WO2020093272A1

WO2020093272A1 - Sulfonyl fluoride-containing compound with high affinity to parp receptor and preparation and use thereof

Info

Publication number: WO2020093272A1
Application number: PCT/CN2018/114371
Authority: WO
Inventors: 杨光; 许红涛
Original assignee: 上海科技大学
Priority date: 2018-11-07
Filing date: 2018-11-07
Publication date: 2020-05-14
Also published as: CN112969689A

Abstract

The present application belongs to the technical field of organic chemistry, and particularly relates to a sulfonyl fluoride-containing compound with high affinity to a PARP receptor, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. The present application provides a compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, the compound having the structural formula shown in formula I. The compound provided by the present application is a novel, safe and highly efficient PARP inhibitor drug, and a positron tomography imaging agent with PARP as a biomarker, with significant social and economic value.

Description

Sulfonyl fluoride-containing compound with high affinity for PARP receptor and preparation and use thereof

Technical field

The present invention relates to the field of organic chemistry, in particular to a sulfonyl fluoride-containing compound with high affinity for PARP receptor or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

Background technique

Positron Emission Computed Tomography is a medically advanced clinical examination imaging technology. The general method is to inject a radionuclide (such as ¹⁸ F, ¹¹ C, etc.) on a certain substance and inject it. After the human body, by detecting the accumulation of the substance in the target tissue to reflect the status of life metabolic activities, so as to achieve the purpose of diagnosis.

PET may be the only new imaging technology that can display biomolecule metabolism, receptors and neural mediator activity on the living body, so how to further promote the application of PET is a hot topic in this field.

Summary of the invention

In view of the above shortcomings of the prior art, the object of the present invention is to provide a sulfonyl fluoride-containing compound with high affinity for PARP receptor or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof , Used to solve the problems in the prior art.

To achieve the above objects and other related objects, one aspect of the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof. The structural formula of the compound is shown in Formula I:

Among them, R1 is selected from groups having affinity for PARP receptors;

R2 is selected from substituted or unsubstituted, branched or unbranched C2-C10 terminal alkenyl, substituted or unsubstituted C6-C20 phenolic hydroxyaryl, substituted or unsubstituted C2-C20 phenolic hydroxyheteroaryl, Substituted or unsubstituted, branched or unbranched C6 ～ C20 (phenol hydroxyaryl) alkyl, substituted or unsubstituted, branched or unbranched C2 ～ C20 (phenol hydroxyheteroaryl) alkyl ;

The -SO ₂ F group is -SO ₂ ¹⁸ F and / or -SO ₂ ¹⁹ F.

Another aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of a PARP receptor inhibitor. The PARP receptor is preferably selected from PARP-1 Receptor, PARP-2 receptor.

Another aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of an imaging agent, preferably the imaging agent uses PARP as a biomarker The developer is preferably a positron tomographic developer.

Another aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of a medicament for diagnosis, prevention or treatment of diseases associated with PARP enzymes, preferably The PARP enzyme-related diseases include cancer, ischemic diseases and neurodegenerative diseases.

Another aspect of the present invention provides a composition comprising the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

BRIEF DESCRIPTION

Figure 1 shows the thermal standard spectrum of compound P4;

Figure 2 shows the UV spectrum of compound P4;

Figure 3 shows the trace of [ ¹⁸ F] P4 on MCF-7 transplanted tumor in nude mice;

Figure 4a shows the uptake curve of [ ¹⁸ F] P4 in tumor tissue and muscle tissue in MCF-7 transplanted nude mice;

Figure 4b shows the uptake curve of tumor tissues and muscle tissues in the pre-injection of Oliparib in MCF-7 transplanted nude mice to saturate the PARP-1 receptor on the tumor surface, and then [ ¹⁸ F] P4 injection after 30 minutes;

Figure 4c shows PARP-1 immunohistochemical staining of tumor tissue;

Figure 4d shows PARP-1 immunohistochemical staining of the muscle tissue opposite to the tumor.

detailed description

After extensive research, the inventors of the present invention have provided a compound against PARP receptor or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, the compound having a high affinity for PARP receptor, while It is also possible to exchange ¹⁹ F in the compound into the radioisotope ¹⁸ F by the method of ¹⁹ F- ¹⁸ F isotope exchange. The obtained ¹⁸ F-labeled compound can be used as a positron emission computed tomography (PET) developer, or As a small molecule of PARP inhibitor, it is a new type of PARP inhibitor that integrates treatment and diagnosis. Based on this, the present invention has been completed

The first aspect of the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. The structural formula of the compound is shown in Formula I:

Among them, R1 is selected from groups having affinity for PARP receptors;

R2 is selected from substituted or unsubstituted, branched or unbranched C2-C10, C2-C6, C2-C3 terminal alkenyl, substituted or unsubstituted C6-C20, C6-C12, C6-C8 phenolic hydroxy aromatic Group, substituted or unsubstituted C2-C20, C2-C12, C2-C8, C2-C6 phenolic hydroxyheteroaryl, substituted or unsubstituted, branched or unbranched C6-C20, C6-C12, C6 ~ C8 (phenol hydroxyaryl) alkyl, substituted or unsubstituted, branched or unbranched C2-C20, C2-C12, C2-C8, C2-C6 (phenol-hydroxyheteroaryl) alkyl;

The -SO ₂ F group is -SO ₂ ¹⁸ F and / or -SO ₂ ¹⁹ F.

In the present invention, R1 generally has good affinity for PARP receptors, for example, it may include various groups formed by PARP inhibitors, tracers, etc. that have good affinity for PARP receptors, and these groups usually have an affinity for Said has a key role. For example, R1 may be selected from the groups shown in Formula II:

Among them, X, Y, Z form a benzo five-membered aromatic heterocycle, and the hetero atom is selected from N, O or S;

In the R1 group, X may be selected from O, S, N, NR ', C; Y may be selected from C, N; Z may be selected from O, S, N, NR ", C;

R, R ', R "may be independently selected from H, substituted or unsubstituted, branched or unbranched C1-C20, C1-C12, C1-C6, C1-C3 alkyl, wherein The substituent of the group may be selected from hydroxyl, cyano, carbonyl, carboxyl, amide, sulfonyl, halogen atom (fluorine, chlorine, bromine or iodine), etc .;

When X is NR ', R' may be bridged with R to form a benzoheterocycloalkyl, the heterocycloalkyl may be six-membered, seven-membered, eight-membered, nine-membered, ten-membered, the hetero The hetero atom of the cycloalkyl group is selected from N, O, S, P and the like.

In R1, the benzo five-membered aromatic heterocyclic ring formed by X, Y, and Z may be specifically selected from benzimidazole, benzopyrazole, benzothiazole, benzoxazole, benzopyrrole (indole), benzene And furan.

In some specific embodiments of the present invention, the R1 may be selected from the following groups:

In the present invention, R1 may also be a group shown below:

In the present invention, when R2 is selected from a terminal alkenyl group, the terminal of the terminal alkenyl group is connected to -SO ₂ F through a covalent bond, the terminal alkenyl group may be mono- or poly-substituted, and the substitution of the terminal alkenyl group The groups may be independently selected from alkyl groups, alkynyl groups, aryl groups, carbonyl groups, amide groups, sulfonyl groups, halogen atoms (for example, fluorine, chlorine, bromine or iodine), etc .;

When R2 is selected from a phenolic hydroxyaryl group, the phenolic hydroxyl group on the phenolic hydroxyaryl group forms a covalent bond with -SO ₂ F, and the phenolic hydroxyaryl group may be five-membered, six-membered, seven-membered, five-membered and six-membered , Six-membered and six-membered, the phenolic hydroxyaryl group may be mono-substituted or multi-substituted, and the substituents of the phenolic hydroxyaryl group may be independently selected from halogen atoms, the substituents are selected from halogen atom substitutions or The unsubstituted C1-C3 alkyl group and the substituent are selected from halogen atom-substituted or unsubstituted C1-C3 alkoxy groups, which may specifically be, for example, methyl, difluoromethyl, trifluoromethyl, methoxy, tri Fluoromethoxy, fluorine, chlorine, bromine, iodine, etc .;

When R2 is selected from a phenolic hydroxyheteroaryl group, the phenolic hydroxyl group on the phenolic hydroxyheteroaryl group forms a covalent bond with -SO ₂ F, and the phenolic hydroxyheteroaryl group may be five-membered, six-membered, seven-membered, five-membered and Six-membered, six-membered and six-membered, the phenolic hydroxyheteroaryl group may be mono- or polysubstituted, and the substituents of the phenolic hydroxyheteroaryl group may be independently selected from halogen atoms, and the substituent is selected from halogen Atom-substituted or unsubstituted C1-C3 alkyl groups, the substituents are selected from halogen atom-substituted or unsubstituted C1-C3 alkoxy groups, and may specifically be, for example, methyl, difluoromethyl, trifluoromethyl, methyl Oxygen, trifluoromethoxy, fluorine, chlorine, bromine or iodine);

When R2 is selected from (phenol hydroxyaryl) alkyl group, the phenolic hydroxyl group on the phenolic hydroxy group forms a covalent bond with -SO ₂ F, the (phenol hydroxyaryl) alkyl group may be five-membered, six-membered, Seven-membered, five-membered and six-membered, six-membered and six-membered, the (phenolic hydroxyaryl) alkyl group may be mono-substituted or multi-substituted, the (phenolic hydroxyaryl) alkyl group on the aryl group The substituents may be independently selected from halogen atoms, the substituents are selected from substituted or unsubstituted C1-C3 alkyl groups of halogen atoms, the substituents are selected from substituted or unsubstituted C1-C3 alkoxy groups of halogen atoms, alkyl groups The substituents on can be independently selected from alkyl, alkynyl, aryl, carbonyl, amido, sulfonyl, halogen atom (fluorine, chlorine, bromine or iodine), etc .;

When R2 is selected from (phenol hydroxyheteroaryl) alkyl, the phenolic hydroxyl group on the phenol hydroxyheteroaryl group forms a covalent bond with -SO ₂ F, and the (phenol hydroxyheteroaryl) alkyl group may be a five-membered, Six-membered, seven-membered, five-membered and six-membered, six-membered and six-membered, the (phenolic hydroxyheteroaryl) alkyl group may be mono- or polysubstituted, and the (phenolic hydroxyheteroaryl) alkyl group The substituents on the middle aryl group may be independently selected from halogen atoms, the substituents are selected from halogen atoms substituted or unsubstituted C1-C3 alkyl groups, and the substituents are selected from halogen atoms substituted or unsubstituted C1-C3 alkyl groups The substituents on the oxy group and the alkyl group may be independently selected from alkyl groups, alkynyl groups, aryl groups, carbonyl groups, amido groups, sulfonyl groups, halogen atoms (fluorine, chlorine, bromine, or iodine) and the like.

The terminal alkenyl group generally refers to a group where the C = C group of the alkenyl group is located at the end of the molecular chain. The terminal alkenyl group may be a terminal vinyl group, a terminal propenyl group, a terminal butenyl group, a terminal pentenyl group, and the like.

The phenolic hydroxy group generally refers to a ring system having at least one aromatic ring and containing a phenolic hydroxyl group, but without a heteroatom, the aryl group may be phenyl, naphthyl, or the like.

The phenolic hydroxyheteroaryl group generally refers to having at least one aromatic ring, and may optionally contain one or more selected from N, O, and S as heteroatoms, and the heteroaryl group may be pyridyl or pyrimidinyl , Pyrrolyl, furanyl, pyrazolyl, imidazolyl, thienyl, thiazolyl and so on.

The alkyl group generally refers to a saturated aliphatic group, and the alkyl group may be methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like.

In some specific embodiments of the present invention, the R2 is selected from the following groups:

In the present invention, the compound represented by the above formula I may include an enantiomer depending on the presence of a chiral center or an isomer depending on the presence of a double bond (for example, Z, E), specifically, for example, a single isomer Both enantiomers or diastereomers and mixtures thereof may fall within the scope of the present invention.

In the present invention, a solvate generally refers to a compound connected to another molecule (most likely a polar solvent) via a non-covalent bond, especially including hydrates and alcoholates, such as methanolates.

In the present invention, prodrugs generally refer to those derivatives that can be converted into the compounds of the present invention in vivo.

The second aspect of the present invention provides the use of the compound or its pharmaceutically acceptable salts, isomers, prodrugs or solvates in the preparation of PARP receptor inhibitors. In some embodiments of the present invention, the PARP receptor may be a PARP-1 receptor or a PARP-2 receptor.

The third aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of an imaging agent. The imaging agent may use PARP as a biomarker. The developer is a positron tomography developer. In some embodiments of the present invention, the PARP receptor may be a PARP-1 receptor or a PARP-2 receptor.

The fourth aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of a medicament for diagnosis, prevention or treatment of diseases associated with PARP enzymes. PARP enzyme-related diseases include cancer (for example, breast cancer, ovarian cancer, prostate cancer, colon cancer, pancreatic cancer, liver cancer, melanoma, gastric cancer and solid tumors, etc.), various ischemic diseases and neurodegenerative diseases (for example, Parkinson's disease, Alzheimer's disease, etc.).

A fifth aspect of the present invention provides a composition comprising the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. The composition may be a pharmaceutical composition, a developer Compositions, etc., the content of the compound or the pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the composition may generally be a therapeutically effective amount and / or a developing effective amount.

The present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, the method may isotope exchange by the ¹⁹ F- ¹⁸ F fluoride-based compounds exchanged into ¹⁹ F The radioactive isotope ¹⁸ F, the resulting ¹⁸ F-labeled compound can be used as a positron tracer, so that PARP probe molecules containing ¹⁸ F nuclides can be synthesized, and the PARP-1 protein in patients can be dynamically evaluated by PET-CT technology Expression level, which can provide accurate tumor treatment plan based on PARP inhibitors. The compound provided by the invention is a safer and more efficient new PARP inhibitor drug and a positron tomography imaging agent using PARP as a biomarker, and has great social value and economic value.

The following describes the embodiments of the present invention through specific specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through different specific embodiments. The details in this specification can also be based on different viewpoints and applications, and various modifications or changes can be made without departing from the spirit of the present invention.

It should be noted that the process equipment or devices not specifically mentioned in the following embodiments all use conventional equipment or devices in the art.

In addition, it should be understood that one or more of the method steps mentioned in the present invention does not exclude that there may be other method steps before or after the combination step or that other method steps may be inserted between these explicitly mentioned steps unless otherwise Explained; It should also be understood that the combined connection relationship between one or more devices / devices mentioned in the present invention does not exclude that there may be other devices / devices or those mentioned explicitly Other devices / apparatuses can also be inserted between the two devices / apparatuses unless otherwise stated. Moreover, unless otherwise stated, the number of each method step is only a convenient tool to identify each method step, not to limit the order of each method step or to limit the scope of the present invention can be implemented, the relative relationship changes or adjustments, in If there is no substantial change in the technical content, it should also be regarded as the scope of the invention.

Example 1

The overall preparation route of compounds 3a-3f refers to the above figure, and the overall preparation method is as follows:

Under the stirring condition of 0 ° C, in the compound 1 (1 mM) N, N-dimethylformamide (DMF) solution (10 ml), add the corresponding amine (2a-2f) (1.2 mM), which is 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (HATU) (2mM) and N, N-diisopropylethylamine (DIPEA) ( 2mM), continue stirring for 15 minutes. Then, stirring was continued at room temperature until TLC showed that the reaction of Compound 1 was complete. The reaction product was extracted with 1,2-dichloromethane, washed with 5% hydrochloric acid aqueous solution, saturated brine, and water, concentrated, and column chromatography to obtain the compound 3a-3f.

Compound 3a

White solid, (370 mg, 76%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.52 (s, 1H), 9.60 (s, 1H), 8.27 (dd, J = 7.9, 1.5 Hz, 1H) , 7.95 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.44 (ddd, J = 8.1, 5.0, 2.3 Hz, 1H), 7.36 (dd, J = 6.6, 2.3Hz, 1H), 7.27–7.18 (m, 2H), 6.85 (ddd, J = 8.2, 2.5, 1.0Hz, 1H), 6.81 (d, J = 7.3Hz , 1H), 6.78 (t, J = 2.0 Hz, 1H), 4.33 (s, 2H), 3.83–3.35 (m, 6H), 3.25–3.20 (m, 2H). ¹³ C NMR (126 MHz, DMSO) δ169 .67,164.59,159.83,157.86,157.79,155.91,145.22,137.30,135.30,135.27,133.86,132.19,132.13,131.93,129.99,129.58,129.37,128.43,126.54,125.87,124.12,123.97,117.83,117.08,116.47 , 114.29,46.89,41.89,40.56,40.39,40.23,36.95; HRMS-ESI (m / z) [M + H] ⁺ calcd for C ₂₇ H ₂₄ FN ₄ O ₄ , 487.1782, found, 487.1787.

Compound 3b

White solid, (394 mg, 81%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.52 (s, 1H), 9.78 (s, 1H), 8.27 (dd, J = 7.9, 1.4 Hz, 1H) , 7.96 (dt, J = 8.1, 0.9 Hz, 1H), 7.88 (ddd, J = 8.2, 7.2, 1.5 Hz, 1H), 7.81 (td, J = 7.6, 1.2 Hz, 1H), 7.44 (ddd, J = 8.4, 5.0, 2.3 Hz, 1H), 7.36 (dd, J = 6.5, 2.3 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.22 (dd, J = 9.5, 8.5 Hz, 1H) , 6.81 (d, J = 8.6 Hz, 2H), 4.34 (s, 2H), 3.67 (s, 2H), 3.56 (s, 2H), 3.42 (s, 2H), 3.22 (s, 2H); ¹³ C NMR (126MHz, DMSO) δ 170.03,164.57,159.82,159.37,157.85,155.91,145.22,135.30,135.27,133.87,132.19,131.93,129.76,129.59,129.38,128.43,126.54,126.23,125.87,124.16,124.01,116.46 116.28,115.42,46.93,41.94,36.94; HRMS-ESI (m / z) [M + H] + calcd for C ₂₇ H ₂₄ FN ₄ O ₄ , 487.1782, found, 487.1789.

Compound 3c

White solid, (350 mg, 70%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.52 (s, 1H), 9.41 (d, J = 21.4 Hz, 1H), 8.33–8.22 (m, 1H) , 7.98–7.93 (m, 1H), 7.90–7.85 (m, 1H), 7.83 (td, J = 7.5, 1.3Hz, 1H), 7.46–7.41 (m, 1H), 7.37 (dd, J = 6.6, 2.3Hz, 1H), 7.22 (dd, J = 9.5, 8.5Hz, 1H), 7.09–7.01 (m, 2H), 6.84–6.78 (m, 1H), 6.75 (td, J = 7.5, 1.3Hz, 1H ), 4.33 (s, 2H), 3.61 (d, J = 23.9 Hz, 6H), 3.44 (s, 2H), 3.15 (s, 2H); ¹³ C NMR (126MHz, DMSO) δ 170.09, 164.58, 159.84, 157.84 , 155.89,155.34,145.23,135.30,133.87,132.18,132.12,131.94,130.66,129.58,129.42,129.39,128.43,128.10,126.54,125.84,124.15,124.01,122.57,119.46,116.43,116.26,115.62,46.36,46.36 , 36.96,34.43,26.37,26.31; HRMS-ESI (m / z) [M + H] + calcd for C ₂₈ H ₂₆ FN ₄ O ₄ , 501.1938, found, 501.1947.

Compound 3d

White solid, (375 mg, 75%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.51 (s, 1H), 9.23 (s, 1H), 8.31--8.21 (m, 1H), 7.95 (d, J = 7.9Hz, 1H), 7.87 (s, 1H), 7.83 (td, J = 7.5, 1.4Hz, 1H), 7.43 (ddd, J = 8.0, 4.9, 2.3Hz, 1H), 7.36 (dd, J = 6.4, 2.3 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.69–6.60 (m, 3H), 4.33 (s, 2H), 3.69 –3.50 (m, 6H), 3.41 (s, 2H), 3.13 (d, J = 31.7Hz, 2H); ¹³ C NMR (126MHz, DMSO) δ169.59,164.45,159.84,157.81,145.30,137.22,135.28,133.93 , 132.19,132.02,129.79,129.54,129.42,128.36,126.53,125.90,119.90,116.46,116.29,116.05,113.92,47.02,46.67,46.01,45.56,41.99,41.82,41.67,41.28,36.91; HRMS-ESI (m / z) [M + H] + calcd for C ₂₈ H ₂₆ FN ₄ O ₄ , 501.1938, found, 501.1950.

Compound 3e

White solid, (392 mg, 83%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.61 (s, 1H), 9.33 (s, 1H), 8.28 (dd, J = 8.0, 1.4 Hz, 1H) , 7.96 (dd, J = 8.2, 1.0 Hz, 1H), 7.88 (td, J = 7.7, 1.5 Hz, 1H), 7.82 (td, J = 7.6, 1.2 Hz, 1H), 7.42 (ddd, J = 8.1 , 5.1, 2.3 Hz, 1H), 7.32 (dd, J = 6.5, 2.3 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.74 (t , J = 2.0 Hz, 1H), 6.71 (dt, J = 7.4, 1.3 Hz, 1H), 6.66 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 4.33 (s, 2H), 3.77-3.57 ( m, 2H), 3.22–3.04 (m, 2H), 2.39 (t, J = 5.0 Hz, 2H), 2.25 (t, J = 4.9 Hz, 2H); ¹³ C NMR (126 MHz, DMSO) δ 172.49, 164.18, 159.85,157.75,155.81,145.36,139.61,135.25,135.23,133.93,132.01,131.96,129.59,129.52,129.22,129.19,128.35,126.54,125.92,124.36,124.21,119.94,116.44,116.27,116.08,114.49,62 56.51,53.17,52.61,47.04,41.83,36.87; HRMS-ESI (m / z) [M + H] + calcd for C ₂₇ H ₂₆ FN ₄ O ₃ , 473.1989, found, 473.1998.

Compound 3f

White solid, (335 mg, 71%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.62 (s, 1H), 9.32 (s, 1H), 8.28 (dd, J = 8.0, 1.4 Hz, 1H) , 7.99-7.95 (m, 1H), 7.88 (td, J = 7.7, 1.5 Hz, 1H), 7.82 (td, J = 7.6, 1.2 Hz, 1H), 7.43 (ddd, J = 8.5, 5.1, 2.3 Hz , 1H), 7.32 (dd, J = 6.4, 2.3 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 7.11–7.04 (m, 2H), 6.73 (d, J = 8.4 Hz, 2H) , 4.34 (s, 2H), 3.61 (d, J = 6.1 Hz, 2H), 3.36 (s, 2H), 3.15 (t, J = 4.9 Hz, 2H), 2.37 (t, J = 5.2 Hz, 2H) , 2.22 (s, 2H); ¹³ C NMR (126MHz, DMSO) δ164.16,159.84,157.75,156.90,155.80,145.35,135.25,133.92,132.00,131.95,130.66,129.52,129.20,128.35,128.03,126.54,125.91, 124.37,124.22,116.43,116.25,115.39,61.83,55.36,52.96,52.43,47.01,41.80,36.87; HRMS-ESI (m / z) [M + H] + calcd for C ₂₇ H ₂₆ FN ₄ O ₃ , 473.1989 , found, 473.1996.

The overall preparation route of the compounds P1-P6 refers to the above figure. The overall preparation method is as follows:

Under stirring conditions, compound 3a-3f (ImM) in DCM (10ml) was added TEA (2mM), then the flask was filled with SO _₂ F _2, stirred at rt, until TLC indicated compound 3a-3f completion of the reaction . The reaction product was extracted with DCM, washed with 5% aqueous hydrochloric acid solution, saturated brine, and water, concentrated, and column chromatography to obtain the compounds P1-P6.

Compound P1

White solid, (47 mg, 82%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.52 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 8.0 Hz , 1H), 7.86 (t, J = 7.3Hz, 1H), 7.80 (s, 1H), 7.72–7.65 (m, 3H), 7.58 (dt, J = 6.8, 3.8Hz, 1H), 7.44 (dd, J = 8.0, 2.8 Hz, 1H), 7.36 (dd, J = 6.5, 2.3 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 4.33 (s, 2H), 4.28–3.57 (m, 8H ); ¹³ C NMR (126MHz, DMSO) δ165.46,162.58,157.78,156.79,155.81,153.86,147.80,143.15,136.65,133.28,133.26,131.80,130.20,130.13,129.85,129.66,127.54,127.32,126.39,126.14, 124.49,123.80,122.03,121.89,120.63,118.26,116.28,114.41,114.23,44.60,39.63,34.90; HRMS-ESI (m / z) [M + H] + calcd for C ₂₇ H ₂₃ F ₂ N ₄ O ₆ S, 569.1306, found, 569.1310.

Compound P2

White solid, (50 mg, 88%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.53 (s, 1H), 8.33–8.21 (m, 1H), 7.95 (d, J = 8.0 Hz, 1H) , 7.86 (t, J = 7.4 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.72–7.61 (m, 4H), 7.44 (ddd, J = 8.1, 5.1, 2.3 Hz, 1H), 7.38–7.34 (m, 1H), 7.22 (t, J = 9.0 Hz, 1H), 4.34 (s, 2H), 3.76–3.10 (m, 8H); ¹³ C NMR (126MHz, DMSO) δ 168.11, 164.61, 159.84 , 157.87,155.92,150.46,145.20,137.01,135.31,135.29,133.85,132.23,132.17,131.90,130.13,129.58,129.36,129.33,128.44,126.54,125.84,124.08,123.94,121.77,116.45,116.28,46.76 , 36.95; HRMS-ESI (m / z) [M + H] + calcd for C ₂₇ H ₂₃ F ₂ N ₄ O ₆ S, 569.1306, found, 569.1314.

Compound P3

White solid, (45 mg, 77%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.54 (s, 1H), 8.29 (dd, J = 7.9, 1.5 Hz, 1H), 7.96 (d, J = 8.0Hz, 1H), 7.88 (td, J = 7.7, 1.5Hz, 1H), 7.83 (s, 1H), 7.55-7.52 (m, 1H), 7.47 (m, 1H), 7.40 (s, 1H), 7.23 (t, J = 9.0Hz, 1H), 4.35 (s, 2H), 3.96–3.83 (m, 2H), 3.65 (q, J = 30.6, 23.6Hz, 4H), 3.48 (d, J = 24.7Hz , 2H), 3.23 (d, J = 19.0 Hz, 2H); ¹³ C NMR (126MHz, DMSO) δ165.79,162.61,157.83,155.84,153.90,147.34,143.18,133.28,131.81,131.36,130.19,130.13,129.87, 127.56,127.53,127.43,127.40,127.13,126.90,126.42,124.51,123.79,122.11,121.97,118.94,116.27,114.39,114.22,44.92,44.63,43.72,43.25,40.07,39.69,34.93,32.46; HRMS-ESI (HRMS-ESI m / z) [M + H] + calcd for C ₂₈ H ₂₅ F ₂ N ₄ O ₆ S, 583.1463, found, 583.1480.

Compound P4

White solid, (34 mg, 59%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.53 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.0 Hz , 1H), 7.88 (t, J = 7.6Hz, 1H), 7.83 (t, J = 7.5Hz, 1H), 7.53 (t, J = 8.0Hz, 1H), 7.44 (m, 3H), 7.38 (t , J = 7.8Hz, 2H), 7.22 (t, J = 9.0Hz, 1H), 4.34 (s, 2H), 3.86 (d, J = 29.5Hz, 2H), 3.60 (d, J = 19.9Hz, 4H ), 3.45 (d, J = 16.8 Hz, 2H), 3.18 (t, J = 5.1 Hz, 2H); ¹³ C NMR (126 MHz, DMSO) δ 168.88, 164.60, 159.84, 150.04, 145.23, 139.72, 135.31, 133.88, 132.22,132.15,131.94,130.89,130.71,129.59,129.40,128.43,126.54,125.84,122.14,119.33,116.43,116.26,42.02,39.11,36.95; HRMS-ESI (m / z) [M + H] + calcd for C ₂₈ H ₂₅ F ₂ N ₄ O ₆ S, 583.1463, found, 583.1479.

Compound P5

White solid, (50 mg, 91%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.62 (s, 1H), 8.27 (dd, J = 7.9, 1.4 Hz, 1H), 7.99-7.93 (m, 1H), 7.88 (ddd, J = 8.1, 7.2, 1.4 Hz, 1H), 7.81 (td, J = 7.6, 1.2 Hz, 1H), 7.61–7.54 (m, 1H), 7.53 (t, J = 1.8 Hz , 1H), 7.49 (td, J = 7.2, 2.0 Hz, 2H), 7.43 (ddd, J = 8.5, 5.1, 2.3 Hz, 1H), 7.33 (dd, J = 6.5, 2.4 Hz, 1H), 7.22 ( t, J = 9.0Hz, 1H), 4.34 (s, 2H), 3.69–3.62 (m, 2H), 3.59 (s, 2H), 3.18 (t, J = 4.9Hz, 2H), 2.43 (t, J = 5.2 Hz, 2H), 2.28 (t, J = 5.0 Hz, 2H); ¹³ C NMR (126 MHz, DMSO) δ 164.21, 159.84, 157.76, 155.81, 150.25, 145.33, 142.06, 135.26, 135.24, 133.91, 132.05, 131.97 , 131.12,130.08,129.88,129.52,129.23,129.19,128.36,126.53,125.92,124.32,124.17,121.27,120.05,116.43,116.26,60.98,52.98,52.50,46.98,41.76,36.88; HRMS-ESI (m / z ) [M + H] + calcd for C ₂₇ H ₂₅ F ₂ N ₄ O ₅ S, 555.1514, found, 555.1523.

Compound P6

White solid, (48 mg, 87%), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.61 (s, 1H), 8.27 (dd, J = 7.9, 1.4 Hz, 1H), 7.98–7.94 (m, 1H), 7.88 (ddd, J = 8.1, 7.2, 1.4 Hz, 1H), 7.81 (td, J = 7.6, 1.2 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.9Hz, 2H), 7.43 (ddd, J = 8.5, 5.1, 2.3Hz, 1H), 7.31 (dd, J = 6.5, 2.3Hz, 1H), 7.22 (dd, J = 9.4, 8.6Hz, 1H) , 4.33 (s, 2H), 3.67-3.59 (m, 2H), 3.55 (s, 2H), 3.16 (t, J = 4.9Hz, 2H), 2.41 (t, J = 5.1Hz, 2H), 2.26 ( t, J = 5.0 Hz, 2H); ¹³ C NMR (126 MHz, DMSO) δ164.19,159.84,157.76,155.82,149.10,145.34,139.78,135.26,135.24,133.93,132.06,131.99,131.41,129.52,129.20,129.17, 128.35,126.53,125.93,124.31,124.16,121.32,116.45,116.27,61.03,53.08,52.57,47.00,41.77,36.87; HRMS-ESI (m / z) [M + H] + calcd for C ₂₇ H ₂₅ F ₂ N ₄ O ₅ S, 555.1514, found, 555.1526.

Example 2

Cell IC ₅₀ experiment

The use of Trevigen colorimetric PARP assay (commercially available) was used to determine the activity of PARP-1 in the presence of various concentrations of compounds P1-P6. The experiment was performed in a histone-coated 96-well plate. The specific results are shown in Table 1:

Table 1. Inhibitory activity of compounds P1-P6 on PARP1

Example 3

Synthesis of ¹⁸ F / ¹⁹ F-P4

[18F] F- generated from the cyclotron was captured on a QMA Sep-Pak column (Waters, USA) and eluted with a solution containing 2.52 mg KHCO ₃ , 9 mg Kryptofix 2.2.2, 0.72 mL acetonitrile, and 0.18 mL water, followed by Add 1mL of acetonitrile and evaporate at 120 ° C for 3 minutes. Under a nitrogen atmosphere, dry at 120 ° C for 3 minutes and then cool to room temperature. Then add 1mL of acetonitrile and evaporate at 120 ° C for 3 minutes. After the drying was completed, the mixture was cooled to room temperature, an acetonitrile (200 μL) solution containing about 100 μg of sulfonyl fluoride precursor P6 was added under a nitrogen atmosphere, and the isotope exchange reaction was performed for 1 minute. Then, the finally obtained radiolabeled compound was analyzed by HPLC ^{18F / 19F} P6. (Figure 1 and Figure 2)

Example 4

In vivo visualization of MCF-7xenograft mice

Inhale isoflurane (in medical air; induce 5% v / v; maintain 2.0-2.5% v / v) to anesthetize female CD1 nude mice (n = 3) with subcutaneous MCF-7 tumors and place in PT- CT scanner. The mice received a bolus injection of 0.8 MBq ¹⁸ F P4 via the tail vein and immediately started a 60-minute or 120-minute dynamic PET scan (continuous list mode). The reconstructed PET data is automatically registered with the MRI data and then analyzed. (Shown in Figures 3 and 4)

It can be seen that the compounds provided by the present invention have high affinity for PARP receptors, and can be used as PARP inhibitor drugs and positron tomography imaging agents with PARP as biomarkers.

In summary, the present invention effectively overcomes various shortcomings in the prior art and has high industrial utilization value.

The above-mentioned embodiments only exemplarily illustrate the principle and efficacy of the present invention, and are not intended to limit the present invention. Anyone familiar with this technology can modify or change the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or changes made by those with ordinary knowledge in the technical field without departing from the spirit and technical idea disclosed by the present invention should still be covered by the claims of the present invention.

Claims

A compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. The structural formula of the compound is shown in Formula I:

Among them, R1 is selected from groups having affinity for PARP receptors;

R2 is selected from substituted or unsubstituted, branched or unbranched C2-C10 terminal alkenyl, substituted or unsubstituted C6-C20 phenolic hydroxyaryl, substituted or unsubstituted C2-C20 phenolic hydroxyheteroaryl, Substituted or unsubstituted, branched or unbranched C6 ～ C20 (phenol hydroxyaryl) alkyl, substituted or unsubstituted, branched or unbranched C3 ～ C20 (phenol hydroxyheteroaryl) alkyl ;

The -SO 2 F group is -SO 2 18 F and / or -SO 2 19 F.
The compound of claim 1, wherein R1 is selected from the group represented by formula II:

Among them, X, Y, Z form a benzo five-membered aromatic heterocycle, and the hetero atom is selected from N, O or S;

In the R1 group, X is selected from O, S, N, NR ', C; Y is selected from C, N; Z is selected from O, S, N, NR ", C;

R, R ', R "are each independently selected from H, substituted or unsubstituted, branched or unbranched C1-C20, C1-C12, C1-C6, C1-C3 alkyl, wherein, alkyl The substituent of is selected from hydroxyl, cyano, carbonyl, carboxyl, amide, sulfonyl, halogen atom;

When X is NR ', R' may be bridged with R to form a benzoheterocycloalkyl, the heterocycloalkyl is six-membered, seven-membered, eight-membered, nine-membered, ten-membered, the heterocyclic The hetero atom of the alkyl group is selected from N, O, S, and P.
The compound according to claim 2, wherein in R1, the benzo five-membered aromatic heterocycle formed by X, Y, Z is selected from benzimidazole, benzopyrazole, benzothiazole, benzox Azole, benzopyrrole (indole), benzofuran.
The compound of claim 1, wherein R1 is selected from the following groups:
The compound of claim 1, wherein the terminal alkenyl group is mono- or poly-substituted, and the substituents of the terminal alkenyl group are each independently selected from alkyl, alkynyl, aryl, carbonyl, Amido, sulfonyl, halogen atom (for example, fluorine, chlorine, bromine or iodine);

And / or, the phenolic hydroxyaryl group is five-membered, six-membered, seven-membered, five-membered and six-membered, six-membered and six-membered, the phenolic hydroxyaryl group is mono- or multi-substituted, the phenolic hydroxyl group The substituents of the aryl group are each independently selected from halogen atoms, the substituents are selected from substituted or unsubstituted C1-C3 alkyl groups of halogen atoms, and the substituents are selected from substituted or unsubstituted C1-C3 alkoxy groups of halogen atoms;

And / or, the phenolic hydroxyheteroaryl group is five-membered, six-membered, seven-membered, five-membered and six-membered, six-membered and six-membered, the phenolic hydroxyheteroaryl group is mono- or polysubstituted, the The substituents of the phenolic hydroxy heteroaryl group are each independently selected from halogen atoms, the substituents are selected from halogen atom-substituted or unsubstituted C1-C3 alkyl groups, and the substituents are selected from halogen atom-substituted or unsubstituted C1-C3 alkyl groups Oxy;

And / or, the (phenol hydroxyaryl) alkyl group is five-membered, six-membered, seven-membered, five-membered and six-membered, six-membered and six-membered, the (phenolic hydroxyaryl) alkyl group is mono-substituted or Multi-substituted, the substituents of the (phenol hydroxyaryl) alkyl group are each independently selected from halogen atoms, the substituents are selected from substituted or unsubstituted C1-C3 alkyl groups of halogen atoms, and the substituents are selected from halogen atoms Substituted or unsubstituted C1-C3 alkoxy, alkynyl, aryl, carbonyl, amido, sulfonyl, halogen atoms;

And / or, the (phenol hydroxyheteroaryl) alkyl group is five-membered, six-membered, seven-membered, five-membered and six-membered, six-membered and six-membered, the (phenolic hydroxyheteroaryl) alkyl group is Monosubstituted or polysubstituted, the substituents of the (phenol hydroxyheteroaryl) alkyl group are each independently selected from halogen atoms, the substituents are selected from substituted or unsubstituted C1-C3 alkyl groups of halogen atoms, and the substituents are selected from A substituted or unsubstituted C1-C3 alkoxy group, alkyl group, alkynyl group, aryl group, carbonyl group, amide group, sulfonyl group, halogen atom from a halogen atom.
The compound according to claim 1, wherein said R2 is selected from the following groups:
The use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of a PARP receptor inhibitor, the PARP receptor is preferably selected From PARP-1 receptor, PARP-2 receptor.
Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of an imaging agent, preferably the imaging agent is PARP Biomarkers, the imaging agent is preferably a positron tomography imaging agent.
A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of a medicament for diagnosis, prevention or treatment of diseases associated with PARP enzymes Use, preferably, the diseases associated with PARP enzymes include cancer, ischemic diseases and neurodegenerative diseases.
A composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.