- Synthesis and biological activity of new 2,4,6-trisubstituted triazines as potential phosphoinositide 3-kinase inhibitors
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Twenty-five novel 2,4,6-trisubstituted triazines were synthesized and biologically evaluated. Most of the compounds synthesized showed good antiproliferative activity against HCT-116 and MCF-7. Compounds B18 and B19 showed the best antiproliferative activity. Further study showed B18 and B19 inhibited four phosphoinositide 3-kinase isoforms and mammalian target of rapamycin with good potency. These results demonstrate that 2,4,6-trisubstituted triazines are potentially useful phosphoinositide 3-kinase inhibitors for the development of new anticancer drugs.
- Shen, Ying,Wang, Hui-Yan,Xin, Minhang,Zhang, Hao,Zhang, San-Qi
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Read Online
- Development of an Efficient Synthesis of (2-Aminopyrimidin-5-yl) Boronic Acid
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A practical and cost-effective synthesis of (2-aminopyrimidin-5-yl) boronic acid 1b has been developed. Key features of the synthesis include the inexpensive in situ protection of the amine via bis-silylation using TMSCl followed by metal-halogen exchange using n-BuLi and trapping with B(Oi-Pr)3. The water-soluble boronic acid is isolated by a well-designed acid-base sequence providing the target in 80% yield and high purity for the two-step process. The large-scale (15 kg) implementation of a Suzuki-Miyaura borylation to form the pinacol boronic ester is also described.
- Patel, Nitinchandra D.,Zhang, Yongda,Gao, Joe,Sidhu, Kanwar,Lorenz, Jon C.,Fandrick, Keith R.,Mulder, Jason A.,Herbage, Melissa A.,Li, Zhibin,Ma, Shengli,Lee, Heewon,Grinberg, Nelu,Song, Jinhua J.,Busacca, Carl A.,Yee, Nathan K.,Senanayake, Chris H.
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Read Online
- Visible Light-Induced Borylation of C-O, C-N, and C-X Bonds
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Boronic acids are centrally important functional motifs and synthetic precursors. Visible light-induced borylation may provide access to structurally diverse boronates, but a broadly efficient photocatalytic borylation method that can effect borylation of a wide range of substrates, including strong C-O bonds, remains elusive. Herein, we report a general, metal-free visible light-induced photocatalytic borylation platform that enables borylation of electron-rich derivatives of phenols and anilines, chloroarenes, as well as other haloarenes. The reaction exhibits excellent functional group tolerance, as demonstrated by the borylation of a range of structurally complex substrates. Remarkably, the reaction is catalyzed by phenothiazine, a simple organic photocatalyst with MW 200 that mediates the previously unachievable visible light-induced single electron reduction of phenol derivatives with reduction potentials as negative as approximately - 3 V versus SCE by a proton-coupled electron transfer mechanism. Mechanistic studies point to the crucial role of the photocatalyst-base interaction.
- Arman, Hadi D.,Dang, Hang. T.,Haug, Graham C.,He, Ru,Jin, Shengfei,Larionov, Oleg V.,Nguyen, Viet D.,Nguyen, Vu T.,Schanze, Kirk S.
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supporting information
(2020/02/04)
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- Transition metal complex, polymer, mixture, composition and organic electronic device
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The invention discloses a transition metal complex, a polymer, a mixture, a composition and an organic electronic device. The transition metal complex has a structural general formula represented by achemical formula (1), and is simple to synthesize, novel in structure, relatively good in stability, long in service life and good in light emitting performance; the compound represented by the chemical formula (1) is convenient for realizing an efficient, high-brightness and high-stability OLED device, and a relatively good material option is provided for full-color display and illumination application.
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Paragraph 0217-0220; 0336-0339
(2020/05/01)
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- A Monophosphine Ligand Derived from Anthracene Photodimer: Synthetic Applications for Palladium-Catalyzed Coupling Reactions
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Herein, we present an air-stable dianthracenyl monophosphine ligand (diAnthPhos) which can be prepared in two steps from commercially available anthracene derivatives. The ligand exhibits excellent efficiency for palladium-catalyzed coupling reactions. In particular, Miyaura borylation of heterocycle-containing electrophiles can be facilitated employing the diAnthPhos ligand with a broad substrate scope and low catalyst loading. The valuable synthetic utility of the new ligand is further demonstrated by a one-pot Miyaura borylation/Suzuki coupling protocol for heteroaryl-containing substrates.
- Wang, Xin,Liu, Wei-Gang,Tung, Chen-Ho,Wu, Li-Zhu,Cong, Huan
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supporting information
p. 8158 - 8163
(2019/09/07)
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- Early Development Scale-Up of a Structurally-Challenging 5-Lipoxygenase Activating Protein (FLAP) Inhibitor
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A practical and efficient synthesis of the FLAP inhibitor 1 was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of 1: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling.
- Mulder, Jason A.,Gao, Joe,Fandrick, Keith R.,Zeng, Xingzhong,Desrosiers, Jean-Nicolas,Patel, Nitinchandra D.,Li, Zhibin,Rodriguez, Sonia,Lorenz, Jon C.,Wang, Jun,Ma, Shengli,Fandrick, Daniel R.,Grinberg, Nelu,Lee, Heewon,Bosanac, Todd,Takahashi, Hidenori,Chen, Zhidong,Bartolozzi, Alessandra,Nemoto, Peter,Busacca, Carl A.,Song, Jinhua J.,Yee, Nathan K.,Mahaney, Paige E.,Senanayake, Chris H.
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p. 1427 - 1434
(2017/09/22)
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- Synthesis method of 2-aminopyrimidine-5-boronic acid pinacol ester borate
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The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 2-aminopyrimidine-5-boronic acid pinacol ester borate. The synthesis method comprises the following steps: carrying out continuous reaction at the temperature of 50 to 125 DEG C for 3 to 8 hours on 2-amino-5-bromopyrimidine and bisdiboron which serve as raw materials in a proper solvent under the action of specific alkaline potassium acetate and 1,1'-dis(diphenylphosphine) ferrocene] palladium dichloride dichloromethane complex serving as a specific catalyst to generate a 2-aminopyrimidine-5-boronic acid pinacol ester borate coarse product, wherein the amount ratio of the 2-amino-5-bromopyrimidine to the bisdiboron is 1 to (0.95 to 2.1), and the amount ratio of the 2-amino-5-bromopyrimidine to the solvent is 1 to (4.0 to 30); carrying out recrystallization to obtain a 2-aminopyrimidine-5-boronic acid pinacol ester borate pure product. According to the synthesis method, the raw material is relatively easy to obtain, and the operation is easy; the specific alkali and the specific catalyst accelerate the reaction progress and shortens the reaction time; the reaction yield is high, and the purity is high.
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Paragraph 0010-0016
(2017/08/28)
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- BENZODIAZEPINES AS BROMODOMAIN INHIBITORS
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The present invention provides novel benzodiazepine derivatives of Formula I or pharmaceutically acceptable derivatives, polymorphs, salts or prodrugs thereof. Said compounds have potential as bromodomain (BRD) inhibitors.
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Page/Page column 69
(2017/02/28)
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- 2-MORPHOLIN-4,6-DISUBSTITUTED PYRIMIDINE DERIVATIVE, AND PREPARATION METHOD AND PHARMACEUTICAL USE THEREOF
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Disclosed is a 2-morpholin-4,6-disubstituted pyrimidine derivative as shown in formula (I) below, and a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and a pharmaceutical composition thereof and a use thereof, wherein the definition of each group is as shown in the description. The compound has a PI3K kinase inhibition activity, and has a relatively high inhibitive ability and a low cytotoxicity against PIK3CA mutant breast cancer cell strains T47D and MCF-7.
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Paragraph 0093; 0100-0101
(2017/11/11)
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- Preparation of 2-amino-pyrimidine-5-boronic acid frequency that ester method
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A method of preparing 2-aminopyrimidine-5-boronic acid pinacol ester is disclosed. The method includes subjecting 2-chloropyrimidine that is a raw material and NBS to bromization under catalysis of BF3-Et2O to obtain 2-chloro-5-bromopyrimidine; reacting the 2-chloro-5-bromopyrimidine with n-Bu3MgLi at a temperature ranging from -20 DEG C to -10 DEG C; adding methoxyboronic acid pinacol ester or isopropoxyboronic acid pinacol ester; performing boronization to obtain 2-chloropyrimidine-5-boronic acid pinacol ester; adding into ammonia water or a methanol-ammonia solution; and reacting at 80-100 DEG C in a sealed manner to obtain the 2-chloropyrimidine-5-boronic acid pinacol ester. Synthetic process conditions of the method are mild. An ultralow-temperature reaction is avoided. Reactions can be performed continuously. A pure product can be obtained only by simple recrystallization of the final product.
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Paragraph 0019
(2017/01/02)
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- NOVEL HYDROXAMATE DERIVATIVES AND PHARMACEUTICAL COMPOSITION FOR TREATMENT OR PREVENTION OF CANCER CONTAINING THE SAME
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The present invention relates to novel hydroxamate derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the same as active components for preventing or treating cancers. The novel hydroxamate derivatives or pharmaceutically acceptable salts thereof selectively inhibit histone deacetylase-3 which is involved in delivering signals to control a DNA packing structure in cells, and thus resolve toxicity limit of a conventional pan-HDAc inhibitor while effectively inhibiting growth of cancer cells.COPYRIGHT KIPO 2016
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Paragraph 0111; 0112
(2017/01/05)
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- Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors
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Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed
- Zhang, Ji-Quan,Luo, Yong-Jie,Xiong, Yan-Shi,Yu, Yang,Tu, Zheng-Chao,Long, Zi-Jie,Lai, Xiao-Ju,Chen, Hui-Xuan,Luo, Yu,Weng, Jiang,Lu, Gui
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supporting information
p. 7268 - 7274
(2016/08/24)
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- Pyrimidine derivatives and their pharmaceutically acceptable salts, its preparation process and its use in medicine
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The present invention relates to pyrimidine derivatives and salts thereof, preparation method and pharmaceutical use thereof. Specifically, the present invention relates to pyrimidine derivatives of general formula(I), pharmaceutically acceptable salts th
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Paragraph 0154; 0159-0161
(2016/10/10)
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- Development of an asymmetric synthesis of a chiral quaternary FLAP inhibitor
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A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.
- Fandrick, Keith R.,Mulder, Jason A.,Patel, Nitinchandra D.,Gao, Joe,Konrad, Michael,Archer, Elizabeth,Buono, Frederic G.,Duran, Adil,Schmid, Rolf,Daeubler, Juergen,Desrosiers, Jean-Nicolas,Zeng, Xingzhong,Rodriguez, Sonia,Ma, Shengli,Qu, Bo,Li, Zhibin,Fandrick, Daniel R.,Grinberg, Nelu,Lee, Heewon,Bosanac, Todd,Takahashi, Hidenori,Chen, Zhidong,Bartolozzi, Alessandra,Nemoto, Peter,Busacca, Carl A.,Song, Jinhua J.,Yee, Nathan K.,Mahaney, Paige E.,Senanayake, Chris H.
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supporting information
p. 1651 - 1660
(2015/02/19)
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- Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo
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In the present study, a series of m-(4-morpholinoquinazolin-2-yl)benzamides were designed, synthesized and characterized. The antiproliferative activities of the synthesized compounds were evaluated against two human cell lines (HCT-116 and MCF-7). Compounds with IC50 values below 4 μM were further evaluated against U-87 MG and A549 cell lines. Among these evaluated compounds, compound T10 displayed a remarkable antiproliferative effect in vitro. The hoechst staining assay showed that compound T10 caused morphological changes. The cell cycle and apoptosis assay further indicated that compound T10 can arrest HCT-116 cells in G2/M and G0/G1 phase and induce apoptosis. PI3K enzyme assays indicated that compounds T7 and T10 selectively inhibit PI3K±. A Western bolt assay further suggested that compound T10 can block the PI3K/Akt/mTOR pathway. Moreover, compound T10 inhibited tumor growth on a mice S180 homograft model. These findings directly identify m-(4-morpholinoquinazolin-2-yl)benzamide derivatives as novel anticancer agents.
- Wang, Xiao-Meng,Xin, Min-Hang,Xu, Jing,Kang, Bo-Rui,Li, Yan,Lu, She-Min,Zhang, San-Qi
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p. 382 - 395
(2015/05/05)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITORS WITH ZINC BINDING MOIETY
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PROBLEM TO BE SOLVED: To provide phosphoinositide 3-kinase inhibitors with a zinc binding moiety. SOLUTION: There is provided a compound represented by formula (I) in the figure. (X is S, O or the like; Y is CH, N or the like; G1 is optionally substituted N or the like; R1 and R2 are each independently H or the like; C is a substituted heterocycle or the like; B is a linear alkyl or the like; Ra and Rb together with the nitrogen atom coupled to them are morpholino or the like; G2 is an indazole ring or the like; q, r and s are independently from 0 to 1, provided that at least one of them is 1; t is from 0 to 1; n is from 0 to 4; and p is from 0 to 2.) COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0296; 0307
(2016/10/07)
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- COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC DISEASES
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The present invention provides compounds of formula I: [INSERT FORMULA HERE] or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite, such as malaria.
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Page/Page column 70; 71; 95
(2014/06/11)
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K-ras mutation in a subject in need thereof. The method comprises the steps of: (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) administering to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Paragraph 0348; 0349
(2013/05/08)
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- METHOD OF INHIBITING HAMARTOMA TUMOR CELLS
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Dimorpholinopyrimidines are useful for inhibiting growth or proliferation of hamartoma tumor cells. Because the Dimorpholinopyrimidines inhibit the growth and proliferation of hamartoma tumor cells they are also useful in treating PTEN hamartoma tumor syndromes. The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a patient in need thereof an amount of a compound of dimorpholinopyrimidine derivative that is effective to inhibit growth or proliferation of the hamartoma tumor cells.
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Page/Page column 18
(2012/08/28)
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- Rapid synthesis of bis(hetero)aryls by one-pot Masuda borylation-Suzuki coupling sequence and its application to concise total syntheses of meridianins A and G
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3-(Hetero)aryl substituted indoles, 7-azaindoles, and pyrroles can be obtained in a very concise fashion via a one-pot Masuda borylation-Suzuki coupling sequence. The concise total syntheses of the marine natural products meridianins A (5) and G (4i) nice
- Merkul, Eugen,Schaefer, Elisabeth,Mueller, Thomas J. J.
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supporting information; experimental part
p. 3139 - 3141
(2011/06/28)
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- Synthesis and in vitro and in vivo evaluation of phosphoinositide-3-kinase inhibitors
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Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. A series of 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inh
- Burger, Matthew T.,Knapp, Mark,Wagman, Allan,Ni, Zhi-Jie,Hendrickson, Thomas,Atallah, Gordana,Zhang, Yanchen,Frazier, Kelly,Verhagen, Joelle,Pfister, Keith,Ng, Simon,Smith, Aaron,Bartulis, Sarah,Merrit, Hanne,Weismann, Marion,Xin, Xiaohua,Haznedar, Joshua,Voliva, Charles F.,Iwanowicz, Ed,Pecchi, Sabina
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supporting information; experimental part
p. 34 - 38
(2011/04/22)
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- Identification of NVP-BKM120 as a potent, selective, orally bioavailable class i PI3 kinase inhibitor for treating cancer
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Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
- Burger, Matthew T.,Pecchi, Sabina,Wagman, Allan,Ni, Zhi-Jie,Knapp, Mark,Hendrickson, Thomas,Atallah, Gordana,Pfister, Keith,Zhang, Yanchen,Bartulis, Sarah,Frazier, Kelly,Ng, Simon,Smith, Aaron,Verhagen, Joelle,Haznedar, Joshua,Huh, Kay,Iwanowicz, Ed,Xin, Xiaohua,Menezes, Daniel,Merritt, Hanne,Lee, Isabelle,Wiesmann, Marion,Kaufman, Susan,Crawford, Kenneth,Chin, Michael,Bussiere, Dirksen,Shoemaker, Kevin,Zaror, Isabel,Maira, Sauveur-Michel,Voliva, Charles F.
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supporting information; experimental part
p. 774 - 779
(2011/12/03)
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- BIARYL COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are compounds for treatment of KIT, CSF-1R and/or FLT3 kinase mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.
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Page/Page column 177
(2011/04/13)
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K- ras mutation in a subject in need thereof. The method comprises the steps of (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) adminsiterign to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Page/Page column 172
(2011/11/01)
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- 1,4-BENZODIAZEPINONE COMPOUNDS AND THEIR USE IN TREATING CANCER
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The invention provides a family of 1,4-benzodiazepinone compounds and methods for their use as therapeutic agents in treating cancer. Pharmaceutical compositions and methods of making the 1,4-benzodiazepinone compounds are provided.
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Page/Page column 91
(2010/11/04)
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- Preparation of Aminoaryl and Aminoheteroaryl Boronic Acids and Derivatives Thereof
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The invention relates to a method for preparation of aminoaryl- or aminoheteroarylboronic acids and esters and salts thereof in which an optionally substituted aminoaryl or aminoheteroaryl compound is protected at its nitrogen site via condensation with a carbonyl compound, subsequently metalated and converted with a suitable boron compound. Depending on the subsequent work-up and removal of the protective group, the corresponding boronic acid, the anhydride or the boronic acid ester thereof is obtained
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Page/Page column 7
(2008/12/04)
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- PYRIMIDINE DERIVATIVES USED AS PI-3 KINASE INHIBITORS
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Phosphatidylinositol (PI) 3-kinase inhibitor compounds (I), their pharmaceutically acceptable salts, and prodrugs thereof ; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases.
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Page/Page column 89-90
(2010/11/28)
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- New pyrimidylboronic acids and functionalized heteroarylpyrimidines by Suzuki cross-coupling reactions
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We report the synthesis of 2-chloro-5-pyrimidylboronic acid (6) and 2-amino-5-pyrimidylboronic acid (8) by lithium-halogen exchange followed by reaction with triisopropylborate. Their reactivity with heteroaryl halides in Suzuki-Miyaura cross-coupling reactions has been evaluated. New highly functionalized 5-heteroarylpyrimidine derivatives 24-33 (heteroaryl = quinoline, pyridine, pyrimidine, pyrazine, thiophene, benzothiazole) have been obtained in synthetically useful yields. The X-ray structure of 6 reveals extensive intermolecular O-H...N hydrogen bonding in the crystal. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Clapham, Kate M.,Smith, Amy E.,Batsanov, Andrei S.,McIntyre, Laura,Pountney, Adam,Bryce, Martin R.,Tarbit, Brian
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p. 5712 - 5716
(2008/09/17)
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- CHEMICAL COMPOUNDS
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The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof, of the formula (I): which possess B-Raf inhibitory activity and are accordingly useful for their anti-cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm-blooded animal such as man.
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Page/Page column 42-43
(2008/06/13)
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