HETEROARYL PIPERIDINE ETHER ALLOSTERIC MODULATORS OF THE M4 MUSCARINIC ACETYLCHOLINE RECEPTOR
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Abstract
The present invention is directed to heteroarylpiperidine ether compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.
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Citations
22 Claims
- 1. A compound of the formula I:
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12. A compound which is selected from the group consisting of:
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4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidine; 7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2H-chromen-2-one; (4-chloro-6-(4-(3-chloro-4-methylphenoxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; (4-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)piperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol; (4-(4-(benzo[c][1,2,5]oxadiazol-5-yloxy)piperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol; 6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-3-methylquinazolin-4(3H)-one; 6-(4-methoxypiperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; (4-chloro-5-methyl-6-(4-(4-(methylsulfonyl)phenoxy)piperidin-1-yl)pyrimidin-2-yl)methanol; 7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methylisoquinolin-1(2H)-one; methyl 6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate; 3-(4-(3-cyanophenoxy)piperidin-1-yl)-5,6-dimethylpyridazine-4-carbonitrile; 4-chloro-2,5-dimethyl-6-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine; 4-chloro-6-((cis)-3-fluoro-4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine; 4-chloro-5-methyl-6-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine; 4-chloro-5-methyl-2-(methylthio)-6-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine; 4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methyl-2-(methylthio)pyrimidine; methyl 2-(4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)pyrimidin-5-yl)acetate; 2-methoxy-4-(4-(4-methoxyphenoxy)piperidin-1-yl)pyrimidine-5-carbonitrile; 2,5-dimethyl-4-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine; 5-methyl-2-(methylthio)-4-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine; 6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)chroman-4-one; 5-methyl-6-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 3-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)-3,3-difluoropiperidin-4-yl)oxy)benzonitrile 6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)isobenzofuran-1(3H)-one; (4-chloro-6-((cis)-3-fluoro-4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; 6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2,3-dihydro-1H-inden-1-one; (4-chloro-6-(4-((3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; 5-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazin-3-yl)-3-methyl-1,2,4-oxadiazole; (4-chloro-5-methyl-6-(4-((1-methyl-1H-indol-5-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol; 7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-3,4-dihydroquinolin-2(1H)-one; (4-chloro-5-methyl-6-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol; 6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-cyclopropylisoindolin-1-one; 6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methylisoindolin-1-one; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinonitrile; (4-chloro-5-methyl-6-(4-(1,2,3,4-tetrahydroquinolin-7-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol; 6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one; methyl 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinate; 7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one; 6-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; methyl 6-((3R,4S)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate; 7-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one; (4-chloro-5-methyl-6-(4-(3-(methylsulfonyl)phenoxy)piperidin-1-yl)pyrimidin-2-yl)methanol; 6-(((3S,4R)-1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)-2-methylisoindolin-1-one; (4-chloro-5-methyl-6-(4-((2-methylbenzo[d]thiazol-5-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol; methyl 2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinate; dimethyl 2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridine-3,5-dicarboxylate; (4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; 5-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methoxybenzonitrile 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 3-((1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 3-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; (4-chloro-6-((3S,4R)-3-fluoro-4-((2-methylbenzo[d]oxazol-6-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; (4-(4-(benzo[d][1,3]dioxol-5-yloxy)piperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol; (4-chloro-6-(4-(5-fluoro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; 3-((1-(6-chloro-2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 5-((1-(6-chloro-2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)-1-methyl-1H-indazole 4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine; methyl 6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate 5-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)-1H-indazole; 5-((1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-1-methyl-1H-indazole; 4-chloro-2-(methoxymethyl)-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine; 4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-2,5-dimethylpyrimidine; 5-((1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-1-methyl-1H-indazole; 2-((5-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)pyridin-2-yl)oxy)ethan-1-ol; (4-chloro-6-(4-((5-chloro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; 5-((1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methyl-2H-indazole; 5-((1-(6-chloro-2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)-2-methyl-2H-indazole; (4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; 4-(4-(4-methoxyphenoxy)piperidin-1-yl)-2,5-dimethylpyrimidine; methyl 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate; 3-(((3R,4R)-1-(2,5-dimethylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)benzonitrile; 1-((5-((1-(2, 5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)pyridin-2-yl)oxy)-2-methylpropan-2-amine; 4-chloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methyl-2-(methylsulfonyl)pyrimidine; 4-(4-(5-fluoro-6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidine; 3-(((3S,4R)-1-(2,5-dimethylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)benzonitrile; 3-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 2,4-dichloro-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine; 4-chloro-2-(methoxymethyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidine; 6-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)-1H-indazole; 3-(((3R,4S)-1-(2,5-dimethylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)benzonitrile; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-2-(methylthio)pyrimidine; 3-(((3S,4S)-1-(2,5-dimethylpyrimidin-4-yl)-3-fluoropiperidin-4-yl)oxy)benzonitrile; 4-((3S,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidine; 4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2-(methylthio)pyrimidine-5-carbonitrile; 3-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5,6-dimethylpyridazine-4-carbonitrile; 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5-dimethylpyrimidin-4-amine; 4-(4-(3-cyanophenoxy)piperidin-1-yl)-2-methoxypyrimidine-5-carbonitrile; 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-amine; (4-((3S,4R)-4-((1H-indazol-5-yl)oxy)-3-fluoropiperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol; 5-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzofuran-3(2H)-one; (4-chloro-6-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; (4-chloro-5-methyl-6-(4-(1,2,3,4-tetrahydroquinolin-6-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)methanol; (4-chloro-6-(4-((1,3-dihydroisobenzofuran-5-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; 4-(4-(4-methoxyphenoxy)piperidin-1-yl)-2-(methylthio)pyrimidine-5-carbonitrile; 2-(methylthio)-4-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine-5-carbonitrile; 4-chloro-2-cyclopropyl-5-methyl-6-(4-(pyridin-3-yloxy)piperidin-1-yl)pyrimidine; 4-chloro-2-cyclopropyl-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methylpyrimidine; 5-bromo-4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyrimidine; (4-chloro-6-(4-((3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)methanol; (4-(4-((1H-indol-5-yl)oxy)piperidin-1-yl)-6-chloro-5-methylpyrimidin-2-yl)methanol; 6-((1-(6-chloro-2-(hydroxymethyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)isoindolin-1-one; 6-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)isobenzofuran-1(3H)-one; 6-((1-(2,5-dimethylpyrimidin-4-yl)piperidin-4-yl)oxy)isoindolin-1-one; 6-(4-(4-methoxyphenoxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; methyl 2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinate; 3-((1-(2,5,6-Trimethylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile 4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-2,5,6-trimethylpyrimidine; ethyl 6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate ethyl 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate; 6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide;
pyridin-4-ylmethyl 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carboxylate;(R)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-7-yl)pyridazine-3-carboxamide; (R)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-7-yl)pyridazine-3-carboxamide; 6-[4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 6-[4-(1H-indol-5-yloxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 6-[4-(1H-indazol-5-yloxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 2-cyano-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1,3,4-thiadiazol-2-ylmethyl)pyridazine-3-carboxamide; 5-methyl-6-(4-phenoxypiperidin-1-yl)-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 6-[(3S,4R)-4-(3-cyanophenoxy)-3-fluoropiperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; N-bicyclo[1.1.1]pent-2-yl-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1H-1,2,3-triazol-5-ylmethyl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1H-pyrazol-5-ylmethyl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-pyridin-4-ylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(3-methylpyridin-4-yl)methyl]pyridazine-3-carboxamide; 5-methyl-N-(pyridin-4-ylmethyl)-6-[4-(pyridin-3-yloxy)piperidin-1-yl]pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[2-(1H-pyrazol-4-yl)ethyl]pyridazine-3-carboxamide; N-bicyclo[1.1.1]pent-2-yl-6-[4-(1H-indazol-5-yloxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide; 6-{(3S,4R)-3-fluoro-4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; (R)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide; (S)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-methoxy-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-N,5-dimethylpyridazine-3-carboxamide; (S)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide; (R)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide; N-bicyclo[1.1.1]pent-2-yl-6-[4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide; 6-[4-(3-cyanophenoxy)piperidin-1-yl]-N-methoxy-5-methylpyridazine-3-carboxamide; 6-[4-(cyclopropylmethoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]pyridazine-3-carboxamide; 5-methyl-6-{4-[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]piperidin-1-yl}-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-pyridin-3-ylpyridazine-3-carboxamide; 6-((3S,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-((S)-5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide; 6-((3S,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-((R)-5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridazin-4-ylmethyl)pyridazine-3-carboxamide; 6-{4-[(5-fluoro-6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; (R)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide; (S)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[2-(1H-1,2,3-triazol-1-yl)ethyl]pyridazine-3-carboxamide; 5-methyl-6-{4-[(2-methyl-1,3-benzoxazol-6-yl)oxy]piperidin-1-yl}-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 6-[4-(cyclopropylmethoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5-oxopyrrolidin-3-yl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyridin-4-ylmethyl)pyridine-3-carboxamide; N-bicyclo[1.1.1]pent-1-yl-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-bicyclo[1.1.1]pent-2-yl-5-methyl-6-{4-[(2-methyl-1,3-benzoxazol-6-yl)oxy]piperidin-1-yl}pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(2-methylimidazo[1,2-a]pyridin-3-yl)methyl]pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(pyrimidin-4-ylmethyl)pyridazine-3-carboxamide; N-[(3-chloropyridin-4-yl)methyl]-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide; 6-[4-(cyclopropylmethoxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; N-(3-cyanobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-[(3-chloropyridin-4-yl)methyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-[4-(3-chloro-4-methylphenoxy)piperidin-1-yl]-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; N-bicyclo[1.1.1]pent-2-yl-5-methyl-6-{4-[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]piperidin-1-yl}pyridazine-3-carboxamide; N-(2-methoxybenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-7-yl)pyridazine-3-carboxamide; 6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide; N-cyclopropyl-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-[2-(1H-imidazol-1-yl)ethyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyridazine-3-carboxamide; (S)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide; (R)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyridazine-3-carboxamide; (R)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyridazine-3-carboxamide; (S)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyridazine-3-carboxamide; N-(1,3-benzodioxol-5-ylmethyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1H-1,2,4-triazol-5-ylmethyl)pyridazine-3-carboxamide; N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-cyclopentyl-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-(4-cyanobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-6-yl)pyridazine-3-carboxamide; N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[4-(methylsulfonyl)benzyl]pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl]pyridazine-3-carboxamide; N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-(2,3-dihydro-1H-inden-2-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-(2-cyanobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-[(1R)-2,3-dihydro-1H-inden-1-yl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(2-oxopyrrolidin-3-yl)pyridazine-3-carboxamide; N-(3,5-difluoro-4-methoxybenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-[(1 S)-1-(4-methoxyphenyl)ethyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-(2-chloro-4-fluorobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; (S)—
N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;(R)—
N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide;6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1-methylcyclopentyl)pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-N-[4-methoxy-3-(trifluoromethyl)benzyl]-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyridazine-3-carboxamide; N-[(1R)-1-(4-methoxyphenyl)ethyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-N,2,5-trimethylpyridine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-[4-(2,2,2-trifluoroethyl)phenyl]-pyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-2,5-dimethylpyridine-3-carboxamide; 6-[4-(3-cyanophenoxy)piperidin-1-yl]-N-(isothiazol-4-ylmethyl)-5-methylpyridazine-3-carboxamide; N-benzyl-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-benzyl-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide; N-(2-chlorobenzyl)-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(2-phenylethyl)pyridazine-3-carboxamide; N-[2-(2-chlorophenyl)ethyl]-6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazine-3-carboxamide; N-(2-chlorobenzyl)-6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methylpyridazine-3-carboxamide; 6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyridazine-3-carboxamide; 6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyridazine-3-carboxamide; 6-[4-(3-cyanophenoxy)piperidin-1-yl]-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyridazine-3-carboxamide; 5-[(6-{4-[(6-methoxypyridin-3-yl)oxy]piperidin-1-yl}-5-methylpyridazin-3-yl)carbonyl]-3-pyridin-3-yl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine 3-[(1-{4-methyl-6-[(3-pyridin-3-yl-6,7-dihydroisothiazolo[4,5-c]pyridin-5(4H)-yl)carbonyl]pyridazin-3-yl}piperidin-4-yl)oxy]benzonitrile 6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 5-ethyl-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)pyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxamide; 4-chloro-N′
-isopropyl-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carbohydrazideN-(bicyclo[1.1.1]pentan-1-yl)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; 4-chloro-N-((3-chloropyridin-4-yl)methyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; N-(bicyclo[1.1.1]pentan-1-yl)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; 4-chloro-N-isopropyl-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-5-yl)pyrimidine-2-carboxamide; N-(azetidin-3-yl)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroisoquinolin-7-yl)pyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroquinolin-7-yl)pyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(5,6,7,8-tetrahydroquinolin-6-yl)pyrimidine-2-carboxamide; 4-chloro-N-(2-chlorobenzyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(2-(pyridin-4-yl)propan-2-yl)pyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-2-carboxamide; 4-chloro-6-((3S,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; (R)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidine-2-carboxamide; (S)-4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidine-2-carboxamide; 4-chloro-N-(isothiazol-4-ylmethyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; 4-bromo-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine-2-carboxamide; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-2-(methylsulfonyl)pyrimidine; 4-chloro-2-methoxy-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 2-((4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-yl)amino)ethan-1-ol; 5-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-yl)-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine; 4-((3S,4 S)-3,4-difluoropyrrolidin-1-yl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 4-(3,3-difluoropyrrolidin-1-yl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 6-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine; 6-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-yl)-2-oxa-6-azaspiro[3 0.3 ]heptane; 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-N,5-dimethylpyrimidin-4-amine; 4-chloro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-2-ol; 4-(3,3-difluoroazetidin-1-yl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-(pyrrolidin-1-yl)pyrimidine; 5-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(3,3,3-trifluoropropyl)pyrimidin-4-amine; 6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-N,5-dimethyl-N-(2-(pyridin-2-yl)ethyl)pyrimidin-4-amine; (4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5,6-dimethylpyrimidin-2-yl)methanol; 4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5,6-dimethylpyrimidine; 4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-vinylpyrimidine; 3-((1-(5-methyl-6-(pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 3-((1-(5-methyl-6-vinylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 4-(6-fluoropyridin-3-yl)-6-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 3-((1-(5-methyl-6-(5-methylpyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-propylpyrimidine; 3-((1-(6-(furan-3-yl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 3-((1-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 4-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-(pyridin-3-yl)pyrimidine; 4-(furan-3-yl)-6-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 3-((1-(5-methyl-6-(4-oxo-1,4-dihydroquinazolin-7-yl)pyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 3-((1-(6-(4-fluorophenyl)-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 4-isobutyl-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 4-butyl-6-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 4-(4-fluorophenyl)-6-(4((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyrimidine; 6-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazine-3-carbonitrile; 6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methylpyridazine-3-carbonitrile; 2-(hydroxymethyl)-5-methyl-6-(4-(3-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)piperidin-1-yl)pyrimidine-4-carbonitrile; 3-((1-(6-ethyl-5-methylpyrimidin-4-yl)piperidin-4-yl)oxy)benzonitrile; 6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methylpyridazine-3-carbonitrile; 2-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazin-3-yl)-5-methyl-1,3,4-oxadiazole; 3-(6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylpyridazin-3-yl)-5-methyl-1,2,4-oxadiazole; 5-(difluoromethyl)-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-N-(pyridin-4-ylmethyl)pyridazine-3-carboxamide; 2-amino-6-(4-(3-cyanophenoxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)nicotinamide; and methyl 2-chloro-6-(4-((1,3-dihydroisobenzofuran-5-yl)oxy)piperidin-1-yl)-5-methylnicotinate; or a pharmaceutically acceptable salt thereof.
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14. (canceled)
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15. (canceled)
Specification