Pyrrolo[2,3-D]pyrimidine derivatives as CB2 receptor agonists

Patent metadata

Field	Value
Publication number	US-9580435-B2
Application number	US-201514923186-A
Country	US
Kind code	B2
Filing date	Oct 26, 2015
Priority date	May 2, 2013
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

The invention relates to a compound of formula (I)

wherein A and R 1 to R 3 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is CH 2 or absent;
R 1 and R 2 , together with the nitrogen atom to which they are attached form substituted pyrrolidinyl or 2-oxa-6-azaspiro[3.3]heptyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from halogen, hydroxyl and alkylcarbonyloxy; and
R 3 is halophenyl, alkylsulfonylphenyl, haloalkylphenyl, halopyridinyl, alkyloxadiazolyl, alkyltriazolyl, alkyltetrazolyl, oxolanyl, cycloalkyltetrazolyl or haloalkyl-1H-pyrazolyl;
or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1 , wherein A is CH 2 .

3. A compound according to claim 1 , wherein R 1 and R 2 , together with the nitrogen atom to which they are attached form substituted pyrrolidinyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from halogen and hydroxyl.

4. A compound according to claim 1 , wherein R 1 and R 2 , together with the nitrogen atom to which they are attached form substituted pyrrolidinyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from fluorine and hydroxyl.

5. A compound according to claim 1 , wherein R 1 and R 2 , together with the nitrogen atom to which they are attached form difluoropyrrolidinyl or hydroxypyrrolidinyl.

6. A compound according to claim 1 , wherein R 3 is halophenyl, haloalkylphenyl, alkylsulfonylphenyl, halopyridinyl or alkyloxadiazolyl.

7. A compound according to claim 1 , wherein R 3 is dichlorophenyl, chlorofluorophenyl, trifluoromethylphenyl, methylsulfonylphenyl, chloropyridinyl or methyloxadiazolyl.

8. A compound according to claim 1 selected from
2-tert-butyl-7-[(2-chlorophenyl)methyl]-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-7-[(2-chloro-4-fluorophenyl)methyl]-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)-7-[(2-methylsulfonylphenyl)methyl]pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)-7-[[2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-7-[(2,3-dichlorophenyl)methyl]-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-7-[(2-chloropyridin-3-yl)methyl]-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-7-[(3-chloropyridin-2-yl)methyl]-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidine;
5-[[2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]-3-methyl-1,2,4-oxadiazole;
3-[[2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]-4-methyl-1,2,5-oxadiazole;
2-[[2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]-5-methyl-1,3,4-oxadiazole;
2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)-7-[(4,5-dimethyl-1,2,4-triazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)-7-[(1-methyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-7-[(1-cyclopropyltetrazol-5-yl)methyl]-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidine;
6-[2-tert-butyl-7-[(2-chlorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(3S)-oxolan-3-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(3R)-oxolan-3-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(2-chloro-4-fluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(2-methylsulfonylphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(2-chloropyridin-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(2,3-dichlorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
6-[2-tert-butyl-7-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;
1-[2-tert-butyl-7-[(2-chlorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(2-chloro-4-fluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(2-methylsulfonylphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[[2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(2,3-dichlorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(2-chloropyridin-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(3-chloropyridin-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(1-methyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
[1-[2-tert-butyl-7-[(1-methyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]acetate;
[1-[2-tert-butyl-7-[(2,3-dichlorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]acetate;
[1-[2-tert-butyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]acetate;
1-[2-tert-butyl-7-[(1-cyclopropyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(3R)-oxolan-3-yl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[[3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)-7-[[3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]pyrrolo[2,3-d]pyrimidine;
(3S)-1-[2-tert-butyl-7-[(2,3-dichlorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
(3S)-1-[2-tert-butyl-7-[(2-chloro-4-fluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
(3S)-1-[2-tert-butyl-7-[[2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
(3S)-1-[2-tert-butyl-7-[(2-methylsulfonylphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
(3S)-1-[2-tert-butyl-7-[(2-chloropyridin-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
(3S)-1-[2-tert-butyl-7-[(3-chloropyridin-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
(3S)-1-[2-tert-butyl-7-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
6-[2-tert-butyl-7-[(3-chloropyridin-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane; and
6-[2-tert-butyl-7-[(1-methyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptane.

9. A compound according to claim 1 selected from
2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)-7-[[2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidine;
2-tert-butyl-7-[(3-chloropyridin-2-yl)methyl]-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidine;
3-[[2-tert-butyl-4-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]-4-methyl-1,2,5-oxadiazole;
1-[2-tert-butyl-7-[[2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-butyl-7-[(2-chloropyridin-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol;
1-[2-tert-b

Assignees

• Hoffman-La Roche Inc
• Hoffmann La Roche

Inventors

• Grether Uwe
• Kimbara Atsushi
• Nettekoven Matthias
• Roever Stephan
• Rogers-Evans Mark
• Schulz-Gasch Tanja

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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