- Halogen-Dance-Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2-Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases
-
A series of acyclic nucleoside phosphonates (ANPs) was designed as inhibitors of bacterial adenylate cyclases (ACs), where adenine was replaced with 2-amino-4-arylthiazoles. The target compounds were prepared using the halogen dance reaction. Final AC inh
- ?esnek, Michal,?afránek, Michal,Dra?ínsky, Martin,Tlou??ová, Eva,Mertlíková-Kaiserová, Helena,Hayes, Michael P.,Watts, Val J.,Janeba, Zlatko
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- COMPOUNDS AND USES THEREOF
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The present invention features compounds useful in the treatment of neurological disorders and primary brain cancer. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders and primary brain cancer.
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Page/Page column 361-362
(2020/10/20)
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- NOVEL INHIBITOR OF CYCLIN-DEPENDENT KINASE CDK9
-
The present invention relates to an inhibitor of cyclin-dependent kinase CDK9, having a structure of formula (I). The present invention also provides a method of treating a cancer of a precancerous condition related to CDK9 activity with the inhibitor and a use of the same.
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Paragraph 0059
(2020/03/13)
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- COMPOUNDS AND USES THEREOF
-
The present invention features compounds useful in the treatment of neurological disorders. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders.
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Page/Page column 355-356
(2019/10/15)
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- DIAZANAPHTHALEN-3-YL CARBOXAMIDES AND PREPARATION AND USE THEREOF
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Diazanaphthalene compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of a diazanaphthalene compound or analogs thereof, in the treatment of disorders characterized by the activa
- -
-
Paragraph 0927-0928
(2019/05/15)
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- SUBSTITUTED AMINOTHIAZOLES AS INHIBITORS OF NUCLEASES
-
The invention provides compounds represented by the structural formula (1): wherein R1, R2, R3, R4, R5, R6 are as defined in the claims. The compounds are inhibitors of nucleases, and are useful in particular in a method of treatment and/or prevention of proliferative diseases, neurodegenerative diseases, and other genomic instability associated diseases.
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Page/Page column 14;
(2019/11/12)
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- Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor
-
Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound 40 (JSH-150), which exhibited an IC50 of 1 nM against CDK9 kinase in the biochemical assay and achieved around 300–10000-fold selectivity over other CDK kinase family members. In addition, it also displayed high selectivity over other 468 kinases/mutants (KINOMEscan S score(1) = 0.01). Compound 40 displayed potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer as well as leukemia cell lines. It could dose-dependently inhibit the phosphorylation of RNA Pol II, suppress the expression of MCL-1 and c-Myc, arrest the cell cycle and induce the apoptosis in the leukemia cells. In the MV4-11 cell-inoculated xenograft mouse model, 10 mg/kg dosage of 40 could almost completely suppress the tumor progression. The high selectivity and good in vivo PK/PD profile suggested that 40 would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers.
- Wang, Beilei,Wu, Jiaxin,Wu, Yun,Chen, Cheng,Zou, Fengming,Wang, Aoli,Wu, Hong,Hu, Zhenquan,Jiang, Zongru,Liu, Qingwang,Wang, Wei,Zhang, Yicong,Liu, Feiyang,Zhao, Ming,Hu, Jie,Huang, Tao,Ge, Juan,Wang, Li,Ren, Tao,Wang, Yuxin,Liu, Jing,Liu, Qingsong
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p. 896 - 916
(2018/09/29)
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- AMINOTHIAZOLE COMPOUNDS AS C-KIT INHIBITORS
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The invention relates to c-Kit inhibitors useful in the treatment of cancers, and other -threonine kinase mediated diseases, having the Formula: (I) wherein A, L, R1, R2, R3, and n are described herein.
- -
-
Paragraph 00261
(2018/07/05)
-
- Preparation of 3,4-Substituted-5-Aminopyrazoles and 4-Substituted-2-Aminothiazoles
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3,4-Substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles are frequently used intermediates in medicinal chemistry and drug discovery projects. We report an expedient flexible synthesis of 3,4-substituted-5-aminopyrazoles (35 examples), based on palladium-mediated α-arylation of β-ketonitriles with aryl bromides. A library of 4-substituted-2-aminothiazoles (21 examples) was assembled by a sequence employing Suzuki coupling of newly prepared, properly protected pinacol ester and MIDA ester of 4-boronic acid-2-aminothiazole with (hetero)aryl halides.
- Havel, Stepan,Khirsariya, Prashant,Akavaram, Naresh,Paruch, Kamil,Carbain, Benoit
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p. 15380 - 15405
(2019/01/04)
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- CYANOPYRROLIDINE DERVIVATIVES AS INHIBITORS FOR DUBS
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The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of Cezanne 1 and ubiquitin C-terminal hydrolase 30 or Ubiquitin Specific Peptidase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of cancer. Compounds of the invention include compounds having the formula (I): pharmaceutically acceptable salt thereof, wherein R1a, R1b, R1c, R1d, R1e, R1f and A are as defined herein.
- -
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Page/Page column 47
(2017/07/14)
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- NOVEL COMPOUNDS
-
The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase L1 (UCHL1). The invention further relates to the use of DUB inhibitors in the treatment of cancer and other indications. Compounds of the invention include compounds having the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R8 are as defined herein.
- -
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Page/Page column 76
(2016/04/20)
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- 5-ARYL-THIAZOL-2-YL-AMINE COMPOUNDS AND THEIR THERAPEUTIC USE
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 5-aryl-thiazol-2-yl-amine compounds of the following formula (I) (for convenience, collectively referred to herein as "5AT2A compounds"), which, inter alia, inhibit LIM kinase (LIMK) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit LIMK activity, and in the treatment of diseases and conditions that are mediated by LIMK, that are ameliorated by the inhibition of LIMK activity, etc., including proliferative conditions such as cancer (e.g., breast cancer, prostate cancer, melanoma, glioma, etc.), as well as vasodilation (including, e.g., hypertension, angina, cerebral vasospasm, and ischemia following subarachnoid hemorrhage), neurodegenerative disorders, atherosclerosis, fibrosis, and inflammatory diseases (including, e.g., Crohn's disease and chronic obstructive pulmonary disease (COPD)), and glaucoma (also known as ocular hypertension). (Formula (I))
- -
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Page/Page column 118; 119
(2015/03/13)
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- Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus
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We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIII?). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.
- Décor, Anne,Grand-Ma?tre, Chantal,Hucke, Oliver,O'Meara, Jeff,Kuhn, Cyrille,Forget, Léa Constantineau,Brochu, Christian,Malenfant, Eric,Bertrand-Laperle, Mégan,Bordeleau, Josée,Ghiro, Elise,Pesant, Marc,Fazal, Gulrez,Gorys, Vida,Little, Michael,Boucher, Colette,Bordeleau, Sylvain,Turcotte, Pascal,Guo, Tim,Garneau, Michel,Spickler, Catherine,Gauthier, Annick
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p. 3841 - 3847
(2013/07/27)
-
- TRICYCLIC COMPOUNDS AS ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
-
The present invention describes and claims compounds of the Structural Formula (I), Structural Formula (II), or Structural Formula (III). In Formula (I), R1, R2, R3 and R3' are -H or methyl, or R3 and R3' taken together form a double bond, or R3' is -H and R2 and R3 taken together form a spiro-cyclopropyl substituent, R4 is -H or -F, and R5 is -H, methyl, -Cl or -Br. In Formula (II), R1 is -H, ethyl-, isopropyl-, cyclopropyl-, methyl- or methoxy-, R4 is -H or -F, and "Y" is: (a) -CH2-; (b) -CR6H-O-CR7R8-, wherein R6, R7, and R8 are independently -H or methyl; (c) -CR6H-N(R9)-CR7R8-, wherein R6, R7, and R8 are independently -H or methyl; (d) -CH2-C(R9)(R10)-C(R7)(R8)-, wherein R7, R8, R9 and R10 are independently -H or -methyl, or both R7 and R8 are -F, R9 and R10 are independently -H or -methyl, or both R9 and R10 are -F, or R9 and R10 taken together are (O=), which together with the carbon to which they are attached forms a carbonyl group.
- -
-
Page/Page column 48-49
(2012/02/02)
-
- TRICYCLIC COMPOUNDS AS ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
-
The present invention describes and claims compounds of the Structural Formula I, Structural Formula II, or Structural Formula III: wherein R1, R2, R3 and R3' are -H or methyl, or R3 and R3 taken together form a double bond, or R3' is -H and R2 and R3 taken together form a spiro-cyclopropyl substituent, R4 is -H or -F, and R5 is -H, methyl, -CI or -Br, Formula II wherein R1 is -H, ethyl-, isopropyl-, cyclopropyl-, methyl- or methoxy-, R4 is -H or -F, and "Y" is: (a) -CH2-; (b) -CR6H-0-CR7R8-, wherein R6, R7, and R8 are independently - H or methyl; (c) -CR6H-N(R9)-CR7R8-, wherein R6, R7, and R8 are independently -H or methyl; (d) -CH2-C(R9)(R10)-C(R7)(R8)-, wherein R7, R8, R9 and R10 are independently - H or -methyl, or both R7 and R8 are -F, R9 and R10 are independently -H or -methyl, or both R9 and R10 are -F, or R9 and R10 taken together are (0=), which together with the carbon to which they are attached forms a carbonyl group.
- -
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Page/Page column 49
(2012/02/02)
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- ALKYLSULFINYL-SUBSTITUTED THIAZOLIDE COMPOUNDS
-
A new class of alkylsulfinyl thiazolides is described. These compounds show strong activity against hepatitis viruses
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Page/Page column 29
(2012/05/07)
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- TRICYCLIC PYRAZOL AMINE DERIVATIVES
-
This invention relates to compounds of Formula (I*) as Pi3k inhibitors for treating autoimmune diseases, inflammatory disorders, multiple sclerosis and other diseases like cancers.
- -
-
-
- Utilization of a nitrogen-sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors
-
The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a un
- Lin, Shuqun,Wrobleski, Stephen T.,Hynes Jr., John,Pitt, Sidney,Zhang, Rosemary,Fan, Yi,Doweyko, Arthur M.,Kish, Kevin F.,Sack, John S.,Malley, Mary F.,Kiefer, Susan E.,Newitt, John A.,McKinnon, Murray,Trzaskos, James,Barrish, Joel C.,Dodd, John H.,Schieven, Gary L.,Leftheris, Katerina
-
scheme or table
p. 5864 - 5868
(2010/11/18)
-
- Azole-based inhibitors of AKT/PKB for the treatment of cancer
-
Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
- Zeng, Qingping,Allen, John G.,Bourbeau, Matthew P.,Wang, Xianghong,Yao, Guomin,Tadesse, Seifu,Rider, James T.,Yuan, Chester C.,Hong, Fang-Tsao,Lee, Matthew R.,Zhang, Shiwen,Lofgren, Julie A.,Freeman, Daniel J.,Yang, Suijin,Li, Chun,Tominey, Elizabeth,Huang, Xin,Hoffman, Douglas,Yamane, Harvey K.,Fotsch, Christopher,Dominguez, Celia,Hungate, Randall,Zhang, Xiaoling
-
scheme or table
p. 1559 - 1564
(2010/06/16)
-
- De novo synthesis of a potent LIMK1 inhibitor
-
A potent LIMK1 inhibitor, BMS4, was synthesised in six steps starting from pyrazine-2-carboximidamide, offering a significant improvement over current methods available in the literature.
- Sleebs, Brad E.,Street, Ian P.,Bu, Xian,Baell, Jonathan B.
-
experimental part
p. 1091 - 1096
(2010/06/11)
-
- FLUOROISOQUINOLINE SUBSTITUTED THIAZOLE COMPOUNDS AND METHODS OF USE
-
The invention relates to thiazole compounds of Formula (I) and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein. The invention also relates to the therapeutic use of such thiazole compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
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Page/Page column 57; 59
(2010/08/08)
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- ACETAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS, THEIR PROCESS AND MEDICINAL APPLICATION
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Acetamide derivatives, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or m
- -
-
Page/Page column 27
(2010/12/29)
-
- ALKYLSULFONYL-SUBSTITUTED THIAZOLIDE COMPOUNDS
-
A new class of alkylsulfonyl-substituted thiazolide compounds is described. These compounds show strong activity against hepatitis virus.
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Page/Page column 64; 72; 73
(2009/04/24)
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- TRIAZOLOPYRIDINE COMPOUNDS USEFUL AS KINASE INHIBITORS
-
A compound of Formula (I) and enantiomers, diastereomers and pharmaceutically-acceptable salts thereof. Also disclosed are pharmaceutical compositions containing compounds of Formula (I), and methods of treating conditions associated with the activity of
- -
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Page/Page column 52-53
(2010/01/12)
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- IMIDAZOPYRIDINE AND IMIDAZOPYRAZINE COMPOUNDS USEFUL AS KINASE INHIBITORS
-
A compound of Formula (I) or Formula (II) and enantiomers, diastereomers and pharmaceutically-acceptable salts thereof. Also disclosed are pharmaceutical compositions containing compounds of Formula (I) or Formula (II), and methods of treating conditions
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Page/Page column 62-63
(2010/01/12)
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- SULFOXIMINES AS KINASE INHIBITORS
-
The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
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Page/Page column 73-74
(2008/12/05)
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- ANTIBACTERIAL AGENTS
-
Antibacterial compounds of formula (I) are provided, as well as stereoisomers, pharmaceutically acceptable salts, esters, and prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
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Page/Page column 274-275
(2009/01/24)
-
- Pyrimidine benzamide-based thrombopoietin receptor agonists
-
A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.
- Reiter, Lawrence A.,Subramanyam, Chakrapani,Mangual, Emilio J.,Jones, Christopher S.,Smeets, Marc I.,Brissette, William H.,McCurdy, Sandra P.,Lira, Paul D.,Linde, Robert G.,Li, Qifang,Zhang, Fangning,Antipas, Amy S.,Blumberg, Laura C.,Doty, Jonathan L.,Driscoll, James P.,Munchhof, Michael J.,Ripp, Sharon L.,Shavnya, Andrei,Shepard, Richard M.,Sperger, Diana,Thomasco, Lisa M.,Trevena, Kristen A.,Wolf-Gouveia, Lilli A.,Zhang, Liling
-
p. 5447 - 5454
(2008/03/11)
-
- Phenyl-substituted pyrimidine compounds useful as kinase inhibitors
-
Compounds having the formula (I), and pharmaceutically acceptable salts, and solvates thereof, are useful as kinase inhibitors, wherein: two of X1, X2, and X3 are N, and the remaining one of X1, X2, a
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Page/Page column 69
(2008/06/13)
-
- Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors
-
Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth facto
- Kuo, Gee-Hong,Wang, Aihua,Emanuel, Stuart,DeAngelis, Alan,Zhang, Rui,Connolly, Peter J.,Murray, William V.,Gruninger, Robert H.,Sechler, Jan,Fuentes-Pesquera, Angel,Johnson, Dana,Middleton, Steven A.,Jolliffe, Linda,Chen, Xin
-
p. 1886 - 1900
(2007/10/03)
-