- CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia
-
Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.
- Hansen, Joshua D.,Correa, Matthew,Alexander, Matt,Nagy, Mark,Huang, Dehua,Sapienza, John,Lu, Gang,Lebrun, Laurie A.,Cathers, Brian E.,Zhang, Weihong,Tang, Yang,Ammirante, Massimo,Narla, Rama K.,Piccotti, Joseph R.,Pourdehnad, Michael,Lopez-Girona, Antonia
-
p. 1835 - 1843
(2021/03/09)
-
- PROCESSES FOR PREPARING 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE
-
Provided herein are processes for preparing 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide.
- -
-
Paragraph 0191
(2021/06/11)
-
- Highly selective electroreductive linear dimerization of electron-deficient vinylarenes
-
A direct electroreductive dimerization of electron-deficient vinylarenes for the synthesis of 1,4-diarylbutane has been developed using a simple undivided cell with inexpensive carbon electrodes at room temperature. The control and deuterium-labeling experiments of electroreductive dimerization suggest that the hydrogen source comes from the solvent CH3CN. This protocol provides a mild and efficient route for the construction of C–C bond in moderate to good yields with high regioselectivity and broad substrate scope.
- Ning, Shulin,Zheng, Lianyou,Bai, Ya,Wang, Shutao,Wang, Siyu,Shi, Lingling,Gao, Qiansong,Che, Xin,Zhang, Zhuoqi,Xiang, Jinbao
-
supporting information
(2021/11/16)
-
- Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors
-
Aldosterone synthase (CYP11B2) inhibitors have been explored in recent years as an alternative therapeutic option to mineralocorticoid receptor (MR) antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including the heart, vasculature, kidney, and central nervous system (CNS). A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure-activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound 52, in an in vivo cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1.
- Liu, Yongfu,Wu, Jun,Zhou, Mingwei,Chen, Wenming,Li, Dongbo,Wang, Zhanguo,Hornsperger, Benoit,Aebi, Johannes D.,M?rki, Hans-Peter,Kuhn, Bernd,Wang, Lisha,Kuglstatter, Andreas,Benz, J?rg,Müller, Stephan,Hochstrasser, Remo,Ottaviani, Giorgio,Xin, Jian,Kirchner, Stephan,Mohr, Susanne,Verry, Philippe,Riboulet, William,Shen, Hong C.,Mayweg, Alexander V.,Amrein, Kurt,Tan, Xuefei
-
supporting information
p. 6876 - 6897
(2020/08/14)
-
- Preparation method of methyl 4-bromoacetyl-2-methylbenzoate
-
The invention provides a preparation method of methyl 4-bromoacetyl-2-methylbenzoate. The preparation method comprises the following steps: (1) dissolving 4-bromo-2-methylbenzoic acid in methanol, andperforming an esterification reaction under the catalytic action of sulfuric acid so as to produce a first intermediate compound; (2) performing a reaction between the first intermediate compound with potassium vinyl fluoroborate or vinyl boronic acid under the catalytic action of palladium so as to obtain a second intermediate compound; and (3) performing an alpha-halogenated ketone synthesis reaction on the second intermediate compound under the action of a halogenating reagent so as to obtain the methyl 4-bromoacetyl-2-methylbenzoate. The preparation method has the advantages of low raw material cost, a short route, mild reaction conditions, simple requirements for equipment and experimental conditions, large-scale amplification synthesis and a high application value.
- -
-
Paragraph 0017
(2019/04/26)
-
- BENZAZEPINE DERIVATIVE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF
-
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.
- -
-
Paragraph 0170; 0171
(2019/03/29)
-
- Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1
-
We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.
- Hansen, Joshua D.,Condroski, Kevin,Correa, Matthew,Muller, George,Man, Hon-Wah,Ruchelman, Alexander,Zhang, Weihong,Vocanson, Fan,Crea, Tim,Liu, Wei,Lu, Gang,Baculi, Frans,Lebrun, Laurie,Mahmoudi, Afshin,Carmel, Gilles,Hickman, Matt,Lu, Chin-Chun
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p. 492 - 503
(2018/02/07)
-
- BICYCLIC COMPOUNDS USEFUL AS GPR120 MODULATORS
-
Provided herein are compounds, compositions including them, and methods of modulating GPR120 activity and treating diseases mediated by GPR120 by administering such compounds and compositions.
- -
-
Page/Page column 35; 36
(2018/03/28)
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- Batch and Continuous-Flow One-Pot Processes using Amine Diazotization to Produce Silylated Diazo Reagents
-
A novel synthesis of trimethylsilyldiazomethane (TMSCHN2) by diazotization of trimethylsilylmethylamine (TMSCH2NH2) is reported using batch and continuous flow synthesis. The latter affords a daily production of 275 g (2.4 mol) of TMSCHN2. Other silylated methylamines were also successfully reacted under the developed reaction conditions to furnish various silicon-bearing diazomethane reagents. The applicability of the process is highlighted by disclosure of batch and continuous flow one-pot esterification and 1,3-dipolar cycloaddition processes. Furthermore, the high-yielding esterification of carboxylic acids with silylated and substituted methylamines in continuous flow is disclosed. Finally, work-up and purification procedures are reported for the preparation of a 2-MeTHF solution of TMSCHN2, which can be used in rhodium-catalyzed methylenation and homologation reactions.
- Audubert, Clément,Gamboa Marin, Oscar Javier,Lebel, Hélène
-
supporting information
p. 6294 - 6297
(2017/05/19)
-
- Method for preparing 2-methyl-4-formaldoxime methyl benzoate
-
The invention discloses a method for preparing 2-methyl-4-formaldoxime methyl benzoate. The method comprises the following steps: performing acylating chlorination on 2-methyl-4-bromobenzoic acid, carrying out methanol esterification and cyano substitution, and then performing nucleophilic addition elimination with hydroxylamine hydrochloride under alkaline conditions to obtain a target product. The method has the advantages that the process route is simple; reaction conditions are mild; the product yield is high; the total yield reaches 61 percent; the product quality is high; the appearance is white solid; the purity reaches 99.2 percent.
- -
-
Paragraph 0015
(2017/04/03)
-
- METHODS FOR TREATING CANCER AND THE USE OF BIOMARKERS AS A PREDICTOR OF CLINICAL SENSITIVITY TO THERAPIES
-
A method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising administering the treatment compound to the subject having the cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is a compound of Formula I:
- -
-
Paragraph 00464
(2017/08/01)
-
- ANTIPROLIFERATIVE COMPOUNDS, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES
-
Compounds of formula A-I and B-I, compositions comprising the compounds, methods of making the compounds and methods of their uses are disclosed.
- -
-
Paragraph 00375; 00387
(2017/08/01)
-
- HETEROCYCLIC COMPOUND
-
The present invention provide a heterocyclic compound having a HDAC inhibitory action, and useful for the treatment of autoimmune diseases and/or inflammatory diseases, graft versus host disease, cancers, central nervous diseases including neurodegenerative diseases, Charcot-Marie-Tooth disease and the like, and a pharmaceutical composition comprising the compound. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.
- -
-
Paragraph 1062-1063
(2017/02/09)
-
- COMPOSITIONS AND METHODS FOR INDUCING CONFORMATIONAL CHANGES IN CEREBLON AND OTHER E3 UBIQUITIN LIGASES
-
Provided herein are compositions, therapeutic methods, screening methods, computational methods and biomarkers based upon the elucidation of the interaction among cereblon, its substrates and certain compounds or agents, including small molecules, peptides, and proteins.
- -
-
Paragraph 00471
(2017/07/14)
-
- Development of Bifunctional Inhibitors of Polo-Like Kinase 1 with Low-Nanomolar Activities Against the Polo-Box Domain
-
Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.
- Scharow, Andrej,Knappe, Daniel,Reindl, Wolfgang,Hoffmann, Ralf,Berg, Thorsten
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p. 759 - 767
(2016/04/26)
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- Bruton tyrosine kinases inhibitor
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The invention relates to pyrazolo[3,4-d]pyrimidine derivatives, and a preparation method and application thereof to medicines. Concretely, the invention relates to new pyrazolo[3,4-d]pyrimidine derivatives shown as general formulas I and IA, a preparation method of the derivatives, a pharmaceutical composition containing the derivatives, and application of the derivatives as therapy equipment especially as a Bruton tyrosine kinases inhibitor.
- -
-
Paragraph 0094; 0095; 0096
(2016/10/08)
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- SPIRODIAMINE DERIVATIVES AS ALDOSTERONE SYNTHASE INHIBITORS
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The invention provides compounds having the general formula (I) pharmaceutical compositions containing the compounds and a process for their preparation. The compounds act as aldosterone synthase inhibitors and are for use in the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
- -
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Page/Page column 40; 41
(2016/05/02)
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- A substituted heteroaryl compounds and compositions containing such compounds and use thereof (by machine translation)
-
The present invention provides a substituted heteroaryl compounds and compositions containing such compounds and its use, the invention discloses a formula (I) indicated by the heteroaryl compound, or its crystalline form, a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or compound solvent. The invention of monocyclic the base states compounds and compositions containing such compounds may be used to modulate hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO), but also has good pharmacokinetic parameter characteristic, can improve the compound in animal drug concentration, in order to improve the effect of drugs and safety. (by machine translation)
- -
-
Paragraph 0062; 0063-0064
(2017/04/19)
-
- Novel Imidazoles for the Treatment and Prophylaxis of Respiratory Syncytial Virus Infection
-
The invention provides novel compounds having the general formula: wherein R1, R2, R3 and Q are as described herein, compositions including the compounds and methods of using the compounds.
- -
-
Paragraph 0221; 0222
(2016/11/28)
-
- Aminoheteroaryl benzamides as kinase inhibitors
-
The present invention provides a compound of Formula (I) or a salt thereof; and therapeutic uses of these compounds. The present invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds with a therapeutic co-agent.
- -
-
Page/Page column 379; 380
(2016/02/15)
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- USE OF BIOMARKERS FOR PREDICTING CLINICAL SENSITIVITY TO CANCER TREATMENT
-
A method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising administering the treatment compound to a subject having cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is a compound of Formula (I):
- -
-
Paragraph 00407
(2016/05/02)
-
- HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS AND COMBINATIONS THEREOF
-
Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds and combinations of such compounds and other therapeutic agents.
- -
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Page/Page column 89
(2015/07/07)
-
- Synthesis and biological evaluation of aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists: A potential treatment for neuropathic pain
-
Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain. In this study, we have developed mGluR1 antagonists with an aryl isoxazole scaffold, and identify several compounds that are orally active in vivo. We believe that these compounds can serve as a useful tool for the investigation of the role of mGluR1 and a promising lead for the potential treatment of neuropathic pain.
- Cho, Gyeong Hi,Kim, Taehun,Son, Woo Seung,Seo, Seon Hee,Min, Sun-Joon,Cho, Yong Seo,Keum, Gyochang,Jeong, Kyu-Sung,Koh, Hun Yeong,Lee, Jiyoun,Pae, Ae Nim
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p. 1324 - 1328
(2015/03/14)
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- NRF2 REGULATORS
-
The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.
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-
Page/Page column 571
(2015/07/07)
-
- Modulators of methyl modifying enzymes, compositions and uses thereof
-
Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.
- -
-
Page/Page column 216; 217
(2015/12/26)
-
- SUBSTITUTED BENZOFURANYL AND BENZOXAZOLYL COMPOUNDS AND USES THEREOF
-
The invention generally relates to substituted benzofuranyl and substituted benzoxazolyl compounds, and more particularly to a compound represented by Structural Formula (A) : or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of Structural Formula (A), or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment of cancer (e.g., mantle cell lymphoma), and other diseases and disorders.
- -
-
Paragraph 00412
(2015/01/16)
-
- Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis
-
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclinical characterization based on its favorable properties.
- Lou, Yan,Han, Xiaochun,Kuglstatter, Andreas,Kondru, Rama K.,Sweeney, Zachary K.,Soth, Michael,McIntosh, Joel,Litman, Renee,Suh, Judy,Kocer, Buelent,Davis, Dana,Park, Jaehyeon,Frauchiger, Sandra,Dewdney, Nolan,Zecic, Hasim,Taygerly, Joshua P.,Sarma, Keshab,Hong, Junbae,Hill, Ronald J.,Gabriel, Tobias,Goldstein, David M.,Owens, Timothy D.
-
supporting information
p. 512 - 516
(2015/03/03)
-
- IMIDAZOLES FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS INFECTION
-
The invention provides novel compounds having the general formula: (I) wherein R1, R2, R3 and Q are as described herein, compositions including the compounds and methods of using the compounds.
- -
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Page/Page column 36; 37
(2015/08/06)
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- COMPOSITIONS AND METHODS FOR INDUCING CONFORMATIONAL CHANGES IN CEREBLON OTHER E3 UBIQUITIN LIGASES
-
Provided herein are compositions, therapeutic methods, screening methods, computational methods and biomarkers based upon the elucidation of the interaction among cerebloR, its substrates and certain compounds or agents, including small molecules, peptides, and proteins.
- -
-
Paragraph 00388
(2016/05/02)
-
- SPIROCYCLIC COMPOUNDS AS TRYPTOPHAN HYDROXYLASE INHIBITORS
-
The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.
- -
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Page/Page column 263; 264
(2015/03/28)
-
- Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators
-
NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A-D subunits that mediate a slow Ca2+-permeable component of excitatory synaptic transmission. NMDA receptors have been implicated in a wide range of neurological diseases and thus represent an important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested were over 100-fold selective for recombinant GluN2C-containing receptors over GluN2A/B/D-containing NMDA receptors as well as AMPA and kainate receptors. This series represents the first class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA receptors.
- Zimmerman, Sommer S.,Khatri, Alpa,Garnier-Amblard, Ethel C.,Mullasseril, Praseeda,Kurtkaya, Natalie L.,Gyoneva, Stefka,Hansen, Kasper B.,Traynelis, Stephen F.,Liotta, Dennis C.
-
supporting information
p. 2334 - 2356
(2014/04/17)
-
- Substituted 5,6,11,12-tetradehydrodibenzo[ a, e ]cyclooctenes: Syntheses, properties, and DFT studies of substituted sondheimer-wong diynes
-
Highly strained cyclic acetylenes 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctenes (Sondheimer-Wong diynes) having various substituents on their benzene rings were synthesized successfully by one-pot treatment of the corresponding formyl sulfones with diethyl chlorophosphate/lithium hexamethyldisilazide (LiHMDS) and then lithium diisopropylamide (LDA). When mixtures of two types of formyl sulfones bearing different substituents were subjected to this protocol, the unsymmetrically substituted Sondheimer-Wong diynes could be synthesized in a stepwise manner by isolation of the heterocoupled vinyl sulfone intermediates followed by their treatment with LDA. The UV-vis absorption spectra and cyclic voltammograms of the substituted Sondheimer-Wong diynes were recorded. The electronic effect of substituents on the diynes was investigated in their click reactions and nucleophilic and electrophilic additions.
- Xu, Feng,Peng, Lifen,Shinohara, Kenta,Morita, Takamoto,Yoshida, Suguru,Hosoya, Takamitsu,Orita, Akihiro,Otera, Junzo
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p. 11592 - 11608
(2015/01/09)
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- HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS
-
Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds.
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-
Page/Page column 74
(2014/01/18)
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- FUSED TRICYCLIC AMIDE COMPOUNDS AS MULTIPLE KINASE INHIBITORS
-
Provided are fused tricyclic amide compounds, pharmaceutical compositions comprising at least one such fused tricyclic compound, processes for the preparation thereof, and the use thereof in therapy. Disclosed herein are certain tricyclic amide compounds that can be useful for inhibiting multiple (specifically BRAF and/or EGFR-T790M) kinases and for treating disorders mediated thereby.
- -
-
Page/Page column 114
(2015/01/16)
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- PERFORIN INHIBITING BENZENESULFONAMIDE COMPOUNDS, PREPARATION AND USES THEREOF
-
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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-
Page/Page column 62; 63
(2014/03/25)
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- NEW 3,4-DIHYDRO-2H-ISOQUINOLINE-1-ONE AND 2,3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS
-
The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, A, B, m, n and p are as described herein compositions including the compounds and methods of using the compounds.
- -
-
Page/Page column 42; 43
(2014/12/12)
-
- NEW 3,4-DIHYDRO-2H-ISOQUINOLINE-1-ONE AND 2,3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS
-
The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, A, m, n and p are as described herein, compositions including the compounds and methods of using the compounds.
- -
-
Page/Page column 40
(2014/12/12)
-
- NEW 3,4-DIHYDRO-2H-ISOQUINOLINE-1-ONE AND 2,3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS
-
The invention provides novel compounds having the general formula (I) (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, A, m, n and p described herein, compositions including the compounds and methods of using the compounds.
- -
-
Page/Page column 40; 41
(2014/12/12)
-
- An environmentally-friendly one-pot synthesis of 4-sulfonyl benzoic acids
-
This Letter reports an environmentally-friendly one-pot SNAr reaction of thiols to 4-halobenzoic acid methyl esters to provide 4-substituted sulfone benzoic acids and picolinic acids after bleach-mediated oxidative workup. These acid intermediates were synthesized on gram scale, are perfect partners for library synthesis, and have good physical chemical properties useful for drug discovery.
- Frieman, Bryan A.
-
supporting information
p. 3295 - 3298
(2014/06/09)
-
- SUBSTITUTED 1H-PYRROLOPYRIDINONE DERIVATIVES AS KINASE INHIBITORS
-
The present invention provides novel substituted 1H-Pyrrolopyridinone derivatives of formula (1) as protein kinase inhibitors, in which R1, R2, R3, R4, R5, R6 and 'p' have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting kinase enzyme, more particularly BTK enzyme. The present invention also provides methods for synthesizing and administering the kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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-
Page/Page column 24
(2014/09/03)
-
- NEW BICYCLIC DIHYDROISOQUINOLINE-1-ONE DERIVATIVES
-
The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4? R5, R6, A1, A2, A3, A4, A5 and n are as described herein,compositions including the compounds and methods of using the compounds as aldosterone synthase (CYP11B2 or CYP11B1) inhibitors for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
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-
Page/Page column 164
(2013/06/27)
-
- Characterization of amide bond conformers for a novel heterocyclic template of N-acylhydrazone derivatives
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Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their 1H- and 13C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and 1H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N-acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the ΔG≠ values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond-related conformations.
- Lopes, Alexandra Basilio,Miguez, Eduardo,Kuemmerle, Arthur Eugen,Rumjanek, Victor Marcos,Fraga, Carlos Alberto Manssour,Barreiro, Eliezer J.
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p. 11683 - 11704
(2013/11/06)
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- MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF
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Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein
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Paragraph 00467; 00468
(2013/06/05)
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- 8-ETHYL-6-(ARYL)PYRIDO [2,3-D]PYRIMIDIN-7(8H) -ONES FOR THE TREATMENT OF NERVOUS SYSTEM DISORDERS AND CANCER
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Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders or neurofibromatosis. Also described herein are methods of utilizing PAK inhibitors for the treatment of cancer.
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Paragraph 00617
(2013/04/10)
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- Benzohydroxamic acids as potent and selective anti-HCV agents
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A diverse collection of 40 derivatives of benzohydroxamic acid (BHAs) of various structural groups were synthesized and tested against hepatitis C virus (HCV) in full-genome replicon assay. Some of these compounds demonstrated an exceptional activity, suppressing viral replication at sub-micromolar concentrations. The compounds were inactive against key viral enzymes NS3, and NS5B in vitro assays, suggesting host cell inhibition target(s). The testing results were consistent with metal coordination by the BHAs hydroxamic group in complex with a target(s). Remarkably, this class of compounds did not suppress poliomyelitis virus (PV) propagation in RD cells indicating a specific antiviral activity of BHAs against HCV.
- Kozlov, Maxim V.,Kleymenova, Alla A.,Romanova, Lyudmila I.,Konduktorov, Konstantin A.,Smirnova, Olga A.,Prasolov, Vladimir S.,Kochetkov, Sergey N.
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p. 5936 - 5940
(2013/10/22)
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- AMIDE DERIVATIVE
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Provided are a compound having an excellent hypoglycemic action, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition having an excellent therapeutic effect and/or prophylactic effect on type 1 diabetes, type 2 diabetes, and the like, which cause an increase in the blood sugar level due to abnormal sugar metabolism. A compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, is disclosed.
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Page/Page column 11
(2012/06/01)
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- Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: Structure-activity relationships and assessment in a rat model of nicotine dependence
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Compounds that modulate metabotropic glutamate subtype 2 (mGlu2) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu 2 receptor positive allosteric modulators (PAMs). The effects of N-substitution (R1) and substitutions on the aryl ring (R 2) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu 2 receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.
- Sidique, Shyama,Dhanya, Raveendra-Panickar,Sheffler, Douglas J.,Nickols, Hilary Highfield,Yang, Li,Dahl, Russell,Mangravita-Novo, Arianna,Smith, Layton H.,D'Souza, Manoranjan S.,Semenova, Svetlana,Conn, P. Jeffrey,Markou, Athina,Cosford, Nicholas D.P.
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p. 9434 - 9445
(2013/01/16)
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- Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: Pyrrole regioisomers and propionic acid replacement
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S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.
- Sun, Xicheng,Qiu, Jian,Strong, Sarah A.,Green, Louis S.,Wasley, Jan W.F.,Colagiovanni, Dorothy B.,Mutka, Sarah C.,Blonder, Joan P.,Stout, Adam M.,Richards, Jane P.,Chun, Lawrence,Rosenthal, Gary J.
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supporting information; experimental part
p. 3671 - 3675
(2011/08/06)
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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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Page/Page column 131
(2012/08/29)
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- INHIBITORS OF DIACYLGLYCEROL ACYL TRANSFERASE
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The present invention relates to heterocyclic compounds in all their stereoisomeric and tautomeric forms; and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutically acceptable polymorphs. The invention also relates to processes for the manufacture of the heterocyclic compounds and to pharmaceutical compositions containing them. The said compounds and their pharmaceutical compositions are useful in the prevention and treatment of diseases or disorders mediated by diacylglycerol acyltransferase (DGAT), particularly DGAT1. The present invention further provides a method of treatment of such diseases or disorders by administering a therapeutically effective amount of said compounds or their pharmaceutical compositions, to a mammal in need thereof.
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