Compounds for the treatment of neurodegenerative diseases

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

wherein,

E is independently selected from CR 3 ; and N;

each R 1 , R 3 , R 4 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 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 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 ;

R 2 is selected from hydrogen; alkyl; alkenyl; and alkynyl;

R 5 is independently selected from halogen; —OH; —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 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 1; 0; and 2;

each of Y 1 , Y 2 , Y 3 , Y 4 and Y 5 is independently selected from CZ 1 ; N; and NR 101 ; wherein at least two of Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are selected from CZ 1 ;

L is independently selected from C 1-6 alkylene; —O—; —NH—; —NR 10 —; C 2-6 alkenylene; C 2-6 alkynylene;

wherein each of the C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene includes no heteroatom or one or more heteroatoms, the heteroatoms being selected from the heteroatoms consisting of O, S and N;

wherein each of the C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, is unsubstituted or substituted with one or more Z 2 ;

and wherein a carbon atom or heteroatom of the C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, is unoxidized or 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 aryl; cycloalkyl; cycloalkenyl; cycloalkynyl; and heterocycle;

m is selected from 0; 1; 2; 3; 4 and 5;

each R 8 is independently selected from hydrogen; halogen; alkyl; alkenyl; alkynyl; —OH; —OR 20 ; —SH; —SR 20 ; —S(O)R 21 ; —S(O) 2 R 21 ; —SO 2 NR 22 R 23 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 20 ; —NHS(O) 2 R 20 ; —NHC(O)NR 22 R 23 ; —NR 20 C(O)R 20 ; —NR 10 S(O) 2 R 20 ; —NR 20 C(O)NR 22 R 23 ; —NR 22 R 23 ; -cyano; —COOH; —COOR 20 ; —C(O)NR 22 R 23 ; and —C(O)R 21 ;

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 Z 2 ;

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; —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 2 ;

each Z 2 is independently selected from halogen; —OH; —OR 20 ; —SH; —SR 20 ; —S(O)R 21 ; —S(O) 2 R 21 ; —SO 2 NR 22 R 23 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 20 ; —NHS(O) 2 R 20 ; —NHC(O)NR 22 R 23 ; —NR 20 C(O)R 20 ; —NR 20 S(O) 2 R 20 ; —NR 20 C(O)NR 22 R 23 ; —NR 22 R 23 ; -cyano; —COOH; —COOR 20 ; —C(O)NR 22 R 23 ; and —C(O)R 21 ;

each R 10 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 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 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 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 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 ;

wherein R 12 and R 13 are not directly connected or are taken together in order to form a (4-, 5-, 6-, or 7-membered) heterocycle which is unsubstituted or substituted;

each R 20 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 R 21 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 R 22 and R 23 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 R 22 and R 23 are not directly connected or are taken together in order to form a (4-, 5-, 6-, or 7-membered) non-aromatic heterocycle which is unsubstituted or substituted;

or a solvate, hydrate, salt or prodrug thereof;

wherein the compound is not 6-amino-5-(2,6-dichlorobenzyloxy)-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)nicotinamide; 6-amino-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,6-dichlorobenzyloxy)nicotinamide; or 5-[[6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl]amino]-N-[2-(6-methyl-1H-inden-1-yl)ethyl]pyrimidine-2-carboxamide.

2. The compound of claim 1 , having structural formula (A2) or (A3)

3. The compound of claim 1 , having structural formula (B1), (B2) or (B3),

4. The compound of claim 1 , having structural formula (D1), (D2), (D3) or (D4),

5. The compound of claim 1 , wherein B is aryl and R 8 is selected from hydrogen, halogen, —OH, cyano, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl;

trifluoromethoxy.

6. The compound of claim 1 , wherein L is C 1-6 alkylene, is unsubstituted or substituted by one or more substituents each independently selected from halogen; C 1-6 alkyl ; halo C 1-6 alkyl ; halo C 1-6 alkyloxy.

7. The compound of claim 1 , wherein each of R 1 , R 2 , R 3 , R 4 and R 6 are hydrogen.

8. The compound of claim 1 , having structural formula (I1), (I2), or (I3)

wherein

n is selected from 1; 0; and 2

R 5 is selected from halogen; —OH; trifluoromethyl; trifluoromethoxy; cyano; —C(O)R 11 ; C 1-6 alkyl; C 6-10 aryl; and heterocycle;

each of Y 1 and Y 5 is independently selected from CZ 1 and N;

each Y 4 is CZ 1 ;

each Z 1 is independently selected from hydrogen and halogen;

L is independently selected from —O—; —NH—; —NR 10 ; C 1-6 alkylene; —CH 2 —NH—; and —CH 2 —NH—CH 2 —;

B represents a cyclic structure selected from C 3-8 cycloalkyl; C 6-10 aryl; and heterocycle;

m is selected from 0; 1; and 2;

each R 8 is independently selected from halogen; C 1-6 alkyl; —OH; C 1-6 alkoxy; trifluoromethyl; trifluoromethoxy; and cyano;

each R 10 is C 1-6 alkyl;

each R 11 is C 1-6 alkyl;

and isomers, solvates, hydrates, or salts thereof.

9. The compound of claim 1 , having structural formula (J1), (J2), (J3), or (J4)

wherein

R 5 is selected from halogen; —OH; trifluoromethyl; trifluoromethoxy; cyano; —C(O)R 11 ; C 1-6 alkyl; C 6-10 aryl; and heterocycle;

L is independently selected from —O—; —NH—; —NR 10 ; C 1-6 alkylene; —CH 2 —NH—; and —CH 2 —NH—CH 2 —;

B represents a cyclic structure selected from C 3-8 cycloalkyl; C 6-10 aryl; and heterocycle;

m is selected from 0; 1; and 2;

each R 8 is independently selected from halogen; C 1-6 alkyl; —OH; C 1-6 alkoxy; trifluoromethyl; trifluoromethoxy; and cyano;

each R 10 is C 1-6 alkyl;

each R 11 is C 1-6 alkyl;

and isomers, solvates, hydrates, or salts thereof.

10. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the compound of claim 1 .

11. A method for treating a neurodegenerative disorder in a subject, the method comprising:

administering to a subject in need thereof a compound of claim 1 or a pharmaceutical composition of claim 10 , or 6-amino-5-(2,6-dichlorobenzyloxy)-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)nicotinamide; or 6-amino-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,6-dichlorobenzyloxy)nicotinamide, or 5-[[6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl]amino]-N-[2-(6-methyl-1H-inden-1-yl)ethyl]pyrimidine-2-carboxamide;

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, parkinsonism linked to chromosome 17, and FTDP-17 Parkinson's disease.

12. A method for the preparation of the compounds of claim 1 , and isomers, solvates, hydrates, salts, or prodrugs thereof, the method comprising:

reacting a substituted or unsubstituted (1H-indol-3-yl)methanamine, 2-(1H-indol-3-yl)ethanamine or 3-(1H-indol-3yl)propan-1-amine with a correctly substituted six membered ring derivative bearing an acid halide function in a polar aprotic solvent in the presence of a strong base at a temperature between −10° C. to 100° C.;

reacting a substituted or unsubstituted (1H-indol-3-yl)methanamine, 2-(1H-indol-3-yl)ethanamine or 3-(1H-indo-3-yl)propan-1-amine with a correctly substituted six membered ring derivative bearing one carboxylic acid function in a polar aprotic solvent in the presence of a peptide bond formation coupling agent at a temperature between 0° C. to 50° C.

13. The method according to claim 12 , further comprising:

wherein the six membered ring bears a —CH 2 LG radical, wherein LG is a leaving group, reacting the compound with suitable nucleophiles (e.g. amines, alcohols) in the presence of a strong base or reacting the compound with derivatives in the presence of a palladium or copper catalyst.

14. The method according to claim 13 , wherein the derivatives are selected from boronic acid, stannane, and organozinc derivatives.