Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase

Cee, Victor J.; Cheng, Alan C.; Romero, Karina; Bellon, S.F.; Mohr, Christopher; Whittington, Douglas A.; Bak, Annette; Bready, James; Caenepeel, Sean; Coxon, Angela; Deak, Holly L.; Fretland, Jenne; Gu, Yun; Hodous, Brian L.; Huang, Xin; Kim, Joseph L.; Lin, Jasmine; Long, Alexander; Nguyen, Hanh Nho; Olivieri, Philip R.; Patel, Vinod F.; Wang, Ling; Zhou, Yihong; Hughes, Paul E.; Geuns‐Meyer, Stephanie

doi:10.1016/j.bmcl.2008.11.056

Cited by 54 publications

(48 citation statements)

References 17 publications

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“…In the case of 2-naphthylboronic acid the yield is 87% (2s) whereas benzo[d] [1,3]dioxol-5-ylboronic acid resulted in 2q in 85% yield and (2,3-dihydrobenzo [b] [1,4]dioxin-6-yl) boronic acid afforded 2r in 80% yield. To enhance the substrate scope, the reaction was tested with substituted 2-aminobenzimidazoles.…”

Section: Resultsmentioning

confidence: 93%

“…However, most of these kinds of chemo/regioselective C À N bond formation protocols are realized by metal-catalyzed coupling reactions, which mainly includes BuchwaldHartwig and Ullmann-type reactions promoted by palladium, and/or copper, as catalyst. [2] N-Arylated 2-aminobenzimidazoles, particularly the C-2 À NH 2 arylated 2-aminobenzimidazoles, are a privileged heterocyclic class found in a variety of medicinally important compounds such as Tie-2 kinase inhibitors, [3] aurora kinase inhibitors, [4] and integrin a 4 b 1 antagonists [5] (Figure 1). Thus, the selective N-arylation of these amino-N-heterocycles without protecting one nucleophilic site (e.g., 2-aminobenzimidazole, 3-aminopyrazole, 3-aminoindazole, 5-aminoindazole, 9H-purine-6-amine, 1H-pyrazolo [3,4-d]pyrimidin-4-amine) is synthetically important as it provides direct access to a diverse array of potentially bioactive Narylated derivatives.…”

Section: Introductionmentioning

confidence: 99%

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Copper‐Catalyzed CNH₂ Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

et al. 2016

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A copper(II)-catalyzed selective C À NH 2 arylation of 2-aminobenzimidazoles and related Camino-NH-azoles was achieved in presence of 2,2'-bipyridine and cesium carbonate at 60 8C under open air conditions and this is first method for the coppercatalyzed selective C À NH 2 arylation in the presence of other reactive nucleophilic sites. Previously unexplored heteroaromatics possessing multiple nucleophilic sites that are selectively arylated at the C À NH 2 position are obtained, providing an exceptional tool for rapid delivery of a diverse array of medicinally important C À NH(aryl) derivatives of aminoazoles without any protection/deprotection of ring N À H bonds. It is first example for the selective C À NH 2 arylation of 5-aminoindazole, 4-aminopyrazole, 5-aminopyrazole, 9H-purine-6-amine, and 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives.

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Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Copper‐Catalyzed CNH₂ Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

et al. 2016

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“…16 All heteroatoms were removed, and the missing residues 858-860, 1052-1055, and 1062-1066 were modeled using Modeller9.1.…”

Section: Methodsmentioning

confidence: 99%

A ZebrafishIn VivoPhenotypic Assay to Identify 3-Aminothiophene-2-Carboxylic Acid-Based Angiogenesis Inhibitors

Papakyriakou

Kefalos

Sarantis

et al. 2014

ASSAY and Drug Development Technologies

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Small molecules that inhibit angiogenesis are attractive drug candidates for cancer, retinopathies, and age-related macular degeneration. In vivo, phenotypic screening in zebrafish (Danio rerio) emerges as a powerful methodology to identify and optimize novel compounds with pharmacological activity. Zebrafish provides several advantages for in vivo phenotypic screens especially for angiogenesis, since it develops rapidly, externally, and does not rely on a functional cardiovascular system to survive for several days during development. In this study, we utilize a transgenic line that allows the noninvasive monitoring of angiogenesis at a cellular level. The inhibition of angiogenesis can be observed under a fluorescent stereoscope and quantified. To exemplify the versatility and robustness of the zebrafish screen, we have employed a series of 60 novel compounds that were designed based on a potent VEGFR2 inhibitor. Herein, we report their structure-based design, synthesis, and in vivo zebrafish screening for optimal activity, toxicity, and off-target effects, which revealed six reversible inhibitors of angiogenesis.

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“…[2d] During our work on the N-arylation of nitrogen-containing heterocycles, [3] we became interested in the use of 2-aminobenzimidazoles as potential substrates for chemoselective Narylation reactions. Both N 1 -aryl-2-aminobenzimidazoles and 2-arylaminobenzimidazoles are found in a variety of medicinally important compounds including integrin α 4 β 1 antagonists, [4] mTOR inhibitors, [5] aurora kinase inhibitors, [6] Tie-2 kinase inhibitors, [7] Ca channel blockers, [8] and CXCR2 antagonists. [9 Thus, the selective syntheses of both of these isomers from a common core structure represent attractive alternatives to other previouslyemployed routes [10][11] and could provide rapid access to a diverse array of potentially bioactive 2-aminobenzimidazole derivatives (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

“…Turning our attention to finding conditions for the selective formation of the the N 1 -arylated product (2a), we found that reactions with a Cu-catalyst system (iodobenzene/ bromobenzene, CuI, L5, [17] and Cs 2 CO 3 ) were completely chemoselective, providing no trace either of regioisomer 1a or of any poly-arylated products (entries [7][8]. The use of other ligands (L6-L8) and bases did not alter this chemoselectivity, but rather gave lower yields of 1b (entries 9-13).…”

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confidence: 99%

Catalyst‐Controlled Chemoselective Arylation of 2‐Aminobenzimidazoles

Ueda

Buchwald

2012

Angewandte Chemie

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The chemoselective and complementary Pd-and Cu-catalyzed N-arylation of 2-aminobenzimidazoles is described. Selective N-arylation of the amino-group was achieved with a Pd-catalyzed method, while selective N-arylation of azole nitrogen was achieved with a Cucatalyzed procedure. The utility of these complementary sets of conditions is demonstrated in several two-step, selective syntheses of di-arylated aminoazoles. Keywordspalladium; copper; C-N coupling; aminoazole; N-arylation Transition-metal catalyzed heteroatom-arylation reactions are emerging as valuable tools in organic synthesis, fuelled by the identification of more efficient catalyst systems with increased substrate scopes. [1] The synthetic utility of these transformations is increased if catalysts are both highly reactive and selective. This is particularly important for substrates with multiple heteroatom sites capable of undergoing reaction. Furthermore, the development of complementary sets of catalysts or conditions for the selective arylation of substrates possessing multiple nucleophilic sites enables the rapid, protecting group-free generation of molecular complexity with minimal synthetic manipulations. In this context, we have developed sets of procedures for the Pd-and Cu-catalyzed chemoselective arylation of aminobenzamides, [2a] 5-aminoindole, [2a] 4-(2-aminoethyl)aniline, [2a] amino alcohols, [2b] oxindoles [2c] and aminophenols. [2d] During our work on the N-arylation of nitrogen-containing heterocycles, [3] we became interested in the use of 2-aminobenzimidazoles as potential substrates for chemoselective Narylation reactions. Both N 1 -aryl-2-aminobenzimidazoles and 2-arylaminobenzimidazoles are found in a variety of medicinally important compounds including integrin α 4 β 1 antagonists, [4] mTOR inhibitors, [5] aurora kinase inhibitors, [6] Tie-2 kinase inhibitors, [7] Ca channel blockers, [8] and CXCR2 antagonists. [9 Thus, the selective syntheses of both of these isomers from a common core structure represent attractive alternatives to other previouslyemployed routes [10][11] and could provide rapid access to a diverse array of potentially bioactive 2-aminobenzimidazole derivatives (Scheme 1).While the efficient Cu- [12] and Pd-catalyzed [13] N 1 -arylations of some benzimidazole derivatives with aryl halides have been described, the chemoselective N-arylation of unprotected 2-aminobenzimidazoles with aryl halides has received little attention. [14][15][16] Potential challenges of such an approach include the formation of regioisomers and/or polyarylated products due to the presence of three adjacent nucleophilic nitrogens (N 1 , N 3 and C 2 -amino group), as well as the tautomeric nature of 2-aminobenzimidazoles. Herein, we report the successful development of an orthogonal set of Pd-and Cu-catalyzed chemoselective conditions for the N-arylation of unprotected 2-aminobenzimidazoles and related aminoazoles.We initiated our investigation by examining the Pd-catalyzed coupling of 2-aminobenzimidazole and bromobenze...

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Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase

Cited by 54 publications

References 17 publications

Copper‐Catalyzed CNH₂ Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

Copper‐Catalyzed CNH₂ Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

A ZebrafishIn VivoPhenotypic Assay to Identify 3-Aminothiophene-2-Carboxylic Acid-Based Angiogenesis Inhibitors

Catalyst‐Controlled Chemoselective Arylation of 2‐Aminobenzimidazoles

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Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase

Cited by 54 publications

References 17 publications

Copper‐Catalyzed CNH2 Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

Copper‐Catalyzed CNH2 Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

A ZebrafishIn VivoPhenotypic Assay to Identify 3-Aminothiophene-2-Carboxylic Acid-Based Angiogenesis Inhibitors

Catalyst‐Controlled Chemoselective Arylation of 2‐Aminobenzimidazoles

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Copper‐Catalyzed CNH₂ Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

Copper‐Catalyzed CNH₂ Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles