Dihydropyrrolopyrimidines for the treatment and prophylaxis of hepatitis B virus infection

Patent metadata

Field	Value
Publication number	US-11225482-B2
Application number	US-201816227136-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Jun 29, 2016
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

Abstract

The present invention provides novel compounds having the general formula:wherein R1, R2, A and X 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, 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 phenyl, naphthyl, or heteroaryl, wherein said phenyl, naphthyl and heteroaryl are unsubstituted or substituted with one, two or three substituents independently selected from 2-oxa-6-azaspiro[3.3]heptanyl, azetidinyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylcarbonylpiperazinyl, C 1-6 alkylsulfonylpiperazinyl, diC 1-6 alkylamino, haloC 1-6 alkyl, halogen, morpholinyl, nitro, oxopiperazinyl, piperazinyl, piperidinyl and pyrrolidinyl;
A is N or CH; and
X is a bond or —C(═O)—;
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 or hydrogen;
R 2 is phenyl, naphthyl or heteroaryl, wherein said phenyl and heteroaryl are unsubstituted or substituted with one, two or three substituents independently selected from 2-oxa-6-azaspiro[3.3]heptanyl, azetidinyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylcarbonylpiperazinyl, C 1-6 alkylsulfonylpiperazinyl, diC 1-6 alkylamino, haloC 1-6 alkyl, halogen, morpholinyl, nitro, oxopiperazinyl, piperazinyl, piperidinyl and pyrrolidinyl;
A is N or CH; and
X is a bond or —C(═O)—;
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 phenyl, naphthyl or heteroaryl, wherein said phenyl and heteroaryl are unsubstituted or substituted with one, two or three substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, halogen and nitro; said heteroaryl is 1,2-benzoxazolyl, 1,3-benzothiazolyl, benzimidazolyl, indazolyl, benzofuranyl, imidazo[1,2-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolyl, thiazolyl or thienyl;
A is N; and
X is —C(═O)—;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

4. A compound according to claim 1 , or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof, wherein R 1 is methyl.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof, wherein R 1 is indazolyl, C 1-6 alkylindazolyl, C 1-6 alkoxythienyl, C 1-6 alkylthienyl or halothienyl.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof, wherein R 1 is indazolyl, methylindazolyl, methoxythienyl, bromothienyl or chlorothienyl.

7. A compound according to claim 1 , selected from:
(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)-(5-methylthiazol-2-yl)methanone;
(5-methoxy-2-thienyl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)[4-(trifluoromethyl)thiazol-2-yl]methanone;
(3-fluoro-5-methoxy-phenyl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)-(2-thienyl)methanone;
(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)-(4-methyl-2-thienyl)methanone;
(4-bromo-2-thienyl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)-(5-methyl-2-thienyl)methanone;
(5-chloro-2-thienyl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(4,5-dimethylthiazol-2-yl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(1-methylpyrazol-4-yl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(1-methylindazol-3-yl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(1-methylpyrazol-3-yl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
1H-benzimidazol-2-yl-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(4-methoxyphenyl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(1-ethylpyrazol-3-yl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(5-bromo-2-thienyl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)-(5-nitro-2-thienyl)methanone;
(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)-(2-naphthyl)methanone;
imidazo[1,2-a]pyridin-2-yl-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(3-methylbenzofuran-2-yl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(6-methoxypyrazin-2-yl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
1H-indazol-3-yl-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)-pyrazolo[1,5-a]pyridin-3-yl-methanone;
1,3-benzothiazol-6-yl-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
imidazo[1,2-a]pyridin-3-yl-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
1,2-benzoxazol-3-yl-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone; and
1,3-benzothiazol-2-yl-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

8. A compound according to claim 1 , which is (1-methylindazol-3-yl)-(5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl)methanone; or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

9. A compound according to claim 1 , wherein:
R 1 is C 1-6 alkyl or hydrogen;
R 2 is phenyl substituted with one, two or three substituents independently selected from halogen and C 1-6 alkoxy; or pyridinyl substituted with one or two substituents independently selected from C 1-6 alkoxy, 2-oxa-6-azaspiro[3.3]heptanyl, azetidinyl, C 1-6 alkylamino, C 1-6 alkylcarbonylpiperazinyl, C 1-6 alkylsulfonylpiperazinyl, diC 1-6 alkylamino, halogen, morpholinyl, oxopiperazinyl, piperazinyl, piperidinyl and pyrrolidinyl;
A is N or C; and
X is a bond;
or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.

10. A compound according to claim 1 , or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof, wherein R 2 is pyridinyl substituted with one or two substituents independently selected from C 1-6 alkoxy, azetidinyl, C 1-6 alkylamino, C 1-6 alkylsulfonylpiperazinyl, diC 1-6 alkylamino, halogen, and oxopiperazinyl.

11. A compound according to claim 1 , or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof, wherein R 2 is pyridinyl substituted with one or two substituents independently selected from methoxy, azetidinyl, methylamino, methylsulfonylpiperazinyl, dimethyl amino, fluoro and oxopiperazinyl.

12. A compound according to claim 1 , or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof, wherein A is N.

13. A compound according to claim 1 , selected from:
6-(3,4-difluoro-5-methoxy-phenyl)-2-(2-pyridyl)-5,7-dihydropyrrolo[3,4-d]pyrimidine;
6-(6-fluoro-4-methoxy-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidine;
6-(4,6-difluoro-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-5,7-dihydropyrrolo[3,4-d]pyrimidine;
6-(2,6-difl

Assignees

• Hoffmann La Roche

Inventors

• Cheng Zhanling
• Han Xingchun
• Jiang Min
• Yang Song

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61P31/20

  for DNA viruses · 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