Pyrimidinone derivative, preparation method and application
By designing and preparing a pyrimidone derivative, the problem of insufficient effectiveness of existing PD-1/PD-L1 inhibitors in tumor treatment is solved, and a PD-1/PD- which is significantly better than the prior art has been achieved. L1 inhibitory effect has the prospect of preparing PD-1/PD-L1 inhibitors.
Patent Information
- Application Number
- CN202410597816.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-05-14
- Publication Date
- 2024-12-27
AI Technical Summary
The existing PD-1/PD-L1 inhibitors are not effective in tumor treatment, especially due to the poor tissue penetration ability of macromolecular drugs, which leads to low therapeutic effect. The existing compounds are used to PD-1/PD-L1. The inhibitory effect is not ideal, and the IC50 is higher.
A pyrimidinone derivative was designed, and prepared by reacting specific structural formulas with BMS-1233, NP19, HATU, and DIPEA in N,N-dimethylformamide solution. The HTRF method was used to detect that its IC50 was significantly better than the existing ones. Techniques: The compounds CC-5 and CC-3 provided have significant PD-1/PD-L1 inhibitory effects.
The prepared pyrimidinone derivatives CC-5 and CC-3 have IC50 of 6 nM and 131 nM, respectively, which is significantly better than the compounds in the prior art, and has a more ideal PD-1/PD-L1 inhibitory effect and is applicable to Prospects for the preparation of PD-1/PD-L1 inhibitors.
Smart Images
Figure CN119192139A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to a pyrimidone derivative, a preparation method and an application thereof. Background Art
[0002] At present, the main drugs used in tumor immunotherapy are large molecule biological antibodies. Among them, PD-1 / PD-L1 inhibitors, known as immune checkpoint inhibitors, are listed as one of the most promising tumor treatment targets because they are effective against a variety of tumors, and therefore have attracted much attention.
[0003] However, in the field of tumor treatment, due to the poor tissue penetration and distribution ability of large molecule drugs, they are more susceptible to factors in the tumor growth microenvironment, such as strong vascular permeability, collagen solidification, increased hyaluronic acid, etc. The effective part may be limited to some cancer cells close to the blood vessels, resulting in a low effective response rate of PD-1 / PD-L1 antibodies in patients with solid tumors. The development of small molecule PD-L1 inhibitors is expected to make up for the shortcomings of antibodies in the treatment of solid tumors. There is a necessity for clinical application and market opportunities.
[0004] PCT patent application with publication number WO2015 / 034820A1 discloses a resorcinol diphenyl ether derivative named 1-({3-bromo-4-[(2-methyl-3-phenyl)methoxy))phenyl}-methyl)piperidine-2-carboxylic acid with the following structural formula:
[0005]
[0006] The above PCT patent application discloses that the derivatives can inhibit the mutual binding of programmed cell death receptor 1 / programmed cell death ligand 1 (PD-1 / PD-L1) and can be used to treat tumors.
[0007] However, the inhibitory effect of the compounds disclosed in the above PCT patent application on PD-1 / PD-L1 is not satisfactory. The IC 50 It is only 146nM. In view of this, it is of great significance to synthesize a compound with a more ideal PD-1 / PD-L1 inhibitory effect. Summary of the invention
[0008] In order to solve the problems existing in the prior art, the present invention provides a pyrimidone derivative, a preparation method and an application thereof, wherein the pyrimidone derivative can inhibit the mutual binding of programmed cell death receptor 1 / programmed cell death ligand 1 (PD-1 / PD-L1), and the IC detected by the HTRF method can be 50 It can be found that its inhibitory effect is significantly better than the existing technology and can be applied to the preparation of PD-1 / PD-L1 inhibitors.
[0009] The technical solution adopted by the present invention is: a pyrimidone derivative, characterized in that the derivative has the structural formula:
[0010]
[0011] And the use of the pyrimidone derivatives in the preparation of PD-1 / PD-L1 inhibitors.
[0012] The preparation method of the pyrimidone derivatives is as follows: 1 equivalent of BMS-1233 or NP19, 1 equivalent of 1.2 equivalents of HATU and 1.8 equivalents of DIPEA were added to N,N-dimethylformamide solution for reaction.
[0013] Compared with the prior art, the beneficial effects of this technical solution are:
[0014] The pyrimidone derivatives provided by the method can inhibit the mutual binding of programmed cell death receptor 1 / programmed cell death ligand 1 (PD-1 / PD-L1), wherein the structural formula of CC-5 is: ICs detected using HTRF 50 6nM;
[0015] The structural formula of CC-3 is: ICs detected using HTRF 50 The inhibitory effects of both are significantly better than the compound 1-({3-bromo-4-[(2-methyl-3-phenyl)methoxy))phenyl}-methyl)piperidine-2-carboxylic acid disclosed in the prior art WO2015 / 034820A1, and have the prospect of being used in the preparation of PD-1 / PD-L1 inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 The NMR, mass spectrometry, and liquid chromatography detection images of CC-5;
[0017] Figure 2 These are the nuclear magnetic resonance, mass spectrometry, and liquid chromatography detection images of CC-3. DETAILED DESCRIPTION
[0018] The present invention is described in detail below with reference to the accompanying drawings and embodiments, but the content of the present invention is not limited to the following embodiments.
[0019] A method for preparing a pyrimidone derivative comprises the following steps:
[0020] S1: Add 1 equivalent of BMS-1233 or NP19, 1 equivalent of compound 1, 1.2 equivalents of HATU and 1.8 equivalents of DIPEA to a nitrogen-nitrogen dimethylformamide solution and react at 25°C for 12 hours. The compound 1 is
[0021]
[0022] The reaction principle is as follows:
[0023]
[0024] The prepared pyrimidone derivatives are: compound numbered CC-5, with the structural formula:
[0025] And the compound numbered CC-3, the structural formula is:
[0026]
[0027] The NMR, mass spectrometry and liquid chromatography detection images of the target product CC-5 are shown in the figure below: Figure 1 ; and the identification results are as follows: 3-((4-Chloro-2-((2-(4-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)pyridazin-3-yl)piperazine-1-car bonyl)piperidin-1-yl)methyl)-5-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzonitrile(CC-5).White solid(297mg,12%yield); 1 HNMR(400MHz,DMSO)δ11.38(s,1H),8.09(s,1H),8.02–7.88(m,2H),7.80(t,J=7.0Hz,2H), 7.60(t,J=7.5Hz,1H),7.44(d,J=7.6Hz,3H),7.37(d,J=6.9Hz,1H),7.33–7.24(m,4H),7.19 (d,J=7.3Hz,1H),7.10(s,1H),5.26(d,J=24.9Hz,4H),3.80(s,2H),3.54(dd,J=24.9,10.6H z,8H),2.94(s,1H),2.21(s,3H),2.12(s,1H),1.67(s,3H),1.47(s,2H),1.39–1.17(m,3H). 13C NMR (101MHz, DMSO) δ171.19,163.53,159.01,156.13,153.52,151.19,147.10,142.55,141. 67,140.79,139.09,135.53,134.35,132.75,132.10,131.39,131.05,130.16,129.55,128.6 4,128.24,127.59,127.36,125.93,119.06,113.36,112.89,111.85,108.92,101.07,70.03 ,69.30,52.02,51.93,51.42,51.21,45.23,44.81,44.47,27.96,24.70,16.19.MSm / z:calcd for C 47 H 45 C1N 8 O 5 836.32, found 837.50[M+H] + .HPLC R 2.645min,purity 97.400%.
[0028] The NMR, mass spectrometry and liquid chromatography detection images of the target product CC-3 are shown in Figure 2 ; and the identification results are as follows: 3-((4-Chloro-2-(((1-(4-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)pyridazine-3-yl)piperazin-1-yl)-2-met hyl-1-oxopropan-2-yl)amino)methyl)-5-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)benzonitrile(CC-3).White solid(8.1mg,10%yield); 1H NMR (400MHz, DMSO) δ11.37(s,1H),8.09(s,1H),7.96(d,J=9.6Hz,1H),7.92(s,1H),7. 77(d,J=6.0Hz,2H),7.57(d,J=7.8Hz,1H),7.46(dd,J=12.4,5.3Hz,3H),7.41–7.36(m ,2H),7.32–7.26(m,3H),7.24(d,J=6.1Hz,1H),7.21(d,J=1.9Hz,1H),7.10(s,1H),5. 26(d,J=9.0Hz,4H),4.04(s,4H),3.55(s,2H),3.47(s,6H),2.22(s,3H),1.33(s,6H). 13 CNMR(101MHz,DMSO)δ172.88,163.55,159.03,155.44,153.32,151.27,147.04,14 2.55,141.68,140.91,138.97,135.58,134.36,132.74,132.14,131.44,130.14,13 0.08,129.56,128.66,128.24,127.55,127.37,125.93,123.10,118.99,113.29,11 2.80,111.87,108.92,100.93,70.04,69.29,60.42,45.09,41.52,26.72,16.25.MS m / z:calcd forC 45 H 43 C1N 8 O 5 810.30, found 811.40[M+H] + .HPLC R 2.775min, purity 97.561%.
[0029] The HTRF method was used to detect the inhibitory effects of the compounds numbered CC-5 and CC-3 prepared in the examples on PD-1 / PD-L1. The experimental process and inhibitory effects are as follows:
[0030] Experimental process:
[0031] (1) Add 2 μl of compound dilution to each well of a 96-well plate and centrifuge at 1000 rpm / min for 1 min;
[0032] (2) Add 4 μl (2.5X) PD-1 mixture to each well of the 96-well plate and centrifuge at 1000 rpm / min for 1 min;
[0033] (3) Add 4 μl (2.5X) PD-L1 mixture to each well of the 96-well plate, centrifuge at 1000 rpm / min for 1 min, and incubate at room temperature for 15 min;
[0034] (4) Add 10 μl (2X) test mixture to each well of the 96-well plate and centrifuge at 1000 rpm / min for 1 min;
[0035] (5) Incubate at room temperature for 120 min and read the fluorescence value using a Tecan microplate reader (Ex: 320 nM; Em: 620 and 665 nM);
[0036] (6) The inhibition rate was calculated according to the following formula: Inhibition rate (Inibition) % = (1-(665 nm / 620 nm signal value of each well-average value of the low control group) / (average value of the high control group-average value of the low control group))*100;
[0037] Among them, the high control group is a group without compound treatment, and only an equal amount of DMSO solution is added to the reaction system; the low control group is a group without PD-1 mixed solution, and only an equal amount of detection mixed solution is added. In this detection system, the final concentration of DMSO is 0.5%;
[0038] Inhibitory effect:
[0039] IC of the Example measured in the PD-1 / PD-L1 homogeneous time-resolved fluorescence binding assay 50 , see Table 1:
[0040] Table 1: Inhibitory effects of compounds CC-5 and CC-3 on PD-1 / PD-L1
[0041]
[0042] According to the above in vitro experimental results, it is proved that the prepared pyrimidinone derivatives can inhibit the mutual binding of programmed cell death receptor 1 / programmed cell death ligand 1 (PD-1 / PD-L1), and have the prospect of being used in the preparation of PD-1 / PD-L1 inhibitors; and the inhibitory effect is significantly better than the compound 1-({3-bromo-4-[(2-methyl-3-phenyl)methoxy))phenyl}-methyl)piperidine-2-carboxylic acid disclosed in the prior art WO2015 / 034820A1.
Claims
1. A pyrimidone derivative, characterized in that: The derivative structural formula is:
2. Use of the pyrimidone derivative according to claim 1 in the preparation of PD-1 / PD-L1 inhibitors.
3. The method for preparing the pyrimidone derivatives according to claim 1, characterized in that: 1 equivalent of BMS-1233 or NP19, 1 equivalent of 1.2 equivalents of HATU and 1.8 equivalents of DIPEA were added to N,N-dimethylformamide solution for reaction.