- QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITOR, COMPOSITIONS, METHODS OF MAKING THEM AND THEIR USE
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The present disclosure relates to new compounds or pharmaceutically acceptable salts or stereoisomers thereof of formula I as inhibitors of receptor tyrosine kinases (RTK), in particular extracellular mutants of ErbB-receptors. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the treatment of cancer in mammals (e.g. humans).
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Page/Page column 515
(2020/05/13)
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- Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12CInhibitor for the Treatment of Cancer
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Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.
- Fell, Jay B.,Fischer, John P.,Baer, Brian R.,Blake, James F.,Bouhana, Karyn,Briere, David M.,Brown, Karin D.,Burgess, Laurence E.,Burns, Aaron C.,Burkard, Michael R.,Chiang, Harrah,Chicarelli, Mark J.,Cook, Adam W.,Gaudino, John J.,Hallin, Jill,Hanson, Lauren,Hartley, Dylan P.,Hicken, Erik J.,Hingorani, Gary P.,Hinklin, Ronald J.,Mejia, Macedonio J.,Olson, Peter,Otten, Jennifer N.,Rhodes, Susan P.,Rodriguez, Martha E.,Savechenkov, Pavel,Smith, Darin J.,Sudhakar, Niranjan,Sullivan, Francis X.,Tang, Tony P.,Vigers, Guy P.,Wollenberg, Lance,Christensen, James G.,Marx, Matthew A.
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supporting information
p. 6679 - 6693
(2020/04/20)
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- Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use therefor for effectively treating and/or preventing FGFR-related diseases such as tumors
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The present invention relates to an alkynyl-substituted heterocyclic compound serving as an FGFR inhibitor, a preparation method therefor and a medical use therefor. In particular, the present invention relates to a compound represented by the general formula (I) and its pharmaceutically acceptable salt, a pharmaceutical composition including the compound or its pharmaceutically acceptable salt, a method for treating and/or preventing FGFR-related diseases, particularly tumors, by using the compound or its pharmaceutically acceptable salt, and a preparation method of the compound or its pharmaceutically acceptable salt. The present invention also relates to an use of the compound or its pharmaceutically acceptable salt, or an pharmaceutical composition including the compound or its pharmaceutically acceptable salt in the preparation of a drug for treating and/or preventing FGFR-related diseases, particularly tumors, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.
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Page/Page column 50-52
(2020/02/18)
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- ALKYNYL-SUBSTITUTED HETEROCYCLIC COMPOUND, PREPARATION METHOD THEREFOR AND MEDICAL USE THEREOF
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The present invention relates to an alkynyl-substituted heterocyclic compound acting as an FGFR inhibitor, a preparation method therefor and a medical use thereof. In particular, the present invention relates to a compound as shown in general formula (I) and a pharmaceutically acceptable salt thereof; a pharmaceutical composition including the compound or a pharmaceutically acceptable salt thereof; a method for treating and/or preventing FGFR-associated diseases, particularly tumors, by using the compound or a pharmaceutically acceptable salt thereof; and a preparation method for the compound or a pharmaceutically acceptable salt thereof. The present invention also relates to the use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition including the compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and/or preventing FGFR-associated diseases, particularly tumors, wherein the definition of each substituent group in general formula (I) is the same as that in the description.
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Paragraph 0184; 0185
(2019/07/23)
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- Syn-effect' in the diastereoselective alkylation of 3-[(E)-α,β-unsaturated-γ-substituted]-N-acyloxazolidinones
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Synthetic methods for the formation of alkenes usually produce the E-alkene because it is more stable. However, in isomerization reaction (double bond migration) that takes place in α, β-unsaturated carbonyl compounds, when these carbonyl compounds are exposed to strong bases, furnish Z-alkenes highly stereoselective depending on the γ-substituent in the α, β-unsaturated carbonyl. This stereoselectivity can be attributed to the known Syn-effect. The synthetic value of this methodology is the achievement of chiral alcohol bearing an electron rich Z-alkene, as well as substituted, which was accomplished via removal of the oxazolidinone moiety under treatment with NaBH4, THF-H2O.
- Jiménez, Jacqueline,Ramírez, Juáncarlos,Huelgas, Gabriela,Meléndrez, Ruth,Cabrera-Vivas, Blanca M.,Sansinenea, Estibaliz,Ortiz, Aurelio
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p. 4590 - 4597
(2015/06/08)
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- 4 - IMIDAZOPYRIDAZIN- 1 -YL-BENZAMIDES AND 4 - IMIDAZOTRIAZIN- 1 - YL - BENZAMIDES AS BTK- INHIBITORS
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The present invention relates to 6-5 membered fused pyridine ring compounds according to formula (I) or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of 6-5 membered fused pyridine ring compounds according to formula I in the treatment of Brutons Tyrosine Kinase (Btk) mediated disorders.
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Page/Page column 34
(2013/03/26)
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- 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES AND 4-IMIDAZOTRIAZIN-1-YL-BENZAMIDES BTK-INHIBITORS
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The present invention relates to 6-5 membered fused pyridine ring compounds of formula (I) or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of 6-5 membered fused pyridine ring compounds in the treatment of Bruton's Tyrosine Kinase (Btk) mediated disorders.
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Page/Page column 35
(2013/03/26)
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- Substituted quinazoline derivatives
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This invention provides compounds of formula 1 having the structure wherein: X, R1, R2, R3, R4, Z, X, and n are as defined hereinbefore in the specification, which are useful as antineoplastic agents and in the treatment of certain kidney diseases, such as polycystic kidney disease.
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