cas 761440-16-8, 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine

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Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties
Aiming to identify novel potent ALK and ROS1 dual inhibitors, the relatively bulky piperidine fragment in ceritinib was replaced with substituted imidazolidin-2-one moiety which gave rise to a series of 2,4-diaryl-aminopyrimidine (DAAP) analogs (6–33). SAR studies were conducted based on cellular assays on five cell lines and most compounds exerted moderated to excellent activities. Among them, 15 showed excellent inhibitory activities against ROS1 and ALK positive cell lines, especially Ba/F3G1202R, with IC50 values ranging from 14 to 37 nM. As a continuation, several compounds were tested in enzymatic assays and 15 displayed encouraging activities against wild-type ALK (1.2 nM), ROS1(0.43 nM) as well as extremely resistant ALKL1196M and ALKG1202R mutants with IC50 values of 0.73 nM and 6.7 nM, respectively. To our delight, both cellular and enzymatic results of 15 were in good accordance with western blot assays on H2228 and HCC78 cell lines. Importantly, pharmacokinetic (PK) profiles of 15 were obtained with quite satisfying AUC and Cmax values. Besides, the binding models of 15 with ALKWT, ALKG1202R and ROS1 clearly present the essential interactions within the active site.
Lei, Hongrui,Jiang, Nan,Miao, Xiuqi,Xing, Lingyun,Guo, Ming,Liu, Yang,Xu, Haowen,Gong, Ping,Zuo, Daiying,Zhai, Xin
p. 297 - 309
(2019)
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CHEMICAL PROCESS FOR PREPARING PYRIMIDINE DERIVATIVES AND INTERMEDIATES THEREOF
PROBLEM TO BE SOLVED: To provide a process for preparing ceritinib and/or intermediates thereof. SOLUTION: There is provided a process for preparing (C2-1), an intermediate of ceritinib synthesis, comprising the step of reacting (A) with (B) in a solvent in the presence of at least one catalyst, wherein P is a protecting group and T and X1 independently denote Cl and the like. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0171-0173

(2021/05/21)

CDK inhibitor based on organic arsine as well as preparation method and application of CDK inhibitor
The invention provides a CDK inhibitor based on organic arsine as well as a preparation method and application of the CDK inhibitor. Specifically, the invention providese compounds of Formula I, or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof; and the invention also discloses a preparation method and application thereof. Definitions of allgroups in the formula are shown in the specification.
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(2021/03/31)

Small molecule inhibitors of leucine-rich repetitive kinase 2 and their applications
The present invention provides a small molecule inhibitor of leucine-rich repetitive kinase 2 and applications thereof; compounds as small molecule inhibitors such as compounds shown in formula I of the present invention or isotopic forms thereof, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs. The compound has a high LRRK2 inhibitory activity and has high application value in the preparation of drugs for the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other diseases.
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Paragraph 0078-0082

(2022/01/07)

POTENT AND SELECTIVE DEGRADERS OF ALK
Disclosed are bispecific compounds (degraders) that target ALK or ALK and FAK for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the bispecific compounds to treat diseases and disorders characterized or mediated by aberrant ALK or ALK and FAK activity.
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Paragraph 00212-00213

(2021/09/04)

Chemical Process for Preparing Pyrimidine Derivatives and Intermediates Thereof
The present disclosure relates to a method of synthesizing 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (ceritinib) and/or intermediates thereof, their use as pharmaceuticals and pharmaceutical compositions and the use of intermediates for preparing ceritinib.
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Paragraph 0278; 0280

(2020/02/20)

Preparation method of ceritinib
The invention relates to the field of medicinal chemistry, in particular to a preparation method of Ceritinib. According to the method, 2,5-dichloro-N-(2-(isopropylthio)phenyl)pyrimidine-4-amine is used as a raw material, and compared with the prior art, when the cefacitinib is prepared, impurities are reduced, the condition that impurities in a final product cefacitinib bulk drug exceed the standard is avoided, aftertreatment is simple, the refining frequency is small, and the reaction yield is increased.
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Paragraph 0036-0039

(2020/07/24)

Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants
In order to explore novel ALK and ROS1 dual inhibitors capable of overcoming crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxic activity. In this work, we retained the 2,4-diarylaminopyrimidine scaffold and derivatize the DAAP scaffold with sulfonyl and acrylamide moieties to extend the structure–activity relationship (SAR) study. To our delight, some compounds exhibited excellent inhibitory activity with a double-digit nanomolar level in MTT assay. Four compounds were selected for enzymic assays further, the results led to the identification of a potent ALK and ROS1 dual inhibitor X-17, with IC50 values of 3.7 nM, 2.3 nM, 8.9 nM and 1.9 nM against ALK, ALKL1196M, ALKG1202R and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK.
Chen, Yuxiang,Guo, Ming,Li, Tong,Li, Wei,Wei, Shangfei,Zhai, Xin,Zhao, Tianming,Zhu, Minglin
(2020/09/01)

Ceritinib intermediate and preparation method thereof
The invention discloses a ceritinib intermediate and a preparation method thereof. The preparation method of the ceritinib intermediate comprises the following steps: (1) under anhydrous oxygen-free conditions, in a polar aprotic solvent and under conditions of a metal hydride, performing a N-arylation reaction on an intermediate V and an intermediate IV to obtain an intermediate III; (2) in a solvent and under an acidic condition, hydrolyzing the intermediate III to obtain an intermediate II; and (3) in a solvent, performing a chlorination reaction on the intermediate II to obtain the ceritinib intermediate. The raw materials used in the preparation method provided by the invention are safe and non-toxic, reactions are simple and easy to operate, side reactions are few, water is adopted for post-treatment and even crystallization, thus production costs are reduced, the prepared product has high purity, and the ceritinib intermediate is easy for industrialized production.
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Sheet 0073-0078

(2020/04/17)

2, 4, 5-substituted pyrimidine compound and preparation method and application thereof
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 0045-0046

(2020/08/06)

2,4,5-substituted pyrimidine compound as well as preparation method and application thereof
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 0048-0051

(2020/10/14)

CHEMICAL PROCESS FOR PREPARING PYRIMIDINE DERIVATIVES AND INTERMEDIATES THEREOF
PROBLEM TO BE SOLVED: To provide a method for producing intermediates for preparing ceritinib. SOLUTION: There is provided a method for preparing (C2-1), comprising reacting (A) with (B) in a solvent in the presence of at least one catalyst, wherein P is a protecting group and T and X1 can be independently C1 and the like. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0172; 0173

(2020/01/09)

Preparation method and application of ceritinib intermediate
The invention relates to a preparation method and application of a ceritinib intermediate, in particular to a preparation process of an intermediate which is 2,5-dichloro-N-(2-(isopropylsulfonyl) phenyl)pyrimidine-4-amine, and belongs to the field of medicine synthesis. The preparation method includes the detailed following steps that a compound 1-a, a compound 1-b, palladium acetate, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and alkali are added into a solvent, a reaction is conducted, and then the ceritinib intermediate can be prepared. The route is simple and short, operation is easy,production costs are lowered, and the preparation method is suitable for large-scale industrialized production.
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Paragraph 0025-0037

(2019/05/04)

DIPHENYLAMINOPYRIMIDINE AND TRIAZINE COMPOUND, AND PHARMACEUTICAL COMPOSITION AND USE THEREOF
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

(2019/04/25)

Synthesis and anti-tumor efficacy of novel 2, 4-diarylaminopyrimidine derivatives bearing N-(3-pyridinylmethyl) urea moiety as anaplastic lymphoma kinase inhibitors
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC50 values about 10 nM, which were comparable with positive control LDK378. Compound 5m suppressed phosphorylation of ALK and its downstream proteins, and showed low cytotoxicity on normal human primary fibroblast cells (BJ cells). The binding mode of 5m was proposed by docking simulation, which explains the important role of N-(3-pyridinylmethyl)urea moiety. Furthermore, compound 5m exhibited favorable liver microsomal stability and significant efficacy in H3122 xenograft mice model. Interestingly, compound 5m also showed broader anti-proliferative activity on other human tumor cell lines, which was different from other ALK inhibitors.
Chen, Hong,Li, Ridong,Ning, Xianling,Zhao, Xuyang,Jin, Yan,Yin, Yuxin
p. 141 - 153
(2019/06/11)

Design, synthesis of orally bioavailable novel anaplastic lymphoma kinase (ALK) inhibitor diphenylaminopyrimidine analogs and efficacy study on NCI-H2228 xenografts mice model
Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of non-small cell lung cancer (NSCLC). Within our ALK drug discovery program, we identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 11 showed better in vitro activity and in vivo efficacy with good pharmacokinetic profile. In vivo efficacy of compound 11 was better than standard drug ceritinib in NCI-H2228 xenograft mice model.
Das, Debasis,Wang, Jingbing,Li, Yong,Shi, Jingli,Hong, Jian
p. 1514 - 1517
(2019/04/25)

The novel anti-tumor medicine synthetic method and a pharmaceutically acceptable salt thereof and solid preparation (by machine translation)
The invention discloses a method for synthesis of antineoplastic agent, the chemical name is 5 - chloro - N2 - (3 - amino-acetyl aminophenyl) - N4 - (2 - [...] phenyl) pyrimidine - 2, 4 - diamine. At the same time, its salt, crystalline form research, select and suitable for further development as a preparation of the maleate, tartrate and succinate and its corresponding crystalline form. The invention also provides a to the antineoplastic agent as the active ingredient of the solid preparation, wherein the supplemented with one or more solubilising. The invention solid preparation dissolution characteristic and excellent stability, with clinical application prospect. (by machine translation)
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Paragraph 0041; 0042; 0043

(2018/09/08)

Chemical Process for Preparing Pyrimidine Derivatives and Intermediates Thereof
The present disclosure relates to a method of synthesizing 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (ceritinib) and/or intermediates thereof, their use as pharmaceuticals and pharmaceutical compositions and the use of intermediates for preparing ceritinib.
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Paragraph 0257; 0259

(2018/03/25)

2,4-diarylaminopyrimidine derivative as well as preparation method and application thereof
The invention relates to a 2,4-diarylaminopyrimidine derivative shown as a general formula I and optical isomers thereof, pharmaceutically acceptable salts, solvates or prodrugs, as well as preparation methods thereof and a pharmaceutical composition taking the compound of the general formula I as an active ingredient. In the formula, substituent groups R1, R2, R3, R4, R5, R6 and X have meanings given in the description. The invention further relates to a compound of the general formula I with strong ALK and ROS1 kinase inhibition effects, and further relates to application of the compounds and optical isomers and pharmaceutically acceptable salts thereof in preparation of medicines for treating and/or preventing diseases caused by abnormal expressions of ALK and ROS1, particularly application in preparation of medicines for treating and/or preventing cancers. The structural formula is as shown in the description.
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(2018/07/03)

Method for preparing antitumor drug ceritinib intermediate
The invention belongs to the technical field of medical chemistry, and concretely relates to a method for preparing an antitumor drug ceritinib intermediate. The method utilizes zinc salt as a catalyst under strong alkali conditions to catalyze the production of 2,5-dichloro-N-[2(isopropylsulfonyl)phenyl]pyrimidine-4-amine by using 2-(isopropylsulfonyl)aniline and 2,4,5-trichloropyrimidine as rawmaterials. The method of the invention overcomes the disadvantages of using the noble metal Pd in the prior art, does not need to use an expensive phosphorus-containing ligand, has the advantages of mild reaction conditions and high yield, and has industrial application prospects.
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Paragraph 0029-0056

(2019/01/08)

NOVEL EGFR AND ALK DUAL INHIBITOR
The present application provides a compound of formula I, which is a EGFR and ALK dual inhibitor and can be used alone or in combination with other therapeutic agents to treat diseases such as non-small cell lung cancer. The compounds of the present application are useful in the treatment of diseases carrying the EGFR wild-type gene, or carrying the EGFR T790M mutant gene and/or the EGFR L858R mutant gene and/or the EGFR delE746_A750 mutant gene, or in the treatment of diseases carrying the ALK wild-type gene, ALK F1174L mutant gene and/or ALK F1196M gene and/or EML4-ALK mutant gene and/or NPM-ALK mutant gene, and can be used in the first-line treatment of anaplastic lymphoma kinase (ALK) positive late-stage non-small cell Lung cancer.
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Paragraph 0070; 0071; 0072

(2018/11/21)

Compound used as ALK (anaplastic lymphoma kinase) inhibitor and application thereof
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 0123; 0125; 0126

(2018/11/04)

Synthesis method of ceritinib intermediate
The invention discloses a synthesis method of a ceritinib intermediate. The synthesis method comprises the following steps: under an inert gas atmosphere, adding a compound shown as a formula (3), a compound shown as a formula (2) and organic alkali into an organic solvent; raising the temperature to 100 DEG C from 50 DEG C and reacting to obtain a compound shown as a formula (1). The mol ratio ofthe compound shown as the formula (2) to the compound shown as the formula (3) ranges from (1 to 1) to (1 to 4); the organic alkali is diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undecarbone-7-ene; the mol ratio of the organic alkali to the compound shown as the formula (3) ranges from (0.25 to 1) to (1 to 1); the organic solvent is tetrahydrofuran or acetonitrile; the mass of the organic solvent is 1 to 3 times as much as the mass of the compound shown as the formula (3). The formula (1), the formula (2) and the formula (3) are shown in the description.
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Paragraph 0028-0037

(2018/11/22)

Preparation method for ceritinib and intermediate thereof
The invention provides a preparation method for ceritinib and an intermediate thereof. The method comprises the following steps: (1) coupling the compound 1-dihydrochloride with the compound 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (a compound 3) so as to produce 5-chloro-N2-(2-isopropanolato-5-methyl-4-(piperid-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride (a compound 4, i.e., ceritinib dihydrochloride); and (2) subjecting the compound 4 to dissociation so as to produce ceritinib. The preparation method provided by the invention is low in cost and high in yield, and the purity of the intermediate in each step is 99.5% or above, so high purity of ceritinib is guaranteed. The method is few in steps, simple to operate and suitable for industrial production and has great application value.
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Paragraph 0054; 0055; 0056; 0057; 0058; 0059; 0060

(2017/07/22)

Preparation method of 2, 5-dichloro-N-(2-(isopropyl sulfonyl)phenyl)pyrimidine-4-amine
The invention relates to a preparation method of 2, 5-dichloro-N-(2-(isopropyl sulfonyl)phenyl)pyrimidine-4-amine. The method has the advantages of simple reaction process, high safety, high yield and mass production capacity.
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Paragraph 0020; 0021; 0022

(2017/07/21)

PROCESS FOR THE PREPARATION OF CERITINIB USING "IN SITU" PREPARED 5-METHYL-2-(1 -METHYLETHOXY)-4-(4-PIPERIDINYL)-BENZENAMINE MONOHYDROCHLORIDE (1 :1 ) AS AN INTERMEDIATE
The object of the invention is a preparation method of Ceritinib of formula (I) and its salts wherein 2-isopropylthioaniline is used in the first step. Even under mild conditions, it provides an intermediate, which is further oxidized to a sulfone in a hi
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Page/Page column 11; 12

(2017/03/28)

4-Saturated cyclosubstituted aniline protein kinase inhibitor
The invention discloses a compound being able to adjust the activity of protein kinase and used for treating or preventing protein kinase related diseases, concretely relates to a 4-saturated cyclosubstituted aniline protein kinase inhibitor belonging to a compound for adjusting the activity of anaplastic lymphoma kinase (ALK), and provides a preparation method of the compound and a pharmaceutical use of the compound in treatment or prevention of ALK related diseases.
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(2017/04/29)

A method for preparing color Switzerland for Nepal
The invention discloses a method for preparing ceritinib, belonging to the field of chemical pharmacy. The method comprises the following steps: by taking 3-bromine-4-methylphenol as an initial raw material, performing phenolic hydroxyl isopropylation, nitration, coupling and reduction reaction, obtaining a midbody 1, by further taking o-nitro fluorobenzene as another initial raw material, performing isosulfhydrylation, oxidation, reduction and pyrimidine, obtaining a midbody 2, performing coupling reduction on the midbody 1 and the midbody 1, obtaining ceritinib which is protected by BOC acid anhydride, and finally removing a t-butyloxycarboryl protecting group, and obtaining ceritinib. The method is simple and feasible to operate, relatively high in yield, small in pollution and applicable to industrial production.
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(2017/08/25)

Including zong pyrimidine derivative and use thereof (by machine translation)
The invention relates to the general formulaIThe pyrimidine derivatives including zong shown and its optical isomer, pharmaceutically acceptable salt, solvate or prodrug, their preparation method and as shown in the formula I compound as an active ingredient of the pharmaceutical composition, wherein the substituents R1 , R2 , R3 , Ar, X has the meanings given in the specification. The invention also relates to the compounds of the general formula I has strong ALK and ROS1 kinase inhibitory activity, and also relates to the compounds and its optical isomer, a pharmaceutically acceptable salt thereof for the treatment and/or the prevention of the ROS1 ALK and of diseases caused by the abnormal expression of the pharmaceutical in the application, in particular in preparing and treating and/or preventing cancer of the use of the medicament. (by machine translation)
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(2017/09/21)

Discovery of a potent dual ALK and EGFR T790M inhibitor
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.
p. 497 - 510
(2017/05/22)

A MODIFIED PROCESS FOR THE PREPARATION OF CERITINIB AND AMORPHOUS FORM OF CERITINIB
The present invention is related to an improved process for the preparation of ceritinib with high yield and high purity. The present process is cost effective and feasible in large scale production also. The present invention also related to a stable amorphous form of ceritinib and its preparation. The present invention also relates to a process for the preparation of Crystalline form A of Ceritinib.
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Page/Page column 19

(2017/10/18)

POLYCYCLIC ANAPLASTIC LYMPHOMA KINASE INHIBITOR
Provided is a polycyclic inhibitor of anaplastic lymphoma kinase as represented by Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1, R2, R3, R4, and ring A are as defined in the description. The invention also relates to a method for preparing the compound, a pharmaceutical preparation and a pharmaceutical composition comprising the compound, and use of the compound, the pharmaceutically acceptable salt or stereoisomer thereof in manufacture of a medicament for the treatment and/or prevention of an anaplastic lymphoma kinase-mediated cancer or non-cancer related diseases.
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Paragraph 0182; 0183; 0209; 0210; 0236; 0237; 0257; 0258

(2018/02/06)

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
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
p. 674 - 697
(2017/08/30)

Ceritinib intermediate and preparation method and application thereof
The present invention discloses a ceritinib intermediate and a preparation method and application thereof. The ceritinib intermediate has a structure shown as a formula I, R and R2 are as defined in the specification and claims. The ceritinib intermediate is prepared from a compound of a formula 1 and a benzyl halide compound by substitution reaction and then reduction. After further reduction of the nitro by catalytic hydrogenation and removal of amino-protection, the compound of the formula I is reacted with a compound of a formula III to obtain ceritinib. According to the method, raw materials are readily available and inexpensive, the method does not require special equipment, production cost is greatly reduced, and the method is suitable for industrial application.
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Paragraph 0130-0133

(2017/02/28)

DEUTERATED DIAMINOPYRIMIDINE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING SUCH COMPOUNDS
The present invention related to deuterated diaminopyrimidine compounds and pharmaceutical compositions comprising such compounds. In particular, disclosed are the deuterated diaminopyrimidine compounds shown as formula (I), and the pharmaceutical compositions comprising such compounds or crystal form, pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds of the present invention can be used for treating and/or preventing protein kinase-associated diseases, such as cell proliferative disease, cancer, immune disease and the like.
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Paragraph 0084; 0092

(2016/05/09)

New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof
The present invention relates to the field of pharmaceutical chemistry, to a preparation method of a new intermediate of 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidine-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Ceritinib). According to the present invention, o-fluoronitrobenzene is adopted as a starting raw material, substitution, reduction and condensation are performed to obtain the new intermediate 2-X-5-chloro-N-(2-(isopropyl sulfide)phenyl)pyrimidine-4-amine (X is halogen, p-methyl benzene sulfonyloxy, methyl sulfonyloxy or trifluoromethylsulfonyloxy), the new intermediate can be oxidized to obtain a sulfonyl derivative, and the sulfonyl derivative and 2-isopropoxy-5-methyl-4-(piperidine-4-yl)aniline are subjected to condensation to finally obtain 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidine-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Ceritinib); and the synthesis method has characteristics of readily available raw materials, high yield, mild reaction, simple operation and low production cost, and is suitable for industrial production.
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Paragraph 0026; 0027

(2016/10/10)

PROCESS FOR PREPARATION OF CERITINIB
The present application relates to a process for preparation of ceritinib and intermediates thereof. Specifically, the present application relates to a process for preparation of N-(4-(1-benzyl- 1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)acetamide (VC) comprising treating N-(4-(bromomethyl)-2-isopropoxy-5-methylphenyl)acetamide (IIID) with 1- benzylpiperidin-4-one (IVA). The present application also relates to a process for conversion of N-(4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)-acetamide (VC) to ceritinib or an acid-addition salt thereof.
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(2016/12/26)

Pyridone protein kinase inhibitor
The invention discloses a compound capable of regulating protein kinase activity and used for treating or preventing diseases related to protein kinase, particularly relates to a pyridone protein kinase inhibitor, belongs to compounds for regulating anaplastic lymphoma kinase (ALK) activity, and provides a preparation method of the compounds and pharmaceutical application of the compounds to the treatment or prevention of the diseases related to ALK.
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(2017/04/19)

Design, synthesis and biological evaluation of novel 4-arylaminopyrimidine derivatives possessing a hydrazone moiety as dual inhibitors of L1196M ALK and ROS1
A series of 4-arylaminopyrimidine derivatives possessing a hydrazone moiety were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against ALK-addicted KARPAS299 and ROS1-addicted HCC78, while also showing much less potent activity against A549, H460 and HT-29, whose growth were not dependent on ALK and/or ROS1, as compared with crizotinib and ceritinib. The most promising compound, 7b, showed high antiproliferative effects on ALK-addicted KARPAS299 and ROS1-addicted HCC78?cell lines with IC50of 20?nM and 28?nM, respectively, but showed no inhibitory activity against A549, H460 and HT-29. The enzymatic assay identified 7b as a potent and selective ALK and ROS1 dual inhibitor with IC50of 2.5?nM and 2.7?nM, respectively. It also exhibited good inhibitory activity against the L1196M ALK with an IC50value of 67?nM.
Wang, Yu,Zhang, Guogang,Hu, Gang,Bu, Yanxin,Lei, Hongrui,Zuo, Daiying,Han, Mengting,Zhai, Xin,Gong, Ping
p. 80 - 89
(2016/08/01)

Of tetracyclic Anaplastic lymphoma kinase inhibitors (by machine translation)
The invention belongs to the field of medical technology, in particular to general formula (I) as shown in of tetracyclic Anaplastic lymphoma kinase inhibitor, its pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 1, R 2, R 3, R 4, R 5 and A link like defined in the specification. The invention also relates to methods of preparing such compounds, pharmaceutical preparations comprising these compounds and pharmaceutical composition, the compound and, its pharmaceutically acceptable salts or stereoisomers thereof, in the preparation of the treatment and/or prevention of Anaplastic lymphoma kinase-mediated cancer diseases related to the application of the medicament. (by machine translation)
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Paragraph 0248; 0249; 0250

(2016/10/08)

Tricyclic and fused-cyclic ALK (anaplastic lymphoma kinase) inhibitors
The invention belongs to the technical field of medicines, and particularly relates to tricyclic and fused-cyclic ALK (anaplastic lymphoma kinase) inhibitors represented in a general formula (I), pharmaceutically acceptable salts, esters and solvates of the tricyclic and fused-cyclic ALK inhibitors or stereoisomers of the tricyclic and fused-cyclic ALK inhibitors, wherein definitions of R, R, R, R, a ring A and a ring B are shown in the specification. The invention further relates to a preparation method of the compounds, pharmaceutic preparations and pharmaceutic composition which contain the compounds, as well as an application of the compounds, the pharmaceutically acceptable salts, esters and solvates of the compounds or the stereoisomers of the compounds in preparation of drugs for treating and/or preventing cancer related diseases mediated by ALK.
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Paragraph 0198; 0199; 0200

(2017/06/02)

Novel kinase inhibitors
The present invention relates to a novel kinase inhibitor useful as a medicine for tumor, nerve disorder and mental illness. The purpose of the present invention is to provide a compound having improved blood-aqueous barrier penetrability to neurodegenerative diseases that cancer spreads to brain or progresses in brain. To this end, provided is a compound represented by chemical formula 1 or a pharmaceutically allowable salt thereof.COPYRIGHT KIPO 2017
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Paragraph 0242-0244

(2017/08/02)

Discovery of clinical candidate CEP-37440, a selective inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK)
Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.
Ott, Gregory R.,Cheng, Mangeng,Learn, Keith S.,Wagner, Jason,Gingrich, Diane E.,Lisko, Joseph G.,Curry, Matthew,Mesaros, Eugen F.,Ghose, Arup K.,Quail, Matthew R.,Wan, Weihua,Lu, Lihui,Dobrzanski, Pawel,Albom, Mark S.,Angeles, Thelma S.,Wells-Knecht, Kevin,Huang, Zeqi,Aimone, Lisa D.,Bruckheimer, Elizabeth,Anderson, Nathan,Friedman, Jay,Fernandez, Sandra V.,Ator, Mark A.,Ruggeri, Bruce A.,Dorsey, Bruce D.
p. 7478 - 7496
(2016/09/04)

METHODS OF CHEMOTYPE EVOLUTION
Herein is described a method to rapidly screen a large chemical space for a compound that binds to a target protein through an iterative fragment assembly approach that can be performed at low reagent cost and without requiring purification of the assembled product. The method employs a library of test ligands each of which comprise a ‘bait’ molecule, which is known from prior art or prior screening to have some intrinsic affinity for the target protein, and a test moiety.
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(2015/11/10)

PHOSPHOROUS DERIVATIVES AS KINASE INHIBITORS
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 0440

(2015/09/22)

Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases
We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound 15 possessing IC50 values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model.
Song, Zilan,Yang, Yanhong,Liu, Zhiqing,Peng, Xia,Guo, Junfeng,Yang, Xinying,Wu, Kui,Ai, Jing,Ding, Jian,Geng, Meiyu,Zhang, Ao
p. 197 - 211
(2015/02/19)

CERTAIN PROTEIN KINASE INHIBITORS
Disclosed herein are protein kinase inhibitors, more particu-larly novel pyrimidine derivatives and pharmaceutical com-positions thereof, and method of use thereof
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(2014/05/20)

Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro- N 2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)- N 4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials
The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.
Marsilje, Thomas H.,Pei, Wei,Chen, Bei,Lu, Wenshuo,Uno, Tetsuo,Jin, Yunho,Jiang, Tao,Kim, Sungjoon,Li, Nanxin,Warmuth, Markus,Sarkisova, Yelena,Sun, Frank,Steffy, Auzon,Pferdekamper, Annemarie C.,Li, Allen G.,Joseph, Sean B.,Kim, Young,Liu, Bo,Tuntland, Tove,Cui, Xiaoming,Gray, Nathanael S.,Steensma, Ruo,Wan, Yongqin,Jiang, Jiqing,Chopiuk, Greg,Li, Jie,Gordon, W. Perry,Richmond, Wendy,Johnson, Kevin,Chang, Jonathan,Groessl, Todd,He, You-Qun,Phimister, Andrew,Aycinena, Alex,Lee, Christian C.,Bursulaya, Badry,Karanewsky, Donald S.,Seidel, H. Martin,Harris, Jennifer L.,Michellys, Pierre-Yves
p. 5675 - 5690
(2013/08/23)

COMPOUNDS THAT MODULATE EGFR ACTIVITY AND METHODS FOR TREATING OR PREVENTING CONDITIONS THEREWITH
Provided are compounds and methods for treating or preventing kinase-mediated disorders therewith.
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(2011/11/30)

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
The invention provides novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine and pyridine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70), insulin-like growth factor (IGF-1R), or a combination thereof.
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Page/Page column 30

(2008/12/06)