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Copper-catalyzed selective C-N bond formation with 2-amino, 2-hydroxy and 2-bromo-5-halopyridine
A copper-catalyzed 1,2-diol amination at the electron-rich C-5 position of unprotected 2-amino/2-hydroxy-5-halopyridine provided excellent yields. Selective amination preferably at C-5 in 2-bromo-5-iodopyridine was achieved under the same conditions. The selective, generally mild and economical coupling reaction at C-5 position described herein could be achieved with amines, heterocycles and amides.
Roy, Swarnali,Paul, Barnali,Mukherjee, Ayan,Kundu, Biswajit,Talukdar, Arindam
p. 44366 - 44370
(2017)
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Selective and novel cyclin-dependent kinases 4 inhibitor: synthesis and biological evaluation
A series of novel LEE011 derivatives containing pyridine N-oxide were designed, synthesized and evaluated. Systematic study of the structure-activity relationship (SAR) improves the selectivity for CDK4 and led to the identification of compound 9a. The compound showed comparable CDK4 kinase activity with ribociclib and greater selectivity over the closely related CDK6 kinase. The selective CDK4 inhibitor 9a has been demonstrated the antitumor activity via G1 phase cell cycle arrest, as well as dual CDK4/CDK6 inhibitor ribociclib and significantly down-regulated the activity of CDK4-cyclinD-Rb pathway of tumor cells. Taken together, this compound may act as promising lead compound for further development of new CDK4 inhibitors.
Guo, Qingxiang,Li, Yongtao,Zhang, Chao,Huang, Zhi,Wang, Xin,Nie, Yongwei,Li, Yao,Liu, Yanhua,Yang, Shengyong,Xiang, Rong,Fan, Yan
p. 1666 - 1678
(2018)
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Discovery of novel and orally bioavailable CDK 4/6 inhibitors with high kinome selectivity, low toxicity and long-acting stability for the treatment of multiple myeloma
Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD50 > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t1/2 > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies.
Yuan, Kai,Kuang, Wenbin,Chen, Weijiao,Ji, Minghui,Min, Wenjian,Zhu, Yasheng,Hou, Yi,Wang, Xiao,Li, Jiaxing,Wang, Liping,Yang, Peng
(2021/12/09)

HPK1 ANTAGONISTS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of HPK1, and the treatment of HPK1-mediated disorders.
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(2021/03/19)

Azaindole pyrimidinamine heterocyclic compound as well as preparation method and application thereof
The invention discloses an azaindole pyrimidinamine heterocyclic compound as well as a preparation method and application thereof. The compound is shown as a formula (S). The compound provided by the invention can inhibit malignant proliferation of cancers, has good treatment effect, low toxicity and good drug metabolism characteristics, is not easy to generate drug resistance, and can be used for preparing drugs for treating cancers or tumor-related diseases. The cancers or tumor-related diseases include multiple myeloma, leukemia, breast cancer, prostate cancer, lung cancer, liver cancer, gastric cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer and endometrial cancer.
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(2021/08/14)

Discovery and in Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor
Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor"was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.
Chen, Xing,Yan, Yaoyao,Zhang, Zhaoyan,Zhang, Faming,Liu, Mingming,Du, Leran,Zhang, Haixia,Shen, Xiaobao,Zhao, Dahai,Shi, Jing Bo,Liu, Xinhua
p. 11857 - 11885
(2021/09/02)

CDK6/DYRK2 Double-target inhibitor as well as preparation method and application thereof
The present invention discloses a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the compound and application of the compound in prevention and/or treatment of cancers or tumor-related diseases, especially breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer, human glioma and other diseases. The compound provided by the invention is expected to be developed into a new generation of anti-cancer drugs.
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(2021/02/24)

Intermediate compound as well as preparation method and application thereof
The invention discloses an intermediate compound as well as a preparation method and application thereof. The synthesized intermediate compound is used for preparing targeted anti-cancer drugs, such as CDK4, CDK6, DYRK2 and other inhibitors, and is used for preventing and/or treating cancers or tumor related diseases including breast cancer, prostate cancer, lung cancer, multiple myeloma, leukemia, gastric cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer and human glioma. The intermediate compound is simple in preparation condition, high in reaction yield and stable in performance.
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(2021/07/24)

Anti-cancer quinoxaline pyrimidinamine heterocyclic compound as well as preparation method and application thereof
The invention discloses an anti-cancer quinoxaline pyrimidinamine heterocyclic compound and a preparation method and application thereof, the structure of the compound is shown as a formula (S), and X is selected from C (O) or (CH2) n; n is 0 or 1; R1 is selected from hydrogen and C1-C8 alkyl; R2 is selected from hydrogen, C1-C8 alkyl, morpholine ring or-NR5R6, and R5 and R6 are selected from hydrogen and C1-C8 alkyl; R3 is selected from hydrogen, methoxyl and halogen; and R4 is selected from hydrogen, C1-C8 alkyl,-S (O) 2Me and-C (O) OC1-C3. The invention also discloses a preparation method and application of the compound.
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(2021/07/21)

Method for preparing 4 - (6 -aminopyridine -3 -yl) piperazine -1 - carboxylic acid tert-butyl ester
The invention discloses a method for preparing 4 - (6 - aminopyrid -3 -yl) piperazine -1 - carboxylic acid tert-butyl ester, which comprises the following steps of: reacting 2 - aminopyridine with iodine to generate 2 - amino -5 -iodopyridine. Step II: 2 - amino -5 -iodopyridine was subjected to a coupling reaction to obtain 4 - (6 - aminopyrid -3 -yl) piperazine -1 -carboxylic acid tert-butyl ester. The method has the advantages of short synthetic route, high target product yield and low cost.
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Paragraph 0042; 0050-0054; 0062-0066; 0073-0076

(2021/09/26)

Industrial preparation method 4 - (6 - amino-pyridin -3 -yl) piperazine -1 - carboxylic acid tert-butyl ester
The method adopts 4 - bromo 6 - nitropyridine and piperazine as a starting raw material to prepare high-purity -3 - (-1 -nitropyridine 5 -yl) piperazine -2 - carboxylic acid as a catalyst through nucleophilic substitution reaction in the presence of an organic solvent and water. 1 - (6 - aminopyrid -3 -yl) piperazine is prepared by using an acid as a catalyst in a mixed solvent of an alcohol organic solvent and water to obtain high-purity Boc (4 -aminopyridine 6 -1 -yl) piperazine-3 -carboxylic acid tert-butyl ester. Shallow color 4 - (6 - aminopyrid -3 -yl) piperazine -1 - carboxylic acid tert-butyl ester. The method is simple and convenient to operate, less in environmental pollution, high in yield, low in cost, good in product quality and more suitable for industrial production.
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(2021/11/14)

DERIVATIVES OF 4-(IMIDAZO[L,2-A]PYRIDIN-3-YL)-N-(PYRIDINYL)PYRIMIDIN- 2-AMINE AS THERAPEUTIC AGENTS
A novel class of heteroaryl compounds for use in the prevention and/or treatment of proliferative diseases and conditions including cancers. The compounds are considered to be capable of inhibiting cell proliferation by inhibiting the activity of FLT3 and its mutant forms and/or other protein kinases such as CDKs. The compounds have the general structure I:
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Paragraph 0083; 0089; 00137

(2021/01/29)

CDK6 inhibitor of pyrimidine benzo six-membered ring mother nucleus as well as preparation method and application of CDK6 inhibitor
The invention discloses a CDK6 inhibitor of a pyrimidine benzo six-membered ring mother nucleus and a preparation method and application of the CDK6 inhibitor, the compound structure of the CDK6 inhibitor is shown as a formula (C), and A is selected from O, C (O) or-NR1; R1 is selected from hydrogen or C1-C8 alkyl; B is selected from O or C; X is selected from C, C (O) or-NR2; R2 is selected from hydrogen or C1-C8 alkyl; Y is selected from C (O) or (CH2) n; n is 0 or 1; and Z is selected from hydrogen, C1-C8 alkyl or-C (O) OC1-C3. The invention also discloses a preparation method and application of the compound.
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Paragraph 0048; 0068; 0071-0072

(2021/08/19)

Preparation method of cyclin-dependent kinase inhibitor intermediate
The invention relates to a preparation method of a cyclin-dependent kinase inhibitor intermediate. The preparation method comprises the following steps: S1, carrying out a coupling reaction on 2-amino-5-halogenated pyridine as shown in a formula I and piperazine in the presence of CuI, a ligand, an alkaline substance and a solvent 1 to generate 5-(piperazin-1-yl)pyridine-2-amine as shown in a formula II; and S2, carrying out an oxidation reaction on the formula II 5-(piperazin-1-yl) pyridine-2-amine and di-tert-butyl dicarbonate to generate a compound as shown in a formula III. The preparationmethod overcomes the defect that a large number of precious starting materials are used in the prior art, reduces preparation cost, simplifies preparation process and improves the purity of the produced intermediate.
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(2020/12/29)

Preparation method 5 - (4 -t-butoxycarbonylpiperazine -1 -yl) -2 -aminopyridine (by machine translation)
The invention relates to a preparation method, 5 - (4 -tert-butoxycarbonyl piperazine -1 -yl) -2 - aminopyridine (II). The method utilizes cis -3 - substituted acrylonitrile (III) and nitromethane base to catalyze and lower condensation, then and 1 - t-butoxycarbonylpiperazine condensation to prepare 1 - (5 - nitro - 22Z, 4Z - glutaronitrile -4 - yl) -4 - t-butoxycarbonyl piperazine (V) while pyridine cyclization produces 5 - (4 -butoxycarbonylpiperaz -1 -yl) -2 -aminopyridine (II) . II can be used to prepare palbociclib and Sornil. The raw materials are cheap and easily available, the technological process is simple and convenient, safe, mild, the reaction selectivity is good, and the product purity is high. The route relates to the reaction process atom economy height, less, the green environmental protection. (by machine translation)
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Paragraph 0048; 0051-0052; 0060; 0063-0065; 0068-0069; 0070

(2019/08/07)

PYRIDO[3, 4-D]PYRIMIDINE DERIVATIVE AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
The purpose of the present invention is to provide a compound that has excellent CDK4/6 inhibitory activity. The present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound.
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(2019/10/16)

Inhibiting effect of trisubstituted pyrimidine derivative on protein kinase
The invention discloses a trisubstituted pyrimidine derivative with a structure shown as general formula (I), and pharmaceutically acceptable salt, ester or solvent compound thereof. The derivative isa protein kinase inhibitor, can be used individually or in combination with other drugs for cancer treatment, and has tremendous clinical application value. General formula (I) is shown as the specification.
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(2019/09/14)

Design and synthesis of 4-(Heterocyclic substituted amino)-1h-pyrazole-3-carboxamide derivatives and their potent activity against acute myeloid leukemia (AML)
Fms-like receptor tyrosine kinase 3 (FLT3) has been emerging as an attractive target for the treatment of acute myeloid leukemia (AML). By modifying the structure of FN-1501, a potent FLT3 inhibitor, 24 novel 1H-pyrazole-3-carboxamide derivatives were designed and synthesized. Compound 8t showed strong activity against FLT3 (IC50: 0.089 nM) and CDK2/4 (IC50: 0.719/0.770 nM), which is more efficient than FN-1501(FLT3, IC50: 2.33 nM; CDK2/4, IC50: 1.02/0.39 nM). Compound 8t also showed excellent inhibitory activity against a variety of FLT3 mutants (IC50 50: 1.22 nM). In addition, compound 8t significantly inhibited the proliferation of most human cell lines of NCI60 (GI50 1 μM for most cell lines). Taken together, these results demonstrated the potential of 8t as a novel compound for further development into a kinase inhibitor applied in cancer therapeutics.
Zhi, Yanle,Wang, Zhijie,Yao, Chao,Li, Baoquan,Heng, Hao,Cai, Jiongheng,Xiang, Li,Wang, Yue,Lu, Tao,Lu, Shuai
(2019/11/21)

AN IMPROVED PROCESS FOR THE PREPARATION OF RIBOCICLIB AND ITS SALTS
The invention relates to a process for the preparation of ribociclib of formula V or its salts. The invention provides novel crystalline forms of ribociclib succinate and ribociclib trifluoroacetate. The present invention also relates to pharmaceutical compositions comprising a crystalline form of ribociclib succinate and at least a pharmaceutically acceptable carrier. It further relates to the use of such compositions in the treatment of cancer.
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(2019/05/15)

SUBSTITUTED PYRROLOPYRIMIDINE CDK INHIBITOR, PHARMACEUTICAL COMPOSITION CONTAINING SAME AND USE THEREOF
The present invention belongs to the field of pharmaceutical chemistry, and relates to a substituted pyrrolopyrimidine CDK inhibitor, in particular to a compound as shown in formula I or a pharmaceutically acceptable salt or solvate thereof, as well as a preparation method thereof and a pharmaceutical composition thereof. The present invention also relates to the use of the compound and the pharmaceutical composition thereof in the preparation of a drug for treating diseases associated with CDK inhibition. The compound according to the present invention has a marked inhibitory effect on CDK, excellent drug absorption and significantly superior oral absorption effect.
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(2019/02/09)

PYRIDINE CARBONYL DERIVATIVES AND THERAPEUTIC USES THEREOF AS TRPC6 INHIBITORS
The invention relates to compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein R1 to R7, A, Y and L are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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(2019/05/15)

CRYSTAL FORM, SALT TYPE OF SUBSTITUTED 2-HYDRO-PYRAZOLE DERIVATIVE AND PREPARATION METHOD THEREFOR
A crystal form and a salt type of a substituted 2-hydro-pyrazole derivative, preparation method therefor, and use of the crystal form and the salt type in preparation of a medicament for treating cancers such as breast cancer, lung cancer and the like.
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(2019/07/10)

INHIBITORS OF TRPC6
The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts therefore, wherein R1 to R6, A, U, V, W, X, Y, and Z are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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(2019/09/04)

Method for synthesizing 5-(N-BOC-piperazine-1-group)pyridine-2-amine
The invention relates to a method for synthesizing 5-(N-BOC-piperazine-1-group)pyridine-2-amine, and belongs to the technical field of chemical synthesis. According to the technical scheme, firstly, acompound I and a compound II are subjected to a substitution reaction to synthesize a compound III, and then the compound III is reduced to obtain a product IV; and inorganic salts are added in the reduction process, and generation of an azo impurity V can be effectively inhibited. The method has the beneficial effects that in the nitro reduction process, by adding ammonium chloride, sodium bicarbonate and other inorganic salts for reaction, the generation of the azo impurity can be effectively inhibited, and thus the subsequent treatment phase does not require refining steps to remove the impurity; and while the quality of the product is ensured, the yield of the product is also ensured.
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Paragraph 0031-0062; 0067; 0068

(2019/12/25)

A Palumbo Xilin synthesis of intermediates method (by machine translation)
The present invention provides a Palumbo Xilin synthesis of intermediates method, and in particular relates to technical field of drug synthesis, the invention of the Palumbo vial is means intermediate 4 - (6 - aminopyridin - 3 - yl) piperazine - 1 - carboxylic acid tert-butyl, in order to 2 - amino - 5 - bromo pyridine as the starting material, through oxidation, coupling, reduction to obtain the target product of the process route, to the influence of factors experimental study of the system, compared with the conventional preparation process, the invention process route in the production cost, the operation of the technique, the product yield and purity and environmental protection there are obviously increased and improved. (by machine translation)
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(2018/10/19)

Method for preparing 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate tert-butyl ester
The invention discloses a method for preparing 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate tert-butyl ester. The method for preparing 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate tert-butyl ester comprises the following steps: 2-aminopyridin, piperazine-1-formate tert-butyl ester and NSP-SA-NHS photo catalyst is added to the solvent, and the light reaction is carried out under the condition of the presence of an oxidizing agent to generate 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate tert-butyl ester. According to the method, 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate tert-butyl ester is synthesized by one step. On the one hand, the synthetic route of 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate tert-butyl ester is effectively shortened, the generation of by-productsis effectively reduced and the yield of the target product is improved. On the other hand, only photo catalyst and oxidizing agent are used, so that the preparation method is safe and environment-friendly and low in cost.
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Paragraph 0025; 0026; 0027; 0034; 0041; 0048; 0055; 0062

(2018/10/19)

Pyrimidine and pyrimidine dione CDK4/6 kinase inhibitors and uses thereof
The invention belongs to the field of chemical medicine, relates to pyrimidine and pyrimidine dione CDK4/6 kinase inhibitor and its application, the pyrimidine and pyrimidine dione CDK4/6 kinase inhibitors of formula I shown in the compound or its pharmaceutically acceptable salt, and pharmaceutical compositions containing these compounds and these compounds or compositions of the pharmaceutical preparation in the application, the present invention provides a pyrimidine and pyrimidine dione compounds to CDK4 and CDK6 kinase has better inhibition activity, to breast cancer cell has significant inhibition function, can effectively reduce the incidence of tumor, extension of the tumor to the lives of patients,
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Paragraph 0044; 0045; 0046; 0047

(2018/07/30)

Containing pyrimidine and pyrimidine diketone of preparation for parenteral administration
The invention belongs to the field of medicinal chemistry, and in particular to the pyrimidine and pyrimidine dione or its pharmaceutically acceptable salt for parenteral administration of the preparation, the preparation comprises 1 - phenyl - 3 - methyl - 7 - (5 - piperazin pyridine - 2 - ylamino) pyrimido [4, 5 - d] pyrimidine - 2, 4 (1 H, 3 H) - dione or a pharmaceutically acceptable salt of cyclodextrin inclusion compound and mannitol, the good stability of the preparation for parenteral administration, low moisture absorption, good appearance, can simplify the storage and transportation conditions.
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Paragraph 0022; 0023; 0024

(2018/07/30)

Pyrimidine and pyrimidine dione compounds of the hydrobromide and application thereof
The invention belongs to the field of chemical medicine, relates to a CDK4/CDK6 kinase inhibitory activity of pyrimidine and pyrimidine dione compounds, and pharmaceutical composition containing the compound and the compound or composition in the application of the drug in the preparation, in particular of formula (I) as shown in the composition of the hydrobromide or its solvent, crystallization or prodrug, the compound has excellent solubility and stability, as the formulation study provides better choice,
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Paragraph 0018; 0020; 0021; 0022

(2018/07/30)

Pyrimidine and pyrimidine dione compounds of the maleate and application thereof
The invention belongs to the field of chemical medicine, relates to a CDK4/CDK6 kinase inhibitory activity of pyrimidine and pyrimidine dione compounds, and pharmaceutical composition containing the compound and the compound or composition of the pharmaceutical preparation in the application, and in particular relates to 1 - phenyl - 3 - methyl - 7 - (5 - piperazin pyridine - 2 - ylamino) pyrimido [4, 5 - d] pyrimidine - 2, 4 (1 H, 3 H) - dione maleic acid salt or solvate thereof, crystallization or prodrug, the compound has excellent solubility and stability, for the formulation study provides better choice.
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Paragraph 0016; 0018; 0019; 0020

(2018/07/30)

Antimalarial Lead-Optimization Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space to Circumvent Atypical Dose-Response Curves against Multidrug Resistant Parasite Strains
A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.
Le Manach, Claire,Paquet, Tanya,Wicht, Kathryn,Nchinda, Aloysius T.,Brunschwig, Christel,Njoroge, Mathew,Gibhard, Liezl,Taylor, Dale,Lawrence, Nina,Wittlin, Sergio,Eyermann, Charles J.,Basarab, Gregory S.,Duffy, James,Fish, Paul V.,Street, Leslie J.,Chibale, Kelly
p. 9371 - 9385
(2018/10/24)

A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy
Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system. Here, we designed and synthesized a series of novel CDK4/6 inhibitors with favorable BBB permeability for the treatment of GBM. Compound 11 exhibited a favorable pharmacological profile and significant penetration of the BBB with the Kp value of 4.10 and the Kp,uu value of 0.23 in mice after an oral dose of 10 mg/kg. IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 were 3 nM and 1 nM, respectively. In vivo studies with an orthotopic xenograft mouse model of GBM showed that 11 had tumor growth inhibition values ranging from 62% to 99% for doses ranging from 3.125 to 50 mg/kg, and no significant body weight loss was observed. The increase in life span based on the median survival time of vehicle-treated animals in mice administered a dose of 50 mg/kg was significant at 162% (p 0.0001). These results suggest that compound 11 is a promising candidate for further investigation as an effective drug for the treatment of GBM.
Yin, Lei,Li, Heng,Liu, Wenjian,Yao, Zhenglin,Cheng, Zhenzhen,Zhang, Huabei,Zou, Hui
p. 1 - 28
(2017/12/26)

PREPARATION AND USE OF KINASE INHIBITOR
Disclosed are a preparation method for a kinase inhibitor and a use thereof. The kinase inhibitor is a compound represented by formula (I) wherein the groups are defined as described in the description. The compound of formula (I) has a kinase inhibitory activity and therefore can be used for the preparation of medicines for treating kinase activity-related diseases.
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(2018/03/09)

Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development
Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.
Crawford, James J.,Johnson, Adam R.,Misner, Dinah L.,Belmont, Lisa D.,Castanedo, Georgette,Choy, Regina,Coraggio, Melis,Dong, Liming,Eigenbrot, Charles,Erickson, Rebecca,Ghilardi, Nico,Hau, Jonathan,Katewa, Arna,Kohli, Pawan Bir,Lee, Wendy,Lubach, Joseph W.,McKenzie, Brent S.,Ortwine, Daniel F.,Schutt, Leah,Tay, Suzanne,Wei, Binqing,Reif, Karin,Liu, Lichuan,Wong, Harvey,Young, Wendy B.
p. 2227 - 2245
(2018/03/26)

PROTEIN KINASE INHIBITOR, PREPARATION METHOD AND MEDICAL USE THEREOF
The present invention provides compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, or a pharmaceutically acceptable salt or solvate of the compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, wherein R1 to R7 are as defined in the description. The present invention also provides a preparation method and a medical use of the compounds, The compounds of the present invention have an activity superior or equivalent to the candidate drug LY283521 9 currently under phase III clinical trial, and some of the compounds exhibit better selectivity. Moreover, the preferred compounds exhibit good absorption and good blood-brain distribution when administered orally. The compounds of the present invention thus show promise for development into novel drugs for the treatment of diseases associated with cell proliferation, particularly brain tumors, providing new options for clinicians and patients.
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(2018/10/27)

SUBSTITUTED 2-HYDROGEN-PYRAZOLE DERIVATIVE SERVING AS ANTICANCER DRUG
Disclosed is a substituted 2H-pyrazole derivative serving as a selective CDK4/6 inhibitor. Specifically, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof which serves as a selective CDK4/6 inhibitor.
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(2018/02/04)

PYRIDO[3,4-d]PYRIMIDINE DERIVATIVE AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
The purpose of the present invention is to provide a compound having an excellent CDK4/6 inhibiting activity. The present invention is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.
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(2018/04/19)

Discovery and pharmacological characterization of a novel series of highly selective inhibitors of cyclin-dependent kinases 4 and 6 as anticancer agents
Background and Purpose: Cyclin D-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle and are actively pursued as therapeutic targets in cancer. We sought to discover a novel series of orally bioavailable and highly selective small molecule inhibitors of CDK4/6. Experimental Approach: The discovery of pharmacological inhibitors and optimization for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F)-regulated gene expression and in vitro biopharmaceutical and in vivo pharmacokinetic profiling. Key Results: We discovered several lead compounds that displayed >1000-fold selectivity for CDK4/6 over other members of the CDK family. The lead compounds, 82, 91 and 95, potently inhibited the growth of cancer cells by inducing G1 arrest with a concomitant reduction in the phosphorylation of Rb at S780 and in E2F-regulated gene expression. With a remarkable selectivity for CDK4 over 369 human protein kinases, 91 was identified as a highly potent and orally bioavailable drug candidate. Conclusions and Implications: We have identified unique and new inhibitors of CDK4/6 as potential drug candidates. Compound 91 represents an ideal candidate for further development as targeted cancer therapy.
Tadesse, Solomon,Bantie, Laychiluh,Tomusange, Khamis,Yu, Mingfeng,Islam, Saiful,Bykovska, Nataliya,Noll, Benjamin,Zhu, Ge,Li, Peng,Lam, Frankie,Kumarasiri, Malika,Milne, Robert,Wang, Shudong
p. 2399 - 2413
(2018/05/14)

Synthetic process of important intermediate of anticancer drug palbociclib
The invention relates to a synthetic process of an important intermediate of anticancer drug palbociclib, and belongs to the technical field of organic synthesis. The process comprises the following steps: 5-bromo-2-nitropyridine and tert-butyl 1-piperazinecarboxylate are used as starting materials to obtain 1-tert-butoxycarbonyl-4-(6-nitro-3-pyridyl)piperazine, and under the action of hydrazine hydrate, ferric chloride hexahydrate and activated carbon, the 1-tert-butoxycarbonyl-4-(6-nitro-3-pyridyl)piperazine is reduced to obtain the important intermediate 1-tert-butoxycarbonyl-4-(6-amino-3-pyridyl)piperazine of the anticancer drug palbociclib. According to the process provided by the invention, the reduction method adopted in the process has reaction temperature of 80 DEG C and reactiontime of 14-16 h, recrystallization is performed by utilizing ethanol, and the synthesized target product has purity of 98% and a yield of 98%; and the product synthesized by the method has high purityand simple post-treatment, is suitable for industrial large-scale production, and has a very wide range of applications and potential economic benefits.
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Paragraph 0045-0046; 0049; 0053-0054; 0056; 0060-0061; 0062

(2018/11/27)

Method for synthesis of palbociclib intermediate
The invention provides a method for synthesis of palbociclib intermediate, and belongs to the field of organic synthesis. According to the method, a microchannel reactor or a microreactor is used forreaction, wherein the microchannel reactor or the microreactor comprises more than one preheating module and more than one reaction module group, the preheating module and the reaction module group are connected in series or combined in parallel, and each reaction module group consists of 1-6 reaction modules in series; the synthesis steps are as follows: 1) adding tert-butyl 4- (6-nitro-3-pyridyl)-1-piperazinecarboxylate into an organic solvent, and after an active carbon catalyst with Pd is added, taking the obtained mixture as a material I entering the preheating module of the microchannelreactor or the microreactor; 2) introducing the preheated material I with hydrogen into the reaction module group for reaction, collecting a reaction solution outflow, and performing after treatmentto obtain 4-(6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester. The use of the method for the synthesis of the palbociclib intermediate has the advantages of high yield, high productpurity, and safety and environment-friendliness.
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Paragraph 0034; 0035; 0036; 0037; 0038; 0039-0054

(2018/03/26)

Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation
Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
Tadesse, Solomon,Yu, Mingfeng,Mekonnen, Laychiluh B.,Lam, Frankie,Islam, Saiful,Tomusange, Khamis,Rahaman, Muhammed H.,Noll, Benjamin,Basnet, Sunita K. C.,Teo, Theodosia,Albrecht, Hugo,Milne, Robert,Wang, Shudong
p. 1892 - 1915
(2017/03/17)

Protein kinase inhibitor and its preparation method and medical application
The invention provides a compound shown in the structural formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or their mixture, or a pharmaceutically acceptable salt or solvate of the compound shown in the structural formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or their mixture. The ring A, R1, R2, R3 and R4 are defined in the specification. The invention also provides a preparation method of the compound shown in the structural formula I and a use of the compound in preparation of a drug for treating cell proliferative disorder.
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(2017/05/26)

Synthetic method of cyclopentyl pyrimido pyrroles compound
The invention discloses a synthetic method of a cyclopentyl pyrimido pyrroles compound, which belongs to the field of organic chemical synthesis. Through steps of reduction, oxidation, aldol condensation, aminolysis and nucleophilic substitution, the cyclopentyl pyrimido pyrroles compound is synthesized. The raw materials have the advantages of low cost and easy acquisition, a related intermediate is easily separated and purified, operation is simple, the method is friendly to environment, the purity of the product is high, and the product has good industrial prospect. The prepared cyclopentyl pyrimido pyrroles compound, especially 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazine-1-yl)pyridine-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-methanamide has inhibition effect on cyclin-dependent kinase CDK4/6, and has good clinical treatment effect on melanoma and breast cancer.
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(2017/07/22)

Discovery of Potent and Selective Tricyclic Inhibitors of Bruton's Tyrosine Kinase with Improved Druglike Properties
In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.
Wang, Xiaojing,Barbosa, James,Blomgren, Peter,Bremer, Meire C.,Chen, Jacob,Crawford, James J.,Deng, Wei,Dong, Liming,Eigenbrot, Charles,Gallion, Steve,Hau, Jonathon,Hu, Huiyong,Johnson, Adam R.,Katewa, Arna,Kropf, Jeffrey E.,Lee, Seung H.,Liu, Lichuan,Lubach, Joseph W.,Macaluso, Jen,Maciejewski, Pat,Mitchell, Scott A.,Ortwine, Daniel F.,Dipaolo, Julie,Reif, Karin,Scheerens, Heleen,Schmitt, Aaron,Wong, Harvey,Xiong, Jin-Ming,Xu, Jianjun,Zhao, Zhongdong,Zhou, Fusheng,Currie, Kevin S.,Young, Wendy B.
p. 608 - 613
(2017/06/13)

A selective kinase inhibitors Palbociclib preparation method
The invention provides a novel preparation method for a selective kinases inhibitor Palbociclib for cyclin-dependent kinases CDK4 and CDK6, and belongs to the technical field of medicament preparation. The preparation method comprises taking 4-amino-5-bromo-2-chloropyrimidine as an initial raw material, performing acetylation with N-methoxy-N-methylacetamide to obtain an intermediate 2, performing Friedlaender reaction on the intermediate and a raw material ethyl acetoacetate to obtain an intermediate 3, and performing amino substitution on the intermediate 3 and a halogenated cyclopentane to obtain an intermediate 4; performing substitution reaction on a raw material 5-bromo-2-nitropyridine and a raw material tert-butyl 1-piperazinecarboxylate to obtain an intermediate 5, and reducing the intermediate 5 to obtain an intermediate 6; performing substitution reaction on the intermediate 4 and the intermediate 6, and performing deprotection to obtain the target product 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyrido[2,3-d]pyrimidin-7-one with the yield of 45% or more. A brand-new route is employed, the reaction raw materials are cheap and easy to obtain, reaction conditions are mild, noble metal catalysts are avoided, and the preparation method is suitable for industrialized production.
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(2017/10/06)

2,4-dibasic miazines compound
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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(2017/08/29)

Protection of renal tissues from ischemia through inhibition of the proliferative kinases CDK4 and CDK6
The presently disclosed subject matter relates to methods and compositions for protecting cells and or tissues from damage due to ischemia. In particular, the presently disclosed subject matter relates to the protective action of cyclin dependent kinase 4/6 (CDK4/6) inhibitors administered to subjects that have been exposed to, or that are at risk of, ischemia.
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Page/Page column 22

(2017/11/27)

N-PYRIDINYL ACETAMIDE DERIVATIVES AS INHIBITORS OF THE WNT SIGNALLING PATHWAY
This invention relates to compounds. More specifically, the invention relates to compounds useful as inhibitors of the Wnt signalling pathway. Specifically, inhibitors of Porcupine (Porcn) are contemplated by the invention. In addition the invention contemplates processes to prepare the compounds and uses of the compounds. The compounds of the invention may therefore be used in treating conditions mediated by the Wnt signalling pathway, for example treating cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia; or enhancing the effectiveness of an anti-cancer treatment.
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(2016/05/02)

CYCLIN DEPENDENT KINASE INHIBITORS AND METHODS OF USE
The presently disclosed subject matter relates to methods and compositions for protecting healthy cells from damage due to DNA damaging agents. In particular, the presently disclosed subject matter relates to the protective action of selective cyclin dependent kinase 4/6 (CDK4/6) inhibitors administered to subjects that have been exposed to or that are at risk of exposure to DNA damage.
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(2016/02/29)

METHOD OF PRODUCING PALBOCICLIB AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
The present invention relates to a method of producing palbociclib and to pharmaceutical compositions comprising the same.
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(2016/03/22)