- Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
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The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
- Zhang, Hefeng,Peng, Xia,Dai, Yang,Shao, Jingwei,Ji, Yinchun,Sun, Yiming,Liu, Bo,Cheng, Xu,Ai, Jing,Duan, Wenhu
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supporting information
p. 3956 - 3975
(2021/04/12)
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- AZAINDOLE DERIVATIVE AND USE THEREOF AS FGFR AND C-MET INHIBITOR
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A series of pyrazolopymidine derivatives, and use thereof in the preparation of a medicament for treating disease associated with FGFR and c-Met. The pyrazolopymidine derivative is a compound represented by formula (I), a tautomer, or a pharmaceutically acceptable salt thereof.
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Paragraph 0214
(2021/05/29)
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- N-(AZAARYL)CYCLOLACTAM-1-CARBOXAMIDE DERIVATIVE, PREPARATION METHOD THEREFOR, AND USE THEREOF
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An N-(azaaryl)cyclolactam-1-carboxamide derivative having a structure of formula (I), a preparation method therefor, and a use thereof are disclosed in the application. Each substituent are defined in the specification and claims. The series of compounds of the application can be widely applied in the preparation of drugs for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease, particularly for treating ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic disease, neurodegenerative disease, primary tumor site metastasis or osseous metastasis cancer, and are expected to be developed into a new generation of CSF-1R inhibitor drugs.
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Paragraph 0143; 0154; 0155
(2020/03/23)
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- INHIBITORS OF CYCLIN DEPENDNT KINASE 7 (CDK7)
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The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
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Paragraph 362
(2018/02/28)
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- 2-ARYL- AND 2-HETEROARYL-SUBSTITUTED 2-PYRIDAZIN-3(2H)-ONE COMPOUNDS AS INHIBITORS OF FGFR TYROSINE KINASES
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Provided herein are compounds of the general Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which X, R1, R2, R3, Ring A and z have the meanings given in the specification, which are inhibitors of FGFR1, FGFR2, FGFR3 and/or FGFR4 and are useful in the treatment and prevention of diseases which can be treated with an FGFR inhibitor, including diseases or disorders mediated by FGFR1, FGFR2, FGFR3 and/or FGFR4.
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Paragraph 00407; 00408; 00409; 00410
(2017/05/10)
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- COMPOSITIONS USEFUL FOR TREATING DISORDERS RELATED TO KIT AND PDFGR
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Compounds and compositions useful for treating disorders related to KIT and PDGFR are described herein.
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Paragraph 0227; 0228; 0229
(2017/02/24)
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- FUSED PYRAZOLE DERIVATIVES AS JAK INHIBITORS
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Novel fused pyrazole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 67
(2018/04/11)
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- HETEROARYL COMPOUNDS AND PHARMACEUTICAL APPLICATIONS THEREOF
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The present invention provides herein is a heteroaryl compound or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, as well as a pharmaceutical composition containing the compound disclosed herein. The present invention also provides herein is use of the compound or the pharmaceutical composition thereof disclosed herein in the manufacture of a medicine for treating autoimmune diseases or proliferative diseases.
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Paragraph 00664
(2016/01/25)
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- SUBSTITUTED INDAZOLES AND RELATED HETEROCYCLES
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The present invention relates to substituted indazoles and related heterocycles. These compounds are useful for the prevention and/or treatment of hyperproliferative, inflammatory and degenerative disorders and diseases. Thus, this invention is also concerned with the use of the compounds of the present invention for the the prevention and/or treatment of hyperproliferative, inflammatory and degenerative disorders and diseases as well as pharmaceutical composition, medicaments and kits comprising the substituted indazoles and related heterocycles of the present invention and processes for manufacturing those compounds.
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Page/Page column 106-107
(2016/04/09)
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- COMPOSITIONS USEFUL FOR TREATING DISORDERS RELATED TO KIT
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Compounds and compositions useful for treating disorders related to Kit are described herein.
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Paragraph 0141-0142
(2016/04/26)
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- DGAT1 INHIBITOR AND PREPARATION METHOD AND USE THEREOF
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The present invention discloses a novel DGAT1 inhibitor, especially the compound of formula (I) or a pharmaceutically acceptable salt thereof, preparation and pharmaceutical composition thereof, as well as their uses in the preparation of a medicament for the prevention and treatment of Familial hyperchylomicronemia (FCS), obesity, hyperlipoproteinemia or hypertriglyceridemia.
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Paragraph 0265; 0266
(2016/08/23)
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- 2-(PYRAZOLOPYRIDIN-3-YL)PYRIMIDINE DERIVATIVES AS JAK INHIBITORS
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New 2-(pyrazolopyridin-3-yl)pyrimidine derivatives are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 66
(2016/12/26)
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- PYRAZOLE-ALCOHOL COMPOUNDS AND PHARMACEUTICAL USE THEREOF
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A compound represented by the following formula: or a pharmaceutically acceptable salt thereof, and pharmaceutical use thereof.
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Paragraph 0174-0176
(2015/02/18)
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- N-ACYLPIPERIDINE ETHER TROPOMYOSIN-RELATED KINASE INHIBITORS
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The present invention relates to compounds of Formula (I) described herein and their pharmaceutically acceptable salts, and their use in medicine, in particular as Trk antagonists.
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Page/Page column 202; 203
(2015/07/07)
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- PYRAZINE DERIVATIVES AS FGFR INHIBITORS
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The present invention relates to pyrazine derivatives, and pharmaceutical compositions including the same, that are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.
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Paragraph 0252; 0253
(2014/03/21)
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- PHARMACOLOGICALLY ACTIVE COMPOUNDS
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The present invention relates to compounds of formula (II) wherein X, Y, R2, R3, R4 and Ar are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1 – also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.
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Paragraph 00419
(2014/03/26)
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- INDANYLOXYDIHYDROBENZOFURANYLACETIC ACIDS
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The present invention relates to compounds of general formula I, wherein the groups (Het)Ar and R1 are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
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Paragraph 0353; 0354
(2014/06/24)
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- NEW INDANYLOXYDIHYDROBENZOFURANYLACETIC ACIDS
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The present invention relates to compounds of general formula I, wherein the groups (Het)Ar and R1 are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
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Page/Page column 77
(2014/06/24)
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- Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2- d ][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2- methylpropanamide (GDC-0032): A β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity
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Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.
- Ndubaku, Chudi O.,Heffron, Timothy P.,Staben, Steven T.,Baumgardner, Matthew,Blaquiere, Nicole,Bradley, Erin,Bull, Richard,Do, Steven,Dotson, Jennafer,Dudley, Danette,Edgar, Kyle A.,Friedman, Lori S.,Goldsmith, Richard,Heald, Robert A.,Kolesnikov, Aleksandr,Lee, Leslie,Lewis, Cristina,Nannini, Michelle,Nonomiya, Jim,Pang, Jodie,Price, Steve,Prior, Wei Wei,Salphati, Laurent,Sideris, Steve,Wallin, Jeffery J.,Wang, Lan,Wei, Binqing,Sampath, Deepak,Olivero, Alan G.
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p. 4597 - 4610
(2013/07/19)
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- Tetrahydroquinoline Derivatives And Their Pharmaceutical Use
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Tetrahydroquinoline compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and their use in therapy.
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Page/Page column 49
(2012/08/28)
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- PYRROLOPYRIDAZINE JAK3 INHIBITORS AND THEIR USE FOR THE TREATMENT OF INFLAMMATORY AND AUTOIMMUNE DISEASES
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The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity of JAK3, thereby making them useful for the treatment of inflammatory and autoimmune diseases.
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Page/Page column 210-211
(2012/10/07)
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- BENZOXEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Benzoxepin compounds of Formula I, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, wherein: Z1 is CR1 or N; Z2 is CR2 or N; Z3 is CR3 or N; Z4 is CR4 or N; and where (i) X1 is N and X2 is S, (ii) X1 is S and X2 is N, (iii) X1 is CR7 and X2 is S, (iv) X1 is S and X2 is CR7; (v) X1 is NR8 and X2 is N, (vi) X1 is N and X2 is NR8, (vii) X1 is CR7 and X2 is O, (viii) X1 is O and X2 is CR7, (ix) X1 is CR7 and X2 is C(R7)2, (x) X1 is C(R7)2 and X2 is CR7; (xi) X1 is N and X2 is O, or (xii) X1 is O and X2 is N, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 160
(2011/04/19)
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- TETRAHYDROQUINOLINE DERIVATIVES AND THEIR PHARMACEUTICAL USE
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Tetrahydroquinoline compounds of Formula (I) and salts thereof, pharmaceutical compositions containing such compounds and their use in therapy.
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Page/Page column 107-108
(2011/06/11)
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- INDAZOLE INHIBITORS OF KINASE
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The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A1, A2, A3 and L 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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Page/Page column 21-22
(2011/11/30)
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- KINASE INHIBITORS WITH IMPROVED CYP SAFETY PROFILE
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Compounds that inhibit protein kinases such as Aurora-kinases and the VEGFR and PDGFR families of kinases, with an improved safety profile due to low CYP3A4 inhibition, compositions containing the compounds and methods of treating diseases using the compounds are disclosed.
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Page/Page column 16
(2010/06/19)
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- PYRAZOLO [1, 5-A] PYRIMIDINE DERIVATIVES AS MTOR INHIBITORS
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The present invention provides methods for inhibiting mTOR using pyrazolo[1,5-a]pyrimidine compounds and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with mTOR using such compounds.
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Page/Page column 361
(2010/11/03)
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- AMINO PYRIMIDINE ANTICANCER COMPOUNDS
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Compounds of Formula (1), as shown below and defined herein: and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by FAK.
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Page/Page column 87-88
(2010/12/29)
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- FUSED THIAZOLE DERIVATIVES AS KINASE INHIBITORS
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A series of 5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one and 7,7-dimethyl-5,6,7,8-tetrahydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted benzofused mor
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Page/Page column 35
(2008/06/13)
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- Optimization of a series of multi-isoform PI3 kinase inhibitors
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Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.
- Perry, Benjamin,Beevers, Rebekah,Bennett, Gavin,Buckley, George,Crabbe, Tom,Gowers, Lewis,James, Lynwen,Jenkins, Kerry,Lock, Chris,Sabin, Verity,Wright, Sara
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scheme or table
p. 5299 - 5302
(2009/05/07)
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