- Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R)
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Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.
- Degorce, Sébastien L.,Boyd, Scott,Curwen, Jon O.,Ducray, Richard,Halsall, Christopher T.,Jones, Clifford D.,Lach, Franck,Lenz, Eva M.,Pass, Martin,Pass, Sarah,Trigwell, Catherine
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- Thienopyrimidine derivatives and preparation method thereof
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Disclosed are a thienopyrimidine derivative and a preparation method therefor. Provided is a method for preparing a compound as shown in formula B, which method is characterized by comprising the following steps: subjecting a compound as shown in formula
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- HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS
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Heterocyclic compounds as CDK4 or CDK6 or other CDK inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
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- ATF6 MODULATORS AND USES THEREOF
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Compounds (1-2) as modulators of Activating Transcription Factor 6 (ATF6) are provided. The compounds may find use as therapeutic agents for the treatment of diseases or disorders mediated by ATF6 and may find particular use in the treatment of viral infections, neurodegenerative diseases, vascular diseases, or cancer. (Formula (1-2))
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Paragraph 277
(2021/04/17)
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- HETEROARYLAMINOPYRIMIDINE AMIDE AUTOPHAGY INHIBITORS AND METHODS OF USE THEREOF
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Described herein are compounds that are inhibitors of autophagy and their use in the treatment of disorders such as cancers. (I)
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Paragraph 000231
(2020/11/30)
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- Discovery of 7H-pyrrolo[2,3-d]pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study
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Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC50 = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC50 = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery.
- Wang, Ruifeng,Zhao, Xiangxin,Yu, Sijia,Chen, Yixuan,Cui, Hengxian,Wu, Tianxiao,Hao, Chenzhou,Zhao, Dongmei,Cheng, Maosheng
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- Preparation method of FLT3 and FGFR kinase inhibitor
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The invention discloses a preparation method of an FLT3 and FGFR kinase inhibitor. The preparation method comprises the following steps: S1, performing reacting of 4-nitropyrazole with N-BOC-4-hydroxypyridine to obtain an intermediate 1, and carrying out
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- N-heteroarylsulfonamide derivative, and preparation and application of same
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The invention provides an N-heteroarylsulfonamide derivative, and preparation and an application of same. The derivative includes pharmaceutically acceptable salts and solvates thereof; a test provesthat the N-heteroarylsulfonamide derivative allows specific combination and inhibit or reduce the activity of potassium pathway Kv1.3, so that the derivative can be used for treating autoimmune diseases, caused by abnormal activation of the potassium pathway Kv1.3, of human or animal. An inhibitor in the invention also includes a medicinal composition of the compound. The invention also provides amethod for preparing the compound. The derivative has the general formula as the specification.
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- FUSED RING PYRIMIDINE COMPOUND, INTERMEDIATE, AND PREPARATION METHOD, COMPOSITION AND USE THEREOF
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Disclosed area fused ring pyrimidine compound, and an intermediate, a preparation method, a composition and a use thereof. The fused ring pyrimidine compound is a compound as shown in formula I, a tautomer, an enantiomer, a diastereoisomer, a pharmaceutically acceptable salt, a metabolite, a metabolic precursor or a prodrug thereof, wherein the above-mentioned compound is used for the preparation of a medicine for preventing, remitting or treating one or more of immune system diseases, autoimmune diseases, cell proliferative diseases, allergic disorders and cardiovascular diseases, and the compound has a strong inhibitory effect on the Janues kinase, FGFR kinase, FLT3 kinase and Src family kinase.
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- Substituted heteroaryl compound and composition thereof, and uses of substituted heteroaryl compound and composition thereof
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The present invention provides a substituted heteroaryl compound and a composition thereof, and uses of the substituted heteroaryl compound and the composition, wherein the compound is a compound represented by a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound represented by the formula (I). The present invention further provides a pharmaceutical composition containing the compound, wherein the pharmaceutical composition can regulate activity of protein kinases, particularly Aurora kinases and JAK kinases, and can be used for prevention, treatment, therapy and alleviation of protein kinases, particularly Aurora kinases and JAK kinase activity mediated diseases or disorders.
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- Substituted heteroaryl compounds and composition thereof, and applicaitons of compounds and composition
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The invention provides substituted heteroaryl compounds and a composition thereof, and applicaitons of the compounds and the composition. The compounds are compounds represented by the formula (I) or the formula (II) or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds represented by the formula (I) or the formula (II). The invention also provides the pharmaceutical composition comprising the compounds; the compounds and the pharmaceutical composition can adjust the activity of protein kinase, and are used for prevention, processing, treatment and remission of diseases or disorders mediated by the protein kinase.
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- SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof. They are useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.
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- SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof. They are useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.
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- GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein A, R, W, Q, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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- GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein A, R, W, Q, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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- BIARYL COMPOUNDS USEFUL FOR THE TREATMENT OF HUMAN DISEASES IN ONCOLOGY, NEUROLOGY AND IMMUNOLOGY
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The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.
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Paragraph 0211; 0236
(2015/06/25)
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- SUBSTITUTED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF
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The present disclosure relates to pyrimidine compounds of formula (I), their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to process of preparation of these pyrimidine compounds, and to pharmaceutical compositions containing them. The compounds of the present disclosure are useful in the treatment, prevention or suppression of diseases and disorders mediated by epidermal growth factor receptor (EGFR) family kinases.
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Paragraph 00075
(2015/03/13)
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- INHIBITORS
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This invention relates to compounds of the formula (I):The invention also relates to processes for the preparation of the compound of the formula (I), pharmaceutical agents or compositions containing the compound or a method of using the compound for the
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- VEGFR3 INHIBITORS
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This invention relates to compounds of the formula (I). The invention also relates to processes for the preparation of the compound of the formula (I), pharmaceutical agents or compositions containing the compound or a method of using the compound for the treatment of proliferative diseases, such as cancer as well as the treatment of diseases ameliorated by the control and/or inhibition of lymphanglogenesis.
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Page/Page column 164
(2014/03/22)
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- NOVEL PYRIMIDINE AND PYRIDINE COMPOUNDS AND USAGE THEREOF
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Provided are novel pyrimidine and pyridine compounds of formula (I) or a pharmaceutical acceptable salt thereof, pharmaceutical compositions containing them, a process for preparing them, and their use in therapy of a disease responsive to inhibition of F
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Page/Page column 32; 33
(2014/09/29)
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- NOVEL PYRIMIDINE AND PYRIDINE COMPOUNDS AND THEIR USAGE
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The present invention relates to novel pyrimidine and pyridine compounds of formula (I) or a pharmaceutical acceptable salt thereof, wherein R1, R2, R3, R4, R5, X, Y and G are as defined in the description, to pharmaceutical compositions containing them, a process for preparing them, and their use in therapy of a disease responsive to inhibition of FGFR, for example, cancer.
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Page/Page column 33; 34
(2014/09/29)
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- BENZONITRILE DERIVATIVES AS KINASE INHIBITORS
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Compounds of the formula I, in which R1, R2, X and Y have the meanings indicated in Claim 1, are inhibitors of TBK1 and IKKε and can be employed, inter alia, for the treatment of cancer and inflammatory diseases.
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- 8 - SUBSTITUTED 2 -AMINO - [1,2,4] TRIAZOLO [1, 5 -A] PYRAZINES AS SYK TRYROSINE KINASE INHIBITORS AND GCN2 SERIN KINASE INHIBITORS
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Compounds of the formula I in which R1, R2 and R4 have the meanings indicated in Claim 1, are inhibitors of Syk, and can be employed, inter alia, for the treatment of cancer, rheumatoid arthritis and / or systemic lupus
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Page/Page column 110
(2013/09/12)
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- PYRIMIDINE INHIBITORS OF KINASES
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The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A1, A2, A3, A4, X and Y are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as aurora and KDR.
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- PYRIDINE COMPOUNDS
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The present invention relates to compounds that inhibit of focal adhesion kinase function, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment in warm-blooded animals such as humans of diseases such as cancer.
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- A practical, two-step synthesis of 1-alkyl-4-aminopyrazoles
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A novel synthesis of N1 alkyl-substituted pyrazoles with a free amino group at the C4 position is described. Commercially available 4-nitropyrazole was found to readily undergo Mitsunobu reactions with primary and secondary alcohols. Subsequent reduction of the nitro group via hydrogenation affords 1-alkyl-4-aminopyrazoles, which are valuable intermediates in the synthesis of pharmaceutically active compounds.
- Zabierek, Anna A.,Konrad, Kaleen M.,Haidle, Andrew M.
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p. 2996 - 2998
(2008/09/20)
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