CN115707708A - Wee1 kinase inhibitors - Google Patents

Abstract

The present invention belongs to the technical field of medicine, and specifically relates to a class of dihydropyrazolopyrimidinone Weel kinase inhibitors represented by formula (I), pharmaceutically acceptable salts thereof or stereoisomers thereof, comprising the compound, Pharmaceutical compositions and preparations of pharmaceutically acceptable salts or stereoisomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts or stereoisomers thereof, and said compounds, their pharmaceutically acceptable Use of accepted salts or stereoisomers thereof,

Description

Wee1 kinase inhibitor

technical field

The invention belongs to the technical field of medicine, and in particular relates to a class of dihydropyrazolopyrimidinone Weel kinase inhibitors, pharmaceutically acceptable salts thereof, and stereoisomers thereof, containing the compound, its pharmaceutically acceptable Pharmaceutical compositions and preparations of salts and stereoisomers thereof, processes for preparing said compounds, pharmaceutically acceptable salts and stereoisomers thereof, and said compounds, pharmaceutically acceptable salts and stereoisomers thereof Use of isomers.

Background technique

Cancer is a malignant disease that is difficult to treat all over the world. It is difficult to treat and has a high mortality rate. According to the latest global cancer statistics in 2018, so far, there are an estimated 18.19 million new cancer cases and 9.6 million cancer deaths worldwide. In January 2019, the National Cancer Center released the latest national cancer statistics. About 3.929 million people are diagnosed with malignant tumors nationwide every year, and an average of more than 10,000 people are diagnosed with cancer every day, and 7.5 people are diagnosed with cancer every minute. Cancer has become a major disease affecting the health of Chinese residents, and cancer prevention and treatment is also facing a severe situation.

At present, radiotherapy and chemotherapy are the most effective means of treating cancer besides surgical resection, and radiotherapy is the most effective non-surgical treatment for malignant tumors. Radiation and quite a few cancer drugs can cause DNA damage. After DNA damage, a series of cellular responses such as damaged DNA repair will be triggered to improve the survival of tumor cells, which is also one of the mechanisms of tumor cell resistance to radiotherapy and chemotherapy. If the damaged DNA is not repaired in a timely and complete manner, tumor cells will die due to apoptosis or/and mitotic disorders. Therefore, as long as the repair of these DNA damages is inhibited, the sensitivity of cancer cells to radiotherapy and chemotherapy can be improved and cell proliferation can be inhibited.

Wee1 protein kinase is a member of the serine/threonine protein kinase family, which was first isolated from fission yeast cells (S. pombe) by Nurse et al. In humans, Wee1 contains 647 amino acids and has a molecular weight of 96 kDa. In the pathway of DNA single-strand damage repair, Wee1 is in the downstream of the ATR signaling pathway. After the ATR signaling pathway is activated, it phosphorylates CHK1, and the activated CHK1 activates Wee1, and at the same time inhibits CDC25 (releasing the phosphorylation of the CDK1/Cyclin B complex. to restore its activity of regulating the cell cycle), and then phosphorylate CDK1/Cyclin B, so that the CDK1/Cyclin B complex enters an inactive state, arresting the cell cycle in the G2/M phase, and gaining time for DNA damage repair; In addition, Weel can also arrest the S phase of the cell cycle by phosphorylating CDK2, and regulate the repair of DNA double-strand breaks that occur during DNA replication.

In the entire DDR (DNA damage repair) pathway, Wee1 mainly plays a role in the G2/M phase checkpoint. For tumor cells with p53 mutations, due to the G1/S checkpoint defect, they are more dependent on the G2/M phase checkpoint to repair DNA damage. Mechanistically, Wee1 inhibitors are more sensitive to tumor cells with p53 mutations.

In summary, Wee1 kinase inhibitors can not only synergistically enhance the effect of radiotherapy and chemotherapy, effectively inhibit tumor growth, but also reduce damage to normal cells and reduce side effects. At present, the research on this target drug is still in the clinical trial stage, and no drug has been marketed yet. Therefore, the development of a highly effective Wee1 kinase inhibitor has important clinical significance, whether it is used alone or in combination with other drugs, it has broad market prospects.

Contents of the invention

The technical problem to be solved by the present invention is to provide a dihydropyrazolopyrimidinone compound with novel structure and inhibitory activity on Wee1. Furthermore, this kind of compound can be used to inhibit the activity of Wee1 kinase, thereby enhancing the immunity of the body against tumors. Furthermore, the compound can also be used to treat one or more diseases mediated by Wee1, especially cancer. This type of compound has good inhibitory effect on various cancer cells, has higher exposure in vivo and better drug efficacy in vivo.

Technical scheme of the present invention is as follows:

In one aspect, the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

Wherein, X ₁ and X ₂ are independently selected from C, C(R ³ ) or N;

L is selected from -C(R ⁴ )(R ⁵ )-, -O-, -N(R ⁶ )- or -S-;

^R is selected from C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl optionally substituted by substituents independently selected from halogen, hydroxyl, amino, carboxyl, cyano Base, C _1-6 alkoxy, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl;

Each ^R is independently selected from halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di(C _1-6 alkyl)amino , halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl;

Ring A is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclic group, 6-8 membered monocyclic aryl or 5-8 membered monocyclic heterocyclic group optionally substituted by 1-3 Q1 Aryl;

Ring B is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, 6-8 membered monocyclic aryl or 5-8 membered monocyclic heterocyclic optionally substituted by 1-3 Q2 Aryl;

Ring C is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted by 1-3 Q3;

Each Q1, each Q2, and each Q3 are independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _{1-6 6} alkyl) amino, halogenated C _1-6 alkyl, hydroxy C 1-6 alkyl _, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 alkylthio, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, amino C _1-6 alkylthio;

Each R ³ , R ⁴ , and R ⁵ are independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di( C _1-6 alkyl) amino, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy, C _1-6 alkyl Carbonyl or C _1-6 alkoxy C _1-6 alkyl;

R ⁶ are independently selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl or C _1-6 alkoxy C _{1 -6} alkyl;

m is selected from 0, 1, 2 or 3.

In some of the above embodiments, X ₁ and X ₂ are independently selected from C, CH or N;

L is selected from -CH ₂ -, -O-, -NH or -S-;

R ¹ is selected from C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl;

Each ^R is independently selected from halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di(C _1-6 alkyl)amino , halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl;

Ring A is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl or 5-6 membered monocyclic heteroaryl optionally substituted by 1-2 Q1;

Ring B is selected from phenyl or 5-6 membered monocyclic heteroaryl optionally substituted by 1-2 Q2;

Ring C is selected from 5-7 membered monocyclic cycloalkyl, 8-10 membered fused ring cycloalkyl, 5-7 membered monocyclic heterocyclyl, 8-10 membered fused ring optionally substituted by 1-2 Q3 Heterocyclyl, phenyl, naphthyl, 5-7 membered monocyclic heteroaryl or 8-10 membered condensed heteroaryl;

Each Q1, each Q2, and each Q3 are independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _{1-6 6} alkyl) amino, halogenated C _1-6 alkyl, hydroxy C 1-6 alkyl _, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 alkylthio, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, amino C _1-6 alkylthio;

m is selected from 0, 1 or 2.

In some embodiments, X ₁ and X ₂ are independently selected from C, CH or N;

L is selected from -CH ₂ -, -O-, -NH or -S-;

R ¹ is selected from C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl;

Each ^R is independently selected from halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di(C _1-6 alkyl)amino , halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl;

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl optionally substituted by 1-2 Q2 or 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms or groups independently selected from N, NH, O, S, S(O) or S(O) ₂ ;

Ring C is selected from 5-6 membered monocyclic cycloalkyl, 8-10 membered condensed ring cycloalkyl, 5-6 membered monocyclic heterocyclic group, containing 1-3 heterocyclic groups optionally substituted by 1-2 Q3 Atom or group 8-10 membered fused ring heterocyclic group, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl group or 8-10 membered fused heteroaryl group containing 1-3 heteroatoms or groups , the heteroatoms or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ;

Each Q1, each Q2, and each Q3 are independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _{1-6 6} alkyl) amino, halogenated C _1-6 alkyl, hydroxy C 1-6 alkyl _, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 alkylthio, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, amino C _1-6 alkylthio;

m is selected from 0, 1 or 2.

In certain embodiments, X ₁ and X ₂ are independently selected from CH or N;

L is selected from -CH ₂ -, -O-, -NH or -S-;

^R is selected from methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl or propynyl;

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-Triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl;

Ring C is selected from cyclopentyl, cyclohexyl, phenyl, 5-6 membered monocyclic heterocyclic groups containing 1-3 heteroatoms or groups optionally substituted by 1-2 Q3 or 1-3 5-6 membered monocyclic heteroaryls of heteroatoms or groups, said heteroatoms or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ;

Each Q1, each Q2, and each Q3 are independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _{1-6 6} alkyl) amino, halogenated C _1-6 alkyl, hydroxy C 1-6 alkyl _, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 alkylthio, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, amino C _1-6 alkylthio;

m is selected from 0 or 1.

In certain embodiments, X ₁ and X ₂ are each N; L is NH; R ¹ is propenyl;

Each ^R is independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _{1 -6} alkyl or halogenated C _1-6 alkoxy;

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and _X are in the para position of ring B;

Ring C is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2 ,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl;

Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C _{1-6 alkyl, C 1-6 alkoxy} C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy;

m is selected from 0, 1 or 2.

In certain embodiments, X ₁ and X ₂ are each N;

L is NH;

R ¹ is propenyl;

R ² is selected from halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _{1 -6} alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl;

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and _X are in the para position of ring B;

Ring C is selected from cyclopentyl, cyclohexyl, phenyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, oxazole optionally substituted by 1-2 Q3 Alkyl, thiazolidinyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl;

Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C _{1-6 alkyl, C 1-6 alkoxy} C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy;

m is selected from 0 or 1.

In certain embodiments, X ₁ and X ₂ are each N;

L is NH;

R ¹ is propenyl;

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and _X are in the para position of ring B;

Ring C is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4- Triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl;

Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C _{1-6 alkyl, C 1-6 alkoxy} C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy;

m is selected from 0.

In some embodiments, the compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (I-1):

Each ^R is independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _{1 -6} alkyl or halogenated C _1-6 alkoxy;

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and _X are in the para position of ring B;

Ring C is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted by 1-2 Q3;

Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, _{C 1-6 alkoxy} , halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy;

m is selected from 0, 1 or 2.

In some of the above embodiments, the compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (II):

Among them, ring A, ring C, Q1, Q2, Q3, X 1 , X _{2 ,} L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and m are defined as described in any of the above schemes ; n is selected from 0, 1 or 2.

In some of the above embodiments, the compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (III):

Among them, ring A, ring C, Q1, Q2, Q3, X 1 , X ₂ , L, R ₂ , R ³ , ^{R 4 ,} R ⁵ , R ⁶ , and m are defined as described in any of the above schemes; Since 0, 1 or 2.

In some of the above embodiments, the compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (IV):

Wherein, ring A, ring C, Q1, Q2, Q3, R ² and m are defined as described in any of the schemes above; n is selected from 0, 1 or 2.

In certain embodiments, the compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (IV):

in,

Each ^R is independently selected from halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di(C _1-6 alkyl)amino , halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl;

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring C is selected from pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole optionally substituted by 1-2 Q3 , pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl;

Each Q1, each Q2, and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, _{C 1-6 alkoxy} , halogenated C _{1- 6} alkoxy, hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy;

m is selected from 0 or 1;

n is selected from 0 or 1.

In certain embodiments, the compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (IV):

in,

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring C is selected from pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole optionally substituted by 1-2 Q3 , pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl;

Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, _{C 1-6 alkoxy} , halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy;

m is 0;

n is 0.

In certain embodiments, the compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (IV):

in,

Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring C is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted by 1-2 Q3;

Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, _{C 1-6 alkoxy} , halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy;

m is 0;

n is 0.

In certain embodiments above, R ¹ is selected from C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl. In certain embodiments of the above, R ^is selected from methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl or propynyl. In certain embodiments of the above, R ^is selected from propyl, propenyl or propynyl. In certain embodiments above, R ¹ is selected from propenyl.

In some of the above embodiments, ring A is selected from the following groups optionally substituted with 1-2 Q1:

_X1 is selected from C, -CH- or -N-;

Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, _amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Thio, halogenated C _1-6 alkoxy, halogenated C 1-6 alkylthio _, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, Amino C _1-6 alkylthio.

In some of the above embodiments, ring A is selected from the following groups optionally substituted with 1-2 Q1:

Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, _amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Thio, halogenated C _1-6 alkoxy, halogenated C 1-6 alkylthio _, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, Amino C _1-6 alkylthio.

In some of the above embodiments, ring A is selected from the following groups optionally substituted with 1-2 Q1:

Each Q1 is independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halogenated C _1-6 alkyl, hydroxyl C _1-6 alkyl, amino C _1-6 alkyl _, C _1-6 alkoxy C 1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxyl C _{1 -6} alkoxy or amino C _1-6 alkoxy.

In some of the above embodiments, ring A is selected from the following groups optionally substituted with 1-2 Q1:

In some of the above embodiments, ring A is selected from the following groups optionally substituted with 1-2 Q1:

In some of the above embodiments, ring A is selected from the following groups optionally substituted with 1-2 Q1:

In some of the above embodiments, each Q1 is independently selected from halogen, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy.

In some of the above embodiments, each Q1 is independently selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 Alkoxy or halogenated C _1-6 alkoxy.

In some of the above embodiments, each Q1 is independently selected from methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1- Trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, difluoromethyl or trifluoromethoxy.

In some of the above embodiments, ring B is selected from phenyl optionally substituted by 1-2 Q2 or 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms or groups, said heteroatoms Or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ;

Each Q2 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, _amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Thio, halogenated C _1-6 alkoxy, halogenated C 1-6 alkylthio _, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, Amino C _1-6 alkylthio.

In some of the above embodiments, ring B is selected from phenyl optionally substituted by 1-2 Q2 or 5-6 membered monocyclic heteroaryl containing 1-2 heteroatoms or groups, said heteroatoms or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ; each Q2 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C 1-6 _alkoxy , C _1-6 alkylthio, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, Hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, amino C _1-6 alkylthio.

In some of the above embodiments, ring B is selected from phenyl or 5-6 membered monocyclic heteroaryl containing 1-2 heteroatoms or groups independently selected from N, NH, O, S, S(O) or S(O) ₂ , preferably, L and X ₂ are in the para position of ring B.

In certain embodiments above, ring B is selected from phenyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1, 2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl;

Each Q2 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, _amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Thio, halogenated C _1-6 alkoxy, halogenated C 1-6 alkylthio _, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, Amino C _1-6 alkylthio.

In some of the above embodiments, ring B is selected from phenyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1, 2,4-Triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and _X are in the para position of ring B.

In some of the above embodiments, ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted by 1-2 Q2, preferably, L and _X2 in the paraposition of ring B;

Each Q2 is independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halogenated C _1-6 alkyl, hydroxyl C _1-6 alkyl, amino C _1-6 alkyl _, C _1-6 alkoxy C 1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxyl C _{1 -6} alkoxy or amino C _1-6 alkoxy.

In certain embodiments above, ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and _X are at the para position of ring B.

In certain embodiments of the above, ring B is selected from phenyl.

In some of the above embodiments, Ring C is selected from 5-6 membered monocyclic cycloalkyl, 8-10 membered fused ring cycloalkyl, 5-6 membered monocyclic heterocycle optionally substituted by 1-2 Q3 group, 8-10 membered condensed ring heterocyclic group containing 1-3 heteroatoms or groups, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl group or 1-3 heteroatoms or groups 8-10 membered condensed heteroaryl groups, the heteroatoms or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ;

Preferably, ring C is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl or 5-6 membered monocyclic heteroaryl optionally substituted by 1-2 Q3;

Preferably, ring C is selected from cyclopentyl, cyclohexyl, phenyl, 5-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms or groups optionally substituted by 1-2 Q3 or 1 -3 heteroatoms or groups of 5-6 membered monocyclic heteroaryls, said heteroatoms or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ;

Preferably, ring C is selected from cyclopentyl, cyclohexyl, phenyl, 5-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms or groups optionally substituted by 1-2 Q3 or containing 1 -2 heteroatoms or groups of 5-6 membered monocyclic heteroaryls, said heteroatoms or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ;

Each Q3 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, _amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Thio, halogenated C _1-6 alkoxy, halogenated C 1-6 alkylthio _, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, Amino C _1-6 alkylthio.

In some of the above embodiments, ring C is selected from cyclopentyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, tetrahydroimidazolyl, optionally substituted by 1-2 Q3, Tetrahydropyrazolyl, oxazolidinyl, thiazolidinyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1, 2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl;

Each Q3 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, _amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Thio, halogenated C _1-6 alkoxy, halogenated C 1-6 alkylthio _, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, Amino C _1-6 alkylthio.

In some of the above embodiments, ring C is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3 - triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl;

Each Q3 is independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halogenated C _1-6 alkyl, hydroxyl C _1-6 alkyl, amino C _1-6 alkyl _, C _1-6 alkoxy C 1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxyl C _{1 -6} alkoxy or amino C _1-6 alkoxy.

In some of the above embodiments, Ring C is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted by 1-2 Q3;

Each Q3 is independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halogenated C _1-6 alkyl, hydroxyl C _1-6 alkyl, amino C _1-6 alkyl _, C _1-6 alkoxy C 1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxyl C _{1 -6} alkoxy or amino C _1-6 alkoxy.

In some of the above embodiments, each Q3 is independently selected from C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _{1 -6} alkoxy C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy.

In some of the above embodiments, each Q3 is independently selected from C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl or C _{1 -6} alkoxy C _1-6 alkyl.

In certain embodiments above, X ₁ and X ₂ are independently selected from C, CH or N. In certain embodiments above, X ₁ and X ₂ are each independently selected from CH or N. In certain embodiments above, both X ₁ and X ₂ are N.

In some of the above embodiments, L is selected from -CH(R ⁵ )-, -O-, -N(R ⁶ )- or -S-; R ⁵ is selected from hydrogen, halogen, hydroxyl, amino, C _{1- 6} alkyl, C _1-6 alkoxy, halogenated C 1-6 alkyl _, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _{1- 6} alkoxy C _1-6 alkyl; R ⁶ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl.

In some of the above embodiments, L is selected from -CH(R ⁵ )-, -O-, -N(R ⁶ )- or -S-; R ⁵ is selected from hydrogen, halogen, hydroxyl, amino, methyl, Ethyl, isopropyl, methoxy or trifluoromethyl; R ⁶ is selected from hydrogen, methyl, ethyl or isopropyl.

In certain embodiments of the above, L is selected from _-CH2- , -O-, -NH- or -S-. In certain embodiments of the above, L is selected from -O-, -NH- or -S-. In certain embodiments of the above, L is -NH-.

In certain embodiments above, each ^R is independently selected from halogen, hydroxy, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di( C _1-6 alkyl) amino, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkyl carbonyl.

In certain embodiments above, each ^R is independently selected from halogen, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, hydroxy C _{1 -6} alkyl, amino C _1-6 alkyl or halogenated C _1-6 alkoxy.

In some of the above embodiments, each ^R is independently selected from halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl or halogenated C _1-6 alkoxy base.

In certain embodiments above, m is selected from 0, 1 or 2. In certain embodiments above, m is selected from 0 or 1. In certain embodiments above, m is selected from zero.

In certain embodiments above, n is selected from 0 or 1. In certain embodiments above, n is selected from zero.

Various technical solutions in the present invention can be combined with each other to form new technical solutions, and the formed new technical solutions are also included in the scope of the present invention.

In certain embodiments, the compound represented by the aforementioned general formula (I), general formula (I-1), general formula (II), general formula (III) or general formula (IV), and a pharmaceutically acceptable salt thereof or its stereoisomers, selected from the following compounds:

The present invention also provides a pharmaceutical preparation, which contains the compound described in the aforementioned general formula (I), general formula (I-1), general formula (II), general formula (III) or general formula (IV), its A pharmaceutically acceptable salt or its stereoisomer, and one or more pharmaceutically acceptable carriers and/or diluents; the pharmaceutical preparation can be made into any clinically or pharmaceutically acceptable dosage form.

The present invention also provides a pharmaceutical composition, which comprises the compound described in the aforementioned general formula (I), general formula (I-1), general formula (II), general formula (III) or general formula (IV), A pharmaceutically acceptable salt thereof or a stereoisomer thereof, further comprising one or more second therapeutically active agents selected from the group consisting of mitotic inhibitors, anticancer alkylating agents, anticancer Sexual metabolic antagonists, anticancer platinum coordination compounds, anticancer camptothecin derivatives, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, anticancer tyrosine kinase inhibitors , interferon, retinoid receptor modulator, proteasome inhibitor, topoisomerase inhibitor, biological response modifier, hormonal anticancer agent, angiogenesis inhibitor, aromatase inhibitor, cytostatic agent , targeting antibodies, HMG-CoA reductase inhibitors and protein prenyl transferase inhibitors.

The pharmaceutically acceptable carrier and/or diluent available in the pharmaceutical composition or pharmaceutical preparation of the present invention can be any conventional carrier and/or diluent in the pharmaceutical preparation field, and the selection of specific carrier and/or diluent will depend on the The mode of administration or disease type and state to treat a particular patient.

In another aspect, the present invention also relates to the compound described in the aforementioned general formula (I), general formula (I-1), general formula (II), general formula (III) or general formula (IV), and its pharmaceutically acceptable Use of salts or stereoisomers thereof in the preparation of medicines for preventing and/or treating diseases mediated by Weel and related diseases, the diseases and related diseases being selected from cancer, the cancer including carcinoma in situ and metastasis of cancer.

Further, the present invention also relates to a compound containing the aforementioned general formula (I), general formula (I-1), general formula (II), general formula (III) or general formula (IV), and its pharmaceutically acceptable Use of a pharmaceutical formulation of a salt or a stereoisomer thereof for the manufacture of a medicament for the disease and related conditions selected from cancer, including carcinoma in situ and metastatic cancer.

Further, the present invention also relates to a compound containing the aforementioned general formula (I), general formula (I-1), general formula (II), general formula (III) or general formula (IV), and its pharmaceutically acceptable Use of a pharmaceutical composition of a salt or a stereoisomer thereof and one or more second therapeutically active agents for the preparation of a medicament for the treatment and/or prevention of diseases and related conditions mediated by Weel, said diseases and related disorders are selected from cancers including carcinoma in situ and metastatic cancers.

In the above scheme, the cancers include but not limited to lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer , liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female reproductive tract cancer, lymphoma, neurofibroma, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small Cell lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma, or sarcoma.

In the above scheme, the second therapeutically active agent is selected from the group consisting of mitosis inhibitors, anticancer alkylating agents, anticancer metabolic antagonists, anticancer platinum coordination compounds, anticancer camptothecin derivatives, antitumor Antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, anticancer tyrosine kinase inhibitors, interferons, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, Biological response modifiers, hormonal anticancer agents, angiogenesis inhibitors, aromatase inhibitors, cytostatic agents, targeting antibodies, HMG-CoA reductase inhibitors and protein prenyl transferase inhibitors.

In certain embodiments, the components to be combined (e.g., a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a second therapeutically active agent) may be administered simultaneously or sequentially and separately . For example, the second therapeutically active agent may be administered before, simultaneously with, or after administration of a compound of the invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Furthermore, the individual components to be combined can also be administered jointly in the form of the same formulation or in the form of separate different formulations.

In another aspect, the present invention also provides a method for treating diseases mediated by Weel and related diseases, the method comprising administering an effective amount of the aforementioned general formula (I), general formula (I-1) to patients in need ), the compound described in general formula (II), general formula (III) or general formula (IV), its pharmaceutically acceptable salt or its stereoisomer, the aforementioned preparation or pharmaceutical composition; Leading diseases and related conditions are as defined above.

The "effective amount" refers to the drug dose that can reduce, delay, inhibit or cure the subject's symptoms. The size of the dosage is determined by the way of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the individual signs (gender, weight, height, age) of the subject.

The present invention relates to the compound containing the aforementioned general formula (I), general formula (I-1), general formula (II), general formula (III) or general formula (IV), its pharmaceutically acceptable salt or its Stereoisomer drugs can also be combined with radiotherapy to improve the therapeutic effect of radiotherapy, and can be used as radiotherapy sensitizers.

In another aspect, the compounds of the invention are also useful in the field of cancer therapy as sensitizers to other anticancer agents (second therapeutically active agents). The second therapeutically active agent is as previously described. The sensitizer means, in the field of cancer treatment, a drug that additively or synergistically increases the therapeutic effect of radiation therapy and/or chemotherapy by using it in combination with radiation therapy and/or chemotherapy using an anticancer agent.

【Detailed description of the invention】

In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings generally understood by those skilled in the art. However, in order to better understand the present invention, definitions of some terms are provided below. When the definitions and explanations of the terms provided in the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in the present invention shall prevail.

The "halogen" in the present invention refers to fluorine atom, chlorine atom, bromine atom or iodine atom.

The "C _1-6 alkyl" in the present invention means a linear or branched alkyl group containing 1-6 carbon atoms, including, for example, "C _1-4 alkyl", "C _1-3 alkyl" , "C _1-2 alkyl", "C _2-6 alkyl", "C _2-5 alkyl", "C _2-4 alkyl", "C _2-3 alkyl", "C _{3- 6} alkyl", "C _3-5 alkyl", "C _3-4 alkyl", etc. Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethyl butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C _1-4 alkyl" in the present invention refers to specific examples of C _1-6 alkyl containing 1-4 carbon atoms.

The "C _1-6 alkoxy" in the present invention refers to "C _1-6 alkyl-O-", and the "C _1-6 alkyl" is as defined above. The "C _1-4 alkoxy" in the present invention refers to "C _1-4 alkyl-O-", and the "C _1-4 alkyl" is as defined above.

The "C _1-6 alkylthio" in the present invention refers to "C _1-6 alkyl-S-", and the "C _1-6 alkyl" is as defined above. The "C _1-4 alkylthio" in the present invention refers to "C _1-4 alkyl-S-", and the "C _1-4 alkyl" is as defined above.

"Hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkyl" in the present invention means that one or more hydrogens in C _1-6 alkyl are respectively replaced by one or Substituted by multiple hydroxyl groups, amino groups or halogens. C _1-6 alkyl is as defined above

"Hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, halogenated C _1-6 alkoxy" in the present invention refers to one or more of "C _1-6 alkoxy" Hydrogens are replaced by one or more hydroxy, amino or halo.

"Hydroxy C _1-6 alkylthio, amino C _1-6 alkylthio, halogenated C _1-6 alkylthio" in the present invention refers to one or more of "C _1-6 alkylthio" Hydrogens are replaced by one or more hydroxy, amino or halo.

"C _1-6 alkylamino, di(C _1-6 alkyl) amino" in the present invention refers to C _1-6 alkyl-NH-,

The "C _2-6 alkenyl" in the present invention refers to a straight-chain, branched or cyclic alkenyl group containing at least one double bond and having 2-6 carbon atoms, including, for example, "C _2-4 alkenyl "wait. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl Alkenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hex Dienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl and the like.

The "C _2-6 alkynyl" in the present invention refers to a straight-chain or branched alkynyl containing at least one triple bond and having 2-6 carbon atoms, including, for example, "C _2-4 alkynyl". Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 -hexynyl, 5-methyl-2-hexynyl and the like.

The "3-10 membered cycloalkyl group" in the present invention refers to include "3-8 membered monocycloalkyl group" and "8-10 membered condensed cycloalkyl group".

The "3-8 membered monocycloalkyl" in the present invention refers to a saturated or partially saturated monocyclic cyclic alkyl group containing 3-8 carbon atoms and does not have aromaticity, including "3-8 membered saturated Monocycloalkyl" and "3-8 membered partially saturated monocycloalkyl"; preferably "3-4 membered monocycloalkyl", "3-5 membered monocycloalkyl", "3-6 membered monocycloalkane ", "3-7 membered monocycloalkyl", "4-6 membered monocycloalkyl", "4-7 membered monocycloalkyl", "4-8 membered monocycloalkyl", "5- 6-membered monocycloalkyl", "5-7-membered monocycloalkyl", "5-8-membered monocycloalkyl", "6-7-membered monocycloalkyl", "6-8-membered monocycloalkyl ", "7-8 membered monocycloalkyl", "3-6 membered saturated monocycloalkyl", "5-8 membered saturated monocycloalkyl", "5-7 membered saturated monocycloalkyl", " 5-6 membered saturated monocycloalkyl", etc. Specific examples of the "3-8 membered saturated monocycloalkyl" include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; the "3 - Specific examples of 8-membered partially saturated monocycloalkyl" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1,3-di Alkene, cyclohexa-1,4-diene, cycloheptenyl, cyclohepta-1,3-dienyl, cyclohepta-1,4-dienyl, cyclohepta-1,3,5-triene Base, cyclooctyl, cyclooct-1,3-dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-tri alkenyl, cyclooctatetraenyl.

The "8-10 membered condensed ring group" in the present invention refers to a saturated or partial ring structure containing 8-10 ring atoms formed by sharing two adjacent carbon atoms with each other. Saturated, non-aromatic cyclic group, one ring in the fused ring may be an aromatic ring, but the fused ring as a whole is not aromatic; including "8-9 membered fused ring group", "9-10 Member fused ring group", etc., the condensing method can be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl wait. Examples include, but are not limited to: bicyclo[3.1.0]heptyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptanyl , bicyclo[4.2.0]octyl, octahydropentalenyl, octahydro-1H-indenyl, decalinyl, tetrahydrophenanthryl, bicyclo[3.1.0]hex-2- Alkenyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a- Tetrahydropentalenyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthrenyl, benzocyclopentyl, benzo Cyclohexyl, benzocyclohexenyl, benzocyclopentenyl, etc.

The "3-10 membered heterocyclic group" in the present invention includes "3-8 membered monoheterocyclic group" and "8-10 membered condensed heterocyclic group".

The "3-8 membered monoheterocyclic group" in the present invention refers to a heterocyclic group containing at least one heteroatom or group (for example, containing 1, 2, 3, 4 or 5) and the number of ring atoms is 3-8 saturated or partially saturated and non-aromatic monocyclic ring groups, the heteroatoms are nitrogen atoms, oxygen atoms and/or sulfur atoms, and the ring atoms in the ring structure (such as carbon atom, nitrogen atom or sulfur atom) may be oxo-substituted. The "3-8 membered monoheterocyclic group" in the present invention includes "3-8 membered saturated monoheterocyclic group" and "3-8 membered partially saturated monoheterocyclic group". Preferably, the "3-8 membered monoheterocyclic group" described in the present invention contains 1-3 heteroatoms or groups; preferably, the "3-8 membered monoheterocyclic group" described in the present invention contains 1- 2 heteroatoms or groups, and the heteroatoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8 membered monoheterocyclic group" in the present invention contains 1-2 nitrogen atoms. The "3-8 membered monoheterocyclic group" is preferably "3-7 membered monoheterocyclic group", "3-6 membered monoheterocyclic group", "4-7 membered monoheterocyclic group", "4-6 Monocyclic heterocyclic group", "6-8 monoheterocyclic group", "5-7 monoheterocyclic group", "5-6 monoheterocyclic group", "3-6 saturated monoheterocyclic group ", "5-6 membered saturated monoheterocyclic group", "3-6 membered nitrogen-containing monoheterocyclic group", "3-6 membered saturated nitrogen-containing monoheterocyclic group", "5-6 membered nitrogen-containing monoheterocyclic group" Cyclic group", "5-6 membered saturated nitrogen-containing monoheterocyclic group" and so on. For example, containing only 1 or 2 nitrogen atoms, or containing 1 nitrogen atom and other 1 or 2 heteroatoms (such as oxygen atoms and/or sulfur atoms). Specific examples of "3-8 membered monoheterocyclyl" include, but are not limited to: aziridine group, 2H-aziridine group, diaziridine group, 3H-diaziridine group, aza Cyclobutanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxanyl Dienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydro Thienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridyl, piperidonyl, tetrahydropyridinyl, dihydropiperidinyl, piperazine morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxa Azinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl Azinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl Base etc.

The "8-10 membered condensed heterocyclic group" in the present invention refers to a ring structure containing 8-10 ring atoms and at least one ring structure formed by sharing two adjacent atoms with each other. Atoms are heteroatoms or groups, saturated or partially saturated, non-aromatic cyclic groups, one of the rings in the condensed ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the hetero Atoms are nitrogen atoms, oxygen atoms and/or sulfur atoms, and ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxo, including but not limited to "8-9 membered fused heterocyclic group" , "9-10 membered fused heterocyclic group", etc., the fused methods include but not limited to: 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heterocyclic group and 5-6 membered heterocyclic group Cycloalkyl, benzo 5-6 membered heterocyclic group, benzo 5-6 membered saturated heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5 -6-membered saturated heterocyclic group; 5-6-membered heteroaryl group as defined above; specific examples of the "8-10-membered condensed heterocyclic group" include, but are not limited to: pyrrolidinocyclopropyl, cyclopentyl Aziridyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, pyrrolidinomorpholinyl, piperidinyl Morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidine base, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridopentyl, pyridine Cyclohexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridimidazolidinyl, pyridoxazolidinyl, pyridothiazolidinyl, pyridisoxazolidinyl, pyridylisothiazolidinyl, pyridine Piperidinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidimidazole Alkyl, pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidoisoxazolidinyl, pyrimidoisothiazolidinyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidine Tetrahydropyranyl; tetrahydroimidazo[4,5-c]pyridyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1 ,3] Dioxolyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, 4H-1,3 -Benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furo[3,4-d] Imidazolyl, 4,6-dihydro-1H-thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo [d] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuranoimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclo Penteno[c]pyrrolyl, 4H-1,3-benzoxazinyl, etc.

(亦可称之为2,3-二氢-1H-茚基)；术语“苯并吡咯烷”其结构包括

等；术语“吡啶并四氢呋喃基”其结构包括

前文所定义的其他“定义的其它稠杂环基”的具体实例具有与之类似的环状结构。The term "benzocyclopentyl", its structure refers to

(also known as 2,3-dihydro-1H-indenyl); the structure of the term "benzopyrrolidine" includes

etc.; the term "pyridotetrahydrofuranyl" has a structure including

Specific examples of other "other defined condensed heterocyclic groups" defined above have ring structures similar thereto.

The "6-10 membered aryl group" in the present invention includes "6-8 membered monocyclic aryl group" and "8-10 membered fused ring aryl group".

The "6-8 membered monocyclic aryl group" in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably benzene base.

The "8-10 membered fused ring aryl group" in the present invention refers to a group formed by two or more ring structures sharing two adjacent atoms, containing 8-10 ring carbon atoms, not Saturated, aromatic cyclic group, preferably "9-10 membered fused ring aryl", specific examples include naphthyl and the like.

The "5-10 membered heteroaryl" in the present invention includes "5-8 membered monoheteroaryl" and "8-10 membered condensed heteroaryl".

The "5-8 membered monoheteroaryl" in the present invention refers to an aromatic monoheteroaryl group containing 5-8 ring atoms (wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). ring ring group. A ring atom (such as a carbon atom, a nitrogen atom or a sulfur atom) in a ring structure may be oxo substituted. "5-8 membered monoheteroaryl" includes, for example, "5-7 membered monoheteroaryl", "5-6 membered monoheteroaryl", "5-6 membered nitrogen-containing monoheteroaryl", "6 membered Nitrogen-containing monoheteroaryl", etc., the heteroatom in the "nitrogen-containing heteroaryl" contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and other 1 or 2 heteroatoms (such as oxygen atom and/or sulfur atom), or, contain 2 nitrogen atoms and other 1 or 2 heteroatoms (such as oxygen atom and/or sulfur atom). Specific examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadi Azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole Base, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepanyl, 1,3-diazepanyl alkenyl, azacyclooctatetraenyl, etc. The "5-6 membered monoheteroaryl" refers to a specific example of 5-6 ring atoms in the 5-8 membered heteroaryl.

The "8-10 membered condensed heteroaryl" in the present invention refers to a group formed by two or more ring structures sharing two adjacent atoms with each other, containing 8-10 ring atoms (at least one of which is An unsaturated aromatic ring structure in which the ring atoms are heteroatoms, such as nitrogen atoms, oxygen atoms or sulfur atoms). Optionally, ring atoms (eg carbon, nitrogen or sulfur atoms) in the ring structure can be oxo substituted. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., the condensed way can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5- 6-membered heteroaryl, etc.; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furothiophene, pyrazoloxazole, benzofuryl, benziso Furyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4 -Quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl etc.

"Carbon atom, nitrogen atom or sulfur atom is oxo-substituted" in the present invention refers to forming a structure of C=O, N=O, S=O or SO ₂ .

The term "optionally substituted" in the present invention refers to two situations in which one or more hydrogen atoms on the substituted group can be "substituted" or "not substituted" by one or more substituents.

The "pharmaceutically acceptable salt" in the present invention refers to the salt formed by the acidic functional group (such as -COOH, -OH, -SO ₃ H, etc.) present in the compound and an appropriate inorganic or organic cation (base), including Salts formed by alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as -NH2, etc.) present in compounds and suitable inorganic or organic anions (acids), Salts with inorganic acids or organic acids (eg, carboxylic acids, etc.) are included.

The "isomer" in the present invention means that when the compound of the present invention contains one or more asymmetric centers, it can be used as racemate and racemic mixture, single enantiomer, diastereoisomer mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. If the compounds of the present invention contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers. The compounds described in the present invention may exist in the form of tautomers (one of functional group isomers), which have different points of attachment of hydrogen by displacement of one or more double bonds, for example, ketones and its alkenes The alcohol form is a keto-enol tautomer. The compound of the present invention contains a spiro ring structure. Affected by the three-dimensional structure of the ring, substituents on the ring may exist on both sides of the ring to form relative cis (cis) and trans (trans) isomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereoisomers, racemates, mesoisomers, cis-trans isomers, tautomers, geometric isomers, epimers and their Mixtures and the like are included in the scope of the present invention.

The compounds of the present invention may be prepared in the form of individual enantiomers by enantiospecific synthesis or resolution from enantiomeric mixtures. Conventional resolution techniques include formation of the free base salt of each isomer of the enantiomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), formation of the salt of the enantiomeric pair using an optically active amine, Salts of the acid forms of each enantiomer (followed by fractional crystallization and regeneration of the free acid), formation of each of each enantiomer of the enantiomeric pair using optically pure acids, amines or alcohols The esters or amides of the species (followed by chromatographic separation and removal of the chiral auxiliary) or the resolution of the starting material or the mixture of enantiomers of the final product using various well-known chromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted by a structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% by weight relative to the other stereoisomers Or 99.9% pure by weight. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight. Optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

The "dosage form" mentioned in the present invention refers to the form suitable for clinical use made of medicines, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections) , sterile powder for injection and concentrated solution for injection), spray, aerosol, powder spray, lotion, liniment, ointment, plaster, paste, patch, gargle or suppository, more preferably Powder, tablet, granule, capsule, solution, injection, ointment, gargle, or suppository.

Beneficial Effects of the Invention

1. The compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has excellent Wee1 activity inhibitory effect and anti-tumor cell proliferation activity, which has good pharmacokinetic properties in vivo, long-lasting effect, exposure The amount and bioavailability are high, and it can treat and/or prevent diseases mediated by Wee1.

2. The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have good inhibitory and therapeutic effects on Wee1-mediated cancer in vivo and in vitro.

3. The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers can synergistically enhance the effects of radiotherapy and chemotherapy, effectively inhibit tumor growth, and reduce damage to normal cells and side effects.

4. The preparation process of the compound of the present invention is simple, the drug has high purity and stable quality, and is easy to carry out large-scale industrial production.

specific implementation plan

The technical solution of the present invention will be described below in conjunction with specific embodiments, and the above content of the present invention will be further described in detail, but it should not be understood that the scope of the above subject of the present invention is limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Example 1: 2-allyl-6-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-1-(6-( Preparation of 2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 1)

1. Preparation of 2-(4-nitrophenyl) octahydropyrrolo[1,2-a]pyrazine

Dissolve 1-fluoro-4-nitrobenzene (338 mg, 2.4 mmol) in DMSO (10 mL), add K ₂ CO ₃ (662 mg, 4.8 mmol), octahydropyrrolo[1,2-a]pyrazine ( 300mg, 2.4mmol), react at 70°C for 16h. After the reaction was completed, EA and water were added to the reaction solution, separated and extracted three times, the organic phase was spin-dried, and separated by forward preparation (PE:EA=1:5) to obtain the product (480 mg, yield 81.6%).

2, Preparation of 4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)aniline

Dissolve 2-(4-nitrophenyl)octahydropyrrolo[1,2-a]pyrazine (470mg, 1.9mmol) in methanol (10mL), add palladium on carbon (40mg), and place the mixture on The reaction was carried out at 25°C for 1 h, filtered with suction, and the filtrate was concentrated to obtain the crude product (400 mg).

3. 2-allyl-6-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-1-(6-(2- Preparation of Hydroxypropan-2-yl)pyridin-2yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazole Con[3,4-d]pyrimidin-3-one (76 mg) was dissolved in toluene (3 mL), and 4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)aniline was added (130mg crude product) and DIEA (129mg, 1mmol), react at 25°C for 10h. After the reaction was completed, the reaction solution was spin-dried and purified by reverse phase chromatography (water:acetonitrile=1:3) to obtain the product (25 mg).

Molecular formula: C ₂₉ H ₃₄ N ₈ O ₂ Molecular weight: 526.6LC-MS (M/e): 527.2 (M+H ⁺ )

¹ H-NMR (400MHz, MeOD) δ: 10.1(s,1H), 8.95(s,1H), 8.10(t,1H), 7.75(m,1H), 7.65(m,1H), 7.50–7.60( m,2H),6.90-7.00(m,2H),5.60–5.70(m,1H),5.30(s,1H),5.00(d,1H),4.83(d,1H),4.67(d,2H) ,3.75(m,1H),3.55(m,1H),3.05(m,2H),2.65(t,1H),2.35(t,1H),2.25(t,1H),2.05(m,2H), 1.85(m,1H),1.70(m,2H),1.46(s,6H),1.40(m,1H).

Example 2: (R)-2-allyl-6-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-1- (6-(2-hydroxyprop-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 1-2) preparation

1. Preparation of (R)-2-(4-nitrophenyl)octahydropyrrolo[1,2-a]pyrazine

Dissolve 1-fluoro-4-nitrobenzene (350mg, 2.5mmol) in DMSO (6mL), add K ₂ CO ₃ (685mg, 5.0mmol), (R)-octahydropyrrolo[1,2-a ] Pyrazine (313mg, 2.5mmol), react at 70°C for 7 hours. The reaction was completed, extracted with water (20mL) and ethyl acetate (20mL x2), the organic phase was washed with water (20mL x3), and the crude product was purified by silica gel column chromatography (PE:EA=1:4) to obtain the product (400mg, yield 65.2 %).

2. Preparation of (R)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)aniline

Dissolve (R)-2-(4-nitrophenyl)octahydropyrrolo[1,2-a]pyrazine (400mg, 1.6mmol) in methanol (40mL), add palladium carbon (120mg), and use The gas was replaced by hydrogen three times, reacted at 30° C. for 1 h under a hydrogen atmosphere, filtered to remove the solid, and concentrated to obtain a crude product (350 mg).

3. (R)-2-allyl-6-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-1-(6 Preparation of -(2-hydroxypropan-2-yl)pyridin-2yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[ 3,4-d]Pyrimidin-3-one (100mg, 0.28mmol) was dissolved in toluene (15mL), m-chloroperoxybenzoic acid (63mg, 0.31mmol) was added, and reacted at 25°C for 0.5 hours. The reaction is complete. Add N,N-diisopropylethylamine (180 mg, 1.39 mmol) and (R)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)aniline (67 mg, 0.31mmol), reacted at 25°C for 16h. The crude product was extracted with ethyl acetate (20 mL) and saturated sodium bicarbonate solution (15 mL) and purified by reverse phase chromatography (water: acetonitrile = 1:2) to obtain the product (42 mg, yield 28.5%). Molecular formula: C ₂₉ H ₃₄ N ₈ O ₂ Molecular weight: 526.6LC-MS (M/e): 527.2 (M+H ⁺ )

¹ H-NMR (400MHz,MeOD)δ:10.20-10.05(brs,1H),8.82(s,1H),8.12-8.03(m,1H),7.81-7.75(m,1H),7.65-7.46(m ,3H),6.93(d,J=8.8Hz,2H),5.71-5.60(m,1H),5.32(s,1H),5.00(d,J=9.2Hz,1H),4.90-4.80(m, 1H),4.68-4.67(m,2H),3.80-3.70(m,1H),3.65-3.55(m,1H),3.06-3.01(m,2H),2.75-2.65(m,1H),2.40- 2.32(m,1H),2.27-2.20(m,1H),2.10-1.99(m,2H),1.90-1.80(m,1H),1.78-1.65(m,2H),1.46(s,6H), 1.44-1.35 (m, 1H).

Example 3: (S)-2-allyl-6-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-1- (6-(2-hydroxyprop-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (compound 1-1) preparation

Compound 1-1 was prepared according to the preparation method of compound 1-2, and the raw material (R)-octahydropyrrolo[1,2-a]pyrazine was replaced by (S)-octahydropyrrolo[1,2-a] pyrazine.

Compound 2-4 was prepared by the same or similar method as in Example 1-3.

Experimental program

Exemplary experimental schemes of some compounds of the present invention are provided below to show the advantageous activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental scheme is only an example of the content of the present invention, rather than limiting the scope of the present invention.

Experimental example 1 The compound of the present invention is to the inhibitory experiment of cell proliferation activity

Test method: CellTiter-Glo

Test substance: some compounds of the present invention, see the preparation examples of the present invention for their structural formulas and preparation methods.

AZD1775, prepared according to the method disclosed in the prior art WO2007126128, its structure is as follows:

experimental method

1. Experimental Materials and Reagents

name source Item No. DMEM high glucose medium Gibco 11995-065 RPMI-1640 Medium Gibco A10491-01 MEM medium Gibco 10370-021 FBS (Fetal Bovine Serum) Gibco 10099-141C horse serum Solarbio S9050 sodium pyruvate Gibco 11360-070 Glutamine Gibco 35050-061 Penicillin-Streptomycin-Double Antibody Gibco 1507-063 0.25% trypsin Gibco 25200-072 10×DPBS (Duchenette's Phosphate Buffered Saline) Gibco 14200-075 96-well bottom transparent white plate Corning 3610 Gemcitabine (guitar Xibin) MCE HY-B0003 CTG Promega G7571

2. The ratio of cell culture medium and the number of plates

cell line cell type growth characteristics Plate Density/hole culture medium MIAPaCa2 human pancreatic cancer stick to the wall 2000 DMEM+10%FBS+2.5%HS+1%P.S A431 squamous cell carcinoma stick to the wall 3000 DMEM+10%FBS+1%P.S SK-MES-1 human lung squamous cell carcinoma stick to the wall 2000 EMEM+10%FBS+1%P.S LoVo human colorectal cancer cells stick to the wall 2000 DMEM+10%FBS+1%P.S OVCAR-3 ovarian cancer cells stick to the wall 2000 RPMI-1640+20%FBS+1%P.S

3. Experimental process

3.1 Compound preparation

The 10 mM DMSO solution of the test compound was diluted with 3-fold gradient in DMSO, with 8 concentrations. The 10 mM DMSO solution of the test compound was prepared with DMSO as a 1000-fold solution of the combined concentration, that is, 300 μM, 100 μM, and 30 μM.

A 10 mM stock solution of Gemcitabine was prepared, diluted to 1000 times the highest final concentration, that is, 100 μM, and then diluted to 5 concentrations with 3 times of DMSO.

3.2 Test process

The cells were cultured according to the conditions recommended by the source, until they reached the logarithmic growth phase in good condition, the medium was removed, washed once with PBS, digested with 0.25% trypsin, and the cells were collected after the completion of the complete medium, resuspended to an appropriate concentration, and inoculated into 96 wells plate, 90 μL per well, and incubate for 24 hours at 37°C in a 5% CO ₂ incubator.

Compound single use: compound solution with a final concentration of 1000 times, diluted 100 times in the culture medium, added 10 μL to each well, incubated at 37°C, 5% CO ₂ incubator for 72 hours, and then detected.

Combination of compound and gemcitabine: 1000 times the final concentration of gemcitabine, dilute the culture medium 100 times, add 10 μL to each well, and continue to incubate for 24 hours at 37°C in a 5% CO ₂ incubator. For the compound solution with a final concentration of 1000 times, the culture medium was diluted 20 times, 5 μL was added to each well, and the culture was continued for 24 hours at 37° C. in a 5% CO ₂ incubator for detection.

Place the culture plate at room temperature in advance, add 60 μL of CTG detection solution to each well, avoid light, and shake on an orbital shaker for 2 minutes to lyse the cells. After a total of 20 minutes of reaction, read the luminescence value with a multi-functional microplate reader.

4. Data processing

The data were fitted using non-linear S-curve regression to generate dose-response curves from which _IC50 values were calculated.

Experimental results

Table 1 Compounds of the present invention have single-use in vitro cytostatic activity

Table 2 Compounds of the present invention combined with gemcitabine in vitro cytostatic activity

Note*: The data displayed in combination is the IC ₅₀ value of gemcitabine.

Experimental results

The compound of the present invention has a good inhibitory effect on test cell lines when used alone, and has a significant synergistic effect on inhibiting the proliferation activity of MIAPaCa2 cells when used in combination with gemcitabine.

Claims (11)

1. The compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer,

in, X ₁ and X ₂ are independently selected from C, C(R ³ ) or N; L is selected from -C(R ⁴ )(R ⁵ )-, -O-, -N(R ⁶ )- or -S-; ^R is selected from C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl optionally substituted by substituents independently selected from halogen, hydroxyl, amino, carboxyl, cyano Base, C _1-6 alkoxy, C _1-6 alkylamino, two (C _1-6 alkyl) amino, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl; Each ^R is independently selected from halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di(C _1-6 alkyl)amino , halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl; Ring A is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclic group, 6-8 membered monocyclic aryl or 5-8 membered monocyclic heterocyclic group optionally substituted by 1-3 Q1 Aryl; Ring B is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, 6-8 membered monocyclic aryl or 5-8 membered monocyclic heterocyclic optionally substituted by 1-3 Q2 Aryl; Ring C is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted by 1-3 Q3; Each Q1, each Q2, and each Q3 are independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _{1-6 6} alkyl) amino, halogenated C _1-6 alkyl, hydroxy C 1-6 alkyl _, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 alkylthio, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, amino C _1-6 alkylthio; Each R ³ , R ⁴ , and R ⁵ are independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di( C _1-6 alkyl) amino, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy, C _1-6 alkyl Carbonyl or C _1-6 alkoxy C _1-6 alkyl; ^R is selected from hydrogen, C _1-6 alkyl, halogenated C _{1-6 alkyl, hydroxy C 1-6 alkyl} , amino C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkane base; m is selected from 0, 1, 2 or 3. 2. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, X ₁ and X ₂ are independently selected from C, CH or N; L is selected from -CH ₂ -, -O-, -NH or -S-; R ¹ is selected from C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl; Each ^R is independently selected from halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di(C _1-6 alkyl)amino , halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl; Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl optionally substituted by 1-2 Q2 or 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms or groups independently selected from N, NH, O, S, S(O) or S(O) ₂ ; Ring C is selected from 5-6 membered monocyclic cycloalkyl, 8-10 membered condensed ring cycloalkyl, 5-6 membered monocyclic heterocyclic group, containing 1-3 heterocyclic groups optionally substituted by 1-2 Q3 Atom or group 8-10 membered fused ring heterocyclic group, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl group or 8-10 membered fused heteroaryl group containing 1-3 heteroatoms or groups , the heteroatoms or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ; Each Q1, each Q2, and each Q3 are independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _{1-6 6} alkyl) amino, halogenated C _1-6 alkyl, hydroxy C 1-6 alkyl _, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 alkylthio, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, amino C _1-6 alkylthio; m is selected from 0, 1 or 2. 3. The compound according to claim 2, its pharmaceutically acceptable salt or its stereoisomer, wherein, X ₁ and X ₂ are independently selected from CH or N; L is selected from -CH ₂ -, -O-, -NH or -S-; ^R is selected from methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl or propynyl; Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-Triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl; Ring C is selected from cyclopentyl, cyclohexyl, phenyl, 5-6 membered monocyclic heterocyclic groups containing 1-3 heteroatoms or groups optionally substituted by 1-2 Q3 or 1-3 5-6 membered monocyclic heteroaryls of heteroatoms or groups, said heteroatoms or groups are independently selected from N, NH, O, S, S(O) or S(O) ₂ ; Each Q1, each Q2, and each Q3 are independently selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkylamino, two (C _{1-6 6} alkyl) amino, halogenated C _1-6 alkyl, hydroxy C 1-6 alkyl _, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 alkylthio, halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, hydroxy C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkoxy, amino C _1-6 alkylthio; m is selected from 0 or 1. 4. The compound as claimed in claim 3, its pharmaceutically acceptable salt or its stereoisomer, wherein, X ₁ and X ₂ are N respectively; L is NH; R ¹ is propenyl; R ² is selected from halogen, hydroxyl, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _{1 -6} alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, halogenated C _1-6 alkoxy or C _1-6 alkylcarbonyl; Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and _X are in the para position of ring B; Ring C is selected from cyclopentyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, oxazole optionally substituted by 1-2 Q3 Alkyl, thiazolidinyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl; Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C _{1-6 alkyl, C 1-6 alkoxy} C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy; m is selected from 0 or 1. 5. The compound according to claim 4, its pharmaceutically acceptable salt or its stereoisomer, wherein, X ₁ and X ₂ are N respectively; L is NH; R ¹ is propenyl; Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring B is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and _X are in the para position of ring B; Ring C is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4- Triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl; Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C _{1-6 alkyl, C 1-6 alkoxy} C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy; m is selected from 0. 6. The compound according to any one of claims 1-5, its pharmaceutically acceptable salt or its stereoisomer, which has the structure shown in the following general formula (II):

Among them, ring A, ring C, Q1, Q2, Q3, X 1 , X _{2 ,} L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and m are as defined in any of claims 1-5. One item; n is selected from 0, 1 or 2. 7. the compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, it has the structure shown in following general formula (IV):

in, Ring A is selected from the following groups optionally substituted by 1-2 Q1:

Ring C is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted by 1-2 Q3; Each Q1 and each Q3 are independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkylamino, di(C _1-6 alkyl) amino, halogenated C _1-6 Alkyl, hydroxy C _1-6 alkyl, amino C 1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, _{C 1-6 alkoxy} , halogenated C _1-6 alkoxy , hydroxy C _1-6 alkoxy or amino C _1-6 alkoxy; m is 0; n is 0. 8. The compound of claim 1, its pharmaceutically acceptable salt or its stereoisomer, selected from the following compounds:

9. The pharmaceutical preparation containing the compound described in any one of claims 1-8, its pharmaceutically acceptable salt or its stereoisomer, is characterized in that, comprises one or more pharmaceutically acceptable excipients The pharmaceutical preparation is any pharmaceutically acceptable dosage form. 10. A pharmaceutical composition containing the compound of any one of claims 1-8, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising one or more second therapeutically active agents, The second therapeutically active agent is selected from the group consisting of mitosis inhibitors, anticancer alkylating agents, anticancer metabolic antagonists, anticancer platinum coordination compounds, anticancer camptothecin derivatives, antitumor antibiotics, growth Factor inhibitors, signaling inhibitors, cell cycle inhibitors, anticancer tyrosine kinase inhibitors, interferons, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modulation Anticancer agents, hormonal anticancer agents, angiogenesis inhibitors, aromatase inhibitors, cytostatic agents, targeting antibodies, HMG-CoA reductase inhibitors and protein prenyl transferase inhibitors. 11. The compound described in any one of claims 1-8, its pharmaceutically acceptable salt or its stereoisomer, the pharmaceutical preparation described in claim 19, or the pharmaceutical composition described in claim 10 in preparation Use in medicines for the treatment and/or prevention of Wee1-mediated diseases and related disorders selected from cancer; Preferably, the cancer is selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, Renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female reproductive tract cancer, lymphoma, neurofibroma, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, Non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma, or sarcoma.