- Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia
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Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM), and MEG-01 (GI50 = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.
- Liang, Xiaofei,Liu, Xiaochuan,Wang, Beilei,Zou, Fengming,Wang, Aoli,Qi, Shuang,Chen, Cheng,Zhao, Zheng,Wang, Wenchao,Qi, Ziping,Lv, Fengchao,Hu, Zhenquan,Wang, Li,Zhang, Shanchun,Liu, Qingsong,Liu, Jing
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p. 1984 - 2004
(2016/03/22)
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- FUSED 1,4-DIHYDRODIOXIN DERIVATIVES AS INHIBITORS OF HEAT SHOCK TRANSCRIPTION FACTOR 1
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The present invention relates to compounds of formula I wherein A1, A2 R4 and Q are as defined herein. The compounds of the present invention are inhibitors of heat shock factor 1 (HSF1). In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.
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Paragraph 00182
(2015/04/22)
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- 4-SUBSTITUTED-(3-SUBSTITUTED-1H-PYRAZOLE-5-AMINO)-PYRIMIDINE DERIVATIVES HAVING ACTIVITY OF INHIBITING PROTEIN KINASE AND USE THEREOF
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Provided are derivatives substituted by urea associated with 4-substituted-(3-substituted-1H-pyrazole-5-amino)-pyrimidine-2-amino of formula (I), wherein these compounds may selectively regulate or inhibit an information transmission process controlled by
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Paragraph 0144; 0147; 0148
(2014/07/23)
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- 4-SUBSTITUTED-(3-SUBSTITUTED-1H-PYRAZOLE-5-AMINO)-PYRIMIDINE DERIVATIVES HAVING ACTIVITY OF INHIBITING PROTEIN KINASE AND USE THEREOF
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Provided are derivatives substituted by urea associated with 4-substituted-(3-substituted-1H-pyrazole-5-amino)-pyrimidine-2-amino of formula (I), wherein these compounds may selectively regulate or inhibit an information transmission process controlled by
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Paragraph 0356; 0358
(2015/01/07)
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- THIENO (2, 3B) PYRAZINE COMPOUNDS AS B-RAF INHIBITORS
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The invention relates to compounds according to general Formula (I) or a pharmaceutically acceptable salt thereof. The compounds can be used for the treatment of cancer.
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Paragraph 0156
(2013/04/10)
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- PREPARATION AND METHODS OF USE FOR ORTHO-ARYL 5- MEMBERED HETEROARYL-CARBOXAMIDE CONTAINING MULTI-TARGETED KINASE INHIBITORS
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The present disclosure relates to compounds of the Formula (I): and pharmaceutically acceptable salts, as kinase modulators, compatible with the Type-II inhibition of kinases.
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Page/Page column 96
(2013/03/26)
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- THIENO[3,2-d]PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY ON PROTEIN KINASES
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The present invention relates to a thieno[3,2-d]pyrimidine derivative of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, which has an excellent inhibitory activity on protein kinases, and a pharmaceutical composition comprising the same is effective in preventing or treating abnormal cell growth diseases.
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Paragraph 0407-0409
(2013/03/26)
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- Synthesis of amino-substituted indoles using the Bartoli reaction
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We report herein the concise preparation of a range of functionalised aminoindoles via a new application of the Bartoli reaction. Scope and limitations of the methodology have been extensively studied to reveal the importance of protecting groups and subs
- Wylie, Laura,Innocenti, Paolo,Whelligan, Daniel K.,Hoelder, Swen
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supporting information; experimental part
p. 4441 - 4447
(2012/06/30)
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- Affinity-based probes based on type II kinase inhibitors
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Protein kinases are key components of most mammalian signal transduction networks and are therapeutically relevant drug targets. Efforts to study protein kinase function would benefit from new technologies that are able to profile kinases in complex prote
- Ranjitkar, Pratistha,Perera, B. Gayani K.,Swaney, Daniel L.,Hari, Sanjay B.,Larson, Eric T.,Krishnamurty, Ratika,Merritt, Ethan A.,Villén, Judit,Maly, Dustin J.
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supporting information
p. 19017 - 19025
(2013/01/15)
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- Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives
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Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.
- Hirose, Masaaki,Okaniwa, Masanori,Miyazaki, Tohru,Imada, Takashi,Ohashi, Tomohiro,Tanaka, Yuta,Arita, Takeo,Yabuki, Masato,Kawamoto, Tomohiro,Tsutsumi, Shunichirou,Sumita, Akihiko,Takagi, Terufumi,Sang, Bi-Ching,Yano, Jason,Aertgeerts, Kathleen,Yoshida, Sei,Ishikawa, Tomoyasu
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p. 5600 - 5615
(2012/10/29)
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- THIENO (2, 3B) PYRAZINE COMPOUNDS AS B - RAF INHIBITORS
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The invention relates to compounds according to general Formula (I) or a pharmaceutically acceptable salt thereof. The compounds can be used for the treatment of cancer.
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Page/Page column 44
(2011/12/14)
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- THIENO[3,2-d]PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY ON PROTEIN KINASES
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The present invention relates to a thieno[3,2-d]pyrimidine derivative of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, which has an excellent inhibitory activity on protein kinases, and a pharmaceutical composition comprising the same is effective in preventing or treating abnormal cell growth diseases.
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Page/Page column 56; 57
(2011/08/21)
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- Application of a novel [3+2] cycloaddition reaction to prepare substituted imidazoles and their use in the design of potent DFG-out allosteric B-Raf inhibitors
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B-Raf protein kinase, which is a key signaling molecule in the RAS-RAF-MEK-ERK signaling pathway, plays an important role in many cancers. The B-Raf V600E mutation represents the most frequent oncogenic kinase mutation known and is responsible for increas
- Dietrich, Justin,Gokhale, Vijay,Wang, Xiadong,Hurley, Laurence H.,Flynn, Gary A.
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experimental part
p. 292 - 304
(2010/04/02)
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- HETEROARYL COMPOUNDS AND USES THEREOF
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The present invention provides inhibitors of protein kinases of formula I-a and I-b, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Page/Page column 159; 160
(2010/01/30)
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- PROTEIN KINASE INHIBITORS AND METHODS FOR USING THEREOF
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The invention provides compounds of formula (l) and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, and methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of AIk, AbI, Aurora-A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, CSK, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRalpha, PDGFRbeta, PKCalpha, SAPK2alpha, Src, SIK, Syk, Tie2 and TrkB kinases.
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Page/Page column 35-36
(2009/01/20)
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- SUBSTITUTED QUINAZOLINES WITH ANTI-CANCER ACTIVITY
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The invention relates to chemical compounds of the formula (I): or pharmaceutically acceptable salts thereof, 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 25
(2008/06/13)
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- QUINAZOLINONE DERIVATIVES AND THEIR USE AS B-RAF INHIBITORS
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The invention relates to chemical compounds of the formula (I): or pharmaceutically acceptable salts thereof, 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 96
(2008/06/13)
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- QUINOXALINES AS B RAF INHIBITORS
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The invention relates to chemical compounds of the formula (I) or pharmaceutically acceptable salts thereof, 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 61
(2010/11/08)
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- SUBSTITUTED QUINAZOLONES AS ANTI-CANCER AGENTS
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The invention relates to chemical compounds of the formula (I): or pharmaceutically acceptable salts thereof, 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 75
(2010/02/15)
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- PROTEIN KINASE MODULATORS AND METHOD OF USE
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The present invention relates to chemical compounds having a general formula I wherein A, B, D, E, G, H1-5 and R1-4 are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of these kinases. For example, the compounds are capable of modulating kinase enzymes thereby influencing the process of angiogenesis and treating angiogenesis-related diseases and other poliferative disorders, including cancer and inflammation. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of protein kinases.
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Page/Page column 122
(2010/02/14)
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- USE OF C-KIT INHIBITORS FOR TREATING TYPE II DIABETES
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The present invention relates to a method for treating type II diabetes, comprising administering a compound capable of depleting mast cells to a human in need of such treatment. Such compounds can be chosen from non-toxic, selective and potent c-kit inhibitors.
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Page/Page column 84
(2008/06/13)
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- 2-(3-AMINOARYL) AMINO-4-ARYL-THIAZOLES AND THEIR USE AS C-KIT INHIBITORS
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The present invention relates to the use of masitinib or a pharmaceutically acceptable salt thereof, and in particular of masitinib mesylate, for the preparation of a medicament for the treatment of GIST, to the use of this therapy for the treatment of GIST, and a method of treating mammals, including humans, suffering from GIST by administering to said mammal in need of such treatment an effective dose of masitinib, and in particular masitinib mesylate
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