- Remarkably Efficient Iridium Catalysts for Directed C(sp2)-H and C(sp3)-H Borylation of Diverse Classes of Substrates
-
Here we describe the discovery of a new class of C-H borylation catalysts and their use for regioselective C-H borylation of aromatic, heteroaromatic, and aliphatic systems. The new catalysts have Ir-C(thienyl) or Ir-C(furyl) anionic ligands instead of the diamine-type neutral chelating ligands used in the standard C-H borylation conditions. It is reported that the employment of these newly discovered catalysts show excellent reactivity and ortho-selectivity for diverse classes of aromatic substrates with high isolated yields. Moreover, the catalysts proved to be efficient for a wide number of aliphatic substrates for selective C(sp3)-H bond borylations. Heterocyclic molecules are selectively borylated using the inherently elevated reactivity of the C-H bonds. A number of late-stage C-H functionalization have been described using the same catalysts. Furthermore, we show that one of the catalysts could be used even in open air for the C(sp2)-H and C(sp3)-H borylations enabling the method more general. Preliminary mechanistic studies suggest that the active catalytic intermediate is the Ir(bis)boryl complex, and the attached ligand acts as bidentate ligand. Collectively, this study underlines the discovery of new class of C-H borylation catalysts that should find wide application in the context of C-H functionalization chemistry.
- Chattopadhyay, Buddhadeb,Hassan, Mirja Md Mahamudul,Hoque, Md Emdadul
-
supporting information
p. 5022 - 5037
(2021/05/04)
-
- Synthesis of N-trifluoromethyl amides from carboxylic acids
-
Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.
- Flavell, Robert R.,Liu, Jianbo,Parker, Matthew F. L.,Toste, F. Dean,Wang, Sinan,Wilson, David M.
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supporting information
p. 2245 - 2255
(2021/08/12)
-
- METHODS OF USING REBASTINIB IN THE TREATMENT OF DISORDERS
-
Described herein are methods of treating various disorders in patients in need thereof, comprising administering to the patient the compound of Formula (I) or a pharmaceutically acceptable salt thereof. Exemplary disorders that can be treated by the methods described herein include gynecologic carcinosarcomas, endometrial adenocarcinomas, mesotheliomas, ovarian cancers, pancreatic ductal adenocarcinomas, and lung cancers.
- -
-
Paragraph 0467
(2021/09/10)
-
- Atroposelective Synthesis of Axially Chiral Styrenes via an Asymmetric C–H Functionalization Strategy
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Axially chiral styrenes, which exhibit a chiral axis between a substituted alkene and an aromatic ring, have been largely overlooked. The hurdle is the lower barriers to rotation compared with that of their biaryl counterparts, rendering their asymmetric synthesis more difficult. We report herein the highly atroposelective synthesis via a C?H functionalization strategy of axially chiral styrenes with an open-chained alkene. Various axially chiral styrenes were produced by Pd(II)-catalyzed C?H alkenylation and alkynylation in good yields (up to 99%) and enantioselectivities (up to 99% ee) by using L-pyroglutamic acid as an inexpensive chiral ligand. The potent application of the styrene atropisomers is demonstrated by a Co(III)-catalyzed enantioselective C?H amidation of ferrocene with axially chiral styrene-type acid as chiral ligand. Experimental and computational studies were conducted to elucidate the reaction mechanism. The chiral induction model of the enantioselectivity-determining C?H bond activation step was also provided based on DFT calculations. Atropisomerism, which stems from the hindered rotation around a chiral axis, is widely present in natural products, pharmaceuticals, and chiral catalysts or ligands. In contrast to the well-investigated biaryl atropisomers, the asymmetric synthesis of axially chiral styrenes bearing a chiral axis between an alkene and an aromatic ring remains a significant challenge. Here, we report a highly atroposelective synthesis of styrene atropisomers with open-chained alkene by asymmetric C?H functionalization by using available L-pyroglutamic acid as a chiral ligand. This strategy enables rapid access to a broad range of enantio-enriched axially chiral styrenes under mild conditions in an atom- and step-economical manner. The resulting axially chiral styrenes are important precursors for further elaborations, including the transformation into axially chiral styrene-type acids, which were demonstrated to be efficient chiral ligands in Co(III)-catalyzed enantioselective C?H amidation reactions. An asymmetric C–H functionalization strategy with L-pGlu-OH as chiral ligand has been developed for the atroposelective synthesis of styrene atropisomers with open-chained alkene. The strategy allows quick access to a wide range of enantio-enriched axially chiral styrenes in high yields and enantioselectivities. The axially chiral styrene-derived chiral acids have been demonstrated to be an efficient type of chiral ligands in Co(III)-catalyzed enantioselective C?H amidation reactions.
- Jin, Liang,Yao, Qi-Jun,Xie, Pei-Pei,Li, Ya,Zhan, Bei-Bei,Han, Ye-Qiang,Hong, Xin,Shi, Bing-Feng
-
supporting information
p. 497 - 511
(2020/02/20)
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- Picolinamide compound containing triazole or quinolinone structure and application of picolinamide compound
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The invention provides a picolinamide compound containing a triazole or quinolinone structure and application of the picolinamide compound. According to a technical scheme in the invention, extensiveresearch is conducted on the picolinamide compound, and
- -
-
Paragraph 0104; 0107-0108; 0229-0230
(2020/01/12)
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- Synthesis and evaluation of new thiourea derivatives as antitumor and antiangiogenic agents
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A series of novel thiourea derivatives were synthesized and evaluated by biological activities. Among them, compound 10e containing 3,5-bis(trifluoromethyl)phenyl moiety (R1) at the terminal thiourea and phenylamino (R2) at the terminal acyl position showed the best cytotoxic activities against seven cancer cell lines (NCI-H460, Colo-205, HCT116, MDA-MB-231, MCF-7, HepG2, PLC/PRF/5) and HUVECs. Moreover, compound 10e moderately inhibited various RTKs such as VEGFR2, VEGFR3, and PDGFRβ. Notably, 10e exhibited much better inhibitory effect of tumor formation and antiangiogenic activities than Sorafenib and Regorafenib at the same concentration. Further docking studies suggested that 10e could serve as potential candidate for cancer therapy.
- Bai, Wenjing,Huang, Qiang,Ji, Jianxin,Wei, Wei
-
supporting information
(2020/09/07)
-
- Design, synthesis, and biological evaluation of pyridineamide derivatives containing a 1,2,3-triazole fragment as type II c-Met Inhibitors
-
A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure-activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.
- Xiong, Hehua,Cheng, Jianxin,Zhang, Jianqing,Zhang, Qian,Xiao, Zhen,Zhang, Han,Tang, Qidong,Zheng, Pengwu
-
-
- Design, synthesis and biological evaluation of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment
-
A series of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment were designed, synthesized, and evaluated for their biological activity. Most compounds showed effective inhibitory activity against cancer cell lines of A
- Duan, Yongli,Tang, Qidong,Xiong, Hehua,Zhang, Han,Zhang, Jianqing,Zhang, Qian,Zheng, Pengwu
-
-
- 4 -phenoxypyridine compound containing quinoxalinone and application thereof (by machine translation)
-
The invention belongs to the field of medicines, and particularly relates to 4 -phenoxypyridine compounds containing quinoxalinone and application thereof. The 4 -phenoxypyridine compound containing quinoxalinone has the structure of the general formula (I). The invention also relates to the application of the compound of the general formula (I) to inhibit c-Met kinase and provide 4 -phenoxypyridine compounds containing quinoxalinone and pharmaceutically acceptable salts thereof in preparation of medicines for treating and/or preventing diseases caused by abnormal high expression c-Met kinase. (by machine translation)
- -
-
Paragraph 0141; 0143-0145
(2020/07/13)
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- Synthesis method of Tucatinib and intermediate product thereof
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The invention discloses a synthesis method of Tucatinib, and the method comprises the following step: carrying out substitution reaction on halate of a compound shown in a formula VI or free alkali thereof serving as a raw material and a compound shown in a formula VII under an alkaline condition to obtain a compound shown in a formula VIII. The raw materials used in the whole synthesis route areeasy to obtain, expensive catalysts are not needed, and the method is suitable for large-scale production and beneficial to industrial production of the Tucatinib.
- -
-
Paragraph 0078; 0079
(2020/11/09)
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- Rh-Catalyzed Annulative Insertion of Terminal Olefin onto Pyridines via a C-H Activation Strategy Using Ethenesulfonyl Fluoride as Ethylene Provider
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A Rh(III)-catalyzed annulative insertion of ethylene onto picolinamides was achieved, providing a portal to a class of unique pyridine-containing molecules bearing a terminal olefin moiety for diversification. Application of this method for modification of Sorafenib was also accomplished.
- Li, Chen,Qin, Hua-Li
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p. 4495 - 4499
(2019/06/27)
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- QUINOLINE DERIVATIVES USEFUL AS TYROSINE KINASE INHIBITORS
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Disclosed are imidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure (I) and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R1, X, Y1, Y2, Y3 and Z are as described herein. In certain embodiments, a compound disclosed herein inhibits a cellular TAM receptor, and can be used to treat disease mediated by or involving the TAM receptor family.
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Paragraph 0189
(2019/12/25)
-
- Styryl pyridine compound containing pyridine structure, preparation method and application of styryl pyridine compound in preparation of antitumor drugs (by machine translation)
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The invention belongs to the field, and particularly relates to a styryl pyridine compound containing a pyridine structure, a preparation method and an application of the styryl pyridine compound in preparation of anti-tumor drugs, wherein the compound is a compound as shown in the formula I. The compound of the general formula I has good inhibitory activity on non-small cell lung cancer A549 and liver cancer cell HepepepG2, can be used for preparing antitumor drugs, and is especially suitable for cancers, kidney cancer, lung cancer, thyroid cancer, colon cancer and other tumors. (by machine translation)
- -
-
Paragraph 0021; 0028; 0029
(2019/09/05)
-
- Preparation and application of 2-pyridine carboxamide compound
-
The invention relates to a 2-pyridine carboxamide derivative as shown in a formula I, and pharmaceutically acceptable salt, hydrate, solvate and prodrug thereof. Substituents R1, R2, X and Y have themeanings given in the description. The invention further relates to a compound in the general formula I, and the compound has the strong inhibition effect on FLT-3; the invention further relates to the applications of the compound, and the pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to preparation of drugs for treating diseases caused by abnormal high expression of FLT-3kinase, especially the applications to preparation of drugs for treating and/or preventing cancers.
- -
-
Paragraph 0099-0102
(2019/12/25)
-
- Design, synthesis and biological evaluation of phenylpicolinamide sorafenib derivatives as antitumor agents
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Two series of phenylpicolinamide sorafenib derivatives (14a–k, 15a–k) were designed and synthesized. They were evaluated for IC50 values against three cancer cell lines (A549, Hela, and MCF-7) and VEGFR2/KDR, BRAF, and CRAF kinases. Fourteen target compounds showed moderate to excellent cytotoxicity activity against the different cancer cells with potency from the single-digit μM to nanomole range. What’s more, six of them were equal to more potent than sorafenib against one or more cell lines. Most of the compounds showed bad activity against VEGFR2/KDR, BRAF, or CRAF kinases. The most promising compound 15f showed strong antitumor activities against A549 and MCF-7 cell lines with IC50 values of 5.43 ± 0.74 and 0.62 ± 0.21 μM, which were 1.29–6.79-fold more active than sorafenib (6.53 ± 0.82, 4.21 ± 0.62 μM), respectively and it exhibited moderate IC50 (7.1 μM) than 14f (IC50 = 3.1 μM). Structure–activity relationships (SARs) and docking studies indicated that replacement of diarylurea of sorafenib with phenylpicolinamide moiety benefits to the activity. The position of aryl group and the substitutions of aryl group have a great influence on antitumor activity and selectivity. Small volume groups of aryl group such as (substituted) alkyl groups (–CH3, –CF3), halogen atoms (–F) were favorable to the cytotoxicity. Exact action mechanism of target compounds is not quite clear and further study will be carried out to identify the target in near future.
- Wu, Chunjiang,Xu, Shan,Guo, Yuping,Wu, Jielian,Luo, Rong,Wang, Wenhui,Tu, Yuanbiao,Le Chen,Zhu, Wufu,Zheng, Pengwu
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p. 374 - 387
(2017/10/07)
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- Discovery of novel picolinamide-based derivatives as novel VEGFR-2 kinase inhibitors: Synthesis,: in vitro biological evaluation and molecular docking
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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has emerged as an attractive target for cancer therapy. In our effort, a novel series of picolinamide-based derivatives were designed and synthesized as potent and effective VEGFR-2 inhibitors. All the newly prepared compounds were evaluated in vitro for their antiproliferative activity against A549 and HepG2 cell lines. Among the new compounds, 8j and 8l exhibited better activity against both A549 and HepG2 cell lines. Molecular docking was performed to investigate the binding capacity and binding mode with VEGFR-2 (PDB code: 4ASD).
- Sun, Wuji,Fang, Shubiao,Yan, Hong
-
supporting information
p. 1054 - 1058
(2018/06/27)
-
- Preparation and application of 2-carbamoyl-4-heteroaromatic pyridine compounds
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The invention provides 2-carbamoyl-4-heteroaromatic pyridine derivatives and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof. The substituent groups R1, R2 and Y have definitions in the specification. The invention further relates to compounds with a general formula I having strong effects of inhibiting c-Met kinase, and also relates to an application of the compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of medicines for treating diseases caused by abnormal high expression of the c-Met kinase, particularly an application in preparation of medicines for treating and/or preventing cancers.
- -
-
Paragraph 0082; 0083
(2018/04/02)
-
- Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents
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A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α PDGFR-β c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61 nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2 = 4-F) was benefited to the potency.
- Duan, Yongli,Xu, Shan,Xiong, Hehua,Wang, Linxiao,Zhao, Bingbing,Wang, Ping,Wang, Caolin,Peng, Yiqing,Cai, Shifan,Luo, Rong,Zheng, Pengwu,Tang, Qidong
-
p. 254 - 259
(2018/01/10)
-
- Preparation deuterated diphenylurea (by machine translation)
-
The invention relates to a method for preparing deuterated diphenyl urea. Specifically, the invention provides an intermediate N-(1, 1, 1-3 deuterated methyl) benzo succinimide which can be used for preparing a deuterated diphenyl urea compound and an application of the intermediate in the preparation of the deuterated diphenyl urea compound. The method can be used for conveniently preparing the intermediate with the high purity and various deuterated diphenyl urea compounds in high efficiency.
- -
-
Paragraph 0140; 0142; 0144; 0145
(2018/12/13)
-
- Pyridazinone-containing 4-phenoxy-pyridine compound and application thereof
-
The invention discloses a pyridazinone-containing 4-phenoxy-pyridine compound with structure as shown in formula (I) and application thereof. The in vitro cell activity experiment verifies that the pyridazinone-containing 4-phenoxy-pyridine compound has good effect on inhibiting human lung carcinoma A549, human gastric carcinoma cell BGC-823, human gastric carcinoma cell MKN-45, human lung carcinoma H460 and human colon cancer cell HT-29. The invention also relates to application of the compound as shown in formula I in high inhibition of VEGFR2 kinase, and also relates to the application of the compound and pharmacologically acceptable salt, an aquo-complex a solvent compound or a prodrug in preparation of drugs for treating and/or preventing diseases caused by abnormal high expression ofVEGFR2 kinase, and particularly application in preparation of drugs for treating and/or preventing cancers. The formula refers to the description.
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Paragraph 0047; 0048
(2019/01/16)
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- Pd(II)-Catalyzed, Picolinamide-Assisted, Z-Selective γ-Arylation of Allylamines to Construct Z-Cinnamylamines
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Investigations of Pd(II)-catalyzed, picolinamide-assisted, γ-C(sp2)-H activation and Z-selective arylation of allylamines are reported. The reactions of N-allylpicolinamides with various aryl iodides in the presence of the catalyst Pd(OAc)2 and additive AgOAc have led to the selective γ-arylation of allylamines to construct various cinnamylamines with moderate to good yields and good to high E/Z ratios. To obtain good E/Z ratios, the Pd(II)-catalyzed arylation reaction of N-allylpicolinamides was probed using different additives, directing groups, and reaction conditions. The Pd(II)-catalyzed arylation of an allylamine containing both γ-C(sp2)-H and γ-C(sp3)-H bonds afforded moderate yields of the γ-C(sp2)-H and γ-C(sp3)-H bisarylated cinnamylamines. Although Heck-type γ-arylations of allylamines have generally afforded the E-cinnamylamines, the bidentate directing group picolinamide-directed arylations of allylamines were found to be Z-selective. A plausible mechanism was proposed for the observed regioselectivity and Z-selective arylation of N-allylpicolinamides. Additionally, the Pd(II)-catalyzed arylation of an N-allyl-5-methylisoxazole-3-carboxamide afforded the E-cinnamylamines plausibly via a ligand-free Heck-type reaction mechanism.
- Parella, Ramarao,Babu, Srinivasarao Arulananda
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p. 6550 - 6567
(2017/07/15)
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- Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension
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Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.
- Wu, Deyan,Zhang, Tianhua,Chen, Yiping,Huang, Yadan,Geng, Haiju,Yu, Yanfa,Zhang, Chen,Lai, Zengwei,Wu, Yinuo,Guo, Xiaolei,Chen, Jianwen,Luo, Hai-Bin
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p. 6622 - 6637
(2017/08/17)
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- Highly Cytotoxic Palladium(II) Pincer Complexes Based on Picolinylamides Functionalized with Amino Acids Bearing Ancillary S-Donor Groups
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The reactions of picolinyl and 4-chloropicolinyl chlorides with methyl esters of S-methyl-l-cysteine, l- and d-methionine, and l-histidine afforded a series of functionalized carboxamides, which readily formed pincer-type complexes upon interaction with PdCl2(NCPh)2 in solution under mild conditions. The direct cyclopalladation of the ligands derived was also accomplished in the solid phase, in particular, mechanochemically, although it was complicated by the partial deactivation of the starting amides. The resulting complexes with 5,5- and 5,6-membered fused metallocycles were fully characterized by IR and NMR spectroscopy, including variable-temperature and 2D-NMR studies. In the case of some cysteine- and methionine-based derivatives, the realization of κ3-N,N,S-coordination was supported by X-ray diffraction. The cytotoxic effects of these complexes were examined on HCT116, MCF7, and PC3 human cancer cell lines as well as HEK293 as a representative of normal cells. The comparative studies allowed us to determine that the presence of the sulfide ancillary donor group is crucial for cytotoxic activity of this type of Pd(II) complexes. The main structure-activity relationships and the most promising palladocycles were outlined. The additional studies by gel electrophoresis revealed that 4-chloropicolinyl derivatives, despite the nature of an amino acid, can bind with DNA and inhibit topoisomerase I activity.
- Churusova, Svetlana G.,Aleksanyan, Diana V.,Rybalkina, Ekaterina Yu.,Susova, Olga Yu.,Brunova, Valentina V.,Aysin, Rinat R.,Nelyubina, Yulia V.,Peregudov, Alexander S.,Gutsul, Evgenii I.,Klemenkova, Zinaida S.,Kozlov, Vladimir A.
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p. 9834 - 9850
(2017/08/26)
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- QUINOLINE DERIVATIVES AS SMO INHIBITORS
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Disclosed are quinoline derivatives as hedgehog pathway inhibitors, especially as SMO inhibitors. Compounds of the present invention can be used in treating diseases relating to hedgehog pathway including cancer.
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Paragraph 0170; 0171
(2017/02/28)
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- Synthesis, biological evaluation and docking studies of sorafenib derivatives N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-4(5)-phenylpicolinamides
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Background: Sorafenib is an important VEGFR2/KDR inhibitor which is widely used for the treatment of cancer. Objective: In this paper, two series of sorafenib analogues N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-4- phenylpicolinamides(13a-k) and N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-5-phenylpicolinamides (14a-k) were designed and synthesized. Methods: Their structures were confirmed by various analytical methods, such as 1 H and 13 C NMR, m.p., MS, HRMS. All of them were evaluated for IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Results: Eleven of the synthesized compounds showed moderate to excellent cytotoxicity activity against different cancer cells, whose potency from single-digit μM to nanomolar range. And five of them were equal to more potent than sorafenib against one or more cell lines. The most promising compound 14c showed excellent antitumor activities against PC-3 and MCF-7 cell lines with IC50 values of 2.62±1.07 μM and 1.14±0.92 μM, which were 1.15 to 2.75-fold more active than sorafenib (3.03±1.01 μM, 3.14±1.65 μM), respectively. Conclusion: Structure-activity relationships (SARs) and docking studies indicated that the replacement of diarylurea of sorafenib with phenylpicolinamide moiety benefited to the activity. The position of aryl group and the substituents of aryl group had a great influence on antitumor activity and selectivity. The aryl groups with the substitute of alkyl groups (-CH3), halogen atoms (-F,Cl) were favorable to the cytotoxicity. However, this series of compounds showed moderate activity against VEGFR2/KDR kinase. Mechanism of target compounds was not quite clear and further study will be carried out to identify the possible target.
- Wang, Min,Wu, Chunjiang,Xu, Shan,Zhu, Yan,Li, Wei,Zheng, Pengwu,Zhu, Wufu
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p. 176 - 185
(2017/03/08)
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- Design, synthesis and antitumor activity of Novel Sorafenib derivatives bearing pyrazole scaffold
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Four series of Sorafenib derivatives bearing pyrazole scaffold (8a–m, 9a–c, 10a–e and 11a) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases. Compounds 8b and 8i were more active than that of compounds 8h, 9a, especially the IC50 value of compounds 8b on VEGFR-2 kinase was 0.56 μM. And compound 8b exhibited moderate to good activity toward c-Met and showed moderate to no activity against CRAF, c-Met, EGFR, Flt-3 kinases. Eleven of the target compounds exhibited moderate to good antitumor activities. The most promising compound 8b showed strong antitumor activities against A549, HepG2 and MCF-7 cell lines with IC50 values of 2.84 ± 0.78 μM, 1.85 ± 0.03 μM and 1.96 ± 0.28 μM, which were equivalent to Sorafenib (2.92 ± 0.68 μM, 3.44 ± 0.50 μM and 3.18 ± 0.18 μM). Structure–activity relationships (SARs) and docking studies indicated that the pyrazole scaffolds exerted key effect on antitumor activities of target compounds. Substitutions of aryl group at C-3 positions had a significant impact on the antitumor activities, and 3-Br substitution produced the best potency.
- Wang, Min,Xu, Shan,Lei, Huajun,Wang, Caolin,Xiao, Zhen,Jia, Shuang,Zhi, Jia,Zheng, Pengwu,Zhu, Wufu
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p. 5754 - 5763
(2017/10/09)
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- N,N'-bis-substituted aryl thiourea derivatives and synthetic method and application thereof
-
The invention discloses N,N'-bis-substituted aryl thiourea derivatives which are a series of compounds simultaneously containing various substituted aromatic ring structures and asymmetric substituted thiourea structures and are all novel structural compounds which are not reported in the literature. The biological activity test analysis of all the target compounds includes determination of DPPH antioxidant activity and antiviral activity. Results indicate that, in general, the designed and synthesized compounds are novel in structures and have the antioxidant activity and the antiviral activity revealed for the first time. In addition, the unknown biological activity is not fully elucidated, and thus the compounds are expected to provide a certain material basis for further research and development of new drugs.
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Paragraph 0039; 0045-0047
(2017/04/26)
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- LIVER-TARGETED PRODRUG COMPOSITIONS AND METHODS OF USING THE SAME
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Disclosed are compositions and methods of delivering a drug to a liver cell or liver tissue in a subject. In some forms, the composition is a prodrug of a drug where the drug, a hydrophilic linker, and a liver-targeted glycol ligand are conjugated together. The hydrophilic linker contains or is coupled to the drug via a cleavable bond such that the cleavable bond is cleaved and the drug released after delivery into a target cell.
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-
-
- The structure of the amine-containing thiourea compound and its preparation method and application
-
A disclosed thiourea compounds containing an arylamine structure comprises compounds of a general formula I and pharmaceutically acceptable salts. In the general formula I shown in the specification, R1 is selected from H, C1-C8 alkyl, halogens, -CF3, -OCF3, -NO2, -CN, R2O-, -SO2NH2, -NHSO2R3, -NR4R5, -CONR6R7, -COOR8, R9CO- and disubstituted and trisubstituted combinations thereof, R2, R3, R4, R5, R6, R7, R8 and R9 are respectively H or C1-C8 alkyl, L is selected from -NHR10, -NHOR11, -NR12R13, pyrrolidin-1-yl, 4-piperidyl and (4-methyl-1-piperazinyl)methylene, and R10, R11, R12 and R13 are respectively H, C1-C8 alkyl, cycloalkyl or aryl. The compounds have inhibiting effect on multiple tumor cell strains.
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Paragraph 0068; 0069
(2017/08/08)
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- The sulfonylurea-containing structure of the preparation and application of zola non-nepal derivatives (by machine translation)
-
The invention discloses a sulfonylurea structure containing sorafenib derivative, its geometric isomer and pharmaceutically acceptable salt, hydrate, solvate or prodrug, and application thereof in preparation of drugs treating and/or preventing hyperplastic diseases, application in preparation of drugs treating and/or preventing cancers, and application in preparation of drugs treating and/or preventing lung cancer, liver cancer, gastric cancer, colon cancer and breast cancer.
- -
-
Paragraph 0085; 0086; 0087
(2017/08/26)
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- Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit
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Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a–o, 7a–e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50values of 0.56?±?0.83?μM, 3.88?±?1.03?μM and 3.15?±?0.81?μM, which were 1.03–6.14-fold more active than sorafenib (3.44?±?1.50?μM, 3.18?±?1.43?μM, 3.24?±?0.45?μM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC50value was 0.72?μM. Structure–activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity.
- Wang, Min,Xu, Shan,Wu, Chunjiang,Liu, Xiaobo,Tao, Hong,Huang, Yanli,Liu, Yongchan,Zheng, Pengwu,Zhu, Wufu
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p. 5450 - 5454
(2016/11/09)
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- N-indazole substituted thiourea derivatives and preparation method and application thereof
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The invention discloses N-indazole substituted thiourea derivatives and a preparation method and application thereof and belongs to the technical field of chemical medicine.The thiourea derivatives are a series of compounds simultaneously containing the 1H-indazole ring structure and the asymmetrical thiourea structure, and the compounds are not reported in the literature.The bioactivity test result analysis of the thiourea derivatives show that the compounds are good in antioxidant activity, the average scavenging rate is above 80%, the scavenging rate of the compound 12b, the compound 12c, and the compound 12d and the compound 12h is higher than 90%, the scavenging activity IC50 of the compound 12h on DPPH is 0.14mg/mL; part of the target compounds has certain inhibition activity on herpes viruses, vaccinia viruses, reoviruses, Coxsackie viruses, Feline coronary herpes viruses, HIV viruses and the like, and the compound 12c and the compound 12n are high in antivirus activity; the synthesized compounds hopefully have new bioactivity which is not expounded, and a certain material basis is provided for the development of new medicine.
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Paragraph 0058; 0059
(2016/10/09)
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- Synthesis, activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives
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Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC50values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC50values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC50values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What's more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.
- Wang, Wenhui,Wu, Chunjiang,Wang, Jianqiang,Luo, Rong,Wang, Caolin,Liu, Xiaobo,Li, Jiqing,Zhu, Wufu,Zheng, Pengwu
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p. 6166 - 6173
(2016/12/06)
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- Quinoline compound and its preparation method and application (by machine translation)
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The invention relates to the general formula I shown quinoline derivatives and their pharmaceutically acceptable salt, hydrate, solvate and prodrug, wherein substituent R1 , R2 , X, Y, Z, n has the meaning given in the specification. The invention also relates to the compounds of the general formula I has strong inhibition of c - Met kinase function, and also relates to the compounds and its pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof in the preparation of the treatment because the c - Met kinase abnormal high expression of diseases caused by the use of the medicaments, in particular in preparing and treating and/or preventing cancer of the use of the medicament. (by machine translation)
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Paragraph 0254; 0255
(2017/02/17)
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- Sorafenib derivatives containing chalcone-like structures as well as preparation method and application of Sorafenib derivatives
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The invention discloses Sorafenib derivatives containing chalcone and chalcone-like structures, geometric isomers of the Sorafenib derivatives as well as pharmaceutically acceptable salts, hydrates, solvate or prodrugs of the Sorafenib derivatives, and also discloses a preparation method of the Sorafenib derivatives. The Sorafenib derivatives containing chalcone and the chalcone-like structures, as well as the pharmaceutically acceptable salts, hydrates or solvate of the Sorafenib derivatives, are taken as active ingredients and mixed with pharmaceutically acceptable carriers or excipients, then composition is formed, and clinically acceptable dosage forms are prepared. The compounds are applied to preparation of drugs for treating and/or preventing hyperplastic diseases, preparation of drugs for treating and/or preventing cancers and preparation of drugs for treating and/or preventing prostatic cancer, lung cancer and breast cancer.
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Paragraph 0074; 0076; 0077
(2018/02/04)
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- SORAFENIB ANALOGS AND USES THEREOF
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The present invention provides, inter alia, compounds according to formula I. Also provided are pharmaceutical compositions and kits containing such compounds. Methods for using such compounds, compositions, and kits for treating a subject having system xc-, dysregulation for activating ferroptosis, for inhibiting system xc- in a cell, and for monitoring treatment of a subject having system xc- dysregulation are provided as well.
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Paragraph 0133; 0134
(2015/04/22)
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- Rhodium(III)-catalyzed oxidative olefination of picolinamides: Convenient synthesis of 3-alkenylpicolinamides
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A rhodium(III)-catalyzed selective olefination of picolinamide derivatives has been developed. The reaction shows high regioselectivity, low catalyst loading (0.5 mol%), high yield and good functional group tolerance, providing a convenient strategy for the synthesis of 3-alkenylpicolinamides.
- Zhou, Jun,Li, Bo,Qian, Zhen-Chao,Shi, Bing-Feng
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supporting information
p. 1038 - 1046
(2014/04/03)
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- INHIBITORS OF THE KYNURENINE PATHWAY
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The present application provides novel inhibitors of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase, metabolites thereof, and phannaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. A therapeutically effective amount of one or more of the compounds of formula (I) is useful in treating diseases resulting from dysregulation of the kynurenine pathway. Compounds of formula (I) act by inhibiting the enzymatic activity or expression of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase.
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Page/Page column 210
(2014/12/12)
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- 1,2,4-TRIAZOL-5-ONES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-lR), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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Paragraph 0376
(2014/09/29)
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- N-Acyl-N'-(pyridin-2-yl) Ureas and Analogs Exhibiting Anti-Cancer and Anti-Proliferative Activities
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Described are compounds of Formula 1 which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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Paragraph 0229
(2014/09/29)
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- IMIDAZOLIDINONES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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Paragraph 0318
(2014/10/29)
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- Discovery of nitropyridine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors via a structure-based core refining approach
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As a continuation of our efforts to discover and develop back-up analogs of DAPYs, novel substituted nitropyridine derivatives were designed via a structure-based core refining approach, synthesized and evaluated for their in vitro HIV-1 activity in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against wild-type HIV-1 IIIB. Most notably, the compound 7b was identified as the most promising candidate in inhibiting HIV-1 replication with an EC 50 value of 0.056 μM and a selective index (SI) of 1251, which were much better than those of NVP (EC50 = 0.23 μM) and DLV (EC50 = 0.51 μM). Some other compounds, 7k, 7c, 7j and 7e, were also endowed with a favorable anti-HIV-1 potency (EC50 = 0.034, 0.11, 0.11 and 0.16 μM, respectively). Some antivirally active compounds also showed moderate inhibitory activity against RT. Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogs provide valuable avenues for future molecular optimization.
- Wang, Jun,Zhan, Peng,Li, Zhenyu,Liu, Huiqing,De Clercq, Erik,Pannecouque, Christophe,Liu, Xinyong
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p. 531 - 538
(2014/05/06)
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- 2-AMINOPYRIMIDIN-6-ONES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-IR), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c- FMS, c-KIT, or PDGFR kinases.
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Paragraph 0188
(2014/09/29)
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- FUSED TRICYCLIC UREA COMPOUNDS AS RAF KINASE AND/OR RAF KINASE DIMER INHIBITORS
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Provided are certain fused tricyclic urea compounds and salts thereof, compositions thereof, and methods of use therefor.
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Page/Page column 99
(2015/01/16)
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- PREPARATION METHOD OF FLUORO-SUBSTITUTED DEUTERATED DIPHENYLUREA
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A fluoro-substituted deuterated diphenylurea compound, especially 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-2-(N-(methyl-d3))picolinamide, preparing method and use for treating or preventing tumor and relative diseases thereof.
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Paragraph 0176
(2013/03/26)
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- METHOD AND PROCESS FOR PREPARATION AND PRODUCTION OF DEUTERATED OMEGA-DIPHENYLUREA
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Methods and processes for preparation and production of deuterated ω-diphenylurea are disclosed. Especially, a kind of deuterated ω-diphenylurea compounds which can inhibit phosphokinase and the preparation method of N-(4-chloro-3-(trifluoromethyl)phenye-N′-(4-(2-(N-d3-methylcarbamoyl)-4-pridinyloxy)phenyl)urea are disclosed. The said deuterated diphenylurea compounds can be used for treating or preventing tumors and relative diseases.
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Paragraph 0173
(2013/03/26)
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- Pyrimidin-4-one derivatives and their use in the treatment, amelioration or prevention of a viral disease
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The present invention relates to a compound having the general formula II, optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which is useful in treating, ameloriating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.
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Paragraph 0173-0174
(2013/05/08)
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- DEUTERIUM-SUBSTITUTED OMEGA-DIPHENYLUREA AND DERIVATIVES THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE COMPOUNDS
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This invention relates to deuterated ω-diphenylurea and derivatives and pharmaceutical acceptable salts thereof. And the pharmaceutical compositions comprising the pharmaceutically acceptable carrier and the deuterium-substituted ω-diphenylurea and derivatives and pharmaceutical acceptable salts thereof are also provided. The deuterium-substituted diphenylurea can be used in treatment or prevention of cancer and other related diseases.
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Paragraph 0121-0122
(2013/03/26)
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- METHOD FOR PREPARING DEUTERATED DIPHENYLUREA
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Disclosed are an intermediate compound of N-(1,1,1-trideuterated methyl)phthalimide, and its use in the preparation of deuterated diphenylurea derivative.
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Page/Page column 0072-0074
(2013/03/26)
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- METHOD FOR PREPARING DEUTERATED DIPHENYLUREA
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Disclosed are an intermediate compound of N-(1,1,1-trideuterated methyl)phthalimide, and its use in the preparation of deuterated diphenylurea derivative.
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Paragraph 0115
(2013/03/26)
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