- BENZENESULFONAMIDE DERIVATIVES AS TRAP1 MODULATORS AND USES THEREOF
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The present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be tumor necrosis factor ("TNF") receptor associated protein 1 ("TRAP1") modulators (e.g., TRAP1 activators). The provided compounds may also rescue the activity in PTEN-induced kinase 1 ("PINK1") loss of function contexts. The provided compounds may also improve mitochondrial health, function, quality, quantity, and/or activity, and/or reduce the production of reactive oxygen species. The provided compounds may also refold or solubilize aggregated or misfolded proteins such as α-synuclein. The present disclosure also provides pharmaceutical compositions comprising the provided compounds; kits comprising the provided compounds or pharmaceutical compositions; and methods of using the provided compounds and pharmaceutical compositions (e.g., for treating a disease in a subject in need thereof).
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Paragraph 00297; 00316
(2021/09/26)
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- CYCLIC SULFONAMIDE DERIVATIVES AS TRAP1 MODULATORS AND USES THEREOF
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The present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be tumor necrosis factor ( TNF ) receptor associated protein 1 ( TRAP1 ) modulators (e.g., TRAP1 activators). The provided compounds may also rescue the activity in PTEN-induced kinase 1 ( PINK1 ) loss of function contexts. The provided compounds may also improve mitochondrial health, function, quality, quantity, and/or activity, and/or reduce the production of reactive oxygen species. The provided compounds may also refold or solubilize aggregated or misfolded proteins such as α-synuclein. The present disclosure also provides pharmaceutical compositions comprising the provided compounds; kits comprising the provided compounds or pharmaceutical compositions; and methods of using the provided compounds and pharmaceutical compositions (e.g., for treating a disease in a subject in need thereof).
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Paragraph 00292; 00407-00410
(2021/09/26)
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- PYRIDINESULFONAMIDE DERIVATIVES AS TRAP1 MODULATORS AND USES THEREOF
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The present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be tumor necrosis factor ("TNF") receptor associated protein 1 ("TRAP1") modulators (e.g., TRAP1 activators). The provided compounds may also rescue the activity in PTEN-induced kinase 1 ("PINK1") loss of function contexts. The provided compounds may also improve mitochondrial health, function, quality, quantity, and/or activity, and/or reduce the production of reactive oxygen species. The provided compounds may also refold or solubilize aggregated or misfolded proteins such as a-synuclein. The present disclosure also provides pharmaceutical compositions comprising the provided compounds; kits comprising the provided compounds or pharmaceutical compositions; and methods of using the provided compounds and pharmaceutical compositions (e.g., for treating a disease in a subject in need thereof).
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Paragraph 00288; 00581-00584
(2021/09/26)
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- Inhibitors of matrix metalloproteinases
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Compounds of general formula (I), salts or solvates thereof and pharmaceutical compositions containing same: wherein Z is N or CH or the Z(R1) part is replaced with a covalent bond, m and n is 0, 1, 2 or 3; HET is heteroaryl; X is CF3, halogen, CO-heterocyclyl, COOR3 or CONHR3; R1 is H, (CH2)o-aryl, (CH2)p-heteroaryl, (CH2)q-biphenyl; C(O)—R5; S(O)2—R6; R2 is H, aryl, heteroaryl, Y—(CH2)r-aryl, Y—(CH2)s-heteroaryl, where some of the above substituents may be substituted; Y is O or S; with the exclusion of the compound where HET is 1,3-thiazol, X is COOH, R1 is 4-fluorophenyl and R2 is benzyloxy. The invention also relates to the use of a compound of general formula (I), salts or solvates thereof for the use in the prevention or treatment of diseases where the activation of MMPs is involved in the pathomechanism. In this aspect the use of the above excluded compound is also inventive.
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Page/Page column 33
(2016/11/24)
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- Direct trifluoromethylation of imidazoheterocycles in a recyclable medium at room temperature
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Regioselective C-H trifluoromethylation of imidazoheterocycles with Langlois' reagent in a recyclable mixed medium of 1-butyl-3-methylimidazoliumtetrafluoroborate ([Bmim]BF4) and water at room temperature has been developed. In the presence of
- Ji, Xiao-Ming,Wei, Liang,Chen, Fan,Tang, Ri-Yuan
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p. 29766 - 29773
(2015/05/20)
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- Imidazole-derived agonists for the neurotensin 1 receptor
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A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 (1) and associated analogs, including its naphthyl analog (14) which exhibited similar properties. Compound 1 showed full agonist behavior (79-93%) with an EC50 of 2.0-4.1 μM against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298 nM), consistent with it functioning via the G q coupled pathway, and good selectivity relative to NTR2 and GPR35. In further profiling, 1 showed low potential for promiscuity and good overall pharmacological data. This report describes the discovery, synthesis, and SAR of 1 and associated analogs. Initial in vitro pharmacologic characterization is also presented.
- Hershberger, Paul M.,Hedrick, Michael P.,Peddibhotla, Satyamaheshwar,Mangravita-Novo, Arianna,Gosalia, Palak,Li, Yujie,Gray, Wilson,Vicchiarelli, Michael,Smith, Layton H.,Chung, Thomas D.Y.,Thomas, James B.,Caron, Marc G.,Pinkerton, Anthony B.,Barak, Lawrence S.,Roth, Gregory P.
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supporting information
p. 262 - 267
(2014/01/17)
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- 4-trifluoroacetyl-2-phenyloxazol-5-one: Versatile template for syntheses of trifluoromethylsubstituted heterocycles
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4-Trifluoroacetyl-2-phenyloxazol-5-one (1) is a versatile template for the synthesis of various trifluoromethyl-substituted heterocycles. Cyclocondesation of 1 with hydroxylamine and hydrazine afforded isoxazole and pyrazole, respectively. Another key protocol involves nucleophilic ring opening of 1 with H2O or MeOH to give a-amido trifluoromethyl ketones which are transformed into trifluoromethyl-substituted thiazoles, oxazoles, imidazoles, pyrazoles, and pyrimidines.
- Saijo, Ryosuke,Kurihara, Ken-Ichi,Kawase, Masami
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p. 2533 - 2553
(2014/01/06)
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- Synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups
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Figure presented In this paper, a novel synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups is presented. Anionically activated trifluoromethyl groups react with secondary amines under aqueous conditions to afford tertiary amides. The mechanism involves initial elimination of hydrogen fluoride by an E1cB mechanism to afford an electrophilic quinone methide- or azafulvene-type intermediate that reacts with secondary amines under aqueous conditions to afford the tertiary amide in good yield (up to 99%).
- OMahony, Gavin,Pitts, Andrew K.
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supporting information; experimental part
p. 2024 - 2027
(2010/06/21)
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- Trifluoromethylation of various aromatic compounds by CF3I in the presence of Fe(II) compound, H2O2 and dimethylsulfoxide
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Trifluoromethylation of aromatic and hetero-aromatic compounds by CF3I in the presence of Fe(II) compound, H2O2 and dimethylsulfoxide was investigated. Various trifluoromethylated benzene derivatives, six-membered nitrogen-containing aromatic compounds and five-membered hetero-aromatic compounds were obtained under mild conditions. General orientation of electrophilic substitution of aromatic compounds was observed similarly as reported in other radical trifluoromethylation previously.
- Kino, Tatsuhito,Nagase, Yu,Ohtsuka, Yuhki,Yamamoto, Kyoko,Uraguchi, Daisuke,Tokuhisa, Kenji,Yamakawa, Tetsu
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experimental part
p. 98 - 105
(2010/03/03)
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- Certain pyrazoline derivatives with kinase inhibitory activity
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The present invention provides certain pyrazoline compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutical compositions and methods of using the compositions in the treatment of various diseases.
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Page/Page column 93
(2008/12/06)
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- 3-dimethylhydrazono-1,1,1-trifluoro-2-propanone as a useful synthetic equivalent of trifluoropyruvaldehydeapplication to synthesis of fluorine-containing heterocycles
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3-Dimethylhydrazono-1,1,1-trifluoro-2-propanone (4) which is easily obtainable from formaldehyde dimethylhydrazone and trifluoroacetic anhydride was found to be an usuful synthetic equivalent of trifluoropyruvaldehyde for the synthesis of fluorine-containing heterocycles. With the use of 4, 4-trifluoromethylimidazoles and 2-trifluoromethylquinoxaline were successfully synthesized.
- Kamitori, Yasuhiro
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p. 1185 - 1190
(2007/10/03)
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- Photochemical Perfluoroalkylation of Imidazoles
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Imidazole and its derivatives undergo facile trifluoromethylation or perfluoroalkylation, in methanol solution at ambient temperature, following radical dissociation of RFI by γ or UV irradiation.In the case of imidazole, attack occurs preferen
- Kimoto, Hiroshi,Fujii, Shozo,Cohen, Louis A.
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p. 2867 - 2872
(2007/10/02)
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- Trifluoromethylimidazoles and a method for their preparation
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4(5)-Trifluoromethylimidazoles having optional substituents in the 1 and 2 positions are provided. The novel 4(5)-trifluoromethylimidazoles are prepared by reacting a 1,1-dihalo-3,3,3-trifluoroacetone compound with an appropriate carboxaldehyde and ammoni
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- 2-Pyrazinyl-trifluoromethylimidazoles and a method for their preparation
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4(5)-Trifluoromethylimidazoles having optional substituents in the 1 and 2 positions are provided. The novel 4(5)-trifluoromethylimidazoles are prepared by reacting a 1,1-dihalo-3,3,3-trifluoroacetone compound with an appropriate carboxaldehyde and ammoni
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- 4-Trifluoromethylimidazoles and 5-(4-pyridyl)-1,2,4-triazoles, new classes of xanthine oxidase inhibitors.
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The syntheses of a number of 2-substituted 4-trifluoromethylimidazoles and 3-substituted 5-(4-pyridyl)-1,2,4-triazoles are described. The trifluoromethylimidazoles were prepared from 3,3-dibromo-1,1,1-trifluoroacetone after hydrolysis with aqueous sodium acetate solution and condensation with an aldehyde in the presence of ammonia. Basic hydrolysis of the trifluoromethyl group was found to provide a facile method for the synthesis of imidazole-4-carboxylic acids. In the imidazole series a 2-aryl substituent and a free imino group were required for xanthine oxidase inhibitory activity. The triazoles were obtained through the reaction of an aroylhydrazine and an imino ether followed by thermal ring closure of the intermediate acylamidrazone. As in the imidazole series, a free imino group is an absolute requirement for in vitro activity. Additional structure-activity relationships of these compounds are presented.
- Baldwin et al.
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