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

Patent metadata

Field	Value
Publication number	US-12351575-B2
Application number	US-201916531624-A
Country	US
Kind code	B2
Filing date	Aug 5, 2019
Priority date	Mar 7, 2014
Publication date	Jul 8, 2025
Grant date	Jul 8, 2025

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 method of inhibiting HBV capsid, which method comprises administering an effective amount of a compound of formula I to a patient in need thereof,

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 or ethyl;
R 5 is hydrogen 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, isopropyl, t-butyl, cyclopropyl, methyl-O-carbonylisopropyl, carboxyethyl, 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, carboxyphenyl or carboxyphenylmethyl;
W is —CH 2 —, —C(CH 3 ) 2 —, —O—or carbonyl; and
n is 0 or 1;
or pharmaceutically acceptable salts, or enantiomers thereof.

2. A method of inhibiting HBV capsid, which method comprises administering an effective amount of a compound of formula (IA) to a patient in need thereof,

wherein:
R 1 is halogen or C1-6alkyl;
R 2 is hydrogen or halogen;
R 3 is hydrogen or halogen;
R 4 is C1-6alkyl;
R 5 is hydrogen or carboxy;
R 6 is hydrogen, C1-6alkoxycarbonyl or carboxy-C m H 2m —;
Y is —N(R 7 )—, wherein R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxycarbonyl-C m H 2m —, —C m H 2m —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 m H 2m —, carboxyspiro[3.3]heptyl or carboxyphenyl-C m H 2m —;
W is —CH 2 —or carbonyl; and
m is 0-7;
or pharmaceutically acceptable salts, or enantiomers thereof.

3. A method according to claim 1 , wherein:
R 1 is chloro, bromo or methyl;
Y is —N(R 7 )—, wherein R 7 is hydrogen, methyl, isopropyl, t-butyl, cyclopropyl, methyl-O-carbonylisopropyl, carboxyethyl, 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, carboxyphenyl or carboxyphenylmethyl; and
W is —CH 2 —or carbonyl.

4. A method of inhibiting HBV capsid, which method comprises administering an effective amount of a compound of formula (IAA) to a patient in need thereof,

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 or carboxy;
R 6 is hydrogen;
R 7 is C 1-6 alkyl, C 3-7 cycloalkyl, —C m H 2m —COOH, —C m H 2m —C 3-7 cycloalkyl-COOH or carboxyphenyl; and
m is 1-6;
or pharmaceutically acceptable salts, or enantiomers thereof.

5. A method according to claim 1 , wherein:
R 1 is chloro or methyl;
R 3 is hydrogen or fluoro;
R 6 is hydrogen; and
R 7 is methyl, isopropyl, t-butyl, cyclopropyl, carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl, carboxycyclopropylmethyl, carboxycyclobutylmethyl or carboxyphenyl.

6. A method of inhibiting HBV capsid, which method comprises administering an effective amount of a compound of formula (IB) to a patient in need thereof,

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 pharmaceutically acceptable salts, or enantiomers thereof.

7. A method according to claim 1 , wherein:
R 1 is hydrogen, chloro or bromo;
R 3 is hydrogen or fluoro;
R 5 is hydrogen;
R 6 is hydrogen or carboxymethyl;
Y is —CH 2 —or —O—; and
W is —CH 2 —, —C(CH 3 ) 2 —or —O—.

8. A method of inhibiting HBV capsid, which method comprises administering an effective amount of a compound of formula (ID) to a patient in need thereof,

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 or carboxy;
R 6 is hydrogen or C 1-6 alkoxycarbonyl
X is carbonyl;
Y is —O—or —N(R 7 )—, wherein R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, —C m H 2m —COOH—C m H 2m —C 3-7 cycloalkyl-COOH, hydroxy-C m H 2m —, carboxyspiro[3.3]heptyl or carboxyphenyl-C t H 2t —;
m is 1-6; and
t is 0-6;
or pharmaceutically acceptable salts, or enantiomers thereof.

9. A method according to claim 1 , wherein:
R 1 is chloro, bromo or methyl;
R 3 is hydrogen or fluoro;
R 6 is hydrogen or methyl-O-carbonyl;
X is carbonyl; and
Y is —O—, or —N(R 7 )—, wherein R 7 is hydrogen, methyl, isopropyl, t-butyl, cyclopropyl, carboxy(gemdimethyl)ethyl, carboxy(methyl)ethyl, carboxycyclopropylmethyl, carboxyphenyl, carboxycyclopentyl, carboxycyclohexyl, carboxy(gemdimethyl)propyl, carboxy(gemdimethyl)butyl, carboxycyclobutylmethyl, carboxyspiro[ 3 . 3 ]heptyl, hydroxyethyl or carboxyphenylmethyl.

10. A method of inhibiting HBV capsid, which method comprises administering an effective amount of a compound of formula (IE) to a patient in need thereof,

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 or carboxy;
R 6 is hydrogen or carboxy-C m H 2m —;
Y is —O—or —N(R 7 )—,
wherein R 7 is C 1-6 alkyl, C 3-7 cycloalkyl, —C m H 2m —COOH, —C 3-7 cycloalkyl-C m H 2m —COOH, —C m H 2m —C 3-7 cycloalkyl-COOH, —(C 1-6 alkoxy) C 1-6 alkyl-COOH, —C 1-6 alkyl-O—C 1-6 alkyl-COOH, carboxyspiro[3.3]heptyl or carboxyphenyl-C m H 2m —;
W is —CH 2 —or —C(C 1-6 alkyl) 2 -; and
m is 0-6;
or pharmaceutically acceptable salts, or enantiomers thereof.

11. A method according to claim 1 , wherein:
R 1 is chloro or methyl;
R 3 is hydrogen or fluoro;
R 6 is hydrogen or carboxymethyl;
Y is —O—or —N(R 7 )—, wherein R 7 is isopropyl, methyl, t-butyl, cyclopropyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxy(gemdimethyl)methyl, c

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

• A61K31/519

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

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title