- Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT
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Herein, we report two promising compounds 30 and 36 possessing nanomolar FLT3 inhibitory activities (IC50 = 1.5-7.2 nM), high selectivity over c-KIT (>1000-fold), and excellent anti-AML activity (MV4-11 IC50 = 0.8-3.2 nM). Furthermore, these two compounds efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-ITD, FLT3-D835V/F, FLT3-F691L, FLT3-ITD-F691L, and FLT3-ITD-D835Y. Oral administration of 30 and 36 at 6 mg/kg/d could significantly suppress tumor growth in the MV4-11 cell-inoculated xenograft model, exhibiting tumor growth inhibitory rates of 83.5% and 95.1%, respectively. Importantly, 36 could prolong the mouse survival time in the FLT3-ITD-TKD dual mutation syngeneic mouse model (BaF3-FLT3-ITD-D835Y) at a dose of 6 mg/kg p.o. bid/4W. No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 μM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.
- Tong, Lexian,Wang, Peipei,Li, Xuemei,Dong, Xiaowu,Hu, Xiaobei,Wang, Chang,Liu, Tao,Li, Jia,Zhou, Yubo
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p. 3229 - 3248
(2022/02/23)
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- ARYL SULFONAMIDES AS SMALL MOLECULE STAT3 INHIBITORS
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The present disclosure provides pharmaceutical compositions comprising aryl sulfonamide Stat3 small molecule inhibitors and certain pharmaceutically acceptable salts thereof, and methods of their use for treating cancer.
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Paragraph 00751; 00752
(2021/01/29)
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- Method of preparing Quinoline-5,8-dione derivatives for TGase 2 inhibitor
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I Is -5,8- of the quinoline, dione derivative compound. of Formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of Formula, TGase 2 has, inhibitory effects TGase 2, and thus the pharmaceutical composition may be useful for preventing or treating disorders or diseases mediated by TGase 2 or inhibiting. (by machine translation)
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Paragraph 0340-0343
(2020/04/28)
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- N2-carbamylaryl-2-aminopyrimidine derivative and medical application thereof
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The invention provides an N2-carbamylaryl-2-aminopyrimidine derivative and a medical application thereof. The N2-carbamylaryl-2-aminopyrimidine derivative provided by the invention comprises an optical isomer of the N2-carbamylaryl-2-aminopyrimidine derivative and pharmaceutically acceptable salt thereof. Pharmacodynamic research shows that the traditional Chinese medicine composition has no toxicor side effect, the compound has an FLT3 inhibitory activity. The proliferation inhibition activity is realized on various leukemia cell strains; a medium inhibition effect is achieved on breast cancer cells; moreover, the polypeptide is effective for multiple mutations of AML, such as internal tandem repeat mutation of a near-membrane structural domain and D835 point mutation of an activated ring in a kinase structural domain, almost has no inhibition effect on c-KIT, can overcome drug resistance brought by clinical point mutation, can reduce toxic and side effects of bone marrow inhibition,and can be applied to preparation of antitumor drugs. The structures of the general formulas Ia and Ib of the N2-carbamylaryl-2-aminopyrimidine derivative are shown in the specification,
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Paragraph 0135-0136; 0152-0153
(2020/10/28)
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- Quinoline-5,8-dione derivatives for TGase 2 inhibitor, and the pharmaceutical composition comprising the same
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The present invention relates to a quinolin-5,8-dione derivative compound represented by chemical formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof. The compound represented by chemical formula I of the present invention has a TGase 2 inhibitory effect, and the pharmaceutical composition comprising the same can be usefully used for preventing or treating disorders or diseases mediated by TGase 2 or response to TGase 2 inhibition.COPYRIGHT KIPO 2020
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Paragraph 0219-0222
(2019/10/29)
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- Isoindoline, azaisoindoline, dihydroindenone and dihydroazaindenone inhibitors of Mnk1 and Mnk2
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The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds A1, A2
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Page/Page column 29
(2018/11/21)
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- CARBOLINE DERIVATIVE SERVING AS BROMODOMAIN INHIBITOR
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Disclosed in the present invention is a carboline derivative serving as an bromodomain inhibitor. The carboline derivative in the present invention can be used as an bromodomain inhibitor, and can provide a method and a pharmaceutical composition for controlling diseases intervened by a bromodomain protein.
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Paragraph 0086; 0087
(2018/12/07)
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- COMPOUNDS USEFUL AS CSF1 MODULATORS
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This invention relates to novel compounds and to pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as Colony Stimulating Factor 1 Receptor (cFMS) modulators (e.g. cFMS inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds in treatment and methods of treatment employing the compounds. Specifically, the invention relates to the use of the compounds for the treatment of cancer and autoimmune diseases.
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- NRF2 REGULATORS
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The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.
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- PERFORIN INHIBITING BENZENESULFONAMIDE COMPOUNDS, PREPARATION AND USES THEREOF
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Compounds of formula (la) and pharmaceutically acceptable salts, solvates, and hydrates thereof and related methods of modulatin perforin activity on a cell: wherein Ring A is selected from a 6-10 membered aryl, 5-6 membered cycloalkyi, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl rings comprise at least one heteroatom selected from N, O or S; and wherein the aryl, cycloalkyi, heteroaryl or heterocyclyl rings are optionally substituted with 1 to 3 substituents selected from halo, nitro, -C1-Cealkyl, -C1-Ceaminoalkyl, -C1-C6hydroxyalkyl, -haloC1-C6alkyl, -C1- C6alkoxyl, -haloC1-C6alkyl, -CH2OC(O)CrC6alkyl, -C(O)OC1,-C6alkyI, -NHC(O)C1,-C6alkyl, -NHS(O)2C1- C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NH2, and -C(O)NJJ; Ring B is a 6-10 membered arylene or a 5-6 membered heteroarylene comprising at least one heteroatom selected from N, 0 or S; and wherein the aryl or heteroaryl is optionally, substituted with one or more substituents selected from -NJJ, -OJ, halo,C1 -C6alkyl, -haloC1- C6alkyl, -C1-C6alkoxy, -haloC1-C6alkoxyl, and -C(0)NJJ; Ring C is is selected from a 5-10 membered heteroarylene or a 5-10 membered heterocyclene, each comprising at least one heteroatom selected from N, S and O; Ring D is an optionally substituted benzofused 9-11 membered heterocyclyl or optionally substituted ben2ofused 9-11 membered heteroaryl comprising at least one heteroatom selected from N or O; L is a linker selected from branched and unbranched C1-C4 alkylene, -S(0)2-NH-, -C(0)-NH-, -NH-C(0)-NH-, -S(0)2-NH-C(0)-NH-, -S(0)2-NH-C(0) - and -CH=CH-; wherein Rings B and C, and Rings C and D, are connected to each other via a C-C bond at any of the available C atoms on each respective ring; and J in each occurrence is independently selected from H, optionally substituted C1-C6alkyl or optionally substituted haloC1-C6alkyl.
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- CINNOLINE DERIVATIVES AS AS BTK INHIBITORS
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Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5 are defined in the specification. The compounds are inhibitors of Bruton's tyrosine
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Paragraph 0233-0234
(2013/10/21)
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- SUBSTITUTED 1-CYANOETHYLHETEROCYCLYLCARBOXAMIDE COMPOUNDS 750
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The present invention provides compounds of formula (I), in which y, m, n, R1, R2 and Q are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 119
(2010/11/18)
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- FUSED HETEROCYCLIC DERIVATIVES AND METHODS OF USE
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Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Page/Page column 102
(2010/11/29)
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- BICYCLIC DERIVATIVES AS P38 KINASE INHIBITORS
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New bicyclic derivatives of formula (I); wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.
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Page/Page column 31
(2010/11/25)
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- A short and efficient synthesis of isoindolin-1-ones
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Here, we report a short and efficient synthesis of isoindolin-1-ones. Base-induced cyclization of o-hydroxymethyl-benzamides, which was easily prepared from the corresponding phthalides and amines, led predominantly to N-alkylation in good yield. The reaction proceeded under mild conditions and bromine and nitrile substituents were tolerated. The selectivity is explained by HASB theory. Georg Thieme Verlag Stuttgart.
- Tsuritani, Takayuki,Kii, Satoshi,Akao, Atsushi,Sato, Kimihiko,Nonoyama, Nobuaki,Mase, Toshiaki,Yasuda, Nobuyoshi
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p. 801 - 803
(2007/10/03)
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