- Heterocyclic substituted biphenyl compound as well as preparation method and application thereof
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The invention discloses a heterocyclic substituted biphenyl compound as well as a preparation method and application thereof. According to the present invention, the compound can block the PD-1/PD-L1 signal pathway, and can be used as the immune checkpoint PD-1/PD-L1 small molecule inhibitor; and according to the compound disclosed by the invention, the metabolic stability is improved while the high binding rate with PD-L1 protein is maintained. A hydrophilic group is introduced to a heterocyclic ring, and the PD-1/PD-L1 inhibitory activity is improved.
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- Addition of Fluorine and a Late-Stage Functionalization (LSF) of the Oral SERD AZD9833
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Herein we describe our efforts using a late stage functionalization together with more traditional synthetic approaches to generate fluorinated analogues of the clinical candidate AZD9833. The effects of the addition of fluorine on the lipophilicity, permeability, and metabolism are discussed. Many of these changes were tolerated in terms of pharmacology and resulted in high quality molecules which reached advanced stages of profiling in the testing cascade.
- Scott, James S.,Moss, Thomas A.,Barlaam, Bernard,Davey, Paul R. J.,Fairley, Gary,Gangl, Eric T.,Greenwood, Ryan D. R.,Hatoum-Mokdad, Holia,Lister, Andrew S.,Longmire, David,Polanski, Radoslaw,Stokes, Stephen,Tucker, Michael J.,Varnes, Jeffrey G.,Yang, Bin
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supporting information
p. 2519 - 2525
(2020/11/16)
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- IMMUNOMODULATORS, COMPOSITIONS AND METHODS THEREOF
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Provided are compounds of formula I, pharmaceutical compositions thereof, and methods of using the compounds as immunomodulators. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.
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Page/Page column 17-18
(2020/02/14)
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- Regioselective Functionalization of 4-Methyl-1H-indole for Scalable Synthesis of 2-Cyano-5-formyl-4-methyl-1H-indole
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We report a five-step synthesis of 2-cyano-5-formyl-4-methyl-1H-indole through sequential functionalization of readily available 4-methyl-1H-indole. Cyano and aldehyde functionalities are regioselectively installed at the 2 and 5 position, respectively. T
- Zhang, Jun,Hu, Yun,Wang, Haiyu,Guo, Aixin,Kong, Jianshe,Ma, Rujian,Wu, Tao,Wang, Yi,Li, Lian-Sheng,Mai, Wanping,Ren, Pingda,Deng, Xiaohu
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- METHODS OF PROMOTING BETA CELL PROLIFERATION
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The present disclosure provides methods of promoting proliferation of a pancreatic cell. The methods are useful for the treatment of diabetes and other diseases characterized by impaired glucose tolerance.
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- Propionic Acid Derivatives and Methods of Use Thereof
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Provided herein are compounds and pharmaceutical compositions of formula I where R1, R2, R3, R4, R5 and R6 are as described herein. Also provided pharmaceutically acceptable salts or stereoisomers of these compounds. In addition methods are provided for inhibiting the binding of an integrin to treat various pathophysiological conditions.
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- CHEMICAL COMPOUNDS
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The specification relates to compounds of Formula (I): and pharmaceutically acceptable salts thereof. The specification also relates to processes and intermediates used for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.
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Paragraph 0629; 0630
(2017/11/11)
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- INDAZOLE DERIVATIVES THAT DOWN-REGULATE THE ESTROGEN RECEPTOR AND POSSESS ANTI-CANCER ACTIVITY
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The specification relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof. The specification also relates to processes and intermediates used for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.
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Page/Page column 121
(2017/12/28)
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- HETEROCYCLIC COMPOUNDS AS IMMUNOMODULATORS
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Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or
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Page/Page column 61-62; 102
(2017/06/12)
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- Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL)
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Development of potent small molecule inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compounds, which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compound 1 (MI-136) to identify compounds suitable for in vivo studies in mice. This work resulted in the identification of compound 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications.
- Borkin, Dmitry,Pollock, Jonathan,Kempinska, Katarzyna,Purohit, Trupta,Li, Xiaoqin,Wen, Bo,Zhao, Ting,Miao, Hongzhi,Shukla, Shirish,He, Miao,Sun, Duxin,Cierpicki, Tomasz,Grembecka, Jolanta
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p. 892 - 913
(2016/02/23)
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- THIENOPYRIMIDINE AND THIENOPYRIDINE COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules including but not limited to MLL1, MLL2 and MLL-fusion oncoproteins. Compounds of the disclosure may be used
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- CATALYSTS
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A racemic complex of formula (I), wherein ? M is zirconium or hafnium; ? each X is a sigma ligand; ? L is a divalent bridge selected from -R'2C-, -R'2C-CR'2, -R'2Si-, - R'2Si-SiR'2-, -R'2Ge-, wherein each R' is independently a hydrogen atom, C1-20-hydrocarbyl, tri(C1-20-alkyl)silyl, C6-20-aryl, C7-20-ary- lalkyl or C7-20-alkylaryl; ? R2 and R2' are each independently a C1-20 hydrocarbyl radical optionally containing one or more heteroatoms from groups 14-16; ? R5' is a C1-20 hydrocarbyl group optionally containing one or more heteroatoms from groups 14-16 and optionally substituted by one or more halo atoms.
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Page/Page column 68;69
(2013/03/26)
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- COMPOUNDS
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The present invention relates to novel compounds having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
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Page/Page column 39
(2011/11/12)
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- COMPOUNDS AS AGONISTS OF S1P1 RECEPTORS
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Compounds of formula (I), processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases mediated by S1P1 receptors.
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Page/Page column 80
(2011/11/12)
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- CARBAZOLE CARBOXAMIDE COMPOUNDS USEFUL AS KINASE INHIBITORS
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Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, thereof, are useful as kinase modulators, including Btk modulation.
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Page/Page column 36
(2010/07/04)
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- Chemical and biological studies of nakiterpiosin and nakiterpiosinone
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Nakiterpiosin and nakiterpiosinone are two related C-nor-D-homosteroids isolated from the sponge Terpios hoshinota that show promise as anticancer agents. We have previously described the asymmetric synthesis and revision of the relative configuration of
- Gao, Shuanhu,Wang, Qiaoling,Huang, Lily Jun-Shen,Lum, Lawrence,Chen, Chuo
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supporting information; scheme or table
p. 371 - 383
(2010/03/25)
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- NOVEL FUSED CYCLIC COMPOUND AND USE THEREOF
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A compound represented by the formula (I): wherein each symbol is as defined in the specification, and a salt thereof have a GPR40 receptor activation action and is useful as an insulin secretagogue or a prophylactic or therapeutic drug for diabetes and the like.
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Page/Page column 347-348
(2010/12/29)
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- INHIBITORS OF STEAROYL-COA DESATURASE
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity.
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- 4-PHENYLPIPERIDINE DERIVATIVES AS RENIN INHIBITORS
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Compounds of the present invention having the formula (I) exhibit inhibitory activity on the natural enzyme renin. Thus, compounds of formula (I) may be employed for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
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Page/Page column 70
(2008/06/13)
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- Novel thiophene amidines, compositions thereof, and methods of treating complement-mediated diseases and conditions
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Disclosed is a method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein R1, R2, R3, R4 and R7 are defined in the specification, Z is SO or SO2, and Ar is an aromatic or heteroaromatic group as defined herein.
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- NOVEL THIOPHENE AMIDINES, COMPOSITIONS THEREOF, AND METHODS OF TREATING COMPLEMENT-MEDIATED DISEASES AND CONDITIONS
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Disclosed is a method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (I) or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein R1, R2, R3, R4 and R7 are defined in the specification, Z is SO or SO2, and Ar is an aromatic or heteroaromatic group as defined herein.
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- Synthesis of detomidine and medetomidine metabolites: 1,2,3- Trisubstituted arenes with 4'(5')-imidazolylmethyl groups
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Two synthetic strategies permitted the synthesis of various metabolites of detomidine (1) and medetomidine (4), potent α-2 adrenoceptor agonists that undergo rapid oxidative metabolism at the aromatic methyl group distal to the imidazole ring. In the detomidine series, the addition of a Grignard reagent prepared from 2-((3',4'-dimethoxyphenyl)methoxy)methyl-6-bromotoluene (13) to imidazole-4(5)-carboxaldehyde (7) provided 2-(((3',4'- dimethoxyphenyl)methoxy)methyl)-6-(1'-hydroxy-1'-(5''- imidazolyl)methyl)toluene (14). In a subsequent reduction, it was possible to differentiate between the secondary benzylic hydroxyl group and the primary benzylic hydroxyl group protected as a 3,4-dimethoxybenzyl ether. Removal of the protecting group provided 3-(hydroxymethyl)detomidine (3-HD) (2) and an oxidation furnished 3-carboxydetomidine (3-CD) (3). However, in the medetomidine series, a similar hydrogenolysis of 2-(((3',4'- dimethoxyphenyl)methoxy)methyl)-6-(1'-hydroxy-1'-methyl-1'-(5''- imidazolyl)methyl)toluene (17) failed, and an alternate, longer route involving dehydration and reduction was necessary to secure 3- (hydroxymethyl)medetomidine (3-HM) (5) and following an oxidation, 3- carboxymedetomidine (3-CM) (6). Finally, an expeditious route to 3-CM (6) involved the addition of the Grignard reagent prepared from 2-(3-bromo-2- methylphenyl)-4,4-dimethyl-2-oxazoline (22) to 4-acetyl-1H-imidazole and the hydrogenolysis and hydrolysis of 2-(1-(4,4-dimethyl-2-oxazolyl))-6-(1'-oxo- 1'-(5'-imidazolyl)methyl)toluene (23).
- Stoilov,Watt,Goodman,St. Pyrek
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p. 1645 - 1652
(2007/10/02)
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