6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-9233978-B2
Application number	US-201514640397-A
Country	US
Kind code	B2
Filing date	Mar 6, 2015
Priority date	Mar 7, 2014
Publication date	Jan 12, 2016
Grant date	Jan 12, 2016

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, W and n are as described herein, compositions including the compounds and methods of using the compounds.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is hydrogen, halogen or C 1-6 alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen or halogen;
R 4 is C 1-6 alkyl;
R 5 is hydrogen, hydroxyC 1-6 alkyl, aminocarbonyl, C 1-6 alkoxycarbonyl or carboxy;
R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m —;
X is carbonyl or sulfonyl;
Y is —CH 2 —, —O— or —N(R 7 )—,
wherein R 7 is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl-C m H 2m —, C 1-6 alkoxycarbonyl-C m H 2m —, —C t H 2t —COOH, -haloC 1-6 alkyl-COOH, —(C 1-6 alkoxy)C 1-6 alkyl-COOH, —C 1-6 alkyl-O—C 1-6 alkyl-COOH, —C 3-7 cycloalkyl-C m H 2m —COOH, —C m H 2m —C 3-7 cycloalkyl-COOH, hydroxy-C t H 2t , carboxyspiro[3.3]heptyl, carboxyphenyl-C m H 2m — or carboxypyridinyl-C m H 2m —;

W is —CH 2 —, —C(C 1-6 alkyl) 2 -, —O— or carbonyl;
n is 0 or 1;
m is 0-7; and
t is 1-7;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

2. A compound according to claim 1 , wherein
R 1 is hydrogen, chloro, bromo or methyl;
R 2 is hydrogen or fluoro;
R 3 is hydrogen, chloro or fluoro;
R 4 is methyl, ethyl or propyl;
R 5 is hydrogen, hydroxymethyl, aminocarbonyl, methoxycarbonyl or carboxy;
R 6 is hydrogen, methyl-O-carbonyl or carboxymethyl;
X is carbonyl or sulfonyl;
Y is —CH 2 —, —O—, —N(R 7 )—,
wherein R 7 is hydrogen, methyl, difluoroethyl, isopropyl, isobutyl, t-butyl, cyclopropyl, cyclopropylmethyl, methyl-O-carbonylisopropyl, carboxyethyl, carboxydifluoroethyl, carboxypropyl, carboxybutyl, carboxy(gemdimethyl)methyl, carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl, carboxy(gemdimethyl)butyl, carboxy(methyl)ethyl, carboxy(ethyl)ethyl, carboxy(methoxy)ethyl, carboxycyclobutyl, carboxycyclobutylmethyl, carboxycyclopentyl, carboxycyclohexyl, carboxymethylcyclopropyl, carboxycyclopropylmethyl, carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl, carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl, hydroxymethyl(gemdimethyl)butyl, hydroxy(gemdimethyl)ethyl, carboxyphenyl, carboxypyridinyl or carboxyphenylmethyl;

W is —CH 2 —, —C(CH 3 ) 2 —, —O— or carbonyl; and
n is 0 or 1;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

3. A compound of formula (IA) according to claim 1 ,

wherein
R 1 is halogen or C 1-6 alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen or halogen;
R 4 is C 1-6 alkyl;
R 5 is hydrogen, hydroxyC 1-6 alkyl, aminocarbonyl, C 1-6 alkoxycarbonyl or carboxy;
R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m —;
Y is —N(R 7 )—,
wherein R 7 is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl-C m H 2m —, C 1-6 alkoxycarbonyl-C m H 2m —, —C t H 2t —COOH, -haloC 1-6 alkyl-COOH, —(C 1-6 alkoxy)C 1-6 alkyl-COOH, —C 1-6 alkyl-O—C 1-6 alkyl-COOH, —C 3-7 cycloalkyl-C m H 2m —COOH, —C m H 2m —C 3-7 cycloalkyl-COOH, hydroxy-C t H 2t , carboxyspiro[3.3]heptyl, carboxyphenyl-C m H 2m — or carboxypyridinyl-C m H 2m —;

W is —CH 2 — or carbonyl;
m is 0-7; and
t is 1-7;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

4. A compound according to claim 1 or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein
R 1 is chloro, bromo or methyl;
R 2 is hydrogen or fluoro;
R 3 is hydrogen, chloro or fluoro;
R 4 is methyl, ethyl or propyl;
R 5 is hydrogen, hydroxymethyl, aminocarbonyl, methoxycarbonyl or carboxy;
R 6 is hydrogen, methyl-O-carbonyl or carboxymethyl;
Y is —N(R 7 )—,
wherein R 7 is hydrogen, methyl, difluoroethyl, isopropyl, isobutyl, t-butyl, cyclopropyl, cyclopropylmethyl, methyl-O-carbonylisopropyl, carboxyethyl, carboxydifluoroethyl, carboxypropyl, carboxybutyl, carboxy(gemdimethyl)methyl, carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl, carboxy(gemdimethyl)butyl, carboxy(methyl)ethyl, carboxy(ethyl)ethyl, carboxy(methoxy)ethyl, carboxycyclobutyl, carboxycyclobutylmethyl, carboxycyclopentyl, carboxycyclohexyl, carboxymethylcyclopropyl, carboxycyclopropylmethyl, carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl, carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl, hydroxymethyl(gemdimethyl)butyl, hydroxy(gemdimethyl)ethyl, carboxyphenyl, carboxypyridinyl or carboxyphenylmethyl; and

W is —CH 2 — or carbonyl.

5. A compound of formula (IAA) according to claim 1 ,

wherein
R 1 is halogen or C 1-6 alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen or halogen;
R 4 is C 1-6 alkyl;
R 5 is hydrogen, aminocarbonyl or carboxy;
R 6 is hydrogen;
R 7 is C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C m H 2m —, —C t H 2t —COOH, —C m H 2m —C 3-7 cycloalkyl-COOH or carboxyphenyl;
m is 0-7; and
t is 1-7;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein
R 1 is chloro or methyl;
R 2 is hydrogen or fluoro;
R 3 is hydrogen or fluoro;
R 4 is methyl or ethyl;
R 5 is hydrogen, aminocarbonyl or carboxy;
R 6 is hydrogen; and
R 7 is methyl, isopropyl, isobutyl, t-butyl, difluoroethyl, cyclopropyl, cyclopropylmethyl, carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl, carboxycyclopropylmethyl, carboxycyclobutylmethyl or carboxyphenyl.

7. A compound of formula (IB) according to claim 1 ,

wherein
R 1 is hydrogen or halogen;
R 2 is hydrogen or halogen;
R 3 is hydrogen or halogen;
R 4 is C 1-6 alkyl;
R 5 is hydrogen;
R 6 is hydrogen or carboxymethyl;
Y is —CH 2 — or —O—;
W is —CH 2 —, —C(C 1-6 alkyl) 2 - or —O—; and
n is 0 or 1;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

8. A compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, wherein
R 1 is hydrogen, chloro or bromo;
R 2 is hydrogen or fluoro;
R 3 is hydrogen or fluoro;
R 4 is methyl or ethyl;
R 5 is hydrogen;
R 6 is hydrogen or carboxymethyl;
Y is —CH 2 — or —O—;
W is —CH 2 —, —C(CH 3 ) 2 — or —O—; and
n is 0 or 1.

9. A compound of formula (ID) according to claim 1 ,

wherein
R 1 is halogen or C 1-6 alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen or halogen;
R 4 is C 1-6 alkyl;
R 5 is hydrogen, aminocarbonyl or carboxy;
R 6 is hydrogen or C 1-6 alkoxycarbonyl
X is carbonyl;
Y is —O— or —N(R 7 )— or —CH 2 —,
wherein R 7 is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C m H 2m —, —C t H 2t —COOH—C m H 2m —C 3-7 cycloalkyl-COOH, hydroxy-C t H 2t , carboxyspiro[3.3]heptyl or carboxyphenyl-C m H 2m —;

m is 0-7; and
t is 1-7;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

10. A compound according to claim 1 , or a pharmaceutically acceptable salt, enantiomer,

Assignees

• Hoffmann La Roche

Inventors

• Guo Lei
• Hu taishan
• Kou Buyu
• Lin Xianfeng
• Shen Hong
• Shi Houguang
• Yan Shixiang
• Zhang Weixing
• Zhang Zhisen
• Zhou Mingwei
• Zhu Wei

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P43/00

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

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title