HRP20171069T1 - Inhibitori mtor kinaze za onkološke indikacije i bolesti povezane s putom mtor/p13k/akt - Google Patents

Inhibitori mtor kinaze za onkološke indikacije i bolesti povezane s putom mtor/p13k/akt Download PDF

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HRP20171069T1
HRP20171069T1 HRP20171069TT HRP20171069T HRP20171069T1 HR P20171069 T1 HRP20171069 T1 HR P20171069T1 HR P20171069T T HRP20171069T T HR P20171069TT HR P20171069 T HRP20171069 T HR P20171069T HR P20171069 T1 HRP20171069 T1 HR P20171069T1
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Croatia
Prior art keywords
dihydropyrazino
pyrazin
pyridin
methyl
triazol
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HRP20171069TT
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Jan Elsner
Roy Harris
Branden Lee
Deborah Mortensen
Garrick K. Packard
Patrick Papa
Sophie Perrin-Ninkovic
Jennifer Riggs
Sabita Sankar
John Sapienza
Graziella I. Shevlin
Lida Tehrani
Weiming Xu
Jingjing Zhao
Jason Parnes
Loui Madakamutil
Kimberly Elizabeth Fultz
Rama K. Narla
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Signal Pharmaceuticals, Llc
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Application filed by Signal Pharmaceuticals, Llc filed Critical Signal Pharmaceuticals, Llc
Publication of HRP20171069T1 publication Critical patent/HRP20171069T1/hr

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Claims (19)

1. Spoj koji ima formulu (II): [image] ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer, naznačen time da: R1 je piridil supstituiran s jednim ili više supstituenata neovisno odabranih iz skupine koja sadrži supstituiran ili nesupstituiran C1-8 alkil, supstituiran ili nesupstituiran heterociklil, halogen, aminokarbonil, cijano, hidroksialkil, -OR, i -NR2, pri čemu svaki R je neovisno H, ili supstituiran ili nesupstituiran C1-4 alkil; R2 je supstituiran ili nesupstituiran C1-8 alkil; i R3 je H, ili supstituiran ili nesupstituiran C1-8 alkil; pri čemu izraz "supstituiran" označava supstituciju s bilo kojim od supstituenata koji su navedeni u dodatnim zahtjevima ili sa supstituentima koji su halogen; alkil; hidroksil; alkoksi; alkoksialkil; amino; alkilamino; karboksi; nitro; cijano; tiol; tioeter; imine; imid; amidin; guanidin; enamin; aminokarbonil; acilamino; fosfonato; fosfin; tiokarbonil; sulfonil; sulfon; sulfonamide; keton; aldehid; ester; urea; uretan; oksim; hidroksil amin; alkoksiamin; aralkoksiamin; N-oksid; hidrazin; hidrazid; hidrazon; azid; izocijanat; izotiocijanat; cijanat; tiocijanat; kisik (=O); B(OH)2, O(alkil)aminokarbonil; cikloalkil, koji može biti monociklički ili kondenziran ili ne-kondenziran policiklički; heterociklil, koji može biti monociklički ili kondenziran ili ne-kondenziran policiklički; monociklički ili kondenziran ili ne-kondenziran policiklički aril ili heteroaril; ariloksi; aralkiloksi; heterocikliloksi; ili heterociklil alkoksi.
2. Spoj prema zahtjevu 1, naznačen time da R2 je nesupstituirani C1-8 alkil.
3. Spoj prema zahtjevu 1, naznačen time da R3 je H.
4. Spoj prema zahtjevu 1, naznačen time da spoj je: 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-((cis-4-metoksicikloheksil)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-((trans-4-metoksicikloheksil)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-((trans-4-hidroksicikloheksil)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-(2-metoksietil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-etil-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-((cis-4-hidroksicikloheksil)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-izopropil-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(2-hidroksipiridin-4-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-izopropil-7-(4-metil-6-(lH-l,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(2-aminopiridin-4-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(metilamino)piridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-hidroksipiridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-metoksipiridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-aminopiridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-metil-7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 3-((7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-2-okso-3,4-dihidropirazino[2,3-b]pirazin-1(2H)-il)metil)benzonitril; 1-((trans-4-metoksicikloheksil)metil)-7-(4-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 3-((7-(6-(2-hidroksipropan-2-il)piridin-3-il)-2-okso-3,4-dihidropirazino[2,3-b]pirazin-1 (2H)-il)metil)benzonitril; 7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-1-(2-morfolinoetil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-(2-morfolinoetil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-izopropil-7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-((cis-4-metoksicikloheksil)metil)-7-(2-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-etil-7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-((trans-4-metoksicikloheksil)metil)-7-(2-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-((cis-4-metoksicikloheksil)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-(2-metoksietil)-7-(4-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-(2-metoksietil)-7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-((trans-4-metoksicikloheksil)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-(ciklopentilmetil)-7-(6-(2-hidroksipropan-2-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; (S)-7-(6-(1-hidroksietil)piridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; (R)-7-(6-(1-hidroksietil)piridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-1-((tetrahidro-2H-piran-4-il)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-(4-(trifluorometil)benzil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-(3-(trifluorometil)benzil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-(3-metoksipropil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(4-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-(2-metoksietil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-((tetrahidro-2H-piran-4-il)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-(2-(tetrahidro-2H-piran-4-il)etil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; 1-(1-hidroksipropan-2-il)-7-(2-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on; ili 1-(2-hidroksietil)-7-(2-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on, ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
5. Spoj prema zahtjevu 1, naznačen time da spoj je 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-((cis-4-metoksicikloheksil)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
6. Spoj prema zahtjevu 1, naznačen time da spoj je 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-(2-metoksietil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
7. Spoj prema zahtjevu 1, naznačen time da spoj je 7-(6-(1H-1,2,4-triazol-3-il)piridin-3-il)-1-izopropil-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
8. Spoj prema zahtjevu 1, naznačen time da spoj je 3-((7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-2-okso-3,4-dihidropirazino[2,3-b]pirazin-1(2H)-il)metil)benzonitril ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
9. Spoj prema zahtjevu 1, naznačen time da spoj je 3-((7-(6-(2-hidroksipropan-2-il)piridin-3-il)-2-okso-3,4-dihidropirazino[2,3-b]pirazin-1(2H)-il)metil)benzonitril ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
10. Spoj prema zahtjevu 1, naznačen time da spoj je 1-((cis-4-metoksicikloheksil)metil)-7-(2-metil-6-(1H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
11. Spoj prema zahtjevu 1, naznačen time da spoj je 1-etil-7-(2-metil-6-(4H-1,2,4-triazol-3-il)piridin-3-il)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
12. Spoj prema zahtjevu 1, naznačen time da spoj je 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-((trans-4-metoksicikloheksil)metil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
13. Spoj prema zahtjevu 1, naznačen time da spoj je 7-(6-(2-hidroksipropan-2-il)piridin-3-il)-1-(4-(trifluorometil)benzil)-3,4-dihidropirazino[2,3-b]pirazin-2(1H)-on ili njegova farmaceutski prihvatljiva sol, stereoizomer, ili njegov tautomer.
14. Farmaceutski pripravak naznačen time da sadrži učinkovitu količinu spoja prema bilo kojem od zahtjeva 1 do 13, koji je proizvoljno pogodan za oralnu, parenteralnu, mukoznu, transdermalnu ili topikalnu primjenu.
15. Spoj prema bilo kojem od zahtjeva 1 do 13 ili farmaceutski pripravak prema zahtjevu 14 naznačen time da je za uporabu u postupku liječenja ili sprječavanje raka, upalnih stanja, imunoloških stanja, neurodegenerativnih bolesti, dijabetesa, pretilosti, neuroloških poremećaja, bolesti povezanih sa starenjem ili kardiovaskularnih stanja.
16. Spoj ili farmaceutski pripravak za uporabu prema zahtjevu 15, naznačen time da rak je rak glave, vrata, oka, usta, grla, jednjaka, bronha, grkljana, ždrijela, prsnog koša, kostiju, pluća, debelog crijeva, rektuma, želuca, prostate, mokraćnog mjehura, maternice, vrata maternice, dojke, jajnika, testisa, kože, štitnjače, krvi, limfnih čvorova, bubrega, jetre, gušterače, mozga, središnjeg živčanog sustava, ili solidni tumori i tumori krvotvornih stanica; ili pri čemu upalno stanje je psorijaza, astma, alergijski rinitis, bronhitis, kronična opstruktivna plućna bolest, cistična fibroza, upalna bolest crijeva, sindrom iritabilnog crijeva, Crohnova bolest, mukozni kolitis, ulcerozni kolitis, ili pretilost; ili pri čemu imunološko stanje je reumatoidni artritis, reumatoidni spondilitis, osteoartritis, multipla skleroza, lupus, upalna bolest crijeva, ulcerativni kolitis, Crohnova bolest, miastenija gravis, Gravesova bolest, encefalomijelitis, dijabetes tipa II, dermatomiozitis, ili odbacivanje transplantata; ili pri čemu bolest povezana sa starenjem je rak, pretilost, dijabetes melitus tipa II, autoimuna bolest, kardiovaskularna bolest ili neuronska degeneracija.
17. Spoj prema bilo kojem od zahtjeva 1 do 13 ili farmaceutski pripravak prema zahtjevu 14 naznačen time da je za uporabu za inhibiciju kinaze u stanici koja eksprimira spomenutu kinazu, proizvoljno pri čemu kinaza je mTOR, DNA-PK, ili PI3K, ili njihova kombinacija.
18. In vitro postupak inhibiranja kinaze u stanici koja eksprimira navedenu kinazu, naznačen time da sadrži dovođenje u kontakt navedene stanice s učinkovitom količinom spoja prema bilo kojem od zahtjeva 1 do 13, proizvoljno pri čemu kinaza je mTOR, DNA-PK, ili PI3K, ili njihova kombinacija.
19. Spoj prema bilo kojem od zahtjeva 1 do 13 ili farmaceutski pripravak prema zahtjevu 14 naznačen time da je za uporabu u postupku liječenja ili sprječavanja stanja koja se mogu liječiti ili spriječiti inhibicijom puta kinaze, prema potrebi pri čemu put kinaze je mTOR/PI3K/Akt put; pri čemu stanje je proizvoljno multipli mijelom, limfom plaštenih stanica, difuzni limfom velikih B-stanica, akutni mijeloidni limfom, folikularni limfom, kronična limfocitna leukemija; rak dojke, pluća, endometrija, jajnika, želuca, cerviksa ili prostate; glioblastom; karcinom bubrega; hepatocelularni karcinom; karcinom debelog crijeva; neuroendokrini tumori; tumori glave i vrata; sarkomi; tumorski sindromi koji su izravno ili neizravno proizašli iz genetskih defekata u PTEN, TSC1, TSC2, NF1, AMPK, LKB1, VHL ili PKD1; Cowdenova bolest, Cowdenov sindrom, sindrom sličan Cowdenovom, sindrom Bannayan-Zonana, sindrom Bannayan-Riley-Ruvalcaba, Lhermitte-Duclos-ova bolest, karcinom endometrija, kompleks tuberozne skleroze, limfangioleiomiomatoza, neurofibromatoza 1, sindrom Peutz-Jeghers, karcinom bubrežnih stanica, Hippel-Lindau-ova bolest, Proteusov sindrom, ili policistična bolest bubrega; reumatoidni artritis; reumatoidni spondilitis; osteoartritis; giht; astma, bronhitis; alergijski rinitis; kronična opstruktivna plućna bolest; cistična fibroza; upalna bolest crijeva; sindrom iritabilnog crijeva; mukozni kolitis; ulcerativni kolitis; Crohnova bolest; Huntingtonova bolest; gastritis; ezofagitis; hepatitis; pankreatitis; nefritis; multipla skleroza; eritemski lupus; ateroskleroza; restenoza nakon angioplastike; hipertrofija lijeve klijetke; infarkt miokarda; moždani udar; ishemijska oštećenja srca, pluća, crijeva, bubrega, jetre, gušterače, slezene i mozga; akutno ili kronično odbacivanje presađivanja organa; očuvanje organa za transplantaciju; zatajenje organa ili gubitak udova; bolesti presatka protiv domaćina; endotoksinskog šoka; višestruko zatajenje organa; psorijaza; opekotine zbog izlaganja vatri, kemikalijama ili zračenju; ekcem; dermatitis; presađivanje kože; ishemija; ishemijska stanja povezana s operacijom ili traumatskom ozljedom; epilepsija; Alzheimerova bolest; Parkinsonova bolest; imunološki odgovor na bakterijske ili virusne infekcije; kaheksija; angiogene ili proliferativne bolesti.
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