US 9,284,271 B2 · Compounds for the treatment of neurodegenerative diseases

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. The compounds have the formula (A1), wherein R1, R2, R4, R5, R6, E, n, Y1, Y2, Y3, Y4, Y5, B, R8, and m are as defined in the claims.

A compound of formula (A1) or a stereoisomer, enantiomer or tautomer thereof,

wherein,
E is independently selected from CR3;
and N;
each R1, 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;
and heterocycle-alkynylene;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, includes no heteroatom or 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 is unsubstituted or substituted with one or more 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, is unoxidized or 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;
R5 is independently selected from halogen;
—OH;
—OR10;
—SH;
—Se;
—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, includes no heteroatom or 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 is unsubstituted or substituted with one or more 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, is unoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
n is selected from 0;
1;
and 2;
each of Y1, Y2, Y3, Y4 and Y5 is independently selected from CZ1;
N;
NR101;
and CO;
wherein at least two of Y1, Y2, Y3, Y4 and Y5 are selected from CZ1;
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;
—OR20;
—SH;
—SR20;
—S(O)R21;
—S(O)2R21;
—SO2NR22R23;
trifluoromethyl;
trifluoromethoxy;
nitro;
—NHC(O)R20;
—NHS(O)2R20;
—NHC(O)NR22R23;
—NR20C(O)R20;
—NR10S(O)2R20;
—NR20C(O)NR22R23;
—NR22R23;
-cyano;
—COOR20;
—C(O)NR22R23;
and —C(O)R21;
wherein the alkyl, alkenyl and alkynyl includes no heteroatom or one or more heteroatoms, the heteroatoms being selected from the atoms O, S and N;
wherein the alkyl, alkenyl and alkynyl is unsubstituted or substituted with one or more Z2;
and wherein a carbon atom or heteroatom of the alkyl, alkenyl and alkynyl, is unoxidized or 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 Z2;
each Z2 is independently selected from halogen;
—OH;
—OR20;
—SH;
—SR20;
—S(O)R21;
—S(O)2R21;
—SO2NR22R23;
trifluoromethyl;
trifluoromethoxy;
nitro;
—NHC(O)R20;
—NHS(O)2R20;
—NHC(O)NR22R23;
—NR20C(O)R20;
—NR20S(O)2R20;
—NR20C(O)NR22R23;
—NR22R23;
-cyano;
—COOH;
—COOR20;
—C(O)NR22R23;
and —C(O)R21;
each R10 is independently selected from 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 includes no heteroatom or 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, is unoxidized or 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 the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene includes no heteroatom or 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, is unoxidized or 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 the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene includes no heteroatom or 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, is unoxidized or oxidized 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 (4-, 5-, 6-, or 7-membered) heterocycle which is unsubstituted or substituted;
each R20 is independently selected from alkyl;
alkenyl;
and alkynyl;
wherein the alkyl, alkenyl, alkynyl includes no heteroatom or one or more heteroatoms in the alkyl, alkenyl or alkynyl moiety, the heteroatom selected from O, S and N;
and wherein a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl is unoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
each R21 is independently selected from hydroxyl;
alkyl;
alkenyl;
and alkynyl;
wherein the alkyl, alkenyl or alkynyl includes no heteroatom or one or more heteroatoms in the alkyl, alkenyl or alkynyl moiety, the heteroatom selected from O, S and N;
and wherein a carbon atom or heteroatom of the alkyl, alkenyl or alkynyl is unoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
each R22 and R23 is independently selected from hydrogen;
alkyl;
alkenyl;
and alkynyl;
wherein the alkyl, alkenyl or alkynyl includes no heteroatom or one or more heteroatoms in the alkyl, alkenyl or alkynyl moiety, the heteroatom selected from O, S and N;
wherein a carbon atom or heteroatom of the alkyl, alkenyl or alkynyl is unoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
and wherein R22 and R23 can be taken together in order to form a (4-, 5-, 6-, or 7-membered) non-aromatic heterocycle which is unsubstituted or substituted;
and a solvate, hydrate, salt, pharmaceutically acceptable salt, or prodrug thereof.

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Compounds for the treatment of neurodegenerative diseases

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Compounds for the treatment of neurodegenerative diseases

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Abstract

Claims13