Steroid derivative FXR agonist

Patent metadata

Field	Value
Publication number	US-11667667-B2
Application number	US-202017069691-A
Country	US
Kind code	B2
Filing date	Oct 13, 2020
Priority date	Jan 28, 2016
Publication date	Jun 6, 2023
Grant date	Jun 6, 2023

Abstract

The present invention relates to a compound represented by formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof, and relates to applications thereof in the preparation of drugs for treating FXR related diseases.

First claim

What is claimed is:

1. A compound represented by formula (III),

wherein,
ring A is selected from 5- to 12-membered aryl, 5- to 12-membered heteroaryl, 5_to 6-membered non-aromatic heterocyclyl, or 5- to 6-membered cycloalkyl; and said ring A is optionally substituted with 1, 2 or 3 of R;
L is selected from C 1-6 alkyl, C 1-6 heteroalkyl, or C 2-6 alkenyl, and said L is optionally substituted with 1, 2 or 3 of R;
R is selected from F, Cl, Br, I, OH, CN, NO 2 , NH 2 , C 1-3 all ylamino; N,N-di(C 1-3 alkyl)amino, C 1-3 alkyl, C 1-3 alkyloxy, or C 1-3 alkylthio, and said R is optionally substituted with 1, 2 or 3 R′;
R′ is selected from F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, Me, Et, CH 2 F, CHF 2 , CF 3 , CH 3 O, CH 3 S, NH(CH 3 ), or N(CH 3 ) 2 ;
said “hetero” represents heteroatom or heteroatomic group, selected from —C(═O)NH—, N, —NH—, —C(═NH)—, —S(═O) 2 NH—, —S(═O)NH—, —O—, —S—, ═O, ═S, —C(═O)C—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O) 2 —, or —NHC(═O)NH—;
in any of the above cases, the number of the heteroatom or heteroatomic groups is independently selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

2. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R is selected from F, Cl, Br, I, Me, CF 3 , CHF 2 , CH 2 F, Et, OMe, NH(CH 3 ), or N(CH 3 ) 2 .

3. The compound or the pharmaceutically acceptable salt thereof according to claim wherein ring A is selected from phenyl, pyridyl, pyridin-2(1H)-onyl, pyrimidyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, isoxazolyl, isothiazolyl, bicyclo[1.1.1]pentyl, benzoxazolyl, benzo[d]isoxazolyl, indazolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, 1H-pyrrolo[2,3-B]pyridyl, indolizinyl benzothiazoyl or benzothienyl, and said ring A is optionally substituted with 1, 2 or 3 of R.

4. The compound or the pharmaceutically acceptable salt thereof according to claim 3 , wherein ring A is selected from

and said ring A is optionally substituted with 1, 2 or 3 R.

5. The compound or the pharmaceutically acceptable salt thereof according to claim 4 , wherein ring A is selected from

6. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein ring A is selected from 6- to 10-membered aryl, 5- to 12-membered heteroaryl containing 1 to 2 heteroatoms, 5- to 6-membered non-aromatic heterocyclyl containing 1 to 2 heteroatoms, or 5- to 6-membered cycloalkyl, and said heteroatom is selected from —NH—, N, —O— or —S—, and said ring A is optionally substituted with 1, 2 or 3 of R.

7. The compound or the pharmaceutically acceptable salt thereof according to claim 6 , wherein ring A is selected from 6- to 10-membered aryl, 6- to 10-membered heteroaryl containing 1 to 2 heteroatoms, 5- to 6-membered non-aromatic heterocyclyl containing 1 to 2 heteroatoms, or 5- to 6-membered cycloalkyl, and said heteroatom is selected from —NH—N, O or S, and said ring A is optionally substituted with 1, 2 or 3 of R.

8. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein ring A is selected from

and said ring A is optionally substituted with 1, 2 or 3 R.

9. The compound or the pharmaceutically acceptable salt thereof according to claim 8 , wherein ring A is selected from

10. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein L is selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 alkyl-C(═O)NH—, or C 2-4 alkenyl, and said L is optionally substituted with 1, 2 or 3 R.

11. The compound or the pharmaceutically acceptable salt thereof according to claim 10 , wherein L is selected from

and said L is optionally substituted with 1, 2 or 3 R.

12. The compound or the pharmaceutically acceptable salt thereof according to claim 11 , wherein ring A is selected from

13. The compound or the pharmaceutically acceptable salt thereof according to claim 12 , wherein L is selected from

14. The compound or the pharmaceutically acceptable salt according to claim 1 , wherein ring A is selected from

and L is selected from

15. The compound or the pharmaceutically acceptable salt thereof thereof according to claim 1 , wherein ring A is selected from

and L is selected from

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable carrier.

17. A method of treating Farnesoid X Receptor related diseases, comprising administering a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1 .

18. The method according to claim 17 , wherein the diseases are selected from non-alcoholic fatty liver disease (NAFLD), cholestatic hepatopathy, cholestatic liver diseases, hepatitis C infection, alcoholic liver disease, hepatic fibrosis, primary sclerosing cholangitis (PSC), gallstone, biliary atresia, lower urinary tract symptom and benign prostatic hyperplasia (BPH), ureteral calculi, obesity, type 2 diabetes, arteriosclerosis, hepatic function injury resulting from hypercholesterolemia or hyperlipidemia.

19. The method according to claim 18 , wherein the Farnesoid X Receptor related diseases are selected from the group consisting of chronic liver disease, fibrotic diseases, hypercholesterol diseases, hypertriglyceride diseases or cardiovascular diseases.

20. The method according to claim 19 , wherein the diseases are selected from the group consisting of non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC) or atherosclerosis.

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• He Haiying
• Xiao Hualing
• Li Peng
• Du Chunyan
• Luo Zhi
• Chen Shuhui

Classifications

• C07J33/002

  not condensed · CPC title

• C07J9/00 Primary

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title

• A61P13/08

  of the prostate · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07J43/003 Primary

  not condensed · CPC title