Triazolo[4,5-D]pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9593123-B2
Application number	US-201615050753-A
Country	US
Kind code	B2
Filing date	Feb 23, 2016
Priority date	Sep 6, 2013
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The invention relates to a compound of formula (I)

wherein R 1 to R 4 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
R 1 is haloalkyl, halophenyl, alkoxyphenyl, alkyl-1,2,5-oxadiazolyl, haloalkylphenyl, alkylsulfonylphenyl, halopyridinyl or alkyltetrazolyl;
R 2 is cycloalkyl, isopropyl, alkenyl, piperidinyl, alkylamino, azetidinyl, pyrrolidinyl, cycloalkylamino, alkyloxetanylamino, morpholinyl, (cycloalkyl)(alkyl)amino, haloalkyloxy, alkoxy, cycloalkylalkoxy, cycloalkyloxy, oxetanyloxy, alkyloxetanylalkyloxy, alkynyloxy, alkoxyalkoxy, hydroxyalkyloxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, hydroxyalkylsulfanyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl;
R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, alkylcarbonylamino and alkyl, provided that R 3 and R 4 are not both hydrogen at the same time; and
n is 1 or 2;
or a pharmaceutically acceptable salt or ester thereof;
provided that (S)-1-[3-(4-Methoxy-benzyl)-5-(2,2,2-trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol is excluded.

2. A compound according to claim 1 , wherein R 1 is halophenyl, haloalkylphenyl or alkylsulfonylphenyl.

3. A compound according to claim 1 , wherein R 1 is chlorophenyl, trifluoromethylphenyl or methylsulfonylphenyl.

4. A compound according to claim 1 , wherein R 2 is cycloalkyl, isopropyl, alkylamino, alkoxy, haloalkyloxy or alkylsulfanyl.

5. A compound according to claim 1 , wherein R 2 is cyclobutyl, isopropyl, tert.-butylamino, pentyloxy, isopropyloxy, trifluoroethyloxy, trifluoropropyloxy, ethylsulfanyl or tert.-butylsulfanyl.

6. A compound according to claim 1 , wherein R 3 and R 4 are independently selected from hydrogen, halogen and hydroxyl.

7. A compound according to claim 1 , wherein one of R 3 and R 4 is hydrogen and the other one is hydroxyl, or wherein R 3 and R 4 are both halogen at the same time.

8. A compound according to claim 1 , wherein one of R 3 and R 4 is hydrogen and the other one is hydroxyl, or wherein R 3 and R 4 are both fluorine at the same time.

9. A compound according to claim 1 selected from:
3-[(2-chlorophenyl)methyl]-5-cyclobutyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidine;
5-cyclopropyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-propan-2-yltriazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-5-cyclopropyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidine;
3-[[5-cyclopropyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]-4-methyl-1,2,5-oxadiazole;
(3S)-1-[3-[(2-chlorophenyl)methyl]-5-prop-1-en-2-yltriazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
3-[(2-chlorophenyl)methyl]-5,7-di(piperidin-1-yl)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-N-ethyltriazolo[4,5-d]pyrimidin-5-amine;
5-(azetidin-1-yl)-3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-pyrrolidin-1-yltriazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-N-cyclobutyl-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-5-amine;
N-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-5-amine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-N-(3-methyloxetan-3-yl)triazolo[4,5-d]pyrimidin-5-amine;
4-[3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-5-yl]morpholine;
N-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-N-methyltriazolo[4,5-d]pyrimidin-5-amine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-N-(2,2-dimethylpropyl)triazolo[4,5-d]pyrimidin-5-amine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-N-(oxetan-3-yl)triazolo[4,5-d]pyrimidin-5-amine;
3-[(2-chlorophenyl)methyl]-N-cyclobutyl-7-(3,3-difluoropyrrolidin-1-yl)-N-methyltriazolo[4,5-d]pyrimidin-5-amine;
(3S)-1-[5-(tert-butylamino)-3-[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
N-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin-5-amine;
N-[(3S)-1-[5-(tert-butylamino)-3-[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-yl]acetamide;
N-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin-5-amine;
N-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[(2-methylsulfonylphenyl)methyl]triazolo[4,5-d]pyrimidin-5-amine;
N-tert-butyl-3-[(3-chloropyridin-2-yl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidin-5-amine;
N-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-5-amine;
N-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]triazolo[4,5-d]pyrimidin-5-amine;
N-[(3S)-1-[5-(tert-butylamino)-3-[(3-chloropyridin-2-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-yl]acetamide;
(3S)-1-[5-(tert-butylamino)-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
(3S)-1-[5-(tert-butylamino)-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
(3S)-1-[5-(tert-butylamino)-3-[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]-3-methylpyrrolidin-3-ol;
(3R)-1-[5-(tert-butylamino)-3-[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]-3-methylpyrrolidin-3-ol;
(3S)-1-[3-[(2-chlorophenyl)methyl]-5-morpholin-4-yltriazolo[4,5-d]pyrimidin-7-yl]-3-methylpyrrolidin-3-ol;
(3S)-3-methyl-1-[5-morpholin-4-yl-3-[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
(3S)-1-[3-[(3-chloropyridin-2-yl)methyl]-5-morpholin-4-yltriazolo[4,5-d]pyrimidin-7-yl]-3-methylpyrrolidin-3-ol;
(3S)-3-methyl-1-[3-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-5-morpholin-4-yltriazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
(3R)-1-[3-[(2-chlorophenyl)methyl]-5-morpholin-4-yltriazolo[4,5-d]pyrimidin-7-yl]-3-methylpyrrolidin-3-ol;
(3R)-3-methyl-1-[5-morpholin-4-yl-3-[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
(3R)-3-methyl-1-[3-[(2-methylsulfonylphenyl)methyl]-5-morpholin-4-yltriazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
(3R)-3-methyl-1-[3-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-5-morpholin-4-yltriazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-(1,1,1-trifluoropropan-2-yloxy)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-[(2S)-1,1,1-trifluoropropan-2-yl]oxytriazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-5-(2,2-difluoroethoxy)-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-ethoxytriazolo[4,5-d]pyrimidine;
5-butoxy-3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-(2-fluoroethoxy)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-5-(cyclopropylmethoxy)-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-5-cyclobutyloxy-7-(3,3-difluoropyrrolidin-1-yl)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-(oxetan-3-yloxy)triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)-5-[(3-methyloxetan-3-yl)methoxy]triazolo[4,5-d]pyrimidine;
3-[(2-chlorophenyl)methyl]-7-(3,3-difluoropyrrolidin-1-yl)

Assignees

• Hoffmann La Roche

Inventors

• Grether Uwe
• Nettekoven Matthias
• Rogers-Evans Mark
• Roever Stephan
• Schmitt Sebastien
• Kimbara Atsushi

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/519

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