Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases

1. A compound of structural formula (A5), or a stereoisomer, enantiomer, or tautomer thereof,

wherein,

R 5 is selected from the group consisting of 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;

L is a single bond or is independently selected from the group consisting of —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 S and N, and wherein each of said C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene, can be unsubstituted or substituted; and 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 is cyclic structure selected from the group consisting of cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; and heterocycle;

R 8 is independently selected from the group consisting of 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 ;

m is selected from the group consisting of 0; 1; 2; 3; 4 and 5;

each R 10 is independently selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; and heterocycle-alkynylene;

each R 11 is independently selected from the group consisting of hydroxyl; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; and heterocycle-alkynylene;

each R 12 and R 13 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 R 12 and R 13 are taken together to form a 5-, 6-, or 7-membered unsubstituted or substituted heterocycle;

or a solvate, hydrate, salt or prodrug thereof,

wherein the compound is not 3-isoxazolecarboxamide, 5-(4-chlorophenyl)-N-[2-(5-methyl-1H-indol-3-yl)ethyl]-.

2. The compound of claim 1 , wherein L is an unsubstituted or substituted C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene and

wherein the C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene includes one or more heteroatoms, heteroatoms being selected from the group consisting of S and N.

3. The compound of claim 1 , wherein L is a C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene and

wherein a carbon atom or heteroatom of the C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene, is oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 .

4. The compound of claim 1 , wherein L is a single bond, or C 1-6 alkylene optionally substituted by one or more substituents each independently selected from halogen; C 1-6 alkyl; haloC 1-6 alkyl; and haloC 1-6 alkyloxy.

5. The compound of claim 1 , wherein L is a single bond.

6. The compound of claim 1 , wherein L is —CH 2 —.

7. The compound of claim 1 , wherein B is C 3-8 cycloalkyl; C 6-10 aryl or heterocycle; and R 8 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, trifluoromethoxy.

8. The compound of claim 1 , wherein R 8 is selected from hydrogen; halogen; linear alkyl; linear alkenyl; linear alkynyl; —OH; —OR 10 ; —SH; —SR 10 ; trifluoromethyl; trifluoromethoxy; —NR 12 R 13 ; -cyano.

9. The compound of claim 1 , wherein R 5 is selected from halogen or C 1-6 alkyl; B is selected from C 3-6 cycloalkyl; phenyl, naphthyl, pyridyl, piperidyl, thiazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, triazinyl, pyranyl, isobenzofuranyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, pyrimidinyl, furazanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl or isatinoyl; m is 0, 1, or 2; R 8 is independently selected from hydrogen; halogen; C 1-6 alkyl; —OH; —OR 10 ; —SH; trifluoromethyl; trifluoromethoxy; nitro; —NR 12 R 13 ; -cyano; —COOH; and L is C 1-6 alkylene or a single bond.

10. The compound of claim 1 , wherein R 8 is selected from hydrogen and halogen.

11. The compound of claim 1 , wherein R 5 is halogen.

12. The compound of claim 1 , wherein R 5 is chloro.

13. The compound of claim 1 , wherein L is selected from the group consisting of —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 S and N, and wherein each of said C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene, can be unsubstituted or substituted; and 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 .

14. The compound of claim 1 having structural formula (A6)

15. The compound of claim 1 , wherein said compound is selected from:

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-methoxybenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-cyclopentylisoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-cyanobenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-cyanobenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-cyclopropylisoxazole-3-carboxamide;

5-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2-methoxybenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-(trifluoromethyl)benzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-methoxybenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(furan-2-yl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-methylbenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-cyclohexylisoxazole-3-carboxamide;

5-(3-fluorobenzyl)-N-(2-(5-methyl-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(thiophen-2-yl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(furan-2-ylmethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-methylbenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2-fluoro-3-methoxybenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(furan-3-ylmethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-fluorobenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(thiophen-3-ylmethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(thiophen-2-ylmethyl)isoxazole-3-carboxamide;

N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-5-(3-fluorobenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-(trifluoromethyl)benzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-phenylisoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(pyridin-4-ylmethyl)isoxazole-3-carboxamide;

5-((1H-pyrazol-1-yl)methyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-methoxyphenyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1-methyl-1H-indol-3-yl)ethyl)-5-(3-fluorobenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-chlorophenyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-p-tolylisoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(pyrrolidin-1-ylmethyl)isoxazole-3-carboxamide;

5-(3-fluorobenzyl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3,4-difluorobenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,3-difluorobenzyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3,5-difluorobenzyl)isoxazole-3-carboxamide;

5-(2,5-difluorobenzyl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide;

N-(2-(5-cyano-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide;

5-(2,5-difluorobenzyl)-N-(2-(5-phenyl-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzoyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(hydroxy(phenyl)methyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)difluoromethyl)isoxazole-3-carboxamide;

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)fluoromethyl)isoxazole-3-carboxamide;

N-(2-(5-bromo-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide; and

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((2,5-difluorophenyl)(hydroxy)methyl)isoxazole-3-carboxamide.

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

17. A method for treatment of Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia or Parkinsonism (linked to chromosome 17, FTDP-17) in a subject, the method comprising:

administering to the subject an effective amount of the compound of claim 1 .

18. A method for the treatment of Alzheimer's disease in a subject, the method comprising:

administering to the subject an effective amount of the compound of claim 1 .