Thienopyrimidine derivative and use thereof in medicine

Patent metadata

Field	Value
Publication number	US-10759812-B2
Application number	US-201816476290-A
Country	US
Kind code	B2
Filing date	Jan 22, 2018
Priority date	Jan 22, 2017
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The present invention relates to a thienopyrimidine derivative and use thereof in medicine, and also to a pharmaceutical composition containing the compound. The compound or pharmaceutical composition is used for inhibiting acetyl-CoA carboxylase (ACC). The present invention also relates to a method of preparing such compound and pharmaceutical composition, as well as their use in the treatment or prevention of diseases regulated by acetyl-CoA carboxylase in mammals, especially in humans.

First claim

What is claimed is:

1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

wherein:
Het is —C(═O)NR a R b , —C(═NR)NR a R b , —NH—C(═NR)NR a R b , 3-10 membered heterocyclyl or 5-10 membered heteroaryl; wherein each of 3-10 membered heterocyclyl and 5-10 membered heteroaryl is independently and optionally substituted with H, oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, carboxy and —C(═O)NH 2 ;
R 1 is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
R 2 is —OR or —NR a R b ;
each of R 3 and R 4 is independently H, C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 haloalkyl;
L is —O—, —O-methylene-, —O-ethylene-, —S— or —NH—;
R 5 is C 6-10 aryl or 5-10 membered heteroaryl, wherein each of C 6-10 aryl and 5-10 membered heteroaryl is independently and optionally substituted with 1, 2 or 3 R 6 ; wherein R 6 is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 cyanoalkyl or C 1-6 hydroxyalkyl; and
W is fused cyclyl, bridged cyclyl or spiro cyclyl, wherein fused cyclyl, bridged cyclyl or spiro cyclyl is saturated or partially unsaturated 6-12 membered cyclyl containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; and wherein W is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, —C(═O)OR, —C(═O)NR a R b , —C(═NR)NR a R b , —NH—C(═NR)NR a R b , —SO 2 R, —SO 2 NR a R b , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 cyanoalkyl and C 1-6 hydroxyalkyl;
wherein each R, R a and R b is independently H, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl; or R a and R b , together with the N atom to which they are attached, form 3-10 membered heterocyclyl; and wherein 3-10 membered heterocyclyl is optionally substituted with oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl.

2. The compound of claim 1 , wherein Het is 5-6 membered heterocyclyl or 5-6 membered heteroaryl; and wherein each of 5-6 membered heterocyclyl and 5-6 membered heteroaryl is independently and optionally substituted with H, oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, carboxy and —C(═O)NH 2 .

3. The compound of claim 1 , wherein Het is pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolidyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, wherein each of pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolidyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl is independently and optionally substituted with H, oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, carboxy and —C(═O)NH 2 .

4. The compound of claim 1 , wherein R 1 is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl; and
R 2 is —OR or —NR a R b ;
wherein each R, R a and R b is independently H, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl; or R a and R b , together with the N atom to which they are attached, form 4-6 membered heterocyclyl; and wherein 4-6 membered heterocyclyl is optionally substituted with oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 haloalkyl; and
each of R 3 and R 4 is independently H, C 1-3 alkyl, C 1-3 hydroxyalkyl or C 1-3 haloalkyl.

5. The compound of claim 1 , wherein R 1 is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl or trifluoroethyl; and
R 2 is —OR or —NR a R b ;
wherein each R, R a and R b is independently H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
or R a and R b , together with the N atom to which they are attached, form heterocyclyl selected from heterocyclyl groups represented by formulae (I-a) to (I-k):

wherein the heterocyclyl groups represented by formulae (I-a) to (I-k) are optionally substituted with oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl; and
each of R 3 and R 4 is independently H, methyl, ethyl, n-propyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or 2-fluoroethyl.

6. The compound of claim 1 , wherein R 5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl or 5-6 membered heteroaryl, wherein each of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and 5-6 membered heteroaryl is independently and optionally substituted with 1, 2 or 3 R 6 ; and wherein R 6 is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 cyanoalkyl or C 1-3 hydroxyalkyl.

7. The compound of claim 1 , wherein R 5 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl or pyridazinyl, wherein each of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl and pyridazinyl is independently and optionally substituted with 1, 2 or 3 R 6 ; and wherein R 6 is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, cyanomethyl or cyanoethyl.

8. The compound of claim 1 , wherein W has one of the following structures:

each of X 1 , X 2 and X 3 is independently a bond, —CH 2 —, —O—, —S— or —NH—;
Y is CH or N;
each r, s, t and n is independently 0, 1, 2, or 3; and
each W is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, —C(═O)OH, —C(═O)NH 2 , —C(═NH)NH 2 , —NH—C(═NH)NH 2 , —SO 2 CH 3 , —SO 2 C 2 H 5 , C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylamino, C 1-3 haloalkyl, C 1-3 cyanoalkyl and C 1-3 hydroxyalkyl.

9. The compound of claim 1 , wherein W has one of the following structures:

wherein each W is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, —C(═O)OH, —C(═O)NH 2 , —C(═NH)NH 2 , —NH—C(═NH)NH 2 , —SO 2 CH 3 , —SO 2 C 2 H 5 , methyl, ethyl, isopro

Assignees

• Sunshine Lake Pharma Co Ltd
• North & South Brother Pharmacy Investment Co Ltd

Inventors

• Tang Wanjun
• Yang Xinye
• Gu Zheng
• Li Chenlu
• Zhang Zongyuan
• Wan Zhifu
• Wang Xiaojun
• Zhang Yingjun

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title