- PERK INHIBITING INDOLINYL COMPOUNDS
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Provided herein are compounds of formula (I), compositions, and methods useful for inhibiting PERK and for treating related conditions diseases, and disorders, wherein Q is selected from (Ia), (Ib) ou (Ic).
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Paragraph 0142; 0143
(2021/03/05)
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- Synthesis method of 4-fluoro-7-nitroindole or derivatives of 4-fluoro-7-nitroindole
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The invention is applicable to the technical field of chemical synthesis, and provides a synthesis method of 4-fluoro-7-nitroindole or derivatives thereof, which comprises the following steps: reacting 4-fluoroindole or derivatives thereof, glacial acetic acid and sodium cyanoborohydride to obtain 4-fluoroindoline or derivatives thereof, reacting the 4-fluoroindoline or derivatives thereof, glacial acetic acid and acetic anhydride to obtain N-acetyl-4-fluoroindoline or a derivative thereof, carrying out nitration reaction on N-acetyl-4-fluoroindoline or a derivative thereof to obtain N-acetyl4-fluoro-7-nitroindoline or a derivative thereof, reacting N-acetyl-4-fluorine 7-nitroindoline or derivatives thereof, sodium hydroxide and 1, 4-dioxane to obtain 4-fluoro-7-nitroindoline or derivatives thereof, and reacting 4-fluoro-7-nitroindoline or derivatives thereof, trichloromethane and manganese dioxide to obtain 4-fluoro-7-nitroindoline or derivatives thereof. The synthesis method provided by the invention is mild in reaction condition and easy to operate.
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Paragraph 0036; 0046
(2021/02/06)
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- Synthesis and Photophysical Study of Heteropolycyclic and Carbazole Motif: Nickel-Catalyzed Chelate-Assisted Cascade C-H Activations/Annulations
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Herein, nickel-catalyzed synthesis of polyarylcarbazole through sequential C-H bond activations has been described. Regioselective indole C2/C3 functionalization has been achieved in the presence of indole C7-H, which is quite challenging. In addition, this approach also gives easy access to building a heteropolycyclic motif through C6/C7 C-H functionalization of indoline. This methodology is not limited to aromatic internal alkynes as coupling partners; aliphatic alkynes have also shown good tolerance. Notably, during the optimization the catalytic enhancement with sodium iodide as an additive has been observed. We have also studied the photophysical properties of these highly conjugated molecules.
- Prusty, Namrata,Banjare, Shyam Kumar,Mohanty, Smruti Ranjan,Nanda, Tanmayee,Yadav, Komal,Ravikumar, Ponneri C.
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supporting information
p. 9041 - 9046
(2021/11/30)
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- Sustainable Radical Cascades to Synthesize Difluoroalkylated Pyrrolo[1,2-a]indoles
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We disclose herein a photocatalytic difluoroalkylation and cyclization cascade reaction of N-(but-2-enoyl)indoles with broad substrate scopes in up to 90% isolated yield. This method provides sustainable and efficient access to synthesize difluoroalkylated pyrrolo[1,2-a]indoles with a quaternary carbon center under mild conditions.
- Huang, Honggui,Yu, Menglin,Su, Xiaolong,Guo, Peng,Zhao, Jia,Zhou, Jiabing,Li, Yi
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p. 2425 - 2437
(2018/02/23)
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- 5-SULFAMOYL-2-HYDROXYBENZAMIDE DERIVATIVES
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The invention is directed to substituted salicylamide derivatives. Specifically, the invention is directed to compounds according to Formula (I): wherein R, R1 and R2 are as defined herein, or a pharmaceutically acceptable salt thereof. The compounds of the invention are inhibitors of CD73 and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with CD73 inhibition, such as AIDS, the treatment of HIV, autoimmune diseases, infections, atherosclerosis, and ischemia–reperfusion injury. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting CD73 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 151
(2017/09/27)
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- 4,5,6,7-TETRAHYDRO-1 H-PYRAZOLO[4,3-C]PYRIDIN-3-AMINE COMPOUNDS AS CBP AND/OR EP300 INHIBITORS
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The present invention relates to compounds of formula (I) or formula (II): and to salts thereof, wherein R1-R4 of formula (I) and R1-R3 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.
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Page/Page column 343
(2016/06/14)
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- INDOLINE DERIVATIVES AS INHIBITORS OF PERK
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The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I: (I) wherein R1, R2 and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be usef
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Page/Page column 67; 68
(2015/05/05)
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- 5-HT2C RECEPTOR AGONISTS AND COMPOSITIONS AND METHODS OF USE
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Provided are 5-HT2C receptor agonists. Also provided are methods for weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction, pathological gambling, reward deficiency syndrome, and sex addiction), obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders (including insomnia, fragmented sleep architecture, and disturbances of slow-wave sleep), urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea. Also provided are compositions comprising a selective 5-HT2C receptor agonist, optionally in combination with a supplemental agent, and methods for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product; aiding in smoking cessation and preventing associated weight gain; controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising administering a selective 5-HT2C receptor agonist, optionally in combination with a supplemental agent.
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Page/Page column 196
(2015/05/19)
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- Discovery of a novel series of indoline carbamate and indolinylpyrimidine derivatives as potent GPR119 agonists
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GPR119 has emerged as an attractive target for anti-diabetic agents. We identified a structurally novel GPR119 agonist 22c that carries a 5-(methylsulfonyl)indoline motif as an early lead compound. To generate more potent compounds of this series, structural modifications were performed mainly to the central alkylene spacer. Installation of a carbonyl group and a methyl group on this spacer significantly enhanced agonistic activity, resulting in the identification of 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]propyl 7-fluoro-5-(methylsulfonyl)-2,3-dihydro-1H-indole-1-carboxylate (20). To further expand the chemical series of indoline-based GPR119 agonists, several heterocyclic core systems were introduced as surrogates of the carbamate spacer that mimic the presumed active conformation. This approach successfully produced an indolinylpyrimidine derivative 37, 5-(methylsulfonyl)-1-[6-({1-[3-(propan-2- yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]-2, 3-dihydro-1H-indole, which has potent GPR119 agonist activity. In rat oral glucose tolerance tests, these two indoline-based compounds effectively lowered plasma glucose excursion and glucose-dependent insulin secretion after oral administration.
- Sato, Kenjiro,Sugimoto, Hiromichi,Rikimaru, Kentaro,Imoto, Hiroshi,Kamaura, Masahiro,Negoro, Nobuyuki,Tsujihata, Yoshiyuki,Miyashita, Hirohisa,Odani, Tomoyuki,Murata, Toshiki
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p. 1649 - 1666
(2014/03/21)
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- Discovery of GSK2656157: An optimized PERK inhibitor selected for preclinical development
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We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.
- Axten, Jeffrey M.,Romeril, Stuart P.,Shu, Arthur,Ralph, Jeffrey,Medina, Jesus R.,Feng, Yanhong,Li, William Hoi Hong,Grant, Seth W.,Heerding, Dirk A.,Minthorn, Elisabeth,Mencken, Thomas,Gaul, Nathan,Goetz, Aaron,Stanley, Thomas,Hassell, Annie M.,Gampe, Robert T.,Atkins, Charity,Kumar, Rakesh
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supporting information
p. 964 - 968
(2013/10/22)
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- CHEMICAL COMPOUNDS
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The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I wherein R1, R2 and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer?s disease, stroke, Type 1 diabetes Parkinson disease, Huntington?s disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 187-188
(2011/10/13)
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- Discovery of novel N -β- d -Xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes
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A novel series of N-linked β-d-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl) -1-(β-d-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC50 value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
- Yao, Chun-Hsu,Song, Jen-Shin,Chen, Chiung-Tong,Yeh, Teng-Kuang,Hung, Ming-Shiu,Chang, Chih-Chun,Liu, Yu-Wei,Yuan, Mao-Chia,Hsieh, Chieh-Jui,Huang, Chung-Yu,Wang, Min-Hsien,Chiu, Ching-Hui,Hsieh, Tsung-Chih,Wu, Szu-Huei,Hsiao, Wen-Chi,Chu, Kuang-Feng,Tsai, Chi-Hui,Chao, Yu-Sheng,Lee, Jinq-Chyi
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experimental part
p. 166 - 178
(2011/02/28)
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- PYRROLE ANTIFUNGAL AGENTS
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The invention provides compounds of formula (I), and pharmaceutically and agriculturally acceptable salts thereof; wherein: R1, R2, R3, R4, R5, R6, A1, L1 and n are as defined herein. These compounds and their pharmaceutically acceptable salts are useful in prevention or treatment of a fungal disease. Compounds of formula (I), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.
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- Indole derivatives
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Novel indole derivatives of formula (I) or a pharmaceutically acceptable salt thereof: wherein R1 is fluorine, or chlorine, and R2 is hydrogen, or fluorine, which are SGLT inhibitors and are useful for treatment or prevention of diabetes and related conditions.
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Page/Page column 11
(2008/06/13)
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- Discovery of SB-705498: A potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development
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Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.
- Rami, Harshad K.,Thompson, Mervyn,Stemp, Geoffrey,Fell, Steve,Jerman, Jeffrey C.,Stevens, Alexander J.,Smart, Darren,Sargent, Becky,Sanderson, Dominic,Randall, Andrew D.,Gunthorpe, Martin J.,Davis, John B.
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p. 3287 - 3291
(2007/10/03)
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- N-SUBSTITUTED PIPERIDINE AND PIPERAZINE DERIVATIVES
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This invention relates to compounds of the formula 1 wherein R1, R2, R7, R8, R9, U, V, Z, A, W, X, M, E, L, T and D are defined as in the specification, pharmaceutical compositions containing them and their use in the treatment of central nervous system and other disorders.
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Page/Page column 112-113
(2010/02/12)
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- Indoline and piperazine containing derivatives as a novel class of mixed D2/D4 receptor antagonists. Part 1: Identification and structure-activity relationships
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Optimization of the lead compound 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2,3-dihydro-indol-1-yl)-ethanone 1 by systematic structure-activity relation (SAR) studies lead to two potent compounds 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)- ethanone 2n and 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)- ethanone 7b. Their related synthesis was also reported.
- Zhao, He,Thurkauf, Andrew,He, Xiaoshu,Hodgetts, Kevin,Zhang, Xiaoyan,Rachwal, Stanislaw,Kover, Renata X.,Hutchison, Alan,Peterson, John,Kieltyka, Andrzej,Brodbeck, Robbin,Primus, Renee,Wasley, Jan W.F.
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p. 3105 - 3109
(2007/10/03)
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