C-glycoside derivative
The present invention involves a compound represented by general formula (I), a derivative thereof and a use thereof: wherein R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c and X are defined as in the description.
1. An intermediate useful for preparing a compound of general formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein said intermediate is a compound selected from the group consisting of a compound represented by general formula (II), a compound represented by general formula (III) and a compound represented by general formula (IV), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R 1 and R 2 each independently represent hydrogen, —OH, —OR 6 , alkyl, —CF 3 , —OCHF 2 , —OCF 3 , halogen, —CN, C 2-6 alkynyl, C 2-6 alkenyl, cycloalkyl, C 2-4 alkenyl-C 1-4 alkyl, C 2-4 alkynyl-C 1-4 alkyl, C 2-4 alkenyl-C 1-4 alkoxy, C 2-4 alkynyl-C 1-4 alkoxy, C 3-7 cycloalkyl-C 1-4 alkyl, —NR 7 R 7a , carbonyl, —COOR 6a , —COOH, —COR 7b , —CH(OH)R 7c , —CH(OR 6g )R 7d , —CONR 7 R 7a , —NHCOR 6b , —NHSO 2 R 6c , —NHSO 2 aryl, aryl, —SR 6d , —SOR 6e , —SO 2 R 6f , —SO 2 aryl, or
R 1 and R 2 together with carbon atoms attached thereto form a ring or a 3-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 3 represents OR 8 , a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group, or a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group in which one or more carbon atoms are replaced with one or more heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl, or aryl-(C 1-3 alkyl)carbonyl;
R 8 represents a 6 membered fused-ring group;
R 6 , R 6a , R 6b , R 6c , R 6d , R 6e and R 6f respectively represent alkyl or cycloalkyl, or alkyl or cycloalkyl in which one or more carbon atoms are replaced with one or more heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 7 , R 7a , R 7b , R 7c and R 7d respectively represent hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R 7 and R 7a together with the nitrogen attached thereto form a 3-14 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S, SO and/or SO 2 ;
X represents a chemical bond, NH, O, S, SO, SO 2 or an alkylene, said alkylene can be further substituted by one or more substituents, which comprise halogen, hydroxyl, C 1-4 alkyl, cycloalkyl, C 1-4 alkoxy, C 1-4 alkyl that is substituted by halogen;
wherein the alkyl, the cycloalkyl, the aryl, the heterocyclyl, the spiro-ring group, the bridged-ring group, and the fused-ring group, as mentioned above, can be further substituted by one or more substituents, which comprise halogen, hydroxyl, amino, carboxyl, alkyl, alkoxy, aminosulfonyl, carbamoyl, C 1-4 alkoxy that is substituted by halogen, and C 1-4 alkyl that is substituted by halogen, hydroxyl, amino, and/or carboxyl.
2. The intermediate of claim 1 , wherein
R 1 represents hydrogen, —OH, —OR 6 , alkyl, —CF 3 , —OCHF 2 , —OCF 3 , halogen or —CN;
R 2 represents hydrogen;
R 3 represents OR 8 , a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group, or a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group in which one or more carbon atoms are replaced with one or more heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl, or aryl-(C 1-3 alkyl)carbonyl;
R 8 represents a 6 membered fused-ring group;
X represents a chemical bond or an alkylene, said alkylene can be further substituted by one or more substituents, which comprise halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkyl that is substituted by halogen;
wherein the alkyl, the aryl, the spiro-ring group, the bridged-ring group, and the fused-ring group can be further substituted by one or more substituents, which comprise halogen, hydroxyl, amino, carboxyl, alkyl, alkoxy, aminosulfonyl, carbamoyl, C 1-4 alkoxy that is substituted by halogen, and C 1-4 alkyl that is substituted by halogen, hydroxyl, amino, and/or carboxyl.
3. The intermediate of claim 1 , wherein,
R 1 represents hydrogen, —OH, —OR 6 , alkyl, —CF 3 , —OCHF 2 , —OCF 3 , halogen or —CN;
R 2 represents hydrogen;
R 3 represents OR 8 , a 7-12 membered spiro-ring group, or a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group in which one or more carbon atoms are replaced with one or more heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 8 represents a 6 membered fused-ring group;
R 4 , R 5a , R 5 b and R 5c respectively represent hydrogen;
X is methylene;
wherein the spiro-ring group and the fused-ring group can be further substituted by one or more substituents, which comprise halogen, hydroxyl, amino, carboxyl, alkyl, alkoxy, aminosulfonyl, carbamoyl, C 1-4 alkoxy that is substituted by halogen, and C 1-4 alkyl that is substituted by halogen, hydroxyl, amino, and/or carboxyl.
4. The intermediate of claim 1 , wherein,
R 1 represents halogen or —CN;
R 2 represents hydrogen;
R 3 represents OR 8 , a 7-12 membered spiro-ring group;
R 8 represents a 6 membered fused-ring group;
R 4 , R 5a , R 5b and RSC respectively represent hydrogen;
X is methylene;
wherein the spiro-ring group and the fused-ring group can be further substituted by one or more substituents, which comprise halogen, hydroxyl, amino, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, aminosulfonyl, and carbamoyl.
5. The intermediate of claim 1 , wherein,
R 1 represents halogen or —CN;
R 2 represents hydrogen;
R 3 represents OR 8 , a 7-10 membered spiro-ring group or a 7-10 membered spiro-ring group containing 1-2 heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 8 represents a 6 membered fused-ring group;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen;
X is methylene.
6. The intermediate of claim 1 , wherein,
R 1 represents halogen;
R 2 represents hydrogen;
R 3 represents OR 8 , a 7-10 membered spiro-ring group;
R 8 represents a 6 membered fused-ring group;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen;
X is methylene.
7. The intermediate of claim 1 , wherein R 3 is selected from:
8. process for preparing a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
which process comprises that a compound represented by general formula (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a compound represented by general formula (V), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof are subjected to a nucleophilic reaction,
wherein R 1 and R 2 each independently represent hydrogen, —OH, —OR 6 , alkyl, —CF 3 , —OCHF 2 , —OCF 3 , halogen, —CN, C 2-6 alkynyl, C 2-6 alkenyl, cycloalkyl, C 2-4 alkenyl-C 1-4 alkyl, C 2-4 alkynyl-C 1-4 alkyl, C 2-4 alkenyl-C 1-4 alkoxy, C 2-4 alkynyl-C 1-4 alkoxy, C 3-7 cycloalkyl-C 1-4 alkyl, —NR 7 R 7a , carbonyl, —COOR 6a , —COOH, —COR 7b , —CH(OH)R 7c , —CH(OR 6g )R 7d , —CONR 7 R 7a , —NHCOR 6b , —NHSO 2 R 6c , —NHSO 2 aryl, aryl, —SR 6d , —SOR 6e , —SO 2 R 6f , —SO 2 aryl, or
R 1 and R 2 together with carbon atoms attached thereto form a ring or a 3-14 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 3 represents OR 8 , a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group, or a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group in which one or more carbon atoms are replaced with one or more heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl, or aryl-(C 1-3 alkyl)carbonyl;
R 8 represents a 6 membered fused-ring group;
R 6 , R 6a , R 6b , R 6c , R 6d , R 6e and R 6f respectively represent alkyl or cycloalkyl, or alkyl or cycloalkyl in which one or more carbon atoms are replaced with one or more heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 7 , R 7a , R 7b , R 7c and R 7d respectively represent hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R 7 and R 7a together with the nitrogen attached thereto form a 3-14 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S, SO and/or SO 2 ;
X represents a chemical bond, NH, O, S, SO, SO 2 or an alkylene, said alkylene can be further substituted by one or more substituents, which comprise halogen, hydroxyl, C 1-4 alkyl, cycloalkyl, C 1-4 alkoxy, C 1-4 alkyl that is substituted by halogen;
wherein the alkyl, the cycloalkyl, the aryl, the heterocyclyl, the spiro-ring group, the bridged-ring group, and the fused-ring group, as mentioned above, can be further substituted by one or more substituents, which comprise halogen, hydroxyl, amino, carboxyl, alkyl, alkoxy, aminosulfonyl, carbamoyl, C 1-4 alkoxy that is substituted by halogen, and C 1-4 alkyl that is substituted by halogen, hydroxyl, amino, and/or carboxyl.
9. The process of claim 8 , wherein
R 1 represents hydrogen, —OH, —OR 6 , alkyl, —CF 3 , —OCHF 2 , —OCF 3 , halogen or —CN;
R 2 represents hydrogen;
R 3 represents OR 8 , a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group, or a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group in which one or more carbon atoms are replaced with one or more heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen, (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, arylcarbonyl, or aryl-(C 1-3 alkyl)carbonyl;
R 8 represents a 6 membered fused-ring group;
X represents a chemical bond or an alkylene, said alkylene can be further substituted by one or more substituents, which comprise halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkyl that is substituted by halogen;
wherein the alkyl, the aryl, the spiro-ring group, the bridged-ring group, and the fused-ring group can be further substituted by one or more substituents, which comprise halogen, hydroxyl, amino, carboxyl, alkyl, alkoxy, aminosulfonyl, carbamoyl, C 1-4 alkoxy that is substituted by halogen, and C 1-4 alkyl that is substituted by halogen, hydroxyl, amino, and/or carboxyl.
10. The process of claim 8 , wherein
R 1 represents hydrogen, —OH, —OR 6 , alkyl, —CF 3 , —OCHF 2 , —OCF 3 , halogen or —CN;
R 2 represents hydrogen;
R 3 represents OR 8 , a 7-12 membered spiro-ring group, or a 5-12 membered spiro-ring group, a 5-12 membered bridged-ring group or a 6-14 membered fused-ring group in which one or more carbon atoms are replaced with one or more heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 8 represents a 6 membered fused-ring group;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen;
X is methylene;
wherein the spiro-ring group and the fused-ring group can be further substituted by one or more substituents, which comprise halogen, hydroxyl, amino, carboxyl, alkyl, alkoxy, aminosulfonyl, carbamoyl, C 1-4 alkoxy that is substituted by halogen, and C 1-4 alkyl that is substituted by halogen, hydroxyl, amino, and/or carboxyl.
11. The process of claim 8 , wherein
R 1 represents halogen or —CN;
R 2 represents hydrogen;
R 3 represents OR 8 , a 7-12 membered spiro-ring group;
R 8 represents a 6 membered fused-ring group;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen;
X is methylene;
wherein the spiro-ring group and the fused-ring group can be further substituted by one or more substituents, which comprise halogen, hydroxyl, amino, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, aminosulfonyl, and carbamoyl.
12. The process of claim 8 , wherein
R 1 represents halogen or —CN;
R 2 represents hydrogen;
R 3 represents OR 8 , a 7-10 membered spiro-ring group or a 7-10 membered spiro-ring group containing 1-2 heteroatoms selected from N, O, S, SO and/or SO 2 ;
R 8 represents a 6 membered fused-ring group;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen;
X is methylene.
13. The process of claim 8 , wherein
R 1 represents halogen;
R 2 represents hydrogen;
R 3 represents OR 8 , a 7-10 membered spiro-ring group;
R 8 represents a 6 membered fused-ring group;
R 4 , R 5a , R 5b and R 5c respectively represent hydrogen;
X is methylene.
14. The process of claim 8 , wherein R 3 is selected from: