WO2023036285A1

WO2023036285A1 - Heteroaromatic compound and application thereof

Info

Publication number: WO2023036285A1
Application number: PCT/CN2022/118064
Authority: WO
Inventors: 张军波; 朱曙灏; 齐晓昕
Original assignee: 南京奥利墨斯医药科技有限公司
Priority date: 2021-09-09
Filing date: 2022-09-09
Publication date: 2023-03-16

Abstract

A heteroaromatic compound and an application thereof. Specifically, provided is a compound as represented by formula I, or an optical isomer, raceme, solvate, hydrate, pharmaceutically-acceptable salt, or prodrug thereof. The compound has excellent preventive and therapeutic effects on tumors.

Description

A kind of heteroaromatic compound and its application

technical field

The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a heteroaromatic ring compound and its application.

Background technique

Cancer is one of the major diseases that threaten human health, and there are many new cancer patients every year. Clinically, the main treatment methods adopted for cancer include surgery, radiotherapy and chemotherapy. However, there are many shortcomings in the tumor treatment effect of the existing cancer treatment methods, such as poor anticancer effect and high toxicity and side effects. Therefore, The curative effect of existing cancer treatment methods is not ideal, which limits the effect of tumor treatment and increases the suffering of patients. Therefore, how to improve the therapeutic effect of tumors and reduce the toxicity and side effects has always been a research hotspot in the medical field.

Therefore, there is a need in the art to develop an anticancer drug that improves the therapeutic effect of tumors.

content of the invention,

The object of the present invention is to provide a compound with novel structure and its application in anti-tumor.

The first aspect of the present invention provides a compound of formula I, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its precursor medicine;

in,

Ring A is a substituted or unsubstituted C6-C14 aromatic ring, a substituted or unsubstituted C3-C14 cycloalkane ring, a substituted or unsubstituted 3-14 membered heterocycloalkane ring, or a substituted or unsubstituted 5-14 membered Heteroaromatic ring;

W ₁ and W ₂ are each independently =C(R ₄ )- or =N-;

W ₃ is =C(R ₅ )- or =N-;

W ₄ is =C(R ₆ )- or =N-;

W ₅ is =C(R ₇ )- or =N-;

Z ₁ is a substituted or unsubstituted C1-C6 alkylene group,

-O-, -S-, -N(R ₈ )-;

Z ₂ is a substituted or unsubstituted C3-C14 cycloalkylene, or a substituted or unsubstituted 3-14 membered heterocycloalkylene;

R ₁ and R ₃ are each independently hydrogen or substituted or unsubstituted C1-C8 alkyl;

_R2 is

R ₄ is hydrogen or substituted or unsubstituted C1-C8 alkyl;

R ₅ and R ₆ are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl or halogen; or R ₅ and R ₆ are connected to form a substituted or unsubstituted C6-C12 aromatic ring (such as a benzene ring);

R ₇ is hydrogen, substituted or unsubstituted C1-C8 alkyl or halogen;

R ₈ is hydrogen or substituted or unsubstituted C1-C8 alkyl;

R ₉ and R ₁₀ are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 haloalkyl, (R ₁₁ R ₁₂ )N-substituted or unsubstituted C1-C8 alkane -, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 cycloalkyl-substituted or unsubstituted C1-C10 alkyl-, or substituted or unsubstituted 3-12 membered hetero Cycloalkyl;

R ₁₁ and R ₁₂ are each independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C8 cycloalkyl.

Preferably, any "substituted" means that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on the ring or group are independently substituted by replace.

Preferably, any of the "substituted" means that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on the ring or group are independently selected from The following substituents are substituted: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkyl-C3-C8 cycloalkyl-, C1-C8 haloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 cycloalkylthio, C3-C8 halocycloalkoxy, C3-C8 halocycloalkylthio, halogen, nitro, -CN, =O, hydroxyl, mercapto , amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amido, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6- C12 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, (R ₁₁ R ₁₂ )N-.

Preferably, the heterocycloalkyl, heterocycloalkylene, heteroaryl, heterocycloalkane and heteroaromatic rings have 1-4 (preferably 1, 2, 3 or 4 ) are each independently selected from N, O and S heteroatoms.

Preferably, the heterocyclic ring of the heterocycloalkyl has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.

Preferably, the heterocyclic ring of the heterocycloalkylene has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.

Preferably, the heterocyclic ring of the heteroaryl group has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.

Preferably, the heterocyclic ring of the heterocycloalkane ring has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.

Preferably, the heterocyclic ring of the heteroaromatic ring has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.

Preferably, any of the "substituted" means that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on the ring or group are independently selected from The following substituents are substituted: C1-C6 alkyl, C3-C8 cycloalkyl, C1-C8 alkyl-C3-C8 cycloalkyl-, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 cycloalkylthio, C3-C8 halocycloalkoxy, C3-C8 halocycloalkylthio, halogen, nitro, -CN, =O, hydroxyl, mercapto , amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amido, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C6- C12 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, (R ₁₁ R ₁₂ )N-.

Preferably, any of the "substituted" means that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on the ring or group are independently selected from The following substituents are substituted: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C4 alkyl-C3-C8 cycloalkyl-, C1-C4 haloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 cycloalkylthio, C3-C8 halocycloalkoxy, C3-C8 halocycloalkylthio, halogen, nitro, -CN, =O, hydroxyl, mercapto , amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amido, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 haloalkoxy, C1-C4 haloalkylthio, C6- C12 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, (R ₁₁ R ₁₂ )N-.

Preferably, ring A is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted C3-C10 cycloalkane ring, a substituted or unsubstituted 3-10 membered heterocycloalkane ring or a substituted or unsubstituted 5- 10-membered heteroaromatic ring.

Preferably, Ring A is a substituted or unsubstituted C6-C8 aromatic ring, a substituted or unsubstituted C3-C8 cycloalkane ring, a substituted or unsubstituted 3-8 membered heterocycloalkane ring or a substituted or unsubstituted 5- 8-membered heteroaromatic ring.

Preferably, Ring A is a substituted or unsubstituted 3-membered heterocycloalkane ring, a substituted or unsubstituted 4-membered heterocycloalkane ring, a substituted or unsubstituted 5-membered heterocycloalkane ring, a substituted or unsubstituted 6-membered heterocycloalkane ring Cycloalkane, substituted or unsubstituted 7-membered heterocycloalkane, substituted or unsubstituted 8-membered heterocycloalkane, substituted or unsubstituted 9-membered heterocycloalkane, or substituted or unsubstituted 10-membered heterocycloalkane ring.

Preferably, Ring A is

Wherein, R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ or R ₁₉ are each independently hydrogen or C1-C8 alkyl.

Preferably, Ring A is

Preferably, Z1 is a substituted or unsubstituted C1-C4 alkylene,

-O-, -S-, NR ₈ .

Preferably, Z1 is substituted or unsubstituted methylene, ethylene, propylene, butylene,

-O-, -S-, NR ₈ .

Preferably, Z ₂ is a substituted or unsubstituted C3-C12 cycloalkylene, or a substituted or unsubstituted 3-12 membered heterocycloalkylene.

Preferably, Z ₂ is a substituted or unsubstituted C3-C10 cycloalkylene, or a substituted or unsubstituted 3-10 membered heterocycloalkylene.

Preferably, Z _is a substituted or unsubstituted 3-membered heterocycloalkylene, a substituted or unsubstituted 4-membered heterocycloalkylene, a substituted or unsubstituted 5-membered heterocycloalkylene, a substituted or unsubstituted 6-membered heterocycloalkylene, substituted or unsubstituted 7-membered heterocycloalkylene, substituted or unsubstituted 8-membered heterocycloalkylene, substituted or unsubstituted 9-membered heterocycloalkylene, substituted or unsubstituted Substituted 10-membered heterocycloalkylene, substituted or unsubstituted 11-membered heterocycloalkylene, substituted or unsubstituted 12-membered heterocycloalkylene, substituted or unsubstituted 13-membered heterocycloalkylene or substituted or an unsubstituted 14-membered heterocycloalkylene.

Preferably, _Z2 is

R ₂₀ and R ₂₁ are each independently hydrogen or C1-C8 alkyl.

Preferably, Z ₂

n is 1 or 2.

Preferably, _Z2 is

Preferably, R ₁ and R ₃ are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl.

Preferably, R ₁ and R ₃ are each independently hydrogen or substituted or unsubstituted C1-C4 alkyl.

Preferably, R ₁ and R ₃ are each independently hydrogen or substituted or unsubstituted C1-C2 alkyl.

Preferably, R ₁ is hydrogen.

Preferably, _R3 is hydrogen.

Preferably, R ₄ is hydrogen or substituted or unsubstituted C1-C6 alkyl.

Preferably, R ₄ is hydrogen or substituted or unsubstituted C1-C4 alkyl.

Preferably, _R4 is hydrogen, methyl, ethyl, propyl or butyl.

Preferably, R ₅ and R ₆ are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl or halogen; or R ₅ and R ₆ are connected to form a C6-C10 aromatic ring (such as a benzene ring).

Preferably, R ₅ and R ₆ are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl or halogen; or R ₅ and R ₆ are connected to form a C6-C8 aromatic ring (such as a benzene ring).

Preferably, R ₅ and R ₆ are each independently hydrogen, methyl, ethyl, propyl, butyl or halogen; or R ₅ and R ₆ are connected to form a C6-C8 aromatic ring (such as a benzene ring).

Preferably, _R5 and _R6 are each independently hydrogen, methyl, ethyl, propyl, butyl or halogen; or _R5 and _R6 are connected to form a benzene ring.

Preferably, _R5 and _R6 are each independently hydrogen, methyl, ethyl, propyl, butyl, F, Cl, Br or I; or _R5 and _R6 are connected to form a benzene ring.

Preferably, R ₇ is hydrogen, substituted or unsubstituted C1-C6 alkyl or halogen.

Preferably, R ₇ is hydrogen, substituted or unsubstituted C1-C4 alkyl or halogen.

Preferably, R ₇ is hydrogen, methyl, ethyl, propyl, butyl or or halogen.

Preferably, _R7 is hydrogen, methyl, ethyl, propyl, butyl, F, Cl, Br or I.

Preferably, R ₈ is hydrogen or substituted or unsubstituted C1-C6 alkyl.

Preferably, R ₈ is hydrogen or substituted or unsubstituted C1-C4 alkyl.

Preferably, _R8 is hydrogen, methyl, ethyl, propyl or butyl.

Preferably, each of R ₉ and R ₁₀ is independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, (R ₁₁ R ₁₂ ) N-substituted or unsubstituted C1 -C8 alkyl-, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl-substituted or unsubstituted C1-C10 alkyl-, or substituted or unsubstituted 3- 10-membered heterocycloalkyl.

Preferably, each of R ₉ and R ₁₀ is independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 haloalkyl, (R ₁₁ R ₁₂ ) N-substituted or unsubstituted C1 -C8 alkyl-, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl-substituted or unsubstituted C1-C8 alkyl-, or substituted or unsubstituted 3- 8-membered heterocycloalkyl.

Preferably, each of R ₉ and R ₁₀ is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, (R ₁₁ R ₁₂ ) N-substituted or unsubstituted C1 -C6 alkyl-, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-substituted or unsubstituted C1-C6 alkyl-, or substituted or unsubstituted 3- 6-membered heterocycloalkyl.

Preferably, each of R ₉ and R ₁₀ is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, (R ₁₁ R ₁₂ ) N-substituted or unsubstituted C1 -C4 alkyl-, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-substituted or unsubstituted C1-C4 alkyl-, or substituted or unsubstituted 3- 6-membered heterocycloalkyl.

Preferably, _R9 and _R10 are each independently hydrogen, methyl, ethyl, propyl, butyl, oxetanyl, azetidinyl, 1-methylazetidinyl , haloethyl, cyclobutyl-methyl-, dimethylamino-ethyl-, trifluoromethyl.

Preferably, the structure of the oxetanyl group is:

Preferably, the structure of the azetidinyl group is:

Preferably, the structure of 1-methylazetidinyl is:

Preferably, the structure of the haloethyl group is

Preferably, cyclobutyl-methyl- has the structure:

Preferably, the structure of dimethylamino-ethyl- is:

Preferably, said halogen is F, Cl, Br or I.

Preferably, R ₁₁ and R ₁₂ are each independently hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

Preferably, R ₁₁ and R ₁₂ are each independently hydrogen, C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

Preferably, R ₁₁ and R ₁₂ are each independently hydrogen, methyl, ethyl, propyl or butyl.

Preferably, R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ or R ₁₉ are each independently hydrogen or C1-C6 alkyl.

Preferably, R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ or R ₁₉ are each independently hydrogen or C1-C4 alkyl.

Preferably, R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ or R ₁₉ are each independently hydrogen, methyl, ethyl, propyl or butyl.

Preferably, R ₂₀ and R ₂₁ are each independently hydrogen or C1-C6 alkyl.

Preferably, R ₂₀ and R ₂₁ are each independently hydrogen or C1-C4 alkyl.

Preferably, _R20 and _R21 are each independently hydrogen, methyl, ethyl, propyl or butyl.

Preferably, the pharmaceutically acceptable salt of the compound of formula I comprises compound of formula I with hydrochloric acid, mucic acid, D-glucuronic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid , acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzene Salts of sulfonic acid, aspartic acid or glutamic acid.

Preferably, the compound of formula I is

The second aspect of the present invention provides a composition, which comprises the compound of formula I as described in the first aspect of the present invention, or its optical isomer, or its racemate, or its solvate , or a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Preferably, the compound as described in the first aspect of the present invention, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, The content of the prodrug thereof is 0.001-99wt%, preferably 0.01-70wt%, more preferably 0.05-40wt%, based on the total weight of the composition.

Preferably, the composition is a pharmaceutical composition.

Preferably, the composition further includes a pharmaceutically acceptable carrier.

Preferably, the dosage form of the composition is an injection preparation, an external preparation or an oral preparation.

Preferably, the injection preparation is an intravenous injection preparation, an arterial injection preparation or an intramuscular injection preparation

Preferably, the dosage form of the composition is solid preparation, liquid preparation or semi-solid preparation.

Preferably, the dosage forms of the composition are tablets, capsules, powders, injections, powder injections, emulsions, infusions, oral liquids, aerosols, ointments, gels, microspheres, and creams.

Preferably, the composition further includes other anticancer drugs.

Preferably, in the composition, the compound of formula I described in the first aspect of the present invention, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutical Acceptable salts, or prodrugs thereof, are used as the sole active ingredient.

The third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutical The above acceptable salts or prodrugs thereof are used for preparing compositions, and the compositions are used for preventing and/or treating tumors.

Preferably, the tumor is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, melanoma, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or a combination thereof.

Preferably, said tumors include human tumors or non-human mammalian tumors.

Preferably, the non-human mammals include (but are not limited to): pets (such as dogs, cats), domestic animals (such as cattle, sheep, horses, pigs), various zoo animals (pandas, elephants), etc.

Preferably, said tumor comprises epithelial cell carcinoma.

Preferably, said tumor comprises adenocarcinoma.

Preferably, said tumor comprises colorectal adenocarcinoma.

Preferably, said tumor comprises colorectal adenocarcinoma epithelial cell carcinoma.

Preferably, the tumors include tumors with BRCA, BLM, WRN, NBS1, FANC, CDK12 and/or CHK2 mutations.

Preferably, the tumor is selected from the group consisting of: recurrent ovarian cancer, epithelial recurrent ovarian cancer, platinum-sensitive or partially sensitive fallopian tube cancer, platinum-sensitive or partially sensitive primary peritoneal cancer, 3 Advanced ovarian cancer with gBRCA gene mutation, HER2-negative metastatic breast cancer with BRCA gene mutation, harmful or suspected harmful gBRCA gene who have received neoadjuvant chemotherapy, adjuvant chemotherapy, or metastatic chemotherapy Mutant, HER2-negative metastatic breast cancer, or a combination thereof.

Preferably, the tumor includes a tumor with BRCA2 gene mutation.

Preferably, the BRCA2 gene mutation includes a mutation leading to BRCA2 gene deletion.

Preferably, the BRCA2 gene mutation includes a mutation leading to no or low expression of the BRCA2 gene.

Preferably, said tumors include BRCA2 gene-deleted tumors.

Preferably, said tumors include tumors with no or low expression of BRCA2 gene.

Preferably, the tumor with no or low expression of the BRCA2 gene refers to the ratio (E1/E0) of the expression E1 of the BRCA2 gene in tumor cells to the expression E0 of the BRCA2 gene in the same type of tumor cells (E1/E0)<1.0, preferably ≤0.7 , more preferably ≤0.6, more preferably ≤0.5, more preferably ≤0.4, more preferably ≤0.3, more preferably ≤0.2, more preferably ≤0.1, more preferably ≤0.05, more preferably ≤0.01, more preferably Preferably ≤0.005, more preferably ≤0.001, more preferably ≤0.0001, more preferably ≤0.00001, more preferably ≤0.000001, more preferably ≤0.0000001.

Preferably, the tumor cells of the same type refer to cells of the same type but without BRCA2 gene mutation.

Preferably, the tumor cells of the same type refer to cells of the same type but with normal or high expression of BRCA2 gene.

Preferably, the tumor cells include DLD-1 cells or DLD-1 BRCA2(-/-) cells.

Preferably, the composition is a pharmaceutical composition.

Preferably, the injection preparation is an intravenous injection preparation, an arterial injection preparation or an intramuscular injection preparation.

Preferably, the composition further includes other anticancer drugs.

In the fourth aspect of the present invention, there is provided a method for inhibiting tumor cells, the method comprising the steps of: combining tumor cells with the compound of formula I as described in the first aspect of the present invention, or its optical isomer, or its external The racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its prodrug can inhibit tumor cells.

Preferably, said method is an in vitro method.

Preferably, the methods are non-therapeutic and non-diagnostic.

Preferably, said contact is in vitro culture contact.

Preferably, the tumor is as described in the third aspect of the present invention.

A fifth aspect of the present invention provides a method for preventing and/or treating tumors, the method comprising:

Administration of the compound of formula I as described in the first aspect of the present invention, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt , or a prodrug thereof, or a composition as described in the second aspect of the present invention, thereby preventing and/or treating tumors.

Preferably, said subjects are humans and non-human mammals.

Preferably, the administration is oral administration, injection administration or topical administration.

Preferably, the injection administration is intravenous injection administration, arterial injection administration or intramuscular injection administration.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

Description of drawings

Fig. 1 is the blood drug concentration-time curve of intravenous administration and oral administration of compound I3, compound I5, compound I15, compound I25, compound I45, compound I57 prepared in the example.

Detailed ways

The present invention unexpectedly develops a compound for the first time, the compound of the present invention has high selective inhibitory effect on PARP1, and the inhibitory effect on PARP2 is weak, therefore, the compound described in the present invention has excellent selective inhibitory effect, thus It has low side effects while exerting excellent antitumor effect. In addition, the compound of the present invention has good druggability, has excellent pharmacokinetics through oral administration and injection administration, shows good bioavailability after oral administration, and is suitable for the development of oral drugs, thereby reducing production costs and improving patient safety. compliance.

the term

As used herein, the terms "comprising", "including", and "containing" are used interchangeably to include not only closed definitions, but also semi-closed, and open definitions. In other words, the terms include "consisting of", "consisting essentially of".

As used herein, the terms "carcinoma", "cancer", "tumor" and "neoplastic" are used interchangeably.

As used herein, "IC ₅₀ " is the half-inhibiting concentration (50% inhibiting concentration), ie the concentration of the inhibitor at which 50% inhibitory effect is achieved.

As used herein, the term "PARP1" refers to polyadenosine diphosphate-ribose polymerase 1, and its English name is PolyADP-ribose polymerase 1.

As used herein, the term "PARP2" refers to polyadenosine diphosphate-ribose polymerase 2, and its English name is PolyADP-ribose polymerase 2.

As used herein, the term "BRCA2" refers to breast cancer gene 2, and its English name is breast cancer gene 2.

It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to produce chemically stable compounds, which can be synthesized by techniques known in the art and methods set forth below. If substituted with more than one substituent group(s), it is understood that the multiple groups may be on the same carbon or on different carbons so long as a stable structure results.

As used herein, the term "substituted" or "substituted" means that a hydrogen atom on a group is replaced by a non-hydrogen atom group, but it needs to meet its valence requirements and the substitution results in a chemically stable compound, that is, it will not spontaneously carry out such as ring Compounds that undergo transformations such as chemicalization and elimination.

As used herein, "R ₁ ", "R1" and "R ¹ " have the same meaning and can be replaced with each other, and other similar definitions have the same meaning.

As used herein, "

" indicates the attachment site of the group.

As used herein, the term "alkyl" refers to a straight chain (ie, unbranched) or branched chain saturated hydrocarbon group containing only carbon and hydrogen atoms, or a combination of straight chain and branched chain groups. When the alkyl group is limited by the number of carbon atoms (such as C1-C6 alkyl group), it refers to the number of carbon atoms contained in the alkyl group (such as 1-6), for example, C1-C4 alkyl group refers to the number of carbon atoms containing 1-4 carbons Atomic alkyl, representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

As used herein, the term "alkylene" refers to a group formed by removing a hydrogen atom from an alkyl group, and the alkyl group is as defined above, when the alkylene group has a limit on the number of carbon atoms (such as C1-C6 alkylene group) refers to the number of carbon atoms contained in the alkylene group (such as 1-6), for example, C1-C4 alkylene refers to an alkylene group containing 1-4 carbon atoms, representative examples include but are not limited to Methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, or the like.

As used herein, the term "halogen" refers to F, Cl, Br or I.

As used herein, the term "halo" means substituted with a halogen.

As used herein, the term "haloalkyl" means that one or more (preferably 1, 2, 3 or 4) hydrogens of an alkyl group are replaced by a halogen, said alkyl and halogen are as defined above, when the haloalkyl A limited number of carbon atoms (such as C1-C8 haloalkyl) refers to the number of carbon atoms (such as 1-8) contained in the haloalkyl group, for example, C1-C6 haloalkyl refers to a haloalkyl group containing 1-6 carbon atoms , representative examples include, but are not limited to, _-CF3 , _-CHF2 , monofluoroisopropyl, difluorobutyl, or similar groups.

As used herein, the term "cycloalkane ring" refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system having a saturated or partially saturated ring. When a cycloalkane ring has a limited number of carbon atoms (such as C3-C12), it refers to the number of ring carbon atoms (such as 3-12) that the cycloalkane ring has. For example, the term "C3-C8 cycloalkane ring" refers to a saturated or partially saturated monocyclic or bicycloalkane ring having 3-8 ring carbon atoms, including cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cycloheptane ring , or similar rings. "Spirocycloalkane" means bicyclic or polycyclic rings that share a single carbon atom (called a spiro atom) between the monocyclic rings, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system . "fused cycloalkane ring" means an all-carbon bicyclic or polycyclic ring in which each ring shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more double bonds, But none of the rings have a fully conjugated π-electron system. "Bridged cycloalkane ring" refers to all carbon polycyclic rings in which any two rings share two carbon atoms that are not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system.

As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group having a saturated or partially saturated ring. When a certain cycloalkyl group is limited by the number of carbon atoms (such as C3-C12), it refers to the number of ring carbon atoms (such as 3-12) that the cycloalkyl group has. For example, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3-8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl , or similar groups. "Spirocycloalkyl" means a bicyclic or polycyclic group in which the single rings share a single carbon atom (called a spiro atom), these may contain one or more double bonds, but none of the rings has fully conjugated pi electrons system. "Fused cycloalkyl" means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more bicyclic bonds, but none of the rings have a fully conjugated π-electron system. "Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system . The following are representative examples of cycloalkyl groups, including but not limited to:

As used herein, the term "cycloalkylene" refers to a group formed by removing a hydrogen atom from a cycloalkyl group as defined above. Representative examples include, but are not limited to: cyclopropylene, cyclopropylene Butyl, cyclopentylene, cycloheptylene, or similar groups.

As used herein, the term "halocycloalkyl" means that one or more (preferably 1, 2, 3 or 4) hydrogens of a cycloalkyl group are replaced by halogen, said cycloalkyl group and halogen being as defined above, When the cycloalkyl group is limited by the number of carbon atoms (such as C3-C8 halocycloalkyl), it means that the cycloalkyl group contains 3-8 ring carbon atoms, for example, C3-C8 halocycloalkyl means that it contains 3 - a halocycloalkyl group of 8 ring carbon atoms, representative examples include, but are not limited to, monofluorocyclopropyl, monochlorocyclobutyl, monofluorocyclopentyl, difluorocycloheptyl, or the like group.

As used herein, the term "alkoxy" refers to the R-O- group, wherein R is an alkyl group, and the alkyl group is as defined herein above, when the alkoxy group has a limit of carbon atoms, such as C1-C8 alkoxy group refers to The alkyl group in the alkoxy group has 1-8 carbon atoms. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or the like.

As used herein, the term "alkylthio" refers to an R-S- group, wherein R is an alkyl group, and the alkyl group is as defined herein above, when the alkylthio group is preceded by a limit of carbon atoms, such as the C1-C8 alkylthio group refers to The alkyl group in the above-mentioned alkylthio group has 1-8 carbon atoms. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, t-butylthio, or the like.

As used herein, the term "haloalkoxy" refers to haloalkyl-O-, the haloalkyl is as defined above, for example, C1-C6 haloalkoxy refers to haloalkoxy containing 1-6 carbon atoms, representative examples Including, but not limited to, monofluoromethoxy, monofluoroethoxy, bisfluorobutoxy, or similar groups.

As used herein, the term "haloalkylthio" refers to haloalkyl-S-, the haloalkyl is as defined above, for example, C1-C6 haloalkylthio refers to haloalkylthio containing 1-6 carbon atoms, representative examples Including, but not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or similar groups.

As used herein, the term "cycloalkoxy" refers to the R-O- group, wherein R is cycloalkyl, and cycloalkyl is as defined herein above, when cycloalkoxy is limited by the number of carbon atoms, such as C3-C8 ring Alkoxy means that the cycloalkyl group in the cycloalkoxy group has 3-8 ring carbon atoms. Representative examples of cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, or the like.

As used herein, the term "cycloalkylthio" refers to an R-S-group, wherein R is a cycloalkyl group, and the cycloalkyl group is as defined herein above, when the cycloalkylthio group has a limit on the number of carbon atoms before it, such as a C3-C8 ring The alkylthio group refers to the cycloalkyl group in the cycloalkylthio group having 3-8 ring carbon atoms. Representative examples of cycloalkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, or the like.

As used herein, the term "halocycloalkoxy" means that one or more (preferably 1, 2, 3 or 4) hydrogens of a cycloalkoxy group are replaced by a halogen, said cycloalkoxy and halogen being as above As defined, when there is a limit on the number of carbon atoms in front of the halocycloalkoxy group (such as C3-C8 halocycloalkoxy group), it means that the number of ring carbon atoms contained in the halocycloalkoxy group (such as 3-8 ), for example, C3-C8 halocycloalkoxy refers to halocycloalkoxy containing 3-8 ring carbon atoms, representative examples include but are not limited to monofluorocyclopropyl-O-, monochlorocyclo Butyl-O-, monofluorocyclopentyl-O-, difluorocycloheptyl-O-, or similar groups.

As used herein, the term "halocycloalkylthio" means that one or more (preferably 1, 2, 3 or 4) hydrogens of a cycloalkylthio group are replaced by a halogen, said cycloalkylthio and halogen being as above As defined, when there is a limit on the number of carbon atoms in front of the halocycloalkylthio group (such as C3-C8 halocycloalkylthio group), it means that the number of ring carbon atoms contained in the halocycloalkylthio group (such as 3-8 ), for example, C3-C8 halocycloalkylthio refers to a halocycloalkylthio group containing 3-8 ring carbon atoms, representative examples include but are not limited to monofluorocyclopropyl-S-, monochlorocyclopropyl Butyl-S-, monofluorocyclopentyl-S-, difluorocycloheptyl-S-, or similar groups.

As used herein, the term "heterocycloalkane ring" refers to a fully saturated or partially unsaturated ring (including but not limited to such as 3-7 membered monocyclic ring, 7-11 membered bicyclic ring, or 8-16 membered tricyclic ring system) , where at least one heteroatom is present in a ring with at least one carbon atom. When the heterocycloalkane ring is limited by the number of members, it refers to the number of ring atoms of the heterocycloalkane ring, for example, a 3-16 membered heterocycloalkane ring refers to a heterocycloalkane ring with 3-16 ring atoms. One or more (such as 1, 2, 3 or 4) heteroatoms can be carried on each heteroatom-containing heterocycloalkane ring, and these heteroatoms are each independently selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein Nitrogen or sulfur atoms can be oxidized, and nitrogen atoms can also be quaternized. Typical monocyclic heterocycloalkane rings include, but are not limited to, azetidine rings, oxetane rings, tetrahydrofuran rings, piperidine rings, piperazine rings, and the like. Multicyclic heterocycloalkane rings include spiro rings, fused rings and bridged piperazine rings; the spiro rings, fused rings and bridged rings involved in the heterocycloalkane rings are optionally connected to other rings through single bonds, or through Any two or more atoms on the ring are further linked with other cycloalkane rings and heterocycloalkane rings.

As used herein, the term "heterocycloalkyl" refers to a fully saturated or partially unsaturated ring (including but not limited to such as 3-7 membered monocyclic ring, 7-11 membered bicyclic ring, or 8-16 membered tricyclic ring system) groups in which at least one heteroatom is present in a ring having at least one carbon atom. When the heterocycloalkyl group is defined by the number of ring atoms, it refers to the number of ring atoms in the heterocycloalkyl group, for example, a 3-16 membered heterocycloalkyl group refers to a heterocycloalkyl group with 3-16 ring atoms. Each heteroatom-containing heterocyclic ring can have one or more (such as 1, 2, 3 or 4) heteroatoms, and these heteroatoms are each independently selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen atom Or sulfur atoms can be oxidized and nitrogen atoms can also be quaternized. Typical monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, piperidinyl, piperazinyl. The polycyclic heterocycloalkyl group includes spiro ring, fused ring and bridged ring heterocyclyl group; wherein the spiro ring, fused ring and bridged ring heterocycloalkyl group are optionally connected with other groups through a single bond, or Further ring connection with other cycloalkane rings and heterocycles through any two or more atoms on the ring.

As used herein, the term "heterocycloalkylene" refers to a group formed by removing a hydrogen atom from a heterocycloalkyl group as defined above. Representative examples include, but are not limited to: Nitrogen Heterobutanyl, oxetanylene, tetrahydrofuranylene, piperidinylene, piperazinylene.

As used herein, the term "aromatic ring" refers to a full-carbon monocyclic or fused polycyclic ring (that is, a ring sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, which is an aromatic ring hydrocarbon compound, when The number of carbon atoms in front of the aromatic ring is limited, such as a C6-C12 aromatic ring, which means that the aromatic ring has 6-12 ring carbon atoms, such as benzene ring and naphthalene ring.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) group with a conjugated π-electron system, and is an aromatic cyclic hydrocarbon compound Groups, when the aryl group is limited by the number of carbon atoms, such as C6-C12 aryl, it means that the aryl group has 6-12 ring carbon atoms, such as phenyl and naphthyl.

As used herein, the term "heteroaromatic ring" refers to an aromatic heterocyclic ring system having one to more (preferably 1, 2, 3 or 4) heteroatoms, at least one of which is present on at least one carbon atom In the ring, which may be a single ring (monocyclic) or multiple rings fused together or linked covalently (bicyclic, tricyclic or polycyclic), each heterocycle containing a heteroatom There may be more than one (

eg

1, 2, 3, 4) heteroatoms each independently selected from the group consisting of oxygen, sulfur and nitrogen. When the heteroaryl ring is limited by the number of members, it refers to the number of ring atoms in the heteroaryl ring. For example, a 5-12 membered heteroaryl ring refers to a heteroaryl ring with 5-12 ring atoms. Representative examples Including but not limited to: pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, pyridine ring, pyrimidine ring, etc.

As used herein, the term "heteroaryl" refers to an aromatic heterocyclic ring system group having one to more (preferably 1, 2, 3 or 4) heteroatoms, wherein at least one heteroatom is present in at least one In a ring of carbon atoms, which may be a monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) group fused together or linked covalently, each containing heteroatoms There may be more than one (such as 1, 2, 3, 4) heteroatoms independently selected from the following group on the heterocycle: oxygen, sulfur and nitrogen. When the heteroaryl group is limited by the number of ring atoms, it refers to the number of ring atoms of the heteroaryl group. For example, a 5-12 membered heteroaryl group refers to a heteroaryl group with 5-12 ring atoms. Representative examples Including but not limited to: pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, pyridyl, pyrimidinyl, etc.

As used herein, the term "carboxy" refers to a -COOH group or -alkyl-COOH group, alkyl is as defined herein above, for example "C ₂ -C ₄ carboxy" refers to -C ₁ -C ₃ alkyl A group of -COOH structure, representative examples of the carboxyl group include (but not limited to): -COOH, -CH ₂ COOH, or similar groups.

As used herein, the term "ester group" refers to a group with RC(O)-O- or -C(O)-OR, wherein R is an alkyl group, and the alkyl group is as defined herein above, for example, "C ₂ - C ₄ ester group" refers to a group of C ₁ -C ₃ alkyl-C(O)-O- structure or a group of -C(O)-OC ₁ -C ₃ alkyl structure, representative of ester group Examples include, but are not limited to: CH ₃ C(O)O-, C ₂ H ₅ C(O)O-, (CH ₃ ) ₂ CHC(O)O-, -C(O)OCH ₃ , -C(O )OC ₂ H ₅ , or similar groups.

As used herein, the term "amido" refers to a group with RC(O)-N- or -C(O)-NR, wherein R is an alkyl group, and the alkyl group is as defined herein above, such as "C ₂ - C ₄ amido group" refers to a group of C ₁ -C ₃ alkyl-C(O)-N-structure or a group of -C(O)-NC ₁ -C ₃ alkyl structure, representative of amido group _Examples include, but are not limited to: _CH3C (O)-N-, _C2H5C (O)-N-, ( _CH3 ) _2CHC (O)-N-, -C(O)-N-CH _3. -C(O)-NC ₂ H ₅ , or similar groups.

As used herein, "-C(O)-" and "

" are used interchangeably.

As used herein, the term "amino" by itself or as part of another substituent is _-NH2 .

As used herein, the term "nitro", alone or as part of another substituent, is _-NO2 .

As used herein, the term "cyano" by itself or as part of another substituent is -CN.

As used herein, the term "hydroxy" is -OH, alone or as part of another substituent.

As used herein, the term "mercapto" alone or as part of another substituent is -SH.

In this specification, all substituents should be construed as being unsubstituted unless explicitly described as "substituted" herein. The term "substituted" means that one or more hydrogen atoms on a specified group are replaced by a specified substituent. The specific substituents are the corresponding substituents described above, or the substituents that appear in each embodiment. Preferably, any "substitution" refers to one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms are replaced by substituents selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkyl-C3 -C8 cycloalkyl-, C1-C8 haloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 cycloalkylthio, C3-C8 halocycloalkoxy, C3- C8 halocycloalkylthio, halogen, nitro, -CN, =O, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amido, C1-C8 alkoxy, C1 -C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, (R ₁₁ R ₁₂ )N -.

In the present invention, the term "prevention" means a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease.

"Treatment" in the present invention includes delaying and terminating the progression of the disease, or eliminating the disease, and does not require 100% inhibition, eradication and reversal. In some embodiments, compounds of the invention reduce, inhibit and/or reverse tumors, e.g., by at least about 10%, at least about 30%, at least About 50%, at least about 80%, or 100%.

active ingredient

As used herein, "compounds of the present invention", "compounds of the present invention", "compounds of formula I of the present invention", "compounds of formula I" and "heteroaromatic compounds of the present invention" are used interchangeably, referring to the formula Compound I, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its prodrug.

Specifically, the compound of formula I, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its prodrug is as described in the present invention mentioned in the first aspect.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. One class of preferred salts is the salt formed by the compound of the present invention and an acid. Suitable acids for forming the salt include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid , propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzenesulfonic acid and other organic acids; And acidic amino acids such as aspartic acid and glutamic acid. A preferred class of salts are metal salts formed from compounds of the present invention and bases. Suitable bases for salt formation include (but are not limited to): sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate and other inorganic bases, Ammonia, triethylamine, diethylamine and other organic bases.

The compounds of the present invention can be converted into their pharmaceutically acceptable salts by conventional methods. For example, the corresponding acid or base solution can be added to the solution of the above compounds. After the salt formation is complete, the solvent is removed under reduced pressure to obtain the corresponding salt of the compound.

polyadenosine diphosphate ribose polymerase

Poly ADP-ribose polymerase (Poly ADP-ribose polymerase) can include polyadenosine diphosphate-ribose polymerase 1 (Poly ADP-ribose polymerase 1, PARP1) and poly ADP-ribose polymerase 2 ( Poly ADP-ribose polymerase 2, PARP2).

Studies have shown that some of the adverse reactions of PARP inhibitors (PARP1 and PARP2 dual inhibitors) come from their inhibition of PARP2, and PARP2 is not necessary for the curative effect. Therefore, selective inhibition of PARP1 will lead to better curative effect and better safety. Therefore, the development of an anti-tumor drug with a highly selective inhibitory effect on PARP1 can reduce its side effects, thereby improving drug compliance of patients.

the tumor

The compounds of the present invention have excellent therapeutic effects on tumors.

In a preferred example of the present invention, the tumor includes, but is not limited to: ovarian cancer, breast cancer, prostate cancer, melanoma, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or a combination thereof.

In a preferred example of the present invention, the tumor includes a human tumor or a non-human mammalian tumor.

In a preferred example of the present invention, the tumor includes epithelial cell carcinoma.

In a preferred example of the present invention, the tumor includes adenocarcinoma.

Preferably, said tumor comprises colorectal adenocarcinoma.

In a preferred example of the present invention, the tumor includes but not limited to tumors with mutations in BRCA, BLM, WRN, NBS1, FANC, CDK12 and/or CHK2.

In a preferred example of the present invention, the tumors include but are not limited to: recurrent ovarian cancer, epithelial recurrent ovarian cancer, platinum-sensitive or partially sensitive fallopian tube cancer, platinum-sensitive or partially sensitive primary Peritoneal cancer, advanced ovarian cancer with gBRCA gene mutation that still progresses after receiving 3 or more lines of chemotherapy, HER2-negative metastatic breast cancer with BRCA gene mutation, harmful or harmful effects of neoadjuvant chemotherapy, adjuvant chemotherapy, and metastatic chemotherapy Suspected deleterious gBRCA gene mutation, HER2-negative metastatic breast cancer, or a combination thereof.

In a preferred example of the present invention, the tumor includes a tumor with BRCA2 gene mutation.

Preferably, said tumors include BRCA2 gene-deleted tumors.

In a preferred example of the present invention, the tumor includes a tumor with no or low expression of BRCA2 gene.

Typically, the tumor cells include DLD-1 cells or DLD-1 BRCA2(-/-) cells.

use

The compounds of the present invention have excellent preventive and therapeutic effects on tumors.

The present invention also provides a method for inhibiting tumor cells, comprising the steps of: mixing tumor cells with the compound described in the present invention, or its optical isomer, or its racemate, or its solvate, or its hydrate, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, thereby inhibiting tumor cells.

Preferably, said method is an in vitro method.

Preferably, the methods are non-therapeutic and non-diagnostic.

Preferably, said contact is in vitro culture contact.

The present invention also provides a method for preventing and/or treating tumors, the method comprising: administering the compound of formula I as described in the present invention, or its optical isomer, or its racemate, or a solvate thereof, or a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a composition according to the present invention, thereby preventing and/or treating tumors.

Preferably, said subjects are humans and non-human mammals.

Composition and method of application

The invention provides a composition, which can be used for preventing and treating tumors. Typically, the composition is a pharmaceutical composition.

The composition of the present invention may also include a pharmaceutically acceptable carrier.

In the present invention, the dosage forms of the composition include (but not limited to) oral preparations, injections, and external preparations.

Typically, the dosage form of the composition includes (but not limited to): tablet, capsule, powder, injection, powder injection, emulsion, infusion, oral liquid, aerosol, ointment, gel, microsphere, cream agent.

The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid, semi-solid, liquid or gel fillers, which are suitable for human or animal use, and must be of sufficient purity and low enough toxicity. "Compatibility" means that each component in the pharmaceutical composition and the active ingredients of the medicine and their mutual blending will not significantly reduce the efficacy of the medicine.

It should be understood that in the present invention, the carrier is not particularly limited, and it can be made from materials commonly used in the art, or prepared by conventional methods, or purchased from the market. Examples of pharmaceutically acceptable carrier parts include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agent (such as sodium lauryl sulfate), buffering agent, chelating agent, thickener, pH regulator, skin penetration enhancer, coloring agent, flavoring agent, stabilizer, antioxidant, preservative , antibacterial agent, pyrogen-free water, etc.

Typically, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, acetic acid, in addition to the active pharmaceutical ingredient. Ethyl esters, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. Besides these inert diluents, the composition can also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, etc.

The pharmaceutical formulation should match the mode of administration. Agents of the invention may also be used together (including before, during or after) other co-therapeutic agents. When using a pharmaceutical composition, a safe and effective amount of the drug is administered to a desired subject (such as a human or a non-human mammal), usually at least about 10 micrograms per kilogram of body weight, and in most cases no more than About 8 mg/kg body weight, preferably the dosage is about 10 microgram/kg body weight to about 1 mg/kg body weight. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

The main advantages of the present invention include:

(1) The compound of the present invention has the advantages of excellent anticancer effect, low toxic and side effects, large safety window, and strong selectivity for specific receptors.

(2) The compound of the present invention has good druggability, has excellent pharmacokinetics through oral administration and injection administration, and shows good bioavailability after oral administration, and is suitable for the development of oral drugs, thereby reducing production costs and improving patient efficacy. compliance.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

The preparation of embodiment 1 compound I1

(1) Synthesis of compound 3

To a solution of compound 1 (1 g) in MeOH (10 mL) was added compound 2 (0.24 g) followed by sodium triacetoxyborohydride (1.98 g) at room temperature, and the mixture was stirred for 2 h. Then saturated _NH4Cl solution was added to the reaction mixture to quench excess sodium triacetoxyborohydride, then diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel flash chromatography (PE/EA=2/1) to give compound 3 as a yellow solid.

MS theoretical: 253; MS found: 254 [M+H] ⁺ .

(2) Synthesis of compound 4

To a solution of compound 3 (0.76g) in MeOH (10mL) was added BoC ₂ O (0.77g) and DMAP (50mg), the mixture was stirred at room temperature for 6 hours, diluted with water and extracted with EA, the organic layer was washed with brine, anhydrous Drying over sodium sulfate, filtration and concentration, purification by silica gel flash chromatography (PE/EA=3/1) gave compound 4 as a yellow solid.

MS theoretical: 353; MS found: 354 [M+H] ⁺ .

(3) Synthesis of compound 5

To a solution of compound 4 (0.8 g) in MeOH (15 mL) was added Pd/C (0.10 g), the mixture was stirred at room temperature under H ₂ for 6 h, filtered and the filtrate was concentrated to give compound 5 as a yellow solid.

MS theoretical: 323; MS found: 324 [M+H] ⁺ .

(4) Synthesis of compound 6

A THF (15 mL) solution of Compound 5 (0.6 g) was added to phenyl chloroformate (0.35 g) at room temperature, and the mixture was stirred at room temperature for 2 hr. After the reaction was completed, the mixture was diluted with water and extracted with EA, the combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 6 as a yellow solid.

MS theoretical: 443; MS found: 444 [M+H] ⁺ .

(5) Synthesis of compound 7

To a mixture of compound 6 (0.6g) DCM (10mL) was added TFA (3mL) at 0-5°C, the mixture was stirred at room temperature for 2 hours, after the starting material was completely consumed, the solvent was evaporated under reduced pressure to give a residue which was dissolved in DMF and neutralized with TEA. The resulting neutralized reaction was diluted with water and extracted with EA, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel flash chromatography (PE/EA=4/1) to give white Solid compound 7.

MS theoretical: 249; MS found: 250 [M+H] ⁺ .

(6) Synthesis of compound 8

At 0°C under nitrogen, a solution of compound 7 (180mg) in THF (5mL) was added dropwise to a solution of LiAlH ₄ (99.7mg) in THF (10mL) within 1 hour, and the mixture was stirred at 0°C for 1.5 hours. The mixture was quenched by dropwise addition of 1M HCl. The reaction mixture was concentrated and diluted with water and 1M HCl solution, filtered, washed with water, ether, and dried to give the crude product. The crude product was suspended with MeOH/DCM and heated to reflux, and the crude product was purified by silica gel column chromatography (PE/EA=1/1) to obtain compound 8 as a white solid.

MS theoretical: 207; MS found: 208 [M+H] ⁺ .

(7) Synthesis of compound 9

SOCl ₂ (445 mg) was added dropwise to a solution of compound 8 (116 mg) in DCM (5 mL) at 0°C under nitrogen, and the mixture was stirred at 0°C for 6 hours. The mixture was concentrated to give compound 9 as a white solid.

MS calc: 225; MS found MS found: 226 [M+H] ⁺ .

(8) Synthesis of Compound I1

To a solution of compound 9 (50 mg) and compound SM2 (58.9 mg) in ACN (10 mL) was added DIEA (85.5 mg), and the mixture was stirred at 70°C for 2 hr. Diluted with water and extracted with EA, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to afford I1 as a white solid.

1H NMR (400MHz, MeOH-d ₆ )δ: 8.36(d, J=2.4Hz, 1H), 8.24(d, J=1.2Hz, 1H), 7.97(d, J=11.2Hz, 1H), 7.51 -7.48(m,1H),7.32(d,J=2.0Hz,1H),4.65(s,2H),4.44(s,2H),3.66-3.48(m,10H),2.95(s,3H), 1.23(d,J=7.2Hz,1H).

MS theoretical: 409; MS found: 410 [M+H] ⁺ .

The preparation of embodiment 2 compound I2

(1) Preparation of compound 2

To a solution of compound 1 (199 mg) in toluene (10 mL) were added compound SM1 (216 mg, 1.00 mmol), Pd ₂ (dba) ₃ (28 mg), X-phos (58 mg) and Cs ₂ CO ₃ (657 mg). The mixture was stirred under nitrogen protection at 100 °C for 12 h. The reaction was filtered through celite. The filtrate was concentrated and the resulting residue was dissolved in EA (ethyl acetate), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give Compound 2 as orange oil.

MS theoretical: 335; MS found: 336 [M+H] ⁺ .

(2) Preparation of compound 3

To a solution of compound 2 (300 mg) in MeOH (10 mL) was added 2N NaOH (5 mL). The mixture was stirred at room temperature for 3 hours. The reaction was concentrated and the residue was diluted with water. The resulting mixture was adjusted to pH=4-5 with 2M HCl. The mixture was extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound 3 as a yellow oil.

MS theoretical: 321; MS found: 322 [M+H] ⁺ .

(3) Preparation of Compound 4

To a solution of compound 3 (265 mg) in DMF (5 mL) was added HATU (760 mg) and DIEA (260 mg). After stirring for 1 hour, _MeNH2 (338 mg) was added and the mixture was stirred overnight. The mixture was diluted with water and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel column chromatography (PE/EA=1/1) gave compound 4 as yellow oil.

MS theoretical: 334; MS found: 335 [M+H] ⁺ .

(4) Preparation of Compound 5

To a solution of compound 4 (180 mg, 0.54 mmol) in EA (5 mL) was added HCl/EA (2 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated to give compound 5 as a yellow solid.

MS theoretical: 234; MS found: 235 [M+H] ⁺ .

(5) Preparation of compound I2

To a mixture of compound 5 (50 mg) and compound 6 (50 mg) in DMF (10 mL) was added DIPEA (130 mg). The mixture was stirred at 70 °C for 2 h and diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by preparative HPLC afforded compound 12 as a yellow solid.

MS theoretical: 420; MS found: 421 [M+H] ⁺ .

H NMR of compound I2: (400MHz, DMSO-d ₆ )δ: 12.16(s, 1H), 8.55(s, 1H), 8.42(br, 1H), 8.27(m, 2H), 7.87(d, J= 8.0Hz, 1H), 7.80-7.78(m, 2H), 7.42(br, 1H), 4.50-3.89(m, 4H), 3.39-3.28(m, 5H), 2.79(d, J＝4.4Hz, 3H ), 2.57 (q, J=7.2Hz, 2H), 1.19 (t, J=7.6Hz, 3H), 1.13 (br, 3H).

The preparation of embodiment 3 compound I3

(1) Synthesis of compound I3-3

Add RuPhosPd (100 mg), Ruphos (100 mg)) and Cs ₂ CO ₃ (4.89 g ), the mixture was stirred at 110° C. for 14 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EA=3/1) to obtain Compound I3-3 as yellow oil.

MS theoretical: 335; MS found: 336 [M+H] ⁺ .

(2) Synthesis of compound I3-4

To a solution of compound I3-3 (0.52 g) in MeOH/H ₂ O (2 mL/10 mL) was added NaOH (0.35 g), the mixture was stirred at room temperature for 2 h and adjusted to pH=4 with 2M HCl, the mixture was extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give compound I3-4 as a yellow solid.

MS theoretical: 321; MS found: 322 [M+H] ⁺ .

(3) Synthesis of compound I3-5

HATU (0.53g) was added to a DMF (15mL) solution of compound I3-4 (0.3g,), and after stirring at room temperature for 0.5h, DIPEA (0.36g) and MeNH2-HCl (0.19g) were added, and the mixture was Stirring at room temperature for 14 h, the reaction mixture was diluted with water and extracted with EtOAc, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EA=2/1) to obtain yellow oil compound I3- 5.

MS theoretical: 334; MS found: 335 [M+H] ⁺ .

(4) Synthesis of compound I3-6

To a mixture of I3-5 (0.2 g) in EA (2 mL) was added HCl/EA (1 mL), the mixture was stirred at room temperature for 5 h and concentrated to give compound I3-6 as a yellow solid.

MS theoretical: 234; MS found: 235 [M+H] ⁺ .

(5) Synthesis of compound I3

To a solution of compound I3-6 (79 mg) and compound 7 (50 mg) in ACN (5 mL) was added DIEA (131 mg), the mixture was stirred at 70 °C for 6 h, the reaction mixture was cooled to room temperature, diluted with water and extracted with EA. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (TFA in H2O/ACN) to afford compound I3 as a white solid.

MS theoretical: 420; MS found: 421 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ of compound I3: 12.18(s, 1H), 8.54(s, 1H), 8.42(s, 1H), 8.27(s, 1H), 7.87(d, J= 8.0Hz,1H),7.81(s,1H),7.78(s,1H),7.41(d,J＝7.2Hz,1H),4.60-4.40(m,4H),3.60-3.10(m,5H), 2.78 (d, J = 5.2Hz, 3H), 2.57 (q, J = 7.6Hz, 2H), 1.20 (t, J = 7.6Hz, 3H), 1.14 (d, J = 5.2Hz, 3H).

The preparation of embodiment 4 compound I4

Synthesis of compound I4

Compound I4 was prepared as a yellow solid by changing the reagents in a similar manner to the preparation of compound I2.

MS theoretical: 420; MS found: 421 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ of compound I4: 12.15(s, 1H), 8.56(s, 1H), 8.43-8.39(m, 1H), 8.32(d, J=2.4Hz, 1H) ,7.87(d,J=8.8Hz,1H),7.78(d,J=9.6Hz,2H),7.48-7.45(m,1H),4.0-3.89(m,4H),3.32-3.24(m,5H ), 2.78 (d, J=4.8Hz, 3H), 2.60-2.51 (m, 2H), 1.49 (s, 3H), 1.19 (d, J=7.6Hz, 3H).

The preparation of embodiment 5 compound I5

(1) Synthesis of compound I5-3

Add RuPhos Pd (100 mg), Ruphos (100 mg)) and Cs ₂ CO ₃ (4.89 g), under N ₂ , the mixture was stirred at 110°C for 14 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was subjected to silica gel column chromatography (PE/EA =3/1) to obtain compound I5-3 as a yellow oil.

MS theoretical: 335; MS found: 336 [M+H] ⁺ .

(2) Synthesis of compound I5-4

NaOH (0.093g) was added to compound I5-3 (0.26g) in MeOH/H2O (2mL/10mL) solution, the mixture was stirred at room temperature for 2h and adjusted to pH=4 with 2M HCl, the mixture was extracted with EA, and the organic layer was washed with Dry over sodium sulfate and concentrate to give compound I5-4 as a yellow solid.

MS theoretical: 321; MS found: 322 [M+H] ⁺ .

(3) Synthesis of compound I5-5

HATU (0.43g) was added to a DMF (10mL) solution of compound I5-4 (0.25g), and after stirring at room temperature for 0.5h, DIPEA (0.30g) and MeNH ₂ -HCl (0.16g) were added, and the mixture was stirred at room temperature After stirring for 14 h, the reaction mixture was diluted with water and extracted with EA, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to give compound 15-5 as a white solid.

MS theoretical: 334; MS found: 335 [M+H] ⁺ .

(4) Synthesis of compound I5-6

To a mixture of compound I5-5 (0.1 g) in EA (2 mL) was added HCl/EA (1 mL), the mixture was stirred at room temperature for 5 h and concentrated to give compound I5-6 as a yellow solid.

MS theoretical: 234; MS found: 235 [M+H] ⁺ .

(5) Synthesis of compound I5

DIEA (61 mg) was added to a solution of compound I5-6 (70 mg) and compound 7 (35 mg) in ACN (5 mL), the mixture was stirred at 70 °C for 8 h, the reaction mixture was cooled to room temperature, diluted with water and extracted with EA, the organic layer was After drying over sodium sulfate, filtration and concentration, the residue was purified by preparative HPLC to give compound 15 as a white solid.

1H NMR(400MHz,DMSO-d6)δ:12.17(s,1H),8.56(s,1H),8.44-8.40(m,1H),8.33(d,J＝4.8Hz,1H),7.88(d, J＝8.8Hz,1H),7.81(s,1H),7.78(s,1H),7.50-7.47(m,1H),4.91-4.85(m,1H),4.06-3.98(m,3H),3.54 -3.44(m,1H),3.25-3.03(m,4H),2.78(d,J=4.8Hz,3H),2.57(q,J=7.6Hz,2H),1.53(s,3H),1.20( t,J=7.6Hz,3H).

MS theoretical value: 420; MS measured value: 421 [M+H] ⁺ .

The preparation of embodiment 6 compound I8

Compound I8 was prepared as a yellow solid by changing the reagents in a similar manner to the preparation of compound I2.

MS theoretical value: 419; MS measured value: 420[M+H] ⁺

¹ HNMR (400MHz, DMSO-d ₆ )δ of compound I8: 11.77(s, 1H), 8.39-8.34(m, 2H), 8.12(d, J=2.8Hz, 1H), 7.89(d, J=8.8 Hz,1H),7.72(s,1H),7.65(s,1H),7.21(dd,J＝8.8,2.8Hz,1H),3.73(d,J＝5.6Hz,2H),3.65-3.61(m ,4H),3.30(d,J=9.6Hz,2H),2.80(d,J=4.8Hz,3H),2.59-2.51(m,3H),1.63 (d,J=8.4Hz,1H),1.17 (t, J=7.6Hz, 3H).

The preparation of embodiment 7 compound I10

(1) Preparation of compound I10-3

To a solution of Compound I10-1 (2.0 g) and Compound I10-2 (2.16 g) in 1,4-dioxane (42 mL) was added RuPhosPd (200 mg), Ruphos (200 mg) and Cs ₂ CO ₃ (9.78 g) . The mixture was then stirred at 110 °C for 14 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=3/1) to obtain compound I10-3 as yellow oil.

MS theoretical: 335; MS found: 336 [M+H] ⁺ .

The remaining steps can be used to prepare white solid compound I10 using a similar method to prepare compound I2.

MS theoretical: 420; MS found: 421 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ of compound I10: 12.18(s, 1H), 8.53(s, 1H), 8.31(q, J=4.8Hz, 1H), 8.11(d, J=2.8Hz ,1H),7.84(d,J=8.8Hz,1H),7.80(s,1H),7.76(s,1H),7.25(dd,J=8.8,2.8Hz,1H),4.55(s,2H) ,3.96-3.92(m,1H),3.76-3.56(m,4H),3.32-3.12(m,3H),2.78(d,J=4.8Hz,3H),2.57(q,J=7.6Hz,2H ), 2.34-2.16 (m, 2H), 1.20 (t, J=7.6Hz, 3H).

The preparation of embodiment 8 compound I11

(1) Synthesis of compound I11-3

To compound I11-1 (480 mgl) and compound I11-2 (524 mg) in 1,4-dioxane solution (10 mL) were added RuPhos Pd (20 mg), Ruphos (20 mg)) and Cs ₂ CO ₃ (2.37 g) , the mixture was stirred at 110° C. for 14 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and purified by silica gel column chromatography (PE/EA=3/2) to obtain a yellow solid compound I11-3.

MS theoretical: 333; MS found: 334 [M+H] ⁺ .

(2) Synthesis of compound I11-4

To a solution of compound I11-3 (0.46 g) in MeOH/H ₂ O (2 mL/10 mL) was added NaOH (0.17 g), the mixture was stirred at room temperature for 2 h and adjusted to pH=4 with 2M HCl. The mixture was extracted with EA, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound I11-4 as a yellow solid.

MS theoretical: 319; MS found: 320 [M+H] ⁺ .

(3) Synthesis of compound I11-5

HATU (0.75g) was added to compound I11-4 (0.42g) DMF solution (5mL), the mixture was stirred at room temperature for 0.5h, DIPEA (0.51g) and MeNH ₂ -HCl (0.27g) were added, and the mixture was stirred at room temperature After stirring for 14 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford compound I11-5 as a white solid.

MS theoretical: 332; MS found: 333 [M+H] ⁺ .

(4) Synthesis of compound I11-6

To a mixture of compound I11-5 (0.1 g) in _CH2Cl2 (2 mL) was added TFA (1 mL), _the mixture was stirred at room temperature for 5 h and concentrated to give compound I11-6 as a yellow solid.

MS theoretical: 232; MS found: 233 [M+H] ⁺ .

(5) Synthesis of compound I11

To a solution of compound I11-6 (70 mg) and compound I11-7 (35 mg) in ACN (5 mL) was added DIEA (61 mg), and the reaction mixture was stirred at 70° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC to give compound I11 as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 12.17(s, 1H), 8.50(d, J=1.6Hz, 1H), 8.33(d, J=5.2Hz, 1H), 7.83-7.78(m, 3H), 7.72-7.69(m, 1H), 6.98-6.90(m, 1H), 4.53(s, 2H), 4.41(s, 2H), 4.16(d, J=19.2Hz, 2H), 2.77(d ,J=5.2Hz,3H),2.57(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H).

MS theoretical: 418; MS found: 419 [M+H] ⁺ .

The preparation of embodiment 9 compound I14

Preparation of Compound I14

To a solution of compound 7 (40 mg) and compound I14-5 (47.6 mg) in ACN (10 mL) was added DIEA (130 mg). The mixture was then stirred at 70 °C for 2 h, then diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to afford compound I14 as a yellow solid.

MS theoretical: 432; MS found: 433 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ of compound I14: 12.15(s, 1H), 8.56(s, 1H), 8.41(q, J=4.8Hz, 1H), 8.32(d, J=2.4Hz ,1H),7.87(d,J=8.8Hz,1H),7.80-7.77(m,2H),7.47(dd,J=8.8,2.8Hz,1H),4.82-3.92(m,4H),3.74- 3.50-3.00(m,5H),2.79(d,J=4.8Hz,3H),2.58(q,J=7.6Hz,2H),1.50(br,3H),1.20(t,J=7.6Hz,3H ).

The preparation of embodiment 10 compound I15

(1) Synthesis of compound I15-2

To a solution of compound I15-1 (1 g) in DMF/H2O (10 mL) was added compound SM3 (1.72 g) and _K2CO3 (1.29 g) _, Pd( _PPh3 ) ₄ (100 mg) under _N2 The mixture was stirred at 100 °C for 5 h, then the reaction solution was cooled to room temperature, diluted with water and extracted with EA, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated, and the residue was subjected to silica gel flash chromatography (PE/EA= 2/1) purification to obtain white solid compound I15-2.

MS theoretical: 318; MS found: 319 [M+H] ⁺ .

(2) Synthesis of compound I15-3

To a solution of compound I15-2 (1 g) in MeOH (10 mL) was added Pd/C (0.10 g), the mixture was stirred at room temperature under H ₂ for 6 h, filtered, and the filtrate was concentrated to give compound I15-3 as a white solid.

MS theoretical: 320; MS found: 321 [M+H] ⁺ .

(3) Synthesis of compound I15-4

To a solution of I15-3 (0.8 g) in MeOH/H ₂ O (2 mL/10 mL) was added NaOH (0.2 g), the mixture was stirred at room temperature for 2 h and adjusted to pH=4 with 2M HCl, the resulting mixture was extracted with EA , the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound I15-4 as a yellow solid.

MS theoretical: 306; MS found: 307 [M+H] ⁺ .

(4) Synthesis of compound I15-5

A solution of compound I15-4 (0.5 g) and HATU (1.24 g) in DMF (15 mL) was stirred at room temperature for 0.5 h, DIEA (0.42 g) and MeNH2-HCl (0.17 g) were added to the mixture, and The mixture was stirred at room temperature for 14 h and diluted with water and extracted with EA, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to give compound I15-5 as a yellow solid.

MS theoretical: 319; MS found: 320 [M+H] ⁺ .

(5) Synthesis of compound I15-6

To a mixture of I15-5 (100 mg) in EA (2 mL) was added HCl/EA (1 mL), the mixture was stirred at room temperature for 3 h and concentrated to give I15-6 as a white solid.

MS theoretical: 219; MS found: 220 [M+H] ⁺ .

(6) Synthesis of compound I15

To a solution of compound I15-6 (42 mg) and compound 7 (35 mg) in ACN (5 mL) was added DIEA (61 mg), the mixture was stirred at 70 °C for 5 h, the reaction mixture was cooled to room temperature and diluted with water and extracted with EA, the organic layer was Dry over sodium sulfate, filter and concentrate. The residue was purified by preparative HPLC to afford compound I15 as a white solid.

¹ H NMR (400MHz, MeOH-d ₆ )δ: 8.62(q, J=2Hz, 1H), 8.53(s, 1H), 8.55(s, 1H), 8.05(d, J=5.2Hz, 1H), 7.92(d, J=2Hz, 1H), 7.85(d, J=7.4Hz, 1H), 4.57(s, 2H), 3.69(d, J=10.8Hz, 2H), 3.25(s, 1H), 2.70 -2.65(m,2H),2.41-2.22(m,2H),2.02-1.99(m,4H),1.28(q,J=7.4Hz,3H).

MS theoretical value: 405; MS measured value: 406[M+H] ⁺ .

The preparation of embodiment 11 compound I18

(1) Synthesis of compound I18-3

To a solution of compound I18-1 (1.0 g) and compound I18-2 (1.02 g) in 1,4-dioxane (25 mL) was added RuPhos Pd (100 mg), Ruphos (100 mg)) and Cs ₂ CO ₃ (5.28 g), the mixture was stirred at 110° C. for 14 h, then adjusted to pH=10 with NaOH, extracted with EA, collected the aqueous phase, then adjusted to pH=4 with HCl, and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated, Compound I18-3 was obtained as a yellow solid.

MS theoretical: 308; MS found: 309 [M+H] ⁺ .

(2) Synthesis of compound I18-4

A DMF (10 mL) solution of compound I18-3 (0.5 g) and HATU (1.2 g) was stirred at room temperature for 0.5 h, DIPEA (0.63 g) and MeNH ₂ -HCl (0.32 g) were added to the mixture, and the mixture Stirred at room temperature for 14 h, diluted with water, extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to give compound I18-4 as a yellow oil.

MS theoretical: 321; MS found: 322 [M+H] ⁺ .

(3) Synthesis of compound I18-5

To a solution of compound I18-4 (0.1 g) in EA (2 mL) was added HCl/EA (2 mL). The mixture was stirred at room temperature for 5 h and concentrated to give compound I18-5 as a white solid.

MS theoretical value: 221; MS measured value: 222[M+H] ⁺

(4) Synthesis of compound I18

To a solution of compound I18-5 (35 mg) and compound I17-6 (50.4 mg) in ACN (5 mL) was added DIPEA (89 mg), the mixture was stirred at 70 °C for 8 h, the reaction mixture was cooled to room temperature and diluted with water and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to afford compound I18 as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.59-8.56 (m, 3H), 7.86 (d, J = 1.8Hz, 3H), 4.46 (s, 2H), 3.68 (s, 4H), 3.40 ( s,4H),2.95(s,3H),2.69-2.67(m,2H),1.29(d,J＝7.4Hz,3H).

MS theoretical value: 407; MS measured value: 408[M+H] ⁺ .

The preparation of embodiment 12 compound I19

(1) Synthesis of Compound I19-2

Add mCPBA (186mgl), Pd2(dba) ₃ (28mg), X-phos (58mg) and Cs ₂ CO ₃ (657mg) to compound I19-1 (210mg) in CHCl ₃ (10mL) solution, the mixture is protected under nitrogen Stirring at 100 °C for 12 h, the reaction mixture was filtered through celite, the filtrate was concentrated and the resulting residue was dissolved in EA, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was subjected to silica gel column chromatography ( PE/EA=1/1) to obtain compound I19-2 as yellow oil.

MS theoretical: 223; MS found: 224 [M+H] ⁺ .

(2) Synthesis of compound I19-3

DBU (338 mgl) and (CH ₃ ) ₃ SiCN (226 mg) were added to compound I19-2 (224 mg) in THF (10 mL), the mixture was stirred overnight, the reaction mixture was diluted with water and extracted with EA, and the organic layer was washed with anhydrous sulfuric acid It was dried over sodium, filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA=3/1) to give compound I19-3 as a yellow oil.

MS theoretical: 232; MS found: 233 [M+H] ⁺ .

(3) Synthesis of compound I19-4

To a solution of compound I19-3 (150 mg) in _C2H5OH (5 mL) was added NaOH (40% aq) (5 mL), _the mixture was stirred at room temperature for 2 h and concentrated to give compound I19-4 as a yellow solid.

MS theoretical value: 250; MS found value: 251 [M+H] ⁺ .

(4) Synthesis of compound I19-5

To a mixture of compound I19-4 (500 mg) in CH ₃ OH (15 mL) was added SOCl ₂ (3 mL), the mixture was stirred at 65° C. for 2 h, the mixture was diluted with water and extracted with EA, the organic layer was washed with brine and dried over anhydrous sodium sulfate , filtered and concentrated, and the residue was purified by preparative HPLC to give compound I19-5 as a yellow solid.

MS theoretical: 265; MS found: 266 [M+H] ⁺ .

(5) Synthesis of Compound I19-6

To a solution of compound I19-5 (270 mg) in 1,4-dioxane (10 mL) was added compound SM1 (186 mg), Pd ₂ (dba) ₃ (28 mg), X-phos (58 mg) and Cs ₂ CO ₃ ( 657 mg), the mixture was stirred under nitrogen protection and 100 ° C for 12 h, the mixture was filtered through celite, the filtrate was concentrated and the resulting residue was dissolved in EA, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the The residue was purified by silica gel column chromatography (PE/EA=1/1) to obtain compound I19-6 as a yellow oil.

MS theoretical: 357; MS found: 358 [M+H] ⁺ .

(6) Synthesis of compound I19-7

To a solution of compound I19-6 (250 mg) in DMF (10 mL) was added HATU (430 mg). After stirring at room temperature for 0.5 h, DIEA (300 mg) and MeNH ₂ .HCl (160 mg) were added, the reaction mixture was stirred at room temperature for 14 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, passed The residue was purified by preparative HPLC to give compound I19-7 as a white solid.

MS theoretical: 370; MS found: 371 [M+H] ⁺ .

(7) Synthesis of Compound I19-8

To a solution of compound I19-7 (100 mg) in DCM (5 mL) was added TFA (2 mL), the reaction mixture was stirred at room temperature for 2 h and concentrated to give compound I19-8 as a yellow solid.

MS theoretical: 270; MS found: 271 [M+H] ⁺ .

(8) Synthesis of compound I19

DIEA (130 mg) was added to a mixture of compound I19-8 (25 mg) and compound SM2 (25 mg) in DMF (7 mL), the mixture was stirred at 70 ° C for 2 h, the mixture was diluted with water and extracted with EA, the organic layer was washed with brine, and the Dried over sodium sulfate, filtered and concentrated, the residue was purified by preparative HPLC to give compound I19 as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 9.05 (d, J=4Hz, 2H), 8.54 (s, 1H), 8.21-8.16 (m, 2H), 7.84-7.75 (m, 3H), 7.69 -7.65(m,1H),7.37-7.36(m,1H),3.88(m,1H),3.30(m,4H),3.00(s,3H),2.90(s,4H),2.70-2.64(m ,2H),1.30-1.27(m,3H).

MS theoretical: 456; MS found: 457 [M+H] ⁺ .

The preparation of embodiment 13 compound I20

(1) Synthesis of compound I20-3

Add RuPhos Pd (200 mg), Ruphos (200 mg)) and Cs ₂ CO ₃ (10.52 g, 32.26 mmol), the mixture was stirred at 110 °C for 14 h, adjusted to pH=10 with NaOH, extracted with EA, the aqueous phase was collected, then adjusted to pH=4 with HCl, and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give compound I20-3 as a yellow solid.

MS theoretical: 321; MS found: 322 [M+H] ⁺ .

(2) Synthesis of compound I20-4

A DMF (10 mL) solution of compound I20-3 (0.50 g) and HATU (0.77 g) was stirred at room temperature for 0.5 h, DIEA (0.53 g) and MeNH ₂ -HCl (0.27 g) were added to the mixture, and stirred at room temperature Stir for 14 h, dilute with water and extract with EA, the organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, and purified by preparative HPLC to obtain compound I20-4 as a yellow oil.

MS theoretical: 334; MS found: 335 [M+H] ⁺ .

(3) Synthesis of compound I20-5

To a mixture of compound I20-4 (0.10 g) in EA (2 mL) was added HCl/EA (1 mL), the mixture was stirred at room temperature for 5 h and concentrated to give compound I20-5 as a white solid.

MS theoretical: 234; MS found: 235 [M+H] ⁺ .

(4) Synthesis of compound I20

DIEA (87 mg) was added to the ACN (5 mL) solution of compound I20-5 (70 mg) and compound 1220-6 (50 mg), the mixture was stirred at 70 ° C for 8 h, the reaction mixture was cooled to room temperature, diluted with water and extracted with EA , the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by preparative HPLC to afford compound I20 as a yellow solid.

¹ H NMR (400MHz, MeOH-d ₆ )δ: 8.61(d, J=2.0Hz, 1H), 8.17(d, J=2.8Hz, 1H), 8.65(s, 1H), 7.88(s, 2H) ,7.28(d,J=2.8Hz,1H),3.63(s,4H),3.49(s,4H),2.89(s,3H),2.72-2.66(m,2H),2.60(s,3H), 1.29(t,J=7.6Hz,3H).

MS theoretical: 420; MS found: 421 [M+H] ⁺ .

The preparation of embodiment 14 compound I21

(1) Synthesis of compound I21-3

Pd ₂ (dba) ₃ (1.97g), Xphos (3.07g) and T -BuONa (3.10g), the mixture was stirred at 110°C for 14h, then adjusted to pH=10 with NaOH, extracted with EA, the aqueous phase was collected, then adjusted to pH=4 with HCl, and extracted with EA, the organic layer was treated with anhydrous sulfuric acid Drying over sodium and concentration afforded compound 121-3 as a yellow solid.

MS theoretical: 325; MS found: 326 [M+H] ⁺ .

(2) Synthesis of compound I21-4

A solution of compound I21-3 (0.4g) and HATU (0.7g) in DMF (10mL) was stirred at room temperature for 0.5h, DIEA (0.48g) and MeNH ₂ -HCl (0.25gl) were added to the mixture and stirred at room temperature After 14 h, diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to give compound I21-4 as a yellow solid.

MS theoretical: 338; MS found: 339 [M+H] ⁺ .

(3) Synthesis of compound I21-5

To a mixture of compound I21-4 (0.1 g) in EA (2 mL) was added HCl/EA (1 mL), the mixture was stirred at room temperature for 5 h and concentrated to give I21-5 as a white solid.

MS theoretical: 228; MS found: 229 [M+H] ⁺ .

(4) Synthesis of compound I21

To a solution of compound I21-5 (65 mg) and compound I21-6 (35 mg) in ACN (5 mL) was added DIEA (61 mg), the mixture was stirred at 70° C. for 8 h, and the reaction mixture was cooled to room temperature. After dilution with water and extraction with EA, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by preparative HPLC to give I21 as a white solid.

¹ H NMR (400MHz, MeOH-d ₆ )δ:8.62-8.58(m,1H),8.20(s,1H),7.91-7.86(m,2H),7.27-7.20(m,1H),4.55(s ,2H),3.69(s,4H),3.46(s,4H),2.91(s,3H),2.68(q,J=7.2Hz,2H),1.29(t,J=7.6Hz,3H).

MS theoretical: 424; MS found: 425 [M+H] ⁺ .

The preparation of embodiment 15 compound I25 and compound I26

(1) Preparation of compound 2

A mixture of compound 1 (10 g) and SeO ₂ (7.92 g) in 1,4-dioxane (100 mL) was stirred at 110° C. for 20 h. The reaction mixture was cooled to room temperature, filtered through celite and washed with EA. The filtrate was concentrated and the residue was purified by silica gel column chromatography (PE/EA=5/1) to obtain Compound 2 as a white solid.

MS theoretical value: 254; MS measured value: 225[M+H] ⁺

(2) Preparation of Compound 3

To a solution of NaH (3.4 g) in anhydrous THF (100 mL) was added dropwise compound 2a (21.6 g) at 0° C. to obtain a gray colored mixture. The resulting mixture was stirred at 0 °C for 10 min and warmed to room temperature over 10 min, stirred at 40 °C for 5 min. The reaction mixture was cooled to -78°C, and then a solution of compound 2 (8 g) in THF (100 mL) was slowly added to the cooled reaction mixture. The mixture was quenched with aqueous _NH4Cl and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA=6/1) to obtain Compound 3 as yellow oil.

MS theoretical value: 322; MS measured value: 323[M+H] ⁺

(3) Preparation of Compound 4

To a solution of compound 3 (6 g) in ethanol (30 mL) was added Pd/C (600 mg) under nitrogen protection. The mixture was stirred overnight at room temperature under the protection of _H2 . The mixture was filtered through celite, washing with ethanol. The filtrate was concentrated and the residue was diluted with 4M HCl in dioxane (25 mL). The resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated, and the resulting solid was washed with ether and dried in vacuo to afford compound 4 as a white solid.

MS theoretical value: 248; MS measured value: 249[M+H] ⁺

(4) Preparation of Compound 5

To a solution of compound 4 (3 g) in 1,4-dioxane (40 mL) was added DDQ (2.99 g). The mixture was stirred at reflux for 3 h and concentrated under reduced pressure. To the residue was added NaHCO ₃ solution (30 mL) and the resulting mixture was stirred at room temperature for 1 h. The solid was filtered off and washed successively with water and ether. Drying under vacuum afforded Compound 5 as a yellow solid.

MS theoretical value: 246; MS measured value: 247[M+H] ⁺

(5) Preparation of Compound 6

To a solution of LiAlH4 (473 mg) in THF (30 mL) was added dropwise a solution of compound 5 (2 g) in THF (80 mL) at 0 °C under nitrogen atmosphere during 1 h. The resulting mixture was stirred at 0 °C for 1.5 h. The reaction mixture was quenched by dropwise addition of 1M HCl (29 mL). The reaction mixture was concentrated and the solid was diluted with water and 1M HCl solution to give a yellow suspension. The solid was collected by filtration, washed with water, ether, and dried to give the crude product. The solid was suspended in a mixture of MeOH/DCM (2/1, 400 mL) and heated to reflux. The solid was filtered off. The filtrate was then concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE/EA=1/1) to obtain compound 6 as a white solid.

MS theoretical value: 204; MS measured value: 205[M+H] ⁺

(6) Preparation of Compound 7

To a solution of compound 6 (1 g) in DCM (50 mL) was added _SOCl2 (2.89 g) dropwise at 0 °C under nitrogen. The resulting mixture was stirred at 0 °C for 6 h. The mixture was concentrated to give compound 7 as a white solid.

MS theoretical: 222; MS found: 223 [M+H] ⁺ .

(7) Preparation of compound I25-1

To a solution of compound 7 (200 mg) and compound SM2 (270 mg) in ACN (10 mL) was added DIEA (390 mg). The mixture was stirred at 70 °C for 2 h. After dilution with water, it was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain yellow solid compound I25-1.

MS theoretical: 407; MS found: 408 [M+H] ⁺ .

(8) Preparation of compound I25-2

To a solution of compound I25-1 (250 mg) in MeOH (20 mL) was added a solution of NaOH (73.6 mg) in water (7 mL). The reaction mixture was stirred at room temperature for 1 h and adjusted to pH=3 with 2M HCl. The resulting mixture was extracted with ethyl acetate. After the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain white solid compound I25-2.

MS theoretical value: 393; MS measured value: 394[M+H] ⁺

(9) Preparation of compound I25

To a DMF solution of compound I25-2 (40 mg) were added HATU (76 mg) and DIPEA (260 mg). After stirring for 1 h, compound B (16.2 mg) was added. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford compound 125 as a white solid.

MS theoretical value: 456; MS measured value: 457[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ of compound I25: 12.20(s, 1H), 8.75(t, J=6.4Hz, 1H), 8.54(d, J=2.0Hz, 1H), 8.37(d ,J=2.8Hz,1H),7.93-(d,J=9.2Hz,1H),7.81(s,1H),7.78(d,J=1.6Hz,1H),7.51(dd,J=9.2,3.2 Hz,1H),6.25-5.98(m,1H),4.53(s,2H),4.21-4.01(m,2H),3.72-3.63(m,2H),3.43-3.28(m,6H),2.57( q,J=7.2Hz,2H), 1.20(t,J=7.2Hz,3H).

(10) Preparation of compound I26

To a solution of compound I25-2 (40 mg) in DMF was added HATU (76 mg) and DIPEA (260 mg, 2 mmol). After stirring for 1 h, compound C (14.9 mg) was added. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford compound 126 as a white solid.

MS theoretical value: 448; MS measured value: 449[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ of compound I26: 12.16(s, 1H), 9.08(d, J=3.2Hz, 1H), 8.77(d, J=2.0Hz 1H), 8.53(d, J＝1.6Hz, 1H), 8.25(d, J＝9.2Hz, 1H), 8.07(dd, J＝9.2, 2.4Hz, 1H), 7.81(s, 1H), 7.75(s, 1H), 4.90( dd,J＝14.0,5.6Hz,1H),4.74(dd,J＝14.4,5.6Hz,1H),4.40(s,2H),3.94-3.87(m,4H),3.65-3.60(m,2H) ,3.48-3.43(m,2H),3.27(br,4H),2.58(q,J=7.2Hz,2H),1.19(t,J=7.2Hz,3H).

The preparation of embodiment 16 compound I27, I54 and I57

(1) Synthesis of compound I27

HATU (68 mg) and DIEA (58.1 mg) were added to a DMF solution of compound I25-2 (35 mg), and after stirring for 1 h, compound D (15.5 mg) was added, and the mixture was stirred at room temperature overnight, and the reaction mixture was diluted with water and washed with EA After extraction, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to give compound 127 as a white solid.

¹ H NMR (400MHz, MeOH-d ₆ ) δ: 8.60(d, J=1.2Hz, 1H), 8.38(d, J=2.4Hz, 1H), 8.02-7.87(m, 3H), 7.49-7.47( m,1H),4.62-4.51(m,4H),4.34-4.27(m,2H),3.70(d,J＝12.8Hz,4H),3.47-3.44(m,4H),3.03-2.99(m, 3H),2.71-2.65(m,2H),1.42-1.27(m,4H).

MS measured value: 462[M+H] ⁺

(2) Synthesis of compound I54

HATU (76 mg) and DIEA (64.5 mg) were added to a DMF solution of compound I25-2 (40 mg), and after stirring for 1 h, compound E (9 mg) was added, the mixture was stirred at room temperature overnight, and the reaction mixture was diluted with water and extracted with EA , the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to afford compound I54 as a yellow oil.

¹ H NMR (400MHz, MeOH-d ₆ )δ: 8.62(d, J=1.6Hz, 1H), 8.32(d, J=2.0Hz, 1H), 7.91(d, J=1.2Hz 1H), 7.87( s,1H),7.57(d,J=2.8Hz,2H),4.59(s,1H),3.65(s,4H),3.52(d,J=4.8Hz,4H),3.10-3.07(m,6H ),2.69-2.67(m,2H),1.29(d,J＝7.4Hz,3H).

MS measured value: 421[M+H] ⁺

(3) Synthesis of compound I57

HATU (76 mg) and DIEA (64.5 mg) were added to a DMF solution of compound I25-2 (40 mg), and after stirring for 1 h, compound F (19.8 mg) was added, and the mixture was stirred at room temperature overnight, and the reaction mixture was diluted with water and washed with EA After extraction, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to give compound 157 as a yellow oil.

¹ H NMR (400MHz, MeOH-d ₆ )δ: 8.60(s, 1H), 8.39(d, J=2.4Hz, 1H), 8.0(d, J=8.4Hz 1H), 7.88(s, 2H), 7.50-7.47(m,1H),4.49(s,2H),4.08(q,J=9.6Hz,2H),3.66(s,4H),3.31-3.29(m,4H),2.69(q,J= 7.6Hz, 2H), 1.29(t, J=7.6Hz, 3H).

MS measured value: 475[M+H] ⁺

The preparation of embodiment 17 compound I28 and compound I45

(1) Synthesis of compound I28

HATU (68 mg) and DIEA (58.1 mg) were added to a DMF solution of compound I25-2 (35 mg), and after stirring for 1 h, compound D (15.3 mg) was added, and the mixture was stirred at room temperature overnight, and the reaction mixture was diluted with water and EA After extraction, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue was purified by preparative HPLC to give compound I28 as a white solid

¹ H NMR (400MHz, DMSO-d ₆ )δ: 11.80(s, 1H), 8.40(s, 1H), 8.35(d, J=6Hz, 1H), 8.27(d, J=4.2Hz, 1H), 7.82(d,J＝8.8Hz,1H),7.75(s,1H),7.63(s,1H),7.41-7.38(m,1H),3.65(s,2H),3.31-3.28(m,6H) ,2.67-2.53(m,7H),1.99-1.92(m,2H),1.85-1.80(m,2H),1.79-1.73(m,2H),1.30(t,J=7.2Hz,3H).

MS measured value: 461[M+H] ⁺

(2) Synthesis of compound I45

HATU (76 mg) and DIEA (64.5 mg) were added to a DMF solution of compound I25-2 (40 mg), and after stirring for 1 h, compound E (17.6 mg) was added, and the mixture was stirred at room temperature overnight, and the reaction mixture was diluted with water and washed with EA After extraction, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to give compound I45 as a yellow oil

¹ H NMR (400MHz, CD3OD) δ: 8.49 (d, J = 2Hz, 1H), 8.28 (d, J = 2.8Hz, 1H), 7.90 (d, J = 8.8Hz 1H), 7.83 (s, 1H) ,7.76(d,J=1.2Hz,1H),7.37-7.34(m,1H),3.74(s,3H),3.52(d,J=6.4Hz,2H),3.40(d,J=5Hz,4H ),2.69-2.65(m,6H),2.58(d,J=6.6Hz,2H),2.31(s,6H),1.28(t,J=7.4Hz,3H).

MS Found: 464[M+H] ⁺

The preparation of embodiment 18 compound I29

(1) Synthesis of compound I29-2

Add compound SM2 (186mg), Pd ₂ (dba) ₃ (28mg), X-phos (58mg) and Cs ₂ CO ₃ (657mg) to the toluene (10mL) solution of compound I29-1 (210mg) , under nitrogen protection , the mixture was stirred at 100°C for 12 h, the reaction mixture was filtered through celite, the filtrate was concentrated and the resulting residue was dissolved in EA, washed with water, dried over anhydrous sodium sulfate, and vacuum filtered, the filter cake was passed through silica gel Purification by column chromatography (PE/EA=1/1) gave yellow oil I29-2.

MS theoretical: 347; MS found: 348 [M+H] ⁺ .

(2) Synthesis of compound I29-3

To compound I29-2 (250 mg) in THF (10 mL) was added MeNH ₂ (338 mg), the mixture was stirred overnight, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, The residue was purified by silica gel column chromatography (PE/EA=5/1) to give yellow oil I29-3.

MS theoretical: 346; MS found: 347 [M+H] ⁺ .

(3) Synthesis of Compound I29-4

To a solution of compound I29-3 (180 mg) in EA (5 mL) was added HCl/EA (2 mL), the mixture was stirred at room temperature for 2 h and concentrated to give I29-4 as a yellow solid.

MS theoretical: 246; MS found: 247 [M+H] ⁺ .

(4) Synthesis of compound I29

DIEA (130 mg) was added to a mixture of compound I29-4 (25 mg) and compound 7 (25 mg) in DMF (7 mL), the mixture was stirred at 70 °C for 2 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was washed with brine, Dried over anhydrous sodium sulfate, filtered and concentrated, the filter cake was purified by preparative HPLC to give I29 as a yellow solid.

¹ H NMR (400MHz,DMSO-d ₆ )δ:8.67(s,1H),8.16(s,1H),7.97-7.95(m,2H),7.86(s,1H),7.29-7.27(m,1H ),4.73(s,2H),4.46(s,1H),4.04(s,1H),3.98(s,1H),3.69-3.61(m,3H),2.94(s,3H),2.71-2.65( m,2H),2.23(s,1H),2.20-2.08(m,3H),1.33-1.26(m,3H).

MS theoretical value: 432; MS measured value: 433[M+H] ⁺

The preparation of embodiment 19 compound I30

(1) Synthesis of compound I30-2

To a solution of compound I30-1 (158 mg) in toluene (10 mL) was added compound SM2 (186 mg), Pd ₂ (dba) ₃ (28 mg), X-phos (58 mg), 0.10 mmol) and Cs ₂ CO ₃ (657 mg) , the mixture was stirred at 100 °C for 12 h under nitrogen, filtered through celite, the filtrate was concentrated and the resulting residue was dissolved in EA, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residual The compound was purified by silica gel column chromatography (PE/EA=1/1) to obtain yellow oil I30-2.

MS theoretical: 347; MS found: 348 [M+H] ⁺ .

(2) Synthesis of compound I30-3

To a solution of compound I30-2 (250 mg) in THF (10 mL) was added MeNH ₂ (338 mg), the mixture was stirred overnight, the resulting reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo , the residue was purified by silica gel column chromatography (PE/EA=1/1) to give yellow oil I30-3.

MS theoretical: 346; MS found: 347 [M+H] ⁺ .

(3) Synthesis of compound I30-4

To a solution of compound I30-3 (180 mg) in EA (5 mL) was added HCl/EA (2 mL), the mixture was stirred at room temperature for 2 h and concentrated to give I30-4 as a yellow solid.

MS theoretical: 246; MS found: 247 [M+H] ⁺ .

(4) Synthesis of compound I30

To a mixture of compound I30-4 (25 mg) and compound 7 (25 mg) in DMF (7 mL) was added DIEA (130 mg), the mixture was stirred at 70 °C for 2 h, the resulting reaction mixture was diluted with water and extracted with EA, and the organic layer was washed with brine , dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC to give I30 as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 8.53(s, 1H), 8.27(s, 1H), 7.97-7.95(d, J=8.8Hz, 1H), 7.86-7.84(d, J=8.8 Hz,1H),7.43-7.40(d,J=6Hz,1H),4.63(s,2H),4.27(s,2H),3.31-3.18(m,4H),2.95(s,3H),2.70- 2.65(m,2H),2.21-2.11(m,4H),1.30-1.26(t, J＝8Hz,3H).

MS theoretical: 432; MS found: 433 [M+H] ⁺ .

The preparation of embodiment 20 compound I31

(1) Synthesis of compound I31-3

Ruphos Pd (10 mg), Ruphos (10 mg) and Cs ₂ CO ₃ (460 mg) were added to a solution of compound I31-1 (100 mg) and compound I31-2 (102 mg) in 1,4-dioxane (10 mL), and The mixture was stirred at 110 °C for 14 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EA=3/2) to give a yellow solid I31-3.

MS theoretical: 347; MS found: 348 [M+H] ⁺ .

(2) Synthesis of compound I31-4

A solution of compound I31-3 (70 mg) and _MeNH2HCl (19.2 mg) in EtOH (5 mL) was stirred at room temperature for 2 h, then diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give I31 as a yellow solid -4.

MS theoretical: 346; MS found: 347 [M+H] ⁺ .

(3) Synthesis of compound I31-5

To a mixture of compound I31-4 (65 mg) in EA (2 mL) was added HCl/EA (1 mL), the mixture was stirred at room temperature for 5 h and concentrated to give I31-5 as a white solid.

MS theoretical: 246; MS found: 247 [M+H] ⁺ .

(4) Synthesis of compound I31

DIEA (61 mg) was added to the ACN (5 mL) solution of compound I31-5 (35 mg) and compound I31-6 (35 mg), the mixture was stirred at 70 ° C for 8 h, the reaction mixture was cooled to room temperature and diluted with water and extracted with EA , the organic layer was dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC to afford I31 as a white solid.

¹ H NMR (400MHz, MeOH-d ₆ )δ: 8.66(d, J=1.6Hz, 1H), 8.33-8.25(m, 1H), 7.95(d, J=8.8Hz, 1H), 7.96-7.91( m,1H),7.89(s,1H),7.44-7.38(m,1H),4.55(s,2H),4.23(s,2H),3.97-3.93(m,2H),3.33-3.31(m, 2H),2.93(s,3H),2.73-2.66(m,2H),2.55-2.46(m,2H),2.36-2.25(m,2H),1.29(t,J＝7.2Hz,3H).

MS theoretical: 432; MS found: 433 [M+H] ⁺ .

The preparation of embodiment 21 compound I39

(1) Synthesis of compound I39-3

To a solution of compound I39-1 (1 g) and compound I39-2 (1 g) in 1,4-dioxane (20 mL) were added RuphosPd (100 mg), Ruphos (100 mg)) and Cs ₂ CO ₃ (4.57 g), The mixture was stirred at 110 °C for 14 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EA=3/2) to give yellow Solid I39-3.

MS theoretical: 349; MS found: 350 [M+H] ⁺ .

(2) Synthesis of compound I39-4

A solution of compound I39-3 (425 mg) and _MeNH2HCl (244 mg) in EtOH (5 mL) was stirred at room temperature for 2 h, then diluted with water and extracted with EA, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow solid I39-4.

MS theoretical: 348; MS found: 349 [M+H] ⁺ .

(3) Synthesis of compound I39-5

To a mixture of compound I39-4 (100 mg) in EA (2 mL) was added HCl/EA (1 mL), the mixture was stirred at room temperature for 5 h and concentrated to give I39-5 as a white solid.

MS theoretical: 248; MS found: 249 [M+H] ⁺ .

(4) Synthesis of compound I39

To a solution of compound I39-5 (35 mg) and compound 7 (35 mg) in ACN (5 mL) was added DIEA (61 mg), the mixture was stirred at 70 °C for 8 h, the reaction mixture was cooled to room temperature and diluted with water and extracted with EA, the organic layer was After drying over anhydrous sodium sulfate, filtration and concentration, the residue was purified by preparative HPLC to give I39 as a white solid.

¹ H NMR (400MHz, MeOH-d ₆ )δ: 8.66(d, J=1.0Hz, 1H), 8.32(s, 1H), 7.96-7.85(m, 3H), 7.46(d, J=8.4Hz, 1H), 4.81(s, 2H), 4.06(d, J=13.2Hz, 1H), 3.61(s, 2H), 3.19-3.13(m, 2H), 2.92(s, 2H), 2.68-2.63(m ,2H),1.67(d,J=6.4Hz,6H),1.27(d,J=7.4Hz,3H).

MS theoretical: 434; MS found: 435 [M+H] ⁺ .

The preparation of embodiment 22 compound I51

(1) Synthesis of compound 5a

A mixture of compound 5 (40 mg) and NaOH (19.5 mg, 0.48 mmol) in EtOH (5 mL) was stirred at room temperature for 4 h, extracted with EA, the collected aqueous phase was adjusted to pH = 4 with HCl and extracted with EA, and the combined organic layers were Drying over anhydrous sodium sulfate and concentration afforded compound 5a as a white solid.

MS theoretical: 218; MS found: 219 [M+H] ⁺ .

(2) Synthesis of compound I51-3

To a mixture of I51-2 (500 mg) in EA (5 mL) was added HCl/EA (2 mL), the mixture was stirred at room temperature for 5 h and concentrated to give compound I51-3 as a white solid.

MS theoretical: 221; MS found: 222 [M+H] ⁺ .

(3) Synthesis of compound I51-4

HATU (78 mg) was added to a solution of compound 5a (30 mg) in DMF (5 mL), and after stirring at room temperature for 0.5 h, DIEA (53 mg) and compound I51-3 (36 mg) were added, and the mixture was stirred at room temperature for 14 h. Diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EA=2/1) to give yellow solid I51-4.

MS theoretical: 421; MS found: 422 [M+H] ⁺ .

(4) Synthesis of Compound I51

A solution of compound I51-5 (20 mg) and MeNH ₂ (5 mg) in EtOH (3 mL) was stirred at room temperature for 4 h, then diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was passed through preparative Purification by HPLC afforded I51 as a white solid.

¹ H NMR (400MHz, MeOH-d ₆ )δ: 8.58(d, J=2.0Hz, 1H), 8.32(d, J=2.8Hz, 1H), 7.97(d, J=8.8Hz, 1H), 7.88 (s,1H),7.79(d,J=1.6Hz,1H),7.53-7.49(m,1H),4.05-3.60(m,4H),3.57-3.40(m,4H),2.94(s,3H ), 2.73-2.65 (m, 2H), 1.30 (t, J=7.2Hz, 3H).

MS theoretical: 420; MS found: 421 [M+H] ⁺ .

Example 23

According to the synthesis method of the above-mentioned examples, the corresponding reagents were changed, and the following compound I5, compound I7, compound I15, compound I16, compound I17, compound I22, compound I23, compound I28 and compound I45 were prepared:

Compound I7:

MS measured value: 419[M+H] ⁺ .

Compound I16:1H NMR(400MHz,DMSO-d6)δ:11.85(s,1H),8.78(s,1H),8.41(s,1H),7.84-7.81(m,1H),7.76(s,1H) ,7.64(s,1H),7.33(d,J=9.2Hz,1H),3.72-3.66(m,6H),2.80(d,J=4.4Hz,3H),2.57-2.50(m,6H), 1.18(t,J=7.6Hz,3H).

MS theoretical value: 407; MS measured value: 408[M+H] ⁺ .

Compound I17: 1H NMR (400MHz, DMSO-d6) δ: 12.17(s,1H),8.65(s,1H),8.51(s,1H),8.42(s,1H),8.36(s,1H),7.80 (s,1H),7.74(s,1H),4.70-4.40(m,4H),3.22-3.12(m,4H),2.78(d,J＝4.8Hz,3H),2.63-2.55(m,4H ),1.20(t,J=7.6Hz,3H).

MS theoretical value: 407; MS measured value: 408[M+H] ⁺ .

Compound I22:1H NMR(400MHz,DMSO-d6)δ:12.16(s,1H),8.52(s,1H),8.33(d,J=4.8Hz,1H),8.27(d,J=2.4Hz,1H ),7.80(s,1H),7.75(s,1H),7.50(s,1H),4.60-4.40(m,2H),3.22-3.12(m,4H),2.75(d,J＝4.8Hz, 3H),2.63-2.55(m,2H),2.45-2.40(m,2H),2.01(s,1H),1.24(s,1H),1.20(t,J＝7.6Hz,3H).

MS theoretical value: 440; MS measured value: 441[M+H] ⁺ .

Compound I23:1H NMR(400MHz,DMSO-d6)δ:8.65(s,1H),8.29(s,1H),7.98(s,1H),7.91(s,1H),7.87(s,1H),4.62 (s,2H),3.52(m,4H),3.30(m,4H),2.93(s,3H),2.69-2.65(m,2H),2.42(m,3H),1.29(t,J＝7.2 Hz,3H).

MS theoretical value: 420; MS measured value 421[M+H] ⁺ .

Example 24 examines the inhibitory effect of the compounds prepared in the examples on PARP1 and PARP2

The PARP chemiluminescence kit (BPS Bioscience, PARP1 Catalog#80551, PARP2Catalog#80552) was used to measure the chemiluminescence value according to the instructions, and the average _IC50 was calculated by calculating the inhibition percentage and making a logarithmic graph of the compound concentration, and measuring the prepared in the example. The inhibitory effect of the compound on PARP1 (Poly ADP-ribose polymerase 1, polyadenosine diphosphate-ribose polymerase 1) and PARP2 (Poly ADP-ribose polymerase2, polyadenosine diphosphate-ribose polymerase 2), the results are shown in Table 1 shown.

Table 1 _The half-inhibitory concentration IC values of the compounds prepared in the examples of the present invention to PARP1 and PARP2

Remarks: "—" means not determined;

"IC ₅₀ " is the half-inhibiting concentration (50% inhibiting concentration), that is, the concentration of the inhibitor when 50% inhibitory effect is achieved.

As can be seen from Table 1, the compound of the present invention has a high selective inhibitory effect on PARP1, and the inhibitory effect on PARP2 is weak, thereby showing that the compound of the present invention has an excellent selective inhibitory effect, thereby in While exerting excellent anti-tumor effect, it has lower side effects.

Embodiment 25 investigates the inhibitory effect of the compound prepared by the embodiment on DLD-1 cells and DLD-1 BRCA2 (-/-) cells

DLD-1 cells are human colorectal adenocarcinoma epithelial cells.

DLD-1 BRCA2 (-/-) cells are DLD-1 cells in which the BRCA2 gene is knocked out, that is, DLD-1 cells in which the BRCA2 gene is deleted.

experimental method

DLD-1 cells and cells (DLD-1 BRCA2(-/-)) were incubated according to ATCC conditions. Transfer 40nL of the compound to a 384-well plate, add 40 μL of culture medium to each well, and inoculate DLD-1BRCA2(-/-) cells or DLD-1 cells at 600 cells per well, and incubate at 37°C and 5% CO2 for 7 After 30 min at room temperature, 20 μL of luminescence reagent was added to each well. After incubation at room temperature for 30 min, the luminescence value was recorded and the average IC ₅₀ was calculated. The results are shown in Table 2.

Table 2 Compounds prepared by the embodiments of the present invention have half-inhibitory concentration IC _values for DLD-1 cells and DLD-1 BRCA2 (-/-) cells

化合物compound	DLD-1 BRCA2(-/-)细胞(μM)DLD-1 BRCA2(-/-) cells (μM)	DLD-1细胞(μM)DLD-1 cells (μM)
化合物I1Compound I1	0.1330.133	>10>10
化合物I2Compound I2	0.7430.743	>10>10
化合物I3Compound I3	0.0060.006	>10>10
化合物I4Compound I4	1.521.52	>10>10
化合物I5Compound I5	0.0080.008	>10>10

化合物I10Compound I10	4.514.51	>10>10
化合物I11Compound I11	0.9330.933	>10>10
化合物I14Compound I14	0.1810.181	>10>10
化合物I15Compound I15	0.0020.002	>10>10
化合物I16Compound I16	0.0170.017	>10>10
化合物I17Compound I17	0.2520.252	>10>10
化合物I18Compound I18	0.0920.092	>10>10
化合物I20Compound I20	6.326.32	>10>10
化合物I21Compound I21	0.0040.004	>10>10
化合物I22Compound I22	0.3700.370	>10>10
化合物I23Compound I23	0.4270.427	>10>10
化合物I25Compound I25	0.0020.002	>10>10
化合物I27Compound I27	0.1570.157	>10>10
化合物I28Compound I28	0.0030.003	>10>10
化合物I29Compound I29	0.9620.962	>10>10
化合物I30Compound I30	1.921.92	>10>10
化合物I31Compound I31	0.6220.622	>10>10
化合物I45Compound I45	0.0710.071	>10>10
化合物I51Compound I51	0.6230.623	>10>10
化合物I57Compound I57	0.0030.003	>10>10

Note: "IC ₅₀ " is the half inhibitory concentration (50% inhibiting concentration), that is, the concentration of the inhibitor when 50% inhibitory effect is achieved.

It can be seen from Table 2 that the compound of the present invention has a significant inhibitory effect on colorectal adenocarcinoma with BRCA2 gene deletion.

Embodiment 26 investigates the pharmacokinetic research of the compound that embodiment prepares

experimental method

ICR mice were given Compound I3, Compound I5, Compound I15, Compound I25, Compound I45, and Compound I57 prepared in the examples respectively under the conditions of intravenous injection and oral gavage administration, wherein the dose of intravenous administration was 2 mg/kg, orally administered The intragastric dose was 10 mg/kg, and blood samples were collected at different time points after administration (n=3). Plasma was separated by centrifugation, and the drug concentration in plasma was determined by liquid chromatography-mass spectrometry, and the main pharmacokinetic parameters were calculated by non-compartmental model method (NCA) of WinNonlin software.

Experimental results

The pharmacokinetic parameters of Compound I3, Compound I5, Compound I15, Compound I25, Compound I45, and Compound I57 prepared in the examples are shown in Table 3 and Figure 1 below:

The pharmacokinetic parameter of table 3 compound I3, I5, I15, I25, I45, I57

Wherein, iv is intravenous administration; po is oral administration;

T _max is the time to reach the maximum blood concentration;

C _max is the maximum blood concentration;

AUC _0-t is the drug-time curve area within 0-24h;

AUC _0-∞ is the drug-time curve area within 0-∞;

t _1/2 is the half-life;

Vss is the steady-state volume of distribution;

CL is the clearance rate.

As can be seen from Table 3 and Fig. 1, the compounds of the present invention have excellent pharmacokinetics through oral administration and injection administration, show good bioavailability after oral administration, and are suitable for the development of oral drugs, thereby Reduce production costs and improve patient compliance.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A compound of formula I, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its prodrug;

in,

Ring A is a substituted or unsubstituted C6-C14 aromatic ring, a substituted or unsubstituted C3-C14 cycloalkane ring, a substituted or unsubstituted 3-14 membered heterocycloalkane ring, or a substituted or unsubstituted 5-14 membered Heteroaromatic ring;

W 1 and W 2 are each independently =C(R 4 )- or =N-;

W 3 is =C(R 5 )- or =N-;

W 4 is =C(R 6 )- or =N-;

W 5 is =C(R 7 )- or =N-;

Z 1 is a substituted or unsubstituted C1-C6 alkylene group,
-O-, -S-, -N(R 8 )-;

Z 2 is a substituted or unsubstituted C3-C14 cycloalkylene, or a substituted or unsubstituted 3-14 membered heterocycloalkylene;

R 1 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C8 alkyl;

R2 is

R 4 is hydrogen or substituted or unsubstituted C1-C8 alkyl;

R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl or halogen; or R 5 and R 6 are connected to form a substituted or unsubstituted C6-C12 aromatic ring (such as a benzene ring);

R 7 is hydrogen, substituted or unsubstituted C1-C8 alkyl or halogen;

R 8 is hydrogen or substituted or unsubstituted C1-C8 alkyl;

R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 haloalkyl, (R 11 R 12 )N-substituted or unsubstituted C1-C8 alkane -, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 cycloalkyl-substituted or unsubstituted C1-C10 alkyl-, or substituted or unsubstituted 3-12 membered hetero Cycloalkyl;

Any of the "substituted" means that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on the ring or group are independently selected from the following group Substituent substituted: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkyl-C3-C8 cycloalkyl-, C1-C8 haloalkyl, C3-C8 halocycloalkyl, C3-C8 Cycloalkoxy, C3-C8 cycloalkylthio, C3-C8 halocycloalkoxy, C3-C8 halocycloalkylthio, halogen, nitro, -CN, =O, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amido, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl , 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, (R 11 R 12 )N-;

R 11 and R 12 are each independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C8 cycloalkyl;

The heterocycloalkyl, heterocycloalkylene, heteroaryl, heterocycloalkane and heteroaryl rings have 1-4 (preferably 1, 2, 3 or 4) independently A heteroatom selected from N, O and S.
The compound of claim 1, wherein the compound of formula I is
A composition, characterized in that, the composition comprises the compound of formula I as claimed in claim 1, or its optical isomer, or its racemate, or its solvate, or its hydrate, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
The composition according to claim 3, wherein said composition is a pharmaceutical composition.
The composition according to claim 3, wherein the dosage form of the composition is an injection preparation, an external preparation or an oral preparation.
A compound of formula I as claimed in claim 1, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its prodrug The use of the method is characterized in that it is used for preparing a composition, and the composition is used for preventing and/or treating tumors.
The use according to claim 6, wherein the tumor is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, melanoma, pancreatic cancer, or a combination thereof.
The use according to claim 6, wherein the tumor is selected from the group consisting of recurrent ovarian cancer, epithelial recurrent ovarian cancer, platinum-sensitive or partially sensitive fallopian tube cancer, platinum-sensitive or partially Sensitive primary peritoneal cancer, advanced ovarian cancer with gBRCA gene mutation that progresses after receiving 3 or more lines of chemotherapy, HER2-negative metastatic breast cancer with BRCA gene mutation, previous neoadjuvant chemotherapy, adjuvant chemotherapy, metastasis Harmful or suspected harmful gBRCA gene mutations, HER2-negative metastatic breast cancer, or a combination thereof.
A method for inhibiting tumor cells, characterized in that the method comprises the steps of: combining tumor cells with the compound of formula I as claimed in claim 1, or its optical isomer, or its racemate, or its The solvate, or its hydrate, or its pharmaceutically acceptable salt, or its prodrug can inhibit tumor cells.
A method for preventing and/or treating tumors, characterized in that the method comprises: administering the compound of formula I as claimed in claim 1, or its optical isomer, or its racemate , or a solvate thereof, or a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, thereby preventing and/or treating tumors.