- Early Process Development of an Irreversible Epidermal Growth Factor Receptor (EGFR) T790 M Inhibitor
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The original synthesis of the irreversible epidermal growth factor receptor (EGFR) T790 M inhibitor 1 was enabled by successful application of ammonium hydroxide to cleanly cleave the N-hydroxymethyl group and by development of high yielding conditions fo
- Tao, Yong,Keene, Nandell F.,Wiglesworth, Kristin E.,Sitter, Barbara,McWilliams, J. Christopher
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- Design and Synthesis of Pyrrolo[2,3-d]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate
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Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson’s disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18 /CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of 18 gave the 2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino] derivative 32 . Optimization of 32 afforded diastereomeric oxolan-3-yl derivatives 44 and 45 , which demonstrated a favorablein vitroPK profile, although they displayed species disconnects in thein vivoPK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.
- Williamson, Douglas S.,Smith, Garrick P.,Mikkelsen, Gitte K.,Jensen, Thomas,Acheson-Dossang, Pamela,Badolo, Lassina,Bedford, Simon T.,Chell, Victoria,Chen, I-Jen,Dokurno, Pawel,Hentzer, Morten,Newland, Samantha,Ray, Stuart C.,Shaw, Terry,Surgenor, Allan E.,Terry, Lindsey,Wang, Yikang,Christensen, Kenneth V.
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- Synthesis and evaluation of FAK inhibitors with a 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine scaffold as anti-hepatocellular carcinoma agents
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Focal adhesion kinase (FAK) is a ubiquitous intracellular non-receptor tyrosine kinase, which is involved in multiple cellular functions, including cell adhesion, migration, invasion, survival, and angiogenesis. In this study, a series of 7H-pyrrolo[2,3-d
- Gong, Chaochao,Huang, Jian,Liu, Yue,Tan, Hanyi,Zhang, Jiawei,Zhang, Qian
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- HETEROARYL DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING SAME AS ACTIVE INGREDIENT
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The present invention relates to a heteroaryl derivative and a pharmaceutical composition for the prevention or treatment of cancer comprising the same as an active ingredient, and a compound according to an aspect of the present invention, a stereoisomer
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Paragraph 0088; 0089
(2021/12/07)
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- PYRROLO-PYRIMIDINE DERIVATIVE COMPOUND, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME COMPOUND AS EFFECTIVE INGREDIENT FOR PREVENTING OR TREATING PROTEIN KINASE-RELATED DISEASE
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The present invention relates to a novel pyrrolo-pyrimidine derivative compound, a preparation method therefor, and a pharmaceutical composition comprising the same compound as an effective ingredient for preventing or treating a protein kinase-related di
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Paragraph 0119; 0120; 0129; 0137; 0145
(2020/08/19)
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- AROMATIC COMPOUNDS FOR USE IN ACTIVATING HEMATOPOIETIC STEM AND PROGENITOR CELLS
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Disclosed herein are new aromatic compounds, compositions that include one or more aromatic compounds, and methods of synthesizing the same. Also disclosed herein are methods of increasing and/or expanding cells, including stem cells, hematopoietic stem cells, progenitor cells, and placenta or cord blood-derived cells, with one or more compounds or compositions described herein. Also disclosed herein are methods of increasing and/or expanding differentiated hematopoietic cells with one or more compounds or compositions described herein.
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Paragraph 0260
(2020/06/19)
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- SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYL TRANSFERASE 5 (PRMT5)
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The disclosure is directed to compounds of Formula I, Formula II, and Formula III [Formulas should be inserted here]. Methods of their use and preparation are also described.
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Paragraph 0443
(2018/05/24)
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- NOVEL HYDRAZIDE CONTAINING COMPOUNDS AS BTK INHIBITORS
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The present invention relates to novel hydrazide containing compounds as Bruton tyrosine kinase inhibitors, process of preparation thereof, and to the use of the compounds in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders involving mediation of Bruton tyrosine kinase in humans.
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Page/Page column 42
(2018/02/03)
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- COMPOUND, COMPOSITIONS, AND METHODS
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Compounds having activity as LRRK2 inhibitors are disclosed. The compounds are of formula (I) including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
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Page/Page column 193
(2017/08/01)
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- NOVEL HYDRAZINO COMPOUNDS AS BTK INHIBITORS
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The present invention relates to novel hydrazino compounds of Formula (I) as Bruton tyrosine kinase inhibitors, process of preparation thereof, and to the use of the compounds in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders involving mediation of Bruton tyrosine kinase in humans.
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Page/Page column 37
(2017/12/27)
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- SUBSTITUTED PYRROLOPYRIMIDINE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are Pyrrolopyrimidine Compounds having the following structure: wherein R1, R2, R3, and L are as defined herein, compositions comprising an effective amount of a Pyrrolopyrimidine Compound, and methods for treating or preventing breast cancer, more particularly triple negative breast cancer, comprising administering an effective amount of such Pyrrolopyrimidine Compounds to a subject in need thereof.
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Paragraph 0221
(2014/07/23)
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- PROTEIN KINASE INHIBITORS
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Compounds, particularly compounds having spleen tyrosine kinase (Syk) inhibition activity, having the following structure: or a pharmaceutically acceptable salt thereof, wherein R1 is structure (a), (b), (c) or (d): and Ra, Rb, Rc, R2, R3, R4, R5, R6 and R7 are as defined herein. Methods associated with preparation and use of the same, as well as pharmaceutical compositions containing the same, are also disclosed, as well as uses of the same to treat a condition or disorder mediated by a Syk and/or JAK kinase.
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Page/Page column 30-31
(2009/04/24)
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- INHIBITORS OF PROTEIN KINASES
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The present invention is directed to compounds of formula (I)-(II) and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of syk and/or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and/or JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by syk and/or JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.
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Page/Page column 98
(2009/12/05)
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- 7-Halogenated 7-deazapurine 2′-deoxyribonucleosides related to 2′-deoxyadenosine, 2′-deoxyxanthosine, and 2′- deoxyisoguanosine: Syntheses and properties
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A series of 7-fluorinated 7-deazapurine 2′-deoxyribonucleosides related to 2′-deoxyadenosine, 2′-deoxyxanthosine, and 2′-deoxyisoguanosine as well as intermediates 4b - 7b, 8, 9b, 10b, and 17b were synthesized. The 7-fluoro substituent was introduced in 2,6-dichloro-7-deaza-9H-purine (11a) with Selectfluor (Scheme 1). Apart from 2,6-dichloro-7-fluoro-7-deaza-9H-purine (11b), the 7-chloro compound 11c was formed as by-product. The mixture 11b/11c was used for the glycosylation reaction; the separation of the 7-fluoro from the 7-chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N-halogenosuccinimides (11a→11c - 11e). Nucleobase-anion glycosylation afforded the nucleoside intermediates 13a - 13e (Scheme 2). The 7-fluoro- and the 7-chloro-7-deaza-2′-deoxyxanthosines, 5b and 5c, respectively, were obtained from the corresponding MeO compounds 17b and 17c, or 18 (Scheme 6). The 2′-deoxyisoguanosine derivative 4b was prepared from 2-chloro-7-fluoro-7-deaza-2′-deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pKa values of the halogenated nucleosides were determined (Table 3). 13C-NMR Chemical-shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7-halogen substituents (Fig. 3). In aqueous solution, 7-halogenated 2′-deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).
- Seela, Frank,Xu, Kuiying
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experimental part
p. 1083 - 1105
(2009/02/07)
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- NOVEL TRICYCLIC NUCLEOSIDES OR NUCLEOTIDES AS THERAPEUTIC AGENTS
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Nucelosides and nucleotides containing a tricyclic base portion thereof are useful for treating infectious diseases and proliferative disorders, such as viral infections or cancer respectively.
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(2010/02/11)
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