- Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance
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The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, andin vivoactivity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.
- Finlay, M. Raymond V.,Barton, Peter,Bickerton, Sue,Bista, Michal,Colclough, Nicola,Cross, Darren A. E.,Evans, Laura,Floc’h, Nicolas,Gregson, Clare,Guérot, Carine M.,Hargreaves, David,Kang, Xiaoming,Lenz, Eva M.,Li, Xu,Liu, Yi,Lorthioir, Olivier,Martin, Matthew J.,McKerrecher, Darren,McWhirter, Claire,O’Neill, Daniel,Orme, Jonathan P.,Mosallanejad, Arash,Rahi, Amar,Smith, Paul D.,Talbot, Verity,Ward, Richard A.,Wrigley, Gail,Wylot, Marta,Xue, Lin,Yao, Tieguang,Ye, Yang,Zhao, Xiliang
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p. 13704 - 13718
(2021/09/28)
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- Compound for inhibiting three-mutant epidermal growth factor receptor tyrosine kinase and application thereof
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The invention discloses a compound for inhibiting three-mutant epidermal growth factor receptor tyrosine kinase, and is characterized in that the structural formula is as follows. Among them: Substituent R1 . One of: Substituent R2 . One of: The substituent X is H or Cl. Substituent R3 To H. One of the following.
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Paragraph 0039; 0111-0115
(2021/09/15)
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- Discovery of a Pyrimidothiazolodiazepinone as a Potent and Selective Focal Adhesion Kinase (FAK) Inhibitor
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Focal adhesion kinase (FAK) is a tyrosine kinase with prominent roles in protein scaffolding, migration, angiogenesis, and anchorage-independent cell survival and is an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual kinase inhibition and/or significant activity on several kinases. Although multitargeted activity is at times therapeutically advantageous, such behavior can also lead to toxicity and confound chemical-biology studies. We report a novel series of small molecules based on a tricyclic pyrimidothiazolodiazepinone core that displays both high potency and selectivity for FAK. Structure-activity relationship (SAR) studies explored modifications to the thiazole, diazepinone, and aniline "tail,"which identified lead compound BJG-03-025. BJG-03-025 displays potent biochemical FAK inhibition (IC50 = 20 nM), excellent kinome selectivity, activity in 3D-culture breast and gastric cancer models, and favorable pharmacokinetic properties in mice. BJG-03-025 is a valuable chemical probe for evaluation of FAK-dependent biology.
- Groendyke, Brian J.,Nabet, Behnam,Mohardt, Mikaela L.,Zhang, Haisheng,Peng, Ke,Koide, Eriko,Coffey, Calvin R.,Che, Jianwei,Scott, David A.,Bass, Adam J.,Gray, Nathanael S.
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supporting information
p. 30 - 38
(2021/01/11)
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- ARYL-PHOSPHORUS-OXYGEN COMPOUND AS EGFR KINASE INHIBITOR
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Disclosed is a class of new aryl-phosphorus-oxygen compounds as shown in formula (I) as EGFR kinase inhibitors, and pharmaceutically acceptable salts thereof.
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Paragraph 0230; 0238; 0239; 0250; 0254; 0255
(2020/06/16)
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- Preparation method of ALK inhibitor Brigatinib
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The invention relates to the technical field of medicines, and relates to a preparation method of a medicine ALK inhibitor AP26113. The method comprises the following steps: (1) carrying out substitution reaction of aromatic amine on 2,4,5-trichloropyrimi
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Paragraph 0051-0054
(2020/06/02)
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- Novel(1,2,4)triazolo(1,5-a)pyridylphosphine oxide and use thereof
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The present invention relates to novel(1,2,4)triazolo(1,5-a)pyridinyl phosphorus oxides and uses thereof. Wherein the compound is a compound represented by a formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a prodrug thereof, and R1 to R5 are as defined in the specification. The compound disclosed by the invention can be used for preparing a medicine for treating and/or preventing cancers.
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Paragraph 0210; 0213-0216
(2020/07/24)
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- Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026
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Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed.
- Takahama, Yuji,Obitsu, Kazuyoshi,Takeguchi, Kazuhiro,Hirasawa, Shun,Kobayashi, Koji,Akiba, Takahiro,Ueda, Norihiro,Orii, Ryoki,Ohigashi, Atsushi,Takahashi, Takumi,Okada, Minoru,Ieda, Shigeru
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p. 512 - 523
(2019/03/07)
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- Discovery of N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a potent and selective anaplastic lymphoma kinase (ALK) inhibitor
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Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule- associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, once-daily oral administration of 14a demonstrated dose-dependent antitumor activity. Here, syntheses and structure-activity relationship (SAR) studies of 1,3,5-triazine derivatives are described.
- Iikubo, Kazuhiko,Kondoh, Yutaka,Shimada, Itsuro,Matsuya, Takahiro,Mori, Kenichi,Ueno, Yoko,Okada, Minoru
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p. 251 - 262
(2018/03/13)
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- PYRIMIDINE DERIVATIVE AND USE THEREOF
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The present invention provides a pyrimidine derivative and a use thereof. The pyrimidine derivative is the compound shown in formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, wherein, R1, R2, R3, R4 and R5 are, for example, as defined in the specification. The compound can act as an ALK inhibitor, and is for preparing an anti-tumor medicament for suppressing an anaplastic lymphoma kinase.
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Paragraph 0140; 0141
(2018/09/27)
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- 2,4-dibasic miazines compound
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The invention belongs to the field of medical chemistry, relates to a 2,4-dibasic miazines compound and specifically relates to a compound shown as formula (I) or a pharmaceutically acceptable salt thereof, a drug compound thereof and an application thereof in treating EGFR or/and ALK mediated diseases.
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- A Anaplastic lymphoma kinase inhibitors (by machine translation)
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The present invention of formula (I) compounds, of formula (I) compounds of the type (II) in the middle of the compound, of formula (III) compound and its preparation method. Formula (I) compound is a small molecule Anaplastic lymphoma kinase (Anaplastic
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Paragraph 0146-0148
(2017/10/14)
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- Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase
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In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
- Huang, Wei-Sheng,Liu, Shuangying,Zou, Dong,Thomas, Mathew,Wang, Yihan,Zhou, Tianjun,Romero, Jan,Kohlmann, Anna,Li, Feng,Qi, Jiwei,Cai, Lisi,Dwight, Timothy A.,Xu, Yongjin,Xu, Rongsong,Dodd, Rory,Toms, Angela,Parillon, Lois,Lu, Xiaohui,Anjum, Rana,Zhang, Sen,Wang, Frank,Keats, Jeffrey,Wardwell, Scott D.,Ning, Yaoyu,Xu, Qihong,Moran, Lauren E.,Mohemmad, Qurish K.,Jang, Hyun Gyung,Clackson, Tim,Narasimhan, Narayana I.,Rivera, Victor M.,Zhu, Xiaotian,Dalgarno, David,Shakespeare, William C.
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p. 4948 - 4964
(2016/06/13)
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- CRYSTALLINE FORMS OF 5-CHLORO-N4-[-2-(DIMETHYLPHOSPHORYL) PHENYL]-N2-{2-METHOXY-4-[4-(4-METHYLPIPERAZIN-1-YL) PIPERIDIN-1-YL] PYRIMIDINE-2,4-DIAMINE
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Crystalline forms of brigatinib, pharmaceutical compositions comprising the same, and methods of their preparation and use of the same are disclosed herein.
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Paragraph 00371
(2016/05/24)
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- PHOSPHOROUS DERIVATIVES AS KINASE INHIBITORS
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The invention features compounds of the general formula: in which the variable groups are as defined herein, and to their preparation and use.
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Paragraph 0446; 0511; 0.618; 0729
(2015/09/22)
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- METHOD FOR PRODUCING DI(ARYLAMINO)ARYL COMPOUND, AND SYNTHETIC INTERMEDIATE THEREFOR
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Provided is a method for producing a di(arylamino)aryl compound that has superior inhibitory activity against the kinase activities of EML4-ALK fusion protein and mutant EGFR protein and is useful as an active ingredient in pharmaceutical compositions for cancer treatment. The production method includes no purification step using silica gel column chromatography or no step possibly producing a mutagenic mesylate ester as a by-product, greatly improves overall yield, and is high yield and low cost and suitable for the industrial production of pharmaceutical products. Also provided is a synthetic intermediate that is useful in the production method.
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- CHEMICAL COMPOUNDS
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The present invention relates to compounds of Formula (I) and/or Formula (Ia): and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds inhibit ALK kinase activity, and thus may be used for the tr
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Page/Page column 26
(2012/02/06)
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- PYRROLOPYRAZINE INHIBITORS OF KINASES
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The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein R1a, R1b, X, and Y are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as Cdc7 and methods of treating diseases such as cancer.
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Page/Page column 34
(2011/02/18)
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- PYRROLOTRIAZINES AS ALK AND JAK2 INHIBITORS
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The present invention provides a compound of formula (I) or a salt form thereof, wherein Q1, Q2, Q3, and Q4 are as defined herein. The compound of formula (I) has ALK and/or JAK2 inhibitory activity, and may be used to treat proliferative disorders.
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Page/Page column 443
(2010/08/05)
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- PYRIMIDINE INHIBITORS OF KINASE ACTIVITY
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Described herein are compounds of formula (I) or pharmaceutical acceptable salts or solvates thereof, wherein G1, L1, R2, R3, n, p, Ar1, and Ar2 are defined in the description. Methods of making said compounds, and compositions comprising said compounds which are useful for inhibiting kinases such as IGF-IR are also disclosed.
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Page/Page column 75
(2010/12/26)
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- PYRIMIDINE INHIBITORS OF KINASE ACTIVITY
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Described herein are compounds of formula (I) or pharmaceutical acceptable salts or solvates thereof, wherein L1, R1, R2, R3, R4, R5, and m are defined in the description. Methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as IGF-IR are also disclosed.
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Page/Page column 84
(2010/12/26)
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- PYRIMIDINE INHIBITORS OF KINASE ACTIVITY
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The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts or solvates thereof, wherein G1, R2, R3, R4, R5, n, p, q, Ar1, and Ar2 are defined in the description. The present invention relates also to methods of making said compounds, and compositions comprising said compounds which are useful for inhibiting kinases such as IGF-IR.
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Page/Page column 64
(2010/12/26)
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- Discovery and optimization of imidazo[1,2-a]pyridine inhibitors of insulin-like growth factor-1 receptor (IGF-1R)
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The optimization of imidazo[1,2-a]pyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, in vitro activity, and in vivo PK profiles of an optimi
- Emmitte, Kyle A.,Wilson, Brian J.,Baum, Erich W.,Emerson, Holly K.,Kuntz, Kevin W.,Nailor, Kristen E.,Salovich, James M.,Smith, Stephon C.,Cheung, Mui,Gerding, Roseanne M.,Stevens, Kirk L.,Uehling, David E.,Mook Jr., Robert A.,Moorthy, Ganesh S.,Dickerson, Scott H.,Hassell, Anne M.,Anthony Leesnitzer,Shewchuk, Lisa M.,Groy, Arthur,Rowand, Jason L.,Anderson, Kelly,Atkins, Charity L.,Yang, Jingsong,Sabbatini, Peter,Kumar, Rakesh
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scheme or table
p. 1004 - 1008
(2009/10/15)
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- 2, 4- DI (PHENYLAMINO) PYRIMIDINES USEFUL IN THE TREATMENT OF NEOPLASTIC DISEASES, INFLAMMATORY AND IMMUNE SYSTEM DISORDERS
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Novel pyrimidine derivatives of formula (I), to processes for their production, their use as pharmaceuticals in the treatment of neoplastic diseases, inflammatory and immune system disorders and to pharmaceutical compositions comprising them.
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