DK2964646T3 - Hidtil ukendte pyrazolderivater - Google Patents

Hidtil ukendte pyrazolderivater Download PDF

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DK2964646T3
DK2964646T3 DK14709590.5T DK14709590T DK2964646T3 DK 2964646 T3 DK2964646 T3 DK 2964646T3 DK 14709590 T DK14709590 T DK 14709590T DK 2964646 T3 DK2964646 T3 DK 2964646T3
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butyl
pyrrolidin
methyl
tert
pyrimidine
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DK14709590.5T
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Uwe Grether
Matthias Nettekoven
Fabienne Ricklin
Stephan Roever
Mark Rogers-Evans
Tanja Schulz-Gasch
Atsushi Kimbara
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Hoffmann La Roche
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Claims (17)

1. Forbindelse med formlen (i)
hvor A1 er -CH- eller nitrogen; A2 er -CH- eller nitrogen; A3 er -(CH2)n- eller -CH2C(0)-; R1 er alkyl, cycloalkyl, alkoxy eller halogen; R2 er alkoxy, substitueret pyrrolidinyl eller substitueret dihydropyrrolyl, hvor substitueret pyrrolidinyl og substitueret dihydropyrrolyl er pyrrolidinyl og dihydropyrrolyl substitueret med én eller flere substituenter, der er uafhængigt valgt blandt halogen, hydroxyl, hydroxyalkyl, alkoxyalkyl og alkylfurazanylalkoxy; R3 er phenyl, substitueret phenyl, substitueret furazanyl, pyridinyl, substitueret pyridinyl, dioxothietanyl, tetrahydrofuranyl, substitueret tetrazolyl eller substitueret triazolyl, hvor substitueret phenyl, substitueret pyridinyl og substitueret triazolyl er phenyl, pyridinyl og triazolyl substitueret med én eller to substituenter, der er uafhængigt valgt blandt alkyl, alkoxy, halogen, halogenalkyl, alkylsulfonyl og cycloalkyl, og hvor substitueret tetrazolyl og substitueret furazanyl er tetrazolyl og furazanyl substitueret med én substituent, der er valgt blandt alkyl, alkoxy, halogen, halogenalkyl, alkylsulfonyl og cycloalkyl; n er 1 eller 2; under forudsætning af, at A1 og A2 ikke begge er carbon samtidig; eller et farmaceutisk acceptabelt salt eller en farmaceutisk acceptabel ester deraf; hvor "alkyl", alene eller i kombination, er en alkylgruppe med lige eller forgrenet kæde og 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-.
2. Forbindelse ifølge krav 1, hvor A1 er nitrogen.
3. Forbindelse ifølge krav 1 eller 2, hvor A2 er nitrogen.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor A3 er -(CFteV-
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R1 er alkyl.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R1 er tert-butyl.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R2 er substitueret pyrrolidinyl, hvor substitueret pyrrolidinyl er pyrrolidinyl substitueret med én eller to substituenter, der er uafhængigt valgt blandt halogen og hydroxyl.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7, hvor R2 er difluorpyrrolidinyl eller hydroxypyrrolidinyl.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 8, hvor R3 er substitueret phenyl, substitueret furazanyl, substitueret pyridinyl, substitueret tetrazolyl eller substitueret triazolyl, hvor substitueret phenyl, substitueret pyridinyl og substitueret triazolyl er phenyl, pyridinyl og triazolyl substitueret med én eller to substituenter, der er uafhængigt valgt blandt alkyl, halogen og halogenalkyl, hvor substitueret tetrazolyl er tetrazolyl substitueret med en substituent, der er valgt blandt alkyl og cycloalkyl, og hvor substitueret furazanyl er furazanyl substitueret med alkyl.
10. Forbindelse ifølge et hvilket som helst af kravene 1 til 9, hvor R3 er trifluormethylphenyl, methylfurazanyl, chlorpyridinyl, methyltetrazolyl, cyclopropyltetrazolyl, dimethyltriazolyl eller methyltriazolyl.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 10, hvor n er 1.
12. Forbindelse ifølge et hvilket som helst af kravene 1 til 11, der er valgt blandt 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-[(4-methoxyphenyl)methyl]-lF/- pyrazol[3,4-d]pyrimidin; l-benzyl-6-te/t-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-lH-pyrazol[3,4- d]pyrimidin; (S)-l-[6-terf--butyl-l-[(2-chlorphenyl)methyl]-lH-pyrazol[3,4-d]pyrimidin-4- yl]-pyrrolidin-3-ol; 6-tert-butyl-l-[(2-chIorphenyl)methyl]-4-(3,3-difluor-pyrrolidin-l-yl)-lH- pyrazol[3,4-d]pyrimidin; 6-tert-butyl-l-[(2-chIorphenyl)methyl]-4-ethoxy-lW-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-l-[(2-chlor-4-fluorpheny])methyl]-4-(3,3-difluor-pyrrolidin-l-yl)- lW-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-[(2-trifluormethylphenyl)methyl]- lH-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-phenethyl-l/V-pyrazol[3,4- d]pyrimidin; 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(4-methyl-furazan-3-ylmethyl)- ltf-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(2-methansulfonyl-benzyl)-lW- pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(2-pyridin-3-yl-ethyl)-lH- pyrazol[3,4-d]pyrimidin; 6-tert-butyl-l-(2-chlor-pyridin-3-ylmethyl)-4-(3,3-difluor-pyrrolidin-l-yl)-lH- pyrazol[3,4-d]pyrimidin; 6-iert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(l,l-dioxo-lA6-thietan-3-yl)-lW- pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(tetrahydro-furan-3-yl)-lH- pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3/3-difluor-pyrrolidin-l-yl)-l-(l-methyl-lAV-tetrazol-5- ylmethyl)-lH-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-l-(l-cyclopropyl-lW-tetrazol-5-ylmethyl)-4-(3,3-difluor-pyrrolidin- l-yl)-lH-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(4,5-dimethyl-4H-[l,2,4]triazol- 3- ylmethyl)-lH-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-l-(4,5-dimethyl-4W-[l,2,4]triazol-3-ylmethyl)-4-(3-fluor-2,5- dihydro-pyrrol-l-yl)-lW-pyrazol[3,4-d]pyrinnidin; 6-tert-butyl-4-(3/3-difluor-pyrrolidin-l-yl)-l-(3-methyl-3AV-[l,2,3]triazol-4- ylmethyl)-l/-/-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3-fluor-2,5-dihydro-pyrrol-l-yl)-l-(3-methyl-3H-[l,2,3]triazol- 4- ylmethyl)-lAV-pyrazol[3,4-d]pyrimidin; 2-[6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-pyrazol[3,4-d]pyrimidin-l-yl]-l- pyndin-4-yl-ethanon; 2-[6-terf--butyl-4-(3,3-difluor-pyrrolidin-l-yl)-pyrazol[3,4-d]pyrimidin-l-yl]-l- pyndin-2-yl-ethanon; (S)-l-[6-tert-butyl-l-[(4-methoxphenyl)methyl]-lAy-pyrazol[3,4-d]pyrimidin- 4-yl]-pyrrolidin-3-ol; 6-cyclopropyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-[(4-methoxyphenyl)methyl]-lA7- pyrazol[3,4-b]pyridin; (S)-l-[6-tert-butyl-l-[(4-methyl-furazan-3-ylmethyl)-lW-pyrazol[3,4- d]pyrimidin-4-yl]-pyrrolidin-3-ol; 6-tert-butyl-4-[(S)-3-(4-methyl-furazan-3-ylmethoxy)-pyrrolidin-l-yl]-l-(4- methyl-furazan-3-ylmethyl)-lH-pyrazol[3,4-d]pyrimidin; 6-cyclopropyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(4-methyl-furazan-3-ylmethyl)- lW-pyrazol[4,3-c]pyridin; 6-cyclopropyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(4-methyl-furazan-3-ylmethyl)- l/V-pyrazol[3,4-b]pyridin; (S)-l-[6-tert-butyl-l-[(2-trifluormethylpheny)methyl]-lW-pyrazol[3,4- d]pyrimidin-4-yl]-pyrrolidin-3-ol; (S)-l-[6-teri--butyl-l-(2-methansulfonyl-benzyl)-lW-pyrazol[3,4-d]pyrimidin- 4-yl]-pyrrolidin-3-ol; (S)-l-[6-te/t-butyl-l-(l-methyl-lH-tetrazol-5-ylmethyl)-lH-pyrazol[3,4- d]pyrimidin-4-yl]-pyrrolidin-3-ol; (S)-l-[6-te/t-butyl-l-(3-chlor-pyridin-ylmethyl)-lH-pyrazol[3,4-d]pyrimidin-4- yl]-pyrrolidin-3-ol; (S)-l-[6-tert-butyl-l-(l-cyclopropyl-lH-tetrazol-5-ylmethyl)-l/y-pyrazol[3,4- d]pyrimidin-4-yl]-pyrrolidin-3-ol; {(R)-l-[6-tert-butyl-l-[(2-trifluormethyphenyl)methyl]-lW-pyrazol[3,4- d]pyrimidin-4-yl]-pyrrolidin-2-yl>-methanol; 6-tert-butyl-4-((/?)-2-methoxymethyl-pyrrolidin-l-yl)-l-[(2- trifluormethyphenyl)methyl]-lW-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-((/?)-2-methoxymethyl-pyrrolidin-l-yl)-l-(4-methyl-furazan-3- ylmethyl)-lH-pyrazol[3,4-d]pyrimidin; 6-chlor-4-(3,3-difluorpyrrolidin-l-yl)-l-[[2-(trifluorrnethyl)phenyl]methyl]pyrazol[3,4-d]pyrimidin og 4-(3,3-difluorpyrrolidin-l-yl)-6-(2,2-dimethylpropoxy)-l-[[2- (trifluormethyl)phenyl]methyl]pyrazol[3,4-d]pyrimidin.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 12 udvalgt blandt 6-tert-butyl-4-(3/3-difluor-pyrrolidin-l-yl)-l-[(2-trifluormethylphenyl)methyl]- lH-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3,3-difluor-pyrrolidin-l-yl)-l-(4-methyl-furazan-3-ylmethyl)- lW-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-l-(2-chlor-pyridin-3-ylmethyl)-4-(3,3-difluor-pyrrolidin-l-yl)-lAV- pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3/3-difluor-pyrrolidin-l-yl)-l-(l-methyl-lW-tetrazol-5- ylmethyO-lAf-pyrazoll^^-dlpyrimidin; 6-tert-butyl-l-(l-cyclopropyl-lAY-tetrazol-5-ylmethyl)-4-(3,3-difluor-pyrrolidin- l-yl)-lH-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3/3-difluor-pyrrolidin-l-yl)-l-(4,5-dimethyl-4fy-[l,2,4]triazol- 3-ylmethyl)-lW-pyrazol[3,4-d]pyrimidin; 6-tert-butyl-4-(3/3-difluor-pyrrolidin-l-yl)-l-(3-methyl-3AV-[l,2,3]triazol-4- ylmethyl)-lAV-pyrazol[3,4-d]pynmidin; (S)-l-[6-te/t-butyl-l-[(4-methyl-furazan-3-ylmethyl)-lW-pyrazol[3,4- d]pyrimidin-4-yl]-pyrrolidin-3-ol og (S)-l-[6-tert-butyl-l-[(2-trifluormethylpheny)methyl]-lf/-pyrazol[3,4- d]pyrimidin-4-yl]-pyrrolidin-3-ol.
14. Fremgangsmåde til fremstilling af en forbindelse ifølge et hvilket som helst af kravene 1 til 13, hvilken fremgangsmåde omfatter ét af følgende trin: (a) omsætning af en forbindelse med formlen (A)
i nærvær af R2H og en base; (b) omsætning af en forbindelse med formlen (B)
i nærvær af R3-A3-X og en base; (c) omsætning af en forbindelse med formlen (C)
i nærvær af MR1, en palladiumkatalysator og en base; eller (d) omsætning af en forbindelse med formlen (D)
i nærvær af MR1, en palladium katalysator og en base; hvor A1 til A3 og R1 til R3 er som defineret i et hvilket som helst af kravene 1 til 13, X er en fraspaltelig gruppe, og M er en passende substitueret metalart.
15. Forbindelse ifølge et hvilket som helst af kravene 1 til 13 til anvendelse som terapeutisk aktivt stof.
16. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 13 og en terapeutisk inert bærer.
17. Forbindelse ifølge et hvilket som helst af kravene 1 til 13 til anvendelse ved behandling eller profylakse af smerte, aterosklerose, aldersrelateret makuladedegeneration, diabetisk retinopati, glaukom, retinal veneokklusion, retrolental fibrose, okulært iskæmisk syndrom, geografisk atrofi, diabetes mellitus, inflammation, inflammatorisk tarmsygdom, iskæmi-reperfusionsskade, akut leversvigt, leverfibrose, lungefibrose, nyrefibrose, systemisk fibrose, akut transplantatafvisning, kronisk transplantatnefropati, diabetisk nefropati, glomerulonefropati, kardiomyopati, hjertesvigt, myokardieiskæmi, myokardieinfarkt, systemisk sklerose, termisk skade, forbrænding, arhypertrofi, keloider, gingivitis, pyreksi, levercirrose eller -tumorer, regulering af knoglemasse, neurodegeneration, amyotrofisk lateral sklerose, multipel sklerose, apopleksi, transitorisk iskæmisk attak eller uveitis.
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