Nitrogenous tricyclic compounds and uses thereof in medicine
Nitrogenous tricyclic compounds and uses thereof in medicine, in particular, a novel nitrogenous tricyclic compound used as an FXR active regulator and a stereoisomer, a geometrical isomer, a tautomer, a N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and use of the compound in the manufacture of a drug for treating a disease and/or disorder regulated by FXR. A pharmaceutically acceptable composition containing the compound and a method of treating a disease and/or disorder mediated by FXR comprising administering the compound or pharmaceutical composition thereof.
1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof,
wherein
X is N or CH;
Y is O, S or NH;
each R a and R b is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl or C 1-6 alkoxy-C 1-6 alkyl-; or R a and R b , together with the carbon atom to which they are attached, form C 3-8 cycloalkane or 3-8 membered heterocycle which is a saturated or partially unsaturated monocyclic ring comprising one or more heteroatoms selected from O, S or N;
each R 1 , R 2 , R 3 , R 4 and R 5 is independently H, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy or C 1-6 alkoxy-C 1-6 alkyl;
each R 6 , R 7 , R 8 , R 9 and R 10 is independently H, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy or C 1-6 alkoxy-C 1-6 alkyl or C 3-8 cycloalkyl;
R c is C 1-4 alkyl or C 3-6 cycloalkyl;
with the proviso that the compound of Formula (I) is not
2. The compound of claim 1 , wherein each R a and R b is independently C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl or C 1-3 alkoxy-C 1-3 alkyl-; or R a and R b , together with the carbon atom to which they are attached, form C 3-6 cycloalkane or 3-6 membered heterocycle which is a saturated or partially unsaturated monocyclic ring comprising one or more heteroatoms selected from O, S or N.
3. The compound of claim 1 , wherein each R a and R b is independently methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl or 2-n-propoxyethyl; or R a and R b , together with the carbon atom to which they are attached, form cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxacyclopropane, trimethylene oxide or azetidine.
4. The compound of claim 1 , wherein each R 1 , R 2 , R 3 , R 4 and R 5 is independently H, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 haloalkoxy or C 1-3 alkoxy-C 1-3 alkyl.
5. The compound of claim 1 , wherein each R 1 , R 2 , R 3 , R 4 and R 5 is independently H, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, aminomethyl, methoxy, ethoxy, n-propoxy, methylamino, dimethylamino, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 1,2-difluoroethoxy, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl or 2-n-propoxyethyl.
6. The compound of claim 1 , wherein each R 6 , R 7 , R 3 , R 9 and R 10 is independently H, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 haloalkoxy, C 1-3 alkoxy-C 1-3 alkyl or C 3-6 cycloalkyl.
7. The compound of claim 1 , wherein each R 6 , R 7 , R 8 , R 4 and R 10 is independently H, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, aminomethyl, methoxy, ethoxy, n-propoxy, methylamino, dimethylamino, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 1,2-difluoroethoxy, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-n-propoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
8. The compound of claim 1 , wherein R c is methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
9. A compound having one of the following structures:
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or a combination thereof.