- INDOLE COMPOUNDS AS ANDROGEN RECEPTOR MODULATORS
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Provided herein are compounds of formula (V) that bind to BF3 of an androgen receptor (AR), which can modulate the AR for the treatment of Kennedy's disease.
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Page/Page column 40; 72
(2022/02/05)
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- Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore
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Inhibition of glucosylceramide synthase (GCS) is a major therapeutic strategy for Gaucher’s disease and has been suggested as a potential target for treating Parkinson’s disease. Herein, we report the discovery of novel brain-penetrant GCS inhibitors. Assessment of the structure-activity relationship revealed a unique pharmacophore in this series. The lipophilic ortho-substituent of aromatic ring A and the appropriate directionality of aromatic ring B were key for potency. Optimization of the absorption, distribution, metabolism, elimination, toxicity (ADMETox) profile resulted in the discovery of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based scaffold hopping was performed to mitigate safety concerns associated with T-036. The ring opening of T-036 resulted in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent manner in the plasma and cortex of mice. Finally, we discuss the structural aspects of the compounds that impart a unique inhibition mode and lower the cardiovascular risk.
- Daini, Masaki,Fujii, Takahiro,Ikeda, Zenichi,Inazuka, Masakazu,Kakegawa, Keiko,Kasahara, Takahito,Kikuchi, Fumiaki,Kimoto, Kouya,Kohara, Hiroshi,Mikami, Satoshi,Murakami, Masataka,Nakamura, Minoru,Oak, Jeong-Ho,Ohashi, Tomohiro,Oki, Hideyuki,Puenner, Florian,Sasaki, Minoru,Sato, Sho,Seto, Masaki,Suzaki, Tomohiko,Takai, Yuichi,Takami, Kazuaki,Tanaka, Yuta,Wada, Yasufumi,Wang, Junsi,Yamamoto, Takeshi
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p. 4270 - 4290
(2022/03/14)
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- Diverse, Potent, and Efficacious Inhibitors That Target the EED Subunit of the Polycomb Repressive Complex 2 Methyltransferase
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Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved fo
- Bagal, Sharan K.,Barton, Peter,Bloecher, Andrew,Borodovsky, Alexandra,Code, Erin,Fillery, Shaun M.,Gregson, Clare,Hsu, Jessie Hao-Ru,Kawatkar, Sameer P.,Li, Chengzhi,Longmire, David,Nai, Youfeng,Nash, Samuel C.,O' Donovan, Daniel H.,Pike, Andrew,Pike, Kurt G.,Rawlins, Phillip B.,Read, Jon A.,Robinson, James,Shen, Minhui,Tang, Jia,Wang, Peng,Williamson, Beth,Woods, Haley
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p. 17146 - 17183
(2021/12/06)
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- Br?nsted Acid Catalyzed Dearomatization by Intramolecular Hydroalkoxylation/Claisen Rearrangement: Diastereo- and Enantioselective Synthesis of Spirolactams
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Described herein is a novel Br?nsted acid catalyzed intramolecular hydroalkoxylation/Claisen rearrangement, allowing the practical and atom-economic synthesis of a range of valuable spirolactams from readily available ynamides in generally good to excellent yields with excellent diastereoselectivities and broad substrate scope. Importantly, an unexpected dearomatization of nonactivated arenes and heteroaromatic compounds is involved in this tandem sequence. Moreover, an asymmetric version of this tandem cyclization was also achieved by efficient kinetic resolution by chiral phosphoric acid catalysis. In addition, the [3,3]-rearrangement is shown to be kinetically preferred over the related [1,3]-rearrangement by theoretical calculations.
- Chen, Peng-Fei,Wang, Binju,Wu, Peng,Ye, Long-Wu,Zhou, Bo
-
supporting information
p. 27164 - 27170
(2021/11/22)
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- Degradable hydrogel under physiological conditions
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The present invention discloses a hydrogel that can be degraded under physiological conditions. The hydrogel includes at least one backbone moiety and an optional crosslinking moiety, and biodegradable linkers connecting backbone moieties and crosslinking moieties can be degraded by intramolecular cyclization.
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- BENZAZEPINE DERIVATIVE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF
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Disclosed are a benzazepine derivative, a preparation method, a pharmaceutical composition and the use thereof. A compound as shown in formula (I) of the present invention, and an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof have the following structure. The benzazepine derivative of the present invention has a good regulation effect on the TLR family and the related signalling pathway, and in particular, has a good regulation effect on TLR8, can effectively treat, relieve and/or prevent various diseases mediated by TLR family and the TLR-related signalling pathway, and in particular, can effectively treat, relieve and/or prevent various diseases mediated by TLR8, such as cancers, autoimmune diseases, infections, inflammations, transplantation rejections, graft-versus-host diseases, etc.
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- Palladium-Catalyzed Direct C-H Carbonylation of Free Primary Benzylamines: A Synthesis of Benzolactams
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A protocol for palladium-catalyzed C-H carbonylation of readily available free primary benzylamines using NH2 as the chelating group under an atmospheric pressure of CO has been achieved, providing a general, atom- and step-economic approach to
- Zhang, Chunhui,Ding, Yongzheng,Gao, Yuzhen,Li, Shangda,Li, Gang
-
supporting information
p. 2595 - 2598
(2018/05/22)
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- Traceless Directing Group Assisted Cobalt-Catalyzed C?H Carbonylation of Benzylamines
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The first example of cobalt-catalyzed C(sp2)?H carbonylation of benzylamines using a traceless directing group is reported, which was successfully applied to the synthesis of N?unprotected iso-indolinones through direct C?H/N?H bonds activation. This protocol tolerates a variety of functional groups and provides a facile and efficient method for the formal synthesis of (+)-garenoxacin. (Figure presented.).
- Ling, Fei,Ai, Chongren,Lv, Yaping,Zhong, Weihui
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supporting information
p. 3707 - 3712
(2017/10/07)
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- BIOREVERSABLE PROMOIETIES FOR NITROGEN-CONTAINING AND HYDROXYL-CONTAINING DRUGS
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Disclosed are promoieties of the following formula which can be used to form prodrugs of nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent: (I) and pharmaceutical compositions comprising the prodrugs.
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- NRF2 REGULATORS
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The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.
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- SUBSTITUTED HETEROCYCLIC SULFONAMIDE COMPOUNDS USEFUL AS TRPA1 MODULATORS
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The invention is concerned with the compounds of formula I or II: and salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I or II as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.
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Paragraph 0637; 0638
(2015/04/28)
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- PERFORIN INHIBITING BENZENESULFONAMIDE COMPOUNDS, PREPARATION AND USES THEREOF
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Compounds of formula (la) and pharmaceutically acceptable salts, solvates, and hydrates thereof and related methods of modulatin perforin activity on a cell: wherein Ring A is selected from a 6-10 membered aryl, 5-6 membered cycloalkyi, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl rings comprise at least one heteroatom selected from N, O or S; and wherein the aryl, cycloalkyi, heteroaryl or heterocyclyl rings are optionally substituted with 1 to 3 substituents selected from halo, nitro, -C1-Cealkyl, -C1-Ceaminoalkyl, -C1-C6hydroxyalkyl, -haloC1-C6alkyl, -C1- C6alkoxyl, -haloC1-C6alkyl, -CH2OC(O)CrC6alkyl, -C(O)OC1,-C6alkyI, -NHC(O)C1,-C6alkyl, -NHS(O)2C1- C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NH2, and -C(O)NJJ; Ring B is a 6-10 membered arylene or a 5-6 membered heteroarylene comprising at least one heteroatom selected from N, 0 or S; and wherein the aryl or heteroaryl is optionally, substituted with one or more substituents selected from -NJJ, -OJ, halo,C1 -C6alkyl, -haloC1- C6alkyl, -C1-C6alkoxy, -haloC1-C6alkoxyl, and -C(0)NJJ; Ring C is is selected from a 5-10 membered heteroarylene or a 5-10 membered heterocyclene, each comprising at least one heteroatom selected from N, S and O; Ring D is an optionally substituted benzofused 9-11 membered heterocyclyl or optionally substituted ben2ofused 9-11 membered heteroaryl comprising at least one heteroatom selected from N or O; L is a linker selected from branched and unbranched C1-C4 alkylene, -S(0)2-NH-, -C(0)-NH-, -NH-C(0)-NH-, -S(0)2-NH-C(0)-NH-, -S(0)2-NH-C(0) - and -CH=CH-; wherein Rings B and C, and Rings C and D, are connected to each other via a C-C bond at any of the available C atoms on each respective ring; and J in each occurrence is independently selected from H, optionally substituted C1-C6alkyl or optionally substituted haloC1-C6alkyl.
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- CINNOLINE DERIVATIVES AS AS BTK INHIBITORS
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Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5 are defined in the specification. The compounds are inhibitors of Bruton's tyrosine
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Paragraph 0228-0229
(2013/10/21)
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- BIARYL PHOSPHODIESTERASE 1NHIBITORS
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Novel biaryl compounds with phosphodiesterase inhibitory activity of the general formula (I), wherein R1, R2, R3, X, Y, Z1, Z2, Z3, and Z4 have the meanings defined herein, as well as their use as therapeutic agents in the treatment of inflammatory diseases and conditions
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- FUSED PYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
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Novel[1.2.4]triazolo[1,5-a]pyrazine and imidazo[1,2-a]pyrazine compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, and others.
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Page/Page column 28-29
(2009/12/05)
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- 2-METHYLMORPHOLINE PYRIDO-, PYRAZO- AND PYRIMIDO-PYRIMIDINE DERIVATIVES AS MTOR INHIBITORS
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There is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof. There are also provided processes for the manufacture of a compound of Formula (1), and the use of a compound of Formula (1) as a medicament and in the treatment of cancer
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Page/Page column 121
(2008/06/13)
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- HETEROARYL COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are Heteroaryl Compounds having the following structure: (I) wherein R1, R2, L, X, Y, Z, Q, A and B are as defined herein, compositions comprising an effective amount of a Heteroaryl Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heteroaryl Compound to a patient in need thereof.
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Page/Page column 140
(2008/12/05)
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- IMIDAZOLOPYRIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
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Novel imidazolopyridine compounds are disclosed that have a formula represented by Formula (I). The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, ECM degradation, joint degradation and/or inflammation, and others.
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Page/Page column 75
(2008/12/06)
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- Raf inhibitor compounds and methods of use thereof
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Compounds of Formula I are useful for inhibiting Raf kinase and for treating disorders mediated thereby. Methods of using compounds of Formula I, and stereoisomers, geometric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
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Page/Page column 91-92
(2010/11/26)
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- TRIAZOLOPYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE & INFLAMMATORY DISEASES
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Novel [1.2.4]triazolo[1,5-a]pyrazine compounds are disclosed that have a formula represented by the following (formula I). The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, arthritis, inflammation, and others.
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Page/Page column 82
(2008/06/13)
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- IMIDAZOLOPYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
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Novel imidazo[1,2-a]pyrazine compounds are disclosed that have a formula ( I ) represented by the following:The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, arthritis, inflammation, and others.
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Page/Page column 91
(2008/06/13)
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- ISOINDOLONE COMPOUNDS AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR POTENTIATORS
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The present invention is directed to compounds of formula (I), wherein R1 is a ring and n is a number from 1 to 8. The invention also relates to use of the compounds in therapy as metabotropic glutamate receptor modulators, particularly in neurological and psychiatric disorders.
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Page/Page column 66-67
(2008/06/13)
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- SELECTIVE ESTROGEN RECEPTOR MODULATORS
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The present invention relates to a selective estrogen receptor modulators of formula I (I); or a pharmaceutical acid addition salt thereof; and of formula II (II); or a pharmaceutical salt thereof; useful, e.g., for treating endometriosis and/or uterine leiomyoma/leiomyomata.
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Page/Page column 25
(2010/02/13)
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- Kinase inhibitors
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Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
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Page/Page column 26
(2010/01/31)
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