# US 8,772,300 B2 · Phenyl or pyridinyl-ethynyl derivatives > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,772,300 B2 - Document ID: US8772300B2 - Status: Granted - Kind: B2 - Application number: 13/443,911 - Filed: 2012-04-11 - Published: 2012-10-25 - Granted: 2014-07-08 - Earliest claimed: 2011-04-19 - Assignees: Hoffmann-La Roche Inc. - Applicants: Georg Jaeschke; Synese Jolidon; Lothar Lindemann; Antonio Ricci; Daniel Rueher; Heinz Stadler; Eric Vieira - Inventors: Georg Jaeschke; Synese Jolidon; Lothar Lindemann; Antonio Ricci; Daniel Rueher; Heinz Stadler; Eric Vieira - Web page: https://patentgrep.com/patent/US8772300B2 ## CPC - C07D 213/56: Amides - A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics - A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48) - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - A61P 13/10: of the bladder - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/04: Centrally acting analgesics, e.g. opioids - A61P 25/06: Antimigraine agents - A61P 25/08: Antiepileptics; Anticonvulsants - A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia - A61P 25/16: Anti-Parkinson drugs - A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia - A61P 25/22: Anxiolytics - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - A61P 25/34: Tobacco-abuse - A61P 25/36: Opioid-abuse - A61P 27/02: Ophthalmic agents - A61P 29/02: without antiinflammatory effect - A61P 35/00: Antineoplastic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 213/57: Nitriles - C07D 239/28: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms - C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D 407/12: linked by a chain containing hetero atoms as chain links - C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to ethynyl derivatives of formula I wherein Y is N or C—R3; R3 is hydrogen, methyl, halogen or nitrile; R1 is phenyl or pyridinyl, each of which is optionally substituted by halogen, lower alkyl or lower alkoxy; R2/R2′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen, or R2 and R2′ together with the N-atom to which they are attached form a morpholine ring, a piperidine ring or an azetidine ring, each of which is unsubstituted or substituted one or more substituents selected from lower alkoxy, halogen, hydroxy and methyl; R4/R4′ are each independently hydrogen or lower alkyl, or R4 and R4′ together form a C3-5 cycloalkyl-, tetrahydrofuran- or an oxetane-ring; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. Compounds of formula I are positive allosteric modulators (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5). ## Claims ### Claim 1 A compound of formula I wherein Y is N or C—R3, R3 is hydrogen, methyl, halogen or nitrile; R1 is selected from the group consisting of pyridinyl, optionally substituted by halogen, lower alkyl or lower alkoxy, and phenyl substituted by halogen, lower alkyl or lower alkoxy; R2/R2′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen, or R2 and R2′ together with the N-atom to which they are attached form a morpholine ring, a piperidine ring or an azetidine ring, each of which is unsubstituted or substituted one or more substituents selected from lower alkoxy, halogen, hydroxy and methyl; R4/R4′ are each independently hydrogen or lower alkyl, or R4 and R4′ together form tetrahydrofuran- or an oxetane-ring; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 2 A compound of formula IA, wherein Y is N or C—R3; R3 is hydrogen, methyl, halogen or nitrile; R1 is phenyl or pyridinyl, each of which is optionally substituted by halogen, lower alkyl or lower alkoxy; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 3 (depends on 2) The compound of claim 2, selected from the group consisting of 5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(4-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(2,5-difluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-pyridin-3-ylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-chloro-pyridin-3-ylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-fluoro-pyridin-3-ylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(4-fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide; 5-(3-fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide; and 5-(2,5-difluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 4 (depends on 2) The compound of claim 2, selected from the group consisting of 5-(5-chloro-pyridin-3-ylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide; 5-(3-fluoro-phenylethynyl)-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(4-fluoro-phenylethynyl)-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(2,5-difluoro-phenylethynyl)-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-chloro-pyridin-3-ylethynyl)-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 3-fluoro-5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 3-fluoro-5-(4-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(2,5-difluoro-phenylethynyl)-3-fluoro-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-chloro-pyridin-3-ylethynyl)-3-fluoro-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 3-chloro-5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; and 3-cyano-5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 5 (depends on 1) The compound of claim 1, wherein R1 is phenyl substituted by halogen. ### Claim 6 A compound selected from the group consisting of 5-phenylethynyl-pyridine-2-carboxylic acid tert-butylamide; 5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(4-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(2,5-difluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(4-fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butylamide; 5-(3-fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butylamide; 5-(4-fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide; 5-(3-fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide; and 5-m-tolylethynyl-pyrimidine-2-carboxylic acid tert-butylamide; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 7 (depends on 1) The compound of claim 1, selected from the group consisting of 5-(3-chloro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butylamide; 5-(2,5-difluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide; 5-(3-fluoro-phenylethynyl)-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(4-fluoro-phenylethynyl)-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(2,5-difluoro-phenylethynyl)-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 3-fluoro-5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 3-fluoro-5-(4-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(2,5-difluoro-phenylethynyl)-3-fluoro-pyridine-2-carboxylic acid tert-butyl-methyl-amide; and 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid oxetan-3-ylamide; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 8 (depends on 1) The compound of claim 1, selected from the group consisting of 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide; 5-(4-fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide; 5-(2,5-difluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide; 5-(3,4-difluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide; and (2,2-dimethyl-morpholin-4-yl)-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 9 A compound selected from the group consisting of [5-(2,5-difluoro-phenylethynyl)-pyridin-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone; [5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone; (RS)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-(5-phenylethynyl-pyridin-2-yl)-methanone; (RS)-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-(5-phenylethynyl-pyridin-2-yl)-methanone; (RS)-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-methanone; (RS)-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-methanone; 3-chloro-5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; and (3,3-difluoro-azetidin-1-yl)-(5-phenylethynyl-pyrimidin-2-yl)-methanone; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 10 A compound selected from the group consisting of (3,3-dimethyl-piperidin-1-yl)-(5-phenylethynyl-pyrimidin-2-yl)-methanone; (RS)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-(5-phenylethynyl-pyrimidin-2-yl)-methanone; (RS)-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-(5-phenylethynyl-pyrimidin-2-yl)-methanone; (RS)-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-methanone; 3-fluoro-5-phenylethynyl-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide; (RS)-3-fluoro-5-phenylethynyl-pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1-methyl-ethyl)-amide; 3-cyano-5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(3-chloro-phenylethynyl)-pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide; (RS)-5-(3-chloro-phenylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide; and (RS)-5-(3-chloro-phenylethynyl)-pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1-methyl-ethyl)-amide; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 11 (depends on 1) The compound of claim 1, wherein R1 is pyridinyl, optionally substituted by halogen. ### Claim 12 (depends on 1) The compound of claim 1, selected from the group consisting of 5-pyridin-3-ylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-chloro-pyridin-3-ylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-fluoro-pyridin-3-ylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-chloro-pyridin-3-ylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-chloro-pyridin-3-ylethynyl)-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(5-chloro-pyridin-3-ylethynyl)-3-fluoro-pyridine-2-carboxylic acid tert-butyl-methyl-amide; 5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide; 5-(5-chloro-pyridin-3-ylethynyl)-pyridine-2-carboxylic acid methyl-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide; (RS)-5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide; 5-(2-chloro-pyridin-4-ylethynyl)-pyrimidine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide; (R) or (S)-5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide; and (S) or (R)-5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof. ### Claim 13 A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I wherein Y is N or C—R3; R3 is hydrogen, methyl, halogen or nitrile; R1 is selected from the group consisting of pyridinyl, optionally substituted by halogen, lower alkyl or lower alkoxy, and phenyl substituted by halogen, lower alkyl or lower alkoxy; R2/R2′ are each independently hydrogen, lower alkyl or lower alkyl substituted by halogen, or R2 and R2′ together with the N-atom to which they are attached form a morpholine ring, a piperidine ring or an azetidine ring, each of which is unsubstituted or substituted one or more substituents selected from lower alkoxy, halogen, hydroxy and methyl; R4/R4′ are each independently hydrogen or lower alkyl, or R4 and R4′ together form tetrahydrofuran- or an oxetane-ring; or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof and a pharmaceutically acceptable carrier. ### Claim 14 (depends on 3) The compound of claim 3 wherein said compound is 5-(2,5-difluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide or a pharmaceutically acceptable acid addition salt, racemic mixture, corresponding enantiomer, optical isomer, or stereoisomer thereof.