BENZIMIDAZOLE DERIVATIVES AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES
The present invention relates to benzimidazole derivatives and their pharmaceutical compositions and uses, specifically to benzimidazole derivatives of Formula (I), or their stereoisomer, pharmaceutically acceptable salt or solvates thereof, in which R 1 , R 2 , R 3 , R 4 , R 5 and n have the definitions in the description; the present invention further relates to a pharmaceutical composition containing the compounds, methods for preparing the compounds, and use of the compounds for manufacturing of a medicament for prophylaxis and/or treatment of peptic ulcer, ulcer hemorrhage and diseases associated with gastric acid.
1 . A compound of Formula (I′), or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 1 , R 2 , R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkoxyl-C 1-6 alkyl, C 1-6 alkoxyl-C 1-6 alkoxyl, haloC 1-6 alkyl, haloC 1-6 alkoxyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl, phenyl, phenylC 1-6 alkyl, phenyl-C 1-6 alkoxyl or phenoxy;
R 5 represents formula
R 6 and R 7 are independently hydrogen atom, halogen atom, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkoxyl-C 1-6 alkyl, C 1-6 alkoxyl-C 1-6 alkoxyl, haloC 1-6 alkyl, haloC 1-6 alkoxyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, hydroxyl, hydroxyl-C 1-6 alkyl, carboxyl, carboxyl-C 1-6 alkyl, amino, amino-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl, aminosulfonyl, carbamoyl or C 1-6 alkylcarbamoyl,
Ring A and Ring B are independently a 5-membered ring having 1 oxygen atom or sulfur atom, or 5-membered ring having 2 nitrogen atoms, wherein the ring is optionally substituted with 1-4 R 8 ,
R 8 is hydrogen atom, halogen atom, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkoxyl-C 1-6 alkyl, C 1-6 alkoxyl-C 1-6 alkoxyl, haloC 1-6 alkyl, haloC 1-6 alkoxyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, hydroxyl, hydroxyl-C 1-6 alkyl, carboxyl, carboxyl-C 1-6 alkyl, amino, amino-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl, aminosulfonyl, carbamoyl, C 1-6 alkylcarbamoyl or C 1-6 alkylformylamino, and
n is 1 or 2.
2 . The compound of claim 1 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 1 , R 2 , R 3 and R 4 are independently hydrogen atom, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkoxyl-C 1-4 alkyl, C 1-4 alkoxyl-C 1-4 alkoxyl, haloC 1-4 alkyl or halo C 1-4 alkoxyl,
Ring A and Ring B are independently selected from a group consisting of imidazole, 4,5-dihydroimidazole, imidazolidine, pyrazole, 4,5-dihydropyrazole, pyrazolidine, furan, dihydrofuran, which the ring is optionally substituted with 1-4 R 8 ,
R 6 and R 7 are independently hydrogen atom, fluorine atom, chlorine atom, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkoxyl-C 1-4 alkoxyl, fluoro-C 1-4 alkyl, fluoro-C 1-4 alkoxyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxyl, carboxyl, amino, aminosulfonyl, carbamoyl or C 1-4 alkylcarbamoyl,
R 8 is hydrogen atom, fluorine atom, chlorine atom, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkoxyl-C 1-4 alkyl, C 1-4 alkoxyl-C 1-4 alkoxyl, fluoro-C 1-4 alkyl or fluoro-C 1-4 alkoxyl,
n is 1 or 2.
3 . The compound of claim 1 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 1 , R 2 , R 3 and R 4 are independently hydrogen atom, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkoxyl-C 1-4 alkyl, C 1-4 alkoxyl-C 1-4 alkoxyl, haloC 1-4 alkyl or halo C 1-4 alkoxyl,
R 5 represents formula
R 6 and R 7 are independently hydrogen atom,
Ring A and Ring B are independently a 5-membered ring having 1 oxygen atom, which is optionally substituted with 1-4 R 8 ,
R 8 is hydrogen atom, fluorine atom, chlorine atom, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkoxyl-C 1-4 alkyl, C 1-4 alkoxyl-C 1-4 alkoxyl, fluoro-C 1-4 alkyl or fluoro-C 1-4 alkoxyl,
n is 1 or 2.
4 . The compound of claim 3 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 1 , R 2 and R 3 are independently hydrogen atom, methyl, ethyl, methoxyl, ethoxyl, methoxylmethoxyl, 2-methoxylethoxyl, 3-methoxylpropoxy, ethoxylmethoxyl, 2-ethoxylethoxyl, 3-ethoxylpropoxy, propoxymethoxyl, difluoromethyl, trifluoromethyl, difluoromethoxyl, trifluoromethoxyl, 2,2-difluoroethoxyl or 2,2,2-trifluoroethoxyl,
R 4 is hydrogen atom,
R 5 represents
5 . The compound of claim 4 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 1 is hydrogen atom, methyl or methoxyl;
R 2 is methoxyl, 3-methoxylpropoxy or 2,2,2-trifluoroethoxyl;
R 3 is hydrogen atom, methyl or methoxyl;
R 4 is hydrogen atom; and
R 5 represents
6 . The compound of claim 5 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 1 is methyl or methoxyl;
R 2 is methoxyl, 3-methoxylpropoxy or 2,2,2-trifluoroethoxyl;
R 3 is hydrogen atom or methyl;
R 4 is hydrogen atom; and
R 5 represents
7 . The compound of claim 1 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
8 . A compound of Formula (II), or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
HS—R 5 (II)
wherein,
R 5 represents formula
R 6 and R 7 are independently hydrogen atom, halogen atom, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkoxyl-C 1-6 alkyl, C 1-6 alkoxyl-C 1-6 alkoxyl, haloC 1-6 alkyl, haloC 1-6 alkoxyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, hydroxyl, hydroxyl-C 1-6 alkyl, carboxyl, carboxyl-C 1-6 alkyl, amino, amino-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl, aminosulfonyl, carbamoyl or C 1-6 alkylcarbamoyl,
Ring A and Ring B are independently a 5-membered ring having 1 oxygen atom or sulfur atom, or 5-membered ring having 2 nitrogen atoms, which the ring is optionally substituted with 1-4 R 8 ,
R 8 is hydrogen atom, halogen atom, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkoxyl-C 1-6 alkyl, C 1-6 alkoxyl-C 1-6 alkoxyl, haloC 1-6 alkyl, haloC 1-6 alkoxyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, hydroxyl, hydroxyl-C 1-6 alkyl, carboxyl, carboxyl-C 1-6 alkyl, amino, amino-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl, aminosulfonyl, carbamoyl, C 1-6 alkylcarbamoyl or C 1-6 alkylformylamino.
9 . The compound of claim 8 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 6 and R 7 are independently hydrogen atom, fluorine atom, chlorine atom, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkoxyl-C 1-4 alkoxyl, fluoro-C 1-4 alkyl, fluoro-C 1-4 alkoxyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxyl, carboxyl, amino, aminosulfonyl, carbamoyl or C 1-4 alkylcarbamoyl,
Ring A and Ring B are independently selected from a group consisting of imidazole, 4,5-dihydroimidazole, imidazolidine, pyrazole, 4,5-dihydropyrazole, pyrazolidine, furan, dihydrofuran, which the ring is optionally substituted with 1-4 R 8 ,
R 8 is hydrogen atom, fluorine atom, chlorine atom, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkoxyl-C 1-4 alkyl, C 1-4 alkoxyl-C 1-4 alkoxyl, fluoro-C 1-4 alkyl or fluoro-C 1-4 alkoxyl.
10 . The compound of claim 8 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 5 represents formula
R 6 and R 7 are independently hydrogen atom,
Ring A and Ring B are independently a 5-membered ring having 1 oxygen atom, which the ring is optionally substituted with 1-4 R 8 ,
R 8 is hydrogen atom, fluorine atom, chlorine atom, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkoxyl-C 1-4 alkyl, C 1-4 alkoxyl-C 1-4 alkoxyl, fluoro-C 1-4 alkyl or fluoro-C 1-4 alkoxyl
11 . The compound of claim 10 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 5 represents
12 . The compound of claim 11 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 5 represents
13 . The compound of claim 12 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof:
wherein,
R 5 represents
14 . The compound of claim 8 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from: