# US 12,178,805 B2 · Inhibitors of PDE6Delta for use in the prevention and/or treatment of epilepsy and/or neurodegenerative disorders

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 12,178,805 B2
- Document ID: US12178805B2
- Status: Granted
- Kind: B2
- Application number: 16/612,225
- Filed: 2018-05-11
- Published: 2020-08-13
- Granted: 2024-12-31
- Earliest claimed: 2017-05-11
- Assignees: Remynd NV; Katholieke Universiteit Leuven
- Applicants: ReMYND N.V.; Katholieke Universiteit Leuven
- Inventors: Johan Gerard Griffioen; Katrien Princen; Tom François L. Van Dooren; Koen De Witte
- Web page: https://patentgrep.com/patent/US12178805B2

## CPC

- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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.

## Claims

### Claim 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:
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;
E1 is independently selected from CR1 and N;
E2 is independently selected from NR2 and O;
E3 is independently selected from CR3 and N;
Ra is hydrogen and Rb is hydrogen; or Ra and Rb 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 NRb—C(O); C(O); and C(O) NH;
each R1, R3, R4, R5 and R6 is independently selected from hydrogen; halogen; —OH; —OR10; —SH; —SR10; —S(O)R11; —S(O)2R11; —SO2NR12R13; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R10; NHS(O)2R10; —NHC(O)NR12R13; —NR10C(O)R10; —NR10S(O)2R10; —NR10C(O)NR12R13; —NR12R13; -cyano; —COOH; —COOR10; —C(O)NR12R13; —C(O)R11; 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;
R2 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—; —NR10—; C1-6alkylene; C1-6alkenylene; and C1-6alkynylene;
wherein each of said C1-6alkylene, C1-6alkenylene or C1-6alkynylene optionally includes one or more heteroatoms, said heteroatoms being selected from the heteroatoms consisting of O, S and N, and wherein each of said C1-6alkylene, C1-6alkenylene or C1-6alkynylene, is unsubstituted or substituted;
wherein a carbon atom or heteroatom of said C1-6alkylene, C1-6alkenylene or C1-6alkynylene, 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;
R8 is independently selected from hydrogen; halogen; alkyl; alkenyl; alkynyl; —OH; —OR10; —SH; —SR10; —S(O)R11; —S(O)2R11; —SO2NR12R13; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R10; —NHS(O)2R10; —NHC(O)NR12R13; —NR10C(O)R10; —NR10S(O)2R10; —NR10C(O)NR12R13; —NR12R13; -cyano; —COOH; —COOR10; —C(O)NR12R13; and —C(O)R11;
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; —OR10; —SH; —SR10; —S(O)R11; —S(O)2R11; —SO2NR12R13; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R10; NHS(O)2R10; —NHC(O)NR12R13; —NR10C(O)R10; —NR10S(O)2R10; —NR10C(O)NR12R13; —NR12R13; -cyano; —COOH; —COOR10; —C(O)NR12R13; and —C(O)R11;
each Z1 is independently selected from hydrogen; alkyl; and Z;
each R10 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 R101 is independently selected from hydrogen and R10; each R11 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 R12 and R13 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 R12 and R13 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 —CZ1H—; —CZ1—; —C—; —N—; NR101; —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)
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.

### Claim 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:
Compound
code
STRUCTURE
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
D16
D17
D19
D20
D21
D22
D23
D24
D25
D26
D27
D28
D29
D30
D31
D32
D33
D34
D35
D36
D37
D38
D39
D40
D41
D42
D43
D44
D45
D46
D47
D48
D49
D50
D51
D52
D53
D54
D55
D56
D57
D58
D59
D60
D61
D62
D63
D64
D65
D66
D67
D68
D69
D70
D71
D72
D73
D74
D75
D76
D77
D78
D79
D80
D81
D82
D83
D84
D85
D86
D87
D88
D89
D90
D91
D92
D93
D94
D95
D96
D97
D98
D99
D100
D101
D102
D103
D104
D105
D106
D107
D108
D109
D110
D111
D112
D113
D114
D115
D116
D117
D118
D119
D120
D121
D122
D123
D124
D125
D126
D127
D128
D129
D130
D131
D132
D133
D134
D135
D136
D137
D138
D139
D140
D141
D142
D143
D144
D145
D146
D147
D148
D149
D150
D151
D152
D153
D154
D155
D156
D157
D158
D159
D160
D161
D162
D163
D164
D165
D166
D167
D168
D169
D170
D171
D172
D173
D174
D175
D176
D177
D178
D179
D180
D181
D182
D183
D184
D185
D186
D187
D188
D189
D190
D191
D192
D193
D194
D195
D196
D197
D198
D199
D200
D201
D202
D203
D204
D205
D206
D207
D208
D209
D210
D211
D212
D213
D214
D215
D216
and enantiomers, tautomers, solvates, hydrates, salts or prodrugs of any of the foregoing.

### Claim 3 (depends on 1)

The method of claim 1, wherein said compound is a compound of formula (I), or a tautomer thereof,
wherein:
R101 is selected from the group consisting of hydrogen; F, Cl and Br;
R102 is selected from the group consisting of hydrogen, F, Cl and Br;
R103 is selected from the group consisting of hydrogen, F, Cl, and Br;
R104 is selected from the group consisting of hydrogen, F, Cl and Br;
R105 is selected from the group consisting of hydrogen, F, Cl and Br;
with the proviso that at least one of R101, R102, R103, R104 or R105 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.

### Claim 4 (depends on 3)

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)

### Claim 5 (depends on 3)

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.

### Claim 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,
wherein:
R101 is selected from the group consisting of hydrogen; F, Cl and Br;
R102 is selected from the group consisting of hydrogen, F, Cl and Br;
R103 is selected from the group consisting of hydrogen, F, Cl and Br;
R104 is selected from the group consisting of hydrogen, F, Cl and Br;
R105 is selected from the group consisting of hydrogen, F, Cl and Br;
with the proviso that at least one of R101, R102, R103, R104 or R105 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.

### Claim 7 (depends on 6)

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)

### Claim 8 (depends on 6)

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.

### Claim 9 (depends on 6)

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

### Claim 10 (depends on 6)

The method of claim 6, wherein said inhibitor is a compound of formula (I) or a tautomer thereof,
wherein:
R101 is selected from the group consisting of hydrogen, and F;
R102 is selected from the group consisting of hydrogen, and F;
R103 is selected from the group consisting of hydrogen, and F;
R104 is selected from the group consisting of hydrogen, and F;
R105 is selected from the group consisting of hydrogen, and F;
with the proviso that at least one of R101, R102, R103, R104 or R105 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.