DK2139882T3 - 3-Substituerede quinolin- eller quinoxalinderivater og deres anvendelse som inhibitorer af phosphatidylinositol-3-kinase (PI3K) - Google Patents

3-Substituerede quinolin- eller quinoxalinderivater og deres anvendelse som inhibitorer af phosphatidylinositol-3-kinase (PI3K) Download PDF

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DK2139882T3
DK2139882T3 DK08742273.9T DK08742273T DK2139882T3 DK 2139882 T3 DK2139882 T3 DK 2139882T3 DK 08742273 T DK08742273 T DK 08742273T DK 2139882 T3 DK2139882 T3 DK 2139882T3
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nrara
alkyl
nra
phenyl
haloalkyl
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Timothy D Cushing
Xiaolin Hao
Xiao He
Andreas Reichelt
Robert M Rzasa
Youngsook Shin
Dawei Zhang
Yi Chen
Jennifer Seganish
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Amgen Inc
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Claims (10)

1. Forbindelse med strukturen:
eller et hvilket som helst farmaceutisk acceptabelt salt heraf, hvor: X1 er C(R9) eller N; X2 er C(R10) eller N; Y er N(R11), O eller S; n er 0, 1,2 eller 3; R1 er en direkte bundet eller oxygen-koblet mættet, delvis mættet eller umættet 5-, 6- eller 7-leddet monocyklisk ring, der indeholder 0, 1, 2, 3 eller 4 atomer valgt blandt N, O og S, men indeholder ikke mere end et O eller S, hvor de tilgængelige carbonatomer af ringen er substitueret med 0, 1 eller 2 oxo- eller thioxogrupper, hvor ringen er substitueret med 0 eller 1 R2-substituent, og ringen yderligere er substitueret med 0, 1, 2 eller 3 substituenter, der uafhængigt er valgt blandt halogen, nitro, cyano, Ci-4.al-kyl, OC-M-alkyl, OC-i-4-halogenalkyl, NHC-i-4-alkyl, N(Ci4_alkyl)Ci.4.alkyl og C-i-4-halogenalkyl; R2 er valgt blandt halogen, C-i-4.halogenalkyl, cyano, nitro, -C(=0)Ra, -C(=0)0Ra, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -0C(=0)Ra, - 0C(=0)NRaRa, -0C(=0)N(Ra)S(=0)2Ra, -C2-6-alkylNRaRa, -OC2.6-alkylOR3, -SRa, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRaRa, S(=0)2N(Ra)C(=0)Ra, -S(=0)2N(Ra)C(=0)0Ra, -S(=0)2N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Ra, -N(Ra)C(=0)0Ra, -N(Ra)C(=0)NRaRa, - N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Ra, -N(Ra)S(=0)2NRaRa, -NRaC2.6-alkylNRaRa og -NRaC2-6-alkylORa; eller R2 er valgt blandt Ci-6-alkyl, phenyl, benzyl, heteroaryl, heterocyklus, -(Ci-3alkyl)heteroaryl, -(Ci-3.al-kyl)heterocyklus, -0(C-i-3-alkyl)heteroaryl, -0(C-i-3-alkyl)heterocyklus, -NRa(C1-3.alkyl)heteroaryl, -NRa(C1-3.alkyl)heterocyklus, -(Ci.3.alkyl)phenyl, -0(C-i-3-alkyl)phenyl og -NRa(C-i-3.alkyl)phenyl, der alle er substitueret med 0, 1, 2 eller 3 substituenter valgt blandt Ci-4-halogenalkyl, OCi-4-alkyl, Br, Cl, F, I og Ci-4.alkyl; R3 er valgt blandt H, halogen, Ci-4.halogenalkyl, cyano, nitro, -C(=0)Ra, -C(=0)0Ra, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -0C(=0)Ra, - 0C(=0)NRaRa, -0C(=0)N(Ra)S(=0)2Ra, -OC2.6.alkylNRaRa, -OC2.6-alkylOR3, -SRa, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRaRa, S(=0)2N(Ra)C(=0)Ra, -S(=0)2N(Ra)C(=0)0Ra, -S(=0)2N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Ra, -N(Ra)C(=0)0Ra, -N(Ra)C(=0)NRaRa, - N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Ra, -N(Ra)S(=0)2NRaRa, -NRaC2.6.al-kylNRaRa, -NRaC2.6-alkylORa, Ci-6-alkyl, phenyl, benzyl, heteroaryl og heterocyklus, hvor C-i-6-alkyl, phenyl, benzyl, heteroaryl og heterocyklus yderligere er substitueret med 0, 1,2 eller 3 substituenter valgt blandt Ci-6-halogenalkyl, OCi-6-alkyl, Br, Cl, F, I og Ci-6 alkyl; R4 uafhængigt i hvert tilfælde er halogen, nitro, cyano, Ci-4.alkyl, OCi-4.al-kyl, OCi-4.halogenalkyl, NHCi-4-alkyl, N(Ci-4-alkyl)Ci-4.alkyl eller Ci-4.halo-genalkyl; R5 uafhængigt i hvert tilfælde er H, halogen, Ci-6 alkyl, Ci-4.halogenalkyl eller Ci-6 alkyl substitueret med 1,2 eller 3 substituenter valgt blandt halogen, cyano, OH, OCi-4.alkyl, C-i-4.alkyl, C13.halogenalkyl, OCi.4.alkyl, NH2, NHCi.4.alkyl, N(C1-4-alkyl)C1-4.alkyl; eller begge R5-grupper til sammen danner en C3-6-spi roal kyl substitueret med 0, 1, 2 eller 3 substituenter valgt blandt halogen, cyano, OH, OCi-4-alkyl, Ci-4-alkyl, C-i-3-halogenalkyl, OC-i-4-alkyl, NH2, NHC^.alkyl, ISKC^.alkyOC^.alkyl; R6 er valgt blandt H, C-i-6-halogenalkyl, Br, Cl, F, I, ORa, NRaRa, Ci-6-alkyl, phenyl, benzyl, heteroaryl og heterocyklus, hvor Ci-6-alkyl, phenyl, benzyl, heteroaryl og heterocyklus yderligere er substitueret med 0,1,2 eller 3 substituenter valgt blandt C-i-6-halogenalkyl, OC-i-6-alkyl, Br, Cl, F, I og C16-alkyl; R7 er valgt blandt H, C-i-6-halogenalkyl, Br, Cl, F, I, ORa, NRaRa, Ci-6-alkyl, phenyl, benzyl, heteroaryl og heterocyklus, hvor Ci-6-alkyl, phenyl, benzyl, heteroaryl og heterocyklus yderligere er substitueret med 0,1,2 eller 3 substituenter valgt blandt Ci-6-halogenalkyl, OCi-6 alkyl, Br, Cl, F, I og Ci-6-alkyl; R8 er valgt blandt H, halogen, Ci-4-halogenalkyl, cyano, nitro, -C(=0)Ra, -C(=0)0Ra, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -0C(=0)Ra, - 0C(=0)NRaRa, -0C(=0)N(Ra)S(=0)2Ra, -OC2.6-alkylNRaRa, -OC2.6- alkylOR3, -SRa, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRaRa, S(=0)2N(Ra)C(=0)Ra, -S(=0)2N(Ra)C(=0)0Ra, -S(=0)2N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Ra, -N(Ra)C(=0)0Ra, -N(Ra)C(=0)NRaRa, - N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Ra, -N(Ra)S(=0)2NRaRa, -NRaC2.6-al-kylNRaRa, -NRaC2.6-alkylORa, Ci-6-alkyl, phenyl, benzyl, heteroaryl og heterocyklus, hvor Ci-e-alkyl, phenyl, benzyl, heteroaryl og heterocyklus yderligere er substitueret med 0, 1,2 eller 3 substituenter valgt blandt Ci-6-halogenalkyl, OC-i-6-alkyl, Br, Cl, F, I og C-i-6-alkyl; R9 er valgt blandt H, halogen, Ci-4.halogenalkyl, cyano, nitro, -C(=0)Ra, -C(=0)0Ra, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -0C(=0)Ra, - 0C(=0)NRaRa, -0C(=0)N(Ra)S(=0)2Ra, -OC2.6-alkylNRaRa, -OC2.6- alkylOR3, -SRa, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRaRa, S(=0)2N(Ra)C(=0)Ra, -S(=0)2N(Ra)C(=0)0Ra, -S(=0)2N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Ra, -N(Ra)C(=0)0Ra, -N(Ra)C(=0)NRaRa, - N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Ra, -N(Ra)S(=0)2NRaRa, -NRaC2.6-al-kylNRaRa, -NRaC2-6-alkylORa, C1-6 alkyl, phenyl, benzyl, heteroaryl og he-terocyklus, hvor Ci-6alkyl, phenyl, benzyl, heteroaryl og heterocyklus yderligere er substitueret med 0,1,2 eller 3 substituenter valgt blandt halogen, C-i-4-halogenalkyl, cyano, nitro, -C(=0)Ra, -C(=0)0Ra, - C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -0C(=0)Ra, -0C(=0)NRaRa, -0C(=0)N(Ra)S(=0)2Ra, -OC2.6-alkylNRaRa, -OC2.6-alkylORa, -SRa, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRaRa, -S(=0)2N(Ra)C(=0)Ra, S(=0)2N(Ra)C(=0)0Ra, -S(=0)2N(Ra)C(=0)NRaRa, -NRaRa, N(Ra)C(=0)Ra, -N(Ra)C(=0)0Ra, -N(Ra)C(=0)NRaRa, N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Ra, -N(Ra)S(=0)2NRaRa, -NRaC2.6-al-kylNRaRa, -NRaC2-6-alkylORa; eller R9 er en mættet, delvis mættet eller umættet 5-, 6- eller 7-leddet monocyklisk ring, der indeholder 0, 1, 2, 3 eller 4 atomer valgt blandt N, O og S, men indeholder ikke mere end et O eller S, hvor de tilgængelige carbonatomer af ringen er substitueret med 0, 1 eller 2 oxo- eller thioxogrupper, hvor ringen er substitueret med 0, 1, 2, 3 eller 4 substituenter valgt blandt halogen, Ci-4-halogenalkyl, cyano, nitro, -C(=0)Ra, -C(=0)0Ra, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -0C(=0)Ra, -0C(=0)NRaRa, -0C(=0)N(Ra)S(=0)2Ra, -OC2.6-alkylNRaRa, -OC2-6-alkylORa, -SRa, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRaRa, - S(=0)2N(Ra)C(=0)Ra, -S(=0)2N(Ra)C(=0)0Ra, -S(=0)2N(Ra)C(=0)NRaRa, -NRaRa, -N(RaC(=0)Ra, -N(Ra)C(=0)0Ra, -N(Ra)C(=0)NRaRa, - N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Ra, -N(Ra)S(=0)2NRaRa, -NRaC2.6-al-kylNRaRa og -NRaC2.6-alkylORa; R10 er H, Ci-3.alkyl, C-i-3-halogenalkyl, cyano, nitro, C02Ra, C(=0)NRaRa, -C(=NRa)NRaRa, -S(=0)2N(Ra)C(=0)Ra, -S(=0)2N(Ra)C(=0)0Ra, - S(=0)2N(Ra)C(=0)NRaRa, S(=0)Rb, S(=0)2Rb eller S(=0)2NRaRa; R11 er H eller Ci-4.alkyl; Ra uafhængigt i hvert tilfælde er H eller Rb; og Rb uafhængigt i hvert tilfælde er phenyl, benzyl eller Ci-6-alkyl, hvor phenyl, benzyl og Ci-6 alkyl er substitueret med 0, 1, 2 eller 3 substituenter valgt blandt halogen, Ci-4alkyl, Ci-3-halogenalkyl, -OCi-4.alkyl, -NH2, -NHC-M-alkyl, -N(C1 -4-alkyl)C1 -4-alkyl; og hvor "Ca-p-alkyl" betyder en alkylgruppe, der omfatter et minimum af a- og et maksimum af β-carbonatomer i et forgrenet, cyklisk eller lineært forhold eller en hvilken som helst kombination af de tre, hvor α og β repræsenterer hele tal, og hvor alkylgruppen også kan indeholde en eller to dobbelteller tripelbindinger.
2. Forbindelse ifølge krav 1 med strukturen:
3. Forbindelse ifølge krav 1 med strukturen:
4. Forbindelse ifølge krav 1 med strukturen:
5. Forbindelse ifølge krav 1, hvor R3 er F, Cl eller Br; og n er 0.
6. Forbindelse ifølge krav 1, hvor R1 er phenyl substitueret med 0 eller 1 R2-substituenter, og phenyl yderligere er substitueret med 0, 1, 2 eller 3 substituen-ter, der uafhængigt er valgt blandt halogen, nitro, cyano, Ci-4-alkyl, OCi-4-alkyl, OCi-4.halogenalkyl, NHCi-4-alkyl, N(Ci4-alkyl)Ci-4.alkyl og Ci-4.halogenalkyl.
7. Forbindelse ifølge krav 1, hvor R1 er en direkte bundet eller oxygen-koblet mættet, delvis mættet eller umættet 5-, 6- eller 7-leddet monocyklisk ring, der indeholder 1, 2, 3 eller 4 atomer valgt blandt N, O og S, men ikke indeholder mere end et O eller S, hvor de tilgængelige carbonatomer af ringen er substitueret med 0, 1 eller 2 oxo- eller thioxogrupper, hvor ringen er substitueret med 0 eller 1 R2-substituent, og ringen yderligere er substitueret med 0, 1, 2 eller 3 substituenter, der uafhængigt er valgt blandt halogen, nitro, cyano, Ci-4.alkyl, OCi-4.alkyl, OCi-4.halogenalkyl, NHCi-4.alkyl, N(Ci-4-alkyl)Ci-4.alkyl og Ci-4.halo-genalkyl.
8. Forbindelse ifølge krav 1 til anvendelse ved behandling af rheumatoid arthritis, spondylitis ankylopoetica, osteoarthritis, psoriatisk arthritis, psoriasis, inflammatoriske sygdomme og autoimmunsygdomme, inflammatoriske tarmlidelser, inflammatoriske øjenlidelser, inflammatoriske eller ustabile blærelidelser, hudsygdomme med inflammatoriske komponenter, kroniske inflammatoriske til stande, autoimmunsygdomme, systemisk lupus erythematosus (SLE), myesthe-nia gravis, rheumatoid arthritis, akut dissemineret encephalomyelitis, idiopatisk thrombocytopenisk purpura, multipel sklerose, Sjøgrens syndrom og autoimmun hæmolytisk anæmi, allergisk tilstande og hypersensitivitet.
9. Forbindelse ifølge krav 1 til anvendelse ved behandling af cancer, som er medieret af, afhængig af eller associeret med p110δ-aktivitet.
10. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge krav 1 og en farmaceutisk acceptabel diluent eller bærer.
DK08742273.9T 2007-03-23 2008-03-24 3-Substituerede quinolin- eller quinoxalinderivater og deres anvendelse som inhibitorer af phosphatidylinositol-3-kinase (PI3K) DK2139882T3 (da)

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