- Discovery of novel 2,4‐dianilinopyrimidine derivatives containing 4‐(Morpholinomethyl)phenyl and n‐substituted benzamides as potential fak inhibitors and anticancer agents
-
Focal adhesion kinase (FAK) is responsible for the development and progression of various malignancies. With the aim to explore novel FAK inhibitors as anticancer agents, a series of 2,4‐ dianilinopyrimidine derivatives 8a–8i and 9a–9g containing 4‐(morpholinomethyl)phenyl and N‐ substituted benzamides have been designed and synthesized. Among them, compound 8a dis-played potent anti‐FAK activity (IC50 = 0.047 ± 0.006 μM) and selective antiproliferative effects against H1975 (IC50 = 0.044 ± 0.011 μM) and A431 cells (IC50 = 0.119 ± 0.036 μM). Furthermore, compound 8a also induced apoptosis in a dose‐dependent manner, arresting the cells in S/G2 phase and inhibiting the migration of H1975 cells, all of which were superior to those of TAE226. The docking analysis of compound 8a was performed to elucidate its possible binding modes with FAK. These results established 8a as our lead compound to be further investigated as a potential FAK inhibitor and anticancer agent.
- Han, Chun,Han, Jing,Hu, Xiaoqin,Li, Mengyao,Shen, Kemin,Su, Feng,Wang, Shijun,Wang, Zhijun,Wu, Lintao,Wu, Xi
-
-
- PYRIMIDINE COMPOUND, PREPARATION METHOD THEREOF AND MEDICAL USE THEREOF
-
The present invention discloses a pyrimidine compound, a preparation method thereof and a medical use thereof. Specifically, the present invention discloses a pyrimidine compound represented by formula (I), pharmaceutically acceptable salts thereof, a preparation method thereof, and a use thereof as a cyclin-dependent kinase 9 (CDK9) inhibitor, particularly for the treatment of cancer. The definition of each group in formula (I) is the same as that in the specification.
- -
-
Paragraph 0359; 0420; 0421
(2021/04/10)
-
- Synthesis and biological activity of thieno[3,2-d]pyrimidines as potent JAK3 inhibitors for the treatment of idiopathic pulmonary fibrosis
-
Idiopathic pulmonary fibrosis (IPF) is a serious and fatal lung disease, with a median survival of only 3–5 years from diagnosis. Janus kinase 3 (JAK3) has a well-established role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA) and autoimmune-related pulmonary fibrosis. In this study, through the use of a conformationally-constrained design strategy, a series of thieno[3,2-d]pyrimidines were synthesized as potent JAK3 inhibitors for the treatment of IPF. Among them, the most potent JAK3 inhibitor, namely 8e (IC50 = 1.38 nM), significantly reduced the degree of airsacculitis and fibrosis according to hematoxylin-eosin (HE) staining assay for the lung tissue in the bleomycin (BLM)-induced pulmonary fibrosis mouse model. The clear reduction of the lung collagen deposition by the determination of Masson and hydroxyproline (HYP) content also demonstrated its efficacy in the treatment of fibrosis. In addition, 8e also reduced the expression of the inflammatory markers IL-6, IL-17A, TNF-α and malondialdehyde (MDA) in lung tissue, which indicated its higher anti-inflammatory activity compared with that of the reference agents (nintedanib and gefitinib). Furthermore, it possessed low cytotoxicity against normal human bronchial epithelia (HBE) cells (IC50 > 39.0 μM) and C57BL mice. All these evaluated biological properties suggest that 8e may be a potential JAK3 inhibitor for the treatment of IPF.
- Zhu, Yanming,Zheng, Xu,Wang, Changyuan,Sun, Xiuli,Sun, Huijun,Ma, Tengyue,Li, Yanxia,Liu, Kexin,Chen, Lixue,Ma, Xiaodong
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-
- Thiourea-Catalyzed C?F Bond Activation: Amination of Benzylic Fluorides
-
We describe the first thiourea-catalyzed C?F bond activation. The use of a thiourea catalyst and Ti(OiPr)4 as a fluoride scavenger allows the amination of benzylic fluorides to proceed in moderate to excellent yields. Preliminary results with S- and O-based nucleophiles are also presented. DFT calculations reveal the importance of hydrogen bonds between the catalyst and the fluorine atom of the substrate to lower the activation energy during the transition state.
- Houle, Camille,Savoie, Paul R.,Davies, Clotilde,Jardel, Damien,Champagne, Pier Alexandre,Bibal, Brigitte,Paquin, Jean-Fran?ois
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p. 10620 - 10625
(2020/07/24)
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- Exploiting the Tolerant Region i of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility an
-
Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfon
- Huang, Boshi,Chen, Wenmin,Zhao, Tong,Li, Zhenyu,Jiang, Xiangyi,Ginex, Tiziana,Vílchez, David,Luque, Francisco Javier,Kang, Dongwei,Gao, Ping,Zhang, Jian,Tian, Ye,Daelemans, Dirk,De Clercq, Erik,Pannecouque, Christophe,Zhan, Peng,Liu, Xinyong
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p. 2083 - 2098
(2019/03/07)
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- 4-(saturated aliphatic ring-pyrimidine/pyridine substituted)amino-1H-3-pyrazol carboxamide FMS-like tyrosine kinase 3 (FLT3) inhibitor and application thereof
-
The invention relates to 4-(saturated aliphatic ring-pyrimidine/pyridine substituted)amino-1H-3-pyrazol carboxamide FMS-like tyrosine kinase 3 (FLT3) inhibitor, an application thereof, or pharmaceutically acceptable salt, solvate, isomer, ester, acid, met
- -
-
Paragraph 0088; 0119-0121
(2019/10/02)
-
- HISTONE METHYLTRANSFERASE EZH2 INHIBITOR, PREPARATION METHOD AND PHARMACEUTICAL USE THEREOF
-
The invention relates to a histone methyltransferase EZH2 inhibitor, a preparation method and pharmaceutical use thereof. In particular, the invention relates to a compound represented by the general formula (I), a preparation method thereof, a pharmaceut
- -
-
Paragraph 0351-0352
(2019/11/22)
-
- Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia
-
A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC50 values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC50: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD50: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.
- Wang, Yue,Zhi, Yanle,Jin, Qiaomei,Lu, Shuai,Lin, Guowu,Yuan, Haoliang,Yang, Taotao,Wang, Zhanwei,Yao, Chao,Ling, Jun,Guo, Hao,Li, Tonghui,Jin, Jianlin,Li, Baoquan,Zhang, Li,Chen, Yadong,Lu, Tao
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p. 1499 - 1518
(2018/03/05)
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- Discovery of the selective and efficacious inhibitors of FLT3 mutations
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Fms-like tyrosine kinase 3 (FLT3) is among the most frequently mutated protein in acute myeloid leukemia (AML), which has been confirmed as an important drug target for AML chemotherapy. Starting from the lead compound LT-106-175, a series of 1-H-pyrazole-3-carboxamide derivatives were synthesized to improve the FLT3 inhibitory potency and selectivity. Among them, compound 50 was identified as a highly potent and selective FLT3 inhibitor (IC50 = 0.213 nM), which showed equal activities against various mutants of FLT3 including FLT3 (ITD)-D835V and FLT3 (ITD)-F691L that is resistant to quizartinib. Compound 50 also exhibited efficacy against the human AML cell line MV4-11 (IC50 = 16.1 nM) harboring FLT3-ITD mutants. Inversely, compound 50 displayed no cytotoxicity to FLT3-independent cells, and the biochemical analyses showed that its effects were related to the inhibition of FLT3 signal pathways. Additionally, compound 50 induced apoptosis in MV4-11 cell as demonstrated by flow cytometry. Moreover, compound 50 showed enhanced metabolic stability. Altogether, it was concluded that compound 50 could be a promising FLT3 inhibitor for further developing therapeutic remedy of AML.
- Zhi, Yanle,Li, Baoquan,Yao, Chao,Li, Hongmei,Chen, Puzhou,Bao, Jiyin,Qin, Tianren,Wang, Yue,Lu, Tao,Lu, Shuai
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p. 303 - 315
(2018/06/12)
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- Selective, Catalytic, and Dual C(sp3)-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions
-
By using cheap and innocuous reagents, such as NaClO2, NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp3)-H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3-morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/intramolecular C-N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3-morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.
- Chamorro-Arenas, Delfino,Osorio-Nieto, Urbano,Quintero, Leticia,Hernández-García, Luís,Sartillo-Piscil, Fernando
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p. 15333 - 15346
(2019/01/03)
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- Unmodified Fe3O4 nanostructure promoted with external magnetic field: safe, magnetically recoverable, and efficient nanocatalyst for N- and C-alkylation reactions in green conditions
-
Transition metal compounds have emerged as suitable catalysts for organic reactions. Magnetic compounds as soft Lewis acids can be used as catalysts for organic reactions. In this report, the Fe3O4 nanostructures were obtained from Fe2+ and Fe3+-salts, under an external magnetic field (EMF) without any protective agent. The X-ray photoelectron spectroscopy, scanning electron microscopy, and energy dispersive X-ray spectroscopy tools were used to characterize these magnetic compounds. The two-dimensional (2-D, it showed nanometric size in the two dimensions, nanorod structure) Fe3O4 compound showed high catalytic activity and stability in N- and C-alkylation reactions. A diverse range of N- and C-alkylation products were obtained in moderate to high yield under green and mild conditions in air. Also the N- and C-alkylation products can be obtained with different selectivity and yield by exposure reactions with EMF. Results of alkylation reactions showed that the presence of Fe(II) and Fe(III) species on the surface of magnetic catalysts (phase structure of magnetic compounds) are essential as very cheap active sites. Also, morphology of magnetic catalysts had influence on their catalytic performances. After the reaction, the catalyst/product(s) separation could be easily achieved with an external magnet and more than 95% of catalyst could be recovered. The catalyst was reused at least four times without any loss of its high catalytic activity for N- and C-alkylation reactions.
- Rafiee, Ezzat,Joshaghani, Mohammad,Abadi, Parvaneh Ghaderi-Shekhi
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p. 2503 - 2522
(2018/01/04)
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- Synthesis, β-hematin inhibition studies and antimalarial evaluation of new dehydroxy isoquine derivatives against Plasmodium berghei: A promising antimalarial agent
-
Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I
- Valverde, Edgar A.,Romero, Angel H.,Acosta, María E.,Gamboa, Neira,Henriques, Genesis,Rodrigues, Juan R.,Ciangherotti, Carlos,López, Simón E.
-
supporting information
p. 498 - 506
(2017/11/13)
-
- Beta-carboline derivative targeted to CDK and DNA and preparation method and medical application thereof
-
The invention discloses a beta-carboline derivative targeted to CDK and DNA and a preparation method and medical application thereof. The beta-carboline derivative has a structure shown in the general formula I in the description. The compound can be applied in combination with other antitumor drugs and can also be applied in combination with radiotherapy. The antitumor drugs or radiotherapy and the compound can be applied at the same time or at different times. The combined therapy can perform a synergistic effect, and thus the therapeutic effect can be easily improved.
- -
-
Paragraph 0089; 0090
(2017/06/02)
-
- Design, synthesis and evaluation of derivatives based on pyrimidine scaffold as potent Pan-Raf inhibitors to overcome resistance
-
Simutaneous targeting all Raf isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRafWTphenotypic melanoma and BRafV600Ephenotypic colon cells. The western blot results for the Erk inhibition in human melanoma SK-Mel-2?cell lines showed I-41 inhibited the proliferation of SK-Mel-2?cell lines without paradoxical activation of Erk, which supported I-41 may become a good candidate compound to overcome the resistance of melanoma against the current BRafV600Einhibitor therapy. I-41 also have a favorable pharmacokinetic profile in rat. Synthesis, SAR, lead selection, and evaluation of the key compounds studies are described.
- Wang, Lu,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Zhi, Yanle,Zhang, Li,Mao, Tianxiao,Zhou, Xiang,Chen, Yadong,Lu, Tao,Tang, Weifang
-
supporting information
p. 86 - 106
(2017/03/02)
-
- Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance
-
Selective BRafV600E inhibitors with DFG-in conformation have been proven effective against a subset of melanoma. However, representative inhibitor vemurafenib rapidly acquires resistance in the BRafWT cells through a CRaf or BRafWT dependent manner. Simultaneous targeting of all subtypes of Raf proteins offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Herein, we describe the design and characterization of a series of compounds I-01-I-22, based on a pyrimidine scaffold with DFG-out conformation as Pan-Raf inhibitors. Among them, I-15 binds to all Raf protomers with IC50 values of 12.6 nM (BRafV600E), 30.1 nM (ARaf), 19.7 nM (BRafWT) and 17.5 nM (CRaf) and demonstrates cellular activity against BRafWT phenotypic melanoma and BRafV600E phenotypic colorectal cancer cells. The western blot results for the P-Erk inhibition in human melanoma SK-Mel-2 cell line showed that I-15 inhibited the proliferation of the SK-Mel-2 cell line at concentrations as low as 400 nM, without paradoxical activation of Erk as vemurafenib, which supported that I-15 may become a good candidate compound to overcome the resistance of melanoma induced by vemurafenib. I-15 also has a favorable pharmacokinetic profile in rats. Rational design, synthesis, SAR, lead selection and evaluation of the key compounds studied are described.
- Wang, Lu,Zhu, Gaoyuan,Zhang, Qing,Duan, Chunqi,Zhang, Yanmin,Zhang, Zhimin,Zhou, Yujun,Lu, Tao,Tang, Weifang
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supporting information
p. 3455 - 3465
(2017/04/26)
-
- HETEROCYCLIC COMPOUND
-
The present invention provides a heterocyclic compound having a CDK8 and/or CDK19 inhibitory effect. The present invention provides a compound represented by formula (I) (in the formula, the symbols are as defined in the description) or a salt thereof.
- -
-
Paragraph 0615; 0616
(2017/04/11)
-
- Heterocyclic compound
-
本發明提供一種具有CDK8/19抑制活性之雜環化合物。本發明提供一種如下式代表之化合物(其中各代號均如本文之定義)或其鹽。 The present invention provides a heterocyclic compound possessing CDK8/19 inhibitory activity. The present invention provides a compound represented by the formula wherein each symbol is as defined herein, or a salt thereof.
- -
-
Paragraph 0157
(2017/09/28)
-
- Mitsunobu Reaction Using Basic Amines as Pronucleophiles
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A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C-N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C-N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43-93% yields. Importantly, C-N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system.
- Huang, Hai,Kang, Jun Yong
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p. 6604 - 6614
(2017/07/15)
-
- Design, synthesis and antiproliferative activity of novel benzothiazole derivatives conjugated with semicarbazone scaffold
-
Two series of novel benzothiazole derivatives conjugated with semicarbazone scaffold were designed and synthesized through a structure-based molecular hybridization strategy. All the target compounds were evaluated for their cytotoxicity in vitro against three cancer cell lines (HT-29, MKN-45 and H460) by standard MTT assay. The pharmacological results indicated that seven compounds (17h-n) exhibited comparable or even better antiproliferative activity in comparison with reference drugs Sorafenib and PAC-1. Particularly, compound 17i displayed remarkable cytotoxicity against tested three cancer cell lines with IC50 values of 0.84, 0.06 and 0.52 μM, which were 4.3-, 36.6-, 4.2-folds more potent than Sorafenib and 1.2-, 13.7-, 6.9-times more active than PAC-1, respectively.
- Bao, Guanglong,Du, Baoquan,Ma, Yuxiu,Zhao, Meng,Gong, Ping,Zhai, Xin
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p. 489 - 498
(2016/07/19)
-
- Quinoline derivatives and their use
-
The invention discloses a quinoline derivative and a usage thereof, a compound with a structure as shown in a formula (I) and or a pharmaceutically acceptable salt of the compound. The compound or the pharmaceutically acceptable salt thereof disclosed by the invention can be applied to the field of preparation of drugs for preventing or treating tumors.
- -
-
Paragraph 0099-0103; 0111; 0112
(2017/03/14)
-
- Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket
-
Based on the crystallographic studies of diarylpyrimidines (DAPYs), we embarked on incorporating the hydrophilic piperidyl or morpholinyl group into the known DAPY derivatives bearing the pyridine moiety as a core structure, with the double aim to exploit additional interactions with the HIV-1 NNRTI binding pocket (NNIBP), as well as to improve the compound solubility. The antiviral evaluation result show that the most potent compounds I-8b2, I-8b3, I-8b4 and I-8c3 exhibited anti-HIV-1 (IIIB) strain activity ranging from 7.4 nM to 9.4 nM (SI = 168-1283), superior to FDA-approved drugs of nevirapine (NVP), lamivudine (3TC) and delavirdine (DLV), and comparable to etravirine (ETV), zidovudine (AZT) and efavirenz (EFV). Additionally, compounds I-8c2 and I-8c3 showed moderate activity against NNRTI resistant strains baring mutations K103N and Y181C with EC50 values of 6.2 mM and 6.8 mM, respectively. Preliminary structure-activity relationships (SARs), reverse transcriptase inhibition efficacy and molecular modeling of selected compounds are also presented. These outcomes support our design hypothesis and demonstrate that the piperidyl group modified pyridine-typed DAPY derivatives are highly potent NNRTIs with improved water solubility.
- Chen, Wenmin,Zhan, Peng,Daelemans, Dirk,Yang, Jiapei,Huang, Boshi,De Clercq, Erik,Pannecouque, Christophe,Liu, Xinyong
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p. 352 - 363
(2016/06/13)
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- COLORED CHARGED SILSESQUIOXANES
-
The present invention provides compounds of Formula (1A), wherein Formula (II) is Formula (III) and Formula (1B) wherein Formula (IV) is Formula (V) and electrophoretic devices comprising the compounds of formula (1A) or (1B).
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-
Paragraph 0818; 0820; 0821-0822
(2018/02/10)
-
- TETRACYCLIC ANTHRAQUINONE DERIVATIVES
-
Disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, W, n are defined as in the present application.
- -
-
Paragraph 0101
(2015/02/02)
-
- Tetracyclic Anthraquinone Derivatives
-
Disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, W, n are defined as in the present application.
- -
-
Paragraph 0219
(2015/06/24)
-
- POLYCYCLIC SUBSTITUTED PYRAZOLE KINASE ACTIVITY INHIBITORS AND USE THEREOF
-
The present invention relates to the field of medicinal chemistry, and in particular relates to 4-(five-membered heterocyclic pyrimidine/pyridine substituted) amino-1H-3-pyrazolecarboxamide derivatives, the preparation method thereof, pharmaceutical compo
- -
-
Paragraph 0080
(2016/01/01)
-
- Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents
-
A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC 50 = 0.25 μM) exhibited excellent antitumor activity with IC 50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity.
- Ma, Junjie,Chen, Dong,Lu, Kuan,Wang, Lihui,Han, Xiaoqi,Zhao, Yanfang,Gong, Ping
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p. 257 - 269
(2014/09/29)
-
- Novel 1H-pyrazole-3-carboxamide derivatives: Synthesis, anticancer evaluation and identification of their DNA-binding interaction
-
Four novel 1H-pyrazole-3-carboxamide derivatives were synthesized, and their antiproliferative effect on cancer cells, kinase inhibition, and in particular, the DNA-binding interaction were investigated to interpret the antitumor mechanisms. A DNA minor g
- Lu, Yi,Ran, Ting,Lin, Guowu,Jin, Qiaomei,Jin, Jianling,Li, Hongmei,Guo, Hao,Lu, Tao,Wang, Yue
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p. 238 - 246
(2014/04/17)
-
- Regioselective borylation of the C-H bonds in alkylamines and alkyl ethers. Observation and origin of high reactivity of primary C-H bonds beta to nitrogen and oxygen
-
Borylation of aliphatic C-H bonds in alkylamines and alkyl ethers to form primary aminoalkyl and alkoxyalkyl boronate esters and studies on the origin of the regioselectivity of these reactions are reported. The products of these reactions can be used directly in Suzuki-Miyaura cross-coupling reactions or isolated as air-stable potassium trifluoroborate salts. Selective borylation of the terminal C-H bond at the positions β to oxygen and nitrogen occurs in preference to borylation of the other terminal C-H bonds. Experimental studies and computational results show that C-H bond cleavage is the rate-determining step of the current borylation reactions. The observed higher reactivity of C-H bonds at the terminal position of ethylamines and ethers results from a combination of attractive Lewis acid-base and hydrogen-bonding interactions, as well as typical repulsive steric interactions, in the transition state. In this transition state, the heteroatom lies directly above the boron atom of one boryl ligand, creating a stabilizing interaction between the weak Lewis acid and Lewis base, and a series of C-H bonds of the substrate lie near the oxygen atoms of the boryl ligands, participating in a set of weak C- H···O interactions that lead to significant stabilization of the transition state forming the major product.
- Li, Qian,Liskey, Carl W.,Hartwig, John F.
-
supporting information
p. 8755 - 8765
(2014/07/07)
-
- Base-promoted N-alkylation using formamides as the N-sources in neat water
-
An efficient catalyst-free, alternative method for the C-N bond formation reaction of alkyl electrophiles using formamides as the N-sources was achieved under mild conditions. The reaction possesses the advantages of a broad range of substrates scope and wide functional group tolerance. It should also be noted that this process was performed using the environmentally benign water as the sole solvent, and high yield can also be achieved in ten-gram scale.
- Chen, Wen-Xin,Zhang, Cai-Yun,Shao, Li-Xiong
-
p. 880 - 885
(2014/01/23)
-
- Discovery and structure-activity relationships of pyrrolone antimalarials
-
In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 ~ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.
- Murugesan, Dinakaran,Mital, Alka,Kaiser, Marcel,Shackleford, David M.,Morizzi, Julia,Katneni, Kasiram,Campbell, Michael,Hudson, Alan,Charman, Susan A.,Yeates, Clive,Gilbert, Ian H.
-
supporting information
p. 2975 - 2990
(2013/05/23)
-
- HETEROCYCLIC UREA COMPOUNDS
-
The present invention provides a compound of the following formula, racemates, enantiomers and salts thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture
- -
-
Page/Page column 63
(2013/07/05)
-
- Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers
-
A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized co
- Tang, Li,Zhao, Liying,Hong, Lingjuan,Yang, Fenyan,Sheng, Rong,Chen, Jianzhong,Shi, Ying,Zhou, Naimin,Hu, Yongzhou
-
p. 5936 - 5944
(2013/09/23)
-
- Highly efficient amination in neat water of benzyl chlorides with dialkylformamides catalysed by N-heterocyclic carbene-palladium(II)-1- methylimidazole complex
-
Dialkylformamides are excellent N-sources in the amination of benzyl chlorides when catalysed by a NHC-Pd(II)-Im complex. In the presence of NaOH and the catalyst, variously substituted benzyl chlorides and five different dialkylformamides reacted smoothly to afford the corresponding N,N-dialkyl-benzylamines in good to almost quantitative yields in eco-friendly solvent water at 50 °C within 3 h.
- Chen, Wen-Xin,Zhang, Cai-Yun,Lu, Jian-Mei
-
p. 611 - 614
(2013/11/06)
-
- Development of a solvent selection guide for aldehyde-based direct reductive amination processes
-
A range of alternative, more environmentally conservative solvents have been evaluated for use within the direct reductive amination reactions of aldehydes using borane-based reductants. The data generated has been used to develop a guide to facilitate replacement of less desirable chlorinated solvents, such as DCE, from these widely used synthetic processes.
- McGonagle, Fiona I.,MacMillan, Donna S.,Murray, Jane,Sneddon, Helen F.,Jamieson, Craig,Watson, Allan J. B.
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supporting information
p. 1159 - 1165
(2013/06/05)
-
- Palladium-catalyzed substitution and cross-coupling of benzylic fluorides
-
Benzylic fluorides are suitable substrates for Pd(0)-catalyzed Tsuji-Trost substitution using carbon, nitrogen, oxygen, and sulfur nucleophiles and for cross-coupling with phenylboronic acid. For the bifunctional substrate 4-chlorobenzyl fluoride, fine-tuning of the reaction conditions allows for the regioselective displacement of either the chlorine or fluorine substituent. The leaving group ability of fluoride vs other groups displaced in substitution is CF3CO2 ≈ p-NO2C6H 4CO2 ≈ OCO2CH3 > F > CH3CO2, a ranking similar to allylic fluorides under Pd catalysis.
- Blessley, George,Holden, Patrick,Walker, Matthew,Brown, John M.,Gouverneur, Veronique
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supporting information; experimental part
p. 2754 - 2757
(2012/07/16)
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- A fast and highly efficient method for the synthesis of tertiary amines in aqueous medium
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A facile and highly efficient method for the synthesis of tertiary amines by the reaction of secondary amines with benzylic bromides and 1,1'-dibromo p/o-xylenes in aqueous dioxane and NaOH is described. The reactions are dually promoted by the base in short time (15 min.) at ambient conditions in aqueous medium.
- Adimurthy, Subbarayappa,Joshi, Girdhar
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experimental part
p. 771 - 775
(2011/01/04)
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- ROMP-derived oligomeric phosphates for application in facile benzylation
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The development of new ROMP-based oligomeric benzyl phosphates (OBP n) is reported for use as soluble, stable benzylating reagents. These oligomeric reagents are readily synthesized from commercially available materials and conveniently polymerized and purified in a one-pot process, affording bench-stable, pure white, free-flowing solids on multigram scale. Utilization in benzylation reactions with a variety of nucleophiles is reported.
- Long, Toby R.,Maity, Pradip K.,Samarakoon, Thiwanka B.,Hanson, Paul R.
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supporting information; experimental part
p. 2904 - 2907
(2010/09/30)
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- 4-(Phenylaminomethylene)isoquinoline-1,3(2H,4H)-diones as potent and selective inhibitors of the cyclin-dependent kinase 4 (CDK4)
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The cyclin-dependent kinases (CDKs), as complexes with their respective partners, the cyclins, are critical regulators of cell cycle progression. Because aberrant regulations of CDK4/cyclin D1 lead to uncontrolled cell proliferation, a hallmark of cancer, small-molecule inhibitors of CDK4/cyclin D1 are attractive as prospective antitumor agents. The series of 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione derivatives reported here represents a novel class of potent inhibitors that selectively inhibit CDK4 over CDK2 and CDK1 activities. In the headpiece of the 4-(phenylaminomethylene) isoquinoline-1,3(2H,4H)-dione, a basic amine substitutent is required on the aniline ring for the CDK4 inhibitory activity. The inhibitory activity is further enhanced when an aryl or heteroaryl substituent is introduced at the C-6 position of the isoquinoline-1,3(2H,4H)-dione core. We present here SAR data and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
- Tsou, Hwei-Ru,Otteng, Mercy,Tran, Tritin,Floyd Jr., M. Brawner,Reich, Marvin,Birnberg, Gary,Kutterer, Kristina,Ayral-Kaloustian, Semiramis,Ravi, Malini,Nilakantan, Ramaswamy,Grillo, Mary,McGinnis, John P.,Rabindran, Sridhar K.
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experimental part
p. 3507 - 3525
(2009/04/07)
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- Aqueous-mediated N-alkylation of amines
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Direct N-alkylation of primary amines to secondary/tertiary amines and of secondary amines to tertiary amines has been achieved in excellent yields by employing alkyl, benzylic and allylic halides in the presence of NaHCO 3 in an aqueous medium at an elevated temperature. Amines of different stereoelectronic nature react with ease with different halides. The selective formation of secondary amines and the formation of three different substituted tertiary amines are some of the interesting features of this methodology. Reaction in an aqueous medium, operationally convenient conditions, excellent yields and innocuous byproducts, and the absence of transition-metal catalysts, expensive bases, solid supports and the formation of undesired quaternary ammonium salts makes this method a green chemical process. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Singh, Chingakham B.,Kavala, Veerababurao,Samal, Akshaya K.,Patel, Bhisma K.
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p. 1369 - 1377
(2008/09/17)
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- COMPOUNDS
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A compound of formula (I): compositions and medicaments containing the same as well as processes for the preparation and use of such compounds, compositions and medicaments, particularly in diseases associated with inappropriate Aurora activity.
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Page/Page column 82-83
(2010/11/26)
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- Development of an efficient synthesis of the pyrrolquinolone PHA-529311
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An efficient synthesis of N-(4-chlorobenzyl)-2-(2-hydroxyethyl)-8- (morpholin-4-ylmethyl)-6-oxo-6H-pyrrol[3.2.1-ij]quinoline-5-carboxamide (5) was developed. The route was chosen due to its reasonable length (seven steps), solubility of intermediates, and capabilities of the pilot and production facilities. The critical transformations in this route were the selective iodination of an aniline, formation of the quinolone, and Sonogashira coupling/pyrrole formation. In addition, removal of residual palladium and copper from the penultimate and final products, which was of lower concern during the discovery phase of development, became a difficult process chemistry issue on scale-up.
- Dorow,Herrinton, Paul M.,Hohler, Richard A.,Maloney, Mark T.,Mauragis, Michael A.,McGhee, William E.,Moeslein, Jeffery A.,Strohbach, Joseph W.,Veley, Michael F.
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p. 493 - 499
(2012/12/22)
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- THIA-TETRAAZAACENAPHTHYLENE KINASE INHIBITORS
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The present invention is directed to novel thia-tetraazaacenaphthylene compounds of Formula (I): and pharmaceutically acceptable forms thereof and their synthesis and use as inhibitors of ATP-protein kinase interactions.
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Page/Page column 96
(2008/06/13)
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- Development of high-load, soluble oligomeric sulfonate esters via ROM polymerization: Application to the benzylation of amines
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The development of high-load, soluble oligomeric sulfonate esters, generated via ROM polymerization, and their utility in the facile benzylation of an array of amines is reported. These polymeric sulfonate esters exist as free-flowing powders, are stable
- Zhang, Mianji,Moore, Joel D.,Flynn, Daniel L.,Hanson, Paul R.
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p. 2657 - 2660
(2007/10/03)
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- Substituted indolines which inhibit receptor tyrosine kinases
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Indolinones of the formula having an inhibitory effect on receptor tyrosine kinases and cyclin/CDK complexes, as well as on the proliferation of endothelial cells and various tumor cells. Exemplary are: (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone, and (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-metboxycarbonyl-2-indolinone.
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Page column 42
(2008/06/13)
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- Substituted alkylamine derivatives and methods of use
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Selected amines are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Page 49; 112
(2010/02/05)
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- Substituted alkylamine derivatives and methods of use
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Selected heterocyclic compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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- Pyrroloquinolones as antiviral agents
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The present invention provides a compound of formula I which is useful as antiviral agents, in particular, as agents against viruses of the herpes family.
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- Quinolinecarboxamides as antiviral agents
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The present invention provides a compound of formula I which is useful as antiviral agents, in particular, as agents against viruses of the herpes family.
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