WO2023061368A1 - Hydroximic acid derivative and use thereof - Google Patents

Abstract

The present invention provides a hydroximic acid derivative and a use thereof, which relate to the field of biomedicine. The hydroximic acid derivative is a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof. The present invention provides a compound with good inhibitory activity on HDAC and PARP. The compound has a good inhibition effect on both HDAC and PARP, and can be used for preparing a PARP/HDAC double-target inhibitor which prevents and/or treats diseases mitigated by PARP and/or HDAC activity inhibition, such as tumors, ischemic diseases, diabetes, inflammatory diseases and the like. Meanwhile, the compound has a synthetic lethality effect, and can be used as a chemotherapeutic drug sensitizer and a radiotherapy sensitizer in combination with other anti-tumor drugs to improve the treatment effect and reduce adverse reactions. Moreover, the compound provided by the present invention improves the compliance of patients, has greater pharmacoeconomic advantages, and has a good application prospect.

Description

A Class of Hydroxamic Acid Derivatives and Their Applications technical field

The invention relates to the field of biomedicine, in particular to a class of hydroxamic acid derivatives and applications thereof.

Background technique

Polyadenosine diphosphate-ribose polymerase (PARP) is an important DNA repair enzyme that exists in eukaryotic cells and has a protease that catalyzes the ribosylation of polyadenosine diphosphate (poly ADP). It recognizes DNA single-strand breaks and initiates repair. This repair acts on many proteins, involving chromosome stability, DNA damage repair, gene transcription, cell growth, death and apoptosis, and is closely related to inflammation, tumors, aging and other diseases in terms of physiology and pathology.

PARP inhibitors can inhibit PARP activity, enhance the effect of radiotherapy and DNA damage chemotherapy drugs, and can also selectively kill tumor cells with DNA repair defects when used alone. The application of PARP inhibitors in tumor therapy is mainly based on two mechanisms: first, PARP inhibitors can inhibit the repair process of DNA single-strand damage, but this DNA single-strand damage can be transformed into double-strand damage during DNA replication to form a replication fork. Strand damage (DSB), and this DSB can still be repaired by homologous recombination (HR) pathway. If tumor cells have homologous recombination repair defects (including BRCA1/2 mutations), making DSB damage irreparable, it will lead to the synthetic lethal effect of PARP inhibitors and homologous recombination repair defects on tumor cells. Single-drug PARP inhibitors have significant inhibitory effects on BRCA1 and BRCA2 mutated breast and ovarian cancer cells. Second, BRCA1/2 is only a part of HR repair, and other proteins such as EMSY and PTEN are also important for the HR pathway. If these genes are mutated or silenced in the HR repair pathway, PARP inhibitors may produce single-drug resistance through synthetic lethal effects. tumor activity.

Histone deacetylase (HDAC) is a class of proteases that play an important role in the structural modification of chromosomes and the regulation of gene expression. In general, the acetylation of histones is conducive to the dissociation of DNA and histone octamers, and the relaxation of nucleosome structure, so that various transcription factors and co-transcription factors can specifically bind to DNA binding sites and activate genes transcription. In the nucleus, the process of histone acetylation and histone deacetylation is in a dynamic balance, and is regulated by histone acetyltransferase (histone acetyltransferase, HAT) and histone deacetylase (histone deacetylase, HDAC). HAT transfers the acetyl group of acetyl-CoA to specific lysine residues at the amino terminal of histones, HDAC deacetylates histones, binds tightly to negatively charged DNA, makes chromatin dense and coiled, and gene transcription is inhibited .

In cancer cells, the overexpression of HDAC leads to the increase of the binding force between histone and DNA, which leads to abnormal allosteric changes of chromosomes. Inhibiting the activity of HDAC can effectively inhibit the proliferation of cancer cells, induce cell cycle arrest and promote cell apoptosis. In addition, HDAC inhibitors can increase DNA damage, interfere with double-strand break repair (DSB) recognition, and inhibit DNA repair. Studies have shown that HDAC is closely related to homologous recombination repair, and inhibiting the activity of HDAC will affect the function of a series of proteins, including RAD51 and its analogues, RAD52, RAD54, BRCA1, BRCA2.MRN, and the damage detection molecule ATM that initiates DNA repair responses , ATR, etc.

Timothy A Y et al. pointed out (Yap T A et al., CA Cancer J Clin.2011; 61(1):31-49.) PARP not only has a synergistic lethal effect with BRCA deficiency, but also genes related to homologous recombination deficiency Interactions, including ATM.Rad51.CHK, etc. It has been reported in the literature that the combined use of PARP inhibitors and HDAC inhibitors has a synergistic effect, which can promote the accumulation of DNA damage and reduce the response of the homologous recombination pathway in tumor cells, thereby promoting the death of various tumor cells and inhibiting homologous recombination repair. Tumor cells that have not been deleted in the pathway also have a good killing effect. However, the combined drug has the disadvantages of complex pharmacokinetics, possible drug interactions, and more toxic and side effects. A single small molecule with multi-target inhibitory activity promises to avoid these problems. Therefore, it is of great significance to study a small molecular compound with PARP/HDAC dual-target inhibitory activity.

Contents of the invention

In order to solve the above problems, the invention provides a class of hydroxamic acid derivatives and applications thereof, and its technical scheme is as follows:

The present invention provides a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof:

in,

X ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

X ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Z ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Z ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₈ alkyl;

Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl , substituted or unsubstituted 3-10 membered saturated heterocyclic group, substituted or unsubstituted 3-10 membered unsaturated heterocyclic group;

The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ ~C ₈ alkyl, C ₁ ~C ₈ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituent of the heteroaryl group is selected from C ₁ ~C ₈ alkyl, C ₁ ~C ₈ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

n represents the number of substituents R ₁ on the A ring, an integer selected from 0 to 5, and when n is 0, it means that there is no substituent on the A ring.

further,

X ₁ is selected from none, O or NR ₂ ;

X ₂ is selected from none or CR ₃ R ₄ ;

Z ₁ is selected from none or CR ₃ R ₄ ;

Z ₂ is selected from none, O or NR ₂ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, and when n is 0, it means that there is no substituent on the A ring.

further,

X ₁ is selected from none, O or NR ₂ ;

X ₂ is selected from none or CR ₃ R ₄ ;

Z ₁ is selected from none or CR ₃ R ₄ ;

Z ₂ is selected from none, O or NR ₂ ;

And X ₂ and Z ₁ cannot be CR ₃ R ₄ or none at the same time;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

And Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

Preferably,

X ₁ and X ₂ are both nil or not nil at the same time;

Z ₁ and Z ₂ are both nil or not nil at the same time;

_Y1 and _Y2 are not the same.

further,

Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

Preferably,

A ring selected from

R ₁ ' is selected from halogen.

Further, the compound is shown in formula II:

in,

X ₁ is selected from O or NR ₂ ;

X ₂ is selected from CR ₃ R ₄ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ; and Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

Preferably,

Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

More preferably,

A ring selected from

R ₁ ' is selected from halogen.

Further, the compound is shown in formula III:

in,

X ₁ is selected from O or NR ₂ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ; and Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

R ₂ and R ₅ are independently selected from hydrogen, C ₁ -C ₄ alkyl;

Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

Preferably,

Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

More preferably,

A ring selected from

R ₁ ' is selected from halogen.

Further, the compound is shown in formula IV:

in,

X ₁ is selected from O or NR ₂ ;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

Preferably,

Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

More preferably,

A ring selected from

R ₁ ' is selected from halogen.

Further, the compound is shown in formula V:

in,

Z ₁ is selected from CR ₃ R ₄ ;

Z ₂ is selected from O or NR ₂ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ; and Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

Preferably,

Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

More preferably,

A ring selected from

R ₁ ' is selected from halogen.

Further, the compound is shown in formula VI:

in,

Z ₂ is selected from O or NR ₂ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ; and Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

R ₂ and R ₅ are independently selected from hydrogen, C ₁ -C ₄ alkyl;

Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

Preferably,

Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

More preferably,

A ring selected from

R ₁ ' is selected from halogen.

Further, the compound is shown in formula VII:

in,

Z ₂ is selected from O or NR ₂ ;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

Preferably,

Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ to C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two substituents on the same carbon atom form a double bond to connect O;

n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

More preferably,

A ring selected from

R ₁ ' is selected from halogen.

Further, the compound is shown in formula VIII:

in,

X ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

X ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Z ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Z ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₈ alkyl;

Preferably,

X ₁ is selected from none, O or NR ₂ ;

X ₂ is selected from none or CR ₃ R ₄ ;

Z ₁ is selected from none or CR ₃ R ₄ ;

Z ₂ is selected from none, O or NR ₂ ;

And X ₂ and Z ₁ cannot be CR ₃ R ₄ or none at the same time;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

And Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

More preferably, the compound is shown in formula VIIIa:

in,

X ₁ is selected from O or NR ₂ ;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

Alternatively, the compound is shown in formula VIIIb:

in,

Z ₂ is selected from O or NR ₂ ;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl.

Further, the compound is shown in formula IX:

in,

X ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

X ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Z ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Z ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₈ alkyl;

Preferably,

X ₁ is selected from none, O or NR ₂ ;

X ₂ is selected from none or CR ₃ R ₄ ;

Z ₁ is selected from none or CR ₃ R ₄ ;

Z ₂ is selected from none, O or NR ₂ ;

And X ₂ and Z ₁ cannot be CR ₃ R ₄ or none at the same time;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

And Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

More preferably, the compound is shown in formula IXa:

in,

X ₁ is selected from O or NR ₂ ;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

Alternatively, the compound is shown in formula IXb:

in,

Z ₂ is selected from O or NR ₂ ;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl.

Further, the compound is shown in formula X:

in,

X ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

X ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Z ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Z ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₈ alkyl;

R ₁ ' is selected from halogen;

Preferably,

X ₁ is selected from none, O or NR ₂ ;

X ₂ is selected from none or CR ₃ R ₄ ;

Z ₁ is selected from none or CR ₃ R ₄ ;

Z ₂ is selected from none, O or NR ₂ ;

And X ₂ and Z ₁ cannot be CR ₃ R ₄ or none at the same time;

Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

And Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

R ₁ ' is selected from halogen;

More preferably, the compound is shown in formula Xa:

in,

X ₁ is selected from O or NR ₂ ;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

R ₁ ' is selected from halogen;

Alternatively, the compound is shown in formula Xb:

in,

Z ₂ is selected from O or NR ₂ ;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

R ₁ ' is selected from halogen.

Further, the compound is one of the following compounds:

The present invention also provides the aforementioned compounds, or their salts, or their stereoisomers, or their solvates, or their hydrates, or their prodrugs in the preparation of drugs for inhibiting PARP and/or HDAC activity use.

Further, the medicament is a medicament for treating ischemic diseases, diabetes or inflammatory diseases.

Further, the drug is a chemotherapeutic drug sensitizer, a radiotherapy sensitizer or a drug for treating tumors;

Preferably, the tumor is breast cancer, ovarian cancer, pancreatic cancer or prostate cancer.

The present invention also provides a pharmaceutical preparation, which is one or more of the aforementioned compounds, or their salts, or their stereoisomers, or their solvates, or their hydrates, or their prodrugs It is a preparation prepared by adding pharmaceutically acceptable excipients or auxiliary ingredients to the active ingredient.

The present invention also provides a pharmaceutical composition, which comprises the aforementioned compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, and a chemotherapeutic drug or a radiotherapy drug .

The present invention also provides the use of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug and chemotherapeutic drug or radiotherapy drug in the preparation of combined drug.

The preparation of the present invention is composed of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, or one or more of the aforementioned pharmaceutical compositions It is the active ingredient, plus pharmaceutically acceptable excipients or auxiliary ingredients prepared according to conventional methods. Its dosage form includes but not limited to: tablet, granule, capsule, oral liquid and other pharmaceutically acceptable dosage forms. The pharmaceutical composition and its preparation are used in the treatment of diseases that can directly or indirectly produce clinical beneficial effects through the inhibition of PARP and/or HDAC.

The diseases improved by PARP and/or HDAC activity inhibition in the present invention include but not limited to the prevention and/or treatment of ischemic diseases, diabetes and inflammatory diseases.

The foregoing compounds of the present invention, or salts thereof, or stereoisomers thereof, or solvates thereof, or hydrates thereof, or prodrugs thereof are used as adjuvant means for cancer treatment or for strengthening radiotherapy or chemotherapeutic agents against tumors When inhibiting and/or killing cells, the cancer includes but not limited to breast cancer, ovarian cancer, pancreatic cancer or prostate cancer.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

Definition of terms used in the present invention: Unless otherwise stated, the initial definition provided by a group or term herein applies to the group or term throughout the specification; for terms that are not specifically defined herein, they should be based on the disclosure and context , giving the meanings a person skilled in the art can assign to them.

In the present invention, the structure of the compound refers to a structure that can exist stably.

"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

In the present invention, the minimum and maximum values of carbon atom content in hydrocarbon groups are indicated by prefixes, for example, the prefix (C _a ~ C _b ) alkyl means any alkyl group containing "a" to "b" carbon atoms . Thus, for example, C ₁ -C ₈ alkyl refers to straight or branched chain alkyl containing 1 to 8 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl base, tert-butyl, etc.

Halogen is fluorine, chlorine, bromine or iodine.

"Substituted or unsubstituted" means that the group may be substituted or unsubstituted.

"Aryl" refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, eg, phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated π-electron system on the carbon atoms in the ring. The 6-10 membered aryl group means that the aryl group contains 6-10 carbon atoms.

"Heteroaryl" refers to an aryl group in which one or more carbon atoms are replaced by a heteroatom (such as nitrogen, oxygen, or sulfur, etc.). The 5-10 membered heteroaryl group means that the number of atoms on the heteroaryl skeleton is 5-10.

"Cycloalkyl" means an all-carbon monocyclic alkyl group or a bridged, fused, spirocycloalkyl group. 3-10 members means that the cycloalkyl group consists of 3-10 carbon atoms.

"Saturated heterocyclyl" means that one or more carbon atoms in a cycloalkyl group are replaced by heteroatoms (such as nitrogen, oxygen, or sulfur, etc.).

"Unsaturated heterocyclyl" is a partially unsaturated cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms (such as nitrogen, oxygen, or sulfur, etc.).

"Two substituents on the same carbon atom form a double bond connecting O" refers to the formation of

structure. "NR ₂ " refers to the formation of

structure. "CR ₃ R ₄ " refers to the formation of

structure.

"Salt" in the present invention means "pharmaceutically acceptable salt". "Pharmaceutically acceptable salts" means those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:

(1) Salt formation with acid, obtained by reacting the free base of the parent compound with inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, phosphoric acid, metaphosphoric acid, sulfuric acid, Sulfurous acid and perchloric acid, etc. Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxy Benzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, tea-1-sulfonic acid, tea-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, Succinic acid or malonic acid, etc.

(2) The acidic proton present in the parent compound is replaced by a metal ion or a salt formed by coordination with an organic base, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, an organic base such as ethylamine, diethylamine Amine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, tromethamine, N -Methylglucamine etc.

The term "solvate" means that the compound of the present invention forms a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes but is not limited to water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran , Dichloromethane.

The term "stereoisomer" means that the chiral carbon atom involved in the compound of the present invention can be in R configuration, or S configuration, or a combination thereof.

PARP plays a key role in the repair of cellular DNA damage. At the same time, PARP is also involved in DNA methylation modification and transcription, cell signal transduction, cell cycle regulation and cell mitosis. Studies have shown that PARP inhibitors have anticancer effects, and more importantly, PARP inhibitors can cause synthetic lethal effects when used in combination with other anticancer drugs. For example, the combined use of PARP inhibitors and chemotherapy drugs can not only reduce the adverse reactions of chemotherapy drugs, but also improve their therapeutic effect. Therefore, PARP inhibitors can not only treat PARP-related diseases, but also act as drugs for treating tumors, as well as chemotherapeutic drug sensitizers and radiotherapy sensitizers, and have a remarkable effect in tumor treatment.

The present invention provides a class of compounds that have good inhibitory activity on both HDAC and PARP. These compounds have good inhibitory effects on both HDAC and PARP, and can be used to prepare PARP/HDAC dual-target inhibitors for the prevention and/or treatment of Diseases improved by inhibition of PARP and/or HDAC activity, such as tumors, local ischemic diseases, diabetes, inflammatory diseases, etc. At the same time, the compound of the invention has a synthetic lethal effect, can be used as a chemotherapeutic drug sensitizer and a radiotherapy sensitizer, and can be used in combination with other antitumor drugs to improve the therapeutic effect and reduce adverse reactions. In addition, the compound of the invention improves the patient's compliance, has advantages in pharmacoeconomics, and has good application prospects.

Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed ways

The raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.

Example 1, 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidine- 1-yl)-N-hydroxypyrimidine-5-carboxamide (Compound 1)

A: 4-Aminomethylpiperidin-1-yl-pyrimidine-5-carboxylic acid methyl ester

In a 500ml three-necked flask, add 200 milliliters of N,N-dimethylacetamide, 34.3 grams (0.3mol) of compound 4-aminomethylpiperidine and 65.5 milliliters (0.375mol) of N,N-diisopropylethyl Amine, at room temperature, add 25.9 g (0.15 mol) of methyl 4-chloropyrimidine-5-carboxylate dropwise while stirring in 100 ml of N,N-dimethylacetamide solution, after 3 hours, the reaction solution was slowly Pour into the stirred ice-water mixture, then extract three times with 300 ml ethyl acetate respectively, combine the organic phases, wash twice with an appropriate amount of saturated saline, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain light yellow Waxy. Then recrystallized with isopropyl ether, precipitated solid, filtered, and dried to obtain 25.3 g of the target compound as light yellow powder, ESI-MS: m/z 251.1.

B: 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidine-1- base)-pyrimidine-5-carboxylic acid methyl ester

To a 500ml three-necked flask, add 14.9 grams (50 mmol) of 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, N,N-dimethyl Formamide 200ml, at room temperature, under stirring, then add 20.8 g (55 mmol) of O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), and after 2 hours, add 4-aminomethylpiperidine- 1-yl-pyrimidine-5-carboxylic acid methyl ester 12.5 g (50 mmol). Stirring overnight, the next day, the reaction solution was slowly poured into a stirred ice-water mixture, then extracted with ethyl acetate, washed, dried, and concentrated to obtain a yellow solid, which was purified by column chromatography to obtain 21 grams of the target compound . ESI-MS: m/z 531.2.

C: 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidine-1- base)-pyrimidine-5-carboxylic acid

2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidin-1-yl )-pyrimidine-5-methyl carboxylate 21 grams, join in the 500 milliliter one-necked flask, then add methanol 200 milliliters, after stirring and dissolving, under ice-water bath, add 50 milliliters of water again, 6.7 grams (0.16mol) hydrogenation Lithium monohydrate. After 4 hours, it was detected by TLC that the hydrolysis was complete, and 2M hydrochloric acid was added dropwise until neutral. Rotary evaporation under reduced pressure to remove methanol, and then use 2M hydrochloric acid to adjust the pH of the solution to about 5, a large amount of powdery solids precipitated, filtered, washed with water, and dried to obtain 15.8 grams of light yellow powdery solids, which can be directly purified without further purification. for the next reaction.

D: 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidine-1- base)-pyrimidine-5-carboxylic acid (tetrahydropyran-2-oxyl)-amine

In a 250ml round bottom flask, add the 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide obtained in the previous step )methyl)piperidin-1-yl)-pyrimidine-5-carboxylic acid, 100ml of tetrahydrofuran and 30ml of N,N-dimethylformamide, after stirring and dissolving, add 2.6ml of N,N-diisopropylethylamine and 2.46g O-benzotriazole-tetramethyluronium hexafluorophosphate, stirred at room temperature for one hour, then added 0.89g O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, TLC monitoring reaction process , after the reaction was complete, concentrated under reduced pressure to remove tetrahydrofuran, the residue was extracted with ethyl acetate, the ethyl acetate phase was combined, concentrated, and column chromatographed to obtain 14.8 g of the target compound.

E: 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidine-1- base)-N-hydroxypyrimidine-5-carboxamide (compound 1)

In a 100ml single-necked bottle, add 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl ) piperidin-1-yl)-pyrimidine-5-carboxylic acid (tetrahydropyran-2-oxyl group)-amine 2.0g and 20ml ethyl acetate hydrochloric acid gas solution, stirring reaction at room temperature, TLC monitoring reaction process, After the reaction was complete, the precipitated solid was filtered and then recrystallized with methanol to obtain 1.1 g of the product with a yield of 70%. ESI-MS: m/z 532.21[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d6) δ: 1.10(dd,2H), 1.76(d,2H), 1.89(m,1H), 2.94( t,2H),3.15(t,2H),4.33(s,2H),4.70(d,2H),7.20(t,1H),7.45(m,1H),7.55(d,1H),7.86(dt ,2H),7.98(d,1H),8.27(d,1H),8.34(m,1H),8.66(s,2H),8.99(s,1H),11.04(s,1H),12.60(s, 1H).

F: 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidine-1- base)-pyrimidine-5-carboxybenzyloxyamine

In a 250ml round bottom flask, add 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl )piperidin-1-yl)-pyrimidine-5-carboxylic acid 2.6g, tetrahydrofuran 100ml and N,N-dimethylformamide 30ml, after stirring and dissolving, add N,N-diisopropylethylamine 2.6ml and O -Benzotriazole-tetramethyluronium hexafluorophosphate 2.46g, stirred at room temperature for one hour, then added O-benzyl hydroxylamine hydrochloride 1.2g, TLC monitored the reaction progress, after the reaction was complete, concentrated under reduced pressure to remove tetrahydrofuran , the residue was extracted with ethyl acetate, the ethyl acetate phases were combined, concentrated, and column chromatographed to obtain 2.0 g of pure product.

G: 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidine-1- base)-N-hydroxypyrimidine-5-carboxamide (compound 1)

In a 100ml single-necked bottle, add 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl) Piperidin-1-yl)-pyrimidine-5-carboxylate benzyloxyamine 1.8g, methanol 20ml, stir to dissolve, add 0.2g palladium carbon, and feed hydrogen, TLC monitors the reaction process. After the reaction was complete, the reaction solution was filtered, concentrated, and recrystallized with methanol to obtain 1.1 g of the product with a yield of 74%. ESI-MS: m/z 532.21[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d6) δ: 1.10(dd,2H), 1.76(d,2H), 1.89(m,1H), 2.94( t,2H),3.15(t,2H),4.33(s,2H),4.70(d,2H),7.20(t,1H),7.45(m,1H),7.55(d,1H),7.86(dt ,2H),7.98(d,1H),8.27(d,1H),8.34(m,1H),8.66(s,2H),8.99(s,1H),11.04(s,1H),12.60(s, 1H).

Example 2, 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (compound 2)

A: Methyl 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-5-carboxylate

Into a 250ml one-necked flask, add 8.1 grams (50mmol) of the compound 2H-indazole-7-carboxylic acid, 100ml of N,N-dimethylformamide, stir at room temperature, and then add 8.1 grams of N,N-carbonyldiimidazole (50mmol), there was gas evolution, and after 2 hours, 12.5 g (50mmol) of 4-aminomethylpiperidin-1-yl-pyrimidine-5-carboxylic acid methyl ester was added. Stir overnight, and the next day, slowly pour the reaction solution into the stirred ice-water mixture, and a light yellow solid precipitates out. After standing for 3 hours, filter, wash with water, and dry to obtain a light yellow powder product, which is the target compound 17.2 g was directly used in the next reaction without further purification. ESI-MS: m/z 395.2.

B: 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-5-carboxylic acid

Add 17.2 g of methyl 2-(4-((2H-indazole-7-carboxamide) methyl) piperidin-1-yl)-5-carboxylate into a 500 ml single-necked flask, and then add 150 ml of methanol After stirring and dissolving, add 50 milliliters of water and 6.3 grams (0.15 mol) of lithium hydroxide monohydrate under an ice-water bath. After 4 hours, it was detected by TLC that the hydrolysis was complete, and 2M hydrochloric acid was added dropwise until neutral. Rotary evaporation under reduced pressure to remove methanol, and then use 2M hydrochloric acid to adjust the pH of the solution to about 5, a large amount of powdery solids precipitated, filtered, washed with water, and dried to obtain 13.8 grams of light yellow powdery solids, which were directly used in the next step without purification. One step reaction. ESI-MS: m/z 381.1 [M+H].

C: 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-pyrimidine-5-carboxylic acid (tetrahydropyran-2-oxyl)-amine

In a 250ml round bottom flask, add 3.8g of 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-5-carboxylic acid, 100ml tetrahydrofuran and 30ml N,N- Dimethylformamide, stir to dissolve, add 5.3ml N,N-diisopropylethylamine and 4.93g O-benzotriazole-tetramethyluronium hexafluorophosphate, stir at room temperature for one hour, then add 1.76 g O-(tetrahydro-2H-pyran-2-yl) hydroxylamine, TLC monitors the reaction process, after the reaction is complete, concentrate under reduced pressure to remove tetrahydrofuran, the residue is extracted with ethyl acetate, the ethyl acetate phases are combined, concentrated, The target compound was obtained by column chromatography.

D: 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (compound 2)

In a 100ml single-necked bottle, add 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-pyrimidine-5-carboxylic acid (tetrahydropyran-2-oxo Base)-amine 3.0g, and the hydrochloric acid gas solution of 30ml ethyl acetate, stirring reaction at room temperature, TLC monitors the reaction process, after the reaction is complete, the precipitated solid is filtered, and the product is obtained by methanol recrystallization, yield 75% . ESI-MS: m/z 418.16[M+Na] ⁺ ; ¹ H NMR (600MHz, DMSO-d6) δ: 1.18(dd,2H), 1.83(d,2H), 1.97(m,1H), 2.97( t,2H),3.28(t,2H),4.74(d,2H),7.19(t,1H),7.95(d,2H),8.16(s,1H),8.69(s,1H),8.81(t ,1H).

E: 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-pyrimidine-5-carboxylic acid benzyloxyamine

In a 250ml round bottom flask, add 3.04g of 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-5-carboxylic acid, 100ml tetrahydrofuran and 30ml N,N- Dimethylformamide, stir to dissolve, add 4.19ml N,N-diisopropylethylamine and 3.94g O-benzotriazole-tetramethyluronium hexafluorophosphate, stir at room temperature for one hour, then add 1.9 g O-benzylhydroxylamine hydrochloride, TLC monitors the reaction process, after the reaction is complete, concentrate under reduced pressure to remove tetrahydrofuran, the residue is extracted with ethyl acetate, the ethyl acetate phase is combined, concentrated, and passed through the column to obtain the target compound.

F: 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (compound 2)

In a 100ml one-mouth bottle, add 2.4g of 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-pyrimidine-5-carboxylic acid benzyloxyamine, stir to dissolve Add 0.3 g of palladium carbon, 25 ml of methanol, and feed hydrogen, and monitor the progress of the reaction by TLC. After the reaction is complete, the reaction solution is filtered, concentrated, and recrystallized with methanol to obtain the product with a yield of 78%. ESI-MS: m/z 418.16[M+Na] ⁺ ; ¹ H NMR (600MHz, DMSO-d6) δ: 1.18(dd,2H), 1.83(d,2H), 1.97(m,1H), 2.97( t,2H),3.28(t,2H),4.74(d,2H),7.19(t,1H),7.95(d,2H),8.16(s,1H),8.69(s,1H),8.81(t ,1H).

Example 3, 2-((1-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidine-4- base) methylamino)-N-hydroxypyrimidine-5-carboxamide (compound 3)

A: Methyl 2-(piperidin-4-ylmethylamino)pyrimidine-5-carboxylate

In a 100ml single-necked bottle, add 4.0g of 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylaminopyrimidine-5-carboxylic acid methyl ester, and 40ml of ethyl acetate hydrochloric acid gas solution, room temperature Under stirring reaction, TLC monitors the reaction process, after the reaction is complete, the precipitated solid is filtered to obtain 2.8 g of the target product.

B: 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yl)methanol Amino)pyrimidine-5-carboxylic acid methyl ester

In a three-necked flask, add 5.96 grams of 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, 100ml of N,N-dimethylformamide, At room temperature, under stirring, add 8.3 grams of O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), and after 2 hours, add 2-(piperidin-4-ylmethylamino)pyrimidine-5 - methyl formate 5 g. Stirring overnight, the next day, the reaction solution was slowly poured into a stirred ice-water mixture, then extracted with ethyl acetate, washed, dried, and concentrated to obtain a yellow solid, which was purified by column chromatography to obtain 7.6 g of the target compound . ESI-MS: m/z 532.21[M+H] ⁺

C: 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yl)methanol Amino)pyrimidine-5-carboxylic acid

2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yl)methylamino ) 10 grams of pyrimidine-5-methyl carboxylate was added to the flask, and then 100 milliliters of methanol was added. After stirring and dissolving, under an ice-water bath, 50 milliliters of water and 4.2 grams of lithium hydroxide monohydrate were added. After 4 hours, it was detected by TLC that the hydrolysis was complete, and 2M hydrochloric acid was added dropwise until neutral. Rotary evaporation under reduced pressure to remove methanol, and then use 2M hydrochloric acid to adjust the pH of the solution to about 5, a large amount of powdery solids precipitated, filtered, washed with water, and dried to obtain 15.8 grams of light yellow powdery solids, which can be directly purified without further purification. for the next reaction.

D: 2-((1-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yl) Methylamino)-N-hydroxypyrimidine-5-carboxylic acid (tetrahydropyran-2-oxyl)-amine

In a round bottom flask was added 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidine-4 -yl)methylamino)pyrimidine-5-carboxylic acid 2.6g, tetrahydrofuran 100ml and N,N-dimethylformamide 30ml, after stirring and dissolving, add N,N-diisopropylethylamine 2.6ml and 2.46g O- Benzotriazole-tetramethyluronium hexafluorophosphate, stirred at room temperature for one hour, then added 0.89g O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, TLC monitored the reaction process, until the reaction was complete Afterwards, THF was removed by concentration under reduced pressure, the residue was extracted with ethyl acetate, and the ethyl acetate phases were combined, concentrated, and column chromatographed to obtain the target compound.

E: 2-((1-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yl) Methylamino)-N-hydroxypyrimidine-5-carboxamide (Compound 3)

In a 100ml single-necked bottle, sequentially add 2-((1-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piper Pyridin-4-yl)methylamino)-N-hydroxypyrimidine-5-carboxylic acid (tetrahydropyran-2-oxyl group)-amine 2.0g and 20ml ethyl acetate hydrochloric acid gas solution, stirring reaction at room temperature, TLC Monitor the reaction process, after the reaction is complete, the precipitated solid is filtered, and then recrystallized with methanol to obtain product 1.12g, yield 65%.ESI-MS: m/z 532.21[M+H] ⁺ ; ¹ H NMR ( 600MHz, DMSO-d6)δ:1.13(dd,2H),1.71(d,2H),1.85(m,1H),2.78(t,2H),3.08(t,2H),4.31(s,2H), 4.58(d,2H),7.18(t,1H),7.43(m,1H),7.54(d,1H),7.87(dt,2H),7.88(d,1H),8.20(d,1H),8.31 (m,1H), 8.61(s,2H), 8.92(s,1H), 10.94(s,1H), 12.56(s,1H).

F: 2-((1-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yl) Methylamino)-N-hydroxypyrimidine-5-carboxybenzyloxyamine

In a round bottom flask was added 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidine-4 -yl)methylamino)pyrimidine-5-carboxylic acid 2.6g, tetrahydrofuran 100ml and N,N-dimethylformamide 30ml, after stirring and dissolving, add N,N-diisopropylethylamine 2.6ml and O-benzo Triazole-tetramethyluronium hexafluorophosphate 2.46g, stirred at room temperature for one hour, then added 1.2g of O-benzyl hydroxylamine hydrochloride, TLC monitored the reaction process, after the reaction was complete, concentrated under reduced pressure to remove tetrahydrofuran, the residue Extract with ethyl acetate, combine the ethyl acetate phases, concentrate and column chromatography to obtain 1.8g of pure product.

G: 2-((1-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yl) Methylamino)-N-hydroxypyrimidine-5-carboxamide (compound 3)

In a 100ml single-necked bottle, 2-((1-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidine- 4-base) methylamino)-N-hydroxypyrimidine-5-carboxylate benzyloxyamine 2g, methanol 25ml, add 0.2g palladium carbon after stirring and dissolving, and feed hydrogen, TLC monitors the reaction process. After the reaction is complete, the The reaction solution was filtered, concentrated, and recrystallized with methanol to obtain 1.3g of the product.ESI-MS: m/z 532.21[M+H] ⁺ ; ^1H NMR (600MHz, DMSO-d6) δ: 1.13(dd, 2H), 1.71(d,2H),1.85(m,1H),2.78(t,2H),3.08(t,2H),4.31(s,2H),4.58(d,2H),7.18(t,1H),7.43 (m,1H),7.54(d,1H),7.87(dt,2H),7.88(d,1H),8.20(d,1H),8.31(m,1H),8.61(s,2H),8.92( s,1H), 10.94(s,1H), 12.56(s,1H).

Example 4, 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)-N-hydroxypyrimidine-5-carboxamide (compound 4)

A: Methyl 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)pyrimidine-5-carboxylate

Into a 250ml one-necked flask, add 8 grams of compound 2H-indazole-7-carboxylic acid, 100ml of N,N-dimethylformamide, at room temperature, under stirring, then add 8 grams of N,N-carbonyldiimidazole (50mmol) , Gas evolved, and after 2 hours, 12.5 grams of methyl 2-(piperidin-4-ylmethylamino)pyrimidine-5-carboxylate was added. Stir overnight, and the next day, slowly pour the reaction solution into the stirred ice-water mixture, and a light yellow solid precipitates out. After standing for 3 hours, filter, wash with water, and dry to obtain a light yellow powder product, which is the target compound 16.8 g was directly used in the next reaction without further purification. ESI-MS: m/z 395.2.

B: 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)pyrimidine-5-carboxylic acid

Add 16g of methyl 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)pyrimidine-5-carboxylate into a 500ml single-necked flask, and then add 150ml of methanol After stirring and dissolving, add 50 ml of water and 6 g of lithium hydroxide monohydrate under an ice-water bath. After 4 hours, it was detected by TLC that the hydrolysis was complete, and 2M hydrochloric acid was added dropwise until neutral. Rotary evaporation under reduced pressure to remove methanol, and then adjust the pH of the solution to about 5 with 2M hydrochloric acid, a large amount of powdery solids precipitated, filtered, washed with water, and dried to obtain 12.5 grams of light yellow powdery solids, which were directly used in the next step without purification. One step reaction. ESI-MS: m/z 381.1 [M+H].

C: 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)pyrimidine-5-carboxylic acid (tetrahydropyran-2-oxyl)-amine

In a 250ml round bottom flask, add 3.5g of 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)pyrimidine-5-carboxylic acid, 100ml tetrahydrofuran and 30ml N,N -Dimethylformamide, stir and dissolve, add 5ml N,N-diisopropylethylamine and 4.54g O-benzotriazole-tetramethyluronium hexafluorophosphate, stir at room temperature for one hour, then add 1.62 g O-(tetrahydro-2H-pyran-2-yl) hydroxylamine, TLC monitors the reaction process, after the reaction is complete, concentrate under reduced pressure to remove tetrahydrofuran, the residue is extracted with ethyl acetate, the ethyl acetate phases are combined, concentrated, Column chromatography obtained 3.3 g of the target compound with a yield of 75%.

D: 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)-N-hydroxypyrimidine-5-carboxamide (compound 4)

In the three-necked flask, add 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)pyrimidine-5-carboxylic acid (tetrahydropyran-2-oxyl) -Amine 5.0g, and 50ml of ethyl acetate hydrochloric acid gas solution, stirring reaction at room temperature, TLC monitoring reaction process, after the reaction is complete, the precipitated solid is filtered, recrystallized with methanol to obtain 2.89g of product, yield 70% . ESI-MS: m/z 418.16[M+Na] ⁺ ; ¹ H NMR (600MHz, DMSO-d6) δ: 1.24(dd,2H), 1.78(d,2H), 1.98(m,1H), 3.07( t,2H),3.48(t,2H),4.54(d,2H),7.21(t,1H),7.88(d,2H),8.09(s,1H),8.65(s,1H),8.76(t ,1H).

E: 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)-pyrimidine-5-carboxylic acid benzyloxyamine

In a 250ml round bottom flask, add 2.8g of 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)pyrimidine-5-carboxylic acid, 100ml tetrahydrofuran and 30ml N,N -Dimethylformamide, stir to dissolve, add 4.19ml N,N-diisopropylethylamine and 3.88g O-benzotriazole-tetramethyluronium hexafluorophosphate, stir at room temperature for one hour, then add 1.9g of O-benzylhydroxylamine hydrochloride, TLC to monitor the reaction process, after the reaction was complete, concentrated under reduced pressure to remove tetrahydrofuran, the residue was extracted with ethyl acetate, the ethyl acetate phase was combined, concentrated, and passed through the column to obtain 2.78g of the target compound.

F: 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)-N-hydroxypyrimidine-5-carboxamide (Compound 4)

In a 100ml single-necked bottle, add 2.4g of 2-((1-(2H-indazole-7-formyl)piperidin-4-yl)methylamino)-pyrimidine-5-carboxylic acid benzyloxyamine, 20ml of methanol, After stirring and dissolving, 0.3 g of palladium carbon was added, and hydrogen gas was introduced, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction solution was filtered, concentrated, and recrystallized with methanol to obtain 1.52 g of the product, with a yield of 78%. ESI-MS: m/z 418.16[M+Na] ⁺ ; ¹ H NMR (600MHz, DMSO-d6) δ: 1.24(dd,2H), 1.78(d,2H), 1.98(m,1H), 3.07( t,2H),3.48(t,2H),4.54(d,2H),7.21(t,1H),7.88(d,2H),8.09(s,1H),8.65(s,1H),8.76(t ,1H).

The compounds listed in Table 1 can all be prepared by methods similar to the above examples. The reaction process was monitored by TLC, and the purification was carried out by conventional column chromatography or recrystallization.

Table 1. The remaining compound numbers, structures and characterization data of the present invention

The beneficial effects of the present invention are demonstrated through specific test examples below.

Test example 1, HDAC/PARP1 biological activity test

A. Experimental method and principle

1. PARP1 enzyme experiment

PARP is a nuclear enzyme present in eukaryotic cells that catalyzes poly ADP ribosylation. PARP plays an important role in DNA damage repair and maintenance of genome stability. When DNA is damaged, the PARP enzyme is activated, binds to DNA, and catalyzes polyadenosine diphosphate-ribosylation, thereby initiating the damage control and repair process of DNA.

PARP-1 is involved in the recognition of DNA gaps. After recognizing DNA gaps, the activated PARP-1 forms a homodimer and catalyzes the decomposition of NAD+ into nicotinamide and ADP ribose, and uses the latter as raw materials to poly-ADP-ribosylate nuclear receptor proteins. HT Universal Chemiluminescent PARP Assay Kit With Histone-coated Strip Wells (Cat#4676-096-K) was purchased from TREVIGEN, and the activity of PARP1 was determined by detecting polyadenosine diphosphate-ribose bound to biotin on histone by chemiluminescent method . AZD2281 is a positive drug.

2. HDAC enzymatic experiment

The imbalance of histone acetylation state caused by abnormal histone deacetylase (HDAC) is closely related to the occurrence and development of tumors. Histone deacetylase inhibitors can cause the accumulation of acetylated nucleosomal histones in vitro and in vivo, increase the expression level of p21 gene, inhibit the proliferation of tumor cells, induce cell differentiation or apoptosis, and can be used for various Treatment of hematologic malignancies and solid tumors.

HDAC can deacetylate the substrate Boc-lys(AC)-AMC under certain conditions, and then hydrolyze the substrate under the action of trypsin to generate AMC, which can emit fluorescence with a wavelength of 460nm at an excitation wavelength of 355nm , so the activity of the enzyme can be reflected by detecting the change of the product amount. In this experiment, HDAC enzyme was extracted from Hela cell nucleus. LBH-589 is a positive drug.

B. Experimental data

The inhibitory results of the compounds of the present invention on HDAC and PARP1 are shown in Table 2.

Table 2. The inhibitory results of compounds of the present invention to HDAC and PARP1

Note: - means not determined

The above test results show that the compound of the present invention has inhibitory activity on HDAC and PARP at the same time, both reaching the nanomolar level. Among them, the inhibition rates of compound 11 and compound 13 on HDAC and PARP both reached more than 90%. It shows that the compound of the present invention can be used to prepare HDAC/PARP dual-target inhibitors.

Test example 2, MTT method cell proliferation inhibitory activity test

In vitro cell proliferation inhibition test adopts MMT method, using the following 9 cell lines: human breast cancer cell MDA-MB-436, human breast cancer cell HCC1937, human breast ductal carcinoma cell HCC1395, human breast cancer cell HCC1428, human breast cancer cell SUM -149PT, human breast cancer MDA-MB-231, human breast cancer MCF7, human cervical cancer Hela, non-mutated triple-negative breast cancer MDA-MB-157.

A. Experimental method and principle

The detection principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystal formazan (Formazan) and deposit in the cells, while dead cells have no such function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and its light absorption value is measured at a wavelength of 490nm with a microplate reader. Within a certain range of cell numbers, the amount of MTT crystal formation is proportional to the number of cells. According to the measured absorbance value (OD value), the number of living cells is judged. The larger the OD value, the stronger the cell activity (if the drug toxicity is measured, it means that the drug toxicity is less).

B. Experimental data

The results of the inhibitory activity of the compounds of the present invention on some human tumor cells are shown in Table 3:

Table 3. Cytostatic activity data of some compounds

Note: - indicates low activity, not determined

The test results show that the compound involved in the present invention has good in vitro tumor cell proliferation inhibitory activity and has good application prospects.

In summary, the present invention provides a class of compounds that have good inhibitory activity on both HDAC and PARP. These compounds have good inhibitory effects on both HDAC and PARP, and can be used to prepare PARP/HDAC dual-target inhibitors, prevent and/or Or treat diseases improved by inhibition of PARP and/or HDAC activity, such as tumors, local ischemic diseases, diabetes, inflammatory diseases and the like. At the same time, the compound of the invention has a synthetic lethal effect, can be used as a chemotherapeutic drug sensitizer and a radiotherapy sensitizer, and can be used in combination with other antitumor drugs to improve the therapeutic effect and reduce adverse reactions. In addition, the compound of the invention improves the patient's compliance, has advantages in pharmacoeconomics, and has good application prospects.

Claims (20)

1. A compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof:

   

   in,

   X ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

   X ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

   Z ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

   Z ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

   Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

   R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₈ alkyl;

   Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl , substituted or unsubstituted 3-10 membered saturated heterocyclic group, substituted or unsubstituted 3-10 membered unsaturated heterocyclic group;

   The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ ~C ₈ alkyl, C ₁ ~C ₈ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituent of the heteroaryl group is selected from C ₁ ~C ₈ alkyl, C ₁ ~C ₈ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

   n represents the number of substituents R ₁ on the A ring, an integer selected from 0 to 5, and when n is 0, it means that there is no substituent on the A ring.
2. The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, is characterized in that:

   X ₁ is selected from none, O or NR ₂ ;

   X ₂ is selected from none or CR ₃ R ₄ ;

   Z ₁ is selected from none or CR ₃ R ₄ ;

   Z ₂ is selected from none, O or NR ₂ ;

   Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

   R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

   Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, and when n is 0, it means that there is no substituent on the A ring.
3. The compound according to claim 2, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, is characterized in that:

   X ₁ is selected from none, O or NR ₂ ;

   X ₂ is selected from none or CR ₃ R ₄ ;

   Z ₁ is selected from none or CR ₃ R ₄ ;

   Z ₂ is selected from none, O or NR ₂ ;

   And X ₂ and Z ₁ cannot be CR ₃ R ₄ or none at the same time;

   Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

   And Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

   R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

   Preferably,

   X ₁ and X ₂ are both nil or not nil at the same time;

   Z ₁ and Z ₂ are both nil or not nil at the same time;

   _Y1 and _Y2 are not the same.
4. The compound according to claim 2, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, is characterized in that:

   Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ to C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two substituents on the same carbon atom form a double bond to connect O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   Preferably,

   A ring selected from

   

   R ₁ ' is selected from halogen.
5. The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, is characterized in that: said compound is shown in formula II:

   

   

   in,

   X ₁ is selected from O or NR ₂ ;

   X ₂ is selected from CR ₃ R ₄ ;

   Y ₁ and Y ₂ are independently selected from N and CR ₅ ; and Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

   R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

   Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   Preferably,

   Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   More preferably,

   A ring selected from

   

   R ₁ ' is selected from halogen.
6. The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, is characterized in that: said compound is shown in formula III:

   

   in,

   X ₁ is selected from O or NR ₂ ;

   Y ₁ and Y ₂ are independently selected from N and CR ₅ ; and Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

   R ₂ and R ₅ are independently selected from hydrogen, C ₁ -C ₄ alkyl;

   Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   Preferably,

   Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   More preferably,

   A ring selected from

   

   R ₁ ' is selected from halogen.
7. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, wherein the compound is as shown in formula IV:

   

   in,

   X ₁ is selected from O or NR ₂ ;

   R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

   Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   Preferably,

   Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   More preferably,

   A ring selected from

   

   R ₁ ' is selected from halogen.
8. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, wherein the compound is as shown in formula V:

   

   in,

   Z ₁ is selected from CR ₃ R ₄ ;

   Z ₂ is selected from O or NR ₂ ;

   Y ₁ and Y ₂ are independently selected from N and CR ₅ ; and Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

   R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

   Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   Preferably,

   Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   More preferably,

   A ring selected from

   

   R ₁ ' is selected from halogen.
9. The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, is characterized in that: said compound is shown in formula VI:

   

   in,

   Z ₂ is selected from O or NR ₂ ;

   Y ₁ and Y ₂ are independently selected from N and CR ₅ ; and Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

   R ₂ and R ₅ are independently selected from hydrogen, C ₁ -C ₄ alkyl;

   Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   Preferably,

   Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

   R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

   The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

   The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

   The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

   n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

   More preferably,

   A ring selected from

   

   R ₁ ' is selected from halogen.
10. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, wherein the compound is as shown in formula VII:

    

    in,

    Z ₂ is selected from O or NR ₂ ;

    R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

    Ring A is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

    R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, O or S, and the number of heteroatoms is 1, 2 or 3;

    The substituent of the alkyl group is selected from substituted or unsubstituted 5-10 membered heteroaryl groups; the heteroatoms in the heteroaryl group are N, O or S, and the number of heteroatoms is 1, 2 or 3;

    The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

    The substituent of the heteroaryl group is selected from C ₁ ~C ₄ alkyl, C ₁ ~C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or two on the same carbon atom The substituent forms a double bond connecting O;

    n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

    Preferably,

    Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl;

    R ₁ is a substituent on ring A, independently selected from substituted or unsubstituted C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, substituted or unsubstituted 3-6 membered cycloalkyl , A substituted or unsubstituted 3-6 membered saturated heterocyclic group; the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2 or 3;

    The substituent of the alkyl group is selected from substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl , substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted dihydrophthalazinyl;

    The substituents of the cycloalkyl and heterocyclic groups are selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano; or the same carbon atom The two substituents on form a double bond to connect O;

    The substituents of the indazolyl, indolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophthalazinyl are selected from C ₁ -C ₄ alkane group, C ₁ -C ₄ alkoxy group, halogen, hydroxyl group, amino group, carboxyl group, nitro group, cyano group; or two substituents on the same carbon atom form a double bond to connect O;

    n represents the number of substituents _R1 on the A ring, an integer selected from 0, 1, 2 or 3, when n is 0, it means that there is no substituent on the A ring;

    More preferably,

    A ring selected from

    

    R ₁ ' is selected from halogen.
11. The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, is characterized in that: said compound is shown in formula VIII:

    

    in,

    X ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    X ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Z ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Z ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

    R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₈ alkyl;

    Preferably,

    X ₁ is selected from none, O or NR ₂ ;

    X ₂ is selected from none or CR ₃ R ₄ ;

    Z ₁ is selected from none or CR ₃ R ₄ ;

    Z ₂ is selected from none, O or NR ₂ ;

    And X ₂ and Z ₁ cannot be CR ₃ R ₄ or none at the same time;

    Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

    And Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time; R ₂ , R ₃ , R ₄ , and R ₅ are independently selected from hydrogen, C ₁ -C ₄ alkyl;

    More preferably, the compound is shown in formula VIIIa:

    

    in,

    X ₁ is selected from O or NR ₂ ;

    R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

    Alternatively, the compound is shown in formula VIIIb:

    

    in,

    Z ₂ is selected from O or NR ₂ ;

    R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl.
12. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, wherein the compound is as shown in formula IX:

    

    in,

    X ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    X ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Z ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Z ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

    R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₈ alkyl;

    Preferably,

    X ₁ is selected from none, O or NR ₂ ;

    X ₂ is selected from none or CR ₃ R ₄ ;

    Z ₁ is selected from none or CR ₃ R ₄ ;

    Z ₂ is selected from none, O or NR ₂ ;

    And X ₂ and Z ₁ cannot be CR ₃ R ₄ or none at the same time;

    Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

    And Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time;

    R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₄ alkyl;

    More preferably, the compound is shown in formula IXa:

    

    in,

    X ₁ is selected from O or NR ₂ ;

    R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

    Alternatively, the compound is shown in formula IXb:

    

    in,

    Z ₂ is selected from O or NR ₂ ;

    R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl.
13. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, wherein the compound is as shown in formula X:

    

    in,

    X ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    X ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Z ₁ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Z ₂ is selected from none, O, S, NR ₂ or CR ₃ R ₄ ;

    Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

    R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from hydrogen, C ₁ -C ₈ alkyl;

    R ₁ ' is selected from halogen;

    Preferably,

    X ₁ is selected from none, O or NR ₂ ;

    X ₂ is selected from none or CR ₃ R ₄ ;

    Z ₁ is selected from none or CR ₃ R ₄ ;

    Z ₂ is selected from none, O or NR ₂ ;

    And X ₂ and Z ₁ cannot be CR ₃ R ₄ or none at the same time;

    Y ₁ and Y ₂ are independently selected from N and CR ₅ ;

    And Y ₁ and Y ₂ cannot be selected from N at the same time, but can be selected from CR ₅ at the same time; R ₂ , R ₃ , R ₄ , and R ₅ are independently selected from hydrogen, C ₁ -C ₄ alkyl;

    R ₁ ' is selected from halogen;

    More preferably, the compound is shown in formula Xa:

    

    in,

    X ₁ is selected from O or NR ₂ ;

    R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

    R ₁ ' is selected from halogen;

    Alternatively, the compound is shown in formula Xb:

    

    in,

    Z ₂ is selected from O or NR ₂ ;

    R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl;

    R ₁ ' is selected from halogen.
14. The compound, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug according to any one of claims 1-13, characterized in that: the compound is as follows One of the compounds:

    

    
15. The compound according to any one of claims 1 to 14, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof is used in preparation for inhibiting PARP and/or HDAC activity use in medicines.
16. The use according to claim 15, characterized in that: the medicine is a medicine for treating local ischemic diseases, diabetes or inflammatory diseases.
17. The use according to claim 15, characterized in that: the drug is a chemotherapeutic drug sensitizer, a radiotherapy sensitizer or a drug for treating tumors;

    Preferably, the tumor is breast cancer, ovarian cancer, pancreatic cancer or prostate cancer.
18. A pharmaceutical preparation, characterized in that: it is the compound described in any one of claims 1 to 14, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a precursor thereof One or more of the medicines are active ingredients, plus pharmaceutically acceptable excipients or auxiliary ingredients.
19. A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 14, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its precursor medicines, as well as chemotherapy or radiation medicines.
20. The compound described in any one of claims 1 to 14, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug and chemotherapeutic drug or radiotherapy drug in the preparation of combined drug use in .