Arylthiazolyl piperidines and related compounds as modulators of survival motor neuron (smn) protein production

A compound of the formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• X is N or CH;
• X is CH, A is CR2, B is CR1, D is N, and E is N;
• X is CH, A is N, B is CR1, D is N, and E is N;
• X is CH, A is N, B is CR1, D is N, and E is CR6;
• X is CH, A is N, B is CR1, D is CR5, and E is N;
• or
• X is CH, A is R1, B is CR2, D is N, and E is N;
• R7 is hydrogen, halogen, C1-C2alkyl, or C1-C2alkoxy;
• R1 is an optionally substituted mono-, bi-, or tricyclic group having at least one aromatic or heteroaromatic ring;
• R2 is hydrogen, halogen, C1-C2alkyl, C1C2alkoxy, trifluoromethyl, or trifluoromethoxy;
• R3 is 1 to 4 substituents independently chosen from hydrogen, halogen, C1-C2alkyl, and C1C2alkoxy;
• R4 is cyano, amino, (C═O)R10, —(C═O)NR10R11, (C═O)OR10, —NR12(C═O)R10, —NR12(C═O)OR10, or a 5-membered heteroaryl group containing at least 2 nitrogen atoms;
• wherein
• R10 and R11 are independently chosen from hydrogen, C1-C4alkyl, (cycloalkyl)C0-C4alkyl, (heterocycloalkyl)C0-C4alkyl, (phenyl)C0-C2alkyl, (pyridyl)C0-C2alkyl, and thienyl;
• and
• R12 is hydrogen or C1-C2alkyl.

A compound or salt thereof, wherein the compound is:

• 1-(4-(4-cyanophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-fluorophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-chlorophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-methylphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-trifluoromethylphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-bromophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-(methylsulfonyl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-methoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-bromophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-bromophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(biphenyl-4-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-nitrophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-phenylthiazol-2-yl)piperidine-4-carboxamide;
• 4-(4-(4-bromophenyl)thiazol-2-yl)morpholine;
• 4-(4-bromophenyl)-2-(piperidin-1-yl)thiazole;
• 1-(4-(3-fluorophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-chlorophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-methoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-(methylsulfonyl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-nitrophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-fluorophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-chlorophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-(trifluoromethyl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-methoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-(methylsulfonyl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-nitrophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• ethyl 1-(4-(4-bromophenyl)thiazol-2-yl)piperidine-4-carboxylate;
• 1-(4-(4-acetylphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(benzo[d][1,3]dioxol-5-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(naphthalen-1-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-oxo-4H-chromen-6-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(thiophen-2-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3,5-dimethylisoxazol-4-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-aminophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(pyridin-3-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-acetylphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(naphthalen-2-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-aminophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-cyanophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-(dimethylamino)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(6-(piperidin-1-yl)pyridin-3-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-acetamidophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-(dimethylcarbamoyl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-(dimethylamino)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(dibenzo[b,d]thiophen-1-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(1-methyl-1H-indol-5-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(biphenyl-2-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2-cyanophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(benzofuran-2-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-bromophenyl)thiazol-2-yl)piperidine-4-carboxylic acid;
• 1-(4-(4-bromophenyl)thiazol-2-yl)-N-methylpiperidine-4-carboxamide;
• 1-(4-(4-bromophenyl)thiazol-2-yl)-N,N-dimethylpiperidine-4-carboxamide;
• 1-(4-(4-bromophenyl)thiazol-2-yl)-N-phenylpiperidine-4-carboxamide;
• N-benzyl-1-(4-(4-bromophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• (1-(4-(4-bromophenyl)thiazol-2-yl)piperidin-4-yl)(morpholino)methanone;
• (1-(4-(4-bromophenyl)thiazol-2-yl)piperidin-4-yl)(piperidin-1-yl)methanone;
• (1-(4-(4-bromophenyl)thiazol-2-yl)piperidin-4-yl)(piperazin-1-yl)methanone;
• 1-(4-(4-bromophenyl)thiazol-2-yl)-N-phenethylpiperidine-4-carboxamide;
• 1-(4-(4-bromophenyl)thiazol-2-yl)-N-(3-phenylpropyl)piperidine-4-carboxamide;
• 1-(4-(4-bromophenyl)thiazol-2-yl)-N-(4-phenylbutyl)piperidine-4-carboxamide
• 1-(4-(4-bromophenyl)pyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-aminophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3,4,5-trimethoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3,5-dimethoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-(methylthio)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(4-bromophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3-(dimethylamino)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3-(dimethylamino)phenyl)pyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-(dimethylamino)phenyl)pyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-isopropoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-phenoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(2,3-dihydrobenzofuran-6-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-(benzyloxy)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-ethoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-(4-methylpiperazin-1-yl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-tert-butylphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-(dimethylamino)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 4-(4-bromophenyl)-2-(methylsulfonyl)thiazole;
• 1-(4-(4-bromophenyl)thiazol-2-yl)piperidine-4-carbonitrile;
• tert-butyl 1-(4-(4-bromophenyl)thiazol-2-yl)piperidin-4-ylcarbamate;
• 1-(2-(3-(dimethylamino)phenyl)pyrimidin-4-yl)piperidine-4-carboxamide;
• 1-(4-(4-morpholinophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-isobutoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-isopropoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 4-(4-bromophenyl)-2-(piperazin-1-yl)thiazole;
• 1-(4-(4-carbamoylphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-(4-(4-bromophenyl)thiazol-2-yl)piperazin-1-yl)ethanone;
• 1-(4-(4-bromophenyl)thiazol-2-yl)piperidin-4-amine;
• 2-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4-(4-bromophenyl)thiazole;
• N-(1-(4-(4-bromophenyl)thiazol-2-yl)piperidin-4-yl)acetamide;
• (4-(4-(4-bromophenyl)thiazol-2-yl)piperazin-1-yl)(furan-2-yl)methanone;
• (4-(4-(4-bromophenyl)thiazol-2-yl)piperazin-1-yl)(phenyl)methanone;
• 4-(4-bromophenyl)-2-(4-(phenylsulfonyl)piperazin-1-yl)thiazole;
• 4-(4-bromophenyl)-2-(4-(methylsulfonyl)piperazin-1-yl)thiazole;
• 4-(4-(4-bromophenyl)thiazol-2-yl)piperazine-1-carboxamide;
• 1-(5-p-tolylthiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3-fluorophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(4-chlorophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3-isopropoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(benzo[d][1,3]dioxol-5-yl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(4-p-tolylpyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-isopropoxyphenyl)pyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)pyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1,3,4-thiadiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3-(dimethylamino)phenyl)-1,3,4-thiadiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-p-tolyl-1,3,4-thiadiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(4-(methylthio)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 2-(4-(1H-imidazol-2-yl)piperidin-1-yl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)thiazole;
• 3-(2-(4-(1H-imidazol-2-yl)piperidin-1-yl)thiazol-5-yl)-N,N-dimethylaniline;
• 1-(5-(3-(pyrrolidin-1-yl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3-(piperidin-1-yl)phenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3-morpholinophenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(1-(5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)thiazol-2-yl)piperidin-4-yl)ethanone;
• 1-(1-(5-(3-(dimethylamino)phenyl)thiazol-2-yl)piperidin-4-yl)ethanone;
• 1-(6-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)pyrimidin-4-yl)piperidine-4-carboxamide;
• 1-(6-(3-(dimethylamino)phenyl)pyrimidin-4-yl)piperidine-4-carboxamide;
• 1-(4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1,3,5-triazin-2-yl)piperidine-4-carboxamide;
• 1-(4-(3-(dimethylamino)phenyl)-1,3,5-triazin-2-yl)piperidine-4-carboxamide;
• ethyl 1-(5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)thiazol-2-yl)piperidine-4-carboxylate;
• 1-(4-(3-(dimethylamino)phenyl)-5-methylpyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)thiazol-2-yl)piperidine-4-carboxylic acid;
• 1-(4-(3-(dimethylamino)phenyl)-5-fluoropyrimidin-2-yl)piperidine-4-carboxamide;
• 1-(5-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-4-carboxamide;
• 1-(5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)thiazol-2-yl)-N-phenylpiperidine-4-carboxamide;
• 1-(2-(3-(dimethylamino)phenyl)-5-fluoropyrimidin-4-yl)piperidine-4-carboxamide;
• or
• 1-(5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)thiazol-2-yl)piperidine-4-carboxamide .