Dihydropyrimidine compounds and their application in pharmaceuticals

Patent metadata

Field	Value
Publication number	US-9498479-B2
Application number	US-201415022562-A
Country	US
Kind code	B2
Filing date	Nov 18, 2014
Priority date	Nov 19, 2013
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

Provided herein are dihydropyrimidine compounds and their pharmaceutical applications, especially for use in treating and preventing HBV diseases. Specifically, provided herein are compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein the variables of the formulas are as defined in the specification. Also provided herein is the use of the compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof for treating and preventing HBV diseases.

First claim

What is claimed is:

1. A compound having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof,

wherein
R 1 is C 6-10 aryl or C 1-9 heteroaryl;
R 3 is a 5-membered heteroaryl group;
A is a bond, —O—, —S— or —NR 5 —;
R is

wherein, W is CR 4 or N;
each of R 2 , R 4 and R 5 is independently hydrogen or C 1-4 alkyl;
Y is —(CR 8 R 8a ) k —S(═O) q — or —(CR 7 R 6 ) n —;
Q is —(CR 8 R 8a ) k —;
each R 7 is independently hydrogen, F or alkyl;
each R 6 is independently F or alkyl;
or R 6 and R 7 , together with the carbon atom to which they are attached, form —C(═CH 2 )— or —C(═O)—;
each R 8 and R 8a is independently hydrogen, cyano or alkyl;
each R 9 is independently —(CR 10 R 10a ) t —OH, triazolyl, tetrazolyl, —(CR 10 R 10a ) m —C(═O)O—R 11 , —(CR 10 R 10 ) k —C(═O)O—(CR 10 R 10a ) k —OC(═O)O—R 11 , —S(═O) q OR 11 , —(CR 10 R 10a ) k —S(═O) q N(R 11 ) 2 , —(CR 10 R 10a ) k —C(═O)O—(CR 10 R 10a ) k —OC(═O)—R 11 , —(CR 10 R 10a ) k —C(═O)O—(CR 10 R 10a ) k —C(═O)O—R 11 , —(CR 10 R 10a ) t —N(R 11 ) 2 , —(CR 10 R 10a ) t —OC(═O)—R 11 , or —(CR 10 R 10a ) k —C(═O)N(R 11 ) 2 ;
each R 10 and R 10a is independently hydrogen, halogen, haloalkyl or alkyl, or R 10 and R 10a , together with the carbon atom to which they are attached, form cycloalkyl, heterocyclyl or —C(═O)—;
each R 11 is independently hydrogen, alkyl, alkoxy, hydroxy, alkyl-S(═O) q —, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heterocyclyl-S(═O) q —, heteroaryl-S(═O) q —, cycloalkyl-S(═O) q — or aryl-S(═O) q —;
each n is independently 1, 2 or 3;
each t and m is independently 1, 2, 3 or 4;
each q is independently 1 or 2; and
each k is independently 0, 1, 2, 3 or 4;
wherein each alkoxy, alkyl-S(═O) q —, aryl, heteroaryl, arylalkyl, heterocyclyl-S(═O) q —, heteroaryl-S(═O) q —, cycloalkyl-S(═O) q — and aryl-S(═O) q — described in R 11 , alkyl described in R 6 , R 7 , R 8 , R 8a , R 10 , R 10a , and R 11 , haloalkyl described in R 10 and R 10a , heterocyclyl and cycloalkyl described in R 10 , R 10a , and R 11 , triazolyl and tetrazolyl described in R 9 , a 5-membered heteroaryl group described in R 3 , C 1-4 alkyl described in R 1 , R 4 and R 5 , and C 6-10 aryl and C 1-9 heteroaryl described in R 1 , is optionally and independently substituted with one or more substituents independently selected from hydrogen, fluoro, chloro, bromo, iodo, oxo (═O), methylene (═CH 2 ), alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, amino, aryl, heteroaryl, heterocyclyl, cycloalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethylsulfonyl.

2. The compound according to claim 1 , wherein
R is

wherein, Y is —(CR 8 R 8a ) k —S(═O) q — or —(CR 7 R 6 ) n —;
Q is —(CR 8 R 8a ) k —;
each R 7 is independently hydrogen, C 1-4 alkyl or F;
each R 6 is independently F or C 1-4 alkyl;
or R 6 and R 7 , together with the carbon atom to which they are attached, form —C(═CH 2 )— or —C(═O)—;
each R 8 and R 8a is independently hydrogen or C 1-4 alkyl;
each R 9 is independently —(CR 10 R 10a ) t —OH, triazolyl, tetrazolyl, —(CR 10 R 10a ) m —C(═O)O—R 11 , —(CR 10 R 10a ) k —C(═O)O—(CR 10 R 10a ) k —OC(═O)O—R 11 , —S(═O) q OR 11 , —(CR 10 R 10a ) k —S(═O) q N(R 11 ) 2 , —(CR 10 R 10a ) k —C(═O)O—(CR 10 R 10a ) k —OC(═O)—R 11 , —(CR 10 R 10a ) k —C(═O)O—(CR 10 R 10a ) k —C(═O)O—R 11 , —(CR 10 R 10a ) t —N(R 11 ) 2 , —(CR 10 R 10a ) t —OC(═O)—R 11 , or —(CR 10 R 10a ) k —C(═O)N(R 11 ) 2 ;
each R 10 and R 10a is independently hydrogen, halogen, C 1-4 haloalkyl or C 1-4 alkyl, or R 10 and R 10a , together with the carbon atom to which they are attached, form C 3-6 cycloalkyl, C 2-9 heterocyclyl or —C(═O)—; and
each R 11 is independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-S(═O) q —, C 6-10 aryl, C 1-9 heteroaryl, C 3-6 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl-C 1-6 -alkyl, C 2-9 heterocyclyl-S(═O) q —, C 1-9 heteroaryl-S(═O) q —, C 3-6 cycloalkyl-S(═O) q — or C 6-10 aryl-S(═O) q .

3. The compound according to claim 2 , wherein
R is

wherein, each R 7 is independently hydrogen, methyl, ethyl or F;
each R 6 is independently F, methyl or ethyl;
or R 6 and R 7 , together with the carbon atom to which they are attached, form —C(═CH 2 )— or —C(═O)—;
each R 8 and R 8a is independently hydrogen, methyl, ethyl or propyl;
each R 9 is independently —(CR 10 R 10a ) t —OH, triazolyl, tetrazolyl, —(CR 10 R 10a ) m —C(═O)O—R 11 , —(CR 10 R 10a ) k —C(═O)O—(CR 10 R 10a ) k —OC(═O)O—R 11 , —S(═O) q OR 11 , —(CR 10 R 10a ) k —S(═O) q N(R 11 ) 2 , —(CR 10 R 10a ) k —C(═O)O—(CR 10 R 10a ) k —OC(═O)—R 11 , —(CR 10 R 10a ) k —C(═O)O—(CR 10 R 10a ) k —C(═O)O—R 11 , —(CR 10 R 10a ) t —N(R 11 ) 2 , —(CR 10 R 10a ) t —OC(═O)—R 11 , or —(CR 10 R 10a ) k —C(═O)N(R 11 ) 2 ;
each R 10 and R 10a is independently hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, ethyl, propyl, or R 10 and R 10a , together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or —C(═O)—; and
each R 11 is independently hydrogen, C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 alkyl-S(═O) 2 —, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(═O) 2 —, cyclobutyl-S(═O) 2 —, cyclopentyl-S(═O) 2 —, cyclohexyl-S(═O) 2 —, naphthyl-S(═O) 2 — or phenyl-S(═O) 2 —.

4. The compound according to claim 1 , wherein
R 1 is phenyl;
R 3 is thiazolyl or 1-methyl-1H-imidazolyl; and
each of R 2 , R 4 and R 5 is independently hydrogen, methyl or ethyl;
wherein each thiazolyl and 1-methyl-1H-imidazolyl described in R 3 , phenyl described in R 1 , and methyl and ethyl described in R 2 , R 4 and R 5 , is optionally and independently substituted with one or more substituents independently selected from hydrogen, C 1-4 alkyl, fluoro, chloro or bromo.

5. The compound according to claim 1 having Formula (II) or (IIa), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide or a pharmaceutically acceptable salt thereof,

wherein
R 2 is hydrogen or C 1-4 alkyl;
R 3 is thiazolyl or 1-methyl-1H-imidazolyl;
R is

wherein each R 7 is independently hydrogen, C 1-4 alkyl or F;
each R 6 is independently F or C 1-4 alkyl;
or R 6 and R 7 , together with the carbon atom to which they are attached, form —C(═CH 2 )— or —C(═O)—;
Q is —(CR 8 R 8a ) k —;
each R 8 and R 8a is independently hydrogen or C 1-4 alkyl;
each R 9 is independently —(CR 10 R 10a ) t —O

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Zhang Yingjun
• Liu Xinchang
• Zou Zhifu
• Liang Jinsheng
• Goldmann Siegfried
• Ren Qingyun

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title