DK2648511T3 - Pyrazolylguanidin-f1f0-atpasehæmmere og terapeutiske anvendelser deraf - Google Patents

Pyrazolylguanidin-f1f0-atpasehæmmere og terapeutiske anvendelser deraf Download PDF

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DK2648511T3
DK2648511T3 DK11846595.4T DK11846595T DK2648511T3 DK 2648511 T3 DK2648511 T3 DK 2648511T3 DK 11846595 T DK11846595 T DK 11846595T DK 2648511 T3 DK2648511 T3 DK 2648511T3
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alkyl
group
cycloalkyl
haloalkyl
halogen
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Gary D Glick
Alexander R Hurd
Clarke B Taylor
Chad A Vanhuis
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Lycera Corp
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Claims (26)

1. Forbindelse repræsenteret ved formlen I:
herunder alle stereoisomerer, geometriske isomerer og tautomerer; eller et farmaceutisk acceptabelt salt eller solvat af en hvilken som helst af de førnævnte; hvor: A1 er phenylen eller en 6-leddet heteroarylengruppe; A2 er
R1 for hver forekomst uafhængigt betegner halogen, halogenalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxy, (Ci-C6)-alkoxy, cyano, -CO2R8, -C(0)R9, -S(0)R9, -SO2R9, -SO2N(R10)(R11), -C(O)N(R10)(R11), -N(R10)(R11) eller -N(R8)C(0)(R9); R2 er hydrogen eller alkyl; R3 eraryl, aralkyl, cycloalkyl, -(C(R8)2)m-cycloalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, -(C(R8)2)m-heterocycloalkyl, alkyl, halogenalkyl, hydroxyalkyl, -(C(R8)2)m-alkoxy, -(C(R8)2)m-0-(C(R8)2)m-alkoxy eller -(C(R8)2)m-CN, hvor arylgruppen, aralkylgruppen, cycloalkylgruppen, heteroarylgruppen, heteroaralkylgruppen og heterocycloalkylgruppen hver eventuelt er substitueret med 1,2 eller 3 substituenter, som er uafhængigt valgt fra gruppen bestående af halogen, halogenalkyl, hydroxy, alkyl, cycloalkyl, hydroxyalkyl, (CrC6)-alkoxy, cyano og -(CrC6)-alkylen-C02R8; R4 er hydrogen, alkyl eller -C(0)R9; eller R3 og R4 sammen med det nitrogenatom, hvortil de er bundet, udgør en 3- til 7-leddet heterocyklisk ring, som eventuelt er substitueret med 1, 2 eller 3 substituenter, der er uafhængigt valgt fra gruppen bestående af halogen, halogenalkyl, hydroxy, al kyl, cycloalkyl og (Ci-CeJ-alkoxy; R5 er hydrogen eller alkyl; R6 er halogenalkyl; R7 er hydrogen, halogen, alkyl eller halogenalkyl; R8 for hver forekomst uafhængigt betegner hydrogen, alkyl eller cycloalkyl; eller to forekomster af R8, som er bundet til det samme carbonatom, sammen med carbonatomet udgør en mættet carbocyklisk ring; R9 for hver forekomst uafhængigt betegner al kyl eller cycloalkyl; R10 og R11 hver for hver forekomst uafhængigt betegner hydrogen, alkyl eller cycloalkyl; eller R10 og R11 sammen med det nitrogenatom, hvortil de er bundet, udgør en 3- til 7-leddet heterocyklisk ring, som eventuelt er substitueret med 1,2 eller 3 substituenter, der er uafhængigt valgt fra gruppen bestående af halogen, halogenalkyl, hydroxy, alkyl, cycloalkyl og (Ci-C6)-alkoxy; n er 0,1,2 eller 3; og m er 1,2, 3, 4 eller 5.
2. Forbindelse ifølge krav 1, hvor A1 er phenylen.
3. Forbindelse ifølge krav 1 eller 2, hvor A2 er:
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor R1 er halogen eller halogenalkyl.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor R1 er chlor, fluor eller trifluormethyl.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R2 og R4 er hydrogen.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R3 er (i) alkyl eller cycloalkyl eller (ii) (C(R8)2)m-alkoxy.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R3 er aryl eller aralkyl, som hver eventuelt er substitueret med 1,2 eller 3 substituenter, der er uafhængigt valgt fra gruppen bestående af halogen, halogenalkyl, alkyl og cycloalkyl.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R3 er phenyl, som er substitueret med 1 eller 2 substituenter, der er uafhængigt valgt fra gruppen bestående af chlor, fluor og trifluormethyl.
10. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R3 er benzyl, som er substitueret med 1 eller 2 substituenter, der er uafhængigt valgt fra gruppen bestående af chlor, fluor og trifluormethyl.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 10, hvor R6 er trifluormethyl.
12. Forbindelse ifølge et hvilket som helst af kravene 1 til 11, hvor n er 1 eller 2.
13. Forbindelse ifølge krav 1, hvor forbindelsen er repræsenteret ved formlen I-A1:
herunder alle stereoisomerer, geometriske isomerer og tautomerer; eller et farmaceutisk acceptabelt salt eller solvat af en hvilken som helst af de førnævnte; hvor: R1 og R2 hver for hver forekomst uafhængigt betegner hydrogen, chlor, fluor eller -CF3; R3 er alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl eller (Ci-C6)-alkylen-(Ci-C6)-alkoxy, hvor cycloalkylgruppen, arylgruppen, aralkylgruppen, heteroarylgruppen og heteroaralkylgruppen hver eventuelt er substitueret med 1,2 eller 3 substituenter, der er uafhængigt valgt fra gruppen bestående af halogen, halogenalkyl, hydroxy, alkyl, (Ci-C6)-alkoxy og cyano; og R4 er halogenalkyl.
14. Forbindelse ifølge krav 13, hvor R1 og R2 er chlor eller fluor.
15. Forbindelse ifølge krav 13 eller 14, hvor R3er: (i) alkyl eller cycloalkyl; (ii) (Ci-C6)-alkylen-(Ci-C6)-alkoxy eller (iii) benzyl, som er substitueret med 1 eller 2 substituenter, der er uafhængigt valgt fra gruppen bestående af chlor, fluor og trifluormethyl.
16. Forbindelse ifølge krav 13 eller 14, hvor R3 er phenyl, som er substitueret med 1 eller 2 substituenter, der er uafhængigt valgt fra gruppen bestående af chlor, fluor og trifluormethyl.
17. Forbindelse ifølge et hvilket som helst af kravene 13 til 16, hvor R4 er trifluormethyl.
18. Forbindelse, som er repræsenteret ved formlen Il-A:
herunder alle stereoisomerer, geometriske isomerer og tautomerer; eller et farmaceutisk acceptabelt salt eller solvat af en hvilken som helst af de førnævnte; hvor: A1 er phenylen eller en 6-leddet heteroarylengruppe; X er -[C(R5)2]m eller -[C(R5)2]P-C(0)-[C(R5)2]P; R1 for hver forekomst uafhængigt betegner halogen, halogenalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxy, (Ci-C6)-alkoxy, cyano, -CO2R6, -C(0)R7, -SO2R7, -S02N(R8)(R9), -C(0)N(R8)(R9), -N(R8)(R9) eller -N(R6)C(0)(R7); R2 er hydrogen eller alkyl; R3 er hydrogen, aryl, aralkyl, cycloalkyl, -(C(R6)2)m-cycloalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, -(C(R6)2)m-heterocycloalkyl, alkyl, halogenalkyl, hydroxyalkyl, -(C(R6)2)m-alkoxy, -(C(R6)2)m-0-(C(R6)2)m-alkoxy eller -(C(R6)2)m-CN, hvor arylgruppen, aralkylgruppen, cycloalkylgruppen, heteroarylgruppen, heteroaralkylgruppen og heterocycloalkylgruppen hver eventuelt er substitueret med 1,2 eller 3 substituenter, som er uafhængigt valgt fra gruppen bestående af halogen, halogenalkyl, hydroxy, alkyl, cycloalkyl, hydroxyalkyl, (Ci-Ce)-alkoxy, cyano og -(Ci-C6)-alkylen-C02R6; eller R3 og en enkelt forekomst af R5 sammen med de atomer, hvortil de er bundet, udgør en mættet heterocyklisk ring; R4 er alkyl, cycloalkyl, halogenalkyl, cyano, aryl, aralkyl, heteroaryl, heteroaralkyl, -C02R6 eller -C(0)N(R8)(R9), hvor cycloalkylgruppen, arylgruppen, aralkylgruppen, heteroarylgruppen og heteroaralkylgruppen hver eventuelt er substitueret med 1 eller 2 substituenter, som er uafhængigt valgt fra gruppen bestående af halogen, halogenalkyl, hydroxy, alkyl, hydroxyalkyl, (Ci-Ce)-alkoxy og cyano; R5 for hver forekomst uafhængigt betegner hydrogen eller alkyl; eller R3 og en enkelt forekomst af R5 sammen med de atomer, hvortil de er bundet, udgør en mættet heterocyklisk ring; R6 for hver forekomst uafhængigt betegner hydrogen, alkyl eller cycloalkyl; eller to forekomster af R6, som er bundet til det samme carbonatom, sammen med carbonatomet udgør en mættet carbocyklisk ring; R7 for hver forekomst uafhængigt betegner alkyl eller cycloalkyl; R8 og R9 hver for hver forekomst uafhængigt betegner hydrogen, alkyl eller cycloalkyl; eller R8 og R9 sammen med det nitrogenatom, hvortil de er bundet, udgør en 3- til 7-leddet heterocyklisk ring, som eventuelt er substitueret med 1,2 eller 3 substituenter, der er uafhængigt valgt fra gruppen bestående af halogen, halogenalkyl, hydroxy, alkyl, cycloalkyl og (Ci-C6)-alkoxy; n erO, 1,2 eller 3; m for hver forekomst uafhængigt betegner 1,2, 3, 4 eller 5; og p for hver forekomst uafhængigt betegner 0,1 eller 2.
19. Forbindelse ifølge krav 1 eller krav 18, hvor forbindelsen er valgt fra nedenstående liste eller et farmaceutisk acceptabelt salt deraf:
20. Forbindelse valgt fra nedenstående liste eller et farmaceutisk acceptabelt salt deraf:
21. Farmaceutisk sammensætning, som omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 20 og en farmaceutisk acceptabel bærer.
22. Farmaceutisk sammensætning ifølge krav 19 eller krav 20, hvor forbindelsen er en forbindelse ifølge krav 17.
23. Forbindelse ifølge et hvilket som helst af kravene 1 til 20 til anvendelse ved behandling af en lidelse valgt fra gruppen bestående af en lidelse i immunsystemet, en inflammatorisk lidelse, en kardiovaskulær sygdom, et myelom, et lymfom, en cancer og en bakterieinfektion.
24. Forbindelse ifølge et hvilket som helst af kravene 1 til 20 til anvendelse ved hæmning afen FiFo-ATPase.
25. Forbindelse ifølge et hvilket som helst af kravene 1 til 20 til anvendelse ved behandling af inflammatorisk tarmsygdom.
26. Forbindelse ifølge et hvilket som helst af kravene 1 til 20 til anvendelse ved behandling af psoriasis, Crohns sygdom eller colitis ulcerosa.
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