Amide derivatives as positive allosteric modulators and methods of use thereof

1. A compound of formula (III):

wherein

R 1 is alkylcarbonyl, hydrogen, or methyl;

R 2 is hydrogen or methyl;

a is a single or double bond;

X 1 is N or CH;

X 2 is CH when a is a double bond, and X 2 is CH 2 or —CH 2 CH 2 — when a is a single bond;

X 3 and X 4 are independently N or CH;

T 1 and T 2 are independently hydrogen, alkyl, aryl, cycloalkyl, halo, haloalkyl, or R 3 -L 2 -, wherein at least one of T 1 and T 2 is other than hydrogen;

L 2 is O or S; and

R 3 is alkyl, aryl, cycloalkyl, or haloalkyl;

or a pharmaceutically acceptable salt, ester, or amide thereof.

2. The compound of claim 1 , selected from the group consisting of:

2-(1H-indol-5-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]acetamide;

N-{4-[(difluoromethyl)thio]phenyl}-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-(4-isopropoxyphenyl)acetamide;

N-(4-ethoxyphenyl)-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-(4-methoxyphenyl)acetamide;

2-(1H-indol-5-yl)-N-(4-propoxyphenyl)acetamide;

2-(1H-indol-5-yl)-N-[4-(trifluoromethoxy)phenyl]acetamide;

2-(1H-indol-5-yl)-N-[4-(2,2,2-trifluoroethoxy)phenyl]acetamide;

2-(1H-indol-5-yl)-N-(6-isopropoxypyridin-3-yl)acetamide;

N-(6-ethoxypyridin-3-yl)-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-(6-methoxypyridin-3-yl)acetamide;

2-(1H-indol-5-yl)-N-(6-propoxypyridin-3-yl)acetamide;

2-(1H-indol-5-yl)-N-[6-(trifluoromethoxy)pyridin-3-yl]acetamide;

2-(1H-indol-5-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]acetamide;

2-(1H-indol-5-yl)-N-(6-phenoxypyridin-3-yl)acetamide;

2-(1H-indol-5-yl)-N-(6-isopropoxypyridazin-3-yl)acetamide;

N-(6-ethoxypyridazin-3-yl)-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-(6-methoxypyridazin-3-yl)acetamide;

2-(1H-indol-5-yl)-N-(6-propoxypyridazin-3-yl)acetamide;

2-(1H-indol-5-yl)-N-[6-(4-methylphenoxy)pyridin-3-yl]acetamide;

2-(1H-indol-5-yl)-N-[5-(4-methylphenoxy)pyridin-2-yl]acetamide;

2-(1H-indol-5-yl)-N-(5-isopropoxypyridin-2-yl)acetamide;

N-(5-ethoxypyridin-2-yl)-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-(5-methoxypyridin-2-yl)acetamide;

2-(1H-indol-5-yl)-N-(5-propoxypyridin-2-yl)acetamide;

2-(1H-indol-5-yl)-N-[5-(trifluoromethoxy)pyridin-2-yl]acetamide;

2-(1H-indol-5-yl)-N-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]acetamide;

2-(1H-indol-5-yl)-N-(5-phenoxypyridin-2-yl)acetamide;

2-(1H-indol-6-yl)-N-(4-isopropoxyphenyl)acetamide;

N-(4-ethoxyphenyl)-2-(1H-indol-6-yl)acetamide;

2-(1H-indol-6-yl)-N-(4-methoxyphenyl)acetamide;

2-(1H-indol-6-yl)-N-(4-propoxyphenyl)acetamide;

2-(1H-indol-6-yl)-N-[4-(trifluoromethoxy)phenyl]acetamide;

2-(1H-indol-6-yl)-N-[4-(2,2,2-trifluoroethoxy)phenyl]acetamide;

2-(1H-indol-6-yl)-N-(6-isopropoxypyridin-3-yl)acetamide;

N-(6-ethoxypyridin-3-yl)-2-(1H-indol-6-yl)acetamide;

2-(1H-indol-6-yl)-N-(6-methoxypyridin-3-yl)acetamide;

2-(1H-indol-6-yl)-N-(6-propoxypyridin-3-yl)acetamide;

2-(1H-indol-6-yl)-N-[6-(trifluoromethoxy)pyridin-3-yl]acetamide;

2-(1H-indol-6-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]acetamide;

2-(1H-indol-6-yl)-N-(6-phenoxypyridin-3-yl)acetamide;

2-(1H-indol-6-yl)-N-(6-isopropoxypyridazin-3-yl)acetamide;

N-(6-ethoxypyridazin-3-yl)-2-(1H-indol-6-yl)acetamide;

2-(1H-indol-6-yl)-N-(6-methoxypyridazin-3-yl)acetamide;

2-(1H-indol-6-yl)-N-(6-propoxypyridazin-3-yl)acetamide;

2-(1H-indol-6-yl)-N-[6-(4-methylphenoxy)pyridin-3-yl]acetamide;

2-(1H-indol-6-yl)-N-[5-(4-methylphenoxy)pyridin-2-yl]acetamide;

2-(1H-indol-6-yl)-N-(5-isopropoxypyridin-2-yl)acetamide;

N-(5-ethoxypyridin-2-yl)-2-(1H-indol-6-yl)acetamide;

2-(1H-indol-6-yl)-N-(5-methoxypyridin-2-yl)acetamide;

2-(1H-indol-6-yl)-N-(5-propoxypyridin-2-yl)acetamide;

2-(1H-indol-6-yl)-N-[5-(trifluoromethoxy)pyridin-2-yl]acetamide;

2-(1H-indol-6-yl)-N-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]acetamide;

2-(1H-indol-6-yl)-N-(5-phenoxypyridin-2-yl)acetamide;

N-(1H-indol-5-ylmethyl)-5-[(trifluoromethyl)thio]pyridine-2-carboxamide;

2-(1H-indol-5-yl)-N-{6-[(trifluoromethyl)thio]pyridin-3-yl}acetamide;

2-(1H-indol-5-yl)-N-{5-[(trifluoromethyl)thio]pyridin-2-yl}acetamide;

2-(1H-indol-5-yl)-N-{6-[(trifluoromethyl)thio]pyridazin-3-yl}acetamide;

2-(1H-indol-5-yl)-N-(6-phenylpyridin-3-yl)acetamide;

2-(1H-indol-5-yl)-N-(5-phenylpyridin-2-yl)acetamide;

N-1,1′-biphenyl-4-yl-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-(6-phenylpyridazin-3-yl)acetamide;

2-(1H-indol-6-yl)-N-{6-[(trifluoromethyl)thio]pyridin-3-yl}acetamide;

2-(1H-indol-6-yl)-N-{5-[(trifluoromethyl)thio]pyridin-2-yl}acetamide;

2-(1H-indol-6-yl)-N-{6-[(trifluoromethyl)thio]pyridazin-3-yl}acetamide;

2-(1H-indol-6-yl)-N-(6-phenylpyridin-3-yl)acetamide;

2-(1H-indol-6-yl)-N-(5-phenylpyridin-2-yl)acetamide;

2-(1H-indol-6-yl)-N-(6-phenylpyridazin-3-yl)acetamide;

N-1,1′-biphenyl-4-yl-2-(1H-indol-6-yl)acetamide;

2-(1H-indol-5-yl)-N-[4-(trifluoromethyl)phenyl]acetamide;

2-(1H-indol-5-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]acetamide;

2-(1H-indol-5-yl)-N-[6-(trifluoromethyl)pyridazin-3-yl]acetamide;

N-(4-cyclopropylphenyl)-2-(1H-indol-5-yl)acetamide;

N-(6-cyclopropylpyridin-3-yl)-2-(1H-indol-5-yl)acetamide;

N-(5-cyclopropylpyridin-2-yl)-2-(1H-indol-5-yl)acetamide;

N-(6-cyclopropylpyridazin-3-yl)-2-(1H-indol-5-yl)acetamide;

N-[4-(3-chlorophenoxy)phenyl]-2-(1H-indol-5-yl)acetamide;

N-[4-(2,5-dichlorophenoxy)phenyl]-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-{4-[4-(trifluoromethoxy)phenoxy]phenyl}acetamide;

N-[4-(4-chlorophenoxy)phenyl]-2-(1H-indol-5-yl)acetamide;

N-[6-(3-chlorophenoxy)pyridin-3-yl]-2-(1H-indol-5-yl)acetamide;

N-[6-(2,5-dichlorophenoxy)pyridin-3-yl]-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-{6-[4-(trifluoromethoxy)phenoxy]pyridin-3-yl}acetamide;

N-[6-(4-chlorophenoxy)pyridin-3-yl]-2-(1H-indol-5-yl)acetamide;

N-[5-(3-chlorophenoxy)pyridin-2-yl]-2-(1H-indol-5-yl)acetamide;

N-[5-(2,5-dichlorophenoxy)pyridin-2-yl]-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-{5-[4-(trifluoromethoxy)phenoxy]pyridin-2-yl}acetamide;

N-[5-(4-chlorophenoxy)pyridin-2-yl]-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-[6-(phenylthio)pyridin-3-yl]acetamide;

N-{6-[(2,5-dichlorophenyl)thio]pyridin-3-yl}-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-(6-{[3-(trifluoromethoxy)phenyl]thio}pyridin-3-yl)acetamide;

2-(2-methyl-1H-indol-5-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]acetamide;

2-(1H-indol-5-yl)-N-{4-[(trifluoromethyl)thio]phenyl}acetamide;

N-{4-[(difluoromethyl)thio]phenyl}-2-(1H-indol-5-yl)acetamide;

2-(1H-indol-5-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]acetamide;

2-(1H-indol-5-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]acetamide;

2-(1H-indol-5-yl)-N-(4-phenoxyphenyl)acetamide;

2-(1H-indol-5-yl)-N-{3-[(trifluoromethyl)thio]phenyl}acetamide; and

N-(6-chloropyridin-3-yl)-2-(1H-indol-5-yl)acetamide;

or a pharmaceutically acceptable salt, ester, or amide thereof.

3. A compound selected from N-[(1-acetyl-1H-indol-5-yl)methyl]-6-(2,2,2-trifluoroethoxy)nicotinamide or N-[(1-acetyl-2,3-dihydro-1H-indol-5-yl)methyl]-4-[(trifluoromethyl)thio]benzamide.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (III) as in claim 1 in combination with a pharmaceutically acceptable carrier.

5. A method of identifying an α7 NNR agonist comprising allowing the compound of formula (III) as in claim 1 to interact with cells or cell lines endogenously expressing α7 NNRs or cells expressing recombinant α7 NNRs in a fluorescent medium and measuring changes in such fluorescence.