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Pyrimidine derivative used as Wee1 inhibitor

A technology of drugs and compounds, applied in the field of anti-tumor drug preparation, can solve the problems of cell apoptosis and DNA damage that cannot be repaired

Inactive Publication Date: 2021-03-05
WIGEN BIOMEDICINE TECH SHANGHAI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibit checkpoint function, DNA damage cannot be repaired, and cells undergo apoptosis

Method used

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  • Pyrimidine derivative used as Wee1 inhibitor
  • Pyrimidine derivative used as Wee1 inhibitor
  • Pyrimidine derivative used as Wee1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Compound 1

[0063]

[0064] synthetic route:

[0065]

[0066] Step 1: Synthesis of compound 1-1

[0067] Dissolve tert-butyl 3-hydroxymethylpiperazine-1-carboxylate (1.0 g, 4.63 mmol) and 1,2-difluoro-4-nitrobenzene (809 mg, 5.1 mmol) in DMF (20 mL), add DIPEA (1.8g, 13.89mmol), heated up to 120°C and reacted overnight. After the reaction was monitored by LC-MS, water (100mL) was added to the reaction system, extracted with EA (50mL*2), the organic phase was combined, and the organic phase was washed with saturated saline ( 50mL) washed with anhydrous Na 2 SO 4 After drying, the filtrate was concentrated and the residue was subjected to column chromatography (PE / EA=10 / 1to 5 / 1) to obtain a yellow solid compound (600 mg, yield 60%), ESI-MS m / z: 356.1 [M+H] + .

[0068] Step 2: Synthesis of Compound 1-2

[0069] Compound 1-1 ((3.6g, 10mmol) was dissolved in DMF (30mL), ice bathed, NaH (60% content, 440mg, 11mmol) was added, and the temperature was ...

Embodiment 2

[0081] Example 2: Compound 2

[0082]

[0083] synthetic route:

[0084]

[0085] Step 1: Synthesis of Compound 2-1

[0086] Dissolve compound 1-3 (706mg, 3.0mmol) in 1,2-dichloroethane (20mL), add acetone (1mL), AcOH (180mg, 3.0mmol), r.t.stir for 1h, add NaBH(OAc) 3 (1.26g, 6mmol), r.t. reacted overnight, LC-MS monitored the completion of the reaction, concentrated, the residue was dissolved in EA (30mL), saturated NaHCO 3 solution (30mL), washed with anhydrous Na 2 SO 4 After drying, the filtrate was concentrated, and the residue was subjected to column chromatography (DCM / MeOH=100 / 1 to 20 / 1) to obtain a yellow solid (400 g, yield 48%), ESI-MS m / z: 278.1 [M+H] + .

[0087] Step 2: Synthesis of compound 2-2

[0088] Compound 2-1 (400mg, 1.44mmol) was dissolved in MeOH (30mL), Pd / C (10%, 80mg) was added, and H 2 , r.t. reacted overnight, LC-MS monitored after the reaction was completed, filtered, and the filtrate was concentrated to obtain a light yellow solid co...

Embodiment 3

[0092] Example 3: Compound 3

[0093]

[0094] Using oxetane and compound 1-3 as raw materials, compound 3 was obtained by using a synthesis method similar to that of Example 2.

[0095] 1 H NMR (400MHz, DMSO-d 6)δ:9.98(s,1H),8.76(s,1H),7.94(t,J=7.9Hz,1H),7.72(d,J=8.1Hz,1H),7.58(dd,J=7.7,0.9 Hz,1H),7.15(d,J=9.3Hz,2H),6.79(d,J=8.9Hz,1H),5.67-5.56(m,1H),5.28(s,1H),4.81-4.73(m ,3H),4.64-4.48(m,4H),4.22(d,J=10.5Hz,1H),3.87-3.70(m,2H),3.64(d,J=11.6Hz,1H),2.96(t, J=9.9Hz, 1H), 2.79(d, J=10.9Hz, 2H), 2.63-2.50(m, 2H), 2.09-2.00(m, 1H), 1.70-1.60(m, 1H), 1.43(s ,6H); ESI-MS m / z:571.2[M+H] + .

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Abstract

The invention discloses a pyrimidine derivative used as a Weel inhibitor. The invention relates to a novel compound shown as a formula (1A) or a formula (1B) and / or pharmaceutically acceptable salt thereof, a composition containing the compound shown as the formula (1A) or the formula (1B) and / or pharmaceutically acceptable salt thereof, a preparation method and application of the compound servingas a Wee1 inhibitor in preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a new compound with Weel kinase inhibitory effect, a preparation method thereof and the use of the compound in the preparation of antitumor drugs. Background technique [0002] Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoints. Cell cycle checkpoints include the G1 phase checkpoint for the transition from G1 (cell resting phase) to the S phase (DNA synthesis phase), the G2 phase checkpoint for the transition from G2 (cell division preparation phase) to the M (cell division phase) phase, and the M The spindle checkpoint for the metaphase (middle phase of cell division) to anaphase (late phase of cell division) transition. Wee-1 protein kinase plays an important role in the G2 phase checkpoint. The entry of cells into the M phase depends on the activity of CDK1 kinase. Wee-1 inhibits the activity of CDK1 by phosphorylatin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/5383A61K31/519A61P35/00A61P35/02
CPCC07D519/00A61P35/00A61P35/02A61K31/519A61K31/5383C07D487/04C07D487/14C07D471/14
Inventor 樊后兴谢雨礼
Owner WIGEN BIOMEDICINE TECH SHANGHAI CO LTD
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