Novel spiroheterocyclic compounds as mglu5 antagonists

A compound of Formula II

• R1 is carbon, nitrogen, oxygen or sulfur;
• R3 is an alkyl group, an optionally substituted mono-, bi- or tricyclic C1-C13 heterocyclic group containing 1 to 5 heteroatoms selected from N, O, and S;
• an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted C3-C6 cycloalkyl group, or an optionally substituted C3-C6 cycloalkenyl group;
• R4 is absent or is an optionally substituted mono- or bicyclic C1-C9 heterocyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted alkyl group, hydroxy, alkoxy, thiol, thioalkyl, amino, N-alkylamino, or N,N-dialkylamino or a halogen atom;
• R5 is absent or is optionally substituted alkyl, hydroxy, alkoxy, thiol, thioalkyl, amino, alkylamino, dialkylamino, cyano, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, N-alkoxy-N-alkylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heterocyclyaminocarbonyl heterocyclyaminocarbonyl, each one optionally substituted or a halogen atom;
• or
• when R1 is a carbon atom, R4 and R5 are joined together to form an optionally substituted methylene group, a keto group, an oxime each one optionally substituted with alkyl, cycloalkyl, halogen or a heterocyclic group;
• or
• when R1 is a carbon atom, R4 and R5 are each oxygen, nitrogen, or sulfur linked to each other through an optionally substituted C2-C3 alkylene group;
• m is 1-3;
• n is 1-2;
• and
• is a single or double bond;
• and
• enantiomers, diastereomers, and N-oxides thereof;
• and
• pharmaceutically acceptable salts thereof.

A compound of Formula III

• wherein:
• R1 is carbon, nitrogen, oxygen or sulfur;
• R2 is a bond, a CH group or a CH2 group;
• R3 is an alkyl group, an optionally substituted mono-, bi- or tricyclic C1-C13 heterocyclic group containing 1 to 5 heteroatoms selected from N, O, and S;
• an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted C3-C6 cycloalkyl group, or an optionally substituted C3-C6 cycloalkenyl group;
• R4 is absent or is an optionally substituted mono- or bicyclic C1-C9 heterocyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted alkyl group, hydroxy, alkoxy, thiol, thioalkyl, amino, N-alkylamino, or N,N-dialkylamino or a halogen atom;
• R5 is absent or is optionally substituted alkyl, hydroxy, alkoxy, thiol, thioalkyl, amino, alkylamino, dialkylamino, cyano, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, N-alkoxy-N-alkylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heterocyclyaminocarbonyl heterocyclyaminocarbonyl, each one optionally substituted or a halogen atom;
• or
• when R1 is a carbon atom, R4 and R5 are joined together to form an optionally substituted methylene group, a keto group, an oxime each one optionally substituted with alkyl, cycloalkyl, halogen or a heterocyclic group;
• or
• when R1 is a carbon atom, R4 and R5 are each oxygen, nitrogen, or sulfur linked to each other through an optionally substituted C2-C3 alkylene group;
• m is 1-3;
• n is 1-2;
• and
• is a single or double bond;
• and
• enantiomers, diastereomers, and N-oxides thereof;
• and
• pharmaceutically acceptable salts thereof.

A compound selected from the group consisting of:

• 8-(6-Methyl-3-nitropyridin-2-yl)-3-(phenylethynyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(3-Nitropyridin-2-yl)-3-(phenylethynyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-[(6-methylpyridin-2-yl)ethynyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-(thien-2-ylethynyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-(pyridin-2-ylethynyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 3-[(2-Fluorophenyl)ethynyl]-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 3-[(3-Fluorophenyl)ethynyl]-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 3-[(4-Fluorophenyl)ethynyl]-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 3-(2-Furylethynyl)-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-prop-1-ynyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 3-[(3-Chlorophenyl)ethynyl]-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-[(3-methylphenyl)ethynyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 3-[(3-Methoxyphenyl)ethynyl]-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 3-{[8-(6-Methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]ethynyl}benzonitrile
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-(thien-3-ylethynyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-(pyridin-3-ylethynyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenylethynyl]-1-oxa-2,8-diaza-spiro[4.5]dec-2-ene
• 3-(3-Methylbut-1-ynyl)-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diaza-spiro[4.5]dec-2-ene
• 3-Hex-1-ynyl-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 2-{[8-(6-Methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]ethynyl}benzonitrile
• 3-[3-(3-Chlorophenylethynyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]pyrazine-2-carbonitrile
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-[(2-methylphenyl)ethynyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 3-[(2-Chlorophenyl)ethynyl]-8-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-(pyrazin-2-ylethynyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene
• 8-(6-Methyl-3-nitropyridin-2-yl)-3-(phenylethynyl)-1-oxa-8-azaspiro[4.5]dec-3-ene
• 3-[(3-Chlorophenyl)ethynyl]-7-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene
• 7-[(3-Chlorophenyl)ethynyl]-2-(6-methyl-3-nitropyridin-2-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene
• 9-(6-Methyl-3-nitropyridin-2-yl)-4-(2-phenylethynyl)-1-oxa-9-azaspiro[5.5]undec-4-ene
• 9-(6-Methyl-3-nitropyridin-2-yl)-4-(2-phenylethynyl)-1-oxa-9-azaspiro[5.5]undec-3-ene
• 3-[(3-Chlorophenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Chlorophenyl)ethynyl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-one
• 3-[(3-Chlorophenyl)ethynyl]-8-methylene-1-oxa-2-azaspiro[4.5]dec-2-ene
• 3-[(3-Chlorophenyl)ethynyl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-one O-methyloxime
• 7-(6-Methyl-3-nitropyridin-2-yl)-3-[(6-methylpyridin-2-yl)ethynyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene
• 7-(6-Methyl-3-nitropyridin-2-yl)-3-(phenylethynyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene
• 3-[(3-Fluorophenyl)ethynyl]-7-(6-methyl-3-nitropyridin-2-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene
• 2-(6-Methyl-3-nitropyridin-2-yl)-7-(phenylethynyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene
• 3-{[7-(6-Methyl-3-nitropyridin-2-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-3-yl]ethynyl}phenol
• 7-[(3-Fluorophenyl)ethynyl]-2-(6-methyl-3-nitropyridin-2-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene
• 3-[(3-Chlorophenyl)ethynyl]-8-(pyridin-2-ylmethylene)-1-oxa-2-azaspiro[4.5]dec-2-ene
• 3-[(3-Chlorophenyl)ethynyl]-8-(pyridin-2-ylmethyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol
• 3-[(3-Chlorophenyl)ethynyl]-8-(pyridin-2-ylmethyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol
• 3-(Phenylethynyl)-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-(2-Phenylethynyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-one
• 3-(2-Phenylethynyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-one oxime
• 3-(Phenylethynyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-one O-(2-oxotetrahydrofuran-3-yl)oxime
• 3-[(6-Methylpyridin-2-yl)ethynyl]-8-pyridin-2-yl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile
• 3-[(5-Fluoropyridin-2-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(6-Methylpyridin-2-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(6-Fluoropyridin-2-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(6-Fluoropyridin-3-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Nitrophenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Methoxyphenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Chloro-5-fluorophenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Methyphenyll)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Ethoxyphenyll)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Trifluoromethoxyphenyll)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-tert-Butylphenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-(1,9,12-Trioxa-2-azadispiro[4.2.4.2]tetradec-2-en-3-ylethynyl)benzonitrile
• 3-[(3-Fluorophenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Ethylphenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Isopropylphenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(4-Chloropyridin-2-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(4-Methylpyridin-2-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Trifluoromethylphenyl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-{[4-(Trifluoromethyl)pyridin-2-yl]ethynyl}-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(5-Chloropyridin-3-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 1-(2-Furyl)-3-(1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-en-3-yl)prop-2-yn-1-one
• 4-Hydroxy-2-({[3-(phenylethynyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ylidene]amino}oxy)butanoic acid
• 3-[(3-Chlorophenyl)ethynyl]-1,8-dioxa-2-azaspiro[4.5]dec-2-ene
• 3-[(6-Methylpyridin-2-yl)ethynyl]-1,8-dioxa-2-azaspiro[4.5]dec-2-ene
• 3-[(4-Chloropyridin-2-yl)ethynyl]-1,8-dioxa-2-azaspiro[4.5]dec-2-ene
• 3-[(3-Chlorophenyl)ethynyl]-1-oxa-8-thia-2-azaspiro[4.5]dec-2-ene 8,8-dioxide
• 3-[(3-Chlorophenyl)ethynyl]-1,7-dioxa-2-azaspiro[4.5]dec-2-ene
• 3-[(3-Chlorophenyl)ethynyl]-1,9-dioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Chlorophenyl)ethynyl]-1,9-dioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Methylphenyl)ethynyl]-1,9-dioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-{[2-(6-Methyl-3-nitropyridin-2-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl]ethynyl}phenol
• 3-{[2-(6-Methyl-3-nitropyridin-2-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl]ethynyl}benzonitrile
• 3′-[(3-Chlorophenyl)ethynyl]-2,3-dihydro-4′H-spiro[indene-1,5′-isoxazol]-3-ol
• 3′-[(3-Chlorophenyl)ethynyl]-4′H-spiro[indene-1,5′-isoxazol]-3(2H)-one
• 3′-[(3-Chlorophenyl)ethynyl]-N-methoxy-4′H-spiro[indene-1,5′-[1,2]oxazol]-3(2H)-imine
• 10-[(3-Chlorophenyl)ethynyl]-1,8-dioxa-9-azadispiro[3.2.4.2]tridec-9-ene (isomer 1)
• 10-[(3-Chlorophenyl)ethynyl]-1,8-dioxa-9-azadispiro[3.2.4.2]tridec-9-ene (isomer 2)
• 3-[(3-Chlorophenyl)ethynyl]-1,9,13-trioxa-2-azadispiro[4.2.5.2]pentadec-2-ene
• 3′-[(6-Methylpyridin-2-yl)ethynyl]-2,3-dihydro-4′H-spiro[indene-1,5′-[1,2]oxazol]-3-ol
• 3-[(3-Chlorophenyl)ethynyl]-1-oxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(3-Chlorophenyl)ethynyl]-8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-ene
• 3-[(3-Methylphenyl)ethynyl]-1-oxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3-[(6-Methoxypyridin-3-yl)ethynyl]-1,9,12-trioxa-2-azadispiro[4.2.4.2]tetradec-2-ene
• 3′-[(6-Methylpyridin-2-yl)ethynyl]-4′H-spiro[indene-1,5′-[1,2]oxazol]-3(2H)-one
• N-Methoxy-3′-[(6-methylpyridin-2-yl)ethynyl]-4′H-spiro[indene-1,5′-[1,2]oxazol]-3(2H)-imine
• 3-[(3-Chlorophenyl)ethynyl]-N,N-dimethyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxamide
• 3-[(3-Chlorophenyl)ethynyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxamide
• 9-[(3-Chlorophenyl)ethynyl]-7-oxa-8-azadispiro[3.1.4.1]undec-8-ene
• 3-[(3-Methylphenyl)ethynyl]-1,9,13-trioxa-2-azadispiro[4.2.5.2]pentadec-2-ene
• 7-[(3-Chlorophenyl)ethynyl]-5-oxa-6-azaspiro[3.4]oct-6-ene
• 10-[(3-Chlorophenyl)ethynyl]-2,8-dioxa-9-azadispiro[3.2.4.2]tridec-9-ene
• 3-[(4-Chloropyridin-2-yl)ethynyl]-8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-ene
• Ethyl 3-[(6-methylpyridin-2-yl)ethynyl]-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylate
• 3′-[(3-Chlorophenyl)ethynyl]-1H,4′H-spiro[isochromene-4,5′-[1,2]oxazole]
• {3-[(3-Chlorophenyl)ethynyl]-1-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl}(4-methylpiperazin-1-yl)methanone
• 1-({3-[(3-Chlorophenyl)ethynyl]-1-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl}carbonyl)imidazolidin-2-one
• [7-[2-(3-Chlorophenyl)ethynyl]-9-oxa-3,8-diazaspiro[4.4]non-7-en-3-yl]-pyrrolidin-1-yl-methanone
• [7-[2-(3-Chlorophenyl)ethynyl]-9-oxa-3,8-diazaspiro[4.4]non-7-en-3-yl]-(1-piperidyl)methanone
• 1-[7-[2-(3-Chlorophenyl)ethynyl]-9-oxa-3,8-diazaspiro[4.4]non-7-ene-3-carbonyl]-3-methylsulfonyl-imidazolidin-2-one
• 3-[(3-Chlorophenyl)ethynyl]-N-ethyl-N-(propan-2-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxamide
• 7-[2-(3-Chlorophenyl)ethynyl]-N-methoxy-N-methyl-9-oxa-3,8-diazaspiro[4.4]non-7-ene-3-carboxamide
• 7-[2-(3-Chlorophenyl)ethynyl]-N-(4-pyridyl)-9-oxa-3,8-diazaspiro[4.4]non-7-ene-3-carboxamide
• Ethyl 3-[(3-chlorophenyl)ethynyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate
• 8,8-Difluoro-2-[2-(6-methyl-2-pyridyl)ethynyl]-4-oxa-3-azaspiro[4.5]dec-2-ene
• 6-[2-(3-Chlorophenyl)ethynyl]-2,8-dioxa-7-azaspiro[3.4]oct-6-ene
• 2-[2-(3-Chlorophenyl)ethynyl]-4-oxa-3-azaspiro[4.5]dec-2-ene
• 2-[2-(3-Chlorophenyl)ethynyl]-8-(difluoromethylene)-4-oxa-3-azaspiro[4.5]dec-2-ene
• 2-[2-(3-Chlorophenyl)ethynyl]-4-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxamide
• [2-[2-(3-Chlorophenyl)ethynyl]-4-oxa-3,8-diazaspiro[4.5]dec-2-en-8-yl]-(2-furyl)methanone
• 2-[2-(3-Chlorophenyl)ethynyl]-N-methoxy-N-methyl-4-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxamide
• 2-[2-(3-Chlorophenyl)ethynyl]-N,N-diethyl-4-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxamide
• (3-Chlorophenyl)-[2-[2-(3-chlorophenyl)ethynyl]-4-oxa-3,8-diazaspiro[4.5]dec-2-en-8-yl]methanone
• Ethyl 2-[2-(3-chlorophenyl)ethynyl]-4-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxylate
• [2-[2-(3-Chlorophenyl)ethynyl]-4-oxa-3,8-diazaspiro[4.5]dec-2-en-8-yl]-pyrrolidin-1-yl-methanone
• 2-[2-(3-Chlorophenyl)ethynyl]-N,N-dimethyl-4-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxamide