DK2968286T3 - 2-aminopyrimidin-6-oner og analoger, der har anti-cancer og anti-proliferative aktiviteter - Google Patents

2-aminopyrimidin-6-oner og analoger, der har anti-cancer og anti-proliferative aktiviteter Download PDF

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DK2968286T3
DK2968286T3 DK14764032.0T DK14764032T DK2968286T3 DK 2968286 T3 DK2968286 T3 DK 2968286T3 DK 14764032 T DK14764032 T DK 14764032T DK 2968286 T3 DK2968286 T3 DK 2968286T3
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methyl
pyridin
alkyl
oxy
pyrimidin
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Michael D Kaufman
Daniel L Flynn
Yu Mi Ahn
Timothy Malcolm Caldwell
Lakshminarayana Vogeti
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Deciphera Pharmaceuticals Llc
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Claims (15)

1. Forbindelse med Formel I, eller et farmaceutisk acceptabelt salt, enantiomer, stereoisomer eller tautomer deraf,
Formel I hvori A er taget fra gruppen, der består af -N(R2)R3 og G; G er valgt fra gruppen, der består af
og hvor symbolet (**) er punktet for fastgørelse til pyrimidinringen; hver G-molekyldelen kan være yderligere substitueret med en, to eller tre R4-molekyldele; W er C5-C6-heteroaryl, phenyl, -NHC(0)R6, -NHC(0)R7, -NHC(0)N-(R8)R9 eller -C(0)N(R8)R9, og hvor hver C5-C6-heteroaryl eller phenyl eventuelt er substitueret med en, to eller tre R5-molekyldele; X1 og X2 er hver for sig og uafhængigt hydrogen eller C1-C6-alkyl; R1 er hydrogen, C1-C6-alkyl, deutero-C1-C6-alkyl, hvor al kyl kæden er delvist eller fuldstændigt deutereret, eller forgrenet C3-C8-alkyl; R2 er hydrogen, C1-C6-alkyl, deutero-C1-C6-alkyl, hvor alkylkæden er delvist eller fuldstændigt deutereret, forgrenet C3-C8-alkyl, C3-C8- cycloalkyl, fluor-C1-C6-alkyl, hvori alkylen er helt eller delvis fluoreret, -(CH2)m-OR8 eller en 3-8-leddet heterocyklisk ring, hvor hver alkylen eventuelt er substitueret med C1-C4-alkyl; R3 er hydrogen, C1-C6-alkyl, deutero-C1-C6-alkyl, hvor a I kyl kæden er delvist eller fuldstændigt deutereret, forgrenet C3-C8-alkyl, C3-C8-cycloalkyl, fluor-C1-C6-alkyl, hvori alkylen er helt eller delvis fluoreret, eller en 3 -8-leddet heterocyklisk ring; hver R4 er hver for sig og uafhængigt hydrogen, halogen, C1-C6-alkyl, fluor-C1-C6-alkyl, hvor alkylkæden er delvist eller fuldstændigt fluoreret, forgrenet C3-C8-alkyl, C3-C8-cycloalkyl, -(CH2)m-OR8, -(CH2)m.NR8(R9), -(CH2)m-R7, eller cyano, hvor hver alkylen eventuelt er substitueret med C1-C4-alkyl; hver R5 er hver for sig og uafhængigt hydrogen, C1-C6-alkyl, deutero-C1 -C6-alkyl, hvor alkylkæden er delvist eller fuldstændigt deutereret, forgrenet C3-C8-alkyl, halogen, cyano, fluor-C1-C6-alkyl, hvori alkylkæden er delvist eller fuldstændigt fluoreret, -(CH2)m-C(0)NR8(R9), -(CH2)m-C(0)R7, -(CH2)m-OR8, -(CH2)m-NR8(R9) eller -(CH2)m-R7, hvor hver alkylen eventuelt er substitueret med C1-C4-alkyl; hver R6 er hver for sig og uafhængigt hydrogen, C1-C6-alkyl, forgrenet C3-C8-alkyl, C3-C8-cycloalkyl, -(CH2)m-CN, -(CH2)m-OR8, -(CH2)m-NR8(R9) eller -(CH2)m-R7, hvor hver alkylen eventuelt er substitueret med C1-C4-alkyl; hver R7 er uafhængigt og hver for sig valgt fra gruppen, der består af
og hvor symbolet (##) er punktet for fastgørelse til henholdsvis W, R5-eller R6-molekyldele, der indeholder en R7-molekyldel; hver R7 er eventuelt substitueret med -(R10)p; hver R8 og R9 er hver for sig og uafhængigt hydrogen, C1-C6-alkyl, fluor-C1-C6-alkyl, hvor alkylkæden er delvist eller fuldstændigt fluoreret eller forgrenet C3-C8-alkyl; hver R10 er hver for sig og uafhængigt C1-C6-alkyl, -(CH2)m-CN, -(CH2)m-OR3, -(CH2)m-NR8(R9) eller -(CH2)m-C(0)-R6, hvor hver alkyl eller alkylen eventuelt er substitueret med en eller to C1-C6-alkyl; hvor hver alkylen eventuelt er substitueret med C1-C4-alkyl hvert m er hver for sig og uafhængigt 0,1,2 eller 3; og hvert p er 0, 1, 2 eller 3.
2. Forbindelsen ifølge krav 1, hvilken forbindelse er en forbindelse med Formel la,
Formel la eller et farmaceutisk acceptabelt salt, enantiomer, stereoisomer eller tautomer deraf.
3. Forbindelsen ifølge krav 2, hvilken forbindelsen er en forbindelse med Formel Ib
Formula Ib
4. Forbindelsen ifølge krav 1, hvilken forbindelse er en forbindelse med Formel le,
Formula Ic eller et farmaceutisk acceptabelt salt, enantiomer, stereoisomer eller tautomer deraf.
5. Forbindelsen ifølge krav 4, hvilken forbindelse er en forbindelse med Formel Id
Formel Id.
6. Forbindelse ifølge krav 3 eller 5, hvor en af X1 og X2 er C1-C6-alkyl, og den anden er hydrogen.
7. Forbindelsen ifølge krav 6, hvor R1 er hydrogen eller C1-C6-alkyl.
8. Forbindelse, der er valgt fra gruppen, som består af 2-(ethylamino)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl )oxy)pyrid in-2-yl)pyrim idin-4(3H )-on, 2-(dimethylamino)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl )oxy)pyrid in-2-yl)pyrim idin-4(3H )-on, 2-(isopropylamino)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl )oxy)pyrid in-2-yl)pyrim idin-4(3H )-on, 2-(ethylamino)-5-(6-methyl-5-((6,-methyl-[2,3'-bipyridin]-4yl)oxy)pyridin-2- yl)pyrimidin-4(3H)-on, 2-(ethylamino)-5-(6-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl )oxy)pyrid in-2-yl)pyrim idin-4(3H )-on, 2-((2-methoxyethyl)amino)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, 5-(6-methyl-5-((2-(1-methyl-IH-pyrazol-4-yl)pyridin-4yl)oxy)pyridin-2-yl)-2- (methylamino)pyrimidin-4(3H)-on, 2-(ethylamino)-5-(5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, 5-(6-methyl-5-((2-( 1 -methyl-1 H-pyrazol-4-yl )pyrid in-4-yl)oxy)pyrid in-2-yl )-2-(pyrrolidin-l-yl)pyrimidin-4(3H)-on, 2-sopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, 4- ((6-(2-(isopropylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yl)oxy)-N-methylpicolinamid, 5- (6-methyl-5-((2-( 1 -methyl-1 H-pyrazol-4-yl )pyrid in-4-yl )oxy)pyrid in-2-yl )-2-morpholinopyrimidin-4(3H)-on, 5-(6-methyl-5-((2-( 1 -methyl-1 H-pyrazol-4-yl )pyrid in-4-yl )oxy)pyrid in-2-yl )-2-(piperidin-1-yl)pyrimidin-4(3H)-on, 2-(cyclopropylamino)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl )oxy)pyrid in-2-yl )pyrim idin-4(3H)-on, 2- (cyclopentylamino)-5-(6-methyl-5-((2-(1 -methyl-1 H-pyrazol-4-yl)pyridin4yl)oxy)pyndin-2-yl)pynmidin-4(3H)-on, 3- methyl-5-(6-methyl-5-((2-(1 -methyl-1 H-pyrazol-4-yl)pyndin-4yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4(3H)-on, 2-(cyclopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, 2-(isopropylamino)-5-(4-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, N-(4-((6-(2-(isopropylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-methylpyridin-3- yl)oxy)pyridin-2-yl)acetamid, 5-(4-methyl-5-((2-(1 -methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl )-2-(pyrrolidin-1 -yl)pyrimidin-4(3H)-on, 5-(5-((2-(1-ethyl-IH-pyrazol-4-yl)pyridin-4yl)oxy)-6-methylpyridin-2-yl)-2-isopropylamino)pyrimidin-4(3H)-on, (R)-2-((1 -methoxypropan-2-yl)amino)-5-(6-methyl-5-((2-(1 -methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, (R) -2-(2-(methoxymethyl)pyrrolidin-l-yl)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol- 4- yl)pyndin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, (S) -2-(3-(dimethylamino)pyrrolidin-1 -yl)-5-(6-methyl-5-((2-(1 -methyl-1 H-pyrazol- 4- yl)pyridin-4-yl)oxy)pyridin-2yl)pyrimidin-4(3H)-on, 2-(ethylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, 2-((2-methoxyethyl)amino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl )pyridin4-yl)oxy)pyrid in-2-yl)pyrim id in-4(3H )-on, 5- (6-methyl-5-((2-(1 -methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4(3H)-on, 2-(tert-butylamino)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on, 5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl )-2-(neopentylamino)pyrimidin-4(3H)-on og 2-(3,3-d ifluoropyrrolidin-1 -yl)-5-(6-methyl-5-((2-(1 -methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on.
9. Forbindelsen 2-(ethylamino)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)-pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on.
10. Forbindelsen 2-(isopropylamino)-5-(6-methyl-5-((2-(1-methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on.
11. Forbindelsen 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1 -methyl-1 H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-on.
12. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1-11 og en farmaceutisk acceptabel bærer.
13. Sammensætningen ifølge krav 12, der yderligere omfatter et additiv, som er valgt blandt adjuvanser, excipienser, fortyndingsmidler eller stabilisatorer.
14. Forbindelse ifølge et hvilket som helst af kravene 1-11 eller et farmaceutisk acceptabelt salt deraf til anvendelse i behandling af cancer, gastrointestinale stromale tumorer, hyperproliferative sygdomme, metaboliske sygdomme, neurodegenerative sygdomme, faste tumorer, melanomer, glioblastomer, ovariecancer, pancreascancer, prostatacancer, lungecancer, brystcancer, nyrecancer, levercancer, osteosarkom, multiple myelomer, cervikale carcinomer, metastaser af primære tumorsteder, cancer, der er metastatisk i knogler, papillær thyroid carcinom, ikke-småcellet lungecancer, colon cancer, reumatoid arthritis, slidgigt, multipel sklerose, autoimmun nephritis, lupus, Crohns sygdom, astma, kronisk obstruktiv lungesygdom, osteoporose, mastocytose eller mastcellelukæmi.
15. Forbindelse ifølge et hvilket som helst af kravene 1-11 eller et farmaceutisk acceptabelt salt deraf til anvendelse ved behandling af glioblastomer, brystcancer, pancreascancer, metastaser af primære tumorsteder, eller cancere, der er metastaserende i knogler.
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