Pyrazol derivatives

Patent metadata

Field	Value
Publication number	US-9694012-B2
Application number	US-201615332398-A
Country	US
Kind code	B2
Filing date	Oct 24, 2016
Priority date	Mar 7, 2013
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

The invention relates to a compound of formula (I)

wherein A 1 to A 3 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 method for the treatment of pain, atherosclerosis, diabetic retinopathy, inflammatory bowel disease, ischemia-reperfusion injury, kidney fibrosis, diabetic nephropathy, liver cirrhosis or tumors, multiple sclerosis, or stroke, which method comprises administering to a patient in need thereof an effective amount of a compound of formula (I)

wherein
A 1 is CH or N;
A 2 is CH or N;
A 3 is —(CH 2 ) n — or —CH 2 C(O)—;
R 1 is alkyl, cycloalkyl, alkoxy or halogen;
R 2 is substituted pyrrolidinyl or substituted dihydropyrrolyl, wherein substituted pyrrolidinyl and substituted dihydropyrrolyl are pyrrolidinyl and dihydropyrrolyl substituted with one or two substituents independently selected from halogen, hydroxyl, hydroxyalkyl, alkoxyalkyl and alkylfurazanylalkoxy;
R 3 is phenyl, substituted phenyl, substituted furazanyl, pyridinyl, substituted pyridinyl, dioxothietanyl, tetrahydrofuranyl, substituted tetrazolyl or substituted triazolyl, wherein substituted phenyl, substituted furazanyl, substituted pyridinyl and substituted triazolyl are phenyl, pyridinyl and triazolyl substituted with one or two substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, alkylsulfonyl and cycloalkyl, and wherein substituted tetrazolyl and substituted furazanyl are tetrazolyl and furazanyl substituted with one substituent selected from alkyl, alkoxy, halogen, haloalkyl, alkylsulfonyl and cycloalkyl;
n is 0, 1 or 2;
provided that A 1 and A 2 are not both CH at the same time;
or a pharmaceutically acceptable salt or ester thereof.

2. The method according to claim 1 , wherein A 1 is N.

3. The method according to claim 1 , wherein A 2 is N.

4. The method according to claim 1 , wherein A 3 is —(CH 2 ) n —.

5. The method according to claim 1 , wherein R 1 is alkyl.

6. The method according to claim 1 , wherein R 1 is tert.-butyl.

7. The method according to claim 1 , wherein R 2 is substituted pyrrolidinyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from halogen and hydroxyl.

8. The method according to claim 1 , wherein R 2 is difluoropyrrolidinyl or hydroxypyrrolidinyl.

9. The method according to claim 1 , wherein R 3 is substituted phenyl, substituted furazanyl, substituted pyridinyl, substituted tetrazolyl or substituted triazolyl, wherein substituted phenyl, substituted pyridinyl and substituted triazolyl are phenyl, pyridinyl and triazolyl substituted with one or two substituents independently selected from alkyl, halogen and haloalkyl, wherein substituted tetrazolyl is tetrazolyl substituted with one substituent selected from alkyl, and cycloalkyl, and wherein substituted furazanyl is furazanyl substituted with alkyl.

10. The method according to claim 1 , wherein R 3 is trifluoromethylphenyl, methylfurazanyl, chloropyridinyl, methyltetrazolyl, cyclopropyltetrazolyl, dimethyltriazolyl or methyltriazolyl.

11. The method according to claim 1 , wherein n is 1.

12. The method according to claim 1 wherein the compound of formula (I) is selected from:
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-d]pyrimidine;
1-Benzyl-6-tert-butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine;
(S)-1-[6-tert-Butyl-1-[(2-chlorophenyl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;
6-tert-Butyl-1-[(2-chlorophenyl)methyl]-4-(3,3-difluoro-pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-1-[(2-chlorophenyl)methyl]-4-ethoxy-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-1-[(2-chloro-4-fluorophenyl)methyl]-4-(3,3-difluoro-pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-[(2-trifluoromethylphenyl)methyl]-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(4-methyl-furazan-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(2-methanesulfonyl-benzyl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(2-pyridin-3-yl-ethyl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-1-(2-chloro-pyridin-3-ylmethyl)-4-(3,3-difluoro-pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(1,1-dioxo-1λ6-thietan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(tetrahydro-furan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(1-methyl-1H-tetrazol-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-1-(1-cyclopropyl-1H-tetrazol-5-ylmethyl)-4-(3,3-difluoro-pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(4,5-dimethyl-4H-[1,2,4]triazol-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-1-(4,5-dimethyl-4H-[1,2,4]triazol-3-ylmethyl)-4-(3-fluoro-2,5-dihydro-pyrrol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(3-methyl-3H-[1,2,3]triazol-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3-fluoro-2,5-dihydro-pyrrol-1-yl)-1-(3-methyl-3H-[1,2,3]triazol-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine;
2-[6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridin-4-yl-ethanone;
2-[6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridin-2-yl-ethanone;
(S)-1-[6-tert-Butyl-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;
6-Cyclopropyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyridine;
(S)-1-[6-tert-Butyl-1-(4-methyl-furazan-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;
6-tert-Butyl-4-[(S)-3-(4-methyl-furazan-3-ylmethoxy)-pyrrolidin-1-yl]-1-(4-methyl-furazan-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine;
6-Cyclopropyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(4-methyl-furazan-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine;
6-Cyclopropyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-(4-methyl-furazan-3-ylmethyl)-1H-pyrazolo[3,4-b]pyridine;
(S)-1-[6-tert-Butyl-1-[(2-trifluoromethylphenyl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;
(S)-1-[6-tert-Butyl-1-(2-methanesulfonyl-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;
(S)-1-[6-tert-Butyl-1-(1-methyl-1H-tetrazol-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;
(S)-1-[6-tert-Butyl-1-(3-chloro-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;
(S)-1-[6-tert-Butyl-1-(1-cyclopropyl-1H-tetrazol-5-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;
{(R)-1-[6-tert-Butyl-1-[(2-trifluoromethylphenyl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-2-yl}-methanol;
6-tert-Butyl-4-((R)-2-methoxymethyl-pyrrolidin-1-yl)-1-[(2-trifluoromethylphenyl)methyl]-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-((R)-2-methoxymethyl-pyrrolidin-1-yl)-1-(4-methyl-furazan-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidine;
6-Chloro-4-(3,3-difluoropyrrolidin-1-yl)-1-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidine; and
4-(3,3-Difluoropyrrolidin-1-yl)-6-(2,2-dimethylpropoxy)-1-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidine.

13. The method according to claim 1 wherein the compound of formula (I) is selected from:
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-[(2-trifluoromethylphenyl)methyl]-1H-pyrazolo[3,4-d]pyrimidine;
6-tert-Butyl-4-(3,3-difluoro-pyrrolidin-

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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