CN117229260B - Double-target inhibitor of DNA polymerase theta and poly ADP ribose polymerase 1, preparation method and medical application thereof - Google Patents

Double-target inhibitor of DNA polymerase theta and poly ADP ribose polymerase 1, preparation method and medical application thereof Download PDF

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CN117229260B
CN117229260B CN202311502119.4A CN202311502119A CN117229260B CN 117229260 B CN117229260 B CN 117229260B CN 202311502119 A CN202311502119 A CN 202311502119A CN 117229260 B CN117229260 B CN 117229260B
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compound
pharmaceutically acceptable
dna polymerase
poly adp
acceptable salt
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CN117229260A (en
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向华
马露雨
骆国顺
杨铭
陈巍
肖茂旭
陶文祥
哈斯
熊爽爽
祝佳程
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China Pharmaceutical University
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Abstract

The invention discloses a DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double-target inhibitor, a preparation method and medical application thereof. The compound disclosed by the invention is shown as a general formula (I), can simultaneously target Pol theta and PARP1, plays a double role of inhibiting Pol theta and PARP1, and can be used for preparing medicines for treating cancers defective in homologous recombination repair pathway (HR).。

Description

Double-target inhibitor of DNA polymerase theta and poly ADP ribose polymerase 1, preparation method and medical application thereof
Technical Field
The invention relates to a compound and a preparation method and application thereof, in particular to a double-target inhibitor of DNA polymerase theta and poly ADP ribose polymerase 1, a preparation method and medical application thereof.
Background
Targeting DNA repair defects has become an effective cancer treatment strategy. However, cancers with defective DNA repair often rely on backup DNA repair pathways, which are "deadly spots" that can be targeted to eliminate cancer cells, and are the basis for synthetic lethality. The success of Poly ADP Ribose Polymerase (PARP) inhibitors in the treatment of brca-deficient breast and ovarian cancers demonstrates synthetic lethality. PARP inhibitors are drugs that inhibit tumor growth by preventing DNA repair from leading to cell death. PARP enzyme inhibitors (such as olaparib, lu Kapa, nilaparib, fluzopanib, pamp Mi Pani and talazapanib) have been approved for the treatment of breast and ovarian cancer in BRCA mutant patients. Several other drugs (e.g., verapali) are being tested clinically for breast, prostate and ovarian cancer. The use of PARP inhibitors is not without side effects, but one of the major hurdles to long-term use of PARP inhibitors is the development of neutropenia dose dependency, thus requiring dose reduction in clinical practice, but this would impair the therapeutic effect. Other anticancer drugs (e.g., alkylating agents such as chlorambucil) may have serious side effects such as bone marrow suppression, increased long-term risk of further cancer, infertility, and allergic reactions.
Pol theta comprises a C-terminal DNA polymerase domain and an N-terminal atpase/helicase domain belongs to the HELQ class of SF2 helicase superfamily. In homologous recombination-deficient cells, pol θ can undergo error-prone DNA synthesis at the site of DNA damage via the alt-EJ pathway. Studies have shown that the helicase domain of Pol theta inhibits HR pathway by disrupting the formation of Rad51 nucleoprotein complex that is involved in the initiation of HR dependent DNA repair reactions following ionizing radiation. This anti-recombinase activity of Pol theta promotes the alt-EJ pathway. Furthermore, the helicase domain of Pol θ contributes to micro-homology mediated strand annealing. When the ssDNA cantilever contains a micro-homology greater than 2 bp, pol theta effectively facilitates end-ligation in the alt-EJ pathway by this annealing activity. This reannealing activity is achieved by coupling of Rad51 interactions followed by atp enzyme mediated displacement of Rad51 from DSB damage sites. After annealing, the primer strand of the DNA can be extended by the polymerase domain of piomicron theta.
The pomicron is not substantially expressed in normal cells, but is upregulated in breast, lung and ovarian cancers. Furthermore, an increase in o theta expression is associated with a poor prognosis for breast cancer. Studies have shown that cancer cell deficiency HR, NHEJ or ATM is highly dependent on the expression of p omicronlθ.
Disclosure of Invention
The invention aims to: the invention provides a compound serving as a double-target inhibitor of DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1), which can simultaneously target Pol theta and PARP1 and play a double role of inhibiting Pol theta and PARP 1. It is another object of the present invention to provide a process for preparing the above compound or a pharmaceutically acceptable salt thereof. It is another object of the present invention to provide a pharmaceutical composition. It is a final object of the present invention to provide the use of said compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of cancer having homologous recombination defects.
The technical scheme is as follows: the invention provides a double-target inhibitor of DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) shown in a general formula (I), a tautomer or a pharmaceutically acceptable salt thereof:
；
wherein:
x is-CH or N;
y is-CH or N;
R 1 is C 1 -C 4 Alkyl or H;
w is-CH or N;
linker is any one of the following structures:
；
a is any one of the following structures:
；
R 2 is any one of the following structures:
。
the DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double target inhibitor, its tautomer or pharmaceutically acceptable salt, when X is-CH, Y is N, R 1 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the When X is N and Y is-CH, R 1 H.
A dual-target inhibitor of DNA polymerase θ (Pol θ) and poly ADP ribose polymerase 1 (PARP 1), a tautomer or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:
。
the use of the DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double-target inhibitor, tautomer or pharmaceutically acceptable salt thereof in preparing the Pol theta inhibitor.
The use of the DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double-target inhibitor, tautomer or pharmaceutically acceptable salt thereof in preparing the PARP1 inhibitor.
The use of the DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double-target inhibitor, tautomer or pharmaceutically acceptable salt thereof in preparing medicaments for treating or preventing homologous recombination repair pathway (HR) defect type cancers.
The pharmaceutical composition comprises the DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double-target inhibitor, a tautomer or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
The DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double-target inhibitor, tautomer or pharmaceutically acceptable salt thereof or the application of the pharmaceutical composition in preparing medicines for treating or preventing colon cancer, breast cancer, ovarian cancer and pancreatic cancer.
The preparation method of the DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double-target inhibitor, tautomer or pharmaceutically acceptable salt thereof comprises the following steps:
(a) The compound M and M-1 are subjected to substitution reaction to prepare a compound M-2;
(b) The compound M-5 is prepared by SUZUKI reaction of the compound M-3 and the compound M-4;
(c) Hydrolyzing the compound M-5 under alkaline conditions to obtain a compound M-6;
(d) The compounds M-2 and M-6 are reacted with an amide condensing agent HATU to produce compound M-7;
(e) Removing Boc protecting group from compound M-7 under acidic condition to produce compound M-8;
(f) Compounds M-8 and R 2 Generating a compound P under the action of an amide condensing agent EDC and HOBT;
；
the group A is:
；
compound M-4 is a group A with a bond-B- (OH) below 2 Is of a structure of (2);
the group M is:
；
the compound M is a group M, H is connected to the left side of the group M, and-CO-O-C (CH) 3 ) 3 Is of a structure of (2);
R 2 the method comprises the following steps:
；
x is-CH or N;
y is-CH or N;
R 1 is C1-C4 alkyl or H;
w is-CH or N.
The preparation method of the DNA polymerase theta (Pol theta) and poly ADP ribose polymerase 1 (PARP 1) double-target inhibitor, tautomer or pharmaceutically acceptable salt thereof comprises the following specific reaction reagents and conditions:
(a) DIPEA, DMF, 50-70℃； (b) Pd(dppf)Cl 2 , K 2 CO 3 , 1,4-Dioxane : H 2 o (7-9: 1), 70-90 ℃; (c) NaOH, meOH, 40-60 ℃; (d) HATU, DIPEA, DMF, room temperature; (e) EA, HCl/EA, room temperature; (f) EDC, HOBT, DIPEA, DMF, room temperature.
The beneficial effects are that: compared with the prior art, the compound has the double-target inhibition activity of Pol theta and PARP1, can play a stronger role in resisting proliferation activity on homologous recombination repair pathway (HR) defective cancer cells, and can reduce toxic and side effects caused by combined administration while playing an anti-tumor role.
Drawings
FIG. 1 shows the apoptosis test results of the negative control group;
FIG. 2 shows the experimental results of the effect of Olaparib on apoptosis;
FIG. 3 shows experimental results of the effect of Novobiocin on apoptosis;
FIG. 4 is a graph showing the experimental results of the effect of olaparib+Novobiocin on apoptosis;
FIG. 5 shows the experimental results of the effect of P9 on apoptosis;
FIG. 6 shows the results of cell cycle experiments for the negative control group;
FIG. 7 is a graph showing the results of an experiment of the effect of Olaparib on cell cycle;
FIG. 8 shows experimental results of the effect of Novobiocin on cell cycle;
FIG. 9 is a graph showing the experimental results of the effect of olaparib+Novobiocin on cell cycle;
FIG. 10 shows the experimental results of the effect of P9 on cell cycle.
Detailed Description
The nuclear magnetic resonance spectrum data of the final product and the intermediate in the examples are obtained in DMSO-d 6 Or CDCl 3 -d 3 TMS is used as an internal standard and is measured by a 300 MHz or 400 MHz nuclear magnetic resonance apparatus of Bruker company; high Resolution Mass Spectra (HRMS) were all determined by the agilent model Q-TOF 6520 mass spectrometer.
Reagents used in the synthesis, purification and isolation of the compounds are: (1) column chromatography silica gel: 200 or 300 mesh silica gel is purchased from Qingdao ocean chemical industry; (2) HSGF254 TLC thin layer chromatography plate: purchased from the tobacco stand chemical institute; (3) The conventional solvents used in the column chromatography elution system, such as petroleum ether, methylene chloride, ethyl acetate, methanol, etc., and the chemical reagents required for the reaction, are commercially available chemical or analytical pure products unless specified otherwise.
Example 1: synthesis of 4- (4-fluoro-3- (4- (3- (2-methoxyphenyl) isonicotinyl) piperazine-1-carbonyl) benzyl) phthalazin-1 (2H) one (P1)
The synthetic route is as follows:
step 1:
at room temperature, combiningObject 1 (1.0 g, 6.28 mmol) and Compound 2 (1.2 g, 5.48 mmol) were dissolved in 8 ml 1, 4-dioxane, and potassium carbonate (1.5 g, 10.96 mmol), 1 ml water and Pd (dppf) Cl were added sequentially 2 (144 mg, 0.03 mmol) and under nitrogen at 80℃overnight. TLC monitored the reaction was complete. After the reaction cooled to room temperature, water was added, extracted with ethyl acetate, washed with water, saturated brine, and anhydrous Na 2 SO 4 Drying, distilling under reduced pressure, and column chromatography to obtain white solid 1.0. 1.0 g.
Step 2:
compound 3 (1.0 g, 4.11 mmol) was dissolved in 10 mL methanol and water (1:1), naOH (493 mg, 12.33 mmol) was added, the reaction was allowed to proceed for 3h at 50℃and TCL was monitored for reaction completion. Concentrating the reaction solution until no fraction flows out, regulating the pH to 4-5 by using 10% dilute hydrochloric acid, precipitating white solid, carrying out suction filtration, and drying at 50 ℃ to obtain white solid 800 mg. Directly drop without purification.
Step 3:
compound 4 (0.8 g, 3.49 mmol) and compound 5 (550 mg, 3.0 mmol) were dissolved in 3 ml DMF and HATU (1.3 g, 3.5 mmol), DIPEA (1.2 g, 8.74 mmol), N were added sequentially 2 The reaction was allowed to proceed overnight at room temperature under protection, and TCL was monitored for completion. Adding water, extracting with ethyl acetate, washing with water, saturated salt water, and anhydrous Na 2 SO 4 Drying, distilling under reduced pressure, and column chromatography to obtain white solid 0.3. 0.3 g.
Step 4:
compound 6 (0.3 g, 0.76 mmol) was dissolved in 1 mL ethyl acetate, 1 mL ethyl acetate hydrochloride solution was added to react at room temperature for 2h, and after tlc monitoring the reaction was completed, the yellow solid 250 mg was obtained by concentrating under reduced pressure. Directly drop without purification.
Step 5:
compound 8 (0.27 g, 0.9 mmol), EDCI (172 mg, 0.9 mmol), HOBT (121.5 mg, 0.9 mmol), DIPEA (390 mg, 3.0 mmol) were dissolved in 2 ml DMF, reacted at room temperature under N2 protection 0.5 h, added compound 7 (0.25 g, 0.75 mmol) and reacted at room temperature overnight under N2 protection. TCL monitors the completion of the reaction. Adding water, extracting with ethyl acetate, washing with water, saturated salt water, and anhydrous Na 2 SO 4 Drying, distilling under reduced pressure, and column chromatography to obtain white solid 80 mg. 1 H NMR (300 MHz, Chloroform-d) δ 8.70 (d, J = 17.7 Hz, 2H), 8.48 (dt, J = 6.2, 2.8 Hz, 1H), 7.79 (dq, J = 6.8, 3.6 Hz, 3H), 7.71 (dd, J = 6.2, 3.2 Hz, 1H), 7.45 – 7.33 (m, 4H), 7.09 – 6.99 (m, 4H), 4.28 (d, J = 4.4 Hz, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 3.16 (d, J = 71.8 Hz, 5H).
Example 2: synthesis of N- (5- (7- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) -7-azaspiro [3.5] nonan-2-yl) oxy) -1,3, 4-thiadiazol-2-yl) -3- (2-methoxyphenyl) isonicotinamide (P2)
Step 1, step 2, step 4, step 5 specific operation reference compound P1 synthesis
Step 3
Compound 9 (1.0 g, 5.56 mmol) and compound 10 (0.7 g, 3.70 mmol) were dissolved in 10 ml DMF and DIPEA (1.4 g, 11.1 mmol), N was added 2 Under protection, at 60 ℃ overnight. TCL monitors the completion of the reaction. Adding water, extracting with ethyl acetate, washing with water, saturated salt water, and anhydrous Na 2 SO 4 Drying, distilling under reduced pressure, and column chromatography to obtain yellow solid 200 mg.
Step 6:
compound 8 (190 mg, 0.61 mmol), EDCI (117 mg, 0.61 mmol), HOBT (82.4 mg, 0.61 mmol), DIPEA (160 mg, 1.23 mmol) were dissolved in 2 ml DMF and reacted at room temperature under N2 protection for 0.5 h, compound 13 (200 mg, 0.46 mmol), N were added 2 The reaction was allowed to proceed overnight at room temperature under protection. TCL monitors the completion of the reaction. Adding water, extracting with ethyl acetate, washing with water, saturated salt water, and anhydrous Na 2 SO 4 Drying, distilling under reduced pressure, and column chromatography to obtain pale yellow solid 50 mg. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J = 5.0 Hz, 1H), 8.59 (s, 1H), 8.26 (dd, J = 7.8, 1.5 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.91 (dd, J = 7.1, 1.5 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.61 (d, J = 5.0 Hz, 1H), 7.50 – 7.32 (m, 4H), 7.25 (t, J = 9.0 Hz, 1H), 7.11 – 6.95 (m, 2H), 4.33 (s, 2H), 3.52 (s, 3H), 3.48 (s, 2H), 3.33 (s, 3H), 3.16 (d, J = 5.2 Hz, 3H).
Example 3:
synthesis of P3
Referring to the synthetic method of example 2, compound 9 was replaced with 5-bromo-2-aminothiazole, with the other conditions unchanged. 1 H NMR (300 MHz, Chloroform-d) δ 8.80 – 8.62 (m, 2H), 8.44 (s, 1H), 7.84 – 7.65 (m, 4H), 7.57 (d, J = 5.0 Hz, 1H), 7.42 – 7.27 (m, 4H), 7.04 (q, J = 8.2, 7.2 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H), 4.28 (s, 2H), 3.88 (s, 2H), 3.58 (d, J = 4.0 Hz, 3H), 3.47 – 3.45 (m, 4H), 2.99 (d, J = 58.7 Hz, 2H).
Example 4:
synthesis of P4
Referring to the synthetic procedure of example 2, compound 10 was replaced with N-Boc-3-hydroxymethyl azetidine, with the other conditions unchanged. 1 H NMR (300 MHz, Chloroform-d) δ 8.81 (d, J = 5.2 Hz, 1H), 8.64 (s, 1H), 8.39 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.76 (q, J = 6.6, 5.4 Hz, 4H), 7.50 – 7.33 (m, 3H), 7.14 – 7.00 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 4.29 (s, 2H), 3.98 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H), 3.57 – 3.47 (m, 4H), 2.53 (s, 1H).
HRMS (ESI): m/z, Calcd. For C 35 H 28 FN 7 O 5 S [M+Na]+, 700.17489, Found 700.17216.
Example 5:
synthesis of P5
Referring to the synthetic method of example 2, compound 10 was replaced with 2-hydroxy-7-azaspiro [3-4 ]]Nonane-7-carboxylic acid tert-butyl ester, the other conditions being unchanged. 1 H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J = 31.4 Hz, 2H), 8.32 – 8.20 (m, 1H), 8.02 – 7.79 (m, 4H), 7.62 (s, 1H), 7.42 – 7.27 (m, 4H), 7.12 – 6.95 (m, 2H), 5.17 (s, 1H), 4.34 (d, J = 9.9 Hz, 2H), 3.51 (s, 5H), 3.07 (d, J = 21.3 Hz, 2H), 2.5 (s, 2H)，1.96 (s, 2H), 1.61 (s, 2H), 1.45 (s, 2H).
Example 6:
synthesis of P6
Step 1
CeCl3.7H2O (260 mg, 1.4 mmol), cuI (132.5 mg, 1.4 mmol), I2 (1182 mg, 9.34 mmol) were dissolved in 10 ml acetonitrile and stirred at room temperature for 30 min, then compound 15 (477 mg, 4.67 mmol) was added and stirring was continued for 10 min, after addition of compound 14 (530 mg, 3.5 mmol), stirring was continued at room temperature for 4H, after the reaction was completed, the reaction mixture was diluted with CH2Cl2 with 10% Na each 2 SO 3 The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4 and column chromatographed to give 300 mg as a pale yellow solid.
Step 2
Compound 16 (100 mg, 0.43 mmol) was dissolved in 3 ml methanol: to water (1:1), naOH (52 mg, 1.3 mmol) was added, and the mixture was reacted at 50℃for 3 hours, concentrated under reduced pressure, and pH was adjusted to 4-5 with 10% HCl solution to precipitate a pale yellow solid 92 mg.
Step 3
Compound 17 (92 mg, 0.45 mmol), compound 13 (65 mg, 0.15 mmol), EDCI (86.3 mg, 0.45 mmol), HOBT (61 mg, 0.45 mmol) were dissolved in 3 ml DMF and Et3N (122.4 mg, 1.2 mmol) was added and reacted overnight at room temperature under N2. Water was added to precipitate a pale yellow solid, which was slurried in methanol to give 80 mg. 1 H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.59 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 5.0 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.10 – 6.96 (m, 2H), 4.40 (s, 2H), 3.87 (s, 2H), 3.57 (s, 4H), 3.52 (s, 3H).
Example 7:
synthesis of P7
Referring to the synthetic method of example 2, compound 10 was replaced with 6-hydroxy-2-azaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester, the other conditions were unchanged. 1 H NMR (300 MHz, Chloroform-d) δ 11.63 (d, J = 9.2 Hz, 1H), 8.63 (d, J = 22.3 Hz, 2H), 8.45 – 8.27 (m, 1H), 7.97 (ddd, J = 11.1, 7.3, 2.4 Hz, 1H), 7.71 (qd, J = 3.9, 1.9 Hz, 3H), 7.59 (d, J = 5.7 Hz, 1H), 7.39 – 7.28 (m, 2H), 7.22 (dt, J = 7.6, 1.9 Hz, 1H), 7.06 – 6.92 (m, 2H), 6.84 (dd, J = 8.3, 2.7 Hz, 1H), 5.09 (p, J = 7.1 Hz, 1H), 4.27 (s, 2H), 3.67 (dd, J = 8.5, 6.1 Hz, 4H), 3.56 (d, J = 6.0 Hz, 3H), 2.21 (ddd, J = 32.2, 14.1, 6.5 Hz, 4H).
Example 8:
synthesis of P8
Referring to the synthetic method of example 2, compound 10 was replaced with N-Boc-4-piperidinemethanol, with the other conditions unchanged. 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 5.0 Hz, 1H), 8.60 (s, 1H), 8.26 (ddd, J = 7.7, 4.2, 1.6 Hz, 2H), 7.97 (dd, J = 7.7, 6.1 Hz, 2H), 7.91 – 7.77 (m, 3H), 7.62 (d, J = 5.1 Hz, 1H), 7.36 (dd, J = 7.4, 1.7 Hz, 3H), 7.27 – 7.15 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.00 – 6.95 (m, 1H), 4.32 (t, J = 9.0 Hz, 4H), 3.51 (s, 3H), 3.14 – 2.66 (m, 2H), 2.20 – 2.05 (m, 1H), 2.04 – 1.37 (m, 4H).
Example 9:
synthesis of P9
Referring to the synthetic method of example 2, compound 1 was replaced with 5-chloro-2-methoxyphenylboronic acid, compound 2 was replaced with 4-bromo-6-methylnicotinic acid methyl ester, and compound 10 was replaced with N-Boc-4-piperidinemethanol, with the other conditions unchanged. 1 H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 12.60 (s, 1H), 8.68 (s, 1H), 8.25 (dd, J = 7.6, 1.5 Hz, 1H), 8.01 – 7.75 (m, 4H), 7.46 – 7.40 (m, 3H), 7.35 (s, 2H), 7.22 (t, J = 9.0 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 4.35 – 4.25 (m, 4H), 3.49 (s, 3H), 2.91 (dt, J = 73.2, 12.7 Hz, 2H), 2.56 (s, 3H), 2.31 – 1.53 (m, 4H).
Example 10:
synthesis of P10
Referring to the synthetic method of example 2, compound 1 was replaced with 5-fluoro-2-methoxyphenylboronic acid, compound 2 was replaced with 4-bromo-6-methylnicotinic acid methyl ester, and compound 10 was replaced with 2-hydroxy-7-azaspiro [3-4 ]]Nonane-7-carboxylic acid tert-butyl ester, the other conditions being unchanged. 1 H NMR (300 MHz, Chloroform-d) δ 8.97 (d, J = 3.6 Hz, 1H), 8.47 (dt, J = 6.7, 3.3 Hz, 1H), 7.82 – 7.68 (m, 3H), 7.31 (dd, J = 6.0, 2.9 Hz, 2H), 7.21 (d, J = 4.8 Hz, 1H), 7.14 – 6.97 (m, 3H), 6.85 (dt, J = 9.0, 3.5 Hz, 1H), 5.25 (d, J = 7.5 Hz, 1H), 4.30 (d, J = 8.5 Hz, 2H), 3.65 (d, J = 2.3 Hz, 3H), 3.22 (s, 2H), 2.73 (d, J = 3.9 Hz, 3H), 2.64 – 2.44 (m, 2H), 1.74 (t, J = 6.2 Hz, 2H), 1.59 (s, 2H).
Example 11:
synthesis of P11
Referring to the synthetic method of example 2, compound 10 was replaced with2, 7-diazaspiro [3.5]]Nonane-7-carboxylic acid tert-butyl ester, the other conditions being unchanged. 1 H NMR (300 MHz, DMSO-d6) δ 12.62 (s, 2H), 8.68 (s, 1H), 8.58 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.99 – 7.82 (m, 3H), 7.60 (d, J = 5.1 Hz, 1H), 7.34 (d, J = 6.9 Hz, 4H), 7.22 (t, J = 8.9 Hz, 1H), 7.08 – 6.97 (m, 2H), 4.32 (s, 2H), 3.87 – 3.71 (m, 4H), 3.51 (s, 3H), 3.12 (s, 4H), 1.80 (s, 2H), 1.66 (s, 2H).
Example 12:
synthesis of P12
Referring to the synthetic method of example 2, compound 1 was replaced with 5-chloro-2-methoxyphenylboronic acid, compound 2 was replaced with 4-bromo-6-methylnicotinic acid methyl ester, and compound 10 was replaced with 2-hydroxy-7-azaspiro [3-4 ]]Nonane-7-carboxylic acid tert-butyl ester, the other conditions being unchanged. 1 H NMR (300 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.46 – 8.37 (m, 1H), 7.81 – 7.66 (m, 3H), 7.33 – 7.21 (m, 4H), 7.14 (s, 1H), 7.01 (t, J = 8.6 Hz, 1H), 6.80 (dd, J = 8.8, 4.9 Hz, 1H), 5.19 (q, J = 7.0 Hz, 1H), 4.28 (d, J = 7.0 Hz, 2H), 3.76 – 3.12 (m, 7H), 2.65 (d, J = 2.1 Hz, 3H), 2.05 (d, J = 11.1 Hz, 4H), 1.70 (d, J = 6.3 Hz, 4H).
Example 13:
synthesis of P13
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Referring to the synthetic method of example 2, compound 1 was replaced with 2-fluoro-6-methoxyphenylboronic acid, compound 2 was replaced with 4-bromo-6-methylnicotinic acid methyl ester, and compound 10 was replaced with 2-hydroxy-7-azaspiro [3-4 ]]Nonane-7-carboxylic acid tert-butyl ester, the other conditions being unchanged. 1 H NMR (300 MHz, DMSO-d6) δ 12.62 (d, J = 2.3 Hz, 1H), 8.80 (s, 1H), 8.30 – 8.22 (m, 1H), 8.02 – 7.79 (m, 3H), 7.46 – 7.27 (m, 4H), 7.21 (td, J = 8.9, 3.4 Hz, 1H), 6.97 – 6.84 (m, 2H), 5.17 (dt, J = 13.9, 6.7 Hz, 1H), 4.32 (s, 2H), 3.57 (s, 3H), 3.07 (d, J = 22.8 Hz, 2H), 2.56 (s, 2H), 1.98 (dd, J = 21.9, 9.3 Hz, 2H), 1.53 (d, J = 45.6 Hz, 4H).
Example 14:
synthesis of P14
Step 1
Compound 1 (1.0 g, 4.63 mmol) and compound 2 (0.62 g, 7.0 mmol) were dissolved in 8 ml toluene at room temperature, cesium carbonate (4.6 g, 13.8 mmol), X-phos (0.12 mg, 0.24 mmol) and Pd (dba) 3 (0.22 g, 0.24 mmol) were added sequentially and reacted overnight at 100℃under nitrogen. TLC monitored the reaction was complete. After the reaction was cooled to room temperature, water was added, extraction was performed with ethyl acetate, washing was performed with water, saturated brine, dried over anhydrous Na2SO4, and distillation was performed under reduced pressure, followed by column chromatography to obtain 600mg of a pale yellow solid.
Step 2, 3,4, 5,6
Reference is made to steps 2, 3,4, 5,6 in example 2. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.45 (d, J = 4.9 Hz, 1H), 8.25 (dd, J = 7.7, 1.6 Hz, 1H), 7.97 (d, J = 7.4 Hz, 1H), 7.92 – 7.79 (m, 2H), 7.62 (d, J = 4.9 Hz, 1H), 7.46 – 7.32 (m, 2H), 7.22 (t, J = 9.0 Hz, 1H), 4.32 (d, J = 3.7 Hz, 4H), 3.72 (dd, J = 5.9, 3.2 Hz, 4H), 3.12 – 3.05 (m, 4H), 3.03 – 2.70 (m, 2H), 1.92 – 1.54 (m, 2H).
Example 15:
synthesis of P15
Step 1
Compound 1 (2.0 g, 6.71 mmol) was dissolved in anhydrous THF, liAlH4 (0.83 g, 20.13 mmol) was slowly added and reacted for 2h at 0 ℃, after tlc monitoring the reaction was completed, the reaction night was poured into 1M dilute hydrochloric acid at 0 ℃ and suction filtered to give grey solid 800 mg.
Step 2, 3
Refer to step 3,4 in example 2. 1 H NMR (300 MHz, Chloroform-d) δ 8.71 (t, J = 3.5 Hz, 1H), 8.64 (s, 1H), 8.40 – 8.35 (m, 1H), 7.72 (h, J = 5.5, 5.0 Hz, 4H), 7.41 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.02 (dt, J = 10.6, 8.2 Hz, 2H), 6.89 (d, J = 8.3 Hz, 1H), 5.43 (s, 2H), 4.27 (s, 2H), 3.62 (d, J = 2.0 Hz, 3H).
Example 16:
synthesis of P16
Step 1
Compound 1 (4.5 g, 22.61 mmol) and compound 2 (4.2 g, 27.13 mmol) were dissolved in THF and NaHCO was added in portions 3 (7.6. 7.6 g, 90.45 mmol) and the reaction mixture was reacted at 25℃overnight, after which the reaction was quenched by TLC, extracted with ethyl acetate, anhydrous Na 2 SO 4 Drying and distillation under reduced pressure gave 6.0. 6.0 g as a yellow solid.
Step 2
Compound 3 (2.0 g, 6.75 mmol) was dissolved in 70 ml methanol and Pd/C (0.6 g, 5.64 mmol) was added and reacted overnight at room temperature under an H2 atmosphere. After the TLC monitoring reaction was completed, celite was filtered, distilled under reduced pressure, and slurried with methanol to give 4.6 g of the compound.
Step 3
Compound 4 (0.6 g, 2.6 mmol) was dissolved in 8 ml 1, 4-dioxane, DDQ (0.58 g, 2.9 mmol) was added and reacted overnight at room temperature. After the TLC monitoring reaction was completed, the reaction solution was poured into 20 ml saturated NaHCO3 solution, stirred for 20 min, suction filtered and the filter cake was washed three times with water. 0.5 g of compound 5 was obtained.
Step 4
Compound 5 (0.49 g, 2.11 mmol) was dissolved in 5 ml THF, liAlH4 (0.25 g, 6.25 mmol) was added at 0deg.C, the reaction was maintained at 0deg.C for 1.5 h, after TLC monitoring was completed, the reaction solution was poured into 1M diluted hydrochloric acid at 0deg.C, and the solid was suction filtered and washed with water three times to give a gray solid of 0.3 mg.
Steps 5,6 refer to steps 3, 6 of example 2. 1 H NMR (300 MHz, Chloroform-d) δ 8.71 (dd, J = 7.5, 4.3 Hz, 1H), 8.65 (s, 1H), 7.77 – 7.68 (m, 2H), 7.32 (dd, J = 7.4, 1.4 Hz, 2H), 7.08 (t, J = 8.0 Hz, 1H), 7.00 – 6.89 (m, 2H), 6.81 (d, J = 8.2 Hz, 1H), 5.23 (s, 2H), 3.60 (s, 3H), 3.00 (q, J = 7.5 Hz, 2H), 1.37 (t, J = 7.4 Hz, 3H).
Example 17:
activity test
Determination of in vitro Pol theta inhibition Activity by ADP-GloTM luminescence method
Experimental materials
ADP-Glo ™ kinase assay kit (Promega); ssDNA (Genscript); POLQ protein (In house); novobiocin (MCE); 96-well plates (Nunc); 384 well Plates (PE); a centrifuge (Cence); microplate reader (BMG).
Test method
50 μl of compound was added to 384 well dilution plates, and each column was diluted 1:3 with DMSO for 10 spots in series. Each row of 0.1 μl diluted compound solution was transferred to 384 assay plates with Echo, 2 replicates per column. 5 μl of enzyme working solution was added to 384 well plates, centrifuged at 1000 rpm for 1 min and incubated at 25℃for 10 min. 5 μl (ssDNA and ATP) of working fluid was added, centrifuged at 1000 rpm for 1 min and incubated at 25℃for 60 min. 5 μl of ADP-Glo ™ reagent solution was added, centrifuged at 1000 rpm for 1 min and incubated at 25℃for 40 min. 10. Mu.L of ADP-Glo ™ kinase assay solution was added and centrifuged at 1000 rpm for 1 minute.
Experimental results
Colorimetric assay for in vitro PARP1 inhibitory Activity
1. Experimental materials
PARP1 colorimetric assay kit (cat# 80580, BPS Bioscience); PBS (Cat# 21600-010, gibco); tween-20 (cat#p9416, sigma); ELISA stop solution (Cat#C1058, solarbio)
2. Measurement method
1) Diluting a10 x PARP buffer solution with deionized water to obtain a 1x PARP buffer solution, diluting the composite stock solution to 1 mu M for later use with DMSO, and diluting a1 mu M compound solution to 10 nM with the 1x PARP buffer solution. Washing the tray 3 times with 200 [ mu ] L/hole PBST, adding 200 [ mu ] L/hole blocking buffer solution, and incubating for 90 min at room temperature. The tray was washed 3 more times with 200 μl/well PBST.
2) Preparing a main mixed solution: n hole x (2.5 mu L10 x PARP buffer+2.5 mu L10 x PARP detection liquid+5 mu L activated DNA+15 mu L distilled water), and 25 mu L of each hole is added.
3) The uniform compound was diluted by adding 5 μl/well and the same volume of 1x PARP buffer containing 10% DMSO was added to the carrier control well and blank well. PARP1 was thawed on ice and diluted to 1.0 ng/ul with 1x PARP buffer. 20 [ mu ] L of diluted PARP enzyme is added into a non-blank hole. 20 μl/well 1×parp buffer was added to the blank wells. The reaction was carried out at room temperature for 60 minutes. The trays were washed 3 times with 200 μl/well PBST.
4) streptavidin-HRP was diluted 1:50 with blocking buffer, 50 μl of diluted streptavidin-HRP was added per well and incubated for 30 min at room temperature. The tray was washed 3 times with 200 μl/well PBST, 100 μl/well HRP colorimetric substrate was added for 20 min at room temperature, 100 μl/well 2M sulfuric acid was added, and OD 450 nm was read on a microplate reader.
(II) results of experiments
Antiproliferative assays of (III) Compounds
1. Experimental materials
HCT116 cells, mcCoy's 5A incomplete medium (KEL biotech); HCC1937 cells (Guangzhou Cellcook Biotech), RPMI 1640 incomplete medium (Guangzhou Cellcook Biotech); MDA-MB-436 cells (Guangzhou Cellcook Biotech); MDA-MB-468 cells; l-15 Medium (Guangzhou Cellcook Biotech) SKOV-3 cells (Guangzhou Cellcook Biotech); capan-1 cells (Woheprunocel Life technologies Co., ltd.); IMDM incomplete culture mediumThe marsupronosia life technology company limited); fetal bovine serum (Guangzhou Cellcook Biotech); ESCO CO 2 An incubator; microscope (Jiangnan Yongxin XD-202); centrifuge (DM 0412); a microplate reader (Thermo); autoclaving (Zealway).
2. Test method
Taking cells in logarithmic growth phase, pouring out old culture medium, washing twice with PBS, adding 1 mL of 0.25% trypsin solution for digestion for 1 min, observing cell rounding under a microscope, adding 4 mL of fresh culture medium containing 10% fetal bovine serum for stopping digestion, transferring the solution to a centrifuge tube, centrifuging at 1000 r/min for 5 min, and discarding the supernatant. Cells were resuspended in 1 mL medium and counted. After counting was completed, cells were seeded in 96-well plates at a concentration of 3000-7000 cells per well, 100 μl per well. The 96-well plate with the cells spread is placed at 37 ℃ and 5% CO 2 The incubator continues to incubate 12 h. The drugs were diluted in gradient to 100. Mu. Mol/L, 33.3. Mu. Mol/L, 11.1. Mu. Mol/L, 3.7. Mu. Mol/L, 1.2. Mu. Mol/L, 0.4. Mu. Mol/L with medium, and then added to 96-well plates at 100. Mu.L per well, with three multiplex wells per concentration. Adding medium containing solvent in corresponding concentration into control group, adding blank medium with the same volume into zeroing hole, and placing in 5% CO 2 Incubate at 37℃for 5 days. mu.L MTT (5 mg/mL) was added to each well, and after mixing well, the mixture was treated with 5% CO 2 Culturing in a 37 ℃ incubator in dark for 4 h. The liquid in the 96-well plate was removed, 100 μl DMSO was added to each well, and the mixture was placed on a micro-shaker and shaken to completely dissolve the crystals at the bottom. The 96-well plate was then placed in an microplate reader for detection, absorbance was measured at 570 nm, a curve was drawn and the inhibition of the drug to cells and IC50 were calculated. Inhibition ratio = ((control mean OD value-experimental mean OD value)/(control mean OD value-blank mean OD value)) ×100%.
3. Experimental results
(IV) apoptosis and cell cycle experiments
1. Experimental materials
MDA-MB-436 cells (Jiangsu Kaiki Biotechnology Co., ltd.). L-15 complete medium, 6 well cell culture plate (U.S. Corning Incorporated 3516), annexin V-APC/7-AAD apoptosis detection kit (KGA 1024, china Jiangsu Kaiki biotechnology Co., ltd.), and cell cycle detection kit (KGA 511, china Jiangsu Kaiki biotechnology Co., ltd.)
2. Experimental procedure
Apoptosis experimental procedure: the cells in the logarithmic growth phase are digested and inoculated into a six-hole plate, after the cells are attached to the wall, the corresponding medicine-containing culture medium is added according to the group setting, and meanwhile, a negative control group is established; after 72h drug action, cells were harvested by digestion with 0.25% pancreatin (EDTA-free); the cells were washed twice with PBS (centrifugation 1000 rpm,5 min) and 1X 10 was collected 6 A cell; adding 500 mu L Binding Buffer suspension cells; adding 5 mu L Annexin V-APC, uniformly mixing, adding 5 mu L7-AAD, and uniformly mixing; light-shielding at room temperature for 5-15 min; apoptosis was detected by flow cytometry. Detection was performed on a flow cytometer within 1 h. The green fluorescence of Annexin V-FITC is detected by FITC channel (FL 1), and the PI red fluorescence is detected by PI channel (FL 2). Wherein, the flow cytometer parameters are: excitation wavelength ex=488 nm, emission wave FL1 (em=525±20 nm); FL2 (em=585±21 nm). Early apoptosis, late apoptosis, death, and proportion of normal cells were analyzed with FlowJo software.
Cell cycle experimental procedure: the cells were washed twice with PBS (centrifugation 1000 rpm,5 min) and collected 5X 10 5 A cell; fixing the prepared single cell suspension with 70% ethanol for 2 hr (or overnight), preserving at 4deg.C, and washing off the fixing solution with PBS before dyeing; 3. adding 100 mu L of RNase A into the water bath at 37 ℃ for 30 min; adding 400 mu L of PI for dyeing and mixing uniformly, and keeping out of light for 30 min at 4 ℃; and (5) detecting by a machine, and recording red fluorescence at an excitation wavelength 488 nm.
3. Experimental results
As shown in fig. 1-5, compound P9 can significantly induce MDA-MB-436 apoptosis after 72h administration, the total apoptosis rate is 26.71%, and the pro-apoptotic effect is significantly better than that of the positive drug Olaparib (8.95%), novobiocin (6.44%) and the combination of both (14.22%). As shown in fig. 6-10, compound P9 can block the cell cycle at G2/M phase after 72h of administration.

Claims (10)

1. A dual-target inhibitor of DNA polymerase θ and poly ADP-ribose polymerase 1 or a pharmaceutically acceptable salt thereof, as shown in formula (I):
；
wherein:
x is-CH or N;
y is-CH or N;
R 1 is C 1 -C 4 Alkyl or H;
w is-CH or N;
linker is any one of the following structures:
；
a is any one of the following structures:
；
R 2 is any one of the following structures:
。
2. the double-target inhibitor of DNA polymerase θ and poly ADP-ribose polymerase 1 or pharmaceutically acceptable salt thereof according to claim 1, wherein when X is-CH and Y is N, R 1 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the When X is N and Y is-CH, R 1 H.
3. A dual-target inhibitor of DNA polymerase θ and poly ADP-ribose polymerase 1, or a pharmaceutically acceptable salt thereof, characterized by any one compound selected from the group consisting of:
。
4. use of the DNA polymerase θ and poly ADP ribose polymerase 1 dual target inhibitor or pharmaceutically acceptable salt thereof of claim 1 in the preparation of a Pol θ inhibitor.
5. Use of the DNA polymerase θ and poly ADP ribose polymerase 1 dual target inhibitor or pharmaceutically acceptable salt of claim 1 in the preparation of a PARP1 inhibitor.
6. Use of a DNA polymerase θ and a poly ADP ribose polymerase 1 dual target inhibitor or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for treating or preventing cancer that is deficient in homologous recombination repair pathways.
7. A pharmaceutical composition comprising a dual-target inhibitor of DNA polymerase θ and poly ADP-ribose polymerase 1 of claim 1, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
8. Use of the DNA polymerase θ and poly ADP ribose polymerase 1 dual-target inhibitor or pharmaceutically acceptable salt thereof of claim 1 or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating or preventing colon cancer, breast cancer, ovarian cancer, pancreatic cancer.
9. A method of preparing a dual-target inhibitor of DNA polymerase θ and poly ADP-ribose polymerase 1 or a pharmaceutically acceptable salt thereof as claimed in claim 1, comprising the steps of:
(a) The compound M and M-1 are subjected to substitution reaction to prepare a compound M-2;
(b) The compound M-5 is prepared by SUZUKI reaction of the compound M-3 and the compound M-4;
(c) Hydrolyzing the compound M-5 under alkaline conditions to obtain a compound M-6;
(d) The compounds M-2 and M-6 are reacted with an amide condensing agent HATU to produce compound M-7;
(e) Removing Boc protecting group from compound M-7 under acidic condition to produce compound M-8;
(f) Compounds M-8 and R 2 Generating a compound P under the action of an amide condensing agent EDC and HOBT;
；
the group A is:
；
compound M-4 is a group A with a bond-B- (OH) below 2 Is of a structure of (2);
the group M is:
；
the compound M is a group M, H is connected to the left side of the group M, and-CO-O-C (CH) 3 ) 3 Is of a structure of (2);
R 2 the method comprises the following steps:
；
x is-CH or N;
y is-CH or N;
R 1 is C1-C4 alkyl or H;
w is-CH or N.
10. The method for preparing the double-target inhibitor of the DNA polymerase theta and the poly ADP-ribose polymerase 1 or the pharmaceutically acceptable salt thereof according to claim 9, wherein the specific reaction reagents and conditions are as follows:
(a) DIPEA, DMF, 50-70℃； (b) Pd(dppf)Cl 2 , K 2 CO 3 , 1,4-Dioxane : H 2 o (7-9: 1), 70-90 ℃; (c) NaOH, meOH, 40-60 ℃; (d) HATU, DIPEA, DMF, room temperature; (e) EA, HCl/EA, room temperature; (f) EDC, HOBT, DIPEA, DMF, room temperature.
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