HRP20171655T1 - Derivati aminopirimidina za upotrebu kao modulatori aktivnosti kinaze - Google Patents

Derivati aminopirimidina za upotrebu kao modulatori aktivnosti kinaze Download PDF

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HRP20171655T1
HRP20171655T1 HRP20171655TT HRP20171655T HRP20171655T1 HR P20171655 T1 HRP20171655 T1 HR P20171655T1 HR P20171655T T HRP20171655T T HR P20171655TT HR P20171655 T HRP20171655 T HR P20171655T HR P20171655 T1 HRP20171655 T1 HR P20171655T1
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phenyl
cancer
amino
hal
pyrimidin
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HRP20171655TT
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Ruoxi Lan
Bayard R. Huck
Xiaoling Chen
Lizbeth Celeste DESELM
Yufang Xiao
Hui QIU
Constantin Neagu
Igor Mochalkin
Theresa L. Johnson
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Merck Patent Gmbh
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Claims (8)

1. Spoj s Formulom (I) [image] ili njegova farmaceutski prihvatljiva sol, solvat ili solvat soli, naznačen time da: X je N ili CH; Y je N ili CR2; E je nerazgranata ili razgranata alkilna poveznica koja ima 1, 2, 3, 4, 5, 6 ili 7 C atoma, koji mogu biti nesupstituirani ili mono- ili disupstituirani s Hal, OH, CN ili NH2, u kojoj jedna CH3 skupina može biti zamijenjena s Cyc1, Cyc2, CONH2, CF3, i u kojoj jedna, dvije ili tri CH2 skupine mogu biti zamijenjene s -O- ili -NH-, te u kojoj jedna CH skupina može biti zamijenjena s -N-; ili ako Y je CNH2, E može također biti -CH(R3)-NH-CO- ili -CO-NH-CH(R3)-; R1 je CN, CONH2, Hal, LA, O(LA), Ar, Cyc1 ili Cyc2; R2 je H, NH2, Hal ili CN; R3 je H ili LA, Hal je F, Cl, Br ili I; LA je nerazgranati ili razgranati, ravni zasićeni ili djelomično nezasićeni lanac ugljikovodika koji ima 1, 2, 3 4, 5 ili 6 C atoma, pri čemu 1, 2 ili 3 H atoma mogu biti zamijenjeni s Hal ili OH; Ar je mono- ili biciklički aromatski homo- ili heterocikal koji ima 0, 1, 2, 3 ili 4 N, O i/ili S atoma i 5, 6, 7, 8, 9, ili 10 skeletnih atoma, koji mogu biti nesupstituirani ili, međusobno neovisno, mono- ili di-supstituirani s Hal, LA, OH, SH, O(LA), NH2, NH(LA), N(LA)2, NO2 CN, OCN, COOH, COO(LA), CONH2, CONH(LA), CON(LA)2, NHCO(LA), NHCONH(LA), NHCONH2, CHO i CO(LA), i/ili monosupstituirani s Cyc2 ili O-Cyc2; Cyc1 je 3, 4, 5 ili 6 člani monociklički alifatski homo- ili heterocikal koji ima 0-2 heteroatoma, koji se biraju od O, S i N, koji mogu biti mono- ili disupstituirani s Hal, LA, NH2, NH(LA), N(LA)2, HO(LA)-; Cyc2 je 5 ili 6 člani monociklički aromatski homo- ili heterocikal koji ima 0-3 heteroatoma, koji se biraju od O, S i N, koji mogu biti mono- ili di-supstituirani s Hal ili LA; i n je 1 ili 2.
2. Spoj prema zahtjevu 1 u kojem ostatci koji nisu detaljnije naznačeni imaju značenje navedeno za Formulu (I), prema zahtjevu 1, naznačen time da u njemu u Podformuli 1 X je N, ili u Podformuli 2 Y je N ili CH, ili u Podformuli 3 R1 je Hal, LA, O(LA), Cyc1 ili Cyc2, ili u Podformuli 4 Ar je fenil ili piridil, koji je nesupstituiran ili mono- ili disupstituiran s Hal, LA ili O(LA), ili u Podformuli 5 E je metilna poveznica koja je supstituirana s aminometilom, pri čemu je amino skupina od aminometila nesupstituirana, ili mono- ili disupstituirana s LA, ili E je metilna poveznica koji je supstituirana s (azetidin-1-il)metil, ili u Podformuli 7 X je N, Y je N ili CH, R1 je Hal, LA, O(LA), Cyc1 ili Cyc2, ili u Podformuli 8 X je N, Y je N ili CH, Ar je fenil ili piridil, koji je nesupstituiran ili mono- ili disupstituiran s Hal, LA ili O(LA), ili u Podformuli 9 X je N, Y je N ili CH, E je metilna poveznica koja je supstituirana s aminometilom, pri čemu je amino skupina od aminometila nesupstituirana, ili mono- ili disupstituirana s LA, ili E je metilna poveznica koja je supstituirana s (azetidin-1-il)metil, ili u Podformuli 10 X je N, Y je CNH2, E je -CH(R3)-NH-CO- ili -CO-NH-CH(R3)-, R1 je Hal, LA, O(LA), Cyc1 ili Cyc2, R3 je H ili LA, ili u Podformuli 11 X je N, Y je CNH2, E je -CH(R3)-NH-CO- ili -CO-NH-CH(R3)-, R1 je Hal, LA, O(LA), Cyc1 ili Cyc2, R3 je H ili LA, Ar je fenil ili piridil, koji je nesupstituiran ili mono- ili disupstituiran s Hal, LA ili O(LA), ili u Podformuli 12 X je N, Y je CNH2, E je -CH(R3)-NH-CO- ili -CO-NH-CH(R3)-, R3 je H ili LA, Ar je fenil ili piridil, koji je nesupstituiran ili mono- ili disupstituiran s Hal, LA ili O(LA), ili u Podformuli 13 X je N, Y je N ili CH, E je metilna poveznica koja je supstituirana s aminometilom, pri čemu je amino skupina od aminometila nesupstituirana, ili mono- ili disupstituirana s LA, ili E je metilna poveznica koja je supstituirana s (azetidin-1-il)metil, Ar je fenil ili piridil, koji je nesupstituiran ili mono- ili disupstituiran s Hal, LA ili O(LA), R1 je Hal, LA, O(LA), Cyc1 ili Cyc2, ili njegova farmaceutski prihvatljiva sol, solvat ili solvat soli.
3. Spoj prema zahtjevu 1, naznačen time da se bira iz skupine koja sadrži: 6-{4-[(S)-2-amino-1-(4-trifluorometil-fenil)-etil]-piperazin-1-il}-5-(4-fluorofenil)-pirimidin-4-ilamin; 6-{4-[2-amino-1-(4-kloro-3-fluoro-fenil)-etil]-piperazin-1-il}-5-(4-fluoro-fenil)-pirimidin-4-ilamin; 6-(4-(2-amino-1-(4-(trifluorometoksi)fenil)etil)piperazin-1-il)-5-(1H-pirazol-4-il)pirimidin-4-amin; 6-{4-[(R)-2-amino-1-(6-kloro-piridin-3-il)-etil]-piperazin-1-il}-5-(4-fluoro-fenil)-pirimidin-4-ilamin; 6-{4-[(S)-2-amino-1-(4-trifluorometil-fenil)-etil]-piperidin-1-il}-5-(4-fluoro-fenil)-pirimidin-4-ilamin; {4-[6-amino-5-(4-fluoro-fenil)-pirimidin-4-il]-piperazin-1-il}-(6-trifluorometil-piridin-3-il)-acetonitril; 6-{4-[3-azetidin-1-il-1-(4-kloro-fenil)-propil]-piperazin-1-il}-5-(4-fluorofenil)-pirimidin-4-ilamin; (S)-6-(4-(2-amino-1-(4-(trifluorometil)fenil)etil)piperazin-1-il)-5-(1H-pirazol-4-il)pirimidin-4-amin; 6-{4-[2-amino-1-(3-fluoro-fenil)-etil]-piperazin-1-il}-5-(4-fluoro-fenil)-pirimidin-4-ilamin; 6-(4-(2-(azetidin-1-il)-1-(4-(trifluorometil)fenil)etil)piperazin-1-il)-5-(4-fluorofenil)pirimidin-4-amin; 6-(4-(2-(dimetilamino)-1-(4-(trifluorometil)fenil)etil)piperazin-1-il)-5-(4-fluorofenil)pirimidin-4-amin; 6-(4-(2-amino-1-(4-(trifluorometil)fenil)etil)piperidin-1-il)-5-(1H-pirazol-4-il)pirimidin-4-amin; N-{3-amino-1-[6-amino-5-(4-fluoro-fenil)-pirimidin-4-il]-pirrolidin-3-ilmetil}-2,4-difluoro-benzamid; 6-{4-[2-amino-1-(6-trifluorometil-piridin-3-il)-etil]-piperazin-1-il}-5-(4-fluorofenil)-pirimidin-4-ilamin; 6-{4-[(S)-2-amino-1-(4-kloro-fenil)-etil]-piperazin-1-il}-5-etil-pirimidin-4-ilamin; 6-(4-(2-amino-1-(4-(trifluorometil)-fenil)etil)piperazin-1-il)-5-vinilpirimidin-4-amin; 6-(4-(2-amino-1-(4-(trifluorometil)fenil)etil)piperazin-1-il)-5-etoksipirimidin-4-amin; [(S)-1-(4-kloro-fenil)-propil]-amid 4-amino-1-[6-amino-5-(1H-pirazol-4-il)-pirimidin-4-il]-piperidin-4-karboksilne kiseline; 6-{4-[2-amino-1-(4-trifluorometil-fenil)-etil]-piperazin-1-il}-5-kloro-pirimidin-4-ilamin i njihove farmaceutski prihvatljive soli ili solvati.
4. Farmaceutski pripravak naznačen time da kao aktivni sastojak sadrži spoj prema bilo kojem od zahtjeva 1 do 3, ili njegovu farmaceutski prihvatljivu sol ili solvat, zajedno s farmaceutski prihvatljivim nosačem.
5. Spoj prema bilo kojem od zahtjeva 1 do 3, ili njegova farmaceutski prihvatljiva sol ili solvat, naznačen time da je za upotrebu kao lijek.
6. Spoj prema bilo kojem od zahtjeva 1 do 3, ili njegova farmaceutski prihvatljiva sol ili solvat, naznačen time da je za upotrebu za liječenje raka.
7. Spoj, ili njegova farmaceutski prihvatljiva sol ili solvat, koji je za upotrebu za liječenje raka prema zahtjevu 6, naznačen time da je navedeni rak odabran iz skupine koja sadrži rak mozga, pluća, debelog crijeva, epidermoida, rak skvamoznih stanica, rak mokraćnog mjehura, rak želuca, rak gušterače, rak dojke, rak glave, rak vrata, renalni karcinom, rak bubrega, rak jetre, rak jajnika, rak prostate, kolorektalni karcinom, rak maternice, rektuma, rak jednjaka, rak testisa, ginekološki karcinom, rak štitnjače, melanom, hematološke maligne tvorbe kao što je akutna mijelogena leukemija, multipli mijelom, kronična mijelogena leukemija, leukemija mijeloidnih stanica, gliom i Kapozijev sarkom.
8. Komplet (kit) naznačen time da sadrži odvojena pakiranja a. učinkovite količine spoja prema jednom ili više zahtjeva 1 do 3 ili njegovu farmaceutski prihvatljivu sol ili solvat, te b. učinkovite količine daljnjeg aktivnog sastojka lijeka.
HRP20171655TT 2011-09-12 2012-09-12 Derivati aminopirimidina za upotrebu kao modulatori aktivnosti kinaze HRP20171655T1 (hr)

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US201161533606P 2011-09-12 2011-09-12
PCT/US2012/054877 WO2013040044A1 (en) 2011-09-12 2012-09-12 Aminopyrimidine derivatives for use as modulators of kinase activity
EP12766773.1A EP2755958B9 (en) 2011-09-12 2012-09-12 Aminopyrimidine derivatives for use as modulators of kinase activity

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US (3) US9321760B2 (hr)
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JP (1) JP6082011B2 (hr)
KR (1) KR101992505B1 (hr)
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