DK3083620T3 - Modulatorer af gpr6 på basis af tetrahydropyridopyraziner - Google Patents

Modulatorer af gpr6 på basis af tetrahydropyridopyraziner Download PDF

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DK3083620T3
DK3083620T3 DK14833425.3T DK14833425T DK3083620T3 DK 3083620 T3 DK3083620 T3 DK 3083620T3 DK 14833425 T DK14833425 T DK 14833425T DK 3083620 T3 DK3083620 T3 DK 3083620T3
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piperidin
pyrazin
difluorophenoxy
dihydropyrido
isopropylamino
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Jason Brown
Stephen Hitchcock
Maria Hopkins
Shota Kikuchi
Holger Monenschein
Holly Reichard
Kristin Schleicher
Hukai Sun
Todd Macklin
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Takeda Pharmaceuticals Co
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Claims (16)

1. Forbindelse med formlen I
eller et farmaceutisk acceptabelt salt deraf, hvor Ri er valgt fra den gruppe, der består af: C3-8-cycloalkyl, der eventuelt kan være substitueret med 1 til 3 substituenter, som uafhængigt er valgt fra den gruppe, der består af: Ci-4-alkoxy, halogen, hydroxy og Ci-4-alkyl, der eventuelt kan være substitueret med Ci-4-alkoxy, halogen og hydroxy C3-6-heterocyclyl, der eventuelt kan være substitueret på carbonatomerne i ringen med 1 til 4 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, halogen og hydroxyl, og som eventuelt kan være substitueret på et hvilket som helst nitrogenatom i ringen med en Ci-4-alkyl C6-io-aryl, der eventuelt kan være substitueret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, cyano, halogen, hydroxy, amino, trifluormethyl og trifluormethoxy, og Ci-io-heteroaryl, der eventuelt kan være substitueret med 1 til 3 substituenter på carbonatom, som uafhængigt er valgt fra den gruppe, der består af amino, Ci-8-alkylamino, Ci-9-amid, C1-4-alkyl, Ci-4-alkoxy, cyano, halogen, hydroxyl, oxo, trifluormethyl og trifluormethoxy, og som eventuelt kan være substitueret på et nitrogenatom i ringen med en Ci-4-alkyl Xi er N, og X2 er CH, eller Xi er CH, og X2 er N, eller Xi er N, og X2 er N når Xi er N, er Z valgt fra den gruppe, der består af C1-6-alkylen, Ci-6-haloalkylen, -C (0) - og -S(0)2- når Xi er CH, er Z valgt fra den gruppe, der består af C1-6-alkylen, Ci-6-haloalkylen, -0-, -C(0)-, NH-, -S-, -S (0) - og - S(0)2-
q er O, 1, eller 2 s er O, 1, eller 2 R.2 er -OR5 eller -NR6R7 R3, taget hver gang, uafhængigt er valgt fra den gruppe, der består af: Ci-6-alkyl, C3-8-cycloalkyl og tritluormethyl p er 0, 1, eller 2 R4, taget hver gang, uafhængigt er valgt fra den gruppe, der består af Ci-6-alkyl, hydroxy og halogen r er 0 eller 1 Rs er valgt fra den gruppe, der består af Ci-6-alkyl og C3-8-cycloalkyl R6 er valgt fra den gruppe, der består af hydrogen og Ci-6-alkyl R7 er valgt fra den gruppe, der består af: Ci-6-alkyl, der eventuelt kan være substitueret med 1 til 7 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkoxy, Ci-9-amid, amino, Ci-s-alkylamino, C1-5-oxycarbonyl, cyano, C3-8-cycloalkyl, halogen, hydroxy og C3-6-heterocyclyl, der eventuelt kan være substitueret på et hvilket som helst nitrogenatom i ringen med Ci-4-alkyl-; C1-10-heteroaryl; og phenyl, der eventuelt kan være substituteret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, Ci-9-amid, amino, Ci-s-alkylamino, Ci-5-oxycarbonyl, cyano, halogen, hydroxyl, nitro, Ci-s-sulfonyl og trifluormethyl C3-8-cycloalkyl C6-io-aryl, der eventuelt kan være substitueret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, cyano, halogen, hydroxy, amino, trifluormethyl og trifluormethoxy Ci-10-heteroaryl, der eventuelt kan være substitueret med 1 til 3 substituenter på carbonatom, som uafhængigt er valgt fra den gruppe, der består af amino, Ci-s-alkylamino, Ci-9-amid, C1-4-alkyl, Ci-4-alkoxy, cyano, halogen, hydroxyl, oxo, trifluormethyl og trifluormethoxy, og som eventuelt kan være substitueret på et nitrogenatom i ringen med en Ci-4-alkyl C3-6-heterocyclyl, der eventuelt kan være substitueret på carbonatomerne i ringen med 1 til 4 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, halogen og hydroxyl, og som eventuelt kan være substitueret på et hvilket som helst ringnitrogenatom med en Ci-4-alkyl X3 er valgt fra den gruppe, der består af CH2 og CHR4, og X4 er NR8, eller X3 er NR8 ,og X4 er valgt fra den gruppe, der består af CH2 og CHR4 R8 er valgt fra den gruppe, der består af Ci-6-alkyl, C1-6 -haloalkyl, C3-8-cycloalkyl, -S(O)2~R9, -C(0)-Rio, -C (0)-N (Ru) (R12) , og -C (0) -OR13 R9 er valgt fra den gruppe, der består af Ci-6-alkyl, C3-8-cycloalkyl og phenyl, der eventuelt kan være substitueret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, Ci-9-amid, amino, Ci-8-alkylamino, Ci-5-oxycarbonyl, cyano, halogen, hydroxyl, nitro, Ci-8-sulf onyl og trif luormethyl Rio er valgt fra den gruppe, der består af: hydrogen Ci-6-alkyl, der eventuelt kan være substitueret med 1 til 7 substituenter, som uafhængigt er valgt fra den gruppe, der består af: Ci-4-alkoxy, Ci-9-amid, amino, Ci-8-alkylamino, C1-5-oxycarbonyl, cyano, C3-8-cycloalkyl, halogen, hydroxy og C3-6-heterocyclyl, som eventuelt kan være substitueret på et hvilket som helst nitrogenatom i ringen med Ci-4-alkyl, C1-10 -heteroaryl og phenyl, der eventuelt kan være substitueret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af: Ci-4-alkyl, Ci-4-alkoxy, Ci-9-amid, amino, Ci-8-alkylamino, Ci-5-oxycarbonyl, cyano, halogen, hydroxyl, nitro, Ci-8-sulf onyl og trif luormethyl C3-8-cycloalkyl C6-io-aryl, der eventuelt kan være substitueret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, cyano, halogen, hydroxy, amino, trifluormethyl og trifluormethoxy Ci-10-heteroaryl, der eventuelt kan være substitueret med 1 til 3 substituenter på carbonatom, som uafhængigt er valgt fra den gruppe, der består af amino, Ci-8-alkylamino, Ci-9-amid, C1-4-alkyl, Ci-4-alkoxy, cyano, halogen, hydroxyl, oxo, trifluormethyl og trifluormethoxy, og som eventuelt kan være substitueret på et nitrogenatom i ringen med en Ci-4-alkyl C3-6-heterocyclyl, der eventuelt kan være substitueret på carbonatomerne i ringen med 1 til 4 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, halogen og hydroxy, og som eventuelt kan være substitueret på et hvilket som helst nitrogenatom i ringen med en Ci-4-alkyl Ru er valgt fra den gruppe, der består af hydrogen og C1-6-alkyl R12 er valgt fra den gruppe, der består af hydrogen, Ci-6-alkyl og C3-8-cycloalkyl, eller Ru og R12, der er taget sammen med det nitrogenatom, som de er bundet til, danner et 4- til 7-leddet mættet ring, som eventuelt kan have 1 ekstra heteroatom i ringen, som er valgt fra gruppen N, 0 og S, hvor det 4- til 7-leddede mættede ring eventuelt kan være substituteret på et hvilket som helst af carbonatomerne i ringen med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af: cyano halogen hydroxy amino C3-6-heterocyclyl, der eventuelt kan være substitueret på carbonatomerne i ringen med 1 til 4 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, halogen og hydroxy, og som eventuelt kan være substitueret på et hvilket som helst nitrogenatom i ringen med en Ci-4-alkyl Ci-9-amid Ci-6-alkyl, der eventuelt kan være substitueret med 1 til 7 substituenter, som uafhængigt er valgt fra den gruppe, der består af: Ci-4-alkoxy, Ci-9-amid, amino, Ci-8-alkylamino, C1-5-oxycarbonyl, cyano, C3-8-cycloalkyl, halogen, hydroxy og C3-6-heterocyclyl, der eventuelt kan være substitueret på et hvilket som helst nitrogenatom i ringen med Ci-4-alkyl-; C1-10 -heteroaryl og phenyl, der eventuelt kan være substituteret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, Ci-9-amid, amino, C1-8-alkylamino, Ci-5-oxycarbonyl, cyano, halogen, hydroxyl, nitro, Ci-s-sulf onyl og trif luormethyl og Ci-4-alkoxy, og hvor den 4- til 7-leddede mættede ring er substitueret på et hvilken som helst ekstra nitrogenatom i ringen med en substituent, som er valgt fra den gruppe, der består af: hydrogen, C3-8-cycloalkyl og Ci-6-alkyl, der eventuelt kan være substituteret med 1 til 7-substituenter, som uafhængigt er valgt fra den gruppe, der består af: Ci-4-alkoxy, Ci-9-amid, amino, Ci-s-alkylamino, Ci-5-oxycarbonyl, cyano, C3-8-cycloalkyl, halogen, hydroxy og C3-6-heterocyclyl, der eventuelt kan være substitueret på et hvilket som helst nitrogenatom i ringen med Ci-4-alkyl-; C1-10 -heteroaryl og phenyl, der eventuelt kan være substituteret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, Ci- 9- amid, amino, Ci-s-alkylamino, Ci-5-oxycarbonyl, cyano, halogen, hydroxyl, nitro, Ci-s-sulf onyl og trif luormethyl, og R13 er valgt fra den gruppe, der består af Ci-6-alkyl og C3-8-cycloalkyl.
2. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge krav 1, hvor Xi er CH, og X2 er N.
3. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge krav 1, hvor Xi er N, og X2 er N.
4. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge krav 3, hvor X3 er valgt fra den gruppe, der består af CH2 og CHR4, og X4 er NRs.
5. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 4, hvor Ri er C6- 10- aryl, der eventuelt kan være substitueret med 1 til 5 substituenter, som uafhængigt er valgt fra den gruppe, der består af Ci-4-alkyl, Ci-4-alkoxy, cyano, halogen, hydroxy, amino, trifluormethyl og trifluormethoxy.
6. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 5, hvor Z er Ci-6~ alkylen.
7. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 5, hvor Z er -0-.
8. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 5, hvor Z er -C(0)
9. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 8, hvor R2 er -NR6R7 ·
10. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge krav 1, som er valgt fra den gruppe, der består af: cyclopropyl(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)- yl)methanon 1- (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethan-l-on 2- (4-(2,4-difluorphenoxy)piperidin-l-yl)-N-isopropyl-6- (methylsultonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin 2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)-N-(2-methoxyethyl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 2- (4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)- 7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(tetrahydrofuran-2-yl)methanon 3- (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-3-oxopropannitril 4- ((1-(6-acetyl-3-(isopropylamino)-5,6,7,8- tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorbenzonitril 1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-Ί, 8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxypropan-l-on cyclopropyl(3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanon 1- (3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethan-l-on 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-N-isopropyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 2- (4-(4-cyano-2-fluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 3- fluor-4-((1-(3-(isopropylamino)-6-methyl-5,6,7,8- tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4- yl)oxy)benzonitril (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)- 7.8- dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(morpholino)methanon 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2-(isopropylamino)-N-(2-methoxyethyl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2-(isopropylamino)- 7.8- dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(tetrahydrofuran-2-yl)methanon 3- (3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-3-oxopropannitril (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)- 7.8- dihydropyrido[3,4-b]pyrazin-6(5H)-yl) (isoxazol-5- yl)methanon 4- ((1-(6-acetyl-2-(isopropylamino)-5,6,7,8- tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorbenzonitril 4-((1-(6-(cyclopropancarbonyl)-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorbenzonitril 2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-N-isopropyl-6-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3- amin 2- (4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)-6-(methyl-L-prolyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)- 7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)(pyrrolidin-1-yl)methanon 1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluorethan-l-on 3- fluor-4-((1-(2-(isopropylamino)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4- yl)oxy)benzonitril 3-fluor-4-((1-(2-(isopropylamino)-6-(2-methoxyacetyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitril 3-fluor-4-((1-(2-(isopropylamino)-6-methyl-5,6,7,8- tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4- yl)oxy)benzonitril 3-(4-(4-cyano-2-fluorphenoxy)piperidin-l-yl)-2- (isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 1-(3-(2,2-difluorethylamino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-5-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)ethanon N-(2,2-difluorethyl)-2-(4-(2,4-difluorphenoxy)piperidin-l-yl)- 5-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4- b]pyrazin-3-amin 1-(3-(2,2-difluorethylamino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-5-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2-methoxyethanon 1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-5-methyl-7, 8- dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon N-(2,2-difluorethyl)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)- 5-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-5-methyl-7,8-dihydropyrido[3,4- b]pyrazin-6(5H)-yl)-2-methoxyethanon 1-(3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2- (isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-N-isopropyl-5-methyl- 6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 1-(3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2- (isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methoxyethanon cyclopropyl(3-(2,2-difluorethylamino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanon cyclopropyl(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanon cyclopropyl(3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2-(isopropylamino)-5-methyl-7 , 8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)methanon 1-(3-(2,2-difluorethylamino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-5-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2,2-difluorethanon 1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-5-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2,2-difluorethanon 1-(3-(4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 1- (2-(4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 2- (4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-3- (isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 1- (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 2- (2,2-difluorethylamino)-3-(4-(2,4-difluorphenoxy)piperidin- 1-yl)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 1-(2-((2,2-difluorethyl)amino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4- b]pyrazin-6(5H)-yl)-2-methoxyethanon (R)-1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4- b]pyrazin-6(5H)-yl)-2-methoxypropan-l-on 1- (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 1- (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2,2-difluorethanon 2- (4-(2,4-difluorphenoxy)piperidin-l-yl)-N-isopropyl-5-methyl- 6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin 2- (4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)-N,N,5-trimethy1-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 3- (4-(2,4-difluorphenoxy)piperidin-l-yl)-2-(isopropylamino)- N,N,5-trimethy1-7 , 8-dihydropyrido[3,4-b]pyrazin-6 (5H)- carboxamid 2- (2,2-difluorethylamino)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl) -N,N,5-trimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 3- (4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 1-(3-((2,2-difluorethyl)amino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)ethan-1-on N-(2,2-difluorethyl)-2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin methyl 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxylat 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-6-(2-fluorethyl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin (R) -1-(2-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)- yl)ethan-l-on 1-(3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon N-cyclopropyl-2-(4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin N-cyclopropyl-3-(4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin N-cyclopropyl-3-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl) -6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin (S) -N-cyclopropyl-3-(4- ((2,4 — difluorphenyl)fluormethyl)piperidin-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin (R)-N-cyclopropyl-3- (4-((2,4 — difluorphenyl)fluormethyl)piperidin-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 3-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 1- (3-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)- yl)ethanon 3-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-2-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 3-(4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-2- (isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 2- (4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin 2-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-N-isopropyl-6-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin 1-(2-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 2- (4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-3- (isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid (5-chlor-2-fluorphenyl)(1-(2-(isopropylamino)-6-methyl- 5.6.7.8- tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-l-yl )methanon 1- (3- (4- (5-chlor-2-fluorbenzoyl)piperidin-l-yl)-2- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 3- (4-(5-chlor-2-fluorbenzoyl)piperidin-l-yl)-2- (isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-N-isopropyl-6-methyl- 5.6.7.8- tetrahydropyrido[3,4-b]pyrazin-2-amin 1- (3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 2- (4-(2,4-difluorphenoxy)piperidin-l-yl)-N-isopropyl-6-methyl- 5.6.7.8- tetrahydropyrido[3,4-b]pyrazin-3-amin 2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid (5-chlor-2-fluorphenyl)(1-(3-(isopropylamino)-6-methyl- 5.6.7.8- tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-l-yl )methanon 1- (2- (4- (5-chlor-2-fluorbenzoyl)piperidin-l-yl) -3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 2- (4-(5-chlor-2-fluorbenzoyl)piperidin-l-yl)-3- (isopropylamino)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 1- (2-(tert-butylamino)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl) -7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 2- (tert-butylamino)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 1-(2-((2,2-difluorethyl)amino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4- b]pyrazin-6(5H)-yl)ethanon 1- (2-(cyclobutylamin)-3-(4-(2-fluor-4- methoxyphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)ethanon 2- (cyclobutylamino)-3-(4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl )-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 1-(3-(cyclobutylamin)-2-(4-(2-fluor-4- methoxyphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4- b]pyrazin-6(5H)-yl)ethanon 3- (cyclobutylamino)-2-(4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl )-N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid 3-(2,2-difluorethylamino)-2-(4-(2,4-difluorphenoxy)piperidin-l-yl) -N,N-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid N-(2,2-difluorethyl)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2,2-difluorethanon (S) -1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2-methoxypropan-l-on 1-(3-(2,2-difluorethylamino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2,2-difluorethanon 1-(3-(2,2-difluorethylamino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2,2-difluorethanon (S)-1-(3-(2,2-difluorethylamino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2-methoxypropan-l-on (R)-1-(3-(2,2-difluorethylamino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2-methoxypropan-l-on 1-(2-(cyclopropylamino)-3-(4-(2,4-difluorphenoxy)piperidin-1- yl)-5-methyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 2-(cyclopropylamino)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-N,N,5-trimethy1-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid N-cyclopropyl-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-5,6-dimethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 1- (2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)ethanon 2- (2,2-difluorethylamino)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl) -N,N,7-trimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carboxamid N-(2,2-difluorethyl)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin 1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7-methyl-7,8-dihydropyrido[4,3— b]pyrazin-6(5H)-yl)-2,2-difluorethanon 1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2-methoxyethanon N-(2,2-difluorethyl)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)- 7-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin (2 S)-1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2-methoxypropan-l-on (2R)-1-(2-(2,2-difluorethylamino)-3-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)-2-methoxypropan-l-on cyclopropyl(2-(2,2-difluorethylamino)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-7-methyl-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)methanon 6-(2,2-difluorethyl)-3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amin (S)-1-(2-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on (S)-2-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carbaldehyd (R) -2-(4-((2,4-difluorphenyl)fluormethyl)piperidin-l-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carbaldehyd 1- (3- (4- (3-fluorphenylsulfonyl)piperidin-l-yl)-2- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 1-(2-(isopropylamino)-3-(4-(3-methoxyphenylsulfonyl)piperidin-l-yl) -7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 1-(3-(4-((2-fluorphenyl)sulfonyl)piperidin-l-yl)-2-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-ion 1-(3-(4-(4-fluorphenylsulfonyl)piperidin-l-yl)-2- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon 3-(4-(2,4-difluorphenoxy)piperidin-l-yl)-2-(isopropylamino)- 7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-carbaldehyd 1-(3-(4-(2-fluor-4-methoxyphenylsulfonyl)piperidin-l-yl)-2-(isopropylamino)-7,8-dihydropyrido[4,3-b]pyrazin-6(5H)-yl)ethanon (S) -1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-((1- methoxypropan-2-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on (R) -1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-((1- methoxypropan-2-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on 1-(3-(cyclobutylamino)-2-(4-(2,4-difluorphenoxy)piperidin-l-yl) -7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on (S) -1-(3-(sec-butylamino)-2-(4-(2,4-difluorphenoxy)piperidin-l-yl) -7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on (R)-1-(3-(sec-butylamino)-2-(4-(2,4-difluorphenoxy)piperidin-l-yl) -7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on 1- (2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)propan-1-on methyl 2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)- carboxylat 2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-6-(2-fluorethyl)-N- isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin 1-(2-(4-(2,4-difluorbenzyl)piperazin-l-yl)-3-(isopropylamino)- 7.8- dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on 1- (3-(cyclobutylamino)-2-(4-(2,4-difluorbenzyl)piperazin-l-yl) -7, 8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on 2- (4-(2,4-difluorbenzyl)piperazin-l-yl)-N-isopropyl-6- (methylsultonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin 1-(2-(4-(2,4-difluorbenzyl)piperazin-l-yl)-3-(isopropylamino)-7, 8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)propan-l-on tert-butyl 4-(6-acetyl-3-(isopropylamino)-5,6,7,8- tetrahydropyrido[3,4-b]pyrazin-2-yl)piperazin-1-carboxylat (ls,3s)-3 - ( (6-acetyl-2-(4-(2,4-difluorbenzyl)piperazin-l-yl)- 5.6.7.8- tetrahydropyrido[3,4-b]pyrazin-3- yl)amino)cyclobutylacetat 1-(2-(4-(2,4-difluorbenzyl)piperazin-l-yl)-3-(((ls,3s)-3-hydroxycyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on 1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-d3-ethan-l-on (ls,3s)-3-((6-acetyl-2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-5,6,7, 8-tetrahydropyrido[3,4-b]pyrazin-3-yl)amino)cyclobutylacetat 1-(2-(4-(2,4-difluorbenzyl)piperazin-l-yl)-3-(isopropylamino)-7, 8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-2-methylpropan-l-on 1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(((ls,3s)-3-hydroxycyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on 1-(2-(4-(2,4-difluorbenzyl)piperazin-l-yl)-3-(((lr,3r)-3-fluorcyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on 4-((4-(6-acetyl-3-(isopropylamino)-5,6,7,8- tetrahydropyrido[3,4-b]pyrazin-2-yl)piperazin-l-yl)methyl)-3-fluorbenzonitril (lr,3r)-3-((6-acetyl-2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-5,6,7, 8-tetrahydropyrido[3,4-b]pyrazin-3- yl)amino)cyclobutylacetat 1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3-(((lr,3r)-3-hydroxycyclobutyl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-l-on (S)-1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon (S)-1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-3- (tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)propan-l-on 1-(3-((3,3-difluorcyclobutyl)amino)-2-(4-(2,4- difluorphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4— b]pyrazin-6(5H)-yl)ethan-l-on N-cyclobutyl-2-(4-(2,4-difluorphenoxy)piperidin-l-yl)-6-(methylsultonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amin (R) -1-(2-(4-(2,4-difluorbenzyl)piperazin-l-yl)-3- (tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon (S) -1-(2-(4-(2,4-difluorbenzyl)piperazin-l-yl)-3- (tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon og (S)-1-(2-(4-(2,4-difluorbenzyl)piperazin-l-yl)-3- (tetrahydrofuran-3-ylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)propan-l-on.
11. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge krav 1, som er 1-(2-(4-(2,4-difluorphenoxy)piperidin-l-yl) -3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon.
12. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge krav 1, som er 1-(2-(4-(2-fluor-4- methoxyphenoxy)piperidin-l-yl)-3-(isopropylamino)-7,8- dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanon.
13. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge krav 1, som er 1-(3-(cyclobutylamino)-2-(4-(2-fluor-4-methoxyphenoxy)piperidin-l-yl)-7,8-dihydropyrido[3,4- b]pyrazin-6(5H)-yl)ethanon.
14. Farmaceutisk sammensætning, der omfatter en forbindelse eller et farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 13 og et farmaceutisk acceptabel excipiens.
15. Sammensætning eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 13 til anvendelse som lægemiddel.
16. Sammensætning eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 13 til anvendelse ved behandling af en lidelse, der er valgt blandt Parkinsons sygdom, levodopa-inducerede dyskinesier, Huntingtons sygdom, stofmisbrug, spiseforstyrrelser, kognitive lidelser, skizofreni, bipolære lidelser og depression.
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