- Design, synthesis, biological evaluation and molecular modeling of novel 1H-pyrazolo[3,4-d]pyrimidine derivatives as BRAFV600E and VEGFR-2 dual inhibitors
-
Aiming to explore novel BRAFV600E and VEGFR-2 dual inhibitors, a series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed, synthesized and biologically evaluated in this study. Most of the synthesized 1H-pyrazolo[3,4-d]pyrimidine compounds displayed moderate to high potent activity in both enzymatic and cellular proliferation assays. Among these compounds, 9e, 9g, 9m and 9u showed remarkably high inhibitory activities against both BRAFV600E and VEGFR-2 kinase comparable to positive control Sorafenib. Particularly, compound 9u also showed potent anti-proliferative activity against BRAFV600E-expressing A375 (IC50 = 1.74 μM) and H-29 (IC50 = 6.92 μM) as well as VEGFR-2-expressing HUVEC (IC50 = 5.89 μM), which was also comparable to Sorafenib. Furthermore, kinase selectivity profile showed that 9u had almost poor or no significant inhibitory activity against wild-type BRAF and 15 other tested protein kinases. Flow cytometric analysis showed that compound 9u mainly arrested the A375 and HUVEC cell lines in the G0/G1 stage with a concentration-dependent effect. In addition, the molecular docking and molecular dynamics simulations suggested that 9u adopted a similar binding pattern with Sorafenib at the ATP-binding sites of BRAFV600E and VEGFR-2. Taken together, these results indicated that compound 9u may serve as novel lead compound in research on more effective BRAFV600E and VEGFR-2 dual inhibitors.
- Wang, Yuanyuan,Wan, Shanhe,Li, Zhonghuang,Fu, Yu,Wang, Guangfa,Zhang, Jiajie,Wu, Xiaoyun
-
p. 210 - 228
(2018/06/12)
-
- CYCLIC DI-NUCLEOTIDE COMPOUNDS AND METHODS OF USE
-
Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.
- -
-
Paragraph 0249
(2017/10/11)
-
- (1H-pyrazolo[3,4-d]pyrimidine)-4-amino derivative and application of same as IDO inhibitor to drug preparation
-
The invention discloses a (1H-pyrazolo[3,4-d]pyrimidine)-4-amino derivative and a preparation method thereof, and application of the derivative as an IDO inhibitor. The derivative provided by the invention can be used for preventing and/or treating a plurality of diseases, such as Alzheimer's disease, cataract, infections related to cellular immune activation, autoimmune diseases, AIDS, cancers, depression or metabolic disorder of tryptophan.
- -
-
Paragraph 0049; 0050
(2017/08/31)
-
- Bisarylureas based on 1H-Pyrazolo[3,4-d]pyrimidine Scaffold as Novel Pan-RAF inhibitors with potent anti-proliferative activities: Structure-based design, synthesis, biological evaluation & molecular modelling studies
-
RAF (Ras activating factor) kinases are important and attractive targets for cancer therapy. With the aim of discovering RAF inhibitors that bind to DFG-out inactive conformation created by the movement of Asp-Phe-Gly (DFG), we conducted structure-based drug design using the X-ray cocrystal structures of BRAF (v-raf murine sarcoma viral oncogene homolog B1), starting from bisarylurea derivative based on 1H-pyrazolo[3,4-d]pyrimidine scaffold 1a. Most of the synthesized compounds showed good to excellent inhibitory activities against BRAFV600E kinase, possessed moderate to potent anti-proliferative activities against four tumor cell lines (A375, HT-29, PC-3 and A549) and good selectivity towards cancer cells rather normal cells (Madin-Darby canine kidney, MDCK). The most promising compound, 1v, exhibited potent inhibitory activity against not only BRAFV600E (half maximal inhibitory concentration, IC50 = 23.6 nM) but also wild-Type BRAF (IC50 = 51.5 nM) and C-RAF (IC50 = 8.5 nM), and effective cellular anti-proliferative activities against A375, HT-29, PC-3 and A549 cell lines as well as a very good selectivity profile. Moreover, compound 1v mainly arrested the A375 cell line in the G0/G1 stage, and showed significant suppression of MEK (mitogen-Activated protein kinase kinase) phosphorylation in A375 and HT-29 cell lines. Taken together, the optimal compound 1v showed excellent in vitro potency as a pan-RAF inhibitor. In addition, the promise of compound 1v was further confirmed by molecular dynamics simulation and binding free energy calculations.
- Fu, Yu,Wang, Yuanyuan,Wan, Shanhe,Li, Zhonghuang,Wang, Guangfa,Zhang, Jiajie,Wu, Xiaoyun
-
-
- 1-(2-tetrahydropyrane)-1H-pyrazole[3, 4-d] pyrimidine compound having anti-tumor activity and preparation method thereof
-
The invention discloses a 1-(2-tetrahydropyrane)-1H-pyrazole[3, 4-d] pyrimidine compound having anti-tumor activity. A general formula of the compound is shown as follows. The invention further discloses a synthesis method of the compound and a medicinal composition containing the compound. The invention further discloses application of the medicinal composition in treating diseases caused by protein kinase activity abnormality. The pyrazole [3, 4-d] pyrimidine compound which is novel in structure and remarkable in anti-tumor activity is developed. The compound can be used as a double-target inhibitor of BRAF/VEGFR-2 kinase and has good effect and wide application prospect in the aspect of treating the diseases caused by protein kinase activity abnormality.
- -
-
Paragraph 0049; 0050; 0051; 0052
(2017/08/28)
-
- 1H-pyrazolo[3,4-d]pyrimidin compound and preparation method and application thereof
-
The invention discloses a 1H-pyrazolo[3,4-d]pyrimidin compound and a preparation method and application thereof. The 1H-pyrazolo[3,4-d]pyrimidin compound has the structural formula as shown in the description. Meanwhile, the invention discloses the preparation method of the 1H-pyrazolo[3,4-d]pyrimidin compound and application of the 1H-pyrazolo[3,4-d]pyrimidin compound to preparation of medicines for treating protein kinase activity abnormity related diseases. The invention provides the 1H-pyrazolo[3,4-d]pyrimidin compound which is novel in structure and has remarkable anti-tumor activities, and the 1H-pyrazolo[3,4-d]pyrimidin compound can serve as a double-target inhibitor of BRAF/VEGFR-2 kinase and has a favorable effect and a wide application prospect in the aspect of treating diseases caused by protein kinase activity abnormity.
- -
-
Paragraph 0075; 0076; 0077; 0078
(2018/03/13)
-
- Palladium-catalyzed regioselective direct C–H arylation of?pyrazolo[3,4-d]pyrimidines
-
Nitrogenous bicycles are an apparently endless field of organic and biological research. In this study, we disclose an efficient pathway to the synthesis of the pyrazolo[3,4-d]pyrimidine scaffold in three steps from allopurinol. This key intermediate was engaged in the first example of regioselective C–H arylation catalyzed by palladium to access a library of 3-substituted-1-methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidines.
- El Hafi, Mohamed,Naas, Mohammed,Loubidi, Mohammed,Jouha, Jabrane,Ramli, Youssef,Mague, Joel T.,Essassi, El Mokhtar,Guillaumet, Gérald
-
p. 927 - 933
(2017/09/06)
-
- Structure-metabolism relationships in human-AOX: Chemical insights from a large database of aza-aromatic and amide compounds
-
Aldehyde oxidase (AOX) is a metabolic enzyme catalyzing the oxidation of aldehyde and aza-aromatic compounds and the hydrolysis of amides, moieties frequently shared by the majority of drugs. Despite its key role in human metabolism, to date only fragmentary information about the chemical features responsible for AOX susceptibility are reported and only "very local" structure-metabolism relationships based on a small number of similar compounds have been developed. This study reports a more comprehensive coverage of the chemical space of structures with a high risk of AOX phase I metabolism in humans. More than 270 compounds were studied to identify the site of metabolism and themetabolite(s). Both electronic [supported by density functional theory (DFT) calculations] and exposure effects were considered when rationalizing the structure-metabolism relationship.
- Lepri, Susan,Ceccarelli, Martina,Milani, Nicolò,Tortorella, Sara,Cucco, Andrea,Valeri, Aurora,Goracci, Laura,Brink, Andreas,Cruciani, Gabriele
-
p. E3178 - E3187
(2017/04/24)
-
- Discovery and preliminary structure–activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties
-
Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50value of 5.3 μM. The structure–activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.
- Qian, Shan,He, Tao,Wang, Wei,He, Yanying,Zhang, Man,Yang, Lingling,Li, Guobo,Wang, Zhouyu
-
p. 6194 - 6205
(2016/12/06)
-
- 3,3-DIFLUORO-PIPERIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
-
Disclosed are chemical entities of Formula (I): wherein X, Y, Z, R1, R3, R4 and R5 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).
- -
-
Paragraph 0149
(2016/09/22)
-
- Discovery of novel allopurinol derivatives with anticancer activity and attenuated xanthine oxidase inhibition
-
A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC50 values of 25.5 and 35.2 μM against human hepatoma carcinoma cell lines, BEL-7402 and SMMC-7221, respectively. The anticancer activity of 4 was comparable to that of Tanespimycin (17-N-allylamino-17-demethoxy geldanamycin, 17-AAG) that inhibited the growth of BEL-7402 and SMMC-7221 cells at IC50 values of 12.4 and 9.85 μM, respectively. However, unlike allopurinol, which is also a strong inhibitor of XOD, compound 4 is a much weaker XOD inhibitor, suggesting that the anticancer activities of the allopurinol derivatives may not be associated with XOD inhibition. Moreover, the cytotoxicity of 4 toward normal cells is significantly lower than that of 17-AAG, making 4 a promising lead compound for further optimization of structure-activity relationships that may lead to anticancer agents of clinical utility.
- Li, Yong,Cao, Ting-Ting,Guo, Shanchun,Zhong, Qiu,Li, Cai-Hu,Li, Ying,Dong, Lin,Zheng, Shilong,Wang, Guangdi,Yin, Shu-Fan
-
-
- SUBSTITUTED QUINOXALINES AND BENZOTRIAZINE P70S6 KINASE INHIBITORS
-
The invention provides compounds that inhibit or modulate the activity of p70S6 kinase, the compounds being of the formula (0), or a salt, tautomer or N-oxide thereof; wherein: X1 is N or N+(0-); X2 is N or CH; Q1 is an optionally substituted C1-8 alkylene; Q2 is a bond or an optionally substituted C1-8 alkylene group; R1 is selected from hydrogen and a group Cy1; Cy1 is an optionally substituted 4 to 7 membered monocyclic non-aromatic carbocyclic or heterocyclic group containing 0, 1 or 2 heteroatom ring members selected from O and S and oxidised forms of S; R2, R3 and R4 are the same or different and each is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms; Ar1 is an optionally substituted monocyclic 5 or 6-membered aryl or heteroaryl ring containing 0, 1 or 2 heteroatom ring members selected from O, N and S, or a naphthyl ring Ar2 is an optionally substituted bicyclic 8 to 1 1 -membered heteroaryl group containing 1, 2, 3 or 4 heteroatom ring members selected from O, N and S. The compounds are useful in medicine, for example in the treatment of a disease or condition selected from cancers (e.g. triple negative breast cancer, brain tumours and brain metastases arising from non-brain cancers), neurodevelopmental diseases (e.g. Fragile X syndrome) and neurodegenerative diseases.
- -
-
Page/Page column 94
(2016/11/14)
-
- DIFLUOROETHYLPYRIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
-
Disclosed are chemical entities of formula (I) wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.
- -
-
Paragraph 0185
(2016/02/16)
-
- 4-POSITION SUBSTITUTED PYRAZOLOPYRIMIDINE DERIVATIVE, AND USE THEREOF IN DRUG PREPARATION
-
The invention belongs to the technical field of organic synthetic drugs, and particularly relates to a pyrazolopyrimidine derivative and a preparation method and medical uses thereof. The invention provides a new pyrazolopyrimidine derivative mainly having position 4 substituted, i.e., position substituted by Y in formula I. The pyrazolopyrimidine derivative of the invention has a structural formula I as follows: The invention provides a new pyrazolopyrimidine derivative and a simple, efficient and low-cost preparation method thereof. The pyrazolopyrimidine derivative of the invention has good inhibitory activity for multiple kinases, has inhibitory action on multiple solid tumors, leukemia and autoimmune diseases, provides a new effective choice for preparation of kinase inhibitors, medicines for autoimmune diseases, angiogenesis inhibitors and antitumor drugs, and has good application prospect.
- -
-
Paragraph 0101
(2015/07/15)
-
- Novel Hinge-Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure-Activity Relationship Study on Tofacitinib Bioisosteres
-
The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.
- Gehringer, Matthias,Forster, Michael,Pfaffenrot, Ellen,Bauer, Silke M.,Laufer, Stefan A.
-
supporting information
p. 2516 - 2527
(2015/08/24)
-
- Synthesis of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines from 4,6-dichloropyrimidine-5-carboxaldehyde: Insights into selectivity and reactivity
-
Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5- carboxaldehyde with both aromatic and aliphatic hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective, high-yielding, and operationally simple manner are presented. For aromatic hydrazines, the reaction is performed at a high temperature in the absence of an external base. For aliphatic hydrazines, the reaction proceeds at room temperature in the presence of an external base. The observed selectivity and reactivity trends are rationalized through consideration of the proposed reaction mechanism. The 1-substituted 4-chloropyrazolo[3,4-d]pyrimidine products serve as versatile synthetic intermediates, through further functionalization of the 4-chloride moiety, enabling the rapid generation of a structurally diverse array of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines. Georg Thieme Verlag Stuttgart. New York.
- Morrill, Christie,Babu, Suresh,Almstead, Neilg.,Moon, Young-Choon
-
p. 1791 - 1806
(2013/07/26)
-
- An alternative synthetic approach for the synthesis of biologically relevant 1,4-disubstituted pyrazolo[3,4-d]pyrimidines
-
A versatile approach for the synthesis of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines has been developed. Starting from commercially available allopurinol, TBAF mediated N1-functionalization and subsequent C4 nucleophilic substitution, under microwave assisted- or standard heating conditions, granted access to highly functionalized pyrazolo[3,4-d]pyrimidines of potential biological interest.
- Radi, Marco,Bernardo, Vincenzo,Vignaroli, Giulia,Brai, Annalaura,Biava, Mariangela,Schenone, Silvia,Botta, Maurizio
-
supporting information
p. 5204 - 5206
(2013/09/02)
-
- Selective synthesis of 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines
-
Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5- carboxaldehyde with various hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective and high-yielding manner are presented. For aromatic hydrazines, the reaction is performed in the absence of an external base, which promotes exclusive hydrazone formation. The hydrazones subsequently cyclize at an elevated temperature to form the desired pyrazolo[3,4-d]pyrimidine products. For aliphatic hydrazines, the reaction sequence proceeds as a single step in the presence of an external base.
- Babu, Suresh,Morrill, Christie,Almstead, Neil G.,Moon, Young-Choon
-
supporting information
p. 1882 - 1885
(2013/06/05)
-
- Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant
-
Starting from our in-house library of pyrazolo[3,4-d]pyrimidines, a cross-docking simulation was conducted on Bcr-Abl T315I mutant. Among the selected compounds (2a-e), the 4-bromo derivative 2b showed the best activity against the Bcr-Abl T315I mutant. Deeper computational studies highlighted the importance of the bromine atom in the para position of the N1 side chain phenyl ring for the interaction with the T315I mutant. A series of 4-bromo derivatives was thus synthesized and biologically evaluated. Compound 2j showed a good balance of different ADME properties, high activity in cell-free assays, and a submicromolar potency against T315I Bcr-Abl expressing cells. In addition, it was converted into a water-soluble formulation by liposome encapsulation, preserving a good activity on leukemic T315I cells and avoiding the use of DMSO as solubilizing agent. In vivo studies on mice inoculated with 32D-T315I cells and treated with 2j showed a more than 50% reduction in tumor volumes.
- Radi, Marco,Tintori, Cristina,Musumeci, Francesca,Brullo, Chiara,Zamperini, Claudio,Dreassi, Elena,Fallacara, Anna Lucia,Vignaroli, Giulia,Crespan, Emmanuele,Zanoli, Samantha,Laurenzana, Ilaria,Filippi, Irene,Maga, Giovanni,Schenone, Silvia,Angelucci, Adriano,Botta, Maurizio
-
p. 5382 - 5394
(2013/07/26)
-
- Synthesis and biological evaluation of pyrazolo[4,3-d]pyrimidine analogues
-
A series of pyrazolo[3,4-d]pyrimidine analogues 3, 4 , 5aef, 6aef with various amines and ester groups at C-4 and N-1 were synthesized and evaluated for antitumour activity. They were also evaluated for xanthine oxidase inhibitory activity, with most compounds having no significant impact. Compound 5e had the strongest activity against human hepatoma carcinoma cells 7402 and 7221, with half-maximal inhibitory concentration values of 4.55 and 6.28, respectively. Structureeactivity relationship studies indicate that chlorine atoms in the structure of 4-((4-(substituted amides)phenyl)amino pyrazolo[4,3-d] pyrimidine analogues is crucial for antitumour activity.
- Yuan, Li,Song, ChangWei,Li, CaiHu,Li, Ying,Dong, Lin,Yin, ShuFan
-
p. 152 - 157
(2013/10/01)
-
- Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo
-
We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish- based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin -4-yloxy)phenyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.
- Yang, Ling-Ling,Li, Guo-Bo,Ma, Shuang,Zou, Chan,Zhou, Shu,Sun, Qi-Zheng,Cheng, Chuan,Chen, Xin,Wang, Li-Jiao,Feng, Shan,Li, Lin-Li,Yang, Sheng-Yong
-
p. 1641 - 1655
(2013/04/10)
-
- 4 SUBSTITUTED PYRAZOLOPYRIMIDINES
-
The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions
- -
-
Page/Page column 23
(2012/07/14)
-
- 4 SUBSTITUTED PYRAZOLOPYRIMIDINES USEFUL AS PKC-THETA INHIBITORS
-
The present invention relates to compounds of formulae (I) and (IA) useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.
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Page/Page column 48; 49
(2011/11/30)
-
- HETEROARYL BTK INHIBITORS
-
The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.
- -
-
Page/Page column 126
(2011/04/14)
-
- Heterocyclic Compounds Useful as RAF Kinase Inhibitors
-
The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
- -
-
Page/Page column 18
(2009/01/24)
-
- GPR119 Receptor Agonists
-
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.
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-
Page/Page column 28
(2009/12/05)
-
- RAF KINASE MODULATORS AND METHODS OF USE
-
The present invention comprises a new class of compounds capable of modulating the activity of Raf kinase and, accordingly, useful for treatment of Raf kinase mediated diseases, including melanomas, tumors and other cancer-related conditions. The compounds have a general Formula (I) wherein each of A1, A2, A3, A4, A5, A6, A7, A8, A9, bond B, X, rings Z1 and Z2, R1 and R3 are defined herein. The invention further comprises pharmaceutical compositions, methods for treatment of Raf kinase mediated diseases, and intermediates and processes useful for the preparation of compounds of the invention.
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Page/Page column 42; 63-64
(2009/01/24)
-
- P70 S6 KINASE INHIBITORS
-
The present invention provides p70 S6 kinase inhibitors of the formula: pharmaceutical formulations comprising them, and methods for their use.
- -
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Page/Page column 36-37
(2009/01/20)
-
- 3-(SUBSTITUTED AMINO)-PYRAZOLO[3,4-d]PYRIMIDINES AS EPHB AND VEGFR2 KINASE INHIBITORS
-
The invention relates to novel pyrazolo[3,4-d]pyrimidines of the formula in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
- -
-
Page/Page column 59
(2010/11/27)
-
- Azaindazole compounds and methods of use
-
Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.
- -
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Page/Page column 9
(2008/06/13)
-
- Substituted pyrazolopyrimidines
-
The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions that include substituted heterobicyclic pyrimidines of Formula (I): wherein R1, R2, R3, R4, R5, X, W, and ring A are as defined herein; pharmaceutical compositions of substituted heterobicyclic pyrimidines of Formula (I); and their use in the treatment of chronic neurodegenerative diseases, neurotraumatic diseases, depression and/or diabetes. More particularly, the present invention relates to substituted pyrazolopyrimidines of Formula (I).
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-
Page/Page column 36
(2008/06/13)
-
- NITROGENOUS FUSED BICYCLIC COMPOUND
-
A novel nitrogenous fused bicyclic compound represented by the following general formula [1] or a pharmacologically acceptable salt of the compound. They have excellent SK channel blocking activity and are useful as a medicine. [I] (In the formula, R 0 represents hydrogen, halogeno, etc.; R 1 represents a group represented by the formula (a) or (b); A represents a group represented by the formula (X) or (Y); D 1 , D 2 and D 3 each represents N or CH; R 2 represents halogeno or optionally halogenated lower alkyl, etc.; R 3 represents hydrogen or lower alkyl; and Q represents lower alkylene.)
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Page/Page column 60
(2010/11/26)
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- INHIBITORS OF Akt ACTIVITY
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Invented are novel thiophene compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
- -
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Page/Page column 181
(2010/11/27)
-
- AKT PROTEIN KINASE INHIBITORS
-
The present invention provides compounds, including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula: A-L-CR where CR is a cyclical core group, L is a linking group and A is as defined herein. Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.
- -
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Page/Page column 115; 162-163
(2008/06/13)
-
- Design, synthesis, and structure-activity relationships of pyrazolo[3,4-d]pyrimidines: A novel class of potent enterovirus inhibitors
-
A series of pyrazolo[3,4-d]pyrimidines were synthesized and their antiviral activity was evaluated in a plaque reduction assay. It is very interesting that this class of compounds provide remarkable evidence that they are very specific for human enteroviruses, in particular, coxsackieviruses. Some derivatives proved to be highly effective in inhibiting enterovirus replication at nanomolar concentrations. SAR studies revealed that the phenyl group at the N-1 position and the hydrophobic diarylmethyl group at the piperazine largely influenced the in vitro antienteroviral activity of this new class of potent antiviral agents. It was found that the pyrazolo[3,4-d]pyrimidines with a thiophene substituent, such as compounds 20-24, in general exhibited high activity against coxsackievirus B3 (IC50=0.063-0.089μM) and moderate activity against enterovirus 71 (IC50=0.32-0.65μM) with no apparent cytotoxic effect toward RD (rhabdomyosarcoma) cell lines (CC5025μ M).
- Chern, Jyh-Haur,Shia, Kak-Shan,Hsu, Tsu-An,Tai, Chia-Liang,Lee, Chung-Chi,Lee, Yen-Chun,Chang, Chih-Shiang,Tseng, Sung-Nien,Shih, Shin-Ru
-
p. 2519 - 2525
(2007/10/03)
-