# US 6,723,744 B2 · Indole carboxylic acids as thyroid receptor ligands > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 6,723,744 B2 - Document ID: US6723744B2 - Status: Granted - Kind: B2 - Application number: 10/255,180 - Filed: 2002-09-24 - Published: 2003-04-24 - Granted: 2004-04-20 - Earliest claimed: 2001-09-26 - Assignees: Pfizer Inc. - Inventors: Gary E. Aspnes; Yuan-Ching P. Chiang - Web page: https://patentgrep.com/patent/US6723744B2 ## CPC - C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals - A61P 3/04: Anorexiants; Antiobesity agents - A61P 3/06: Antihyperlipidemics - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61P 5/14: of the thyroid hormones, e.g. T3, T4 - A61P 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61P 9/06: Antiarrhythmics - 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 9/12: Antihypertensives - A61P 17/00: Drugs for dermatological disorders - A61P 17/14: for baldness or alopecia - A61P 19/10: for osteoporosis - A61P 25/24: Antidepressants - A61P 27/06: Antiglaucoma agents or miotics - A61P 35/00: Antineoplastic agents - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract A compound of the formula wherein W, R1, R2, R3, R4, R5, R6, R7, R8 and R13 are as defined herein, useful in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, thyroid cancer and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss. ## Claims ### Claim 1 A compound of the formula or the pharmaceutically acceptable salt thereof; wherein W is oxygen, CH2, CF2, NR12, S(O)m wherein m is 0, 1 or 2; R1, R2, and R3 are each independently selected from the group consisting of hydrogen, halo, cyano, trifluoromethyl, trifluomethoxy and (C1-C6)alkyl; R4 is hydrogen, halo, cyano, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, —OR9, —S(O)2NR10R11, —C(O)NR10R11, —C(O)R10, —CH(OH)R10, —NR12C(O)R10, —NR12C(O)NR10R11, —NR12S(O)2R10 or —S(O)nR10 wherein n is 0, 1 or 2; R5 is hydroxy, or, (C1-C4)alkoxy; R6 is hydrogen, —C(O)CH3, (C1-C6)alkyl, or phenyl(C1-C6)alkyl; R7 is hydrogen or (C1-C6)alkyl; R8 is OR12 or NR9R12; R9 for each occurrence is independently hydrogen, (C1-C12)alkyl, (C3-C10)cycloalkyl; R10 for each occurrence is independently hydrogen, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl; R11 for each occurrence is independently hydrogen, (C1-C6)alkyl, (C3-C10) cycloalkyl or (C3-C9)cycloalkyl(C1-C6)alkyl; R12 for each occurrence is independently hydrogen or (C1-C6)alkyl; and R13 is hydrogen, halo or (C1-C6)alkyl. ### Claim 2 (depends on 1) A compound according to claim 1, wherein W is oxygen. ### Claim 3 (depends on 1) A compound according to claim 1, wherein R1 and R2 are each independently halo, cyano or (C1-C6)alkyl. ### Claim 4 (depends on 1) A compound according to claim 1, wherein R3 is hydrogen or (C1-C4)alkyl. ### Claim 5 (depends on 1) A compound according to claim 1, wherein R4 is halo, (C1-C12)alkyl, —C(O)NR10R11, —S(O)2NR10R11, —S(O)2R10, —C(O)R10, or —CH(OH)R10. ### Claim 6 (depends on 1) A compound according to claim 1, wherein R10 is hydrogen, (C1-C8)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloaklyl(C1-C6)alkyl, (C6-C10)aryl or halo(C6-C10)aryl. ### Claim 7 (depends on 1) A compound according to claim 1, wherein R11 is hydrogen, (C1-C6)alkyl, (C3-C9)cycloalkyl or (C3-C9)cycloalkyl(C1-C6)alkyl. ### Claim 8 (depends on 1) A compound according to claim 1, wherein R5 is hydroxy. ### Claim 9 (depends on 1) A compound according to claim 1, wherein R6 is hydrogen or (C1-C6)alkyl. ### Claim 10 (depends on 1) A compound according to claim 1, wherein R7 is hydrogen or (C1-C4)alkyl. ### Claim 11 (depends on 1) A compound according to claim 1, wherein R8 is OR12 wherein R12 is hydrogen or (C1-C6)alkyl. ### Claim 12 (depends on 1) A compound according to claim 1, wherein R13 is hydrogen, chloro, fluoro, methyl or isopropyl. ### Claim 13 (depends on 1) A compound according to claim 1, wherein W is oxygen; R1 and R2 are each independently halo, cyano or (C1-C6)alkyl; R3 is hydrogen or (C1-C4)alkyl; R4 is halo; R5 is hydroxy; R6 is hydrogen or (C1-C6)alkyl; R7 is hydrogen or (C1-C4)alkyl, R8 is OR12 wherein R12 is hydrogen or (C1-C6)alkyl, and R13 is hydrogen, chloro, fluoro, methyl or isopropyl. ### Claim 14 (depends on 1) A compound according to claim 1, wherein W is oxygen; R1 and R2 are each independently halo, cyano or (C1-C6)alkyl; R3 is hydrogen or (C1-C4)alkyl; R4 is (C1-C12)alkyl; R5 is hydroxy; R6 is hydrogen or (C1-C6)alkyl; R7 is hydrogen or (C1-C4)alkyl; R8 is OR12 wherein R12 is hydrogen or (C1-C6)alkyl, and R13 is hydrogen, chloro, fluoro, methyl or isopropyl. ### Claim 15 (depends on 1) A compound according to claim 1, wherein W is oxygen; R1 and R2 are each independently halo, cyano or (C1-C6)alkyl; R3 is hydrogen or (C1-C4)alkyl; R4 is —C(O)NR10R11; R10 is hydrogen, (C1-C8)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl; R11 is hydrogen, (C1-C6)alkyl, (C3-C9)cycloalkyl or (C3-C9)cycloalkyl(C1-C6)alkyl; R5 is hydroxy; R6 is hydrogen or (C1-C6)alkyl; R7 is hydrogen or (C1-C4)alkyl; R8 is OR12 wherein R12 is hydrogen or (C1-C6)alkyl, and R13 is hydrogen, chloro, fluoro, methyl or isopropyl. ### Claim 16 (depends on 1) A compound according to claim 1, wherein W is oxygen; R1 and R2 are each independently halo, cyano or (C1-C6)alkyl; R3 is hydrogen or (C1-C4)alkyl; R4 is —S(O)2NR10R11; R10 is hydrogen, (C1-C8)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl; R11 is hydrogen, (C1-C6)alkyl, (C3-C9)cycloalkyl or (C3-C9)cycloalkyl(C1-C6)alkyl; R5 is hydroxy; R6 is hydrogen or (C1-C6)alkyl; R7 is hydrogen or (C1-C4)alkyl; R8 is OR12 wherein R12 is hydrogen or (C1-C6)alkyl, and R13 is hydrogen, chloro, fluoro, methyl or isopropyl. ### Claim 17 (depends on 1) A compound according to claim 1, wherein W is oxygen; R1 and R2 are each independently halo, cyano or (C1-C6)alkyl; R3 is hydrogen or (C1-C4)alkyl; R4 is —S(O)2R10; R10 is hydrogen, (C1-C8)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl; R5 is hydroxy; R6 is hydrogen or (C1-C6)alkyl; R7 is hydrogen or (C1-C4)alkyl; R8 is OR12 wherein R12 is hydrogen or (C1-C6)alkyl, and R13 is hydrogen, chloro, fluoro, methyl or isopropyl. ### Claim 18 (depends on 1) A compound according to claim 1, wherein W is oxygen; R1 and R2 are each independently halo, cyano or (C1-C6)alkyl; R3 is hydrogen or (C1-C4)alkyl; R4 is —C(O)R10 ; R10 is hydrogen, (C1-C8)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl; R5 is hydroxy; R6 is hydrogen or (C1-C6)alkyl; R7 is hydrogen or (C1-C4)alkyl; R8 is OR12 wherein R12 is hydrogen or (C1-C6)alkyl, and R13 is hydrogen, chloro, fluoro, methyl or isopropyl. ### Claim 19 (depends on 1) A compound according to claim 1, wherein W is oxygen; R1 and R2 are each independently halo, cyano or (C1-C6)alkyl; R3 is hydrogen or (C1-C4)alkyl; R4 is —CH(OH)R10; R10 is hydrogen, (C1-C8)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(C1-C6)alkyl; R5 is hydroxy; R6 is hydrogen or (C1-C6)alkyl; R7 is hydrogen or (C1-C4)alkyl; R8 is OR12 wherein R12 is hydrogen or (C1-C6)alkyl, and R13 is hydrogen, chloro, fluoro, methyl or isopropyl. ### Claim 20 (depends on 1) A compound according to claim 1, selected from the group consisting of: 5-(4-Hydroxy-3-isopropyl-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(4-hydroxy-3-isopropyl-phenoxy)-1H-indole-2-carboxylic acid; 5-(3-sec-butyl-4-hydroxy-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-[3-(4-Fluoro-benzyl)-4-hydroxy-phenoxyl]-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-{3-[(4-Fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-[3-(2-Cyclopentyl-1-hydroxy-ethyl)-4-hydroxy-phenoxyl]-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-[3-(4-Fluoro-benzoyl)-4-hydroxy-phenoxyl]-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-[3-(Cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxyl]-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-(3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(4-hydroxy-3-isopropyl-phenoxy)-1-methyl-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(4-hydroxy-3-isopropyl-phenoxy)-3-methyl-1H-indole-2-carboxylic acid; 5-[3-(4-Fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-[3-(4-Fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,4,6-trimethyl-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 4-Chloro-5-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-[4-hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl-phenoxy]-1H-indole-2-carboxylic acid; 5-[3-(4-Fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-1,4,6-trimethyl-1H-indole-2-carboxylic acid; 5-3-[(4-Fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy)-3,4,6-trimethyl-1H-indole-2-carboxylic acid; 5-[3-(4-Fluoro-benzyl)-4-hydroxy-phenoxy]-3,4,6-trimethyl-1H-indole-2-carboxylic acid; 5-(3-Cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 5-(3-Cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-(3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-(4-Hydroxy-3-isopropyl-phenoxy)-3,4,6-trimethyl-1H-indole-2-carboxylic acid; 5-(4-Hydroxy-3-isopropyl-phenoxy)-1,4,6-trimethyl-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-[3-(4-fluoro-benzenesulfonyl-4-hydroxy-phenoxy]-3-methyl-1H-indole-2-carboxylic acid; 5-(3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-[4-Hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl)-phenoxy]-4,6-dimethyl-1H -indole-2-carboxylic acid; 4,6-Dichloro-5-3-[(4-fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy-1H-indole-2-carboxylic acid; 5-(4-Hydroxy-2,3-dimethyl-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid, and; 4,6-Dichloro-5-(4-hydroxy-2,3-dimethyl-phenoxy)-1H-indole-2-carboxylic acid. ### Claim 21 (depends on 1) A method for treating obesity, in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in treating such a condition. ### Claim 22 (depends on 1) A pharmaceutical composition for treating obesity, in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such treatments and a pharmaceutically acceptable carrier. ### Claim 23 (depends on 1) A compound according to claim 1, selected from the group consisting of: 5-(3-sec-Butyl-4-hydroxy-phenoxy)-1,4,6-trimethyl-1H-indole-2carboxylic acid; 4,6-Dichloro-5-(4-hydroxy-3-methylcarbamoyl-phenoxy)-1H-indole-2-carboxylic acid; 5-(3-Butylcarbamoyl-4-hydroxy-phenoxy)-4,6-dichloro-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(4-hydroxy-3-isopropylcarbamoyl-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(4-hydroxy-3-nonylcarbamoyl-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cyclopentylcarbamoyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cycloheptylcarbamoyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cyclooctylcarbamoyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-[3-(cyclohexylmethyl-carbamoyl)-4-hydroxy-phenoxy]-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-[3-(1-cyclohexyl-(R)-ethylcarbamoyl)-4-hydroxy-phenoxy]-1H-indole-2 carboxylic acid; 4,6-Dichloro-5-[3-(1-cyclohexyl-(S)-ethylcarbamoyl)-4-hydroxy-phenoxy]-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-{3-[(1-cyclohexyl-(R)-ethyl)-methyl-carbamoyl]-4-hydroxy-phenoxy}-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-{3-[(1-cyclohexyl-(S)-ethyl)-methyl-carbamoyl]-4-hydroxy-phenoxy}-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-[3-(cyclohexyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-[3-(cyclohexylmethyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-ethanesulfonyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 6-Dichloro-5-(4-hydroxy-3-methanesulfonyl-phenoxy)-1H-indole-2-carboxylic acid ethyl ester; 4,6-Dichloro-5-(4-hydroxy-3-methanesulfonyl-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 4,6-Dichloro-5-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-1H-indole-2-carboxylic acid; 5-(3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-1-isopropyl-4,6-dimethyl-1H-indole-2-carboxylic acid; 1-Benzyl-5-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid; 5-(3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-1,4,6-trimethyl-1H-indole-2-carboxylic acid; 5-(3-Cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-1-ethyl-4,6-dimethyl-1H-indole-2-carboxylic acid; and; 5-(3-Cyclopentylacetyl-4-hydroxy-phenoxy)-4,6-dimethyl-1H-indole-2-carboxylic acid.