# US 10,117,850 B2 · Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases

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- Number: US 10,117,850 B2
- Document ID: US10117850B2
- Status: Granted
- Kind: B2
- Application number: 15/215,750
- Filed: 2016-07-21
- Published: 2016-11-10
- Granted: 2018-11-06
- Earliest claimed: 2009-06-11
- Assignees: Katholieke Universiteit Leuven, K.U.Leuven R&D; Remynd NV
- Applicants: Katholieke Universiteit Leuven, K.U.Leuven R&D; reMYND
- Inventors: Gerard Griffioen; Tom Van Dooren; Veronica Rojas de la Parra; Arnaud Marchand; Sara Allasia; Amuri Kilonda; Patrick Chaltin
- Web page: https://patentgrep.com/patent/US10117850B2

## CPC

- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/4245: Oxadiazoles
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/497: containing further heterocyclic rings
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- 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
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.

## Claims

### Claim 1

A method for the treatment of a neurodegenerative disorder in a subject, the method comprising administering to the subject an effective amount of a compound of formula (AA1) or a stereoisomer, enantiomer or tautomer thereof; or of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the compound of formula (AA1)
wherein,
a maximum of 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;
Q is independently selected from NRb—C(O); and C(O)NH;
Ra is hydrogen or taken together with Rb to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom;
Rb is hydrogen or taken together with Ra to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom;
each of R1, R3, R4, and R6 is independently selected from the group consisting of 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 the 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, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; and
wherein a carbon atom or heteroatom of the 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 the group consisting of hydrogen; alkyl; alkenyl; and alkynyl;
n is selected the group consisting of 0, 1, and 2;
B is cyclic structure selected from the group consisting of cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; and heterocycle;
m is selected from the group consisting of 0; 1; 2; 3; 4 and 5;
R8 is independently selected from the group consisting of 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 the alkyl, alkenyl and alkynyl optionally includes one or more heteroatoms, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkyl, alkenyl and alkynyl can be unsubstituted or substituted with Z; and
wherein a carbon atom or heteroatom of the 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 R10 is independently selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene;
wherein the 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, the heteroatom selected from O, S and N; and
wherein a carbon atom or heteroatom of the 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 R11 is independently selected from the group consisting of hydroxyl; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene;
wherein the 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, the heteroatom selected from the group consisting of O, S and N; and
wherein a carbon atom or heteroatom of the 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 the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene;
wherein the 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, the heteroatom selected from the group consisting of O, S and N; and
wherein a carbon atom or heteroatom of the 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;
or wherein R12 and R13 are taken together to form a 5-, 6-, or 7-membered unsubstituted or substituted heterocycle;
wherein L is:
(a) independently selected from the group consisting of —O—; —NH—; —NR10—; C1-6alkylene; C1-6alkenylene; and C1-6alkynylene;
wherein a carbon atom or heteroatom of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene, can be oxidized to form a C═S, N═O, N═S, S═O or S(O)2; and wherein each of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene optionally includes one or more heteroatoms, the heteroatoms being selected from the group consisting of S and N, and wherein each of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene, can be unsubstituted or substituted;
R5 is selected from the group consisting of 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 the 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, the heteroatoms being selected from the atoms O, S and N;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; and
wherein a carbon atom or heteroatom of the 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; and
each of X, Y, T, W and V form with the dotted lines one of the cycles having one of the structural formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIIa), (XIVa), (XVa), (XVIIa), (XVIIIa), (XIXa), (XXIa), (XXIIa), (XXIIIa) or (XXIVa),
or (b) a single bond; and X, Y, T, W and V form with the dotted lines a cycle of formula (IIIa),
R5 is selected from the group consisting of 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; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; and heterocycle-alkynylene;
wherein the 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, the heteroatoms being selected from the group consisting of O, S and N;
wherein the 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 the 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 the left side of the formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIIa), (XIVa), (XVa), (XVIIa), (XVIIIa), (XIXa), (XXIa), (XXIIa), (XXIIIa), (XXIVa) is attached to Q and the right side thereof is attached to L;
wherein when X, Y, T, W, and V form with the dotted lines a cycle of formula (Ia), and E2 is NH, n is 1, E1 and E3 are CH and Ra, R4, and R6 are H, then Q is not —NH—CO— wherein the right side of —NH—CO— is attached to the cycle of formula (Ia);
each Z1 is independently selected from the group consisting of hydrogen; alkyl; and Z;
each Z is independently selected from the group consisting of 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; and
each R101 is independently selected from the group consisting of hydrogen and R11; or a solvate, hydrate, salt or prodrug thereof; and
wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy, with the proviso that said compound is not:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-ethylphenyl)-2-oxopyrrolidine-3-carboxamide.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the compound has structural formula (AA2), (AA3) or (AA4)

### Claim 3 (depends on 1)

The method according to claim 1, wherein the compound has structural formula: (AB2) or (AB2′),

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound has structural formula: (A1)

### Claim 5 (depends on 1)

The method according to claim 1, wherein the compound has structural formula (A2)

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound has structural formula: (A2′)

### Claim 7 (depends on 1)

The method according to claim 1, wherein B is C3-8cycloalkyl or C6-10-aryl and R8 is selected from the group consisting of hydrogen, halogen, cyano, C1-6alkoxy, and trifluoromethyl; trifluoromethoxy.

### Claim 8 (depends on 1)

The method according to claim 1, wherein L is C1-6alkylene, optionally substituted by one or more substituents each independently selected from halogen; C1-6alkyl, haloC1-6alkyl; haloC1-6alkyloxy.

### Claim 9 (depends on 1)

The method according to claim 1, wherein each of R1, R2, R3, R4 and R6 is hydrogen.

### Claim 10 (depends on 1)

The method according to claim 1, wherein Ra and Rb taken together form a piperidine ring.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the compound has structural formula: (AB4′),

### Claim 12 (depends on 1)

The method according to claim 1, wherein the compound has structural formula: (A9),

### Claim 13 (depends on 1)

The method according to claim 1, wherein the compound has structural formula: (A4′),

### Claim 14 (depends on 1)

The method according to claim 1, wherein the compound has structural formula: (A10),

### Claim 15 (depends on 1)

The method according to claim 1, wherein the compound has structural formula: (AB4″),

### Claim 16 (depends on 1)

The method according to claim 1, wherein the compound has structural formula of (A7) or (A8),

### Claim 17

A method for the treatment of neurodegenerative disorders in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to formula (AA1) or a stereoisomer, enantiomer or tautomer thereof, wherein,
a maximum of 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;
Q is independently selected from NRb—C(O); and C(O)NH;
Ra is hydrogen or taken together with Rb to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom;
Rb is hydrogen or taken together with Ra to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom;
R1 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; and alkynyl;
each R3, R4, 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; heterocycle-alkynylene;
wherein the 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, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; and
wherein a carbon atom or heteroatom of the 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 the group consisting of hydrogen; alkyl; alkenyl; and alkynyl;
R5 is selected from the group consisting of 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; —S(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 the 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, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; and
wherein a carbon atom or heteroatom of the 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;
n is selected the group consisting of 0, 1, and 2;
B is cyclic structure selected from the group consisting of cycloalkyl; cycloalkenyl;
cycloalkynyl; aryl; and heterocycle;
m is selected from the group consisting of 0; 1; 2; 3; 4 and 5;
R8 is independently selected from the group consisting of 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 the alkyl, alkenyl, or alkynyl optionally include one or more heteroatoms selected from the group consisting of O, S and N;
wherein said alkyl, alkenyl, or alkynyl can be unsubstituted or substituted with Z; and
wherein a carbon atom or heteroatom of the alkyl, alkenyl, and alkynyl can be oxidized to form a C═O, N═O, N═S, S═O or S(O)2;
each R10 is independently selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene;
wherein the 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, the heteroatom selected from the group consisting of O, S and N; and
wherein a carbon atom or heteroatom of the 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 R11 is independently selected from the group consisting of hydroxyl; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene;
wherein the 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, the heteroatom selected from O, S and N; and
wherein a carbon atom or heteroatom of the 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 the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene;
or wherein R12 and R13 are taken together to form a 5-, 6-, or 7-membered unsubstituted or substituted heterocycle;
wherein the 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, the heteroatom selected from O, S and N;
wherein a carbon atom or heteroatom of the 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 L is independently selected from the group consisting of —O—; —NH—; —NR10—; C1-6alkylene; C1-6alkenylene; and C1-6alkynylene;
wherein a carbon atom or heteroatom of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene, can be oxidized to form a C═S, N═O, N═S, S═O or S(O)2;
wherein each of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene optionally includes one or more heteroatoms, the heteroatoms being selected from the group consisting of S and N; and
wherein each of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene, can be unsubstituted or substituted;
and each of X, Y, T, W and V form with the dotted lines one of the cycles having one of the structural formula (Ia), (Ha), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIIa), (XIVa), (XVa), (XVIa), (XVIIa), (XVIIIa), (XIXa), (XXa), (XXIa), (XXIIa), (XXIIIa) or (XXIVa), wherein the left side of the formula (Ia), (Ha), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (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;
wherein when X, Y, T, W, and V form with the dotted lines a cycle of formula (Ia), and E2 is NH, n is 1, E1 and E3 are CH and Ra, R4, and R6 are H, then Q is not —NH—CO— wherein the right side of —NH—CO— is attached to the cycle of formula (Ia);
each Z1 is independently selected from the group consisting of hydrogen; alkyl; and Z;
each Z is independently selected from the group consisting of 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; and
each R101 is independently selected from the group consisting of hydrogen and R10;
wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, Parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.

### Claim 18 (depends on 17)

The method according to claim 17, wherein Ra and Rb taken together form a piperidine ring.

### Claim 19

A method for the treatment of neurodegenerative disorders in a subject, the method comprising administering to the subject an effective amount of a compound according to formula (A1), or a stereoisomer, enantiomer or tautomer thereof
wherein,
a maximum of two dotted lines selected from the five dotted lines of formula (A1) are a double bond;
each R1, R3, R4 and R6 is independently selected from the group consisting of hydrogen; halogen; —OH; —OR10; —SH; —SR10; —S(O)R11; —S(O)2R11; —SO2NR12R13; trifluoromethyl; trifluoromethoxy; nitro; —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; and heterocycle-alkenylene; heterocycle-alkynylene;
wherein said alkyl, cycloalkyl; 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; and
wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be taken together 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 or 2;
B represents a cyclic structure selected from the group consisting of cycloalkyl;
cycloalkenyl; cycloalkynyl; aryl; and heterocycle;
m is selected from 0; 1; 2; 3; 4 and 5;
R8 is independently selected from the group consisting of hydrogen; halogen; alkyl; alkenyl; C2-18alkynyl; —OH; —OR10; —SH; —SR10; —S(O)R11; —S(O)2R11; —SO2NR12R13; trifluoromethyl; trifluoromethoxy; nitro; —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; and
wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl and alkynyl, can be taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
each Z is independently selected from the group consisting of halogen; —OH; —OR10; —SH; —SR10; —S(O)R11; —S(O)2R11; —SO2NR12R13; trifluoromethyl; trifluoromethoxy; nitro; —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 and Z;
each R10 is independently selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; C5-14arylalkenylene; 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; and
wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be taken together 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 the group consisting of 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) or alkynyl(ene) moiety, said heteroatom selected from O, S and N; and
wherein two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be taken together 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 the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocyclealkylene; heterocyclealkenylene, and heterocyclealkynylene;
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 two or more hydrogen atoms on a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)2; and
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;
L is:
(a) independently selected from —O—; —NR10—; C1-3alkylene; C1-6alkenylene; C1-6alkynylene;
wherein each of said C1-3alkylene, C1-6alkenylene or C1-6alkynylene optionally includes one or more heteroatoms, said heteroatoms being selected from the heteroatoms consisting of S and N, and wherein each of said C1-3alkylene, C1-6alkenylene or C1-6alkynylene, can be unsubstituted or substituted; and
wherein two or more hydrogen atoms on a carbon atom or heteroatom of said C1-3alkylene, C1-6alkenylene or C1-6alkynylene, can be taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)2; and
R5 is selected from the group consisting of halogen; —OH; —OR10; —SH; —SR10; —S(O)R11; —S(O)2R11; —SO2NR12R13; trifluoromethyl; trifluoromethoxy; nitro; —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 the 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, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; and
wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)2; each of X, Y, T, W and V form with the dotted lines one of the cycles having one of the structural formula (Ia), (Ha), (IIIa), (IVa), (Va), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIIa), (XIVa), (XVa), (XVIIa), (XVIIIa), or (XIXa),
wherein when X, Y, T, W and V form with the dotted lines a cycle of formula (Ia), and E2 is NH, n is 1, E1 and E3 are CH and Ra, R4, R6 are H, then Q is not —NH—CO— wherein the right side of —NH—CO— is attached to the cycle of formula (Ia); or
(b) a single bond; and X, Y, T, W and V form with the dotted lines a cycle of formula (IIIa),
R5 is selected from the group consisting of halogen; —OH; —OR10; —SH; —SR10; —S(O)R11; —S(O)2R11; —SO2NR12R13; trifluoromethyl; trifluoromethoxy; nitro; —NR10C(O)R10; —NR10S(O)2R10; —NR10C(O)NR12R13; —NR12R13; -cyano; —COOH; —COOR10; —C(O)NR12R13; —C(O)R11; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; and heterocycle-alkynylene;
wherein the 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, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; and
wherein two or more hydrogen atoms on a carbon atom or heteroatom of the alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
or a solvate, hydrate, or salt thereof; and
wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, Parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy,
with the proviso that said compound is not:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-ethylphenyl)-2-oxopyrrolidine-3-carboxamide.