PARP protein degradation agent as well as preparation method and application thereof

[0034] The preparation of the compound shown in embodiment 1 formula 1-1

[0035]

[0036] Formula 1-1

[0037] A mixture of Nutlin acid intermediate (123.31 mg, 0.25 mmol), HATU (70 mg, 0.184 mmol) and DIEA (90 μL) was stirred in a round bottom flask in dry DMF (3.78 mL) at room temperature for 0.5 h. Then, a solution of niraparib (79 mg, 0.25 mmol) in 0.5 mL of anhydrous DMF was slowly added. The reaction mixture was stirred at room temperature for 12 hours. The water and the mixture were washed once with saturated aqueous NaCl by quenching the reaction, and the ethyl acetate was extracted with diethyl ether. The organic layer was washed with anhydrous Na 2 SO4 was dried and evaporated in vacuo to get crude product which was further purified by silica gel column chromatography (DCM:MeOH=40:1) to give the product.

[0038] 1 H NMR (400MHz, Chloroform-d) δ9.18–8.96 (m, 1H), 8.54 (d, J=5.4Hz, 1H), 8.32 (dd, J=6.7, 3.6Hz, 1H), 7.99–7.75 ( m,3H),7.61(dd,J=8.4,3.4Hz,1H),7...

[0039] The preparation of the compound shown in embodiment 2 formula 1-2

[0040]

[0041] Formula 1-2

[0042] A mixture of Nutlin acid intermediate (123.31 mg, 0.25 mmol), HATU (70 mg, 0.184 mmol) and DIEA (90 μL) was stirred in a round bottom flask in dry DMF (3.78 mL) at room temperature for 0.5 h. Then, add NH 2 -PEG 1 -COOtBu (33.26 mg, 0.25 mmol) in 0.5 mL of dry DMF. The reaction mixture was stirred at room temperature for 12 hours. The water and the mixture were washed once with saturated aqueous NaCl by quenching the reaction, and the ethyl acetate was extracted with diethyl ether. The organic layer was washed with anhydrous Na 2SO4 was dried and evaporated in vacuo to get crude product which was further purified by silica gel column chromatography (DCM:MeOH=40:1) to give the product.

[0043] To a solution of Nutlin derivative ester (140 mg, 0.020 mmol) in DCM (1 mL) was added TFA (2 mL) at 0°C. After stirring at room temperature for 17 hours, the resultin...

[0046] Example 3 The compound represented by formula 1-3 was prepared according to the above preparation method.

[0047]

[0048] Formula 1-3

[0049] 1 H NMR (400MHz, Chloroform-d) δ9.07(s, 1H), 8.56(s, 1H), 8.33(d, J=7.1Hz, 1H), 8.04(s, 1H), 7.88(dq, J= 25.5,9.0,8.1Hz,3H),7.61(d,J=8.5Hz,1H),7.41(dd,J=19.7,8.8Hz,2H),7.15–6.78(m,8H),6.56(d,J =8.0Hz,1H),6.49(s,1H),6.07(s,1H),5.59(d,J=9.5Hz,1H),5.49(d,J=9.4Hz,1H),4.85–4.67(m ,1H),4.66–4.53(m,1H),4.13(d,J=7.5Hz,1H),3.99(q,J=14.5,12.8Hz,2H),3.86(d,J=8.0Hz,6H) ,3.74(d,J=14.1Hz,1H),3.64(dd,J=12.2,5.1Hz,4H),3.58–3.38(m,5H),3.30(s,1H),3.13(d,J=10.6 Hz, 3H), 2.98(s, 1H), 2.91(s, 1H), 2.67(dd, J=21.5, 9.3Hz, 4H), 2.25–1.99(m, 2H), 1.37(d, J=16.6Hz ,6H).[M+H]1100.