# US 7,745,479 B2 · 1,5-substituted indol-2-yl amide derivatives > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,745,479 B2 - Document ID: US7745479B2 - Status: Granted - Kind: B2 - Application number: 11/604,412 - Filed: 2006-11-27 - Published: 2007-05-31 - Granted: 2010-06-29 - Earliest claimed: 2005-11-30 - Assignees: Hoffmann-La Roche Inc. - Inventors: Matthias Nettekoven; Jean-Marc Plancher; Hans Richter; Olivier Roche; Valerie Runtz-Schmitt; Sven Taylor - Web page: https://patentgrep.com/patent/US7745479B2 ## CPC - C07D 401/12: linked by a chain containing hetero atoms as chain links - A61P 3/04: Anorexiants; Antiobesity agents - A61P 3/06: Antihyperlipidemics - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 401/14: containing three or more hetero rings - C07D 403/12: linked by a chain containing hetero atoms as chain links - C07D 403/14: containing three or more hetero rings - C07D 405/14: containing three or more hetero rings - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to compounds of formula I wherein R1 to R4 and G are as defined in the description and claims and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors. ## Claims ### Claim 1 A compound of formula I, wherein: R1 is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower halogenoalkoxy and lower hydroxyalkyl, lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl and lower heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups; R2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower halogenoalkoxy and lower hydroxyalkyl, lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl and lower heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups; or R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated or partly unsaturated heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenoalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; R3 is selected from the group consisting of lower hydroxyalkyl, lower cyanoalkyl, lower alkoxycarbonyl, phenylsulfonyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, cyano, lower halogenoalkyl, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; and heteroaryl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower alkoxy, halogen, lower halogenoalkyl, lower halogenoalkoxy, morpholino and cyano; R4 is hydrogen or halogen; G is a group selected from wherein m is 0, 1 or 2; R5 is selected from lower alkyl, lower halogenoalkyl, cycloalkyl, halogenocycloalkyl, lower cycloalkylalkyl and lower phenylalkyl; n is 0, 1 or 2; R6 is lower alkyl; p is 0, 1 or 2; q is 0, 1 or 2; A is selected from CR12R12′, O and S; R7, R7′, R8, R8′, R9, R9′, R12 and R12′ independently from each other are selected from the group consisting of hydrogen, lower alkyl, hydoxy, halogen and dialkylamino, or R8 and R12 together form a double bond; R10 is lower alkyl; R11 is C3-C6-alkyl; and pharmaceutically acceptable salts thereof. ### Claim 2 (depends on 1) The compound according to claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated or partly unsaturated heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenoalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. ### Claim 3 (depends on 1) The compound according to claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, 2,5-dihydropyrrole, pyrrolidine, azepane, piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenoalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. ### Claim 4 (depends on 1) The compound according to claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, 4,4-difluoropiperidine and pyrrolidine. ### Claim 5 (depends on 1) The compound according to claim 1, wherein R1 is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl, lower dialkylcarbamoylalkyl, phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower halogenoalkoxy or lower hydroxyalkyl, lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl and lower heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups and R2 is hydrogen or lower alkyl. ### Claim 6 (depends on 1) The compound according to claim 1, wherein R3 is selected from the group consisting of lower cyanoalkyl, lower alkoxycarbonyl, phenylsulfonyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, cyano, lower halogenoalkyl, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; and heteroaryl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower alkoxy, halogen, lower halogenoalkyl, lower halogenoalkoxy, morpholino and cyano. ### Claim 7 (depends on 1) The compound according to claim 1, wherein R3 is lower cyanoalkyl or lower alkoxycarbonyl. ### Claim 8 (depends on 1) The compound according to claim 1, wherein R3 is phenylsulfonyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, cyano, lower halogenoalkyl, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl. ### Claim 9 (depends on 1) The compound according to claim 1, wherein R3 is lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl. ### Claim 10 (depends on 1) The compound according to claim 1, wherein R3 is phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl. ### Claim 11 (depends on 1) The compound according to claim 1, wherein R3 is heteroaryl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower alkoxy, halogen, lower halogenoalkyl, lower halogenoalkoxy and cyano. ### Claim 12 (depends on 11) The compound according to claim 11, wherein R3 is a heteroaryl group selected from pyridyl, pyrimidinyl, furanyl and thienyl. ### Claim 13 (depends on 1) The compound according to claim 1, wherein R4 is hydrogen. ### Claim 14 (depends on 1) The compound according to claim 1, wherein G signifies wherein m is 0, 1 or 2 and R5 is selected from lower alkyl, cycloalkyl, lower cycloalkylalkyl and lower phenylalkyl. ### Claim 15 (depends on 1) The compound according to claim 1, wherein R5 is lower alkyl. ### Claim 16 (depends on 1) The compound according to claim 1, wherein G signifies wherein p is 0, 1 or 2, q is 0, 1 or 2, A is selected from CR12R12′, O and S and R7, R7′, R8, R8′, R9, R9′, R12 and R12′ independently from each other are selected from the group consisting of hydrogen, lower alkyl, hydoxy, halogen and dialkylamino, or R8 and R12 together form a double bond. ### Claim 17 (depends on 16) The compound according to claim 16, wherein A is CR12R12′, p is 0, q is 1 and R7, R7′, R8, R8′, R9, R9′, R12 and R12′ independently from each other are selected from hydrogen or lower alkyl. ### Claim 18 (depends on 1) The compound according to claim 1, selected from the group consisting of (4,4-difluoro-piperidin-1-yl)-[1-(4-fluoro-benzenesulfonyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone, [1-benzyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone, (4,4-difluoro-piperidin-1-yl)-[1-(4-fluoro-benzyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone, 2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indole-1-carboxylic acid methyl ester, [2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-acetonitrile, [1-(3,5-difluoro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(3-trifluoromethoxy-phenyl)-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(4-trifluoromethoxy-phenyl)-1H-indol-2-yl]-methanone, [1-(2-chloro-pyridin-4-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, [1-(6-chloro-pyridin-3-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(2-methoxy-phenyl)-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[1-(4-fluoro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[1-(3-fluoro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone, [1-(3-chloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(3-methoxy-phenyl)-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-phenyl-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-p-tolyl-1H-indol-2-yl]-methanone, [1-(4-chloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone [1-(3,4-dichloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 5-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-pyridine-2-carbonitrile, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(4-methoxy-phenyl)-1H-indol-2-yl]-methanone, 3-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-benzonitrile, 4-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-benzonitrile, [5-(1-isopropyl-piperidin-4-yloxy)-1-phenyl-1H-indol-2-yl]-morpholin-4-yl-methanone, [1-(4-chloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone, [1-(3,4-dichloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone, [5-(1-isopropyl-piperidin-4-yloxy)-1-p-tolyl-1H-indol-2-yl]-morpholin-4-yl-methanone, [5-(1-isopropyl-piperidin-4-yloxy)-1-(4-methoxy-phenyl)-1H-indol-2-yl]-morpholin-4-yl-methanone, 4-[5-(1-isopropyl-piperidin-4-yloxy)-2-(morpholine-4-carbonyl)-indol-1-yl]-benzonitrile, 5-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-2-fluoro-benzonitrile, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(2-methoxy-pyrimidin-5-yl)-1H-indol-2-yl]-methanone, 4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-thiophen-3-yl-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-pyridin-2-yl-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-thiophen-2-yl-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(6-morpholin-4-yl-pyridin-3-yl)-1H-indol-2-yl]-methanone, (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-pyridin-3-yl-1H-indol-2-yl]-methanone, [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone, [6-bromo-1-(2-chloro-pyridin-4-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone, [6-bromo-1-(2-chloro-pyridin-4-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, [5-(1-cyclobutyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (4-hydroxy-4-methyl-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-methanone, and [5-(1-cyclobutyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone, and pharmaceutically acceptable salts thereof. ### Claim 19 (depends on 1) A process for the manufacture of compounds according to formula Ia or formula Ib, comprising the steps of: a) treating a compound of the formula II wherein R1, R2 and R4 are as defined in claim 1, with a suitable base in a suitable solvent under anhydrous conditions and reacting the intermediate anion with an alkylating or acylating agent of the formula III R3—X III, wherein X signifies a leaving group and R3 is selected from the group consisting of lower hydroxyalkyl, lower cyanoalkyl, optionally substituted lower phenylalkyl, lower alkoxycarbonyl and optionally substituted phenylsulfonyl, wherein R3 is selected from the group consisting of lower hydroxyalkyl, lower cyanoalkyl, optionally substituted lower phenylalkyl, lower alkoxycarbonyl and optionally substituted phenylsulfonyl, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt, or alternatively, b) reacting a compound of formula II wherein R1, R2 and R4 are as defined in claim 1, with an optionally substituted phenyl- or heteroaryl boronic acid of the formula IV wherein R3 signifies optionally substituted aryl or heteroaryl, in the presence of a catalyst and basic conditions to obtain a compound of the formula wherein R3 signifies optionally substituted aryl or optionally substituted heteroaryl, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt. ### Claim 20 (depends on 1) A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier and/or adjuvant. ### Claim 21 (depends on 1) A method for the treatment of obesity in a human being or animal, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 in combination or association with a therapeutically effective amount of a compound selected from the group consisting of a lipase inhibitor, an anorectic agent, a selective serotonin reuptake inhibitor and an agent that stimulates metabolism of body fat, to said human being or animal in need thereof. ### Claim 22 (depends on 1) A method of treatment of type II diabetes in a human being or animal, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 in combination or association with a therapeutically effective amount of an anti-diabetic agent to said human being or animal in need thereof.