761446-44-0 | Page 8 of 10 | pyrazoles-derivatives

Himmelbauer, Martin K. team published research on Journal of Medicinal Chemistry in 2019 | 761446-44-0

761446-44-0, 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is a useful research compound. Its molecular formula is C10H17BN2O2 and its molecular weight is 208.07 g/mol. The purity is usually 95%., Formula: C10H17BN2O2

Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. 761446-44-0, formula is C10H17BN2O2, Name is 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Pyrazoles are a class of compounds that have the ring C3N2 with adjacent nitrogen atoms.Notable drugs containing a pyrazole ring are celecoxib (celebrex) and the anabolic steroid stanozolol. Formula: C10H17BN2O2.

Himmelbauer, Martin K.;Xin, Zhili;Jones, J. Howard;Enyedy, Istvan;King, Kristopher;Marcotte, Douglas J.;Murugan, Paramasivam;Santoro, Joseph C.;Hesson, Thomas;Spilker, Kerri;Johnson, Joshua L.;Luzzio, Michael J.;Gilfillan, Rab;de Turiso, Felix Gonzalez-Lopez research published 《 Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors》, the research content is summarized as follows. Structural anal. of a known ASK1 inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor I (cell IC₅₀ = 1.2μM). The profile of this compound was optimized for CNS penetration following two independent strategies: a rational design approach leading to II and a parallel synthesis approach leading to III. Both analogs are potent ASK1 inhibitors in biochem. and cellular assays (II, cell IC₅₀ = 95 nM; III, cell IC₅₀ = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK assay (II, ER = 5.2; III, ER = 1.5). In vivo PK studies revealed that inhibitor II had moderate CNS penetration (K_p,uu = 0.17) and analog III had high CNS penetration (K_p,uu = 1.0).

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Havel, Stepan team published research on Journal of Organic Chemistry in 2018 | 761446-44-0

Pyrazoles are synthesized by the reaction of α,β-unsaturated aldehydes with hydrazine and subsequent dehydrogenation. 761446-44-0, formula is C10H17BN2O2, Name is 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Substituted pyrazoles are prepared by condensation of 1,3-diketones with hydrazine (Knorr-type reactions). For example, acetylacetone and hydrazine gives 3,5-dimethylpyrazole. Name: 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

Havel, Stepan;Khirsariya, Prashant;Akavaram, Naresh;Paruch, Kamil;Carbain, Benoit research published 《 Preparation of 3,4-Substituted-5-Aminopyrazoles and 4-Substituted-2-Aminothiazoles》, the research content is summarized as follows. 3,4-Substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles are frequently used intermediates in medicinal chem. and drug discovery projects. We report an expedient flexible synthesis of 3,4-substituted-5-aminopyrazoles (35 examples), based on palladium-mediated α-arylation of β-ketonitriles with aryl bromides. A library of 4-substituted-2-aminothiazoles (21 examples) was assembled by a sequence employing Suzuki coupling of newly prepared, properly protected pinacol ester and MIDA ester of 4-boronic acid-2-aminothiazole with (hetero)aryl halides.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Han, Sang Hoon team published research on Journal of Medicinal Chemistry in 2022 | 761446-44-0

Synthetic Route of 761446-44-0, 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is a useful research compound. Its molecular formula is C10H17BN2O2 and its molecular weight is 208.07 g/mol. The purity is usually 95%., 761446-44-0.

Han, Sang Hoon;Goins, Christopher M.;Arya, Tarun;Shin, Woo-Jin;Maw, Joshua;Hooper, Alice;Sonawane, Dhiraj P.;Porter, Matthew R.;Bannister, Breyanne E.;Crouch, Rachel D.;Lindsey, A. Abigail;Lakatos, Gabriella;Martinez, Steven R.;Alvarado, Joseph;Akers, Wendell S.;Wang, Nancy S.;Jung, Jae U.;Macdonald, Jonathan D.;Stauffer, Shaun R. research published 《 Structure-based optimization of ML300-derived, noncovalent inhibitors targeting the severe acute respiratory syndrome coronavirus 3CL protease (SARS-CoV-2 3CL^pro)》, the research content is summarized as follows. Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL^pro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CL^pro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chem. toward probe compound 41 (I)(CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CL^pro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. I demonstrates nanomolar activity in these resp. assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Gulati, Anmol team published research on RSC Medicinal Chemistry in 2021 | 761446-44-0

Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. 761446-44-0, formula is C10H17BN2O2, Name is 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Pyrazole is a weak base, with pKb 11.5 (pKa of the conjugated acid 2.49 at 25 °C).Pyrazole used as a ligand to prepare organometallic compounds. COA of Formula: C10H17BN2O2.

Gulati, Anmol;Yeung, Charles S.;Lapointe, Blair;Kattar, Solomon D.;Gunaydin, Hakan;Scott, Jack D.;Childers, Kaleen K.;Methot, Joey L.;Simov, Vladimir;Kurukulasuriya, Ravi;Pio, Barbara;Morriello, Greg J.;Liu, Ping;Tang, Haiqun;Neelamkavil, Santhosh;Wood, Harold B.;Rada, Vanessa L.;Ardolino, Michael J.;Yan, Xin Cindy;Palte, Rachel;Otte, Karin;Faltus, Robert;Woodhouse, Janice;Hegde, Laxminarayan G.;Ciaccio, Paul;Minnihan, Ellen C.;DiMauro, Erin F.;Fell, Matthew J.;Fuller, Peter H.;Ellis, J. Michael research published 《 Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors》, the research content is summarized as follows. The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson′s disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine 15 and 4,6-diaminopyrimidine 16 as low risk for mutagenicity (defined by a 3-strain Ames neg. result). Anal. of key matched mol. pairs 17 and 18 led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of Et trifluoromethyl pyrazole 23 with excellent LRRK2 potency and expanded selectivity vs. off-target CLK2.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Ghosh, Prithwish team published research on Cell Reports Physical Science in 2022 | 761446-44-0

Name: 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is a useful research compound. Its molecular formula is C10H17BN2O2 and its molecular weight is 208.07 g/mol. The purity is usually 95%., 761446-44-0.

Pyrazoles and pyrimidines have diverse biological and pharmacological activities. 761446-44-0, formula is C10H17BN2O2, Name is 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. There are a number of antimicrobial compounds containing pyrazole moiety as the core unit. Name: 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

Ghosh, Prithwish;Byun, Youjung;Kwon, Na Yeon;Kang, Ju Young;Mishra, Neeraj Kumar;Park, Jung Su;Kim, In Su research published 《 Reactivity of triplet diradical intermediates in aqueous media for transition-metal-free Csp²-H alkylation》, the research content is summarized as follows. Herein, a distinct reaction pathway involving triplet diradical intermediates in the coupling reaction between alkyl pyridinium ylides and electrophilic N-heterocyclic mols. was reported. Alkyl pyridinium ylides generated from alkyl pyridinium salts under basic aqueous conditions underwent addition into iminoamido N-heterocycles, generating triplet diradical intermediates lead to C-H alkylated N-heterocycles I [R = Me, Bn, 2-pyridyl, etc.; R¹ = Br, Ph, 2-thienyl, etc.; R² = Bn, CH₂-2-FC₆H₄, CH₂-2-naphthyl, etc.], II [R³ = Me, allyl, iPr, etc.; R⁴ = H, Cl; R⁵ = Bn, CH₂-4-MeOC₆H₄, CH₂-2-furyl, etc.; X = CH, N] and III [R⁶ = Me, 3-MeC₆H₄; R⁷ = Ph, Bn, 4-EtOC₆H₄, etc.]. The proposed reaction mechanism was supported by ESR and radical scavenging experiments Notably, a wide substrate scope and excellent level of functional group tolerance were attained under cost-effective and straightforward conditions, which revealed the amenability of this protocol in the pharmaceutical and chem. industries. These results were of significant relevance to the organic and medicinal chemists because of the handling simplicity, broad substrate scope, high efficiency, excellent chemoselectivity and the environmentally friendly conditions of the developed methodol.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Gerstenberger, Brian S. team published research on Journal of Medicinal Chemistry in 2020 | 761446-44-0

Application In Synthesis of 761446-44-0, 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is a useful research compound. Its molecular formula is C10H17BN2O2 and its molecular weight is 208.07 g/mol. The purity is usually 95%., 761446-44-0.

Pyrazoles can be selectively lithiated at different carbons and subsequently react with electrophiles depending on the substitution patterns. 761446-44-0, formula is C10H17BN2O2, Name is 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1-Methyl-5-(trifluoromethyl)pyrazole underwent deprotonation and subsequent carboxylation mainly or exclusively at either the 4-position of the heterocycle or at the nitrogen-attached methyl group. Application In Synthesis of 761446-44-0.

Gerstenberger, Brian S.;Ambler, Catherine;Arnold, Eric P.;Banker, Mary-Ellen;Brown, Matthew F.;Clark, James D.;Dermenci, Alpay;Dowty, Martin E.;Fensome, Andrew;Fish, Susan;Hayward, Matthew M.;Hegen, Martin;Hollingshead, Brett D.;Knafels, John D.;Lin, David W.;Lin, Tsung H.;Owen, Dafydd R.;Saiah, Eddine;Sharma, Raman;Vajdos, Felix F.;Xing, Li;Yang, Xiaojing;Yang, Xin;Wright, Stephen W. research published 《 Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases》, the research content is summarized as follows. Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, resp. On the basis of human genetic and emerging clin. data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clin. profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clin. candidate PF-06826647 (22).

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Finlay, M. Raymond V. team published research on Journal of Medicinal Chemistry in 2021 | 761446-44-0

Finlay, M. Raymond V.;Barton, Peter;Bickerton, Sue;Bista, Michal;Colclough, Nicola;Cross, Darren A. E.;Evans, Laura;Floc′h, Nicolas;Gregson, Clare;Guerot, Carine M.;Hargreaves, David;Kang, Xiaoming;Lenz, Eva M.;Li, Xu;Liu, Yi;Lorthioir, Olivier;Martin, Matthew J.;McKerrecher, Darren;McWhirter, Claire;O′Neill, Daniel;Orme, Jonathan P.;Mosallanejad, Arash;Rahi, Amar;Smith, Paul D.;Talbot, Verity;Ward, Richard A.;Wrigley, Gail;Wylot, Marta;Xue, Lin;Yao, Tieguang;Ye, Yang;Zhao, Xiliang research published 《 Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance》, the research content is summarized as follows. The epidermal growth factor receptor (EGFR) harboring activating mutations is a clin. validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clin. use. Resistance to these therapies has emerged due to a variety of mol. events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chem. optimization of a biochem. potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochem. properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clin. relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Dow, Nathan W. team published research on Journal of the American Chemical Society in 2022 | 761446-44-0

Dow, Nathan W.;Pedersen, P. Scott;Chen, Tiffany Q.;Blakemore, David C.;Dechert-Schmitt, Anne-Marie;Knauber, Thomas;MacMillan, David W. C. research published 《 Decarboxylative Borylation and Cross-Coupling of (Hetero)aryl Acids Enabled by Copper Charge Transfer Catalysis》, the research content is summarized as follows. Authors report a copper-catalyzed strategy for arylboronic ester synthesis that exploits photoinduced ligand-to-metal charge transfer (LMCT) to convert (hetero)aryl acids into aryl radicals amenable to ambient-temperature borylation. This near-UV process occurs under mild conditions, requires no prefunctionalization of the native acid, and operates broadly across diverse aryl, heteroaryl, and pharmaceutical substrates. They also report a one-pot procedure for decarboxylative cross-coupling that merges catalytic LMCT borylation and palladium-catalyzed Suzuki-Miyaura arylation, vinylation, or alkylation with organo bromides to access a range of value-added products. The utility of these protocols is highlighted through the development of a heteroselective double-decarboxylative C(sp²)-C(sp²) coupling sequence, pairing copper-catalyzed LMCT borylation and halogenation processes of two distinct acids (including pharmaceutical substrates) with subsequent Suzuki-Miyaura cross-coupling.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Drew, Samuel L. team published research on Journal of Medicinal Chemistry in 2020 | 761446-44-0

Drew, Samuel L.;Thomas-Tran, Rhiannon;Beatty, Joel W.;Fournier, Jeremy;Lawson, Kenneth V.;Miles, Dillon H.;Mata, Guillaume;Sharif, Ehesan U.;Yan, Xuelei;Mailyan, Artur K.;Ginn, Elaine;Chen, Jie;Wong, Kent;Soni, Divyank;Dhanota, Puja;Chen, Pei-Yu;Shaqfeh, Stefan G.;Meleza, Cesar;Pham, Amber T.;Chen, Ada;Zhao, Xiaoning;Banuelos, Jesus;Jin, Lixia;Schindler, Ulrike;Walters, Matthew J.;Young, Stephen W.;Walker, Nigel P.;Leleti, Manmohan Reddy;Powers, Jay P.;Jeffrey, Jenna L. research published 《 Discovery of Potent and Selective PI3Kγ Inhibitors》, the research content is summarized as follows. The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homol. across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the “selectivity” and “alkyl-induced” pockets within the ATP (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4(I), IC₅₀ = 0.064 μM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clin. development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an “alkyl-induced” pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics

Erra, Montse team published research on Journal of Medicinal Chemistry in 2018 | 761446-44-0

Erra, Montse;Taltavull, Joan;Bernal, Francisco Javier;Caturla, Juan Francisco;Carrascal, Marta;Pages, Lluis;Mir, Marta;Espinosa, Sonia;Gracia, Jordi;Dominguez, Maria;Sabate, Mar;Paris, Stephane;Maldonado, Monica;Hernandez, Begona;Bravo, Monica;Calama, Elena;Miralpeix, Montserrat;Lehner, Martin D.;Calbet, Marta research published 《 Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases》, the research content is summarized as follows. Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochem. properties that could translate into better lung retention. This medicinal chem. exercise led to the identification of LAS195319 as a candidate for clin. development.

Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics