- Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic
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Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.
- Ramurthy, Savithri,Taft, Benjamin R.,Aversa, Robert J.,Barsanti, Paul A.,Burger, Matthew T.,Lou, Yan,Nishiguchi, Gisele A.,Rico, Alice,Setti, Lina,Smith, Aaron,Subramanian, Sharadha,Tamez, Victoriano,Tanner, Huw,Wan, Lifeng,Hu, Cheng,Appleton, Brent A.,Mamo, Mulugeta,Tandeske, Laura,Tellew, John E.,Huang, Shenlin,Yue, Qin,Chaudhary, Apurva,Tian, Hung,Iyer, Raman,Hassan, A. Quamrul,Mathews Griner, Lesley A.,La Bonte, Laura R.,Cooke, Vesselina G.,Van Abbema, Anne,Merritt, Hanne,Gampa, Kalyani,Feng, Fei,Yuan, Jing,Mishina, Yuji,Wang, Yingyun,Haling, Jacob R.,Vaziri, Sepideh,Hekmat-Nejad, Mohammad,Polyakov, Valery,Zang, Richard,Sethuraman, Vijay,Amiri, Payman,Singh, Mallika,Sellers, William R.,Lees, Emma,Shao, Wenlin,Dillon, Michael P.,Stuart, Darrin D.
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p. 2013 - 2027
(2019/06/04)
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- ANTIBODY DRUG CONJUGATES (ADCS) WITH NAMPT INHIBITORS
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Conjugate of a binder having formula: (A) wherein AB stands for a binder, Z' stands for a linker and D stands for an active component of Formula (I): and its use as pharmaceuticals.
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Page/Page column 231; 232
(2019/08/26)
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- Histone deacetylase inhibitor taking pyridazinone as mother nucleus structure, and preparation method and applications thereof
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The invention discloses a histone deacetylase inhibitor taking pyridazinone as a mother nucleus structure, and a preparation method and applications thereof. The structure of the inhibitor is shown asa formula I; and the compound shown as the formula I has good histone deacetylase inhibitory activity and anti-tumor cell proliferation effects, and can be used for treating cancers. The structure ofthe inhibitor is shown as the formula I.
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Paragraph 0250-0253
(2019/02/10)
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- N-PHENYL-2-(3-PHENYL-6-OXO-1,6-DIHYDROPYRIDAZIN-1-YL)ACETAMIDE DERIVATIVES FOR TREATING CYSTIC FIBROSIS
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The present disclosure is directed to compounds that modulate, e.g., address underlying defects in cellular processing of CFTR (cystic fibrosis transmembrane conductance regulator) activity.
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Paragraph 0140
(2018/05/24)
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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 00561; 00562; 00563; 00564
(2017/05/10)
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- BIARYL AMIDE COMPOUNDS AS KINASE INHIBITORS
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The present invention provides compounds of Formula (I) as described herein, and salts thereof, and therapeutic uses of these compounds for treatment of disorders associated with Raf kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.
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Paragraph 0215; 0217
(2014/09/29)
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- Isoxazolines as Therapeutic Agents
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The present invention provides compound of Formula (I) biologically active metabolites, pro-drugs, isomers, stereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof wherein the variables are defined herein. The compounds of the invention are useful for treating immunological conditions.
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Paragraph 0887-0888
(2013/03/26)
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- PYRIDAZINONES AND THEIR USE AS BTK INHIBITORS
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Compounds of Formula (I) that inhibit Btk are described herein. Pharmaceutical compositions comprising at least one compound of Formula (I), together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, ar
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Page/Page column 208-209
(2010/06/15)
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- Inhibitors of Bruton's Tyrosine Kinase
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This application discloses 5-phenyl-1H-pyridin-2-one, 6-phenyl-2H-pyridazin-3-one, and 5-Phenyl-1H-pyrazin-2-one derivatives according to generic Formulae I-III: wherein, variables Q, R, X, X′, Y1, Y2, Y2′, Y3, Y4, Y5, m, and n are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formulae I-III and at least one carrier, diluent or excipient.
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Page/Page column 93
(2010/09/07)
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- NOVEL PYRIDINONES AND PYRIDAZINONES
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This application discloses 5-phenyl-1H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one deriva-tives according to generic Formulae I-III : wherein, variables R, X, Y1, Y2, Y3, Y4, n and m are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat in-flammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formulae I-III and at least one carrier, diluent or excipient.
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Page/Page column 68
(2009/10/09)
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- Studies on improved synthesis of 2′-deoxyribonucleosides of pyridazine derivatives
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A number of 2′-deoxyribonucleosides of halogenated pyridazine derivatives were prepared by glycosylation of their respective potassium or DBU salts in acetone. The reaction yielded predominatly β-anomers that could be purified by simple crystallization or column chromatography. Of the studied pyridazines and deoxynucleosides, only 4-bromo-6-chloro-pyridazin-3-one and 6-chloro-2-(2′-deoxyribofuranosyl)pyridazin-3-one showed modest inhibition of CK2 kinase.
- Kazimierczuk, Zygmunt,Kaminski, Jaroslaw,Meggio, Flavio
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p. 889 - 898
(2008/02/03)
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