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Substituted [5,6]cyclic-4(3H)-pyrimidinones as anticancer agents

A technology of pyrimidinyl and substituent groups, applied in the field of novel substituted [5,6]cyclo-4-pyrimidinone compounds, which can solve problems such as unmet medical needs

Active Publication Date: 2019-10-25
ZENJI RES LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been reported in the literature that CDC7 is overexpressed in many cancers, including triple-negative breast cancer, which remains a very unmet medical need

Method used

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  • Substituted [5,6]cyclic-4(3H)-pyrimidinones as anticancer agents
  • Substituted [5,6]cyclic-4(3H)-pyrimidinones as anticancer agents
  • Substituted [5,6]cyclic-4(3H)-pyrimidinones as anticancer agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] 1.1.1) Synthesis of (S)-5-bromo-3-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)thiophene-2-carboxylic acid methyl ester (compound 2)

[0200]

[0201] To a stirred solution of compound 1 (15.00 g, 63.54 mmol) in pyridine (250 mL) was added (S)-2-(Boc-amino)-3-methylbutyric acid (15.18 g, 69.89 mmol) under N 2 The resulting dark red solution was cooled to -5 °C under atmosphere, phosphorus oxychloride (11.67 g, 76.24 mmol) was added dropwise within 20 min, after the addition, the mixture was stirred at 0 °C for 1 h, at room temperature for 1 h, LC-MS shows that most of the starting material is consumed, stop the reaction and add H 2 O (200 mL), then extracted with EtOAc (250 mL*2), the combined organic layers were washed with saturated NaHCO 3 , washed with brine, washed with anhydrous Na 2 SO 4 Drying, concentration in vacuo, the residue was purified by column (EtOAc / Hex 1 / 40 to 1 / 10) to give compound 2 (9.00 g, 32% yield) as a white solid. MS(ESI)(M / Z):[M+...

Embodiment 2

[0243] 2.1.1) Synthesis of (S)-5-bromo-3-(2-((tert-butoxycarbonyl)amino)butanamido)thiophene-2-carboxylic acid methyl ester (compound 8)

[0244]

[0245] To a stirred solution of compound 1 (4.00 g, 16.94 mmol) in pyridine (60 mL) was added (S)-2-[(tert-butoxycarbonyl)amino]butyric acid (3.79 g, 18.64 mmol) under N 2 Cooled to -5 °C under atmosphere and added phosphorus oxychloride (3.11 g, 20.33 mmol) dropwise over 10 min. After addition, the mixture was stirred at 0 °C for 1 h and at room temperature for 1 h. Material is depleted, stop reaction, add H 2 O (80 mL), then extracted with EtOAc (200 mL*2), the combined organic layers were washed with saturated NaHCO 3 , washed with brine, washed with anhydrous Na 2 SO 4 Drying, concentration in vacuo, the residue was purified by column (EtOAc / Hex 1 / 40 to 1 / 10) to give compound 8 (4.50 g, 63% yield) as a white solid. MS(ESI)(M / Z):[M+H]+=421.0,423.0; 1 H NMR(400MHz,DMSO)δ10.63(s,1H),8.12(s,1H),7.63(d,J=6.4Hz,1H),3.93(s,1H)...

Embodiment 3

[0269] 3.1.1) Synthesis of methyl 5-bromo-3-((tert-butoxycarbonyl)amino)thiophene-2-carboxylate (compound 14)

[0270]

[0271] To a stirred solution of compound 1 (3.00 g, 12.71 mmol) in Py (35 mL) was added DMAP (0.16 g, 1.27 mmol) at room temperature, followed by 2 After cooling down to 0° C., di-tert-butyl dicarbonate (3.05 g, 13.98 mmol) was added slowly within 20 minutes. After the addition, the mixture was stirred at room temperature for 15 h. TLC showed that most of the starting material was consumed, and the reaction was stopped. Concentrated in vacuo, the residue was purified by column (EtOAc / Hex 1 / 100 to 1 / 30) to give compound 14 (3.30 g, 77% yield) as a white solid. MS(ESI)(M / Z):[M+H]+=336.9,338.9; 1 H NMR (400MHz, CDCl 3 )δ9.35(s,1H),7.99(s,1H),3.88(s,3H),1.54(s,9H).

[0272] 3.1.2) Synthesis of 5-bromo-3-((tert-butoxycarbonyl)amino)thiophene-2-carboxylic acid (compound 15)

[0273]

[0274] To a stirred solution of compound 14 (3.30 g, 9.82 mmol) in MeO...

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Abstract

The present invention relates to novel substituted [5,6]cyclic-4(3H)-pyrimidinone compounds of formula (I) and their preparation methods. (I) In particular, the present invention relates to novel substituted [5,6]cyclic-4(3H)- pyrimidinone compounds useful as inhibitors of protein kinases, specifically CDC7 (cell division cycle 7) inhibitors.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 509,128, filed May 21, 2017. The entire teachings of the above applications are incorporated herein by reference. technical field [0003] The present invention relates to novel substituted [5,6]cyclo-4(3H)-pyrimidinone compounds and methods for their preparation. In particular, the present invention relates to novel substituted [5,6]cyclo-4(3H)-pyrimidinone compounds useful as protein kinase inhibitors, especially CDC7 (Cell Division Cycle 7) inhibitors. Background technique [0004] CDC7 (cell division cycle 7) is a serine-threonine kinase that plays a key role in DNA synthesis and is required for activation of the DNA replication origin throughout the S phase of the cell cycle. Inhibition of CDC7 in cancer results in lethal S- and M-phase progression, whereas normal cell survival proceeds, most likely by inducing cell cycle arrest at DNA re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519C07D333/52
CPCA61P35/00C07D239/90C07D487/04C07D491/048C07D495/04
Inventor H·张
Owner ZENJI RES LAB
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