DK2776442T3 - [1,2,3]triazolo [4,5-d]pyrimidinderivater som agonister af cannabinoidreceptor 2 - Google Patents

[1,2,3]triazolo [4,5-d]pyrimidinderivater som agonister af cannabinoidreceptor 2 Download PDF

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DK2776442T3
DK2776442T3 DK12780208.0T DK12780208T DK2776442T3 DK 2776442 T3 DK2776442 T3 DK 2776442T3 DK 12780208 T DK12780208 T DK 12780208T DK 2776442 T3 DK2776442 T3 DK 2776442T3
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butyl
tert
triazolo
pyrrolidin
pyrimidine
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Jean-Michel Adam
Caterina Bissantz
Uwe Grether
Atushi Kimbara
Matthias Nettekoven
Stephan Roever
Mark Rogers-Evans
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Hoffmann La Roche
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Claims (26)

1. Forbindelse med formel (I)
(I) hvor A er alkyl, hydroxyalkyl, -CH2C(0)-, -C(O)-, -SO2- eller fraværende; R1 er hydrogen, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, (halo)(haloalkyl)phenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, alkylsulfonylaminophenyl, cyano, cycloalkyl, cycloalkylalkoxy, amino, (alkylsulfonyl)(alkyl)[l,2,4]triazolyl, (halo)(dialkylamino)pyridinyl, (alkyl)(oxy)pyridinyl, nitro-benzo[l,2,5]oxadiazolylaminopyridinyl, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, heteroaryl, haloheteroaryl, alkylheteroaryl, cycloalkylheteroaryl eller haloalkylheteroaryl, hvor heterocyclyl er en tre- til otte-leddet carbocyklisk ring omfattende mindst ét nitrogen- eller oxygenatom, og hvor heteroaryl er pyridinyl, pyrazolyl, oxadiazolyl, furazanyl, tetrazolyl eller triazolyl; R2 er halogen eller -NR3R4 eller -OR5; én af R3 og R4 er hydrogen eller alkyl og den anden er alkyl eller cycloalkyl; eller R3 og R4 sammen med det nitrogenatom til hvilket de er bundet danner heterocyclyl eller substitueret heterocyclyl, hvor heterocyclyl er 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-l-azaspiro[3.3]heptyl, 2-oxa-5-aza-spiro[3.4]octyl, isoxazolidinyl, aziridinyl, dioxoisothiazolidinyl eller oxopyrolidinyl og hvor substitueret heterocyclyl er heterocyclyl substitueret med en til fire substituenter uafhængigt valgt blandt alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, carboxyl, alkoxyalkyl, cyano, alkylamino, dialkylamino, alkylcarbonylamino, alkylcarbonyl(alkylamino), phenyl, alkoxycarbonyl, aminoalkyl, alkylpyrazolyl eller alkylisoxazolyl; R5 er alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl eller oxetanyl; eller et farmaceutisk acceptabelt salt eller ester deraf; hvor "alkyl", alene eller i kombination, er en lige-kædet eller forgrenet-kædet alkylgruppe med 1 til 8 carbonatomer; "cycloalkyl", alene eller i kombination, er en cycloalkylring med 3 til 8 carbonatomer; og "alkoxy", alene eller i kombination, er en gruppe med formlen alkyl-O-; med det forbehold at 3-[(2-chlorphenyl)methyl]-5-(l,l-dimethylethyl)-7-(4-morpholinyl)-3H-l,2,3-triazolo[4,5-d]pyrimidin og N-cyclopropyl-5-(l,l-dimethylethyl)-3-(phenylmethyl)-3H-l,2,3-triazolo[4,5-d]pyrimidin-7-amin er udeladt.
2. Forbindelse ifølge krav 1, hvor A er alkyl eller hydroxyalkyl.
3. Forbindelse ifølge krav 1 eller 2, hvor A er -CFh-, -CH2CH2-, -CFKCFh)- eller -CH(OH)CH2-.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor R1 er hydrogen, alkyl, haloalkyl, hydroxyl, alkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, alkylsulfonylphenyl, cyanophenyl, cycloalkyl, alkylheterocyclyl, hydroxyheterocyclyl, heteroaryl, cycloalkylheteroaryl, haloheteroaryl eller alkylheteroaryl, hvor heterocyclyl er en carbocyklisk ring indeholdende mindst et nitrogenatom og hvor heteroaryl er pyridinyl, pyrazolyl, oxadiazolyl, tetrazolyl eller furazanyl.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R1 er haloalkyl, phenyl, halophenyl, haloalkylphenyl, cyanophenyl, alkylsulfonylphenyl, cycloalkyl, heteroaryl, cycloalkylheteroaryl, haloheteroaryl eller alkylheteroaryl, hvor heteroaryl er pyridinyl, pyrazolyl, oxadiazolyl, tetrazolyl eller furazanyl.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R1 er chlorphenyl, cyclohexyl, dichlorphenyl, pyridinyl, chlorpyridinyl, dichlorpyridinyl, trifluormethyl, chlordifluorphenyl, trifluormethylphenyl, cyanophenyl, phenyl, methylsulfonylphenyl, methyltetrazolyl, methylfurazanyl eller cyclopropyltetrazolyl.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor én af R3 og R4 er hydrogen eller ethyl og den anden er ethyl eller cyclohexyl.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R3 og R4 sammen med det nitrogenatom til hvilket de er bundet danner heterocyclyl eller substitueret heterocyclyl, hvor heterocyclyl er piperidinyl, pyrrolidinyl, azetidinyl eller 2-oxa-6-azaspiro[3.3]heptyl, og hvor substitueret heterocyclyl er heterocyclyl substitueret med en til fire substituenter uafhængigt valgt blandt alkyl, halogen, hydroxyl, hydroxyalkyl og alkoxyalkyl.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R3 og R4 sammen med det nitrogenatom til hvilket de er bundet danner difluorpiperidinyl, difluorpyrrolidinyl, difluorazetidinyl, (methyl)(hydroxyl)azetidinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, tetrafluorpyrrolidinyl, methoxymethylpyrro lidinyl, (hydroxyl)(hydroxymethyl)pyrrolidinyl, (methyl)(hydroxyl)pyrrolidinyl eller 2-oxa-6-azaspiro[3.3]heptyl.
10. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, hvor R5 er methyl, ethyl, isopropyl, pentyl, cyclobutyl, cyclopentyl, cyclopropylmehtyl, cyclopropylethyl, trifluorpropyl eller oxetanyl.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 10 valgt blandt 5-tert-butyl-3-(2-chlorbenzyl)-7-(piperidin-l-yl)-3H-[l,2,3]triazolo[4,5- djpyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(4,4-difluorpiperidin-l-yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(4-methylpiperazin-l-yl)-3H-[l,2,3]triazolo[4,5- djpyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(pyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5- djpyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(3,3-difluorpyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5- djpyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-N-ethyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-amin; 5-tert-butyl-3-(2-chlorbenzyl)-N-cyclohexyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- amin; 5- tert-butyl-3-(2-chlorbenzyl)-N,N-diethyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-amin; 6- (5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-2-oxa-6-azaspiro[3.3]heptan; 7-(azetidin-l-yl)-5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pynmidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(3,3-difluorazetidin-l-yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin; l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)azetidin- 3- ol; l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylazetidin-3-ol; 5-tert-butyl-3-(2-chlorbenzyl)-7-(3-methoxyazetidin-l-yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin; (2S,6R)-4-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)- 2,6-dimethylmorpholin; 4- (5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylmorpholin; (4-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- yl)morpholin-2-yl)methanol; 3- (5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)thiazolidin; 4- (5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)thiomorpholin; 5- tert-butyl-3-(2-chlor-benzyl)-7-(l,l-dioxo-lA6-thiomorpholin-4-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin; 4-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]tnazolo[4,5-d]pynmidin-7-yl)-l,4- oxazepan; 4-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7-yl)-2,2- dimethylmorpholin; 4-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7-yl)-3,3- dimethylmorpholin; 5-tert-butyl-3-(2-chlorbenzyl)-7-((2R,SR)-2,5-dimethylpyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; (S)-l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7- yl)pyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]tnazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol; 5-tert-butyl-3-(2-chlorbenzyl)-7-(3-methoxypyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(2,2-dimethylpyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; 5- tert-butyl-3-(2-chlorbenzyl)-7-(2-methylpyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5-djpyrimidin; 6- (5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-2-oxa-6-azaspiro[3.4]octan; l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)piperidin- 4-ol; (S) -l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)piperidin-3-ol; (R) -l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)piperidin-3-ol; l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-6-oxa-l- azaspiro[3.3]heptan; (S) -5-tert-butyl-3-(2-chlorbenzyl)-7-(3-fluorpyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidiri; (R) -(l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-2-yl)methanol; (S) -(l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7-yl)pyrrolidin-2-yl)methanol; 2-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]tnazolo[4,5-d]pynmidin-7- yl)morpholin; 2-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]tnazolo[4,5-d]pynmidin-7- yl)isoxazolidin; 7-(azindin-l-yl)-5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]tnazolo[4,5-d]pynmidin; (R)-5-tert-butyl-3-(2-chlorbenzyl)-7-(3-fluorpyrrolidin-l-yl)-3H-[l,2,3]tnazolo[4,5-djpyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(3,3,4,4-tetrafluorpyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; (R) -5-tert-butyl-3-(2-chlorbenzyl)-7-(2-(methoxymethyl)pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; (S) -5-tert-butyl-3-(2-chlorbenzyl)-7-(2-(methoxymethyl)pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; (2S,4S)-l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)- 4- fluorpyrrolidin-2-carbonitril; 5- tert-butyl-3-(2-chlor-benzyl)-7-(l,l-dioxo-lA6-isothiazolidin -2-yl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; (4-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- yl)morpholin-3-yl)methanol; (R) -l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-2-carbonitril; (S) -l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-2-carbonitnl; (2S,3S)-l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)- 2-(hydroxymethyl)pyrrolidin-3-ol; (2S,3R)-l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]tnazolo[4,5-d]pynnnidin-7-yl)- 2-(hydroxymethyl)pyrrolidin-3-ol; 5-tert-butyl-3-(2-chlor-benzyl)-7-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 1- [5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol; (3R,4R)-l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- yl]-pyrrolidin-3,4-diol; (3S,4R)-l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- yl]-pyrrolidin-3,4-diol; 4-(5-tert-butyl-3-(4-methoxybenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- yl)morpholin; 4- (5-tert-butyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholin; 5- tert-butyl-3-(2-chlor-4-fluor-benzyl)-7-morpholin-4-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(4-methoxy-benzyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-ethyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-methoxy-ethyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 2- [5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]triazolo[4,5-d]pynmidin-3-yl]-ethanol; 5-tert-butyl-3-cyclohexylmethyl-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidiri; 5-tert-butyl-3-(3-chlor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(4-chlor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2,3-dichlor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2,4-dichlor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2,5-dichlor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2,6-dichlor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-4-fluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-6-fluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-pyndin-2-ylmethyl-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-pyridin-3-ylmethyl-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-pyndin-4-ylmethyl-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2,2,2-tnfluor-ethyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-4,5-difluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-3,6-difluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 3-(2-brom-benzyl)-5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-tnfluormethyl-benzyl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-methoxy-benzyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-tnfluormethoxy-benzyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 2-[5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynnnidin-3- ylmethylj-benzonitril; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-phenethyl-3H-[l,2,3]tnazolo[4,5- d]pyrimidin; 2-[5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]triazolo[4,5-d]pynnnidin-3-yl]- 1- phenyl-ethanon; 5-tert-butyl-3-[(R)-l-(2-chlor-phenyl)-ethyl]-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-[(S)-l-(2-chlor-phenyl)-ethyl]-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 2- [5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynmidin-3-yl]-1-phenyl-ethanol; 5-tert-butyl-3-(2-chlor-3-fluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-5-fluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-oxetan-3-yl-3H-[l,2,3]tnazolo[4,5- d]pyrimidin; [5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynnnidin-3-yl]-(2-chlor-phenyl)-methanon; (3S,5R)-l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]tnazolo[4,5-d]pynnnidin-7- yl]-5-hydroxymethyl-pyrrolidin-3-ol; {(R)-l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]tnazolo[4,5-d]pynnnidin-7-yl]- 4,4-difluor-pyrrolidin-2-yl>-methanol; (R) -l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7-yl]-4,4-difluor-pyrrolidin-3-ol; 5-tert-butyl-3-(2,6-dichlor-3-fluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-pyridin-3-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2,5-dichlor-pyridin-3-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3,6-dichlor-pyridin-2-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(4-methyl-furazan-3-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(3-methyl-[l,2,4]oxadiazol-5- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; 5-tert-butyl-3-[2-(2-chlor-phenyl)-ethyl]-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pynmidin; 5-tert-butyl-3-[2-(3-chlor-phenyl)-ethyl]-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-[2-(4-chlor-phenyl)-ethyl]-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; (S) -l-[5-tert-butyl-3-(4-methoxy-benzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7-yl]-pyrrolidin-3-ol; 5-tert-butyl-3-(2-chlor-benzenesulfonyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(R)-tetrahydro-furan-3-yl-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(S)-tetrahydro-furan-3-yl-3H- [1.2.3] triazolo[4,5-d]pyrimidin; 2-[5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[[4,5-d]pynmidin-3- yl]-l-(2-chlor-phenyl)-ethanon; 5-tert-butyl-3-(2,3-dichlor-6-fluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pynmidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-methanesulfonyl-benzyl)-3H- [1.2.3] triazolo[[4,5-d]pynmidin; 5-tert-butyl-7-(3,3-difluor-pynOlidin-l-yl)-3-(2-pyndin-2-yl-ethyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(3-methyl-oxetan-3-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pynmidin; 2-[5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[[4,5-d]pynmidin-3- yl]-l-(3-chlor-phenyl)-ethanon; 2-[5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynmidin-3-yl]- 1- (4-chlor-phenyl)-ethanon; 2- [5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynnnidin-3-yl]- 1- pyridin-3-yl-ethanon; 2- [5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynnnidin-3-yl]-l-pyridin-4-yl-ethanon; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2,3,6-tnchlor-benzyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-3-tnfluormethyl-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-pyndin-3-yl-ethyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-pyndin-4-yl-ethyl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 5-tert-butyl-3-(2,3-dichlor-6-tnfluormethyl-benzyl)-7-(3,3-difluor-pyrrolidi n-1-yl)-3H-[l,2,3]tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3,4-dichlor-pyridin-2-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(l,l-dioxo-lA6-thietan-3-yl)-3H- [1.2.3] triazolo[4,5-d]pynmidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(l,l-dioxo-tetrahydro-lA6-thiophen- 3-yl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; 2-[5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[[4,5-d]pynnnidin-3- yl]-l-pyridin-2-yl-ethanon; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(5-methyl-[l,3,4]oxadiazol-2- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; 5-tert-butyl-3-(3-chlor-pyridin-4-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(5-methyl-[l,2,4]oxadiazol-3- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(l-methyl-lH-tetrazol-5-ylmethyl)- 3H-[l,2,3]tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-methyl-2H-[l,2,4]tnazol-3- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(5-methanesulfonyl-4-methyl-4H- [1.2.4] tnazol-3-ylmethyl)-3H-[l,2,3]tnazolo[4,5-d]pynmidin; {3-[5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynmidin-3- ylmethyl]-5-chlor-pyndin-4-yl}-dimethyl-annin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(3-tnfluormethyl-lH-pyrazol-4- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; (S)-l-[5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(3-methyl-[l,2,4]oxadiazol-5-ylmethyl)-3H- [1.2.3] tnazolo[4,5-d]pynmidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pynmidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(3,6-dichlor-pyridin-2-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2-chlor-pyridin-3-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2,3-dichlor-benzyl)-3H-[l,2,3]triazolo[[4,5-d]pyrimidin-7- yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2-trifluormethyl-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin- 7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2-methanesulfonyl-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2,5-dimethyl-2H-pyrazol-3- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(3-methyl-3H-[l,2,3]tnazol-4- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(4,5-dimethyl-4H-[l,2,4]tnazol-3- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-methyl-l-oxy-pyndin-3-ylmethyl)- 3H-[l,2,3]tnazolo[4,5-d]pyrimidin; (S)-l-[5-tert-butyl-3-(3,4-dichlor-pyridin-2-ylmethyl)-3H-[l,2,3]tnazolo[4,5-d] pyrimidin-7-yl ]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(5-methyl-[l,2,4]oxadiazol-3-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(5-methyl-[l,3,4]oxadiazol-2-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(l-methyl-lH-tetrazol-5-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2-methyl-2H-[l,2,4]triazol-3-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(4,5-dimethyl-4H-[l,2,4]triazol-3-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(3-methyl-3H-[l,2,3]triazol-4-ylmethyl)-3H- [l,2/3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(3-trifluormethyl-[l,2,4]oxadiazol-5- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(l-cyclopropyl-lH-tetrazol-5-ylmethyl)-7-(3,3-difluor-pyrrolidin-l- yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; (S)-l-{5-tert-butyl-3-[2-(7-nitro-benzo[l,2,5]oxadiazol-4-ylamino)-pyridin-3- ylmethyl]-3H-[l,2,3]tnazolo[4,5-d]pynmidin-7-yl>-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(4-methoxy-benzyl)-3H-[l,2,3]tnazolo[4,5-d]pynmidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(l-cyclopropyl-lH-tetrazol-5-ylmethyl)-3H- [1.2.3] tnazolo[4,5-d]pynmidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2,5-dimethyl-2H-[l,2,4]triazol-3-ylmethyl)-3H- [l/2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2-methyl-l-oxy-pyridin-3-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2,5-dimethyl-2H-[l,2,4]triazol-3- ylmethyl)-3H-[l,2,3]tnazolo[4,5-d]pynmidin; (25.35) -l-[5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pynmidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(l-methyl-lH-tetrazol-5-ylmethyl)-3H- [ 1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(l-cyclopropyl-lH-tetrazol-5-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-3H-[l,2,3]tnazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(2-methanesulfonyl-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(2-methyl-2H-[l,2,4]tnazol-3-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(4,5-dimethyl-4H-[ 1,2,4]triazol-3-ylmethyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(3-methyl-3H-[l,2,3]triazol-4-ylmethyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; (25.35) -l-[5-tert-butyl-3-(2-chlor-pyridin-3-ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol; 5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-7-(3,3,4,4-tetrafluor-pyrrolidin-l-yl)- 3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3-methyl-[l,2,4]oxadiazol-5-ylmethyl)-7-(3,3,4,4-tetrafluor- pyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(5-methyl-[l,3,4]oxadiazol-2-ylmethyl)-7-(3,3,4,4-tetrafluor- pyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(l-methyl-lH-tetrazol-5-ylmethyl)-7-(3,3,4,4-tetrafluor-pyrrolidin- l-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(4,5-dimethyl-4H-[l,2,4]triazol-3-ylmethyl)-7-(3,3,4,4-tetrafluor- pyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3-methyl-3H-[l,2,3]triazol-4-ylmethyl)-7-(3,3,4,4-tetrafluor- pyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)- 3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3-methyl-[l,2,4]oxadiazol-5-ylmethyl)-7-(2-oxa-6-aza- spiro[3.3]hept-6-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(5-methyl-[l,3,4]oxadiazol-2-ylmethyl)-7-(2-oxa-6-aza- spiro[3.3]hept-6-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(l-methyl-lH-tetrazol-5-ylmethyl)-7-(2-oxa-6-aza-spiro[3.3]hept-6- yl)-3H-[l/2/3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(l-cyclopropyl-lH-tetrazol-5-ylmethyl)-7-(2-oxa-6-aza- spiro[3.3]hept-6-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(4,5-dimethyl-4H-[l,2,4]triazol-3-ylmethyl)-7-(2-oxa-6-aza- spiro[3.3]hept-6-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3-methyl-3H-[l,2,3]triazol-4-ylmethyl)-7-(2-oxa-6-aza- spiro[3.3]hept-6-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-methanesulfonyl-benzyl)-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)- 3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)- 3H-[l,2,3]triazolo[4,5-d]pyrimidin; l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-3-one; 5-tert-butyl-3-(2-chlor-benzyl)-7-(3,3-dimethyl-pyrrolidin-l-yl)-3H- [l,2,3]triazolo[4,5-d]pyrinnidin; {l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-3-yl}-methylamin; {l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-3-yl}-dimethylamin; N-{(S)-l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-3-yl>-acetamid; N-{(R)-l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-3-yl}-acetamid; N-{l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-3-yl}-N-methyl-acetamid; 5-tert-butyl-3-(2-chlor-benzyl)-7-(3-phenyl-pyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5- djpyrimidin; N-{l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-3-yl>-N-ethyl-acetamid; l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- azetidin-3-carboxylsyremethylester; 5-tert-butyl-3-(2-chlor-benzyl)-7-(3-methyl-pyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin; C-{(S)-l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-2-yl>-methylamin; 5-tert-butyl-3-(2-chlor-benzyl)-7-[2-(l-methyl-l H-pyrazol-3-yl)-pyrrolidin-l-yl]-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-[2-(2-methyl-2H-pyrazol-3-yl)-pyrrolidin-l-yl]- 3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-[2-(3-methyl-isoxazol-5-yl)-pyrrolidin-l-yl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-[2-(3-methyl-[l,2,4]oxadiazol-5-yl)-pyrrolidin-l- yl]-3H-[l,2,3]triazolo[4,5-d]pyrimidin; l-[5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]- pyrrolidin-3-ol; 5-tert-butyl-3-(2-chlor-benzyl)-7-cyclobutoxy-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-(oxetan-3-yloxy)-3H-[l,2,3]triazolo[4,5- djpyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-methoxy-3H-[l,2,3]triazolo[4,5-d]pyrinnidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-ethoxy-3H-[l,2,3]tnazolo[4,5-d]pynmidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-isopropoxy-3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-cyclopropylmethoxy-3H-[l,2,3]triazolo[4,5- d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-(l-cyclopropyl-ethoxy)-3H-[l,2,3]triazolo[4,5-djpyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-cyclopentyloxy-3H-[l,2,3]tnazolo[4,5- djpyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-(2,2-dimethyl-propoxy)-3H-[l,2,3]tnazolo[4,5- d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-(2,2,2-tnfluor-l-methyl-ethoxy)-3H- [1.2.3] tnazolo[4,5-d]pyrinnidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-((S)-2,2,2-trifluor-l-methyl-ethoxy)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-((R)-2,2,2-trifluor-l-methyl-ethoxy)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; (3S)-l-(3-benzyl-5-tert-butyl-triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol; l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7- yl)pyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-((l-methyl-lH-tetrazol-5-yl)methyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol; l-(5-tert-butyl-3-((l-methyl-lH-tetrazol-5-yl)methyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl)pyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-(2-(trifluormethyl)benzyl)-3H-[l,2,3]tnazolo[4,5-d]pynnnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-(2-(tnfluormethyl)benzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-(2-(methylsulfonyl)benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-(2-(methylsulfonyl)benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-((3-chlorpyridin-2-yl)methyl)-3H-[l,2,3]tnazolo[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-((3-chlorpyridin-2-yl)methyl)-3H-[l,2,3]tnazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-((5-methyl-l,3,4-oxadiazol-2-yl)methyl)-3H- [1.2.3] triazolo[4,5-d]pynnnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-((5-methyl-l,3,4-oxadiazol-2-yl)methyl)-3H- [1.2.3] triazolo[4,5-d]pynnnidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-((3-methyl-l,2,4-oxadiazol-5-yl)methyl)-3H- [1.2.3] triazolo[4,5-d]pynnnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-((3-methyl-l,2,4-oxadiazol-5-yl)methyl)-3H- [1.2.3] triazolo[4,5-d]pynnnidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-((l-methyl-lH-tetrazol-5-yl)methyl)-3H-[l,2,3]triazolo[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-((l-methyl-lH-tetrazol-5-yl)methyl)-3H-[l,2,3]triazolo[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-((4-methyl-l,2,5-oxadiazol-3-yl)methyl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-((4-methyl-l,2,5-oxadiazol-3-yl)methyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl)-3-nnethylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-(3,3,3-trifluorpropyl)-3H-[l,2,3]triazolo[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl-3-(3,3,3-trifluorpropyl)-3H-[l,2,3]triazolo[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-((l-cyclopropyl-lH-tetrazol-5-yl)methyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol; og (R) -l-(5-tert-butyl-3-((l-cyclopropyl-lH-tetrazol-5-yl)methyl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol.
12. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 valgt blandt 5-tert-butyl-3-(2-chlorbenzyl)-7-(4,4-difluorpiperidin-l-yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(3,3-difluorpyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5- djpyrimidin; 5-tert-butyl-3-(2-chlorbenzyl)-7-(3,3-difluorazetidin-l-yl)-3H-[l,2,3]triazolo[4,5- djpyrimidin; l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylazetidin-3-ol; (S) -l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol; (R)-(l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrro lidin-2-yl)methanol; 5-tert-butyl-3-(2-chlorbenzyl)-7-(3,3,4,4-tetrafluorpyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; (R)-5-tert-butyl-3-(2-chlorbenzyl)-7-(2-(methoxymethyl)pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; (2S,3S)-l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]tnazolo[4,5-d]pynmidin-7-yl)- 2-(hydroxymethyl)pyrrolidin-3-ol; 1- [5-tert-butyl-3-(2-chlor-benzyl)-3H-[l,2,3]tnazolo[4,5-d]pynnnidin-7-yl]-3-methyl-pyrrolidin-3-ol; 5-tert-butyl-3-cyclohexylmethyl-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2,6-dichlor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-pyndin-2-ylmethyl-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-pyndin-3-ylmethyl-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2,2,2-tnfluor-ethyl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 5-tert-butyl-3-(2-chlor-3,6-difluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-tnfluormethyl-benzyl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 2- [5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynnnidin-3-ylmethylj-benzonitril; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-phenethyl-3H-[l,2,3]tnazolo[4,5- d]pyrimidin; 5-tert-butyl-3-[(R)-l-(2-chlor-phenyl)-ethyl]-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; 2-[5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-[l,2,3]tnazolo[4,5-d]pynnnidin-3-yl]- 1-phenyl-ethanol; 5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrinnidin; 5-tert-butyl-3-(3,6-dichlor-pyridin-2-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3H- [1.2.3] triazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(l-methyl-lH-tetrazol-5-ylmethyl)- 3H-[l,2,3]triazolo[4,5-d]pyrimidin; 5-tert-butyl-7-(3,3-difluor-pyrrolidin-l-yl)-3-(2-methyl-2H-[l,2,4]triazol-3- ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin; (S)-l-[5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2-chlor-pyridin-3-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(2-methanesulfonyl-benzyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(l-methyl-lH-tetrazol-5-ylmethyl)-3H-[l,2,3]triazolo[4,5- d]pynmidin-7-yl]-pyrrolidin-3-ol; (S)-l-[5-tert-butyl-3-(l-cyclopropyl-lH-tetrazol-5-ylmethyl)-3H- [1.2.3] tnazolo[4,5-d]pynmidin-7-yl]-pyrrolidin-3-ol; 5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-7-(3,3,4,4-tetrafluor-pyrrolidin-l-yl)- 3H-[l,2,3]tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)- 3H-[l,2,3]tnazolo[4,5-d]pyrimidin; 5-tert-butyl-3-(2-chlor-benzyl)-7-((R)-2,2,2-trifluor-l-methyl-ethoxy)-3H- [1.2.3] tnazolo[4,5-d]pyrimidin; (S)-l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pynnnidin-7-yl)-3-methylpyrrolidin-3-ol; (R)-l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]tnazolo[[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (S)-l-(5-tert-butyl-3-(2-(tnfluormethyl)benzyl)-3H-[l,2,3]tnazolo[4,5-d]pyrinnidin-7-yl)-3-methylpyrrolidin-3-ol; (R) -l-(5-tert-butyl·3-(2-(trifluormethyl)benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol; (S) -l-(5-tert-butyl-3-(2-(methylsulfonyl)benzyl)-3H-[l,2,3]triazolo[4,5-d]pynmidin-7-yl)-3-methylpyrrolidin-3-ol; og (R)-l-(5-tert-butyl-3-(2-(methylsulfonyl)benzyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er (S)-l-(5-tert-butyl-3-(2-chlorbenzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol.
14. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er 5-tert-butyl-3-(2-chlorbenzyl)-7-(3,3,4,4-tetrafluorpyrrolidin-l-yl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin.
15. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er 5-tert-butyl-3-(2-chlor-3,6-difluor-benzyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3FI-[l,2,3]triazolo[4,5-d]pyrimidin.
16. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er 5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-7-(3,3-difluor-pyrrolidin-l-yl)-3FI-[l,2,3]triazolo[4,5-d]pyrimidin.
17. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er (S)-l-[5-tert-butyl-3-(4-methyl-furazan-3-ylmethyl)-3FI-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.
18. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er (S)-l-[5-tert-butyl-3-(3-chlor-pyridin-2-ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.
19. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er (S)-l-[5-tert-butyl-3-(2-chlor-pyridin-3-ylmethyl)-3FI-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.
20. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er (S)-l-[5-tert-butyl-3-(l-methyl-lFI-tetrazol-5-ylmethyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol.
21. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er (R)-l-(5-tert-butyl-3-((l-methyl-lH-tetrazol-5-yl)methyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)pyrrolidin-3-ol.
22. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 der er (S)-l-(5-tert-butyl-3-(2-(trifluomnethyl)benzyl)-3FI-[l,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol.
23. Fremgangsmåde til fremstillingen af en forbindelse ifølge et hvilket som helst af kravene 1 til 12 omfattende: (a) omsætning af en forbindelse med formel (A), en tautomer deraf eller en blanding af tautomerer deraf
(A) i tilstedeværelse af et halogeneringsreagens og eventuelt med en base; eller (b) omsætning af en forbindelse med formel (B)
(B) i tilstedeværelsen af NFIR3R4 og eventuelt med en base; hvor A, R1, R3 og R4 er defineret ifølge et hvilket som helst af kravene 1 til 10.
24. Forbindelse ifølge et hvilket som helst af kravene 1 til 22 til anvendelse som terapeutisk aktivt stof.
25. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af kravene 1 til 22 og en terapeutisk inert bærer.
26. Forbindelse ifølge et hvilket som helst af kravene 1 til 22 til anvendelse i behandlingen eller profylakse af smerte, atherosclerose, alders-relateret makulær degeneration, diabetisk retinopati, glaukom, diabetes mellitus, inflammation, inflammatorisk tarmsygdom, iskæmi-reperfusions-skade, akut leversvigt, leverfibrose, lungefibrose, nyrefibrose, systemisk fibrose, akut allograft afstødning, kronisk allograft nefropati, diabetisk nefropati, glomerulonefropati, kardiomyopati, hjertefejl, myokardial iskæmi, myokardial infarkt, systemisk sclerose, termisk skade, forbrænding, hypertrofiske ar, hudsvulster, gingivitis pyrexia, levercirrhose eller tumorer, regulering af knoglemasse, neurodegeneration, slagtilfælde, transiente iskæmiske anfald eller uveitis.
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