Tetrahydropyridopyrimidines for the treatment of HBV infection

Patent metadata

Field	Value
Publication number	US-11104674-B2
Application number	US-201816227076-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Jun 29, 2016
Publication date	Aug 31, 2021
Grant date	Aug 31, 2021

Abstract

The present invention provides novel compounds having the general formula:

wherein R 1 to R 4 , A, W, Q and Y 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 aminoC 1-6 alkyl, aminocarbonylC 1-6 alkyl, C 1-6 alkyl, C 3-7 cycloalkyl, carboxyC 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydrogen or hydroxyC 1-6 alkyl;
R 2 is C 1-6 alkoxy, C 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkyl, halogen or hydrogen;
one of R 3 and R 4 is C 3-7 cycloalkylC 1-6 alkyl, C 1-6 alkyl or hydrogen; and the other one is 1,1-dioxothianyl, aminocarbonylC 1-6 , azetidinyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylazetidinyl, C 1-6 alkylsufonylpiperidinyl, C 1-6 alkylsufonyl, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkylsulfonyl, carboxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkylcarbonyl, phenylcarbonyl, phenylsulfonyl or tetrahydropyranyl; or
R 3 and R 4 together with the nitrogen to which they are attached form 1,1-dioxo-thiazolidinyl; 1,1-dioxo-thiazinanyl; 2-oxa-6-azaspiro[3.3]heptanyl; 2-oxa-7-azaspiro[4.4]nonanyl; 3-oxa-8-azabicyclo[3.2.1]octanyl; 6-oxo-2-oxa-7-azaspiro[3.4]octanyl; azetidinyl; oxoimidazolidinyl;
oxopyrrolidinyl; substituted azetidinyl; substituted morpholinyl; substituted oxooxazolidinyl; substituted oxopiperazinyl; substituted oxopyrrolidinyl; substituted piperazinyl; substituted piperidinyl or substituted pyrrolidinyl; wherein said substituted azetidinyl, substituted morpholinyl, substituted oxooxazolidinyl, substituted oxopiperazinyl, substituted oxopyrrolidinyl, substituted piperazinyl, substituted piperidinyl and substituted pyrrolidinyl are substituted with one, two or three substituents independently selected from aminocarbonyl, aminocarbonylC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkylsulfonyl, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, C 1-6 alkylsulfonylaminocarbonyl, carboxy, carboxyC 1-6 alkyl, cyano, halogen, hydroxy and hydroxyC 1-6 alkyl;
A is N or CH; and
one of W, Q and Y is N, and the others are CH;
with the proviso that N-[2-fluoro-6-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-4-pyridyl]methanesulfonamide and N-[4-fluoro-6-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-2-pyridyl]methanesulfonamide are excluded;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

2. A compound according to claim 1 , wherein:
R 1 is C 1-6 alkyl;
R 2 is halogen;
one of R 3 and R 4 is C 3-7 cycloalkylC 1-6 alkyl, C 1-6 alkyl or hydrogen; the other one is 1,1-dioxothianyl, aminocarbonylC 1-6 , azetidinyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylazetidinyl, C 1-6 alkylsufonylpiperidinyl, C 1-6 alkylsufonyl, C 3-7 cycloalkylcarbonyl, C 3-7 cycloalkylsulfonyl, carboxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkylcarbonyl, phenylcarbonyl, phenylsulfonyl or tetrahydropyranyl; or
R 3 and R 4 together with the nitrogen to which they are attached form 1,1-dioxo-thiazolidinyl; 1,1-dioxo-thiazinanyl; 2-oxa-6-azaspiro[3.3]heptanyl; 2-oxa-7-azaspiro[4.4]nonanyl; 3-oxa-8-azabicyclo[3.2.1]octanyl; 6-oxo-2-oxa-7-azaspiro[3.4]octanyl; azetidinyl; oxoimidazolidinyl;
oxopyrrolidinyl; substituted azetidinyl; substituted morpholinyl; substituted oxooxazolidinyl; substituted oxopiperazinyl; substituted oxopyrrolidinyl; substituted piperazinyl; substituted piperidinyl or substituted pyrrolidinyl; wherein said substituted azetidinyl, substituted morpholinyl, substituted oxooxazolidinyl, substituted oxopiperazinyl, substituted oxopyrrolidinyl, substituted piperazinyl, substituted piperidinyl and substituted pyrrolidinyl are substituted with one, two or three substituents independently selected from aminocarbonyl, aminocarbonylC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkylsulfonyl, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, C 1-6 alkylsulfonylaminocarbonyl, carboxy, carboxyC 1-6 alkyl, cyano, halogen, hydroxy and hydroxyC 1-6 alkyl;
A is N or CH; and
one of W, Q and Y is N, and the others are CH;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

3. A compound according to claim 1 , wherein:
R 1 is C 1-6 alkyl;
R 2 is halogen;
one of R 3 and R 4 is C 3-7 cycloalkylC 1-6 alkyl, C 1-6 alkyl or hydrogen; and the other one is 1,1-dioxothianyl, aminocarbonylC 1-6 alkyl, azetidinyl, C 1-6 alkylcarbonylazetidinyl, C 1-6 alkylsufonylpiperidinyl, carboxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkylcarbonyl, phenylcarbonyl, phenylsulfonyl or tetrahydropyranyl; or
R 3 and R 4 together with the nitrogen to which they are attached form
2-oxa-6-azaspiro[3.3]heptanyl;
2-oxa-7-azaspiro[4.4]nonanyl;
3-oxa-8-azabicyclo[3.2.1]octanyl;
6-oxo-2-oxa-7-azaspiro[3.4]octanyl;
azetidinyl substituted with one or two substituents independently selected from aminocarbonyl, C 1-6 alkoxy, C 1-6 alkoxycarbonylamino, C 1-6 alkoxysulfonylamino, C 1-6 alkylsulfonylaminocarbonyl, carboxy, cyano, halogen, hydroxy and hydroxyC 1-6 alkyl;
morpholinyl substituted with one or two substituents independently selected from aminocarbonyl, C 1-6 alkoxyC 1-6 alkyl, carboxyC 1-6 alkyl and hydroxyC 1-6 alkyl;
oxopyrrolidinyl substituted with one or two substituents independently selected from carboxy and hydroxyC 1-6 alkyl;
piperazinyl substituted with one, two or three substituents independently selected from aminocarbonylC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkylsulfonyl, carboxy and carboxyC 1-6 alkyl;
piperidinyl substituted with one or two substituents independently selected from aminocarbonyl, C 1-6 alkyl sulfonylamino, C 1-6 alkylsulfonylaminocarbonyl and carboxy; or
pyrrolidinyl substituted with one, two or three substituents independently selected from aminocarbonyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylsulfonylaminocarbonyl, C 1-6 alkyl, carboxy, halogen, hydroxy and hydroxyC 1-6 alkyl;

A is N or CH; and
one of W, Q and Y is N, and the others are CH;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

4. A compound according to claim 1 , wherein:
R 1 is C 1-6 alkyl;
R 2 is halogen;
one of R 3 and R 4 is C 3-7 cycloalkylC 1-6 alkyl, C 1-6 alkyl or hydrogen; and the other one is 1,1-dioxothianyl, aminocarbonylC 1-6 alkyl, azetidinyl, C 1-6 alkylcarbonylazetidinyl, C 1-6 alkylsufonylpiperidinyl, carboxyC 1-6 alkyl, hydroxyC 1-6 alkylcarbonyl, phenyl carbonyl; phenylsulfonyl or tetrahydropyranyl; or
R 3 and R 4 together with the nitrogen to which they are attached form
2-oxa-6-azaspiro[3.3]heptanyl;
2-oxa-7-azaspiro[4.4]nonanyl;
3-oxa-8-azabicyclo[3.2.1]octanyl;
6-oxo-2-oxa-7-azaspiro[3.4]octanyl;
azetidinyl substituted with one or two substituents independently selected from aminocarbonyl, C 1-6 alkoxy, C 1-6 alkoxycarbonylamino, C 1-6 alkoxysulfonylamino, C 1-6 alkylsulfonylaminocarbonyl, carboxy, cyano, halogen, hydroxy and hydroxyC 1-6 alkyl;
morpholinyl substituted with one or two substituents independently selected from aminocarbonyl, C 1-6 alkoxyC 1-6 alkyl, carboxy, carboxyC 1-6 alkyl and hydroxyC 1-6 alkyl;
oxopyrrolidinyl substituted with one or two substituents independently selected from carboxy and hydroxyC 1-6 alkyl;
piperazinyl substituted with one, two or three substituents independently selected from aminocarbonylC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkylsulfonyl, carboxy and carboxyC 1-6 alkyl;
piperidinyl substituted with one or two substituents independently selected from aminocarbonyl, C 1-6 alkylsulfonylamino, C 1-6 alkylsulfonylaminocarbonyl and carboxy; or
pyrrolidinyl substituted with one, two or three substituents independently selected from aminocarbonyl, C 1

Assignees

• Hoffmann La Roche

Inventors

• Cheng Zhanling
• Han Xingchun
• Jiang Min
• Wang Jianhua
• Wang Yongguang
• Yang Song

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• 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

• A61P31/20

  for DNA viruses · CPC title