[1,2,3]triazolo[4,5-D]pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9056866-B2
Application number	US-201414250781-A
Country	US
Kind code	B2
Filing date	Apr 11, 2014
Priority date	Nov 8, 2011
Publication date	Jun 16, 2015
Grant date	Jun 16, 2015

Abstract

The invention relates to a compound of formula (I)

wherein A, R 1 and R 2 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 selected from the group consisting of alkyl, hydroxyalkyl, —CH 2 C(O)—, —C(O)—, —SO 2 — and a bond;
R 1 is selected from the group consisting of phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, (halo)(haloalkyl)phenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, alkylsulfonylaminophenyl, cyano, cycloalkyl, cycloalkylalkoxy, amino, (alkylsulfonyl)(alkyl)[1,2,4]triazolyl, (halo)(dialkylamino)pyridinyl, (alkyl)(oxy)pyridinyl, nitro-benzo[1,2,5]oxadiazolylaminopyridinyl, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, heteroaryl, haloheteroaryl, alkylheteroaryl, cycloalkylheteroaryl and haloalkylheteroaryl, wherein said heterocyclyl is a three to eight membered carbocyclic ring comprising at least one nitrogen or oxygen atom, and wherein said heteroaryl is pyridinyl, pyrazolyl, oxadiazolyl, furazanyl, tetrazolyl or triazolyl;
R 2 is —NR 3 R 4 ; wherein
one of R 3 and R 4 is hydrogen or alkyl and the other one is alkyl or cycloalkyl;
or R 3 and R 4 taken together with the nitrogen atom to which they are attached form heterocyclyl or substituted heterocyclyl, wherein said heterocyclyl is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptyl, azetidinyl, thiazolidinyl, thiomorpholinyl, dioxothiomorpholinyl, oxazepanyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-1-azaspiro[3.3]heptyl, 2-oxa-5-aza-spiro[3.4]octyl, isoxazolidinyl, aziridinyl, dioxoisothiazolidinyl or oxopyrrolidinyl and wherein said substituted heterocyclyl is heterocyclyl substituted with one to four substituents independently selected from the group consisting of alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, carboxyl, alkoxyalkyl, cyano, alkylamino, dialkylamino, alkylcarbonylamino, alkylcarbonyl(alkylamino), phenyl, alkoxycarbonyl, aminoalkyl, alkylpyrazolyl or alkylisoxazolyl;
or a pharmaceutically acceptable salt or ester thereof;
with the proviso that said compound is not 3-[(2-chlorophenyl)methyl]-5-(1,1-dimethylethyl)-7-(4-morpholinyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine or N-cyclopropyl-5-(1,1-dimethylethyl)-3-(phenylmethyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine.

2. The compound of claim 1 , wherein R 1 is phenyl, halophenyl or alkylheteroaryl.

3. The compound of claim 2 , wherein said compound is 5-tert-butyl-3-(2-chloro-benzyl)-7-(4,4-difluoro-piperidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

4. The compound of claim 2 , wherein said compound is 5-tert-butyl-3-(2-chloro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

5. The compound of claim 2 , wherein said compound is 1-[5-tert-butyl-3-(2-chloro-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

6. The compound of claim 5 , wherein said compound is (S)-1-[5-tert-butyl-3-(2-chloro-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

7. The compound of claim 2 , wherein said compound is 5-tert-butyl-3-(2-chloro-benzyl)-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

8. The compound of claim 2 , wherein said compound is 5-tert-butyl-3-(2-chloro-3,6-difluoro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

9. The compound of claim 1 , wherein R 1 is haloalkylphenyl.

10. The compound of claim 9 , wherein said compound is 1-(5-tert-butyl-3-(2-(trifluoromethyl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol.

11. The compound of claim 10 , wherein said compound is (S)-1-(5-tert-butyl-3-(2-(trifluoromethyl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol.

12. The compound of claim 1 , wherein R 1 is alkylsulfonylphenyl.

13. The compound of claim 12 , wherein said compound is 1-(5-tert-butyl-3-(2-(methylsulfonyl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol.

14. The compound of claim 13 wherein said compound is (S)-1-(5-tert-butyl-3-(2-(methylsulfonyl)benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol.

15. The compound of claim 2 , wherein said compound is 1-[5-tert-butyl-3-(2-methanesulfonyl-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

16. The compound of claim 15 , wherein said compound is (S)-1-[5-tert-butyl-3-(2-methanesulfonyl-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

17. The compound of claim 1 , wherein R 1 is haloheteroaryl or heteroaryl and said heteroaryl is pyridinyl.

18. The compound of claim 17 , wherein said compound is 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-pyridin-3-ylmethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

19. The compound of claim 17 , wherein said compound is 5-tert-butyl-3-(3-chloro-pyridin-2-ylmethyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

20. The compound of claim 17 , wherein said compound is 1-[5-tert-butyl-3-(2-chloro-pyridin-3-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

21. The compound of claim 20 , wherein said compound is (S)-1-[5-tert-butyl-3-(2-chloro-pyridin-3-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

22. The compound of claim 1 , wherein R 1 is heteroaryl, alkylheteroaryl or haloheteroaryl and heteroaryl is triazolyl or furazanyl.

23. The compound of claim 22 , wherein said compound is 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-(1-methyl-1H-tetrazol-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

24. The compound of claim 22 , wherein said compound is 1-[5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

25. The compound of claim 24 , wherein said compound is (S)-1-[5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

26. The compound of claim 22 , wherein said compound is 1-[5-tert-butyl-3-(1-methyl-1H-tetrazol-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

27. The compound of claim 26 , wherein said compound is (S)-1-[5-tert-butyl-3-(1-methyl-1H-tetrazol-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

28. The compound according to claim 1 , wherein said compound is (S)-1-[5-tert-Butyl-3-(3-chloro-pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.

29. The compound according to claim 1 , wherein said compound is (R)-1-(5-tert-butyl-3-((1-methyl-1H-tetrazol-5-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol.

30. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition according to claim 30 , wherein said compound is 5-tert-butyl-3-(2-chloro-benzyl)-7-(4,4-difluoro-piperidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

32. The pharmaceutical composition according to claim 30 , wherein said compound is 5-tert-butyl-3-(2-chloro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine.

33. The pharmaceutical composition according to claim 30 , wherein said compound is (S)-1-[5-tert-butyl-3-(2-chloro-benzyl)-3

Assignees

• Hoffmann La Roche

Inventors

• Adam Jean-Michel
• Bissantz Caterina
• Grether Uwe
• Kimbara Atsushi
• Nettekoven Matthias
• Roever Stephan
• Rogers-Evans Mark

Classifications

• 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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title