HRP20161396T1 - Derivati 2-(fenil ili pirid-3-il)aminopirimidina kao modulatori lrrk2-kinaze za liječenje parkinsonove bolesti - Google Patents

Derivati 2-(fenil ili pirid-3-il)aminopirimidina kao modulatori lrrk2-kinaze za liječenje parkinsonove bolesti Download PDF

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HRP20161396T1
HRP20161396T1 HRP20161396TT HRP20161396T HRP20161396T1 HR P20161396 T1 HRP20161396 T1 HR P20161396T1 HR P20161396T T HRP20161396T T HR P20161396TT HR P20161396 T HRP20161396 T HR P20161396T HR P20161396 T1 HRP20161396 T1 HR P20161396T1
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methyl
diamine
phenyl
methoxy
trifluoromethyl
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Charles Baker-Glenn
Mark Chambers
Bryan K. Chan
Anthony Estrada
Zachary Sweeney
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F. Hoffmann - La Roche Ag
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Claims (15)

1. Spoj, naznačen time, da ima formulu I: [image] ili njegove farmaceutski prihvatljive soli, u kojoj: m je od 0 do 3; X je: -NRa-; -O-; ili -S(O)r- gdje r je od 0 do 2 i Ra je vodik ili C1-6alkil; Y je C ili N; R 1 je: C 1-6alkil; C2-6alkenil; C2-6alkinil; halo-C1-6alkil; C1-6alkoksi-C1-6alkil; hidroksi-C1-6alkil; amino-C1-6alkil gdje je amino-skupina po izboru supstituirana s jednim ili dva alkila; C 1-6alkilsulfonil-C1-6alkil; C3-6cikloalkil po izboru supstituiran sa C 1-6alkilom; C3-6cikloalkil-C 1-6alkil gdje je udio C3-6cikloalkila po izboru supstituiran sa C 1-6alkilom; tetrahidrofuranil; tetrahidrofuranil-C1-6alkil; oksetanil; ili oksetan-C1-6alkil; ili R 1 i Ra zajedno s atomima na koje su priključeni, mogu tvoriti tročlani do šesteročlani prsten koji može po izboru uključivati dodatni heteroatom odabran od O, N i S, i koji je supstituiran s okso, halo ili C1-6alkilom; R2 je: halo; C1-6alkoksi; cijano; C2-6alkinil; C2-6alkenil; halo-C1-6alkil; halo-C1-6alkoksi; C3-6cikloalkil gdje je udio C3-6cikloalkila po izboru supstituiran sa C1-6alkilom; C3-6cikloalkil-C1-6alkil gdje je udio C3-6cikloalkila po izboru supstituiran sa C1-6alkilom; tetrahidrofuranil; tetrahidrofuranil-C 1-6alkil; acetil; oksetanil; ili oksetan-C1-6alkil; svaki od R3 i R4 je neovisno: halo; C1-6alkil; C1-6alkoksi; C3-6cikloalkiloksi; halo-C1-6alkil; ili halo-C1-6alkoksi; i R5 je peteročlana heteroaril-skupina po izboru supstituirana jednom ili više puta s R6; i R6 je: C1-6alkil; C3-6cikloalkil; C3-6cikloalkil-C1-6alkil; halo; halo-C1-6alkil; C1-6alkoksi; heterociklil; okso; ili -C(O)-NRbRc gdje je svaki od Rb i Rc neovisno vodik ili -C -6alkil.
2. Spoj prema zahtjevu 1, naznačen time, da X je -NH- ili -O-.
3. Spoj prema bilo kojem od zahtjeva 1 do 2, naznačen time, da R1 je: C1-6alkil; C3-6cikloalkil po izboru supstituiran sa C1-6alkilom; ili C3-6cikloalkil-C1-6alkil gdje je udio C3-6cikloalkila po izboru supstituiran sa C1-6alkilom.
4. Spoj prema bilo kojem od zahtjeva 1 do 3, naznačen time, da R1 je C1-6alkil.
5. Spoj prema bilo kojem od zahtjeva 1 do 4, naznačen time, da R2 je: halo; halo-C1-6alkil; ili cijano.
6. Spoj prema bilo kojem od zahtjeva 1 do 5, naznačen time, da R3 je halo ili C1-6alkoksi.
7. Spoj prema bilo kojem od zahtjeva 1 do 6, naznačen time, da R3 je metoksi.
8. Spoj prema bilo kojem od zahtjeva 1 do 7, naznačen time, da m je 0 ili 1.
9. Spoj prema bilo kojem od zahtjeva 1 do 8, naznačen time, da R4 je halo ili metoksi.
10. Spoj prema bilo kojem od zahtjeva 1 do 9, naznačen time, da R5 je: pirazolil; imidazolil; oksadiazolil; tiadiazolil; triazolil; ili tetrazolil; od kojih je svaki po izboru supstituiran jednom ili više puta s R6.
11. Spoj prema bilo kojem od zahtjeva 1 do 10, naznačen time, da R5 je: oksadiazolil; tiadiazolil; triazolil; ili tetrazolil; koji je po izboru supstituiran jednom ili više puta s R6.
12. Spoj prema bilo kojem od zahtjeva 1 do 11, naznačen time, da R5 je: 1-metil-1H-imidazol-2-il; 1-metil-1H-imidazol-5-il; 1,3,5-trimetil-1H-pirazol-4-il; 1-metil-1H-pirazol-5-il; 1-metil-1H-pirazol-4-il; 1,3-dimetil-1H-pirazol-4-il; 1,5-dimetil-1H-pirazol-4-il; 5-(dimetilaminokarbonil)-1-metil-1H-pirazol-4-il; 1-(oksetan-3-il)-1H-pirazol-4-il; 5-(metoksimetil)-3-metil-1H-pirazol-1-il; 1-metil-1H-1,2,3-triazol-5-il; 1H-1,2,4-triazol-1-il; 4-metil-4H-1,2,4-triazol-3-il; 5-metil-1,3,4-oksadiazol-2-il; 3-metil-1,2,4-oksadiazol-5-il; 1-metil-1H-tetrazol-5-il; 2-metil-2H-tetrazol-5-il; 1H-tetrazol-1-il; 2H-tetrazol-5-il; 5-metil-1H-tetrazol-1-il; ili 5-(metoksimetil)-1H-tetrazol-1-il.
13. Spoj prema bilo kojem od zahtjeva 1 do 12, naznačen time, da je odabran iz skupine koju čine: N2-(2-kloro-4-(2H-tetrazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-kloro-4-(1-metil-1H-tetrazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-kloro-4-(2-metil-2H-tetrazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-4 -(1H-1,2,4-triazol-1-il) fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-4-(1-metil-1H-pirazol-4-il)fenil)-N4-metil-5-(trifluorometil) pirimidin-2,4-diamin, N2-(5-fluoro-2-metoksi-4-(3-metil-1,2,4-oksadiazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-kloro-5-metoksi-4-(5-metil-1,3,4-oksadiazol-2-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-4-(1-metil-1H-imidazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(4-metoksi-6-(tiazol-5-il)piridin-3-il)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, 5-kloro-N2-(2-metoksi-4-(1-metil-1H-tetrazol-5-il)fenil)-N4-metilpirimidin-2,4-diamin, N2-(2-kloro-5-metoksi-4-(1-metil-1H-1,2,3-triazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(4-metoksi-6-(tiazol-4-il)piridin-3-il)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(4-metoksi-6-(oksazol-2-il)piridin-3-il)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, 5-kloro-N2-(4-(izoksazol-4-il)-2-metoksifenil)-N4-metilpirimidin-2,4-diamin, 5-kloro-N2-(2-metoksi-4-(1-metil-1H-imidazol-2-il)fenil)-N4-metilpirimidin-2,4-diamin, 5-kloro-N2-(2-metoksi-4-(1-metil-1H-imidazol-5-il)fenil)-N4-metilpirimidin-2,4-diamin, N2-(2-metoksi-4-(1-metil-1H-1,2,3-triazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-4-(2-metil-2H-tetrazol-5-il)fenil)-N4-metil-5-(trifluorometil) pirimidin-2,4-diamin, N2-(2-kloro-5-metoksi-4-(1-metil-1H-imidazol-2-il) fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-4-(1-metil-1H-tetrazol-5-il)fenil)-N4-metil-5-(trifluorometil) pirimidin-2,4-diamin, N2-(2-kloro-5-metoksi-4-(1-metil-1H-imidazol-5-il) fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(5-fluoro-2-metoksi-4-(1-metil-1H-tetrazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, 5-kloro-N2-(2-metoksi-4-(1-metil-1H-1,2,3-triazol-5-il)fenil)-N4-metilpirimidin-2,4-diamin, N2-(2-kloro-5-metoksi-4-(1,3,5-trimetil-1 H-pirazol-4-il) fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-4-(1-metil-1H-pirazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(4-(3,5-dimetilizoksazol-4-il)-2-metoksifenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-4-(1H-tetrazol-1-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-kloro-5-metoksi-4-(1-metil-1H-pirazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N4-etil-N2-(5-fluoro-2-metoksi-4-(5-metil-1,3,4-oksadiazol-2-il)fenil)-5-(trifluorometil)pirimidin-2,4-diamin, N2-(5-fluoro-2-metoksi-4-(5-metil-1,3,4-oksadiazol-2-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-kloro-5-metoksi-4-(3-metil-1,2,4-oksadiazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-kloro-5-metoksi-4-(1-metil-1H-pirazol-4-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, 5-kloro-N2-(2-kloro-4-(5-metil-1,3,4-oksadiazol-2-il)fenil)-N4-metilpirimidin-2,4-diamin, 5-kIoro-N2-(2-kloro-4-(3-metil-1,2,4-oksadiazol-5-il)fenil)-N4-metilpirimidin-2,4-diamin, 5-kloro-N2-(2-metoksi-4-(1-metil-1H-pirazol-4-il)fenil)-N4-metilpirimidin-2,4-diamin, 5-kloro-N2-(2-kloro-5-metoksi-4-(3-metil-1,2,4-oksadiazol-5-il)fenil)-N4-metilpirimidin-2,4-diamin, 5-kloro-N2-(2-kloro-5-metoksi-4-(5-metil-1,3,4-oksadiazol-2-il)fenil)-N4-metilpirimidin-2,4-diamin, N2-(4-(1,3-dimetil-1H-pirazol-4-il)-2-metoksifenil)-N4-metil-5-trifluorometil)pirimidin-2,4-diamin, N2-(4-(1,5-dimetil-1H-pirazol-4-il)-2-metoksifenil)-N4-metil-5-(triflurometil)pirimidin-2,4-diamin, N2-(2-metoksi -4-(4-metil-4H-1,2,4-triazol-3-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, 4-(2-fluoro-5-metoksi-4-(4-(metilamino)-5-(trifluorometil)pirimidin-2-ilamino)fenil)-N,N,1-trimetil-1H-pirazol-5-karboksamid, N2-(5-fluoro-2-metoksi-4-(5-metil-1 H-tetrazol-1-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(5-fluoro-2-metoksi-4-(1-metil-1H-1,2,3-triazol-5-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(5-fluoro-2-metoksi-4-(1-(oksetan-3-il)-1H-pirazol-4-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-5-metil-4-(5-metil-1 H-tetrazol-1-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(2-metoksi-4-(5-(metoksimetil)-1H-tetrazol-1-il)-5-metilfenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, N2-(5-fluoro-2-metoksi-4-(5-(metoksimetil)-3-metil-1H-pirazol-1-il)fenil)-N4-metil-5-(trifluorometil) pirimidin-2,4-diamin, N2-(2-metoksi-4 -(5-(metoksimetil)-3-metil-1H-pirazol-1-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin, i N2-(5-fluoro-2-metoksi-4-(5-(metoksimetil)-1H-tetrazol-1-il)fenil)-N4-metil-5-(trifluorometil)pirimidin-2,4-diamin.
14. Sastav, naznačen time, da obuhvaća: farmaceutski prihvatljiv nosač; i spoj u skladu sa zahtjevom 1.
15. Spoj formule I prema bilo kojem od zahtjeva 1 do 12, naznačen time, da se upotrebljava u prevenciji ili liječenju Parkinsonove bolesti.
HRP20161396TT 2011-11-29 2016-10-25 Derivati 2-(fenil ili pirid-3-il)aminopirimidina kao modulatori lrrk2-kinaze za liječenje parkinsonove bolesti HRP20161396T1 (hr)

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