- DIMETHYLPHOSPHINE OXIDE COMPOUND
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Disclosed is an application of a series of dimethylphosphine oxide compounds in the preparation of an LRRK2 kinase activity inhibitor-related drug, specifically an application of the compound shown in formula (I) or a pharmaceutically acceptable salt thereof in the preparation of an LRRK2 kinase activity inhibitor-related drug.
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Paragraph 0049
(2021/02/25)
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- Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFRT790M/C797SMutants
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A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFRT790M/C797S inhibitors. One of the most potent and selective compounds 18k strongly suppressed the EGFRL858R/T790M/C797S and EGFR19Del/T790M/C797S kinases wit
- Ding, Jian,Ding, Ke,Lai, Mengzhen,Lei, Chong,Li, Shan,Lu, Xiaoyun,Pang, Zilu,Peng, Lijie,Ren, Xiaomei,Tong, Linjiang,Xie, Hua,Yun, Cai-Hong,Zhang, Tao,Zhu, Su-Jie
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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 0048-0050
(2020/06/02)
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- EGFR INHIBITORS, COMPOSITIONS AND METHODS THEREOF
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Provided are compounds of Formula I, methods of using the compounds as EGFR inhibitors, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or inf
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Page/Page column 33
(2020/07/31)
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- 2, 4, 5-substituted pyrimidine compound and preparation method and application thereof
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The invention relates to a preparation method of 2, 4-substituted pyrimidine compound and a preparation method and application thereof. The compound has a molecular structure shown as a formula I or pharmaceutically acceptable salt, solvate, stereoisomer or prodrug molecule thereof. The 2, 4, 5-substituted pyrimidine compound is low in cytotoxicity and has high selective inhibition on EGFR; the compound can inhibit the proliferation of EGFR drug-resistant mutant enzymes (such as T790M/L858R/C797S mutant enzymes) and cell strains thereof at a low concentration (such as nanomole concentration),so that the compound can be used for treating diseases caused by EGFR mutation, and is expected to be developed into a new generation of EGFR inhibitors.
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Paragraph 0049-0050
(2020/08/06)
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- EGFR INHIBITORS, COMPOSITIONS AND METHODS THERE OF
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The present invention relates to compounds of Formula I, methods of using the compounds as EGFR inhibitors, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders s
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Page/Page column 18-19
(2020/10/20)
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- 2,4,5-substituted pyrimidine compound as well as preparation method and application thereof
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The invention relates to a 2,4,5-substituted pyrimidine compound as well as a preparation method and application thereof, and provides pharmaceutically acceptable salt, solvate, stereoisomer or prodrug molecule thereof, wherein the molecular structure of the pharmaceutically acceptable salt, solvate, stereoisomer or prodrug molecule is shown in the specification. The provided 2,4,5-substituted pyrimidine compound is low in cytotoxicity, has high selective inhibition on EGFR, can inhibit the proliferation of EGFR drug-resistant mutant enzymes (such as T790M/L858R/C797S mutant enzymes) and cellstrains thereof at a low concentration (such as nano mole concentration), can be used for treating diseases caused by EGFR mutation, and can be made into a new generation of EGFR inhibitors.
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Paragraph 0060-0063
(2020/10/14)
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- DIPHENYLAMINOPYRIMIDINE AND TRIAZINE COMPOUND, AND PHARMACEUTICAL COMPOSITION AND USE THEREOF
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The invention relates to a diphenylaminopyrimidine and triazine compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, hydrate or solvate thereof: wherein A is C or N; X and Y are independently selected from hydrogen, halo, cyano, trifluoromethyl, alkoxy, alkyl, aryl, alkenyl, alkynyl and nitro; or X and Y, together with the atoms to which they are attached, form a phenyl or an heteroaromatic ring; R1 is R2 is CD3 or CD2CD3; R3 is R4 is hydrogen, methyl, trifluoromethyl, cyano or halo; R5 is hydrogen, alkyl, substituted and unsubstituted phenyl, allyl or propargyl; R6 and R7 are independently selected from hydrogen, alkyl, substituted and unsubstituted phenyl, allyl and propargyl; or R6 and R7, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl group. The compound herein has excellent pharmacodynamic and pharmacokinetic properties and ALK kinase inhibitory activity.
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Paragraph 0091; 0092
(2019/04/25)
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- Polymorphism of novel spiroarylphosphine oxide
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The invention relates to a polymorphic substance of a compound (2-((5-chloro-2-((2-methoxyl-4-(9-methyl-3,9-diaza-sprio[5.5]hendecane-3-yl)phenyl)amino)pyrimidine-4-yl)amino)phenyl)dimethyl phosphineoxide (compound I). The invention further relates to a m
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Paragraph 0114; 0121-0123
(2019/11/20)
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- 2-aminopyrimidine compound and application thereof
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The invention relates to a 2-aminopyrimidine compound and application thereof. The structure of the 2-aminopyrimidine compound is shown as I. The compound can effectively inhibit the activity of EGFRprotein kinase resistance mutants (such as EGFRT790M and
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Paragraph 0165; 0168; 0173-0176
(2019/10/17)
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- DEUTERIUM-MODIFIED BRIGATINIB DERIVATIVES, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME, AND USE THEREOF
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The present invention relates to the field of pharmaceutical chemistry, and relates to a deuterium-modified Brigatinib derivative, preparation method thereof, pharmaceutical composition containing the same and the uses of the deuterium-modified Brigatinib derivative and the pharmaceutical composition thereof in preparing a medicament for treating the disease mediated by anaplastic lymphoma kinase. The deuterium-modified Brigatinib derivative of the present invention has an excellent inhibitory activity on anaplastic lymphoma kinase and has better pharmacodynamic or pharmacokinetic properties relative to Brigatinib.
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Paragraph 0158
(2018/10/15)
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- Compound used as ALK (anaplastic lymphoma kinase) inhibitor and application thereof
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The invention discloses a compound shown in a formula I, and pharmaceutically acceptable salts, stereoisomers, solvates or predrugs. The symptoms are defined in claim requirements. The compound shownin the formula I has good inhibiting activity on ALK (anaplastic lymphoma kinase), and can be used for preparing medicines for adjusting the activity of the ALK activity or treating the ALK-related diseases, especially nonsmall-cell lung cancer drugs. (The formula I is shown in the attached figure.).
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Paragraph 0108; 0110; 0111
(2018/11/04)
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- PHOSPHORUS CONTAINING COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Provided are certain ALK inhibitors, pharmaceutical compositions thereof, and methods of use thereof.
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- Preparation method, intermediate and crystal form of spironolamine arylphosphine oxide
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The invention discloses a preparation method and a crystal form of high-purity spironolamine arylphosphine oxide. The invention further discloses a method for preparing a compound shown as a formula (I) and an intermediate compound.
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Paragraph 0100-0102
(2017/08/30)
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- Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC
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Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy. Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q, L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC.
- Chen, Yongfei,Wu, Jiaxin,Wang, Aoli,Qi, Ziping,Jiang, Taoshan,Chen, Cheng,Zou, Fengming,Hu, Chen,Wang, Wei,Wu, Hong,Hu, Zhenquan,Wang, Wenchao,Wang, Beilei,Wang, Li,Ren, Tao,Zhang, Shanchun,Liu, Qingsong,Liu, Jing
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p. 674 - 697
(2017/08/30)
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- Discovery of a potent dual ALK and EGFR T790M inhibitor
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The mutational activations of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) are validated oncogenic events and the targets of approved drugs to treat non-small cell lung cancer (NSCLC). Here we report highly potent dual small molecule inhibitors of both ALK and EGFR, particularly the T790M mutant which confers resistance to first generation EGFR inhibitors. Dual ALK/EGFR inhibitors may provide an efficient approach to prevent resistance that arises as a consequence of clinically reported reciprocal activation mechanisms. Our lead compound 7c displayed remarkable inhibitory activities against both ALK and EGFR in enzymatic and cellular assays. We demonstrate that 7c is capable of recapitulating the signaling effects and antiproliferative activity of combined treatment with the approved ALK inhibitor ceritinib and T790M EGFR inhibitor osimertinib against patient-derived non-small cell lung cancer cell line, DFCI032 which harbors both EML4-ALK and activated EGFR.
- Jang, Jaebong,Son, Jung Beom,To, Ciric,Bahcall, Magda,Kim, So Young,Kang, Seock Yong,Mushajiang, Mierzhati,Lee, Younho,J?nne, Pasi A.,Choi, Hwan Geun,Gray, Nathanael S.
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p. 497 - 510
(2017/05/22)
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- Homogeneous-phase 'one-pot' preparation method of Brigatinib key intermediate
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The invention belongs to the technical field of drug synthesis, and particularly relates to a homogeneous-phase 'one-pot' preparation method of a Brigatinib key intermediate (II). The preparation method includes the steps: performing coupling reaction on 2-iodoaniline and dimethyl phosphine oxide under the action of catalysts and acid-binding agents; directly performing substitution reaction on reactants and 2, 4, 5-trichloropyrimidine without separation; performing extraction, washing, drying, filtration and concentration to obtain a crude product; performing recrystallization on the crude product to obtain a (2-((2,5-dichloropyrimidine-4-group) amidogen) phenyl) dimethyl phosphine oxide (II). According to the method, two-step reaction is replaced by a homogeneous-phase 'one-pot' method, separation and purification are omitted, steps are decreased, operation is simplified, yield is improved as compared with the prior art, recrystallization replaces column chromatography purification, solvent consumption and emission of 'waste gas, waste water and solid waste' are reduced, and the preparation method is suitable for industrial production.
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Paragraph 0022; 0023; 0025; 0027; 0029; 0031; 0033
(2018/01/19)
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- Diaminopyrimidine compound and composition containing same
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The invention provides a diaminopyrimidine compound and a composition containing the same and discloses the diaminopyrimidine compound shown as in a formula (I) and a drug combination containing the compound or salt thereof acceptable in crystal form and
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Paragraph 0094-0096; 0106; 0107
(2017/06/02)
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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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- Spiro aryl phosphorus oxide or sulfide
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The invention discloses a spiro aryl phosphorus oxide or sulfide as ALK inhibitor, and in particular discloses a compound shown in a formula (I) as an ALK inhibitor or a pharmaceutically acceptable salt thereof.
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Paragraph 0196; 0197; 0198; 0199
(2016/10/08)
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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 00369
(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 0793-0794
(2015/09/22)
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- COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of Formula (I), wherein the variables are as defined herein.
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Page/Page column 43-44
(2013/12/03)
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- COMPOUNDS FOR INHIBITING CELL PROLIFERATION IN EGFR-DRIVEN CANCERS
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The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of formula (I), wherein the variables are as defined herein.
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Page/Page column 37-38
(2012/11/14)
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