- Synthesis and biological evaluation of 4-(pyridine-4-oxy)-3-(tetrahydro-2H-pyran-4-yl)-pyrazole derivatives as novel, potent of ALK5 receptor inhibitors
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The transforming growth factor type β receptor I (TGF-β R1, also known as activin-like kinase 5 or ALK5) plays a significant role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis. Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. Herein, a novel series of 4-(pyridine-4-oxy)-3-(tetrahydro-2H-pyran-4-yl)-pyrazole derivatives was synthesized and identified as ALK5 inhibitors. Among them, compound 8h inhibited ALK5 autophosphorylation and NIH3T3 cell activity with IC50 values of 25 nM and 74.6 nM, respectively. Compound 8h also showed favorable pharmacokinetic profile and ameliorated hERG inhibition. More importantly, 30 mg/kg oral administration of 8h could significantly induce tumour growth inhibition in CT26 xenograft model without obvious toxicity.
- Wang, Hai,Wang, Xiaowei,Wang, Zhenwei,Yu, Zhuangzhuang,Zhang, Yan,Zhao, Liwen
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supporting information
(2022/02/16)
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- Crystal form of quinoline TGF-beta1 inhibitor
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The invention belongs to the field of medical chemistry, and relates to a crystal form of a quinoline TGF-beta1 inhibitor as well as a preparation method and application of the crystal form, in particular to a crystal form of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl) oxy)-7-(3-(trifluoromethyl)-5, 6-dihydro-[1, 2, 4] triazolo [4, 3-a] pyrazine-7 (8H)-yl) quinoline as shown in a formula (I) and a preparation method of the crystal form. The crystal form can be used for preparing medicines for treating and/or preventing cancers, tissue hyperplasia diseases, fibrosis or inflammatory diseases.
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Paragraph 0073; 0075-0077
(2021/10/27)
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- Method for preparing quinoline TGF-β1 inhibitor
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The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of quinoline TGF-β1 inhibitor, in particular to I ((4 -) propyl 1 - (tetrahydro -3 - pyran - 2H - yl) -4 - pyrazole - 1H -yloxy) -4 - (-7 - (trifluoromethyl) 3 -5 dihydro 6 - [- 1] triazolo [2, 4] pyrazine 4 (8H) 3 - a -7-yl) quinoline or a salt thereof. A process for the preparation of a hydrate, solvate or crystal.
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Paragraph 0070-0074
(2021/10/27)
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- Quinoline compound Preparation method and application thereof
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The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a quinoline compound, a preparation method thereof and application thereof as reference control product in 4 - ((1 - cyclopropyl -3 - (tetrahydro - 2H - pyran -4 - yl) - 1H - pyrazole -4 -yloxy) -7 - (3 -trifluoromethyl) -5, 6 - dihydro - [1, 2] pyrazino [4, 4] pyrazine 3 - a (8H) -7 -yl) quinoline bulk drug.
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Paragraph 0047-0051
(2021/10/27)
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- Medicinal salt of quinoline TGF-beta1 inhibitor and preparation method thereof
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The invention belongs to the field of medical chemistry, and relates to a medicinal salt of a quinoline TGF-beta1 inhibitor, or a hydrate, a solvate or a crystal thereof, and a preparation method and application thereof. Specifically, the invention relates to a medicinal salt of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl) oxy)-7-(3-(trifluoromethyl)-5, 6-dihydro-[1, 2, 4] triazolo [4, 3-a] pyrazine-7 (8H)-yl) quinoline as shown in a formula (I), or a hydrate, a solvate or a crystal thereof, and a preparation method thereof. The medicinal salt or the hydrate, the solvate or the crystal thereof can be used for preparing medicines for treating and/or preventing cancers, tissue hyperplasia diseases, fibrosis or inflammatory diseases.
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Paragraph 0044-0048
(2021/10/27)
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- SUBSTITUTED HYDANTOINAMIDES AS ADAMTS7 ANTAGONISTS
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The application relates to substituted hydantoinamides of formula (I) as ADAMTS7 antagonists, to processes for their preparation, their use alone or in combination for the treatment or prophylaxis of diseases, in particular of cardiovascular diseases, including atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), arterial occlusive disease or restenosis after angioplasty. R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, 5- to 6-membered heteroaryl or phenyl; R2 is hydrogen or alkyl; A is 5-membered heteroaryl; Z is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; all groups being optionally substituted.
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Page/Page column 132
(2021/05/21)
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- SUBSTITUTED IMIDAZOLE CARBOXAMIDES AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS
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The invention provides substituted imidazole carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.
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Paragraph 00506
(2021/04/01)
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- 2-aryl-4-(4-pyrazoloxy)pyridine compound as well as preparation method, pharmaceutical composition and application thereof
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The invention relates to a 2-aryl-4-(4-pyrazoloxy)pyridine compound as well as a preparation method, a pharmaceutical composition and application thereof. The 2-aryl-4-(4-pyrazoloxy) pyridine compoundis specifically a 2-aryl-4-(4-pyrazoloxy)pyridine compound with a structural general formula shown in the specification, or a pharmaceutically acceptable salt thereof. The compound can be used as a therapeutic preparation, especially as a TGF-beta signaling pathway inhibitor, and has a good application prospect in preparation of drugs for preventing, alleviating and treating diseases mediated byTGF-beta signaling pathway disorder.
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Paragraph 0044-0045
(2020/05/30)
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- 4-(4-pyrazoloxy)quinoline compound and preparation method thereof, pharmaceutical composition and application for 4-(4-pyrazoloxy)quinoline compound and pharmaceutical composition
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The invention relates to a 4-(4-pyrazoloxy)quinoline compound and a preparation method thereof, a pharmaceutical composition and an application for 4-(4-pyrazoloxy)quinoline compound and pharmaceutical composition The invention specifically provides a 4-(4-pyrazoloxy)quinoline compound with a structural general formula as shown in the specification, or a tautomer, a mesomer, a raceme, an enantiomer, a diastereoisomer or a pharmaceutically acceptable salt thereof. The compound provided by the invention can be used as a therapeutic preparation, specifically as a TGF-beta signaling pathway inhibitor, and has good application prospects in preparation of drugs for prevention, mitigation and treatment of TGF-beta signaling pathway disorder mediated diseases.
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Paragraph 0108-0112; 0113-0114
(2020/07/13)
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- Compound serving as TGF-betaR1 inhibitor and application of compound
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The invention belongs to the field of medical chemistry. The invention relates to a compound serving as a TGF-betaR1 inhibitor and application of the compound. Specifically, the invention provides a compound shown as a formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, the invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds or the composition in treatment and/or prevention of TGF-betaR1 related diseases, such as cancers, tissue hyperplasia diseases, fibrosis and inflammatory diseases. The compound provided by the invention shows significant inhibitory activity on TGF-betaR1 kinase, and is very expected to become a therapeutic agent for TGF-betaR1 related diseases.
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Paragraph 0193-0197
(2020/05/08)
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- TGF-betaR1 inhibitor and application thereof
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The invention belongs to the field of medical chemistry, and particularly relates to a compound serving as a TGF-betaR1 inhibitor and application of the compound. Specifically, the invention providesa compound shown as a formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds or the composition to treatment and/or prevention of TGF-betaR1 related diseases, such as cancers, tissue hyperplasia diseases, fibrosis and inflammatory diseases. The compound provided by the invention shows significant inhibitory activity on TGF-betaR1 kinase, and is very expected to become a therapeutic agent for TGF-betaR1 related diseases.
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Paragraph 0117; 0119-0121
(2020/06/09)
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- Divergent synthesis of N-heterocycles by Pd-catalyzed controllable cyclization of vinylethylene carbonates
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Here, we report a palladium-catalyzed controllable cyclization of vinyl ethylene carbonates that proceeds through formal migration [2+3] and [5+2] cycloadditions, respectively, under mild conditions. The transformation described here affords a series of synthetically versatile 5,7-membered N-heterocycles which are found in natural products and pharmaceuticals with biological and medicinal properties.
- Yang, Yuwen,Yang, Weibo
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supporting information
p. 12182 - 12185
(2018/11/21)
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- Diversity-Orientated Stereoselective Synthesis through Pd-Catalyzed Switchable Decarboxylative C?N/C?S Bond Formation in Allylic Surrogates
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Switchable catalytic transformation of reactants can be a powerful approach towards diversity-orientated synthesis from easily available molecular synthons. Herein, an endogenous ligand-controlled, Pd-catalyzed allylic substitution allowing for either selective C?N or C?S bond formation using vinylethylene carbonates (VECs) and N-sulfonylhydrazones as coupling partners has been developed. This versatile methodology provides a facile, divergent route for the highly chemo- and stereoselective synthesis of functional allylic sulfones or sulfonohydrazides. The newly developed protocol features wide substrate scope (nearly 80 examples), broad functional group tolerance, and potential for the late-stage functionalization of bioactive compounds. The isolation and crystallographic analysis of a catalytically competent π-allyl Pd complex suggests that the pathway leading to the allylic products proceeds through a different manifold as previously proposed for the functionalization of VECs with nucleophiles.
- Deng, Lei,Kleij, Arjan W.,Yang, Weibo
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supporting information
p. 19156 - 19161
(2018/11/30)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 0369
(2017/05/14)
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- AMINOPYRIDYLOXYPYRAZOLE COMPOUNDS
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The present invention relates to novel aminopyridyloxypyrazole compounds that inhibit the activity of transforming growth factor beta receptor 1 (TGFβR1), pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat cancer, preferably colon cancer, melanoma, hepatocellular carcinoma, renal cancer, glioblastoma, pancreatic cancer, myelodysplastic syndrome, lung cancer, and gastric cancer, and/or fibrosis, preferably liver fibrosis and chronic kidney disease.
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Paragraph 0046-0047
(2016/05/02)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 0220
(2015/10/05)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 0337
(2015/08/03)
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- HEXAHYDROPYRROLOTHIAZINE COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R9 are as defined in the specification and which compound has an Αβ production inhibitory effect and may be useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Αβ and typified by Alzheimer-type dementia (AD) or Down's syndrome.
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Page/Page column 100; 101
(2014/02/15)
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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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- Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent γ-Secretase Modulators
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The design and the synthesis of several chemical subclasses of imidazole containing γ-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo p
- Bischoff, Francois,Berthelot, Didier,De Cleyn, Michel,MacDonald, Gregor,Minne, Garrett,Oehlrich, Daniel,Pieters, Serge,Surkyn, Michel,Trabanco, Andres A.,Tresadern, Gary,Van Brandt, Sven,Velter, Ingrid,Zaja, Mirko,Borghys, Herman,Masungi, Chantal,Mercken, Marc,Gijsen, Harrie J. M.
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supporting information
p. 9089 - 9106,18
(2020/10/15)
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- 2-OXO-2- (2-PHENYL-5,6,7,8-TETRAHYDRO-INDOLIZIN-3-YL) -ACETAMIDE DERIVATIVES AND RELATED COMPOUNDS AS ANTIFUNGAL AGENTS
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The invention provides compounds of formula (I), and pharmaceutically and agriculturally acceptable salts thereof: wherein: R1, R2, R3, R4, R5, R6, R7, R8, A1, L1 and n are as defined herein. These compounds and their pharmaceutically acceptable salts are useful in the manufacture of medicaments for use in the prevention or treatment of a fungal disease. Compounds of formula (I), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.
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Page/Page column 14
(2011/02/15)
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