Nitrogenous tricyclic compounds and uses thereof in medicine

Patent metadata

Field	Value
Publication number	US-11208418-B2
Application number	US-201916962080-A
Country	US
Kind code	B2
Filing date	Jan 28, 2019
Priority date	Feb 2, 2018
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Yang Xinye
• Wang Xiaojun
• Wu Junwen
• Chen Hong
• Cao Shengtian
• Zhang Yingjun

Classifications

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D491/044 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61P15/10

  for impotence · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P13/12

  of the kidneys · CPC title