C6)-cycloalkylen, a group L1V, or a group L2W, ortogether with the nitrogen atom to which they are attached form an optionally with at least one substituent XQ substituted 3- to 12-membered mono- or bicyclic heteroaliphatic residue Q which may additionally contain at least one oxygen, sulfur or further nitrogen atom, whereas these one or more additional nitrogen atoms are substituted with R5; XQ independently of each other stand for ═O (carbonyl), halogen, OH, CN, SH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-cyanoalkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxy(C1-C6)-alkylen, (C1-C6)-thioalkyl, (C1-C6)-haloalkyl, (C1-C6)-thiohaloalkyl, (C1-C6)-haloalkoxy, —NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, (C1-C6)-alkylen-NH(C1-C6)-alkyl, (C1-C6)-alkylen-N((C1-C6)-alkyl)2 NH—CHO, NH—CO(C1-C6)-alkyl, N(C1-C6)-alkyl-CO(C1-C6)-alkyl, NH—CO—O(C1-C6)-alkyl, N(C1-C6)-alkyl-CO—O(C1-C6)-alkyl, NH—CO—NH2, NH—CO—NH(C1-C6)-alkyl, NH—CO—N((C1-C6)-alkyl)2, N(C1-C6)-alkyl-CO—NH2, N(C1-C6)-alkyl-CO—NH(C1-C6)-alkyl, N(C1-C6)-alkyl-CO—N((C1-C6)-alkyl)2, NH—SO2—(C1-C6)-alkyl, N(C1-C6)-alkyl-SO2—(C1-C6)-alkyl, CO2H, CO2(C1-C6)-alkyl, CHO, CO(C1-C6)-alkyl, O—CO(C1-C6)-alkyl, CO—NH2, CO—NH(C1-C6)-alkyl, CO—N((C1-C6)-alkyl)2, O—CO—NH(C1-C6)-alkyl, O—CO—N((C1-C6)-alkyl)2, S—(C1-C6)-alkyl, SO(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SOOH, SO2OH, SO2NH2, SO2NH(C1-C6)-alkyl, SO2N((C1-C6)-alkyl)2, C(═N)—NH, NHC(═N)—NH2, —N═C═O, or —S—CN, wherein the aforementioned alkyl chains may be substituted with at least one of the following substituents OH, CN, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, CO2H, CO2(C1-C6)-alkyl or —NH2; R5 is hydrogen, (C1-C6)-alkyl, (C1-C6)-haloalkyl, CO—(C1-C6)-alkyl, SO—(C1-C6)-alkyl, SO2—(C1-C6)-alkyl; L1 is a bond or a branched or straight-chain optionally substituted (C1-C6)-alkylene group connected to the amide nitrogen; V is an optionally with at least one substituent XV substituted 3- to 12-membered mono- or bicyclic aliphatic or heteroaliphatic residue, whereas if one or more nitrogen atoms are present in the mono- or bicyclic heteroaliphatic residue, then at least one of these nitrogen atoms is substituted with R6; XV independently of each other stand for ═O (carbonyl), halogen, OH, CN, SH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-cyanoalkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxy(C1-C6)-alkylen, (C1-C6)-thioalkyl, (C1-C6)-haloalkyl, (C1-C6)-thiohaloalkyl, (C1-C6)-haloalkoxy, —NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, (C1-C6)-alkylen-NH(C1-C6)-alkyl, (C1-C6)-alkylen-N((C1-C6)-alkyl)2 NH—CHO, NH—CO(C1-C6)-alkyl, N(C1-C6)-alkyl-CO(C1-C6)-alkyl, NH—CO—O(C1-C6)-alkyl, N(C1-C6)-alkyl-CO—O(C1-C6)-alkyl, NH—CO—NH2, NH—CO—NH(C1-C6)-alkyl, NH—CO—N((C1-C6)-alkyl)2, N(C1-C6)-alkyl-CO—NH2, N(C1-C6)-alkyl-CO—NH(C1-C6)-alkyl, N(C1-C6)-alkyl-CO—N((C1-C6)-alkyl)2, NH—SO2—(C1-C6)-alkyl, N(C1-C6)-alkyl-SO2—(C1-C6)-alkyl, CO2H, CO2(C1-C6)-alkyl, CHO, CO(C1-C6)-alkyl, O—CO(C1-C6)-alkyl, CO—NH2, CO—NH(C1-C6)-alkyl, CO—N((C1-C6)-alkyl)2, O—CO—NH(C1-C6)-alkyl, O—CO—N((C1-C6)-alkyl)2, S—(C1-C6)-alkyl, SO(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SOOH, SO2OH, SO2NH2, SO2NH(C1-C6)-alkyl, SO2N((C1-C6)-alkyl)2, C(═N)—NH, NHC(═N)—NH2, —N═C═O, or —S—CN, wherein the aforementioned alkyl chains may be substituted with at least one of the following substituents OH, CN, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, CO2H, CO2(C1-C6)-alkyl or —NH2; R6 is hydrogen, (C1-C6)-alkyl, (C1-C6)-haloalkyl, CO—(C1-C6)-alkyl, SO(C1-C6)-alkyl, or SO2(C1-C6)-alkyl; L2 is a bond or a branched or straight-chain optionally substituted (C1-C6)-alkylene group connected to the amide nitrogen; W is an optionally with at least one substituent Z substituted phenyl or 5- or 6-membered heteroaryl which contains at least one oxygen, sulfur or nitrogen atom; and Z independently of each other stand for halogen, OH, CN, SH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, (C1-C6)-thioalkyl, (C1-C6)-haloalkyl (C1-C6)-thiohaloalkyl, (C1-C6)-haloalkoxy, —NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, NH—CHO, NH—CO(C1-C6)-alkyl, N(C1-C6)-alkyl-CO(C1-C6)-alkyl, NH—CO2(C1-C6)-alkyl, N(C1-C6)-alkyl-CO2(C1-C6)-alkyl, NH—CO—NH2, NH—CO—NH(C1-C6)-alkyl, NH—CO—N((C1-C6)-alkyl)2, N(C1-C6)-alkyl-CO—NH2, N(C1-C6)-alkyl-CO—NH(C1-C6)-alkyl, N(C1-C6)-alkyl-CO—N((C1-C6)-alkyl)2, NH—SO2—(C1-C6)-alkyl, N(C1-C6)-alkyl-SO2—(C1-C6)-alkyl, CO2H, CO2(C1-C6)-alkyl, CHO, CO(C1-C6)-alkyl, O—CO(C1-C6)-alkyl, CO—NH2, CO—NH(C1-C6)-alkyl, CO—N((C1-C6)-alkyl)2, O—CO—NH(C1-C6)-alkyl, O—CO—N((C1-C6)-alkyl)2, S—(C1-C6)-alkyl, SO(C1-C6)-alkyl, SO2—(C1-C6)-alkyl, SO2H, SO2OH, SO2NH2, SO2NH(C1-C6)-alkyl, SO2N((C1-C6)-alkyl)2, C(═N)—NH, NHC(═N)—NH2, —N═C═O, or —S—CN, wherein the aforementioned alkyl chains may be substituted with at least one of the following substituents OH, CN, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, CO2H, CO2(C1-C6)-alkyl or —NH2.