One‐Pot Synthesis of 6‐Aminopyrido[2,3‐<i>d</i>]pyrimidin‐7‐ones

Zinchenko, H. M.; Muzychka, L. V.; Kucher, Olexandr V.; Sadkova, Iryna V.; Mykhailiuk, Pavel K.; Смолий, О. Б.

doi:10.1002/ejoc.201801204

Cited by 6 publications

(5 citation statements)

References 54 publications

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“…The first limitation has been recently partially solved in the synthesis of the 4-chloro substituted pyridopyrimidine 33 from the chloro substituted pyrimidine aldehyde 30 ( Figure 14) [33]. The presence of the 4-chloro substituent allows the ulterior substitution by nitrogen nucleophiles.…”

Section: Molecules 2019 24 X For Peer Review 8 Of 21mentioning

confidence: 99%

“…Thus, there are more than 2000 examples of the substitution of a 2-chloropyridopyrimidine by nitrogen nucleophiles in good yields [62] but fewer of the substitution of a 2-bromo substituted compound [100]. Similarly, the substitution of the corresponding 4-chloropyrimidine by nitrogen nucleophiles appears in more than 1800 examples [33] but the same reaction carried out with 4-bromo derivatives only appears in a reference of our research group [52]. Even more frequently, the introduction of nitrogen or oxygen substituents at position C2 is carried out in a two steps protocol in which a methyl thioether is oxidized to the corresponding methyl sulfonyl group (usually with m-CPBA) and subsequently substituted by the nitrogen or oxygen nucleophile.…”

Section: Synthesis From a Preformed Pyridonementioning

confidence: 99%

“…Thus, there are more than 2000 examples of the substitution of a 2-chloropyridopyrimidine by nitrogen nucleophiles in good yields [62] but fewer of the substitution of a 2-bromo substituted compound [100]. Similarly, the substitution of the corresponding 4-chloropyrimidine by nitrogen nucleophiles appears in more than 1800 examples [33] but the same reaction carried out with 4-bromo derivatives only appears in a reference of our research On the other hand, two miscellaneous protocols for the formation of the pyrido[2,3-d]pyrimidine-7(8H)-one scaffold include a Diels-Alder reaction between diethyl acetylenedicarboxylate and a 6-amino-4-oxopyrimidine ring [101] and the photochemical cyclization of N-(pyrimidin-4yl)methacrylamide [14], however, both methodologies proceed in very low yields (1% and 21% respectively).…”

Section: Synthesis From a Preformed Pyridonementioning

confidence: 99%

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Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

et al. 2019

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Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures 2 described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure 2 have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds.

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Section: Molecules 2019 24 X For Peer Review 8 Of 21mentioning

confidence: 99%

Section: Synthesis From a Preformed Pyridonementioning

confidence: 99%

“…Thus, there are more than 2000 examples of the substitution of a 2-chloropyridopyrimidine by nitrogen nucleophiles in good yields [62] but fewer of the substitution of a 2-bromo substituted compound [100]. Similarly, the substitution of the corresponding 4-chloropyrimidine by nitrogen nucleophiles appears in more than 1800 examples [33] but the same reaction carried out with 4-bromo derivatives only appears in a reference of our research On the other hand, two miscellaneous protocols for the formation of the pyrido[2,3-d]pyrimidine-7(8H)-one scaffold include a Diels-Alder reaction between diethyl acetylenedicarboxylate and a 6-amino-4-oxopyrimidine ring [101] and the photochemical cyclization of N-(pyrimidin-4yl)methacrylamide [14], however, both methodologies proceed in very low yields (1% and 21% respectively).…”

Section: Synthesis From a Preformed Pyridonementioning

confidence: 99%

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Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

et al. 2019

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“…These difficulties have reduced the chemical diversity of substituents present at C4 of the resulting pyridopyrimidine to hydrogen, amino, or short alkyl groups. Only the introduction of a chlorine atom at the starting pyrimidine 4 allows the construction of the corresponding 4-chloro-substituted pyrido [2,3-d]pyrimidin-7(8H)-one 1 that could allow the further introduction of diversity at such a position [9].…”

Section: Introductionmentioning

confidence: 99%

Expanding the Diversity at the C-4 Position of Pyrido[2,3-d]pyrimidin-7(8H)-ones to Achieve Biological Activity against ZAP-70

et al. 2021

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Pyrido[2,3-d]pyrimidin-7(8H)-ones have attracted widespread interest due to their similarity with nitrogenous bases found in DNA and RNA and their potential applicability as tyrosine kinase inhibitors. Such structures, presenting up to five diversity centers, have allowed the synthesis of a wide range of differently substituted compounds; however, the diversity at the C4 position has mostly been limited to a few substituents. In this paper, a general synthetic methodology for the synthesis of 4-substituted-2-(phenylamino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones is described. By using cross-coupling reactions, such as Ullmann, Buchwald–Hartwig, Suzuki–Miyaura, or Sonogashira reactions, catalyzed by Cu or Pd, we were able to describe new potential biologically active compounds. The resulting pyrido[2,3-d]pyrimidin-7(8H)-ones include N-alkyl, N-aryl, O-aryl, S-aryl, aryl, and arylethynyl substituents at C4, which have never been explored in connection with the biological activity of such heterocycles as tyrosine kinase inhibitors, in particular as ZAP-70 inhibitors.

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“…Compounds 11 were then reacted with methyl glycinate hydrochloride and 4-methoxybenzaldehyde in the presence of Et 3 N in MeOH. The resulting mixture was heated in 70% AcOH to yield the key intermediates 12 . Compound 8a was obtained by first reacting the intermediate 12a with ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl) ethan-1-amine ( 14a ) via the nucleophilic aromatic substitution, followed by the Pd/C-catalyzed nitro reduction reaction.…”

mentioning

confidence: 99%

Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors

Zhou

et al. 2023

ACS Med. Chem. Lett.

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The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.

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One‐Pot Synthesis of 6‐Aminopyrido[2,3‐d]pyrimidin‐7‐ones

Cited by 6 publications

References 54 publications

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

Expanding the Diversity at the C-4 Position of Pyrido[2,3-d]pyrimidin-7(8H)-ones to Achieve Biological Activity against ZAP-70

Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors

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