Inhibitors of PDE6Delta for use in the prevention and/or treatment of epilepsy and/or neurodegenerative disorders

12178,805

16/612225

May 11, 2018

The present provides compounds and methods for preventing and/or treating epilepsy and/or neurodegenerative disorders. More particularly, the invention provides inhibitors of PDE6δ for use in the prevention and/or treatment of neurodegenerative disorders and/or epilepsy.

ReMYND N.V. (Leuven, BE); Katholieke Universiteit Leuven (Leuven, BE)

ReMYND N.V. (Leuven, BE), Katholieke Universiteit Leuven (Leuven, BE)

1. A method for treating epilepsy in a subject suffering from epilepsy comprising, administering to said subject in need thereof, a therapeutically effective amount of an inhibitor of PDE6δ, wherein said inhibitor of PDE6δ is a compound of formula (AA1); wherein the compound of formula (AA1) has the following structure: [chemical expression included] wherein, each dotted line individually represents an optional double bond, wherein maximally two dotted lines selected from the five dotted lines are a double bond; E 1 is independently selected from CR 1 and N; E 2 is independently selected from NR 2 and O; E 3 is independently selected from CR 3 and N; R a is hydrogen and R b is hydrogen; or R a and R b are taken together to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom; Q is independently selected from NR b —C(O); C(O); and C(O) NH; each R 1 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen; halogen; —OH; —OR 10 ; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 12 R 13 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 10 ; NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; —C(O)R 11 ; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; and heterocycle-alkynylene; wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatoms being selected from the atoms O, S and N; wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; R 2 is selected from hydrogen; alkyl; alkenyl; and alkynyl; n is selected from 0; 1 and 2; L is independently selected from being not present; —O—; —NH—; —NR 10 —; C 1-6 alkylene; C 1-6 alkenylene; and C 1-6 alkynylene; wherein each of said C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene optionally includes one or more heteroatoms, said heteroatoms being selected from the heteroatoms consisting of O, S and N, and wherein each of said C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene, is unsubstituted or substituted; wherein a carbon atom or heteroatom of said C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S—O or S(O) 2 ; B represents a cyclic structure selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; and heterocycle; m is selected from 0; 1; 2; 3; 4 and 5; R 8 is independently selected from hydrogen; halogen; alkyl; alkenyl; alkynyl; —OH; —OR 10 ; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 12 R 13 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; and —C(O)R 11 ; wherein said alkyl, alkenyl and alkynyl optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms O, S and N; wherein said alkyl, alkenyl and alkynyl can be unsubstituted or substituted with Z; wherein a carbon atom or heteroatom of said alkyl, alkenyl and alkynyl, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; each Z is independently selected from halogen; —OH; —OR 10 ; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 12 R 13 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 10 ; NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; and —C(O)R 11 ; each Z 1 is independently selected from hydrogen; alkyl; and Z; each R 10 is independently selected from alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene; wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl (ene), alkenyl (ene) or alkynyl (ene) moiety, said heteroatom selected from O, S and N; wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; each R 101 is independently selected from hydrogen and R 10 ; each R 11 is independently selected from hydroxyl; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene; wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl (ene), alkenyl (ene) and alkynyl (ene) moiety, said heteroatom selected from O, S and N; wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; each R 12 and R 13 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene; wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl (ene), alkenyl (ene) or alkynyl (ene) moiety, said heteroatom selected from O, S and N; wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; wherein R 12 and R 13 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted and each of X, Y, T, W and V is independently selected from —CZ 1 H—; —CZ 1 —; —C—; —N—; NR 101 ; —O—; —S—; or —CO—; and form with the dotted lines one of the cycles having one of the structural formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIa), (XIIIa), (XIVa), (XVa), (XVIa), (XVIIa), (XVIIIa), (XIXa), (XXa), (XXIa), (XXIIa), (XXIIIa) or (XXIVa) [chemical expression included] [chemical expression included] wherein the left side of the formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIa), (XIIIa), (XIVa), (XVa), (XVIa), (XVIIa), (XVIIIa), (XIXa), (XXa), (XXIa), (XXIIa), (XXIIIa), (XXIVa) is attached to Q and the right side thereof is attached to L; and enantiomers, tautomers, solvates, hydrates, salts or prodrugs thereof.

2. A method for treating epilepsy in a subject suffering from epilepsy comprising, administering to said subject in need thereof, a therapeutically effective amount of an inhibitor of PDE6δ, wherein said inhibitor of PDE68 is a compound selected from the group consisting of: [table included] and enantiomers, tautomers, solvates, hydrates, salts or prodrugs of any of the foregoing.

3. The method of claim 1 , wherein said compound is a compound of formula (I), or a tautomer thereof, [chemical expression included] wherein: R 101 is selected from the group consisting of hydrogen; F, Cl and Br; R 102 is selected from the group consisting of hydrogen, F, Cl and Br; R 103 is selected from the group consisting of hydrogen, F, Cl, and Br; R 104 is selected from the group consisting of hydrogen, F, Cl and Br; R 105 is selected from the group consisting of hydrogen, F, Cl and Br; with the proviso that at least one of R 101 , R 102 , R 103 , R 104 or R 105 is not hydrogen; and with the proviso that said compound of formula (I) is not N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(3-fluorophenyl)methyl]isoxazole-3-carboxamide, or a solvate, a hydrate, a salt or a prodrug thereof.

4. The method of claim 3 , wherein said compound of formula (I) is a compound of any one of formula (II), (III), (IV), (V) or (VI) [chemical expression included]

5. The method of claim 3 , wherein said compound of formula (I) is selected from the group consisting of: 5-[(2,4-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide; N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(4-fluorophenyl)methyl]isoxazole-3-carboxamide; 5-[(2,3-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide; 5-[(2,5-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide; N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(2-fluorophenyl)methyl]isoxazole-3-carboxamide; 5-[(3,4-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide; and 5-[(3,5-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide.

6. A method of treating of Alzheimer's disease in a subject suffering from Alzheimer's disease, wherein said method comprises, administering to said subject a therapeutically effective amount of an inhibitor of PDE6δ, wherein said inhibitor is a compound of formula (I) or a tautomer thereof, [chemical expression included] wherein: R 101 is selected from the group consisting of hydrogen; F, Cl and Br; R 102 is selected from the group consisting of hydrogen, F, Cl and Br; R 103 is selected from the group consisting of hydrogen, F, Cl and Br; R 104 is selected from the group consisting of hydrogen, F, Cl and Br; R 105 is selected from the group consisting of hydrogen, F, Cl and Br; with the proviso that at least one of R 101 , R 102 , R 103 , R 104 or R 105 is not hydrogen; and with the proviso that said compound of formula (I) is not N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(3-fluorophenyl)methyl]isoxazole-3-carboxamide, or a solvate, a hydrate, a salt or a prodrug thereof.

7. The method of claim 6 , wherein said compound of formula (I) is a compound of any one of formula (II), (III), (IV), (V) or (VI) [chemical expression included]

8. The method of claim 6 , wherein said compound of formula (I) is selected from the group consisting of: 5-[(2,4-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide; N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(4-fluorophenyl)methyl]isoxazole-3-carboxamide; 5-[(2,3-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide; 5-[(2,5-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide; N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(2-fluorophenyl)methyl]isoxazole-3-carboxamide; 5-[(3,4-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide; and 5-[(3,5-difluorophenyl)methyl]-N-[2-(5-fluoro-1H-indol-3-yl)ethyl]isoxazole-3-carboxamide.

9. The method of claim 6 , wherein said inhibitor is contained within a pharmaceutical composition in a therapeutically effective amount.

10. The method of claim 6 , wherein said inhibitor is a compound of formula (I) or a tautomer thereof, [chemical expression included] wherein: R 101 is selected from the group consisting of hydrogen, and F; R 102 is selected from the group consisting of hydrogen, and F; R 103 is selected from the group consisting of hydrogen, and F; R 104 is selected from the group consisting of hydrogen, and F; R 105 is selected from the group consisting of hydrogen, and F; with the proviso that at least one of R 101 , R 102 , R 103 , R 104 or R 105 is not hydrogen; and with the proviso that said compound of formula (I) is not N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-5-[(3-fluorophenyl)methyl]isoxazole-3-carboxamide, or a solvate, a hydrate, a salt or a prodrug thereof.

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