- Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant
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The receptor tyrosine kinase rearranged during transfection (RET) plays pivotal roles in several cancers, including thyroid carcinoma and non-small cell lung cancer (NSCLC). Currently, there are several FDA-approved RET inhibitors, but their indication is limited to thyroid cancer, and none can overcome their gatekeeper mutants (V804L and V804M). Here, we report the discovery of 9x representing a new chemotype of potent and selective RET inhibitors, using a rational design strategy of type II kinase inhibitors. 9x exhibited both superior antiproliferative activities against NSCLC-related carcinogenic fusions KIF5B-RET and CCDC6-RET and gatekeeper mutant-transformed Ba/F3 cells, with the lowest GI50 of 9 nM, and substantial inhibitory activities against wild-type RET and RET mutant proteins, with the best IC50 of 4 nM. More importantly, 9x also showed nanomole potency against RET-positive NSCLC cells LC-2/ad, but not against a panel of RET-negative cancer cells, such as A549, H3122, A375 or parental Ba/F3 cells, demonstrating its selective ‘on-target’ effect. In mouse xenograft models, 9x repressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that 9x provides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.
- Chen, Guyue,Deng, Xianming,Deng, Zhou,Dong, Chao,Hu, Zhiyu,Li, Li,Li, Xiaoyang,Lian, Wenhua,Liu, Xueyan,Su, Jingyi,Wang, Zheng,Xu, Qingyan,Yang, Yanru,Yang, Zaiyou,Zhang, Baoding
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Read Online
- Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis
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The serine/threonine kinase SGK1 is an activator of the β-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today, no oral disease-modifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic, and safety profile. We describe the identification of a highly selective druglike 1H-pyrazolo[3,4-d]pyrimidine SGK1 inhibitor 17a that matches both safety and pharmacokinetic requirements for oral dosing. Rational compound design was facilitated by a novel hSGK1 co-crystal structure, and multiple ligand-based computer models were applied to guide the chemical optimization of the compound ADMET and selectivity profiles. Compounds were selected for subchronic proof of mechanism studies in the mouse femoral head cartilage explant model, and compound 17a emerged as a druglike SGK1 inhibitor, with a highly optimized profile suitable for oral dosing as a novel, potentially disease-modifying agent for osteoarthritis.
- Halland, Nis,Schmidt, Friedemann,Weiss, Tilo,Li, Ziyu,Czech, J?rg,Saas, Joachim,Ding-Pfennigdorff, Danping,Dreyer, Matthias K.,Strübing, Carsten,Nazare, Marc
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p. 1567 - 1584
(2022/01/03)
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- Pyrazolo[3,4-d]pyrimidine derivatives as irreversible Bruton's tyrosine kinase inhibitors
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4,6-Disubstituted pyrazolo[3,4-d]pyrimidine derivatives were explored as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The structure–activity relationship was established with over 20 derivatives synthesized to determine initial hit compounds, based on activities against BTK enzyme and TMD8 cells. It turns out that introducing 1-acrylamido-4-aminopiperdine (1b) at the C4 position of pyrazolopyrimidine as in 5e, and 3-acrylamido-aniline (1j) as 4-position substituent, such as in 9d, 10d, and 10e, delivered potent in vitro enzyme activities as well as TMD8 cell-based cytotoxicities. Considering kinase selectivity profiles, 5e was selected for in vivo efficacy studies with a murine xenograft model using TMD8 cells, where 5e exhibited moderate tumor growth inhibition activities. Further optimization of 5e and 9d may lead to clinically useful compounds to overcome B-cell-mediated hematologic cancers.
- Achary, Raghavendra,Cho, Sung Yun,Choi, Yunha,Kim, Pilho,Lee, Heung Kyoung,Lee, Joo-Youn,Park, Chi Hoon,Yeom, Hyesu
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supporting information
(2022/02/09)
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- Substituted alkynyl heterocyclic compounds
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The invention relates to substituted alkynyl heterocyclic compounds represented by formula I, and concretely relates to substituted alkynyl heterocyclic compounds having SHP2 inhibitory activity, a preparation method and a pharmaceutical composition thereof, and uses of the compounds and the pharmaceutical composition thereof in the treatment of diseases that benefit from SHP2 enzyme inhibition, such as in the treatment of cancer. In the preparation process, the compounds of the formula I are obtained through reactions such as iodination, amination, upper protection, coupling, deprotection and ring-closure reaction.
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Paragraph 0085-0088
(2021/06/23)
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- Heterocyclic Adenosine Receptor Antagonists
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Heterocyclic compounds useful as antagonists of adenosine receptors, and methods of treatment of diseases using antagonists of adenosine receptors are disclosed herein. Also disclosed herein are pharmaceutical compositions and methods of administration of
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Paragraph 0303; 0304-0305
(2021/09/26)
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- SUBSTITUTED PYRIMIDINES, PHARMACEUTICAL COMPOSITIONS AND THERAPEUTIC METHODS THEREOF
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The invention provide novel pyrimidine derivatives and analogs having inhibitory activities towards certain tyrosine kinases, e.g., Bruton's tyrosine kinase (Btk) and/or Focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), pharmaceutical compositions thereof, and methods of treatment, reduction or prevention of certain diseases or conditions mediated by such by tyrosine kinases, e.g., cancers, tumors, fibrosis, inflammatory diseases, autoimmune diseases, diabetes, or immunologically mediated diseases.
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Paragraph 00275
(2019/03/17)
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- PYRAZOLO AND TRIAZOLO BICYCLIC COMPOUNDS AS JAK KINASE INHIBITORS
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The invention provides compounds of formula (I) or a pharmaceutically-acceptable salt thereof, wherein the variables are defined in the specification, that are inhibitors of JAK kinases, particularly JAK3. The invention also provides crystalline forms, ph
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Page/Page column 78
(2019/02/15)
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- COMPOUNDS
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Disclosed are novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, compositions containing them and their use in the treatment of or prevention of diseases characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis(ALS).
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- Used as inhibitors of FGFR N-(1H-pyrazol-5-yl) pyrimidine and pyrazole -4,6-di-substituted amine compound (by machine translation)
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This invention relates to a kind of used as inhibitors of FGFR N-(1H the [...] pyrazole -5 the [...] ) pyrimidine and pyrazole -4, the 6 [...] disubstituted amine compound. The invention provides a compound of formula I or its pharmaceutically acceptable salt thereof. Also provided is the method for preparing the compound of the formula I, the compound of formula I as pharmaceutical and use in the treatment of cancer . (by machine translation)
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- HETEROCYCLIC HYDROXAMIC ACIDS AS PROTEIN DEACETYLASE INHIBITORS AND DUAL PROTEIN DEACETYLASE-PROTEIN KINASE INHIBITORS AND METHODS OF USE THEREOF
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The present invention relates to novel hydroxamic acids which are specific histone deacetylase (HDAC) inhibitors and/or TTK/Mpsl kinase inhibitors, including pharmaceutically acceptable salts thereof, which are useful for modulating HDAC and/or TTK/Mpsl k
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Paragraph 00413; 00414
(2016/04/26)
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- Discovery of 1-methyl-1 H-imidazole derivatives as potent Jak2 inhibitors
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Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.
- Su, Qibin,Ioannidis, Stephanos,Chuaqui, Claudio,Almeida, Lynsie,Alimzhanov, Marat,Bebernitz, Geraldine,Bell, Kirsten,Block, Michael,Howard, Tina,Huang, Shan,Huszar, Dennis,Read, Jon A.,Rivard Costa, Caroline,Shi, Jie,Su, Mei,Ye, Minwei,Zinda, Michael
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p. 144 - 158
(2014/02/14)
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- N-(4-(AZAINDAZOL-6-YL)-PHENYL)-SULFONAMIDES AND THEIR USE AS PHARMACEUTICALS
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N-(4-(Azaindazol-6-yl)-phenyl)-sulfonamides and their use as pharmaceuticals The present invention relates to N-(4-(azaindazol-6-yl)-phenyl)-sulfonamides of the formula I, wherein Ar, n, X, Z, R1, R2 and R3 have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds which modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase (SGK), in particular of serum and glucocorticoid regulated kinase isoform 1 (SGK-1, SGK1), and are suitable for the treatment of diseases in which SGK activity is inappropriate, for example degenerative joint disorders or inflammatory processes such as osteoarthritis or rheumatism. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use as pharmaceuticals, and pharmaceutical compositions comprising them.
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Page/Page column 90
(2014/09/29)
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- SUBSTITUTED N-(3-(PYRIMIDIN-4-YL)PHENYL)ACRYLAMIDE ANALOGS AS TYROSINE RECEPTOR KINASE BTK INHIBITORS
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In one aspect, the invention relates to substituted N-(3-(pyrimidin-4- yl)phenyl)acrylamide analogs, derivatives thereof, and related compounds, which are useful as inhibitors of the BTK kinase; synthetic methods for making the compounds; pharmaceutical c
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Paragraph 00397
(2014/04/18)
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- SUBSTITUTED N-(3-(PYRIMIDIN-4-YL)PHENYL)ACRYLAMIDE ANALOGS AS TYROSINE RECEPTOR KINASE BTK INHIBITORS
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In one aspect, the invention relates to substituted N-(3-(pyrimidin-4- yl)phenyl)acrylamide analogs, derivatives thereof, and related compounds, which are useful as inhibitors of the BTK kinase; synthetic methods for making the compounds; pharmaceutical c
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Page/Page column 149
(2012/10/18)
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- COMPOUNDS THAT MODULATE EGFR ACTIVITY AND METHODS FOR TREATING OR PREVENTING CONDITIONS THEREWITH
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Provided are compounds and methods for treating or preventing kinase-mediated disorders therewith.
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- PI3K/MTOR KINASE INHIBITORS
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6-morpholin-4-yl-pyrazolo[3,4-d]pyrimidine and 2-morpholin-4-yl-7H- pyrrolo[2,3-d]pyrimidine derivatives have unexpected drug properties as inhibitors of PI3 and/or mTOR kinases and are useful in treating disorders related to abnormal PI3K/mT0R activities such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders.
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Page/Page column 60
(2010/06/15)
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- HETEROCYCLIC JAK KINASE INHIBITORS
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The present invention relates to compounds of Formula (I) and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds provide a treatment for myeloproliferative disorders and cancer
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Page/Page column 101-102
(2010/04/27)
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- THIENOPYRIMIDINE AND PYRAZOLOPYRIMIDINE COMPOUNDS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS
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The invention relates to thienopyrimidine and pyrazolopyrimidine compounds of the Formulas (Ia) and (IIa), or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein compositions comprising the compounds, and methods for making and using the compounds.
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Page/Page column 62
(2009/04/24)
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- 1H-PYRAZOLO[3,4-D]PYRIMIDINE, PURINE, 7H-PURIN-8(9H)-ONE, 3H-[1,2,3]TRIAZOLO[4,5-D]PYRIMIDINE, AND THIENO[3,2-D]PYRIMIDINE COMPOUNDS, THEIR USE AS mTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
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The invention relates to 1H-pyrazolo[3,4-d]pyrimidine, purine, 7H-purin-8(9H)-one, 3H-[1,2,3]triazolo[4,5-d]pyrimidine, and thieno[3,2-d]pyrimidine compounds, compositions comprising the compounds, and methods for making and using the compounds.
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Page/Page column 38
(2009/08/14)
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- PYRAZOLOPYRIMIDINE COMPOUND
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Disclosed is a novel compound having Syk and/or Abl inhibitory activities, which is useful for prevention/treatment of allergic diseases, autoimmune diseases, arthritides and cancers. Specifically disclosed is a pyrazolopyrimidine compound represented by
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Page/Page column 28
(2009/12/07)
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