WO2017128036A1

WO2017128036A1 - Quinazolinone parp-1 inhibitor and preparation method, pharmaceutical composition and use thereof

Info

Publication number: WO2017128036A1
Application number: PCT/CN2016/072135
Authority: WO
Inventors: 徐柏玲; 陈晓光; 姚海平; 季鸣; 金晶; 周洁; 王珂; 赵大龙
Original assignee: 中国医学科学院药物研究所; 北京科莱博医药开发有限责任公司
Priority date: 2016-01-26
Filing date: 2016-01-26
Publication date: 2017-08-03
Also published as: CN110088098B; CN110088098A

Abstract

Disclosed are a new class of quinazoline-2,4 (1H, 3H)-diketone PARP-1 inhibitors, and a preparation method and pharmaceutical composition and a use thereof. In particular, the present invention relates to a quinazoline-2,4 (1H, 3H)-diketone derivative as shown in general formula I and a stereoisomer thereof, pharmaceutically acceptable salts thereof, and a preparation method thereof, a composition comprising one or more of such compounds, and a use of such compounds in the preparation of drugs for preventing and/or treating tumours.

Description

Quinazolinone PARP-1 inhibitor, preparation method thereof, pharmaceutical composition and use thereof

Technical field

The present invention relates to a novel class of quinazoline-2,4-dione PARP-1 inhibitors, physiologically acceptable salts, and processes for their preparation, pharmaceutical compositions containing said compounds, and said compounds as The drug, in particular, is used as an antitumor drug or as a tumor drug sensitizer in combination with an antitumor drug.

Background technique

Poly(ADP-Ribose) polymerase (PARP) is an important protein-modifying enzyme widely distributed in eukaryotic cells, and its target protein is modified by adenosine diphosphate ribose. 17 subtypes including PARP-1, PARP-2, PARP-3, etc. have been found, of which PARP-1 has the largest proportion, and the related research is also the deepest, playing more than 90% of the functions, PARP-1 The primary structure is highly conserved in eukaryotes (eg, human and mouse amino acid sequences have 92% homology) (Virág L et al., Pharmacol. Res. 2002, 45, 375-429; Ferraris DL, J Med Chem, 2010, 53, 4561-4584). Studies have shown that PARP-1 is one of the important functional proteins in the DNA damage repair pathway, and inhibiting the activity of PARP-1 is one of the potentially promising pathways for the creation of anti-tumor drugs (AméJC et al., Bioessays, 2004, 26, 882-893).

Many chemotherapeutic drugs aim to kill tumor cells by damaging DNA. Tumor cells also initiate repair pathways against different chemotherapeutic drugs, and fight against chemotherapeutic drugs to produce drug resistance. The activation of PARP-1 is one of the important repair pathways. Therefore, inhibition of PARP-1 enzyme activity can resist drug resistance of tumor cells and increase the sensitivity of chemotherapy drugs. Therefore, the combination of PARP-1 inhibitors and cytotoxic chemotherapeutic drugs is a potential tumor treatment strategy and one of the most important reasons for the initial attention of PARP-1 inhibitors (Ellisen LW et al., Cancer Cell, 2011, 19, 165). -167; Tentori L et al., Pharmacol Res, 2005, 52, 25-33).

BRCA1 and BRCA2 play an important role in the process of homologous recombination to repair double-strand break DNA. For BRCA-deficient tumor cells, PARP inhibitors can block single-strand break DNA damage repair, and BRCA deficiency causes double-strand break DNA damage repair function. This ultimately leads to tumor cell apoptosis (Drew Y et al., Drug Resist Updat, 2009, 12, 153-156). This mechanism makes BRCA-deficient tumors more sensitive to PARP1 inhibitors. It is based on the above-mentioned "Synthetic lethality" strategy that can be improved The selectivity of PARP-1 inhibitor antitumor drugs to tumor cells reduces the side effects of drugs. (Farmer H et al., Nature, 2005, 434, 917-921; Bryant HE et al., Nature, 2005, 434, 913-917).

There are at least nine PARP inhibitors currently in clinical trials. ABT-888 developed by Abbott is in Phase II/III clinical stage in the treatment of various tumors; AG-014699 developed by Pfizer is currently in Phase II/III clinical stage in the treatment of breast cancer and ovarian cancer; Merck The company's MK-4827 is currently in Phase I/III clinical trials for the treatment of solid tumors (Anwar M, Aslam HM, Anwar S. PARP inhibitors. Hereditary Cancer in Clinical Practice, 2015, 13(1): 1- 4; Lupo B, Trusolino L. Inhibition of poly(ADP-ribosyl)ation in cancer: Old and new paradigms revisited. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 2014, 1846(1): 201-215). AZD2281 (Olaparib), developed by AstraZeneca, was launched in December 2014 and became the first anti-tumor drug to be marketed as a PARP-1 inhibitor.

This patent design synthesizes a new structure of quinazolinedione-based PARP-1 inhibitors, and some compounds have certain selectivity for PARP-1, which can become highly active and low-toxic anti-tumor drugs, or anti-tumor drugs. Agent. This patent aims to find new anti-tumor drugs with anti-tumor activity and improved pharmacokinetic properties or sensitizers for anti-tumor drugs.

Summary of the invention

The technical problem solved by the present invention is to provide a quinazoline-2,4(1H,3H)-dione derivative represented by Formula I, and a stereoisomer and a physiologically acceptable salt thereof, a preparation method thereof, and a medicament Compositions, and their use in the preparation of PARP-1 inhibitors and their potential drugs, in the preparation of anti-tumor drugs or anti-tumor drug sensitizers.

In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

A first aspect of the present invention provides a quinazolinedione derivative as shown in Formula I, and a stereoisomer or a physiologically acceptable salt thereof:

In formula I,

A, B, C, D are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, substituted A C1-3 straight or branched alkyl group wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa ₁ , SRa ₂ , NRa ₃ Rb ₁ , COORa ₄ , CONRa ₅ Rb ₂ , NRa ₆ COORb ₃ , SO ₂ NRa ₇ Rb ₄ , NRa ₈ CORb ₅ , wherein the Ra ₁ , Ra ₂ , Ra ₃ , Rb ₁ , Ra ₄ , Ra ₅ , Rb ₂ , Ra ₆ , Rb ₃ , Ra ₇ , R _b ₄ , Ra ₈ , Rb _{5 is} independently selected from the group consisting of H, methyl, and ethyl;

The stereoisomers resulting from the substitution of A, B, C, D include the (R)-configuration and the (S)-configuration, preferably the (R)-configuration;

X is selected from the group consisting of NR _A , O, S, Se, S=O, SO ₂ , C=O,

When X is NR _A , wherein R _{A is} selected from the group consisting of the following atoms or groups or structural fragments:

(1) Hydrogen, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2-6 straight or branched Alkynyl, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORc ₁ , SRc ₂ , NRc ₃ Rd ₁ , COORc ₄ , CONRc ₅ Rd ₂ , NRc ₆ COORd ₃ , SO ₂ NRc ₇ Rd ₄ , NRc ₈ CORd ₅ , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein said Rc ₁ , Rc ₂ , Rc ₃ , Rd ₁ , Rc ₄ , Rc ₅ , Rd ₂ , Rc ₆ , Rd ₃ , Rc ₇ , Rd ₄ , Rc ₈ , and Rd _{5 are} independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) CORe ₁ , COORe ₂ , CONRe ₃ Rf ₁ , SO ₂ Re ₄ , wherein the Re ₁ , Re ₂ , Re ₃ , Re ₄ , Rf _{1 are} independently selected from H, substituted or unsubstituted C 1 - 6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2-6 straight or branched alkynyl, substituted or unsubstituted C3-7 ring An alkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, said substituent being selected from the group consisting of F, Cl, Br, CN, ORc ₁ , SRc ₂ , NRc ₃ Rd ₁ , COORc ₄ , CONRc ₅ Rd ₂ , NRc ₆ COORd ₃ , SO ₂ NRc ₇ Rd ₄ , NRc ₈ CORd ₅ , cyclopropyl, cyclopropylmethylene, cyclobutene a group, an oxetanyl group, a cyclopentyl group, wherein said Rc ₁ , Rc ₂ , Rc ₃ , Rd ₁ , Rc ₄ , Rc ₅ , Rd ₂ , Rc ₆ , Rd ₃ , Rc ₇ , Rd ₄ , Rc ₈ , Rd _{5 is} independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; 3-8 membered ring oxacycloalkyl and nitrogen heterocycle The alkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-4 straight or branched alkyl, F, Cl, Br, CN, ORc ₁ , SRc ₂ , NRc ₃ Rd ₁ , COORc ₄ , CONRc ₅ Rd ₂ , NRc ₆ COORd ₃ , SO ₂ NRc ₇ Rd ₄ , NRc ₈ CORd ₅ , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rc ₁ , Rc ₂ , Rc ₃ , Rd ₁ , Rc ₄ , Rc ₅ , Rd ₂ , Rc ₆ , Rd ₃ , Rc ₇ , Rd ₄ , Rc ₈ , Rd _{5 are} independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclo The propylene group and the cyclobutyl group; the oxyheterocycloalkyl group and the nitrogen heterocycloalkyl group of the 3-8 membered ring may have one hetero atom or may contain a plurality of hetero atoms at the same time.

R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1) H, F, Cl, Br, CN, NO ₂ , CONRh ₁ Ri ₁ , COORh ₂ , SO ₂ Rh ₃ , SO ₂ NRh ₄ Ri ₂ , wherein Rh ₁ , Ri ₁ , Rh ₂ , Rh ₃ , Rh ₄ , Ri _{2 are} independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) a substituted or unsubstituted C1-4 straight or branched alkyl group, a substituted or unsubstituted C2-4 straight or branched alkenyl group, a substituted or unsubstituted C2-4 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, NO ₂ , CONRh ₁ Ri ₁ , COORh ₂ , SO ₂ Rh ₃ , SO ₂ NRh ₄ Ri ₂ , wherein Rh ₁ , Ri ₁ , Rh ₂ , Rh ₃ , Rh ₄ , and Ri _{2 are} independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, CF ₃ , CH ₂ CF ₃ , CHF ₂ , F, Cl, Br, CN, CONRh ₁ Ri ₁ , COORh ₂ , SO ₂ Rh ₃ , SO ₂ NRh ₄ Ri ₂ , ORh ₅ , SRh ₆ , NRh ₇ Ri ₃ , NRh ₈ CORi ₄ , NRh ₉ COORi ₅ , wherein Rh ₁ , Ri ₁ , Rh ₂ , Rh ₃ , Rh ₄ , Ri ₂ , Rh ₅ , Rh ₆ , Rh ₇ , Ri ₃ , Rh ₈ , Ri ₄ , Rh ₉ , Ri _{5 are} independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene , a cyclobutyl group; a 3-6 membered ring oxacycloalkyl group and a 3-6 membered ring azacycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;

(4) ORj ₁ , NRj ₂ Rk ₁ , SRj ₃ , NRj ₄ CORk ₂ , NRj ₅ COORk ₃ , NRj ₆ SO ₂ Rk ₄ , wherein Rj ₁ , Rj ₂ , Rk ₁ , Rj ₃ , Rj ₄ , Rk ₂ , Rj ₅ , Rk ₃ , Rj ₆ , Rk _{4 are} independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF ₃ , CH ₂ CF ₃ , CHF ₂ ;

R _{5 is} independently selected from the group consisting of H, F, Cl, Br, CN, NO ₂ , ORx ₁ , SRx ₂ , NRx ₃ Ry ₁ , COORx ₄ , CONRx ₅ Ry ₂ , NRx ₆ COORy ₃ , SO ₂ NRx ₇ Ry ₄ , NRx ₈ CORy ₅ , (CH ₂ )n ₁ ORx ₉ , (CH ₂ )n ₂ NRx ₁₀ Ry ₆ , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx ₁ , Rx ₂ , Rx ₃ , Ry ₁ , Rx ₄ , Rx ₅ , Ry ₂ , Rx ₆ , Ry ₃ , Rx ₇ , Ry ₄ , Rx ₈ , Ry ₅ , Rx ₉ , Rx ₁₀ , Ry _{6 are} independently selected From H, C1-3 straight or branched alkyl, halogen substituted C1-C3 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; said halogen includes F, Cl, Br, I; n ₁ and n _{2 are} independently selected from 1, ₂ , 3; n is selected from an integer of 1, 2, 3.

In the formula I, R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} independently preferably selected from the group consisting of H, F, Cl, Br and CN.

In the formula I, the A, D are independently preferably from H, B, C independently from H, methyl, ethyl, propyl, CH ₂ CF ₃ , CHF ₂ ; further, A Preferably, B and D are independently selected from H, C, and are preferably H, methyl, ethyl, propyl, CH ₂ CF ₃ , CHF ₂ .

Preferred compounds of the invention and stereoisomers or physiologically acceptable salts thereof according to the general formula I of the invention include, but are not limited to, the compounds of the formula (IA):

In Formula IA, at least one of A, B, C, and D is not hydrogen.

A, B, C, D are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, substituted A C1-3 straight or branched alkyl group wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa ₁ , SRa ₂ , NRa ₃ Rb ₁ , COORa ₄ , CONRa ₅ Rb ₂ , NRa ₆ COORb ₃ , SO ₂ NRa ₇ Rb ₄ , NRa ₈ CORb ₅ , wherein the Ra ₁ , Ra ₂ , Ra ₃ , Rb ₁ , Ra ₄ , Ra ₅ , Rb ₂ , Ra ₆ , Rb ₃ , Ra ₇ , R _b ₄ , Ra ₈ Rb _{5 is} independently selected from the group consisting of H, methyl, and ethyl.

R _{A is} selected from the group consisting of the following atoms or groups or structural fragments:

R _{5 is} independently selected from the group consisting of H, F, Cl, Br, CN, NO ₂ , ORx ₁ , SRx ₂ , NRx ₃ Ry ₁ , COORx ₄ , CONRx ₅ Ry ₂ , NRx ₆ COORy ₃ , SO ₂ NRx ₇ Ry ₄ , NRx ₈ CORy ₅ , (CH ₂ )n ₁ ORx ₉ , (CH ₂ )n ₂ NRx ₁₀ Ry ₆ , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx ₁ , Rx ₂ , Rx ₃ , Ry ₁ , Rx ₄ , Rx ₅ , Ry ₂ , Rx ₆ , Ry ₃ , Rx ₇ , Ry ₄ , Rx ₈ , Ry ₅ , Rx ₉ , Rx ₁₀ , Ry _{6 are} independently selected From H, C1-3 straight or branched alkyl, halogen substituted C1-C3 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; said halogen includes F, Cl, Br, I; n ₁ and n _{2 are} independently selected from 1, 2, and 3.

In the formula IA, R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} independently preferably selected from H, F, Cl, Br and CN.

In the formula IA, the A, D are independently preferably from H, B, C independently from H, methyl, ethyl, propyl, CH ₂ CF ₃ , CHF ₂ ; further, A Preferably, B and D are independently selected from H, C, and are preferably H, methyl, ethyl, propyl, CH ₂ CF ₃ , CHF ₂ .

Preferred compounds of the invention, and stereoisomers or physiologically acceptable salts thereof, according to the general formula IA of the present invention include, but are not limited to, the compounds of the formula IA-1:

In Formula IA-1, at least one of A', B', C', D' is not hydrogen,

A', B', C', D' are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropene a methyl, substituted C1-3 straight or branched alkyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa ₁ , SRa ₂ , NRa ₃ Rb ₁ , wherein said Ra ₁ , Ra ₂ , Ra ₃ and Rb _{1 are} independently selected from the group consisting of H, methyl, and ethyl.

The stereoisomers resulting from the substitution of A', B', C', D' include the (R)-configuration and the (S)-configuration, preferably the (R)-configuration;

R' _{A is} selected from the group consisting of the following atoms or groups or structural fragments:

(1) Hydrogen, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2-6 straight or branched Alkynyl, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORc ₁ , SRc ₂ , NRc ₃ Rd ₁ , COORc ₄ , CONRc ₅ Rd ₂ , NRc ₆ COORd ₃ , SO ₂ NRc ₇ Rd ₄ , NRc ₈ CORd ₅ , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, wherein Rc ₁ , Rc ₂ , Rc ₃ , Rd ₁ , Rc ₄ , Rc ₅ , Rd ₂ , Rc ₆ , Rd ₃ , Rc ₇ , Rd ₄ , Rc ₈ , and Rd _{5 are} independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene;

(2) CORe ₁ , COORe ₂ , CONRe ₃ Rf ₁ , SO ₂ Re ₄ , wherein the Re ₁ , Re ₂ , Re ₃ , Re ₄ , Rf _{1 are} independently selected from substituted or unsubstituted C1-6 straight A chain or branched alkyl group, a substituted or unsubstituted C2-6 straight or branched alkenyl group, a substituted or unsubstituted C2-6 straight or branched alkynyl group, a substituted or unsubstituted C3-7 cycloalkyl group a substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, said substituent being selected from the group consisting of F, Cl, Br, CN, ORc ₁ , SRc ₂ , NRc ₃ Rd ₁ , COORc ₄ , CONRc ₅ Rd ₂ , NRc ₆ COORd ₃ , SO ₂ NRc ₇ Rd ₄ , NRc ₈ CORd ₅ , cyclopropyl, cyclopropylmethylene, cyclobutyl, An oxetanyl group or a cyclopentyl group, wherein said Rc ₁ , Rc ₂ , Rc ₃ , Rd ₁ , Rc ₄ , Rc ₅ , Rd ₂ , Rc ₆ , Rd ₃ , Rc ₇ , Rd ₄ , Rc ₈ , Rd _{5 is} independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene; 3-8 membered ring of oxacycloalkyl and azacycloalkyl Containing 1 hetero atom, it can also contain multiple heteroatoms at the same time;

(3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORc ₁ , SRc ₂ , NRc ₃ Rd ₁ , COORc ₄ , CONRc ₅ Rd ₂ , NRc ₆ COORd ₃ , SO ₂ NRc ₇ Rd ₄ , NRc ₈ CORd ₅ , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rc ₁ , Rc ₂ , Rc ₃ And Rd ₁ , Rc ₄ , Rc ₅ , Rd ₂ , Rc ₆ , Rd ₃ , Rc ₇ , Rd ₄ , Rc ₈ , and Rd _{5 are} independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, and ring. The propyl group, the propylene propylene group, and the cyclobutyl group; the oxyheterocycloalkyl group and the nitrogen heterocycloalkyl group of the 3-8 membered ring may have one hetero atom or may contain a plurality of hetero atoms at the same time.

R' ₁ , R' ₂ , R' ₃ and R' _{4 are} independently selected from the group consisting of the following atoms or groups or structural fragments, including

R' _{5 is} independently selected from the group consisting of H, F, Cl, Br, CN, NO ₂ , ORx ₁ , SRx ₂ , NRx ₃ Ry ₁ , COORx ₄ , CONRx ₅ Ry ₂ , NRx ₆ COORy ₃ , SO ₂ NRx ₇ Ry ₄ , NRx ₈ CORy ₅ , CH ₂ ORx ₉ , CH ₂ NRx ₁₀ Ry ₆ , C1-C3 linear or branched alkyl, halogen-substituted C1-C3 straight or branched alkyl, C2-4 straight or branched Alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein said Rx ₁ , Rx ₂ , Rx ₃ , Ry ₁ , Rx ₄ , Rx ₅ , Ry ₂ , Rx ₆ , Ry ₃ , Rx ₇ , Ry ₄ , Rx ₈ , Ry ₅ , Rx ₉ , Rx ₁₀ , Ry _{6 are} independently selected from H, methyl, and B. Base, propyl, CF ₃ , CH ₂ CF ₃ , cyclopropyl, cyclopropylmethylene, cyclobutyl; the halogen includes F, Cl, Br, I.

In the formula IA-1, said _{_{R '1, R' 2,}} R '3, R' 4, R '5 are independently preferably selected from H, F, Cl, Br, CN. In the formula IA-1, the A', D' are independently preferably from H, B', C', independently from H, methyl, ethyl, propyl, CH ₂ CF ₃ , CHF ₂ Further, A', B', D' are independently preferably selected from H, C', preferably from H, methyl, ethyl, propyl, CH ₂ CF ₃ , CHF ₂ .

Preferred compounds of the invention and stereoisomers or physiologically acceptable salts thereof according to the general formula I of the invention include, but are not limited to, the compounds of the formula IB:

In the formula IB,

R _{B is} selected from the group consisting of the following atoms or groups or structural fragments:

(1) a substituted or unsubstituted C1-6 straight or branched alkyl group, a substituted or unsubstituted C2-6 straight or branched alkenyl group, a substituted or unsubstituted C2-6 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORc ₁ , SRc ₂ , NRc ₃ Rd ₁ , COORc ₄ , CONRc ₅ Rd ₂ , NRc ₆ COORd ₃ , SO ₂ NRc ₇ Rd ₄ , NRc ₈ CORd ₅ , a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, an oxetanyl group, a cyclopentyl group, wherein Rc ₁ , Rc ₂ , Rc ₃ , Rd ₁ , Rc ₄ , Rc ₅ , Rd ₂ , Rc ₆ , Rd ₃ , Rc ₇ , Rd ₄ , Rc ₈ , Rd _{5 are} independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) CORe ₁ , COORe ₂ , CONRe ₃ Rf ₁ , SO ₂ Re ₄ , wherein the Re ₁ , Re ₂ , Re ₃ , Re ₄ , Rf _{1 are} independently selected from substituted or unsubstituted C1-6 straight A chain or branched alkyl group, a substituted or unsubstituted C2-6 straight or branched alkenyl group, a substituted or unsubstituted C2-6 straight or branched alkynyl group, a substituted or unsubstituted C4-7 cycloalkyl group a substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, said substituent being selected from the group consisting of F, Cl, Br, CN, ORc ₁ , SRc ₂ , NRc ₃ Rd ₁ , COORc ₄ , CONRc ₅ Rd ₂ , NRc ₆ COORd ₃ , SO ₂ NRc ₇ Rd ₄ , NRc ₈ CORd ₅ , cyclopropyl, cyclopropylmethylene, cyclobutyl, An oxetanyl group, a cyclopentyl group, wherein Rc ₁ , Rc ₂ , Rc ₃ , Rd ₁ , Rc ₄ , Rc ₅ , Rd ₂ , Rc ₆ , Rd ₃ , Rc ₇ , Rd ₄ , Rc ₈ , Rd _{5 is} independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; 3-8 membered ring oxacycloalkyl and azacycloalkyl It may contain one hetero atom or multiple hetero atoms at the same time;

In the formula IB, the R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} independently preferably selected from the group consisting of H, F, Cl, Br and CN.

Preferred compounds of the invention, and stereoisomers or physiologically acceptable salts thereof, according to the general formula I of the invention include, but are not limited to, the compounds of the formula IC:

In the formula IC, at least one of A, B, C, and D is not hydrogen.

Y is selected from the group consisting of O, S, Se, S=O, SO ₂ , C=O,

In the general formula IC, R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} independently preferably selected from H, F, Cl, Br and CN.

In the formula IC, the A, D are independently preferably from H, B, C independently from H, methyl, ethyl, propyl, CH ₂ CF ₃ , CHF ₂ ; further, A Preferably, B and D are independently selected from H, C, and are preferably H, methyl, ethyl, propyl, CH ₂ CF ₃ , CHF ₂ .

Preferred compounds of the invention and stereoisomers or physiologically acceptable salts thereof according to the general formula I of the invention include, but are not limited to, the compounds of the formula ID:

In the formula ID,

Y is selected from the group consisting of O, S, Se, S=O, SO ₂ , C=O,

In the general formula ID, R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} independently preferably selected from H, F, Cl, Br and CN.

For the purposes of the present invention, preferred compounds include, but are not limited to:

(1) (S)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2 2-trifluoroacetate

(2) (R)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2 2-trifluoroacetate

(3) 1-(3-(morpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

(4) 1-(3-(Thomamorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

(5) (S)-2-Ethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2- Fluorobenzoyl) piperazine-1-carboxylic acid tert-butyl ester

(6) (R)-2-ethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2- Fluorobenzoyl) piperazine-1-carboxylic acid tert-butyl ester

(7) 1-(3-(4-(2,2,2-Trifluoroacetyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

(8) 1-(3-(1-oxothiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

(9) 1-(3-(1,1-dioxothiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

(10) 1-(3-(4-(2,2,2-Trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

(11) 1-(3-(4-(2,2,2-Trifluoroethyl)piperazine-1-formyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4 ( 1H,3H)-dione

(12) 1-(3-(4-(2,2,2-Trifluoroethyl)piperazine-1-formyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4 ( 1H,3H)-dione

(13)(3S,5R)-3,5-Dimethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)) Tert-butyl 2-fluorobenzoyl)piperazine-1-carboxylate

(14) 1-(3-((3S,5R)-3,5-Dimethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

(15) (R)-1-(3-(3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline- 2,4(1H,3H)-dione

(16) (S)-1-(3-(3-Methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline- 2,4(1H,3H)-dione

(17) (R)-1-(3-(3-Methyl-4-(isobutyryl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

(18) (S)-1-(3-(3-Methyl-4-(isobutyryl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

(19) (R)-1-(3-(3-Methyl-4-(n-propyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

(20) (S)-1-(3-(3-Methyl-4-(n-propyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

(21) (R)-1-(3-(3-Methyl-4-(2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H ,3H)-dione

(22) (S)-1-(3-(3-Methyl-4-(2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H ,3H)-dione

(23) (R)-1-(3-(3-Methyl-4-(cyclopropylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H, 3H)-dione

(24) (S)-1-(3-(3-Methyl-4-(cyclopropylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H, 3H)-two ketone

(25) (R)-1-(3-(3-Methyl-4-(isobutyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

(26) (S)-1-(3-(3-Methyl-4-(isobutyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

(27) (R)-1-(3-(3-Methyl-4-(3-methyl-2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline- 2,4(1H,3H)-dione

(28) (S)-1-(3-(3-Methyl-4-(3-methyl-2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline- 2,4(1H,3H)-dione

(29) (R)-1-(3-(3-ethyl-4-methylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(30) (R)-1-(3-(3-Ethyl-4-isopropylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

(31) (R)-1-(3-(3-ethyl-4-cyclopropanylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

(32) (R)-1-(3-(3-ethyl-4-acetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(33) (R)-1-(3-(3-ethyl-4-trifluoroacetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

(34) (R)-1-(3-(3-ethyl-4-n-propylpiperazin-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

(35) (R)-1-(3-(3-ethyl-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(36) (R)-1-(3-(3-ethyl-4-cyclopropylmethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

(37) (R)-1-(3-(3-ethyl-4-propionylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(38) (R)-1-(3-(3-ethyl-4-trifluoroethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

(39) (S)-1-(3-(3-ethyl-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(40) (S)-1-(3-(3-ethyl-4-cyclopropylmethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

(41) (S)-1-(3-(3-ethyl-4-propionylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(42) (S)-1-(3-(3-ethyl-4-trifluoroethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

(43) (S)-1-(3-(3-ethyl-4-methylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(44) (S)-1-(3-(3-Ethyl-4-isopropylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

(45) (S)-1-(3-(3-ethyl-4-cyclopropanylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

(46) (S)-1-(3-(3-ethyl-4-acetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(47) (S)-1-(3-(3-ethyl-4-trifluoroacetyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

(48) (S)-1-(3-(3-Ethyl-4-n-propylpiperazin-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

(49) 1-(3-(4-Oxopiperidin-1-yl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione.

A second aspect of the present invention provides a method for preparing the compound of the first aspect, which comprises the following steps: R ₁ -R ₄ substituted different quinazolinedione and 3-containing R ₅ substituted The methoxycarbonyl bromide undergoes a selective alkylation reaction under the action of HMDS, and after hydrolysis, contains different 3-((2,4-dioxo-3,4-) substituted by R ₁ -R ₅ Dihydroquinazoline-1(2H)-yl)methyl)benzoic acid is then condensed with piperazine or piperidine derivatives to give a partial 1-benzylquinazolinedione PARP-1 inhibitor, this part The compound can be further deprotected, alkylated, acylated, oxidized to obtain another part of the 1-benzylquinazolinedione derivative, and some of the compounds are subjected to 3-((2,4-dioxo-3). , 4-Dihydroquinazoline-1 (2H)-yl)methyl)benzoic acid methyl ester was obtained by direct aminolysis. Wherein A, B, C, D, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and X are as defined in claim 1.

Reagents and reaction conditions: (a) urea, 140 ° C, 6 h; (b) i) lithium hexamethyldisilazide (HMDS), concentrated sulfuric acid, toluene, reflux, 2 h, ii) substituted 5-(bromo Methyl 2-fluorobenzoate, 145 ° C, 3 h, iii) methanol, hexanes, 70 ° C, 30 min; (c) LiOH, MeOH, H ₂ O, THF, 55 ° C, 2 h; (d) 2 -(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBT), diisopropyl Ethylamine (DIEA), DMF (N,N-dimethylformamide), overnight (overnight);

The definitions of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, B, C, D, and X described above are the same as those of the compound of the first aspect of the invention.

Further, the starting materials and intermediates in the above reaction are easily obtained, and the respective steps can be easily synthesized according to the reported literature or by a person skilled in the art by a conventional method in organic synthesis. The compounds of formula I may exist in solvated or unsolvated forms, and crystallization from different solvents may result in different solvates. The pharmaceutically acceptable salts of the formula I include salts of different acids, such as the salts of the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, Tannin, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid. The pharmaceutically acceptable salts of formula I also include various alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and organics which provide physiologically acceptable cations. Salts of bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris(2-hydroxyethyl)amine. All of these salts within the scope of the invention can be prepared by conventional methods.

A third aspect of the present invention provides a pharmaceutical composition comprising the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable Common carrier.

The composition includes at least one compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, an injection, a sustained release preparation, a controlled release preparation, or various microparticle delivery systems. The pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.

The compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.

The dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.

The compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.

These formulations are prepared according to methods well known to those skilled in the art. The auxiliary materials used for the manufacture of tablets, capsules and coating agents are conventional auxiliaries such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils. Such as corn oil, peanut oil, olive oil and so on. Other auxiliaries such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments and the like may also be present in the formulations containing the compounds of the invention.

In order to form the compound of the present invention into tablets, various excipients known in the art, including diluents, binders, wetting agents, disintegrating agents, lubricants, and glidants, can be widely used. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, or different Propyl alcohol, etc.; the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinyl pyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium hydrogencarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfonate, etc.; lubricant and flow aid The agent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol or the like.

Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.

In order to prepare the administration unit as a capsule, the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule. The various diluents, binders, wetting agents, disintegrants, glidants of the formulations used to prepare the tablets of the present invention are also useful in the preparation of capsules of the compounds of the invention.

In order to prepare the compound of the present invention as an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added. The solubilizing agent or co-solvent may be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulating agent may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like. For preparing a lyophilized powder injection, mannitol, glucose or the like may also be added as a proppant.

In addition, coloring agents, preservatives, perfumes, flavoring agents or other additives may also be added to the pharmaceutical preparations as needed.

The pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.

The pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like. In general, a suitable daily dose of the compound of the invention will range from 1 to 500 mg/kg body weight, preferably from 10 to 400 mg/kg body weight. The above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.

A fourth aspect of the present invention provides the use of the compound of the first aspect of the present invention, and a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the preparation of a PARP-1 inhibitor, in the preparation of prophylaxis and/or treatment The use of a medicament for a disease associated with PARP-1, the use thereof in the preparation of an antitumor drug, and the use of a medicament for the preparation of a tumor associated with a tumor, wherein the tumor is selected from the group consisting of melanoma, gastric cancer, lung cancer, and breast. Cancer, kidney cancer, liver cancer, oral epithelial cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder cancer, glioma.

Beneficial technical effects:

This patent application quinazolinone PARP1 inhibitor has a very strong inhibitory activity, and the PARP1 inhibitory activity reaches a level of 10 ^-8 to 10 ^-10 M. Some of the compounds of this patent have certain selectivity for PARP1 compared to PARP2 inhibitory activity. Represented by Examples 10, 35 and 36, it has a very strong antitumor activity in a variety of tumor animal models, and its inhibitory effect on tumors is stronger than that of clinical candidate drugs ABT-888 or AZD-2281, or tumor inhibitory activity. It is equivalent to the clinical candidate drug ABT-888 or AZD-2281. It is worth noting that the compound can penetrate the blood-brain barrier and thus can be used for the treatment of brain tumors, and pharmacodynamic experiments show that the compound is effective against temozolomide-resistant brain tumors. Another characteristic of the compound is that the compound has less toxicity and is less effective in reducing the platelet and leukocytes through the nude mouse body weight test and blood system index test; and the pharmacokinetic study shows that the drug concentration in the tumor tissue is high. Further reduce the toxic side effects of the compound. Thus, the compounds of the present patent application are potentially highly active, low toxicity anti-tumor drugs.

DRAWINGS

Figure 1. Sensitization of Example 10 to different chemotherapeutic drugs in MX-1 cells.

Figure 2. Sensitization activity of Example 10 on TMZ in various tumor cells.

Figure 3. Antiproliferative activity of Example 10 against TMZ resistant glioma

Figure 4. Example 35 Sensitization of Different Chemotherapeutic Drugs

Figure 5. Antitumor activity of Example 35 on different gliomas

Figure 6. Example 36 sensitization to different chemotherapeutic drugs

Figure 7. Antitumor activity of Example 36 against different gliomas

Figure 8. Sensitization of Compound 10 to TMZ in a MX-1 breast cancer xenograft model

Figure 9. Changes in mouse body weight in MX-1 nude mice xenograft experiments

Figure 10. Changes in blood index in MX-1 nude mice xenografts

Figure 11. Sensitization activity of Example 10 on CisPt in a MX-1 nude mouse xenograft model

Figure 12. Sensitization activity of Example 10 on TMZ in a MCF-7 nude mouse xenograft model.

Figure 13. Sensitization activity of Example 10 on TMZ in a U251/TMZ nude mouse xenograft model

Figure 14. Sensitization of TMZ to Example 35 in a MX-1 breast cancer xenograft model.

Figure 15. Sensitization of TMZ in Example 36 in a MX-1 breast cancer xenograft model

Figure 16. Sensitization of TMZ to Example 35 in the U87MG/Luc in situ glioma model.

Figure 17. Sensitization of TMZ in Example 36 in the U87MG/Luc in situ glioma model.

Figure 18. Life extension curves for Examples 35 and 36 in the U87MG/Luc in situ glioma model

Detailed ways

The invention will be further illustrated by the following examples, without limiting the scope of the invention.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or high resolution mass spectrometry (HRMS). NMR was measured using Varian mercury 300 or Varian mercury 400, solvent for measurement was CDCl3, DMSO-d6, acetone- d6, CD 3 OD, internal standard TMS, chemical shifts are given in ppm as a unit. Mp is the melting point given in ° C and the temperature is not corrected. Silica gel column chromatography generally uses 200 to 300 mesh silica gel as a carrier.

List of abbreviations:

TLC: thin layer chromatography;

CDCl ₃ : deuterated chloroform; DIEA: diisopropylethylamine; TFA: trifluoroacetic acid; TEA: triethylamine

DMF: N,N-dimethylformamide; THF: tetrahydrofuran; PE: petroleum ether; EA: ethyl acetate

Min: minute; rt room temperature; DCM: dichloromethane; h: hour; Et ₃ N: triethylamine

EDC or EDCI: 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride

NBS: N-bromosuccinimide; DMAP: 4-dimethylaminopyridine

AIBN: azobisisobutyronitrile; Boc: tert-butoxycarbonyl

HMDS: lithium hexamethyldisilazide

HBTU: O-benzotriazole-tetramethylurea hexafluorophosphate

HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate

HOBt: 1-hydroxybenzotriazole; TFA: trifluoroacetic acid;

Preparation of intermediates:

(1) Preparation of quinazoline-2,4(1H,3H)-dione

Anthranilic acid (5g, 36.46mmol) and urea (50g, 83.25mmol) were added to the reaction flask, and the temperature was raised to 150 ° C. After 7 h, the temperature was lowered to 100 ° C, a small amount of water was poured, and the mixture was filtered under reduced pressure. Wash with a small amount of water and methanol, dissolve the filter cake with 1 L of hot sodium hydroxide solution, adjust the pH to 3 with concentrated hydrochloric acid at 0 ° C, vacuum filter under reduced pressure, and wash the filter cake with a small amount of water. 4.5 g of a white solid were obtained in a yield of 76.1%.

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm): 11.26 (s, 1H), 11.12 (s, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.60-7.65 (m, 1H) , 7.14 - 7.19 (m, 2H).

M.p.>250 °C.

Prepare the following intermediates according to the above general method

(II) Preparation of methyl 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoate

a) Methyl 2-fluoro-5-bromomethylbenzoate

Methyl 2-fluoro-5methylbenzoate (100 mg, 0.60 mmol), NBS (112 mg, 0.63 mmol), AIBN (60 mg, 0.36 mmol) were sequentially added to the reaction flask, and CCl ₄ (5 mL) was added under Ar atmosphere. After refluxing for 3 h, a small amount of material was evaporated, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated.

^{_{1 H NMR (300MHz, CDCl 3}} ) δ (ppm): 7.96-7.99 (1H, m), 7.53-7.58 (1H, m), 7.10-7.17 (1H, m), 4.48 (2H, s), 3.94 ( 3H, s).

b) 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid methyl ester

The quinazoline-2,4(1H,3H)-dione (411 mg, 2.54 mmol) was added to a reaction flask, and anhydrous toluene (6 mL) was added, followed by HMDS (819 mg, 5.07 mmol, 2.5 eq), concentrated sulfuric acid (4 drops, 0.1 eq), the temperature was raised to reflux, and the reaction was completed at 40 min to give a clear solution, and the solvent and the remaining HMDS were evaporated to dryness under reduced pressure. Methyl 2-fluoro-5-bromomethylbenzoate (938 mg, 3.80 mmol) was added to the reaction residue, and the mixture was reacted at 140 ° C for 3 h. The temperature was lowered to 100 ° C, and dioxane (3 mL) and methanol (2 mL) were added to the reaction flask, and the mixture was stirred at 70 ° C for 30 min, cooled to 0 ° C, and filtered under reduced pressure to yield 413 g of white solid.

^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm): 11.47 (brs, 1H), 8.02 (d, J = 5.7Hz, 1H), 7.86 (d, J = 4.5Hz, 1H), 7.66 (t , J=5.7 Hz, 1H), 7.58-7.61 (m, 1H), 7.23-7.34 (m, 3H), 5.34 (s, 2H), 3.83 (s, 3H); mp 212-214 ° C.

Prepare the following intermediates according to the above general method

(III) Preparation of 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid

Add methyl 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoate (200 mg, 0.61 mmol) to the reaction flask H ₂ O (2 mL), THF (2 mL) and MeOH (4 mL) were added, and then LiOH (82 mg, 1.94 mmol) was added, and the mixture was heated to 55 ° C. The reaction was stopped after 55 min, and the organic solvent was evaporated under reduced pressure. The pH was lowered to 2, filtered under reduced pressure, washed with water and dried to yield 176 g.

^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm): 13.31 (s, 1H), 11.76 (s, 1H), 8.02 (d, J = 5.7Hz, 1H), 7.82 (d, J = 4.2Hz , 1H), 7.66 (t, J = 5.7 Hz, 1H), 7.55 - 7.57 (m, 1H), 7.23 - 7.31 (m, 3H), 5.33 (s, 2H).mp > 250 ° C

Prepare the following intermediates according to the above general method

Example 1

(S)-2-ethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzamide Acyl) piperazine-1-carboxylic acid tert-butyl ester

3-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzoic acid (150 mg, 0.51 mmol), HATU (388 mg, 1.02 mmol), HOBt (138 mg, 1.02 mmol) and TEA (104 mg, 1.02 mmol) were added to the reaction flask, dissolved in about 5 mL of anhydrous DMF, stirred at rt for 15 min, then (S)-N-Boc-2-ethylpiper was added dropwise. piperazine (153mg, 0.76mmol) in DMF to the reaction solution, stirred overnight at rt, the solvent was distilled off under reduced pressure, the addition of about 20mL DCM, washed with saturated NaHCO ₃ (25mL × 2), dried over anhydrous sodium sulfate, silica gel column 150 mg of solid was isolated in a yield of 65.8%.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.70-8.73 (m, 1H), 8.23 (d, J = 7.6Hz, 1H), 7.56-7.62 (m, 1H), 7.24-7.35 (m, 3H), 7.05-7.10 (m, 2H), 5.32 (s, 2H), 4.58-4.62 (m, 1H), 3.84-4.22 (m, 2H), 2.91-3.57 (m, 4H), 1.46-1.69 ( m, 2H), 1.45-1.47 (m, 9H), 0.64-1.27 (m, 5H); mp67-68 ° C.

Example 2

(R)-2-ethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzamide Acyl) piperazine-1-carboxylic acid tert-butyl ester

3-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzoic acid (250 mg, 0.80 mmol), EDC (307 mg, 1.6 mmol), HOBt (217 mg, 1.6 mmol) and DIEA (162 mg, 1.60 mmol) were added to the reaction flask, dissolved in about 3 mL of anhydrous DMF, stirred at rt for 15 min, then (R)-N-Boc-2-ethylpiper was added dropwise. A solution of oxazine (258 mg, 1.20 mmol) in DMF was added to the reaction mixture and stirred at rt overnight. The mixture was poured into 100 mL of water and extracted with 100 mL of EtOAc. EtOAc (100 mL) The mixture was washed with EtOAc (EtOAc) m.

^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm): 11.74 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.64 (m, 1H), 7.22-7.49 (m, 5H) , 5.32 (s, 2H), 4.35-4.40 (m, 1H), 3.74-4.04 (m, 2H), 2.75-3.43 (m, 4H), 1.38-1.40 (m, 9H), 0.46-1.30 (m, 5H); mp72-73 ° C.

Example 3

1-(3-(morpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

3-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzoic acid (180 mg, 0.58 mmol), EDC (223 mg, 1.16 mmol), HOBt (157 mg, 1.16 mmol) and DIEA (118 mg, 1.16 mmol) were added to the reaction flask, dissolved in about 3 mL of anhydrous DMF, stirred at rt for 15 min, then morpholine (75 mg, 0.86 mmol) in DMF was added dropwise. The mixture was stirred at rt. EtOAc (EtOAc m.) , 140 mg of solid was obtained in a yield of 63.8%.

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm): 11.72 (s, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.64 (t, J = 7.6Hz, 1H), 7.43-7.45 (m, 1H), 7.36-7.38 (m, 1H), 7.23-7.29 (m, 3H), 5.32 (s, 2H), 3.61 (m, 3H), 3.44 (m, 2H), 3.32 (m, 1H) ), 3.14 (m, 1H); mp108-110 ° C.

Example 4

1-(3-(thiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

3-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzoic acid (250 mg, 0.80 mmol), EDC (307 mg, 1.6 mmol), HOBt (217 mg, 1.6 mmol) and DIEA (162 mg, 1.60 mmol) were added to the reaction flask, dissolved in about 3 mL of anhydrous DMF, stirred for 15 min at rt, followed by dropwise addition of thiomorpholine (124 mg, 1.20 mmol) in DMF. To the reaction mixture, the mixture was stirred at rt EtOAc. EtOAc EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m Analysis gave 190 mg of solid in a yield of 59.8%.

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm): 11.72 (s, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.65 (t, J = 6.0Hz, 1H), 7.39-7.45 (m, 2H), 7.23-7.33 (m, 3H), 5.32 (s, 2H), 3.84 (m, 2H), 3.37-3.40 (m, 2H), 2.65 (m, 2H), 2.45 (m, 2H) ); mp200-202 ° C.

Example 5

(S)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2,2- Trifluoroacetate

(S)-2-Ethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzene Formyl) piperazine-1-carboxylic acid tert-butyl ester (30mg, 0.06mmol) was added to the reaction flask, about 2mL DCM, 2mL TFA was added sequentially, stirred at room temperature for 5h, solvent and TFA were evaporated under reduced pressure, a small amount of anhydrous ether was added. Filtration under reduced pressure, the filter cake was washed with a small portion of anhydrous diethyl ether and dried to give 25 mg of white powdery solid.

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm): 11.72 (s, 1H), 9.17 (brs, 1H), 8.92 (brs, 1H), 8.02 (d, J = 7.2Hz, 1H), 7.62 -7.66(m,1H), 7.48-7.50(m,1H), 7.39(m,1H), 7.20-7.33(m,3H),5.33(s,2H),4.35-4.48(m,3H×0.5) , 2.75-3.40 (m, 5.5H), 1.59-1.63 (m, 1H), 1.34-1.45 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H × 0.5), 0.65 (t, J = 6.8) Hz, 3H × 0.5); mp149-151 ° C.

Example 6

(R)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2,2- Trifluoroacetate

(R)-2-ethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzene Formyl) piperazine-1-carboxylic acid tert-butyl ester (40mg, 0.08mmol) was added to the reaction flask, about 2mL DCM, 2mL TFA was added in sequence, the reaction was stirred at room temperature for 5h, the solvent and TFA were evaporated under reduced pressure, and a small amount of anhydrous ether was added. Filtration under reduced pressure, the filter cake was washed with diethyl ether.

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm): 11.74 (s, 1H), 9.16 (brs, 1H), 8.91 (brs, 1H), 8.03 (d, J = 7.5Hz, 1H), 7.65 (m, 1H), 7.51 (m, 1H), 7.40 (m, 1H), 7.22-7.35 (m, 3H), 5.33 (s, 2H), 4.36-4.50 (m, 3H x 0.5), 2.73-3.42 (m, 5.5H), 1.63 (m, 1H), 1.36-1.45 (m, 1H), 0.98 (t, J = 7.2 Hz, 3H × 0.5), 0.89 (t, J = 6.9 Hz, 3H × 0.2) , 0.66 (t, J = 6.9 Hz, 3H × 0.3); mp150-152 ° C.

Example 7

1-(3-(4-(2,2,2-trifluoroacetyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) 4-(5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazine-1- Tert-butyl carboxylate

3-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzoic acid (200 mg, 0.64 mmol), HATU (487 mg, 1.28 mmol), HOBt (173 mg, 1.28 mmol) and DIEA (166 mg, 1.28 mmol) were added to the reaction flask, dissolved in about 3 ml of anhydrous DMF, stirred at rt for 15 min, then N-Boc-piperazine (178 mg, 0.96 mmol) was added dropwise. DMF solution was added to the reaction mixture, stirred overnight at rt, the solvent was distilled off under reduced pressure, the addition of about 20mL DCM, washed with saturated NaHCO ₃ (25mL × 2), dried over anhydrous sodium sulfate, silica gel column chromatography to obtain 186mg solid, yield 60.7%.

¹ H NMR (300 MHz, Acetone-d ₆ ) δ (ppm): 10.40 (brs, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.51 (m) , 1H), 7.44 (d, J = 5.1 Hz, 1H), 7.16-7.33 (m, 3H), 5.42 (s, 2H), 3.64 (m, 2H), 3.15-3.44 (m, 6H), 1.43 ( s, 9H); mp144-146 ° C.

b) 1-(3-(Piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2,2-trifluoroacetate

4-(5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazine-1-carboxyl The acid t-butyl ester (40 mg) was added to the reaction flask, and about 2 mL of DCM and 2 mL of TFA were added successively, and the reaction was stirred at room temperature for 5 hours. The solvent and TFA were evaporated under reduced pressure, and then filtered and evaporated. It was washed with diethyl ether and dried to give a crystallite.

^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm): 11.74 (s, 1H), 8.94 (brs, 2H), 8.03 (d, J = 6.6Hz, 1H), 7.65 (d, J = 7.2Hz , 1H), 7.49 (m, 1H), 7.40-7.49 (m, 1H), 7.20-7.34 (m, 3H), 5.32 (s, 2H), 3.79 (m, 2H), 3.35 (m, 2H), 3.10-3.19 (m, 3H), 2.95 (m, 2H); mp128-130 ° C.

c) 1-(3-(Piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2,2-trifluoroacetate ( 150 mg, 0.30 mmol) was dissolved in about 5 mL of anhydrous DCM, and trifluoroacetic anhydride (100 mg, 0.45 mmol) in anhydrous DCM and triethylamine (150 μL, 0.90 mmol) The reaction was continued for 1 h, the starting material disappeared, the reaction was quenched with a small portion of water, and the solvent was evaporated under reduced pressure.

^{1 H NMR (300MHz, Acetone-} d 6) δ (ppm): 10.42 (s, 1H), 8.11 (d, J = 7.5Hz, 1H), 7.63-7.66 (m, 1H), 7.55 (m, 1H) , 7.47-7.50 (m, 1H), 7.19-7.33 (m, 3H), 5.44 (s, 2H), 3.60-3.82 (m, 6H), 3.37-3.44 (m, 2H); mp 202-204 ° C.

Example 8

1-(3-(1-oxothiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

60-% m-CPBA (77 mg, 0.26 mmol) was added to 1-(3-(thiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4 at 0 °C. To a solution of 1H,3H)-dione (100 mg, 0.25 mmol) in EtOAc (5 mL) EtOAc. 76.9%.

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm): 11.73 (s, 1H), 8.02 (d, J = 8.0Hz, 1H), 7.65 (t, J = 7.6Hz, 1H), 7.41-7.47 (m, 2H), 7.20-7.32 (m, 3H), 5.26-5.38 (m, 2H), 4.32-4.36 (m, 1H), 3.64-3.77 (m, 2H), 3.25-3.32 (m, 1H) , 2.67-2.97 (m, 4H); mp186-188 ° C.

Example 9

1-(3-(1,1-dioxothiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

60-% m-CPBA (154 mg, 0.52 mmol) was added to 1-(3-(thiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4 at 0 °C. To a solution of 1H,3H)-dione (100 mg, 0.25 mmol) in EtOAc (5 mL), EtOAc (EtOAc) %.

^{1 H NMR (300MHz, DMSO-} d 6) δ (ppm): 11.75 (s, 1H), 8.02 (d, J = 7.8Hz, 1H), 7.65 (t, J = 7.2Hz, 1H), 7.48-7.51 (m, 2H), 7.18-7.34 (m, 3H), 5.32 (s, 2H), 3.54 (m, 2H), 3.26-3.32 (m, 4H), 2.97 (m, 2H); mp 189-191 ° C.

Example 10

1-(3-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) tert-butyl 4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate

N-Boc piperazine (2 g, 10.74 mmol) was added to the reaction flask under ice-cooling with N ₂ , and dissolved by adding about 100 mL of DCM, and added dropwise to TEA (1.81 mL, 13.02 mmol), followed by dropwise addition of trifluoroethyl The anhydride (1.81 mL, 13.02 mmol) was allowed to react to room temperature overnight, washed with water and silica gel column chromatography.

b) tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate

4-(2,2,2-Trifluoroacetyl)piperazine-1-carboxylic acid tert-butyl ester (2.3 g) was added to the reaction flask, dissolved in about 10 mL of anhydrous THF, and 1 M borane was added dropwise. The tetrahydrofuran solution was warmed to reflux, and the reaction was stopped after 2 h. The solvent was evaporated in vacuo.

c) 1-(2,2,2-trifluoroethyl)piperazine hydrochloride

4-(2,2,2-Trifluoroethyl)piperazine-1-carboxylic acid tert-butyl ester (1.2 g) was added to the reaction flask, and about 8 mL of 2.08 M HCl in dioxane solution was added and stirred at room temperature overnight. The solid was washed with a mixture of diethyl ether and EA to give a white solid which was taken directly to the next.

d) 1-(3-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (134 mg, 0.43 mmol), EDCI (163 mg, 0.85 mmol), HOBt (115 mg, 0.85 mmol) and DIEA (140 mg, 1.08 mmol) were added to the reaction flask, dissolved in about 3 mL of anhydrous DMF, stirred for 15 min at rt, followed by dropwise addition of 1-(2,2,2- A solution of trifluoroethyl)piperazine hydrochloride (104 mg, 0.51 mmol) in DMF was added to the reaction mixture and stirred at rt overnight. The mixture was poured into 100 mL of water and extracted with 100 mL of DCM. The mixture was washed with aq. EtOAc (EtOAc)EtOAc.

^{_{1 H NMR (300MHz, CDCl 3}} ) δ (ppm): 8.80 (s, 1H), 8.23 (dd, J 1 = 7.5Hz, J 2 = 1.2Hz, 1H), 7.58-7.64 (m, 1H), 7.24 -7.42 (m, 3H), 7.04-7.11 (m, 2H), 5.33 (s, 2H), 3.82 (m, 2H), 3.34 (m, 2H), 2.97-3.08 (m, 2H), 2.75-2.79 (m, 2H), 2.63 (m, 2H); mp128-130 ° C.

Example 11

1-(3-(4-(2,2,2-trifluoroethyl)piperazine-1-formyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4(1H,3H )-dione

5-((5-Fluoro-2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (85 mg, 0.24 mmol), EDC (93 mg, 0.48 mmol), HOBt (65 mg, 0.48 mmol) and DIEA (63 mg, 0.48 mmol) were added to the reaction flask, dissolved in about 3 mL of anhydrous DMF, stirred at rt for 15 min, then 1-(2, 2,2-Trifluoroethyl)piperazine hydrochloride (74 mg, 0.36 mmol) in DMF was added to the reaction mixture and stirred at rt overnight. The mixture was poured into 100 mL of water and extracted with 100 mL of DCM. (100 mL), EtOAc (EtOAc)EtOAc.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 10.36 (s, 1H), 7.63 (dd, J ₁ = 14 Hz, J ₂ = 7.6 Hz, 1H), 7.51 (m, 1H), 7.43 ( d, J = 6.0 Hz, 1H), 7.20 (t, J = 8.8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.97 (t, J = 9.6 Hz, 1H), 5.42 (s, 2H), 3.70 (m, 2H), 3.28 (m, 2H), 3.18 (q, J = 10 Hz, 2H), 2.73 - 2.75 (m, 2H), 2.61 (m, 2H); mp 203-205 ° C.

Example 12

1-(3-(4-(2,2,2-trifluoroethyl)piperazine-1-formyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4(1H,3H )-dione

5-((6-Fluoro-2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.45 mmol), EDC (173 mg, 0.90 mmol), HOBt (122 mg, 0.90 mmol) and DIEA (117 mg, 0.90 mmol) were added to the reaction flask, dissolved in about 3 mL of anhydrous DMF, stirred at rt for 15 min, then 1-(2, 2,2-Trifluoroethyl)piperazine hydrochloride (140 mg, 0.68 mmol) in DMF was added to the reaction mixture and stirred at rt overnight. The mixture was poured into 100 mL of water and extracted with 100 m LD The mixture was washed with EtOAc (EtOAc)EtOAc.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ (ppm): 10.55 (s, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.36-7.52 (m, 4H), 7.19 (t, J = 8.8 Hz, 1H), 5.43 (s, 2H), 3.70 (m, 2H), 3.28 (m, 2H), 3.18 (q, J = 10 Hz, 2H), 2.61-2.74 (m, 4H); mp165-166 °C.

Example 13

(3S,5R)-3,5-Dimethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)- 2-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester

a) (3S,5R)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester

2,6-Dimethylpiperazine was dissolved in about 20 mL of anhydrous DCM, and an anhydrous DCM solution of Boc anhydride was added dropwise at 0 ° C. The reaction was continued at 0 ° C for 1 h, washed with water, concentrated, and then purified by silica gel column chromatography. Oil, yield 74.8%.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 3.88-4.01 (m, 2H), 2.76-2.78 (m, 2H), 2.31 (m, 2H), 1.46 (s, 9H), 1.06 (d, J=6.4Hz, 6H).

b) (3S,5R)-3,5-Dimethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl) )-2-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester

5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (100 mg, 0.16 mmol), EDCI (124 mg, 0.64 mmol), HOBt (88 mg, 0.64 mmol) and TEA (66 mg, 0.64 mmol) were added to the reaction flask, dissolved in about 2 mL of anhydrous DMF, stirred at rt for 60 min, then added dropwise (3S, 5R) -3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (104 mg, 0.48 mmol) in DMF solution was added to the reaction mixture and stirred at rt overnight. The reaction solution was poured into 100 mL water and extracted with 100 mL DCM, organic The layers were washed with EtOAc EtOAc EtOAc.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ (ppm): 8.85-8.88 (m, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.58 (t, J = 7.6Hz, 1H), 7.24-7.28 (m, 3H), 7.04-7.10 (m, 2H), 5.33 (s, 2H), 4.78 (m, 1H x 0.6), 3.16-3.95 (m, 5.4H), 1.48 (s, 9H), 1.02- 1.35 (m, 6H); mp87-89 ° C.

Example 14

1-(3-((3S,5R)-3,5-dimethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (50 mg, 0.16 mmol), EDCI (62 mg, 0.32 mmol), HOBt (44 mg, 0.32 mmol) and TEA (33 mg, 0.32 mmol) were added to the reaction flask, dissolved in about 2 ml of anhydrous DMF, stirred at rt for 60 min, then added dropwise (2S,6R)-2,6 A solution of dimethyl piperazine (28 mg, 0.24 mmol) in DMF was added to the reaction mixture, and the mixture was stirred overnight at rt. The mixture was poured into 100 mL of water and extracted with 100 mL of EtOAc. 100 mL) and water (100 mL) were washed with EtOAc EtOAc.

^{_{1 H NMR (300MHz, CDCl 3}} ) δ (ppm): 8.23 (d, J = 6.4Hz, 1H), 7.57-7.63 (m, 1H), 7.24-7.35 (m, 3H), 7.04-7.12 (m, 2H), 5.33 (s, 2H), 4.59-4.64 (m, 1H), 3.27-3.32 (m, 1H), 2.69-2.89 (m, 3H), 2.36-2.44 (m, 1H), 1.14 (d, J=6.0 Hz, 1H), 0.98 (d, J=5.1 Hz, 1H); mp210-212°C.

Example 15

(R)-1-(3-(3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H,3H)-dione

a) (R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylic acid tert-butyl ester

(R)-3-Methyl-N-BOC-piperazine (600 mg, 3.0 mmol) was added to a reaction flask, 20 mL of DCM was added, and triethylamine (0.65 mL, 4.5 mmol) was added to the reaction flask under ice bath. Subsequently, trifluoroacetic anhydride (0.5 mL, 3.6 mmol) was added dropwise, and the reaction was stirred under ice-cooling. After 3 h, the reaction was stopped, 30 mL DCM was added, washed with saturated NaCl solution 20 mL×2, dried over anhydrous magnesium sulfate E: P = 1:8), 800 mg of a colorless oil was obtained, yield 90%.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 4.69 (s, 0.5H), 4.32 (d, J = 13.6 Hz, 0.5H), 3.84 - 4.26 (m, 2H), 3.74 (d, J) =13.6 Hz, 0.5H), 3.42 (dt, J ₁ = 12.0 Hz, J ₂ = 3.6 Hz, 0.5H), 3.08 (t, J = 12.0 Hz, 1.5H), 2.78-3.00 (m, 1.5H) , 1.48 (s, 9H), 1.33 (d, J = 6.8 Hz, 1.5H), 1.25 (d, J = 6.8 Hz, 1.5H);

b) (R)-3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylic acid tert-butyl ester

The compound (R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylic acid tert-butyl ester (750 mg, 2.53 mmol) was added to a reaction flask, and anhydrous THF 10 mL was added. 1M borane THF solution (7.59 mL, 7.59 mmol) was added dropwise, and the mixture was heated to reflux. After 2 h, the heating was stopped. The reaction was stopped the next day, concentrated, and added to 50 mL of DCM, washed with saturated NaHCO ₃ solution, 20 mL × 2 The NaCl solution was washed with 20 mL×2, dried over anhydrous magnesium sulfate, and purified by column chromatography (E:P=1:6) to obtain 500 mg of colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.70 (d, J = 12.8 Hz, 2H), 3.10 - 3.20 (m, 2H), 2.95 - 3.05 (m, 1H), 2.70 - 2.90 (m) , 2H), 2.55-2.70 (m, 2H), 1.46 (s, 9H), 1.60 (d, J = 6.0 Hz, 3H)

c) (R)-2-methyl-1-(2,2,2-trifluoroethyl)piperazine hydrochloride

tert-Butyl (R)-3-methyl-4-(2,2,2-trifluoroethyl)piperazine-l-carboxylate (300 mg, 1.06 mmol) was added to DCM 10 mL, then TFA (0.8 mL, 10.6 mmol) The reaction was stirred at room temperature, and the reaction was quenched after 4 h, then evaporated to dryness

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.92-8.98 (m, 2H), 3.44-3.52 (m, 1H), 3.15-3.26 (m, 3H), 2.92-3.06 (m, 2H), 2.76-2.92 (m, 2H), 2.62-2.70 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H)

d) (R)-1-(3-(3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2 ,4(1H,3H)-dione

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (120 mg, 0.38 mmol) to 10 mL DMF. EDCI (146 mg, 0.76 mmol), HOBt (103 mg, 0.76 mmol), DIEA (0.33 mL, 1.9 mmol) and (R)-N-trifluoroethyl-2-methylpiperazine trifluoroacetate (189 mg, The compound was stirred at room temperature, and the reaction was stopped the next day. Water was added, and water was added, and the mixture was extracted with a mixture of MeOH:DCM=1:10 (30 mL×2), and the organic layer was washed with 20 mL of saturated NaCI (MeOH: DCM = 1 : 50) gave a white solid, 150 mg.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.81 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.25-7.36 ( m, 3H), 7.04-7.10 (m, 2H), 5.33 (s, 2H), 4.23 (brs, 1H), 3.30-3.40 (m, 2H), 2.60-3.21 (m, 6H), 1.15 (d, J = 6.0 Hz, 1.5 H), 0.96 (d, J = 6.0 Hz, 1.5 H); mp 119-121 ° C.

Example 16

(S)-1-(3-(3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H,3H)-dione

a) (S)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylic acid tert-butyl ester

S-1-BOC-3-methylpiperazine (400 mg, 2 mmol) was dissolved in 10 mL of DCM, EtOAc (EtOAc, EtOAc, EtOAc A solution of DCM (5 mL) was slowly warmed to room temperature for 3 h, and the reaction was stopped. The residue was purified by column chromatography (EA: PE = 10:1) to afford 500 mg of colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 4.68 (brs, 0.5H), 4.30-4.34 (m, 0.5H), 3.92-4.18 (m, 3H), 3.72-3.75 (m, 0.5H) ), 3.39-3.46 (m, 0.5H), 2.87-3.08 (m, 2H), 1.48 (s, 9H), 1.33 (d, J = 6.4 Hz, 1.5H), 1.25 (d, J = 6.4 Hz, 1.5H).

b) (S)-3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylic acid tert-butyl ester

(S)-3-Methyl-4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylic acid tert-butyl ester (470 mg, 1.59 mmol) was dissolved in anhydrous 10 mL THF, argon at room temperature Under the protection, 1 M of BH ₃ .THF (5 mL, 5 mmol) was slowly added dropwise. After the dropwise addition was completed, the mixture was heated to 40 ° C for 4 h to stop the reaction. A saturated sodium hydrogencarbonate solution (5 mL) was slowly added to the reaction mixture, stirred for 30 min, and concentrated. , DCM (50 mL) was added, the organic phase was washed with saturated sodium bicarbonate 20 mL×3, brine, 20 mL×2, dried over anhydrous magnesium sulfate. The liquid was 300 mg, and the yield was 66.8%.

1H-NMR (400MHz, CDCl ₃ ) δ (ppm): 3.68-3.73 (m, 2H), 3.12-3.98 (m, 2H), 2.90-2.98 (m, 1H), 2.81-2.88 (m, 1H), 2.55-2.66 (m, 1H), 1.46 (s, 9H), 1.06 (d, J = 6.4 Hz, 3H).

c) (S)-2-methyl-1-(2,2,2-trifluoroethyl)piperazine hydrochloride

(S)-3-Methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylic acid tert-butyl ester (270 mg, 0.956 mmol) was dissolved in DCM (15 mL) 1.5mL, 19.9mmol), reacted at room temperature for 10h, the reaction was stopped, the reaction solution was concentrated, then ethyl acetate (5mL × 2), chloroform (8mL × 2) was added, the solvent and TFA were evaporated under reduced pressure to give a colorless oil. 268mg, yield 100%, directly into the next step.

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 8.86 (brs, 2H), 3.42-3.54 (m, 1H), 3.16-3.26 (m, 3H), 2.94-3.04 (m, 2H) , 2.78-2.87 (m, 2H), 2.64-2.71 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H).

d) (S)-1-(3-(3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2 ,4(1H,3H)-dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.488 mmol) in anhydrous DMF 10 mL, EDCI (187 mg, 0.976 mmol), HOBt (131 mg, 0.976 mmol) and DIEA (315 mg, 2.44 mmol), stirred at room temperature for 30 min, (S)-2-methyl-1-(2,2,2- Trifluoroethyl)piperazine hydrochloride (270 mg, 0.976 mmol) was reacted at room temperature overnight. The reaction mixture was concentrated, EA (50 mL) was added, and the organic phase was protected with sodium bicarbonate solution 20 mL×3, saturated brine 20 mL×2 The organic layer was dried (MgSO4: EtOAc)

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 9.06 (s, 1H), 8.24 (d, J = 7.6Hz, 1H), 7.60 (t, J = 8.0Hz, 1H), 7.25-7.36 ( m, 3H), 7.05-7.10 (m, 2H), 5.33 (s, 2H), 4.23 (s, 1H), 3.32-3.34 (m, 2H), 3.11-3.24 (m, 1H), 2.96-3.07 ( m, 2H), 2.60-2.91 (m, 3H), 1.15 (d, J = 6.0 Hz, 1.5H), 0.97 (d, J = 6.0 Hz, 1.5H).

Example 17

(R)-1-(3-(3-methyl-4-(isobutyryl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

a) (R)-3-methyl-4-(isobutyryl)piperazine-1-carboxylic acid tert-butyl ester

(R)-3-Methyl-N-BOC-piperazine (500 mg, 2.5 mmol) was added to a reaction flask, DCM (20 mL) was added, and triethylamine (0.54 mL, 3. Then, isobutyryl chloride (0.31 mL, 3.0 mmol) was added dropwise, and the reaction was stirred under ice-cooling. After 2h, the reaction was stopped, DCM (30 mL) was added, and the mixture was washed with saturated NaCl solution 20 mL×2, dried over anhydrous magnesium sulfate Chromatography (E: P = 1 : 3) gave 620 mg (yiel.

1H-NMR (400MHz, CDCl3) δ (ppm): 4.80 (brs, 0.5H), 4.36-4.46 (m, 0.5H), 4.05-4.20 (m, 1H), 3.85-4.00 (m, 2H), 3.64 (d, J = 12.8 Hz, 0.5H), 3.23 (t, J = 12.4 Hz, 0.5H), 2.70-3.04 (m, 3.0H), 1.47 (s, 9H), 1.08-1.28 (m, 9H) ;

b) (R)-2-methyl-1-(isobutyryl)piperazine hydrochloride

(R)-3-Methyl-4-(isobutyryl)piperazine-l-carboxylic acid tert-butyl ester (490 mg, 1.81 mmol) was added to DCM (10 mL). The reaction was quenched after 4 h and concentrated to dryness afforded yd.

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.27 (s, 1H), 8.80 (s, 1H), 4.30-4.80 (m, 1.5H), 3.90-4.10 (m, 0.5H) , 3.30-3.40 (m, 0.5H), 3.18-3.28 (m, 2.5H), 3.07 (brs, 1H), 2.73-2.90 (m, 2H), 1.22 (brs, 3H), 1.10 (d, J = 6.4 Hz, 3H)

c) (R)-1-(3-(3-methyl-4-(isobutyryl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (120 mg, 0.38 mmol) to DMF (15 mL) ), EDCI (146 mg, 0.76 mmol), HOBt (103 mg, 0.76 mmol), DIEA (0.33 mL, 1.9 mmol) and (R)-N-isobutyryl-2-methylpiperazine trifluoroacetate (263 mg) , 0.92 mmol), the reaction was stirred at room temperature, the reaction was stopped the next day, water was added, and 30 mL × 2 was extracted with ethyl acetate. The combined organic layer was washed with saturated NaCl solution 15 mL×2, dried over anhydrous magnesium sulfate =1: 60, MeOH: DCM = 1: 40) gave a white solid, 130 mg, yield 73%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.08 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.60 (q, J = 8.0 Hz, 1H), 7.25-.40 (m, 3H), 7.09 (q, J = 7.2 Hz, 2H), 5.27-5.34 (m, 2H), 4.20-5.10 (m, 2H), 3.25-3.80 (m, 3H), 2.60-3.20 (m , 3H), 1.10 - 1.30 (m, 9H); mp 135-137 ° C.

Example 18

(S)-1-(3-(3-methyl-4-(isobutyryl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

a) (S)-3-methyl-4-(isobutyryl)piperazine-1-carboxylic acid tert-butyl ester

The (S) -1-BOC-3- methylpiperazine (300mg, 1.5mmol) was dissolved in DCM (15mL) was added _{Et 3 N (457mg, 4.5mmol)} , was added dropwise under ice-cooling isobutyryl chloride ( 181 mg, 3.45 mmol) of DCM (5 mL), EtOAc (EtOAc)

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 4.80 (brs, 0.5H), 4.40 (brs, 0.5H), 4.12 (brs, 1H), 3.80-4.00 (m, 2H), 3.58-3.69 (m, 0.5H), 3.25-3.40 (m, 0.5H), 2.94-3.07 (m, 1H), 2.75 (brs, 2H), 1.47 (s, 9H), 1.04-1.28 (m, 9H).

b) (S)-2-methyl-1-(isobutyryl)piperazine hydrochloride

(S)-3-Methyl-4-(isobutyryl)piperazine-l-carboxylic acid tert-butyl ester (300 mg, 1.11 mmol) was dissolved in EtOAc (EtOAc) After reacting at room temperature overnight, the reaction mixture was concentrated, then ethyl acetate (6 mL×2), chloroform (6 mL×2), EtOAc (EtOAc) .

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.25 (brs, 1H), 8.78 (brs, 1H), 4.73 (brs, 0.5H), 4.42 (brs, 1H), 3.98 (brs, 0.5H), 3.29-3.45 (m, 1H), 3.18-3.29 (m, 2H), 3.07 (brs, 1H), 2.81-2.99 (m, 3H), 1.14-1.37 (m, 3H), 1.01 (d) , J = 6.4 Hz, 6H).

c) (S)-1-(3-(3-methyl-4-(isobutyryl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.488 mmol) in anhydrous DMF (10 mL), EDCI (187 mg, 0.976 mmol), HOBt (131 mg, 0.976 mmol) and DIEA (315 mg, 2.44 mmol), stirred at room temperature for 30 min, (S)-N-isobutyryl-2-methylpiperazine Trifluoroacetic acid salt (260 mg, 0.976 mmol), reacted for 2 days, the reaction mixture was concentrated, ethyl acetate (50 mL) was added, and the organic phase was protected with sodium bicarbonate solution (15 mL×3) and brine (20 mL×2) The organic layer was dried (MgSO4: EtOAc = EtOAc (EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.97 (brs, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.60 (q, J = 8.0 Hz, 1H), 7.28-7.40 ( m,3H), 7.09 (q, J=8.0Hz, 2H), 5.25-5.40 (m, 2H), 4.28-4.78 (m, 2H), 3.57-3.81 (m, 1H), 3.21-3.55 (m, 2H), 2.85-3.19 (m, 2H), 2.75 (brs, 1H), 1.21-1.35 (m, 3H), 1.15-1.20 (m, 6H).

Example 19

(R)-1-(3-(3-methyl-4-(n-propyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di Ketone

a) (R)-3-methyl-4-(n-propyl)piperazine-1-carboxylic acid tert-butyl ester

(R)-3-Methyl-N-BOC-piperazine (500 mg, 2.5 mmol) was added to a reaction flask, acetonitrile (15 mL) was added, DIEA (0.65 mL, 3.75 mmol) was added, and bromo-n-propane (0.27) was added. The reaction was warmed to 50 ° C. After 30 h, the reaction was quenched and concentrated to dryness eluting with EtOAc (EtOAc: EtOAc)

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 3.78 (d, J = 13.2Hz, 2H), 3.24 (brs, 1H), 2.80-3.00 (m, 2H), 2.69 (brs, 1H), 2.50 (brs, 1H), 2.35 (brs, 2H), 1.50-1.60 (m, 2H), 1.46 (s, 9H), 1.09 (d, J = 4.8 Hz, 3H), 0.91 (t, J = 7.2 Hz) , 3H);

b) (R)-2-methyl-1-(n-propyl)piperazine hydrochloride

Add (R)-2-methyl-4-(isobutyryl)piperazine-1-carboxylic acid tert-butyl ester (490 mg, 1.81 mmol) to DCM (10 mL). The reaction was quenched after 4 h and concentrated to dryness afforded 430 g, m.

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 3.67 (brs, 1H), 3.55 (brs, 3H), 3.10-3.40 (m, 4H), 2.99-3.07 (m, 1H), 1.50 -1.70 (m, 2H), 1.33 (t, J = 6.4 Hz, 3H), 0.91 (t, J = 7.6 Hz, 3H)

c) (R)-1-(3-(3-methyl-4-(n-propyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -Dione, 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (120 mg, 0.38 mmol), DMF (15 mL), EDCI (146 mg, 0.76 mmol), HOBt (103 mg, 0.76 mmol), DIEA (0.33 mL, 1.9 mmol) and (R)-N-n-propyl-2-methylpiperazine trifluoroacetic acid Salting (263 mg, 0.92 mmol), the reaction was stirred at room temperature, the reaction was stopped the next day, water was added, and a mixture of DCM: MeOH = 10:1 (30 mL × 2), and the organic layer was washed with saturated NaCl solution 15 mL×2, anhydrous sulfuric acid Magnesium drying, column chromatography (MeOH: EtOAc:EtOAc:EtOAc:EtOAc

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.99 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.24 - 7.35 ( m, 3H), 7.04-7.11 (m, 2H), 5.33 (s, 2H), 4.24 (brs, 1H), 3.25-3.40 (m, 2H), 2.80-3.00 (m, 0.5H), 2.75-2.79 (m, 0.5H), 2.50-2.70 (m, 2H), 2.34 (brs, 3H), 1.48 (brs, 2H), 1.14 (d, J = 6.4 Hz, 1.5H), 0.86-0.94 (m, 4.5) H); mp 123-125 ° C.

Example 20

(S)-1-(3-(3-methyl-4-(n-propyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

a) (S)-3-methyl-4-(n-propyl)piperazine-1-carboxylic acid tert-butyl ester

(S)-N-BOC-3-methylpiperazine (300 mg, 1.5 mmol) was dissolved in acetonitrile (20 mL), DIEA (400 mg, 3 mmol) and bromo-n-propane (215 mg, 1.73 mmol), 40 ° C The reaction was stopped for 1 day, and the reaction mixture was concentrated to give a white solid. 260 mg (yield: 71.6%).

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 3.70-3.83 (m, 2H), 3.29 (brs, 1H), 2.65-3.02 (m, 3H), 2.35-2.65 (m, 2H), 1.52 -1.62 (m, 2H), 1.46 (s, 9H), 1.13 (m, 3H), 0.92 (t, J = 7.2 Hz, 3H).

b) (S)-2-methyl-1-(n-propyl)piperazine hydrochloride

(S)-3-Methyl-4-(n-propyl)piperazine-l-carboxylic acid tert-butyl ester (260 mg, 1.07 mmol) was dissolved in EtOAc (EtOAc) After reacting at room temperature overnight, the reaction solution was concentrated, and then ethyl acetate (6 mL×2), chloroform (6 mL×2) was added, and the solvent and TFA were evaporated under reduced pressure to give a white oil (yield: .

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.42 (brs, 2H), 3.40-3.60 (m, 4H), 3.26 (brs, 3H), 3.00-3.17 (m, 2H), 1.50 -1.78 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H).

c) (S)-1-(3-(3-Methyl-4-(n-propyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.488 mmol) in anhydrous DMF (10 mL), EDCI (187 mg, 0.976 mmol), HOBT (131 mg, 0.976 mmol) and DIEA (315 mg, 2.44 mmol), stirred at room temperature for 30 min, (S)-2-methyl-1-(n-propyl) The piperazine hydrochloride (230 mg, 0.976 mmol) was reacted for 2 days. The reaction mixture was concentrated, then DCM (50 mL) was added, and the organic phase was washed with a sodium carbonate solution (15 mL×4) and brine (20 mL×2). Drying over anhydrous magnesium sulfate, EtOAc (EtOAc:EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.20 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.25-7.36 ( m, 3H), 7.04-7.10 (m, 2H), 5.33 (s, 2H), 4.24 (s, 1H), 3.31-3.36 (m, 2H), 2.76-3.06 (m, 2H), 2.55-2.71 ( m, 2H), 2.27-2.44 (m, 2H), 1.43-1.48 (m, 2H), 1.14 (d, J = 6.0 Hz, 1.5H), 0.86-0.94 (m, 4.5H).

Example 21

(R)-1-(3-(3-methyl-4-(2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

a) (R)-3-methyl-4-(2-butenyl)piperazine-1-carboxylic acid tert-butyl ester

(R)-3-Methyl-N-BOC-piperazine (400 mg, 2.0 mmol) was added to a reaction flask, acetonitrile (15 mL) was added, DIEA (0.52 mL, 3.0 mmol) was added and 1-bromo-2- Butene (0.25 mL, 2.4 mmol), the mixture was warmed to 50 ° C, the reaction was stopped after 30 h, concentrated to dryness and purified by column chromatography (D:M=60:1, D:M=50:1) 230 mg, yield 45.2%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.69-5.75 (m, 1H), 5.50-5.60 (m, 1H), 3.83 (d, J = 12.8 Hz, 2H), 3.43 (brs, 1H) ), 3.33 (brs, 1H), 3.10-3.20 (m, 2H), 2.91 (d, J = 6.0 Hz, 1.0H), 2.63 (brs, 1H), 2.40 (brs, 1H), 1.72 (d, J) =6.4 Hz, 2.3H), 1.66 (d, J = 6.8 Hz, 0.7H), 1.45 (s, 9H), 1.15 - 1.20 (m, 3H)

b) (R)-2-methyl-1-(2-butenyl)piperazine hydrochloride

(R)-3-Methyl-4-(2-butenyl)piperazine-l-carboxylic acid tert-butyl ester (210 mg, 0.83 mmol). The reaction was stirred at rt. EtOAc was evaporated.

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.51 (brs, 2H), 6.04-6.09 (m, 1H), 5.52-5.60 (m, 1H), 3.85-3.95 (m, 1H) , 3.75-3.80 (m, 1H), 3.50-3.65 (m, 4H), 3.10-3.35 (m, 3H), 1.75 (d, J = 6.8 Hz, 3H), 1.37 (d, J = 6.8 Hz, 3H )

c) (R)-1-(3-(3-methyl-4-(2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H, 3H)-dione

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (120 mg, 0.38 mmol) to DMF (15 mL) ), EDCI (146 mg, 0.76 mmol), HOBt (103 mg, 0.76 mmol), DIEA (0.33 mL, 1.9 mmol) and (R)-N-2-butenyl-2-methylpiperazine trifluoroacetate (263 mg, 0.92 mmol), the reaction was stirred at room temperature, and the reaction was stopped the next day, water was added, and a mixture of DCM: MeOH = 10:1 (30 mL × 2), and the organic layer was washed with saturated NaCl solution 15 mL×2, dried over anhydrous magnesium sulfate Column chromatography (MeOH: DCM = 1: 50 - 1 : 30) gave a white solid (yield:

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 9.05-9.20 (m, 1H), 8.23 (d, J = 7.6Hz, 1H), 7.60 (t, J = 7.6Hz, 1H), 7.24- 7.38 (m, 3H), 7.03-7.11 (m, 2H), 5.60-5.70 (m, 1H), 5.49 (brs, 1H), 5.33 (s, 2H), 4.26 (brs, 1H), 3.25-3.40 ( m, 3H), 2.85-3.10 (m, 3H), 2.75-2.85 (m, 0.5H), 2.54 (brs, 0.5H), 2.30-2.40 (m, 0.5H), 2.21 (brs, 0.5H), 1.70 (t, J = 6.0 Hz, 2H), 1.65 (brs, 1H), 1.53 (t, J = 6.4 Hz, 1.5H), 0.96 (t, J = 6.4 Hz, 1.5H); mp 194-196 ° C.

Example 22

(S)-1-(3-(3-methyl-4-(2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

a) (S)-3-methyl-4-(2-butenyl)piperazine-1-carboxylic acid tert-butyl ester

(S)-N-BOC-3-methylpiperazine (300 mg, 1.5 mmol) was dissolved in acetonitrile (10 mL), DIEA (390 mg, 3 mmol) and 2-butenyl bromide (233 mg, 1.73 mmol). The reaction was stopped at 50 ° C for 2 days, the reaction was stopped, and the reaction mixture was concentrated and purified by column chromatography (DCM: MeOH = 60:1 - 50:1).

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 5.49-5.66 (m, 2H), 3.77-3.80 (m, 2H), 3.35-3.36 (m, 1H), 3.14 - 3.17 (m, 1H) , 2.79-2.92 (m, 3H), 2.43 (brs, 1H), 2.24 (brs, 1H), 1.71 (d, J = 6.4 Hz, 3H), 1.46 (s, 9H), 1.08 (d, J = 5.2) Hz, 3H).

b) (S)-2-methyl-1-(2-butenyl)piperazine hydrochloride

(S)-3-Methyl-4-(2-butenyl)piperazine-l-carboxylic acid tert-butyl ester (250 mg, 0.983 mmol) was dissolved in DCM (15 mL). After the reaction was stopped for 9 h, the reaction was concentrated, and the reaction mixture was concentrated, then toluene (5 mL×2), chloroform (8 mL×2), and the solvent and TFA were evaporated under reduced pressure to give 260 mg of a yellow oil. .

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.53 (brs, 2H), 6.02-6.11 (m, 1H), 5.52-5.59 (m, 1H), 3.74-3.89 (m, 2H) , 3.54-3.57 (m, 4H), 3.14 - 3.35 (m, 3H), 1.73-1.76 (m, 3H), 1.35-1.39 (m, 3H).

c) (S)-1-(3-(3-methyl-4-(2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H, 3H)-dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.488 mmol) in anhydrous DMF (10 mL), EDC (187 mg, 0.976 mmol), HOBT (131 mg, 0.976 mmol), and DIEA (315 mg, 2.44 mmol), stirred at room temperature for 30 min, (S)-2-methyl-1-(2-butene) Base piperazine hydrochloride (245 mg, 0.976 mmol), was reacted at room temperature overnight, the reaction was concentrated, DCM (50 mL) was added, and the organic phase was filtered over sodium bicarbonate (20mL×3), brine (20mL×2) The organic layer was dried (MgSO4: MeOH = 60:1 - 40:1 - -30:1). ^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 8.75 (s, 1H), 8.23 (d, J = 7.6Hz, 1H), 7.60 (t, J = 7.2Hz, 1H), 7.25-7.33 ( m, 3H), 7.03-7.10 (m, 2H), 5.59-5.65 (m, 1H), 5.43-5.52 (m, 1H), 5.32 (s, 2H), 4.26 (brs, 1H), 3.25-3.33 ( m,3H), 2.74-2.91 (m, 3H), 2.52 (s, 1H), 2.18-2.30 (m, 1H), 1.64-1.72 (m, 3H), 1.13-1.16 (m, 1.5H), 0.93 -0.96 (m, 1.5H).

Example 23

(R)-1-(3-(3-methyl-4-(cyclopropylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

a) (R)-3-methyl-4-(cyclopropylmethyl)piperazine-1-carboxylic acid tert-butyl ester

(R)-3-Methyl-N-BOC-piperazine (400 mg, 2.0 mmol) was added to a reaction flask, acetonitrile (15 mL) was added, DIEA (0.52 mL, 3.0 mmol) was added, and bromomethylcyclopropane was added ( 0.23 mL, 2.4 mmol), the reaction was warmed to 50 ° C, and the reaction was stopped after 3 days, concentrated to dryness and purified by column chromatography (DCM:MeOH = 50:1).

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 3.86 (d, J = 12.4Hz, 2H), 3.28 (brs, 1H), 3.08 (d, J = 10.0Hz, 1H), 2.95 (brs, 1H), 2.74 (brs, 1H), 2.61 (brs, 1H), 2.48 (brs, 1H), 2.32 (brs, 1H), 1.47 (s, 9H), 1.12 (d, J = 5.6 Hz, 3H), 0.92 (brs, 1H), 0.56-0.58 (m, 2H), 0.15-0.20 (m, 2H)

b) (R)-2-methyl-1-(cyclopropylmethyl)piperazine hydrochloride

(R)-3-Methyl-4-(cyclopropylmethyl)piperazine-l-carboxylic acid tert-butyl ester (390 mg, 1.53 mmol) was added EtOAc (EtOAc) The reaction was stirred and the reaction was quenched after 4 h then concentrated to dryness

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ PPm: 9.56 (brs, 2H), 3.86 (brs, 1H), 3.50 - 3.65 (m, 3H), 3.30 - 3.45 (m, 2.5H), 3.25 - 3.45 (m, 2.5H), 1.32 (d, J = 6.4 Hz, 3H), 1.10 - 1.11 (m, 1H), 0.61 - 0.65 (m, 2H), 0.40 (s, 2H)

c) (R)-1-(3-(3-methyl-4-(cyclopropylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.48 mmol) to DMF (15 mL) ), EDCI (184 mg, 0.96 mmol), HOBt (130 mg, 0.96 mmol), DIEA (0.42 mL, 2.4 mmol) and (R)-N-2-cyclopropylmethyl-2-methylpiperazine trifluoroacetic acid Salt (257 mg, 0.96 mmol), the reaction was stirred at room temperature, and the reaction was stopped the next day, water was added, and a mixture of DCM: MeOH = 10:1, 30 mL × 2, and the organic layer was washed with saturated NaCl solution 15 mL×2, anhydrous magnesium sulfate Drying, column chromatography (MeOH: DCM = 1: 60--1:35) gave 165 mg of white solid.

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 8.97 (s, 1H), 8.23 (d, J = 7.6Hz, 1H), 7.60 (t, J = 8.0Hz, 1H), 7.35 (t, J=6.8 Hz, 1H), 7.24-7.29 (m, 2H), 7.04-7.11 (m, 2H), 5.33 (s, 2H), 4.20-4.40 (m, 1H), 3.25-3.45 (m, 2H) , 3.13 (d, J = 10.0 Hz, 0.5H), 2.98 (brs, 1.5H), 2.55-2.70 (m, 1.5H), 2.30-2.50 (m, 1.5H), 2.23 (brs, 1H), 1.14 (d, J = 5.2 Hz, 1.5H), 0.94 (d, J = 5.2 Hz, 1.5H), 0.83-0.90 (m, 1H), 0.48-0.60 (m, 2H), 0.12 (brs, 2H); Mp 144-146 ° C.

Example 24

(S)-1-(3-(3-methyl-4-(cyclopropylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

a) (S)-3-methyl-4-(cyclopropylmethyl)piperazine-1-carboxylic acid tert-butyl ester

(S)-1-BOC-3-methylpiperazine (300 mg, 1.5 mmol) was dissolved in EtOAc (10 mL), EtOAc (EtOAc) The reaction was stopped at 40 ° C for 2 days, the reaction was stopped, and the reaction mixture was concentrated and purified by column chromatography (DCM:MeOH = 40:1)

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 3.84 (d, J = 13.2Hz, 2H), 3.18-3.25 (m, 1H), 3.04 (d, J = 11.9Hz, 1H), 2.86 ( Brs, 1H), 2.67-2.73 (m, 1H), 2.51 (brs, 1H), 2.40 (brs, 1H), 2.19-2.26 (m, 1H), 1.46 (s, 9H), 1.08 (d, J = 6.4 Hz, 3H), 0.82-0.91 (m, 1H), 0.53-0.59 (m, 2H), 0.12-0.19 (m, 2H).

b) (S)-2-methyl-1-(cyclopropylmethyl)piperazine hydrochloride

(S)-3-Methyl-4-(cyclopropylmethyl)piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.118 mmol) was dissolved in DCM (15 mL). 9h, the reaction was stopped, the reaction solution was concentrated, and then ethyl acetate (5 mL × 2), chloroform (8 mL × 2) was added, and the solvent and TFA were evaporated under reduced pressure to give 290 mg ofyel. step.

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.55 (brs, 2H), 3.88 (brs, 1H), 3.59 (brs, 3H), 3.35 (brs, 2H), 3.11-3.21 (m , 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.03-1.08 (m, 1H), 0.62-0.71 (m, 2H), 0.37-0.45 (m, 2H).

c) (S)-1-(3-(3-methyl-4-(cyclopropylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.488 mmol) in anhydrous DMF (10 mL), EDCI (187 mg, 0.976 mmol), HOBt (131 mg, 0.976 mmol) and DIEA (315 mg, 2.44 mmol), and stirred at room temperature for 30 min, (S)-2-methyl-1-(cyclopropylmethyl) Piperazine hydrochloride (245 mg, 0.976 mmol), reacted at room temperature overnight, the reaction was concentrated, EA (50 mL) The organic phase was washed with a sodium bicarbonate solution (20 mL×3), brine (20 mL×2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (DCM: MeOH=60:1 -40:1 - 30:1 - 25:1) A yellow oil was obtained (140 mg).

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 9.04 (brs, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.60 (t, J = 7.6Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.25-7.31 (m, 2H), 7.06-7.14 (m, 2H), 5.33 (brs, 2H), 4.22-4.39 (m, 1H), 3.26-3.41 (m, 2H) , 3.08-3.15 (m, 0.5H), 2.93-3.02 (m, 1.5H), 2.53-2.70 (m, 2H), 2.42-2.52 (m, 0.5H), 2.34 (brs, 0.5H), 2.18- 2.23 (m, 1H), 1.63 (brs, 0.5H), 1.13 (d, J = 6.0 Hz, 1.5H), 0.93 (d, J = 6.0 Hz, 1.5H), 0.81 - 0.87 (m, 1H), 0.50-0.55 (m, 2H), 0.10-0.18 (m, 2H).

Example 25

(R)-1-(3-(3-methyl-4-(isobutyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

a) (R)-3-methyl-4-(isobutyl)piperazine-1-carboxylic acid tert-butyl ester

(R)-3-Methyl-N-BOC-piperazine (500 mg, 2.5 mmol) was added to a reaction flask, acetonitrile (15 mL) was added, DIEA (0.65 mL, 3.75 mmol) was added, and bromoisobutane was added. 0.32 mL, 3 mmol), the reaction was warmed to 50 ° C, and the reaction was stopped after 30 h, concentrated to dryness and then purified by column chromatography (D: M = 50:1)

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.64 (d, J = 12.8 Hz, 2H), 3.15-3.22 (m, 1H), 2.85 (brs, 1H), 2.70-2.76 (m, 1H) ), 2.30-2.40 (m, 2H), 2.05-2.15 (m, 1H), 1.85-1.95 (m, 1H), 1.65-1.75 (m, 1H), 1.46 (s, 9H), 0.98 (d, J) = 6.4 Hz, 3H), 0.88 (t, J = 4.4 Hz, 6H) b) (R)-2-methyl-1-(isobutyl)piperazine hydrochloride

Add (R)-3-methyl-4-(isobutyl)piperazine-l-carboxylic acid tert-butyl ester (150 mg, 585 mmol) to DCM (5 mL). The reaction was quenched after 4 h and concentrated to dryness afforded 158 g, m.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ (PPm): 9.48 (s, 2H), 3.42-3.85 (m, 3.5H), 3.30-3.43 (m, 1.5H), 3.16 (brs, 3H) , 2.85-2.95 (m, 1H), 2.03 (brs, 1H), 1.33 (d, J = 6.4 Hz, 3H), 0.96 (t, J = 5.6 Hz, 6H),

c) (R)-1-(3-(3-methyl-4-(isobutyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (120 mg, 0.38 mmol), Add DMF (15 mL), EDCI (146 mg, 0.76 mmol), HOBt (103 mg, 0.76 mmol), DIEA (0.33 mL, 1.9 mmol) and (R)-N-2-isobutyl-2-methylpiperazine The fluoroacetic acid salt (154 mg, 0.57 mmol) was stirred at room temperature, and the reaction was stopped the next day, water was added, and a mixture of DCM: MeOH = 10:1 (30 mL × 2), and the organic layer was washed with saturated NaCl solution 15 mL×2 Dry over magnesium sulfate, column chromatography (MeOH: DCM = 1: 60--1: 40).

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 8.82 (s, 1H), 8.23 (d, J = 7.6Hz, 1H), 7.60 (t, J = 7.60Hz, 1H), 7.33 (t, J=6.4 Hz, 1H), 7.24-7.30 (m, 2H), 7.03-7.11 (m, 2H), 5.33 (s, 2H), 4.10 (d, J = 12.0 Hz, 1H), 3.39 (brs, 0.5) H), 3.20-3.35 (m, 2H), 3.11 (brs, 0.5H), 2.69-2.90 (m, 1H), 2.72 (d, J = 12.0 Hz, 0.5H), 2.48 (brs, 0.5H), 2.31-2.40 (m, 1H), 2.23 (brs, 0.5H), 2.11 (brs, 0.5H), 1.94 (d, J = 8.4 Hz, 1H), 1.65-1.75 (m, 1H), 1.07 (d, J = 6.0 Hz, 1.5 H), 0.87 - 0.89 (m, 7.5H); mp 121-123 ° C.

Example 26

(S)-1-(3-(3-methyl-4-(isobutyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

a) (S)-3-methyl-4-(isobutyl)piperazine-1-carboxylic acid tert-butyl ester

(S)-1-BOC-3-methylpiperazine (300 mg, 1.5 mmol) was dissolved in acetonitrile (10 mL), DIEA (390 mg, 3 mmol) and bromoisobutane (270 mg, 1.95 mmol), 55 After reacting for 2 days at ° C, the reaction was quenched, and the reaction mixture was concentrated and purified by column chromatography (DCM: MeOH = 40:1).

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 3.63 (dt, J 1 = 12.8Hz, 3.6Hz, 2H), 3.14 (t, J = 9.6Hz, 1H), 2.84 (brs, 1H), 2.73 (dt, J ₁ = 12.0 Hz, 4.0 Hz, 1H), 2.28-2.38 (m, 2H), 2.09 (t, J = 9.2 Hz, 1H), 1.90 (dd, J ₁ = 12.4 Hz, J ₂ = 5.6 Hz, 1H), 1.68-1.75 (m, 1H), 1.45 (s, 9H), 0.97 (d, J = 6.0 Hz, 3H), 0.88 (t, J = 4.4 Hz, 6H).

b) (S)-2-methyl-1-(isobutyl)piperazine hydrochloride

(S)-3-Methyl-4-(isobutyl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.781 mmol) was dissolved in DCM (15 mL). h, the reaction was stopped, and the reaction liquid was concentrated, and then toluene (5 mL × 2), chloroform (8 mL × 2) was added, and the solvent and the TFA were evaporated under reduced pressure to give 188 mg of a yellow oil.

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.37 (brs, 2H), 3.00-3.70 (m, 7H), 2.87 (brs, 2H), 2.02 (brs, 1H), 1.33 (s , 3H), 0.96 (t, J = 5.2 Hz, 6H).

c) (S)-1-(3-(3-Methyl-4-(isobutyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.488 mmol) in anhydrous DMF (10 mL), HATU (372 mg, 0.976 mmol), HOBt (131 mg, 0.976 mmol) and DIEA (252 mg, 1.95 mmol), stirred at room temperature for 30 min, (S)-2-methyl-1-(isobutyl) The piperazine hydrochloride (140 mg, 0.59 mmol) was reacted at room temperature overnight. The reaction mixture was concentrated, DCM (50 mL) was added, and the organic phase was washed with sodium bicarbonate (20 mL×3) and brine (20 mL×2) The residue was dried over EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 8.74 (brs, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.60 (t, J = 7.6Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.25-7.31 (m, 2H), 7.03-7.11 (m, 2H), 5.33 (s, 2H), 4.08-4.11 (m, 1H), 3.05-3.45 (m, 2.5H) ), 2.84-2.94 (m, 1H), 2.70-2.73 (m, 0.5H), 2.49 (brs, 0.5H), 2.31-2.40 (m, 1H), 2.23 (brs, 0.5H), 2.11 (brs, 0.5H), 1.92-1.95 (m, 1H), 1.69-1.75 (m, 1H), 1.61 (s, 0.5H). 1.07 (d, J = 6.0 Hz, 1.5H), 0.87-0.97 (m, 7.5) H).

Example 27

(R)-1-(3-(3-methyl-4-(3-methyl-2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H,3H)-dione

a) (R)-3-methyl-4-(3-methyl-2-butenyl)piperazine-1-carboxylic acid tert-butyl ester

(R)-3-Methyl-N-BOC-piperazine (400 mg, 2.0 mmol) was added in EtOAc (15 mL), DIEA (0.52 mL, 3.0 mmol) -butene (0.28 mL, 2.4 mmol), the mixture was warmed to 50 ° C, and the reaction was stopped after 20 h, then concentrated to dryness and purified by column chromatography (D:M=60:1 - 40:1) The yield was 59.7%.

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 5.31 (d, J = 6.4Hz, 1H), 3.87 (d, J = 12.4Hz, 2H), 3.44-3.52 (m, 1H), 3.30- 3.42 (m, 1H), 3.18 (brs, 1H), 3.08 (brs, 1H), 2.96 (d, J = 11.2 Hz, 1H), 2.69 (brs, 1H), 2.42 (brs, 1H), 1.78 (s) , 3H), 1.69 (s, 3H), 1.46 (s, 9H), 1.22 (d, J = 5.6 Hz, 3H)

b) (R)-2-methyl-1-(3-methyl-2-butenyl)piperazine hydrochloride

Add (R)-3-methyl-4-(3-methyl-2-butenyl)piperazine-1-carboxylic acid tert-butyl ester (280 mg, 1.04 mmol) to DCM (10 mL), TFA (0.78 mL, 10.4 mmol) was added, and the mixture was stirred at room temperature. After 4 h, the reaction was evaporated and evaporated to dryness

^{1 H-NMR (400MHz, DMSO} -d 6) δ (PPm): 9.55 (brs, 2H), 5.25 (t, J = 7.6Hz, 1H), 3.93 (brs, 1H), 3.74-3.79 (m, 1H ), 3.50-3.75 (m, 4H), 3.05-3.25 (m, 3H), 1.78 (s, 3H), 1.72 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H),

c) (R)-1-(3-(3-methyl-4-(2-methyl-2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2 ,4(1H,3H)-dione

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.48 mmol) to DMF (15 mL) ), EDCI (184 mg, 0.96 mmol), HOBt (130 mg, 0.96 mmol), DIEA (0.42 mL, 2.4 mmol) and (R)-N-3-methyl-2-butenyl-3-methylpiperazine Trifluoroacetic acid salt (257 mg, 0.96 mmol), the reaction was stirred at room temperature, the reaction was stopped the next day, water was added, and a mixture of DCM: MeOH = 10:1, 30 mL × 2, and the organic layer was washed with a saturated NaCl solution (15 mL×2). Drying over anhydrous magnesium sulfate, column chromatography (MeOH: EtOAc: EtOAc:EtOAc:

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 9.03 (s, 1H), 8.23 (d, J = 7.6Hz, 1H), 7.60 (t, J = 8.0Hz, 1H), 7.34 (t, J=6.0 Hz, 1H), 7.24-7.28 (m, 2H), 7.03-7.11 (m, 2H), 5.33 (s, 2H), 5.20-5.28 (m, 1H), 4.20-4.40 (m, 1H) , 3.20-3.40 (m, 3H), 2.90-3.00 (m, 2H), 2.78 (d, J = 11.6 Hz, 1H), 2.53 (brs, 0.5H), 2.13 - 2.45 (m, 1.5H), 1.74 (d, J = 7.6 Hz, 3H), 1.65 (d, J = 2.4 Hz, 3H), 1.15 (d, J = 6.0 Hz, 1.5H), 0.96 (d, J = 6.0 Hz, 1.5H); mp158 -160 ° C.

Example 28

(S)-1-(3-(3-methyl-4-(3-methyl-2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H,3H)-dione

a) (S)-3-methyl-4-(3-methyl-2-butenyl)piperazine-1-carboxylic acid tert-butyl ester

(S)-1-BOC-3-methylpiperazine (300 mg, 1.5 mmol) was dissolved in acetonitrile (10 mL), DIEA (390 mg, 3 mmol) and 3,3-dimethylallyl bromide (258 mg) The reaction was quenched at 50 ° C for 2 days, and the reaction mixture was concentrated and purified by column chromatography (DCM: MeOH=60:1 - 50:1)

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.25 (t, J = 7.6 Hz, 1H), 3.80 (d, J = 12.8 Hz, 2H), 3.37 (dd, J = 13.2 Hz, 5.6 Hz , 1H), 3.17 (t, J = 11.2 Hz, 1H), 2.95-3.00 (m, 1H), 2.82 - 2.88 (m, 2H), 2.46 (brs, 1H), 2.22 - 2.26 (m, 1H), 1.75 (s, 3H), 1.66 (s, 3H), 1.46 (s, 9H), 1.11 (d, J = 6.4 Hz, 3H).

b) (S)-2-methyl-1-(3-methyl-2-butenyl)piperazine hydrochloride

(S)-3-Methyl-4-(3-methyl-2-butenyl)piperazine-1-carboxylic acid tert-butyl ester (280 mg, 0.983 mmol) was dissolved in DCM (15 mL). 1.0 mL), reacted at room temperature for 9 h, the reaction was stopped, the reaction solution was concentrated, then toluene (5 mL×2), chloroform (8 mL×2), and the solvent and TFA were evaporated under reduced pressure to yield 290 mg of a yellow oil. %, go directly to the next step.

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.50 (brs, 2H), 5.26 (t, J = 7.6Hz, 1H), 3.94 (s, 1H), 3.76-3.81 (m, 1H ), 3.50-3.65 (m, 4H), 3.09-3.32 (m, 3H), 1.79 (s, 3H), 1.73 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H).

c) (S)-1-(3-(3-methyl-4-(2-methyl-2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2 ,4(1H,3H)-dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.488 mmol) in anhydrous DMF (10 mL), EDCI (187 mg, 0.976 mmol), HOBt (131 mg, 0.976 mmol), and DIEA (315 mg, 2.44 mmol), stirred at room temperature for 30 min, (S)-2-methyl-1-(3-methyl) 2-butenyl)piperazine hydrochloride (260 mg, 0.976 mmol), mp mp mp EtOAc (EtOAc: EtOAc (EtOAc) Washed with water (20 mL × 2), dried over anhydrous magnesium sulfate, EtOAcjjjjjjjjjj

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 8.88-8.94 (m, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.60 (t, J = 7.2Hz, 1H), 7.26- 7.34 (m, 3H), 7.03-7.10 (m, 2H), 5.32 (s, 2H), 5.22 (s, 1H), 4.29 (brs, 1H), 3.24 - 3.39 (m, 3H), 2.78-2.94 ( m, 3H), 2.54 (s, 1H), 2.19-2.30 (m, 1H), 1.74 (d, J = 7.6 Hz, 3H), 1.65 (d, J = 3.2 Hz, 3H), 0.97-1.16 (m , 3H).

Example 29

(R)-1-(3-(3-ethyl-4-methylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-2-Ethyl-1-(methyl)piperazine hydrochloride

(R)-1-Boc-3-ethylpiperazine (1.0 g, 4.7 mmol), 37% aqueous formaldehyde (0.45 g, 5.6 mmol) and methanol (10 mL) were added to a three-necked flask, stirred at room temperature for 1 h, and then controlled Sodium borohydride (0.53 g, 14.1 mmol) was added portionwise at </RTI> <RTIgt; The reaction mixture was diluted with water (10 mL), and the mixture was evaporated. After concentration under reduced pressure, a solution of hydrogen chloride (10 mL) was added to the residue, and the mixture was stirred at room temperature overnight.

b) (R)-1-(3-(3-ethyl-4-methyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

5-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (1.23 g, 3.9 mmol) (R)- 2-Ethyl-1-(methyl)piperazine hydrochloride (4.7 mmol), HBTU (1.78 g, 4.7 mmol), DMF (10 mL) was added to a three-neck flask, and DIEA (2.03 g, 15.7 mmol) was added dropwise. After completion of the dropwise addition, stirring at room temperature for 2 h, dichloromethane (150 mL) was added to the system, then washed with water (75 mL), 5% aqueous citric acid (30 mL), 5% sodium carbonate (30 mL), and organic The organic layer was dried (MgSO4), evaporated

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 8.96 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.24 - 7.35 (m, 3H) ), 7.04-7.10 (m, 2H), 5.33 (s, 2H), 4.45 (d, J = 12.4 Hz, 1H), 3.34 (brs, 1.5H), 3.15-3.20 (m, 0.5H), 2.87- 2.96 (m, 1.5H), 2.73 (d, J = 10.4 Hz, 0.5H), 2.32 (s, 3H), 1.90-2.28 (m, 1H), 1.34-1.73 (m, 3H), 0.99 (t, J = 7.6 Hz, 2H), 0.71 (t, J = 7.2 Hz, 1H); HRMS (ESI): m/z, calcd. for C ₂₃ H ₂₆ O ₃ N ₄ F [M+H] ⁺ : 425.1984, Found:425.1975

Example 30

(R)-1-(3-(3-ethyl-4-isopropylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-2-ethyl-1-(isopropyl)piperazine hydrochloride

(R)-1-Boc-3-ethylpiperazine (1.0 g, 4.7 mmol) was placed in a reaction flask, tetrahydrofuran (10.0 mL), and acetone (0.55 g, 9.4 mmol) were added, and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (2.50 g, 11.8 mmol) was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was evaporated to dryness. 10 mL of a solution of hydrogen chloride in ethanol, stirred at room temperature overnight, concentrated to dryness under reduced pressure, and taken directly to the next.

b) (R)-1-(3-(3-ethyl-4-isopropyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

5-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (1.23 g, 3.9 mmol) (R)- 2-Ethyl-1-(isopropyl)piperazine hydrochloride (4.7 mmol), HBTU (1.78 g, 4.7 mmol), DMF (10 mL) was added to a three-neck flask, and DIEA (2.03 g, 15.7 mmol) was added dropwise. After completion of the dropwise addition, stirring at room temperature for 2 h, dichloromethane (150 mL) was added to the system, followed by washing with water (75 mL), 5% aqueous citric acid (30 mL), 5% sodium carbonate (30 mL), and organic phase. The residue was dried over EtOAc (EtOAc)EtOAc.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 11.74 (s, 1H), 9.05-9.20 (m, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.60-7.70 (m, 1H) , 7.48-7.58 (m, 1H), 7.14-7.42 (m, 4H), 5.20-5.50 (m, 2H), 4.30-4.60 (m, 1H), 3.87 (brs, 0.5H), 2.90-3.60 (m , 6H), 2.68 (brs, 0.5H), 1.54-1.94 (m, 2H), 0.90-1.40 (m, 8H), 0.59 (brs, 1H); HRMS (ESI): m/z, calcd. for C ₂₅ H ₃₀ O ₃ N ₄ F[M+H] ⁺ :453.2297,found:453.2291

Example 31

(R)-1-(3-(3-ethyl-4-cyclopropanylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-2-Ethyl-1-(cyclopropanoyl)piperazine hydrochloride

(R)-1-Boc-3-ethylpiperazine (1.0 g, 4.7 mmol), cyclopropylcarbonyl chloride (0.73 g, 7.0 mmol), triethylamine (1.43 g, 14.1 mmol), 25 mL of dichloro Methane was added to the reaction flask, and reacted at room temperature for 4 hours. After the reaction was completed, the mixture was washed with water (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. 10 mL of hydrogen chloride solution was added to the system and stirred at room temperature overnight. Concentrate to dryness and directly into the next step.

b) (R)-1-(3-(3-ethyl-4-cyclopropanoyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

5-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (1.23 g, 3.9 mmol) (R)- 2-Ethyl-1-(isopropyl)piperazine hydrochloride (4.7 mmol), HBTU (1.78 g, 4.7 mmol), DMF (10 mL) was added to a three-neck flask, and DIEA (2.03 g, 15.7 mmol) was added dropwise. After completion of the dropwise addition, stirring at room temperature for 2 h, dichloromethane (150 mL) was added to the system, and then washed with water (75 mL) and 5% aqueous citric acid (30 mL). After washing with 5% sodium carbonate (30 mL), EtOAcjjjjjjjjjj .

¹ H-NMR (400MHz, CDCl ₃ ) δ ppm: 9.22 (brs, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.58-7.62 (m, 1H), 7.24-7.37 (m, 3H), 7.08 -7.10(m,2H), 5.27-5.34(m,2H), 4.27-4.71(m,3H),2.81-3.41(m,4H),1.30-1.90(m,3H),1.01(brs,3H) , 0.55-0.85 (m, 4H); HRMS (ESI): m/z, calcd. for C ₂₆ H ₂₈ O ₄ N ₄ F [M+H ⁺ ]: 479.2089, found: 479.2080

Example 32

(R)-1-(3-(3-ethyl-4-acetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-2-Ethyl-1-(acetyl)piperazine hydrochloride

(R)-1-Boc-3-ethylpiperazine (1.0 g, 4.7 mmol), acetyl chloride (0.55 g, 7.0 mmol), triethylamine (1.43 g, 14.1 mmol), 25 mL dichloromethane The mixture was reacted for 4 h at room temperature. After the reaction was completed, the mixture was washed with water (10 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Dry and go directly to the next step.

b) (R)-1-(3-(3-ethyl-4-acetyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

5-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (1.23 g, 3.9 mmol) (R)- 2-Ethyl-1-(acetyl)piperazine hydrochloride (4.7 mmol), HBTU (1.78 g, 4.7 mmol), DMF (10 mL) was added to a three-neck flask, and DIEA (2.03 g, 15.7 mmol) was added dropwise. After completion of the dropwise addition, stirring at room temperature for 2 h, dichloromethane (150 mL) was added to the system, then washed with water (75 mL), 5% aqueous citric acid (30 mL), 5% sodium carbonate (30 mL), and organic The organic layer was dried (MgSO4), filtered, evaporated

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 8.92-8.96 (m, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.58-7.62 (m, 1H), 7.26-7.35 (m, 3H) , 7.08-7.12 (m, 2H), 5.25-5.40 (m, 2H), 4.55-4.80 (m, 1H), 2.70-3.85 (m, 6H), 2.06-2.16 (m, 3H), 1.58-1.80 ( m, 1.5H), 1.40-1.55 (m, 0.5H), 0.90-1.05 (m, 2H), 0.60-0.70 (m, 1H); HRMS (ESI): m/z, calcd. for C ₂₄ H ₂₆ O ₄ N ₄ F[M+H ⁺ ]: 453.1933, found: 453.1925

Example 33

(R)-1-(3-(3-ethyl-4-trifluoroacetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-2-Ethyl-1-(trifluoroacetyl)piperazine hydrochloride

(R)-1-Boc-3-ethylpiperazine (1.0 g, 4.7 mmol), trifluoroacetic anhydride (1.47 g, 7.0 mmol), triethylamine (1.43 g, 14.1 mmol), 25 mL dichloromethane Adding to the reaction flask, reacting at room temperature for 4 h, after completion of the reaction, washing with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Concentrate to dryness and directly into the next step.

b) (R)-1-(3-(3-ethyl-4-trifluoroacetyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

5-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (1.23 g, 3.9 mmol) (R)- 2-Ethyl-1-(trifluoroacetyl)piperazine hydrochloride (4.7 mmol), HBTU (1.78 g, 4.7 mmol), DMF (10 mL) was added to a three-neck flask, and DIEA (2.03 g, 15.7 mmol) was added dropwise. After the dropwise addition, stirring at room temperature for 2 h, dichloromethane (150 mL) was added to the system, followed by washing with water (75 mL), 5% aqueous citric acid (30 mL), 5% sodium carbonate (30 mL), and organic phase. The residue was dried over anhydrous sodium sulfate (MgSO4)

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 9.11 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.59 to 7.63 (m, 1H), 7.26-7.38 (m, 3H), 7.05 -7.14 (m, 2H), 5.27-5.41 (m, 2H), 4.67-4.80 (m, 1.5H), 4.33-4.41 (m, 0.5H), 3.72-4.01 (m, 1H), 3.41-3.56 ( m, 2H), 2.94-3.18 (m, 2H), 1.60-1.80 (m, 2H), 0.83-1.01 (m, 3H); HRMS (ESI): m/z, calcd. for C ₂₄ H ₂₃ O ₄ N ₄ F ₄ [M+H ⁺ ]: 507.1650, found: 507.1643

Example 3

(R)-1-(3-(3-ethyl-4-n-propylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-2-ethyl-1-(n-propyl)piperazine hydrochloride

(R)-1-Boc-3-ethylpiperazine (1.0 g, 4.7 mmol) was added to a reaction flask, tetrahydrofuran (10.0 mL), and propionaldehyde (0.55 g, 9.4 mmol) were stirred at room temperature for 1 h. Add sodium triacetoxyborohydride (2.50 g, 11.8 mmol), and stir at room temperature for 1 h. After the reaction was completed, the reaction mixture was evaporated to dryness. Dry and go directly to the next step.

b) (R)-1-(3-(3-ethyl-4-n-propyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

5-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (1.23 g, 3.9 mmol) (R)- 2-Ethyl-1-(n-propyl)piperazine hydrochloride (4.7 mmol), HBTU (1.78 g, 4.7 mmol), DMF (10 mL) was added to a three-neck flask, and DIEA (2.03 g, 15.7 mmol) was added dropwise. After completion of the dropwise addition, stirring at room temperature for 2 h, dichloromethane (150 mL) was added to the system, followed by washing with water (75 mL), 5% aqueous citric acid (30 mL), 5% sodium carbonate (30 mL), and organic phase. The residue was dried over EtOAc (EtOAc m.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 8.23 (d, J = 8.0 Hz, 1H), 7.58-7.64 (m, 1H), 7.23-7.35 (m, 3H), 7.03-7.10 (m, 2H) , 5.33 (s, 2H), 4.05 (brs, 1H), 3.50 (brs, 0.5H), 3.20-3.45 (m, 2H), 3.00-3.20 (m, 1H), 2.88 (d, J = 10.8 Hz, 0.5H), 2.75 (d, J = 11.6 Hz, 0.5H), 2.55-2.70 (m, 1H), 2.22 - 2.45 (m, 2.5H), 1.60-1.70 (m, 1H), 1.40-1.56 (m , 3H), 1.24-1.39 (m, 1H), 0.98 (t, J = 7.2 Hz, 1.5H), 0.89 (t, J = 7.2 Hz, 2.5H), 0.63 (t, J = 7.2 Hz, 1H) ;HRMS(ESI): m/z,calcd.for C ₂₅ H ₃₀ O ₃ N ₄ F[M+H ⁺ ]:453.2297,found:453.2294

Example 35

(R)-1-(3-(3-ethyl-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-3,4-diethylpiperazine-1-carboxylic acid tert-butyl ester

(R)-N-Boc-3-ethyl-piperazine (1 g, 4.67 mmol), EtOAc (20 mL), EtOAc (EtOAc (EtOAc) The reaction was warmed to 50 ° C. After 30 h, the reaction was quenched and concentrated to dryness. EtOAc (EtOAc:EtOAc:EtOAc Mg, yield 66.3%.

b) (R)-1-ethyl-2-ethylpiperazine trifluoroacetate

(R)-3,4-Diethylpiperazine-1-carboxylic acid tert-butyl ester (710 mg, 2.93 mmol) was added to DCM (15 mL). The reaction was concentrated to dryness to give EtOAc (EtOAc):

c) (R)-1-(3-(3-ethyl-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (628 mg, 2 mmol) to DMF (30 mL) , EDC (786 mg, 4 mmol), HOBt (540 mg, 4 mmol), DIEA (1.74 mL, 10 mmol), and (R)-1-ethyl-2-ethylpiperazine trifluoroacetate (742 mg, 2.9 mmol), The reaction was stirred at room temperature, and then the mixture was evaporated to dryness. EtOAc (EtOAc m. Column chromatography (DCM: MeOH = 60:1, EtOAc: MeOH = 40:1)

¹ H-NMR (400MHz, CDCl ₃ ) δ ppm: 8.66 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.58-7.66 (m, 1H), 7.23 - 7.35 (m, 3H), 7.04 -7.10 (m, 2H), 5.33 (s, 2H), 4.18 (brs, 1H), 3.47 (brs, 2.5H), 3.05-3.15 (m, 0.5H), 2.91 (brs, 2H), 2.67 (brs) , 3H), 1.71 (brs, 1H), 1.61 (brs, 1H), 1.04 (brs, 3H), 1.04 (brs, 2H), 0.68 (brs, 1H); HRMS (ESI): m/z, calcd. For C ₂₄ H ₂₈ O ₃ N ₄ F[M+H] ⁺ : 439.2140, found: 439.2138.

Example 36

(R)-1-(3-(3-ethyl-4-cyclopropylmethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-4-cyclopropylmethyl-3-ethylpiperazine-1-carboxylic acid tert-butyl ester

(R)-N-Boc-3-ethylpiperazine (1 g, 4.67 mmol), acetonitrile (20 mL) was added, DIEA (1.63 mL, 9.34 mmol) was added, and bromomethylcyclopropane (0.68 mL, 7 mmol) was added. The reaction was warmed to 50 ° C. The reaction was quenched after 24 h, EtOAc (EtOAc)

b) (R)-1-(cyclopropylmethyl)-2-ethylpiperazine trifluoroacetate

Add (R)-4-cyclopropylmethyl-3-ethylpiperazine-1-carboxylic acid tert-butyl ester (640 mg, 2.38 mmol) to DCM (15) The reaction was stirred at rt. EtOAc (3 mL).

c) (R)-1-(3-(3-ethyl-4-cyclopropylmethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (628 mg, 2 mmol) to DMF (30 mL) , EDC (786 mg, 4 mmol), HOBt (540 mg, 4 mmol), DIEA (1.74 mL, 10 mmol) and (R)-1-cyclopropylmethyl-2-ethylpiperazine trifluoroacetate (621 mg, 2.2 (mmol), the reaction was stirred at room temperature, the reaction was stopped the next day, water was added, and the mixture was extracted with DCM: MeOH = 10:1 (50 mL × 2). The organic layer was combined and washed with saturated NaCI solution (30 mL×2). Magnesium drying, column chromatography (DCM: MeOH = 60:1)ield

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 9.29 (brs, 1H), 8.23 (d, J = 7.6Hz, 1H), 7.60-7.61 (m, 1H), 7.35 (s, 1H), 7.24-7.28 (m, 2H), 7.03-7.10 (m, 2H), 5.33 (s, 2H), 4.13 (s, 1H), 3.44-3.49 (m, 0.5H), 3.26-3.38 (m, 2H) , 3.06-3.08 (m, 1H), 2.93-2.96 (m, 0.5H), 2.58-2.64 (m, 1H), 2.10-2.53 (m, 1H), 2.38-2.45 (m, 1H), 2.24-2.31 (m, 1H), 1.64-1.67 (m, 0.5H), 1.43-1.53 (m, 2H), 1.34-1.35 (m, 0.5H), 0.98 (t, J = 7.2 Hz, 2H), 0.82-0.84 (m, 1H), 0.65 (t, J = 7.2 Hz, 1H), 0.52 - 0.53 (m, 2H), 0.11 (s, 2H); HRMS (ESI): m/z, calcd. for C ₂₆ H ₃₀ O ₃ N ₄ F[M+H] ⁺ : 465.2297, found: 465.2296.

Example 37

(R)-1-(3-(3-ethyl-4-propionylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-2-Ethyl-1-(propionyl)piperazine hydrochloride

(R)-1-Boc-3-ethylpiperazine (1.0 g, 4.7 mmol), propionyl chloride (0.73 g, 7.0 mmol), triethylamine (1.43 g, 14.1 mmol), 25 mL dichloromethane The mixture was reacted at room temperature for 4 h. After completion of the reaction, the mixture was washed with water (10 mL×2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. To the end, go directly to the next step.

b) (R)-1-(3-(3-ethyl-4-propionyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

5-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (1.23 g, 3.9 mmol) (R)- 2-Ethyl-1-(propionyl)piperazine hydrochloride (4.7 mmol), HBTU (1.78 g, 4.7 mmol), DMF (10 mL) was added to a three-neck flask, DIEA (2.03 g, 15.7 mmol) was added dropwise. After the completion of the dropwise addition, stirring at room temperature for 2 h, into the system Dichloromethane (150 mL) was added, EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography (EtOAc EtOAc EtOAc)

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.13-9.18 (m, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.57-7.62 (m, 1H), 7.25-7.37 (m) , 3H), 7.06-7.12 (m, 2H), 5.34 (s, 2H), 4.65-4.71 (m, 1H), 3.89 (s, 0.5H), 3.70-3.73 (m, 0.5H), 3.43-3.56 (m, 0.5H), 3.28-3.40 (m, 1.5H), 3.00-3.20 (m, 1H), 2.87-2.93 (m, 2H), 2.33 - 2.44 (m, 2H), 1.65-1.75 (m, 1H), 1.42-1.47 (m, 2H), 1.16-1.18 (m, 3H), 0.93-0.97 (m, 1H), 0.61-0.67 (m, 1H); HRMS (ESI): m/z, calcd. For C ₂₅ H ₂₈ O ₄ N ₄ F[M+H ⁺ ]: 467.2089,found:467.2081

Example 38

(R)-1-(3-(3-ethyl-4-trifluoroethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (R)-2-Ethyl-1-(trifluoroethyl)piperazine hydrochloride

(R)-1-Boc-3-ethylpiperazine (1.0 g, 4.7 mmol), trifluoroacetic anhydride (1.47 g, 7.0 mmol), triethylamine (1.43 g, 14.1 mmol), 25 mL dichloromethane After adding to the reaction flask, the mixture was reacted at room temperature for 4 hours. After the reaction was completed, 10 mL × 2 purified water was washed, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to dryness, and the residue was added to tetrahydrofuran (10 mL) and borane tetrahydrofuran solution was added dropwise ( 12 mL, 11.8 mmol), after completion, the mixture was warmed to reflux and stirred for 4 h. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. Go directly to the next step.

b) (R)-1-(3-(3-ethyl-4-trifluoroethyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

5-((2,4-Dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (1.23 g, 3.9 mmol) (R)- 2-Ethyl-1-(trifluoroethyl)piperazine hydrochloride (4.7 mmol), HBTU (1.78 g, 4.7 mmol), DMF (10 mL) was added to a three-neck flask, and DIEA (2.03 g, 15.7 mmol) was added dropwise. After the dropwise addition, stirring at room temperature for 2 h, dichloromethane (150 mL) was added to the system, followed by washing with water (75 mL), 5% aqueous citric acid (30 mL), 5% sodium carbonate (30 mL), and organic phase. The residue was dried over anhydrous sodium sulfate (MgSO4)

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 8.65 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.58-7.62 (m, 1H), 7.26-7.34 (m, 3H) ), 7.04-7.09 (m, 2H), 5.32 (s, 2H), 3.91 (brs, 1H), 3.64-3.70 (m, 0.5H), 3.38-3.41 (m, 0.5H), 3.29 (brs, 1H) ), 3.04-3.18 (m, 3H), 2.89-2.92 (m, 1H), 2.70-2.74 (m, 0.5H), 2.55-2.68 (m, 1H), 2.47 (brs, 0.5H), 1.48-1.58 (m, 2H), 1.00 (t, J = 7.2 Hz, 2H), 0.64 (t, J = 7.2 Hz, 1H); HRMS (ESI): m/z, calcd. for C ₂₄ H ₂₅ O ₃ N ₄ F ₄ [M+H ⁺ ]: 493.1857, found: 493.1848

Example 39

(S)-1-(3-(3-ethyl-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (S)-3,4-Diethylpiperazine-1-carboxylic acid tert-butyl ester

(S)-3-Ethyl-N-BOC-piperazine (535 mg, 2.5 mmol), EtOAc (20 mL), EtOAc (EtOAc (EtOAc) The reaction was warmed to 50 ° C, and the reaction was quenched after 30 h, concentrated to dryness and purified by column chromatography (D:M=60:1, D:M=50:1) to afford 450 mg as a yellow oil.

b) (S)-1,2-diethylpiperazine trifluoroacetate

Add (S)-3,4-diethylpiperazine-l-carboxylic acid tert-butyl ester (420 mg, 1.75 mmol) to DCM (10 mL). The reaction was quenched and concentrated to dryness afforded 430 g, m.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ ppm: 9.61 (brs, 2H), 3.19-3.80 (m, 9H), 1.91 (brs, 1H), 1.69 (brs, 1H), 1.23 (t, J = 7.2 Hz, 3H), 1.10 (t, J = 6.8 Hz, 1H), 0.94 (t, J = 7.6 Hz, 2H).

c) (S)-1-(3-(3-ethyl-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (420 mg, 1.34 mmol) was added in DMF (20 mL) ), EDC (515 mg, 2.68 mmol), HOBt (362 mg, 2.68 mmol), DIEA (1.17 mL, 6.7 mmol) and 446 mg (1.74 mmol) of compound (S)-N-ethyl-2-ethylpiperazine Acetate, the reaction was stirred at room temperature, the reaction was stopped the next day, water was added, and the mixture was extracted with DCM:MeOH = 10:1 (50 mL×2), and the organic layer was washed with saturated NaCI solution (30 mL×2). Drying with magnesium, EtOAc (EtOAc:EtOAc:EtOAc:EtOAc

¹ H-NMR (400MHz, CDCl ₃ ) δ ppm: 9.04 (brs, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.24 - 7.35 (m, 3H) ), 7.03-7.11 (m, 2H), 5.33 (s, 2H), 4.13 (brs, 1H), 3.25-3.50 (m, 2.5H), 3.00-3.10 (m, 0.5H), 2.72-2.90 (m , 2H), 2.33 (brs, 1H), 1.62-1.72 (m, 1H), 1.48-1.53 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.6 Hz, 2H), 0.65 (t, J = 7.6 Hz, 1H).

Example 40

(S)-1-(3-(3-ethyl-4-cyclopropylmethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (S)-(cyclopropylmethyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester

(S)-1-Boc-3-ethylpiperazine (100 mg, 0.469 mmol) was dissolved in acetonitrile (5 mL), DIEA (121 mg, 0.938 mmol) and cyclopropylmethyl bromide (73 mg, 0.54 mmol) The reaction was quenched at 50 ° C for 20 h, and the reaction was concentrated. EtOAc EtOAc m.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 2.85-3.85 (m, 5H), 2.25-2.67 (m, 4H), 1.42-1.66 (m, 11H), 0.88 (t, J = 7.6 Hz) , 3H), 0.82-.085 (m, 1H), 0.48-0.50 (m, 2H), 0.07-0.09 (m, 2H).

b) (S)-2-Ethyl-1-(cyclopropylmethyl)piperazine trifluoroacetate

(S)-4-(Cyclopropylmethyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester (52 mg, 0.194 mmol) was dissolved in DCM (6 mL). After 3 h, the reaction was stopped, and the reaction mixture was concentrated, and then ethyl acetate (5 mL, EtOAc, EtOAc (EtOAc)

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 9.44 (brs, 2H), 3.27-3.88 (m, 6H), 3.08-3.26 (m, 3H), 1.58-1.70 (m, 1H) , 1.00-1.11 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H), 0.60-0.70 (m, 2H), 0.34-0.44 (m, 2H).

c) (S)-1-(3-(3-Cyclopropylmethyl-4-isopropylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (80 mg, 0.25 mmol) in anhydrous DMF (5mL), EDC (96mg, 0.50mmol), HOBt (68mg, 0.50mmol) and DIEA (160mg, 1.25mmol), stirred at room temperature for 30min, added (S)-2-ethyl-1-(cyclopropylmethyl) The piperazine trifluoroacetate (40 mg, 0.15 mmol) was reacted at room temperature overnight, the reaction was concentrated, ethyl acetate (50 mL) was added, and the organic phase was saturated with sodium bicarbonate (20 mL) It is washed with carbonic acid, dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (DCM: MeOH=50:1 - 30:1) 120 mg of the product was recrystallized from chloroform / EtOAc (yield: EtOAc)

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 8.64 (s, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.55-7.63 (m, 1H), 7.32-7.37 (m, 1H ), 7.23-7.31 (m, 2H), 7.02-7.13 (m, 2H), 5.32 (s, 2H), 4.14 (s, 1H), 3.22-3.51 (m, 2.5H), 3.00-3.10 (m, 1H), 2.88-2.97 (m, 0.5H), 2.20-2.65 (m, 4H), 1.44-1.69 (m, 2H), 0.98 (t, J = 7.2 Hz, 1.7H), 0.82 (s, 1H) , 0.65 (t, J = 7.2 Hz, 1.3H), 0.48-0.58 (m, 2H), 0.07-0.14 (s, 2H).

Example 41

(S)-1-(3-(3-ethyl-4-propionylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

(S)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2,2 - trifluoroacetate (70mg, 0.138mmol) was dissolved in DCM (5mL) was added dropwise under _{Et 3 N (45mg, 0.414mmol)} , an ice bath was added propionyl chloride (20mg, 0.207mmol) in DCM (1.0mL The solution was allowed to react to room temperature for 2.5 h, and the reaction was stopped. The reaction mixture was diluted with DCM (15 mL), and the organic phase was saturated with sodium bicarbonate (10 mL×2), saturated ammonium chloride (10 mL×2), saturated salt Washed with water (10 mL × 2), dried over anhydrous magnesium sulfate, EtOAc (EtOAc: EtOAc EtOAc The alkane was recrystallized to give a white solid, 40 mg, yield 62.5%, mp 128-130 °.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 8.13 - 8.85 (m, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.55 - 7.63 (m, 1H), 7.24 - 7.41 (m) , 3H), 7.04-7.13 (m, 2H), 5.34 (s, 2H), 4.47-4.68 (m, 2H), 3.21-3.73 (m, 3H), 2.77-3.15 (m, 2H), 2.26-2.47 (m, 2H), 1.59-1.80 (m, 2H), 1.12-1.23 (m, 3H), 0.90-1.01 (m, 2H), 0.56-0.73 (m, 1H).

Example 42

(S)-1-(3-(3-ethyl-4-trifluoroethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (S)-4-(Trifluoroacetyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester

The (S) -1-Boc-3- ethylpiperazine (300mg, 1.40mmol) was dissolved in DCM (10mL) was added _{Et 3 N (172mg, 1.68mmol)} , was added dropwise under ice-cooling, trifluoroacetic anhydride (325 mg, 1.54 mmol) in DCM (5 mL), EtOAc EtOAc (EtOAc) .

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.00-4.53 (m, 3H), 3.71-3.87 (m, 1H), 3.29-3.33 (m, 0.5H), 2.78-3.04 (m, 2.5) H), 1.62-1.84 (m, 2H), 1.48 (s, 9H), 0.91-0.97 (m, 2H).

b) (S)-4-(Trifluoroethyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester

(S)-4-(Trifluoroacetyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester (390 mg, 1.26 mmol) was dissolved in anhydrous THF (8 mL). 1M of BH ₃ .THF (3.8 mL, 3.8 mmol) was added, and the mixture was heated to 40 ° C for 12 h, the reaction was stopped, and a saturated sodium hydrogencarbonate solution (5 mL) was slowly added to the reaction mixture, stirred for 30 min, concentrated, and added. The organic phase was washed with saturated sodium bicarbonate (20 mL×4) and brine (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (P:E=20:1-15: 1) A yellow oily liquid 300 mg was obtained in a yield of 80.4%.

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 3.27-3.70 (m, 3.5H), 2.95-3.20 (m, 2.5H), 2.85-2.92 (m, 1H), 2.55-2.63 (m, 1H), 2.43-2.52 (m, 1H), 1.45-1.58 (m, 11H), 0.91 (t, J = 7.2 Hz, 3H).

c) (S)-2-Ethyl-1-(trifluoroethyl)piperazine trifluoroacetate

(S)-4-(Trifluoroethyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester (260 mg, 0.877 mmol) was dissolved in DCM (10 mL). The reaction was stopped, and the reaction mixture was concentrated, and then ethyl acetate (5 mL×2), chloroform (8 mL×2), and the solvent was evaporated.

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 8.88 (brs, 2H), 3.40-3.49 (m, 1H), 3.22-3.31 (m, 1H), 2.96-3.11 (m, 4H) , 2.70-2.84 (m, 3H), 1.59-1.66 (m, 1H), 1.41-1.48 (m, 1H), 0.84 (t, J = 7.2 Hz, 2H).

d) (S)-1-(3-(3-ethyl-4-trifluoroethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (190 mg, 0.614 mmol) in anhydrous DMF (10 mL), EDC (236 mg, 1.228 mmol), HOBt (169 mg, 1.228 mmol), DIEA (400 mg, 3.07 mmol) and (S)-2-ethyl-1-(trifluoroethyl)piperazine The acetate (180 mg, 0.614 mmol) was reacted at room temperature overnight, the reaction mixture was concentrated, ethyl acetate (50 mL) was added, and the organic phase was washed with saturated sodium hydrogen carbonate solution (20 mL×3) and brine (20 mL×2) Drying with anhydrous magnesium sulfate, EtOAc (EtOAc: EtOAc) .

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.00 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 6.8 Hz, 1H), 7.25-7.36 ( m,3H),7.04-7.10(m,2H),5.33(s,2H),3.87-3.95(m,1H), 3.46-3.73(m,1H), 3.40(d,J=13.2Hz,0.5H ), 3.30 (s, 1H), 2.98-3.21 (m, 3H), 2.88-2.94 (m, 0.5H), 2.48-2.76 (m, 2H), 1.32-1.64 (m, 2H), 1.00 (t, J = 7.2 Hz, 1.6 H), 0.64 (t, J = 7.2 Hz, 1.4 H).

Example 43

(S)-1-(3-(3-ethyl-4-methylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

(S)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2,2 -Trifluoroacetic acid salt (50 mg, 0.098 mmol) was dissolved in anhydrous methanol (5 mL), EtOAc (0.11 mL, <RTI ID=0.0> 2h, the reaction was stopped, the reaction mixture was concentrated, DCM (20 mL) was added, the organic phase was washed with saturated aqueous ammonium chloride (20mL × 2), brine (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, column chromatography (DCM: MeOH = 20:1) EtOAc (EtOAc: EtOAc)

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 8.71 (s, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.60 (t, J = 8.0Hz, 1H), 7.26-7.35 ( m, 3H), 7.04-7.10 (m, 2H), 5.32 (s, 2H), 4.45 (d, J = 13.2 Hz, 1H), 2.73-3.35 (m, 4H), 2.33 (s, 3H), 2.05 -2.13 (m, 1H), 1.33-1.79 (m, 3H), 0.99 (t, J = 7.2 Hz, 1.5H), 0.72 (t, J = 7.2 Hz, 1.5H).

Example 44

(S)-1-(3-(3-ethyl-4-isopropylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (S)-tert-butyl 4-(isopropyl)-3-ethylpiperazine-1-carboxylate

(S)-1-Boc-3-ethylpiperazine (200 mg, 0.93 mmol) was added to the reaction flask, methanol (2 mL), acetone (2 mL) was added, and a catalytic amount of acetic acid was added thereto to stir the reaction at room temperature. After 10 h, NaBH was added. ₃ CN (174 mg, 1.86 mmol) was stirred at room temperature. The reaction was stirred at the next day, and then the mixture was stirred, and the mixture was evaporated to ethyl acetate (15 mL) and ethyl acetate (30 mL×2). The mixture was washed with EtOAc EtOAc m.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 3.50-3.80 (m, 1.5H), 2.90-3.40 (m, 2.5H), 2.71 (brs, 1H), 2.30-2.55 (m, 2H) , 1.55-1.65 (m, 1H), 1.38-1.50 (m, 10H), 1.15 (d, J = 6.4 Hz, 3H), 0.86-0.96 (m, 6H).

b) (S)-2-Ethyl-1-(isopropyl)piperazine trifluoroacetate

(S)-4-(Isopropyl)-3-ethylpiperazine-l-carboxylic acid tert-butyl ester (80 mg, 0.31 mmol). The reaction was stirred and the reaction was stopped after 4 h, concentrated to dryness and taken directly to next.

c) (S)-1-(3-(3-ethyl-4-isopropylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (80 mg, 0.25 mmol) to DMF (15 mL) ), EDC (96 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), DIEA (0.22 mL, 1.25 mmol) and (S)-2-ethyl-1-(isopropyl)piperazine trifluoroacetate (83 mg, 0.31 mmol), the reaction was stirred at room temperature, and then the mixture was evaporated to dryness. EtOAc EtOAc (EtOAc) Chromatography (MeOH: EtOAc: EtOAc: EtOAc:EtOAc:EtOAc

¹ H-NMR (400MHz, CDCl ₃ ) δ ppm: 8.81 (brs, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.24 - 7.36 (m, 3H) ), 7.04-7.10 (m, 2H), 5.33 (brs, 2H), 4.18 (brs, 1H), 3.00-3.50 (brs, 4H), 2.30-2.90 (m, 3H), 1.50-1.70 (m, 2H) ), 1.10.10.20 (m, 3H), 0.85-1.05 (m, 5H), 0.63-0.73 (m, 1H).

Example 45

(S)-1-(3-(3-ethyl-4-cyclopropanylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (S)-4-(cyclopropanoyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester

The (S) -1-Boc-3- ethylpiperazine 100mg, 0.47mmol) was dissolved in DCM (10mL) was added _{Et 3 N (0.1mL, 0.70mmol)} , was added dropwise under ice-cooling cyclopropanecarbonyl chloride (0.05 mL, 0.56 mmol) in EtOAc (1 mL) EtOAc (EtOAc)EtOAc. The yellow oil was obtained in 100 mg, yield 75%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.00-4.55 (m, 3H), 2.75-3.25 (m, 3H), 4.55-1.75 (m, 3H), 1.03-1.06 (m, 1H) , 0.99 (brs, 2H), 0.90-0.98 (m, 3H), 0.75-0.78 (m, 2H).

b) (S)-2-Ethyl-1-(cyclopropanoyl)piperazine trifluoroacetate

(S)-4-(Cyclopropanoyl)-3-ethylpiperazine-l-carboxylic acid tert-butyl ester (95 mg, 0.34 mmol). The reaction was stirred at room temperature, and after 4 h, the reaction was quenched, concentrated to dryness and taken directly to the next.

c) (S)-1-(3-(3-ethyl-4-cyclopropanylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (80 mg, 0.25 mmol) to DMF (15 mL) ), EDC (96 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), DIEA (0.22 mL, 1.25 mmol) and (S)-2-ethyl-1-(cyclopropanoyl)piperazine trifluoroacetic acid The salt (98 mg, 0.33 mmol) was stirred at room temperature, and the mixture was evaporated to dryness. EtOAc (EtOAc m. Column chromatography (MeOH: DCM = 1 : 60) gave a white solid (yield:

¹ H-NMR (400MHz, CDCl ₃ ) δ ppm: 9.22 (brs, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.58-7.62 (m, 1H), 7.24-7.37 (m, 3H), 7.06 -7.13(m,2H), 5.26-5.34(m,2H), 4.60-4.80(m,1H), 4.40-4.60(m,1H), 4.27(brs,0.5H),3.90-4.07(m,0.5 H), 3.30-3.55 (m, 2H), 2.80-3.20 (m, 2H), 1.60-1.85 (m, 3H), 1.26-1.33 (m, 1H), 1.01 (brs, 3H), 0.55-0.85 ( m, 3H)

Example 46

(S)-1-(3-(3-ethyl-4-acetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (S)-4-(acetyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester

(S)-1-Boc-3-ethylpiperazine (200 mg, 0.933 mmol) was dissolved in anhydrous dichloromethane (6 mL), triethylamine (192 mg, 1.866 mmol) The acid chloride (84 mg, 1.07 mmol) in methylene chloride (3 mL), EtOAcjjjjjjjjjj 230 mg, yield 95.8%.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 4.42-4.54 (m, 1H), 4.93-1.48 (m, 2H), 3.52-3.73 (m, 1H), 3.24-3.30 (m, 0.5H) ), 2.72-2.96 (m, 2.5H), 2.11 (d, J = 4.4 Hz, 4H), 1.52-1.66 (m, 2H), 1.47 (s, 9H), 0.88-0.96 (m, 3H).

b) (S)-2-Ethyl-1-(acetyl)piperazine trifluoroacetate

(S)-4-(Acetyl)-3-ethylpiperazine-l-carboxylic acid tert-butyl ester (170 mg, 0.66 mmol) was dissolved in DCM (10 mL). The reaction was quenched, and the reaction mixture was concentrated, then ethyl acetate (5 mL, EtOAc, EtOAc (EtOAc)

^{1 H-NMR (400MHz, DMSO} -d 6) δ (ppm): 8.77-9.51 (m, 4H), 4.75-4.88 (m, 1H), 3.67-3.99 (m, 2H), 3.38-3.45 (m, 2H), 3.00-3.13 (m, 2H), 2.20 (s, 3H), 1.76-2.03 (m, 2H), 0.93-0.99 (m, 3H).

c) (S)-1-(3-(3-ethyl-4-acetyl-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

Dissolving 5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoic acid (150 mg, 0.477 mmol) in anhydrous DMF (10 mL), EDC (257 mg, 1.34 mmol), HOBt (181 mg, 1.34 mmol) and DIEA (433 mg, 3.35 mmol), and stirred at room temperature for 30 min, (S)-2-ethyl-1-(acetyl) Ethyl trifluoroacetate (160 mg, 0.63 mmol), mp mp mp EtOAc (EtOAc:EtOAcMeOHMeOHMeOH It was washed with MgSO.sub.4, EtOAc.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.91 - 8.95 (m, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.58-7.62 (m, 1H), 7.26-7.35 (m) , 3H), 7.04-7.14 (m, 2H), 5.34 (s, 2H), 4.45-4.72 (m, 2H), 3.25-3.85 (m, 3H), 2.84-3.07 (m, 2H), 2.01-2.17 (m, 3H), 1.62-1.78 (m, 2H), 0.94-0.99 (m, 1.7H), 0.58-0.73 (m, 1.3H).

Example 47

(S)-1-(3-(3-ethyl-4-trifluoroacetyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

(S)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-

dione

2,2,2 - trifluoroacetate (70mg, 0.138mmol) was dissolved in DCM (6mL) was added _{DCM Et 3 N (42mg, 0.413mmol} ), under ice-cooling was added dropwise trifluoroacetic anhydride (45mg, 0.207mmol) of ( The solution was diluted to room temperature for 3 h, and the reaction was stopped. The reaction mixture was concentrated and purified by column chromatography (DCM: MeOH=60:1) , yield 60.9%, mp 127-129 ° C.

¹ H-NMR (400MHz, CDCl ₃ ) δ (ppm): 8.76 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.57-7.63 (m, 1H), 7.26-7.39 (m, 3H) ), 7.05-7.14 (m, 2H), 5.33 (s, 2H), 4.67-4.82 (m, 1H), 4.33-4.50 (m, 1H), 3.73-4.10 (m, 1H), 3.40-3.56 (m) , 2H), 2.87-3.26 (m, 2H), 1.29-1.76 (m, 2H), 0.86-1.01 (m, 3H).

Example 48

(S)-1-(3-(3-ethyl-4-n-propylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) (S)-4-(n-propyl)-3-ethylpiperazine-1-carboxylic acid tert-butyl ester

(S)-1-Boc-3-ethylpiperazine (100 mg, 0.47 mmol) was added to a reaction flask, acetonitrile (10 mL) was added, DIEA (0.16 mL, 0.93 mmol) was added, and bromo-n-propane (0.06 mL) was added. , 0.70 mmol), the reaction was warmed to 50 ° C, the reaction was stopped after 30 h, concentrated to dryness, and then purified by column chromatography (D: M = 50:1) to afford 30 mg of yellow oil, yield 25.2%.

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 2.90-3.80 (m, 4H), 2.73 (brs, 1H), 2.59 (brs, 1H), 2.25-2.40 (m, 3H), 1.23-1.70 (m, 13H), 0.72-0.90 (m, 6H).

b) (S)-2-Ethyl-1-(n-propyl)piperazine trifluoroacetate

(S)-4-(n-propyl)-3-ethylpiperazine-l-carboxylic acid tert-butyl ester (30 mg, 0.34 mmol). The reaction was stirred and the reaction was stopped after 4 h, concentrated to dryness and taken directly to next.

c) (S)-1-(3-(3-ethyl-4-n-propylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

Add 5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (40 mg, 0.127 mmol) to DMF (15 mL) ), EDC (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), DIEA (0.11 mL, 0.635 mmol) and (S)-2-ethyl-1-(n-propyl)piperazine trifluoroacetate (32 mg, 0.12 mmol), the reaction was stirred at room temperature, and then the mixture was evaporated, and the mixture was evaporated to ethyl acetate (30 mL × 2). Chromatography (MeOH: EtOAc: EtOAc:EtOAc:EtOAc:

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 8.79 (brs, 1H), 8.28 (d, J = 7.6 Hz, 1H), 7.63-7.66 (m, 1H), 7.32-7.40 (m, 3H), 7.09 -7.16 (m, 2H), 5.38 (brs, 2H), 4.11 (brs, 1H), 3.55 (brs, 0.5H), 3.37 (brs, 2H), 3.11 (brs, 0.5H), 2.92 (brs, 0.5) H), 0.79 (brs, 0.5H), 2.67 (brs, 1H), 2.30-2.50 (m, 3H), 1.70 (brs, 1H), 1.46-1.61 (m, 2H), 1.37 (brs, 1H), 1.04 (t, J = 7.6 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H), 0.70 (t, J = 7.6 Hz, 1H).

Example 49

1-(3-(4-oxopiperidine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

a) Piperidin-4-one hydrochloride

N-Boc-4 oxopiperidine was added to the reaction flask, and about 5 mL of a 2.08 M HCl solution in dioxane was added, and the mixture was stirred for 5 hr.

b) 1-(3-(4-Oxopiperidin-1-yl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluorobenzoic acid (120 mg, 0.39 mmol), EDCI (150 mg, 0.78 mmol), HOBt (106 mg, 0.78 mmol) and DIEA (79 mg, 0.78 mmol) were added to the reaction flask, dissolved in about 3 mL of anhydrous DMF, stirred at rt for 15 min, then piperidin-4-one hydrochloride was added dropwise. (79 mg, 0.58 mmol) of DMF solution was added to the reaction solution, and stirred at rt overnight. The reaction solution was poured into 100 mL of water and extracted with 100 mL of DCM, and the organic layer was sequentially diluted with 1M HCl (100 mL). Washed with NaCl (100 mL) and water (100 mL).

^{1 H NMR (400MHz, DMSO-} d 6) δ (ppm): 11.72 (s, 1H), 8.02 (d, J = 8.0Hz, 1H), 7.65 (t, J = 7.6Hz, 1H), 7.44-7.49 (m, 1H), 7.22-7.33 (m, 3H), 5.33 (s, 2H), 3.87 (m, 2H), 3.41-3.45 (m, 2H), 2.45-2.49 (m, 2H), 2.22 (m) , 2H).mp 124-126 ° C.

Pharmacological experiment:

Experimental Example 1: Evaluation of enzyme level activity

(1) Evaluation of the inhibitory activity of the compound on PARP1 enzyme

Experimental methods and results:

Compounds were evaluated for inhibition of PARP1 enzyme by double-antibody ELISA quantification of PAR. The specific experimental method was as follows: 100 μl of each well of 50 μg/mL histone was coated with a 96-well 96-well plate at 4° C., and washed with 0.1% Triton 100 PBS and PBS twice. Then set blank control wells, plus enzyme control wells, positive compound control wells and assay wells, blank control wells were added NAD ⁺ (5 pmol) prepared in 35 μl assay buffer, 10 μl purification buffer, 5 μl Sheared DNA (1 μg/ml), plus Add 30 μl of NAD ⁺ (5 pmol), 10 μl of PARP1 (0.005 Units), 5 μl of Sheared DNA (1 μg/ml), 30 μl of NAD ⁺ (5 pmol), 5 μl of ABT-888, and 10 μl of PARP1. (0.005 Units), 5 ul of Sheared DNA (1 μg/ml), assay wells were added 30 μl of NAD ⁺ (5 pmol), 5 μl of each assay compound dilution, 10 μl of PARP1 (0.005 Units), and 5 μl of Sheared DNA (1 μg/ml). A total volume of 50 μl was reacted at room temperature for 1 h. The plates were washed twice with PBS containing 0.1% Triton X-100 and PBS. 50 μl of anti-PAR mouse monoclonal antibody diluted 1:500 in PBS was added, and the mixture was incubated for 1 h at room temperature, and washed twice with 0.1% Triton X-100 in PBS and PBS. Then, 50 μl of goat anti-mouse IgG diluted 1:4000 in PBS was added, incubated for 30 min at room temperature, and washed twice with 0.1% Triton X-100 in PBS and PBS. Further, 50 μl of the TMB reaction solution was added, and the reaction was allowed to stand at room temperature for 15 minutes in the dark, and then the reaction was terminated with 50 μl of an aqueous solution containing 20% concentrated hydrochloric acid. The absorbance was measured at 450 nm. The % inhibition of PARP1 by different dilutions of each compound was calculated. The inhibitory activities of some of the compounds of the examples are shown in Table 1.

(2) Evaluation of compound inhibiting activity of PARP2 enzyme

Compounds were evaluated for their inhibition of PARP2 enzyme by double-antibody ELISA quantification of PAR. The specific experimental method was as follows: 100 μl of each well of 50 μg/mL histone was coated with a 96-well 96-well plate at 4° C., and washed with 0.1% Triton 100 PBS and PBS twice. Then set blank control wells, plus enzyme control wells, positive compound control wells and assay wells, blank control wells were added NAD ⁺ (5 pmol) prepared in 35 μl assay buffer, 10 μl purification buffer, 5 μl Sheared DNA (1 μg/ml), plus Add 30 μl of NAD ⁺ (5 pmol), 10 μl of PARP2 (0.005 Units), 5 μl of Sheared DNA (1 μg/ml), 30 μl of NAD ⁺ (5 pmol), 5 μl of AZD-2281 dilution, 10 μl of PARP2 to the positive control wells. (0.005 Units), 5 ul of Sheared DNA (1 μg/ml), assay wells were added 30 μl of NAD ⁺ (5 pmol), 5 μl of each assay compound dilution, 10 μl of PARP2 (0.005 Units), and 5 μl of Sheared DNA (1 μg/ml). A total volume of 50 μl was reacted at room temperature for 1 h. The plates were washed twice with PBS containing 0.1% Triton X-100 and PBS. 50 μl of anti-PAR mouse monoclonal antibody diluted 1:500 in PBS was added, and the mixture was incubated for 1 h at room temperature, and washed twice with 0.1% Triton X-100 in PBS and PBS. Then, 50 μl of goat anti-mouse IgG diluted 1:4000 in PBS was added, incubated for 30 min at room temperature, and washed twice with 0.1% Triton X-100 in PBS and PBS. Further, 50 μl of the TMB reaction solution was added, and the reaction was allowed to stand at room temperature for 15 minutes in the dark, and then the reaction was terminated with 50 μl of an aqueous solution containing 20% concentrated hydrochloric acid. The absorbance was measured at 450 nm. The % inhibition of PARP2 by different dilutions of each compound was calculated. The inhibitory activities of some of the compounds of the examples are shown in Table 1.

Table 1. Inhibitory activity of PARP1 and PARP2 enzymes by some of the compounds of the invention.

Experimental Example 2: Cell level pharmacodynamic experiment

(1) Anti-proliferative effect of Example 10

PARP inhibitors and BRCA 1/BRCA 2 mutations can cause tumor cell death (especially breast cancer and ovarian cancer) if they act on tumor cells at the same time, and do not affect normal cells. PARP inhibitors are lethal by this synthesis. The principle exerts its anti-tumor effect. In addition, the study also found that PARP inhibitors have similar synergistic effects with other gene deletions. Example 10 In BRCA-deficient tumor cells, the proliferation of these cells was effectively inhibited, and IC _{50 is} shown in Table 2. Example 10 was also effective in inhibiting cell proliferation in some other gene-deficient triple-negative breast cancer cells (Table 3).

Table 2. Antiproliferative activity of Example 10 on BRCA deficient cells

* Cells were incubated with the compound for 72 hours and examined by MTT assay.

Table 3. Anti-proliferative activity of Example 10 on triple-negative breast cancer

(2) Sensitization of chemotherapeutic drugs in Example 10

Inhibition of PARP1/2 enhances the anti-tumor effect of chemotherapy drugs and radiotherapy. Example 10 Significant sensitization of temozolomide (TMZ), topotecan (TPT), cisplatin (CisP), doxorubicin (ADM) in MX-1 breast cancer cells (Fig. 1). In other tumor cells, Example 10 also had a good sensitizing effect on temozolomide (Fig. 2).

In temozolomide-resistant glioma cells, Example 10 overcomes temozolomide resistance and potentiates the effect of temozolomide (Figure 3).

(3) Example 35 sensitizing effect on chemotherapeutic drugs

Example 35 A significant sensitizing effect on temozolomide (TMZ), topotecan (TPT), cisplatin (CisP), doxorubicin (ADM) in MX-1 breast cancer cells (Fig. 4). In brain tumor cells, Example 35 also had a good sensitizing effect on temozolomide (Fig. 5). In temozolomide-resistant glioma cells, Example 35 overcomes temozolomide resistance and potentiates the effect of temozolomide (Figure 5).

(4) Example 36 sensitizing effect on chemotherapeutic drugs

Example 36 has significant sensitizing effects on temozolomide (TMZ), topotecan (TPT), and doxorubicin (ADM) in MX-1 breast cancer cells (Fig. 6). In brain tumor cells, Example 36 also had a good sensitizing effect on temozolomide (Fig. 7). In temozolomide-resistant glioma cells, Example 36 overcomes temozolomide resistance and potentiates the effect of temozolomide (Figure 7).

Experimental Example 3: Pharmacodynamic experiment in animals

Experimental methods and results:

(1) Inhibition of MX-1 breast cancer in combination with TMZ: The antitumor activity of the compound prepared in Example 10 was evaluated using the MX-1 nude mouse xenograft experiment. The method was as follows: 72 female Balb/c nude mice were injected subcutaneously into MX-1 transplanted tumor tissue homogenate to prepare a transplanted tumor model. Six days after modeling, the transplanted tumor volume was 100-300 mm ³ , and the control group and TMZ were randomly grouped. Temozolomide, 50 mg/kg), ABT-888 (25 mg/kg), TMZ+ABT-888 (25 mg/kg), Example 10 (25 mg/kg), TMZ+ Example 10 (12.5 mg/kg) and TMZ+ examples 10 (25 mg/kg) group. TMZ was administered continuously for 5 days once a day, ABT-888, and Example 10 for 8 consecutive days, once daily. During the administration, the body weight of the mice was weighed and the tumor volume was measured. The observation was continued after the end of the administration, and the body weight of the mice and the tumor volume were measured. After TMZ administration for 5 days, ABT-888, and administration of Example 10 for 8 days (Day 12), the tumor volume measurement showed that ABT-888 and Example 10 combined with TMZ can significantly enhance the growth of TMZ on MX-1 xenografts. Inhibition (Figure 8), and the 19th day tumor weight measurement (Table 4) suggests that ABT-888 and Example 10 in combination with TMZ can significantly enhance the growth inhibition of MX-1 xenografts after TMZ is discontinued. effect. In the combination of Compound 10 and TMZ, the tumor inhibition rate reached 86% and 97% at doses of 12.5 mg/kg and 25 mg/kg, which was significantly higher than that of TMZ alone (67%).

Table 4. Sensitization of Compound 10 to TMZ in a MX-1 breast cancer xenograft model

During the course of the experiment, the nude mice of Example 10 alone showed no significant decrease in body weight (weight or increase in body weight), and no other adverse reactions occurred (Fig. 9). In Example 10, the number of neutrophils (A), white blood cells (B), and platelets (C) was comparable to that of the unadministered group (Fig. 10). It can be seen that Example 10 has good safety.

(2) In combination with CisPt, inhibition of MX-1 breast cancer:

Using MX-1 nude mice xenograft experiments, 42 female Balb/c nude mice were injected subcutaneously into MX-1 transplanted tumor tissue homogenate to prepare a transplanted tumor model. Six days after model establishment, the transplanted tumor volume was 100-300 mm ³ and randomized. Grouped control group, CisPt (cisplatin, 6 mg/kg), Olaparib (25 mg/kg), CisPt+Olaparib (25 mg/kg), Example 10 (25 mg/kg), CisPt+ Example 10 (12.5 mg/kg) And CisPt + Example 10 (25 mg/kg) group. CisPt was administered once a week for Olaparib, Example 10 for 8 consecutive days, once daily. During the administration, the body weight of the mice was weighed and the tumor volume was measured. The observation was continued after the end of the administration, and the body weight of the mice and the tumor volume were measured. The results showed that Example 10 had a sensitizing effect on cisplatin (Fig. 11, Table 5).

Table 5. Sensitization of Compound 10 to CisPt in a MX-1 Breast Cancer Xenograft Model

(3) In combination with TMZ, inhibition of MCF-7 breast cancer:

Using MCF-7 nude mice xenograft experiments, 30 female Balb/c nude mice were transplanted with MCF-7 tumors. Six days after modeling, the transplanted tumor volume was 100-300 mm ³ , and the control group, TMZ (Temozolomide) was randomly grouped. , 50 mg/kg), Example 10 (25 mg/kg), TMZ + Example 10 (12.5 mg/kg), TMZ + Example 10 (25 mg/kg) and Taxol (24 mg/kg). TMZ was administered continuously for 5 days, once a day, in Example 10 for 22 days, and in the Example 10 combination group for 14 days, once daily, Taxol was administered every 3 days for 3 times. During the administration, the body weight of the mice was weighed and the tumor volume was measured. The observation was continued after the end of the administration, and the body weight of the mice and the tumor volume were measured. The results show that Example 10 alone has a certain anti-tumor effect on MCF-7 (Fig. 12, Table 6).

Table 6. Antiproliferative activity of Compound 10 in combination with TMZ in a MCF-7 breast cancer xenograft model

(4) In combination with TMZ, inhibition of U251 glioma:

U251/TMZ nude mice xenografts were used in temozolomide-resistant U251/TMZ nude mice. 54 female Balb/c nude mice were transplanted with U251/TMZ tumors. Six days after modeling, the transplanted tumor volume was 100-300 mm ³ , TMZ (temozolomide, 50 mg/kg and 75 mg/kg), AZD-2281 (50 mg/kg), TMZ+AZD-2281 (25 mg/kg), TMZ+AZD-2281 (50 mg/kg), Example 10 (50 mg) /kg), TMZ + Example 10 (25 mg/kg) and TMZ + Example 10 (50 mg/kg) groups. TMZ was administered continuously for 5 days once a day, AZD-2281, and Example 10 for 7 days, once daily. During the administration, the body weight of the mice was weighed and the tumor volume was measured. The observation was continued after the end of the administration, and the body weight of the mice and the tumor volume were measured. The results show that Example 10 has a good sensitizing effect on temozolomide and overcomes the resistance of temozolomide (Fig. 13, Table 7).

Table 7. Sensitization activity of Example 10 on TMZ in a U251/TMZ nude mouse xenograft model

(5) In combination with TMZ, inhibition of MX-1 breast cancer

The antitumor activities of Examples 35 and 36 were evaluated using the MX-1 nude mouse xenograft experiments. The method is as follows: human breast cancer MX-1 tumor cells are collected under aseptic conditions, and the cell density is adjusted to 1×10 ⁷ cells/ml with sterile physiological saline, 0.2 ml is inoculated into the back of the nude mice, and the tumor grows to a diameter. 1 cm in size, taken out under aseptic conditions, homogenized and evenly inoculated into the back of the nude mice. After the tumor was grown to 100-300 mm3 after 7 days, the animals were randomly divided into groups to start administration (denoted as day 0). Oral administration, temozolomide was continuously administered for 5 days, and the test compound was administered continuously for 6 days in the combined administration group, and the test compound single drug group was continuously administered for 10 days. The body weight was weighed three times a week and the length and width of the tumor were measured with a vernier caliper. The nude control group and each single drug group (except the TMZ group) were sacrificed and sacrificed on the 10th day after administration, and the combined administration group and the TMZ group were administered for 17 days. The nude mice were dislocated and sacrificed, the tumor tissues were dissected, weighed and photographed. Finally, the tumor inhibition rate was calculated, and the tumor inhibition rate was used to evaluate the antitumor effect intensity. The experiment was divided into blank control group, TMZ group (50 mg/kg), positive drug Olaparib group (25 mg/kg), Example 35 (25 mg/kg), Example 36 (25 mg/kg), and combined administration of Olaparib (25 mg/kg). +TMZ (50 mg/kg) group, Example 35 (12.5 mg/kg) + TMZ (50 mg/kg) group, Example 35 (25 mg/kg) + TMZ (50 mg/kg) group, Example 36 (12.5) Mg/kg) + TMZ (50 mg/kg) group, Example 36 (25 mg/kg) + TMZ (50 mg/kg) group.

The combined administration group TMZ was continuously administered for 5 days, and each inhibitor was administered for 6 days, and each group had a remarkable tumor suppressing effect (Fig. 14, Fig. 15). Since the TMZ group had a good anti-tumor effect, the persistence of the sensitization effect of each PARP inhibitor on TMZ was continuously observed after stopping the treatment in each group. Tumor growth curves showed that the sensitization effect of TMZ in Examples 35 and 36 lasted until day 14 (day 9 after TMZ withdrawal), and its sensitization effect was superior to Olaparib (Day 12). Animals were treated on day 17, and the combination of Example 35 and Example 36 had a significant antitumor effect compared to the TMZ group (Fig. 14, Fig. 15), which was superior to the Olaparib coadministration group.

(6) Inhibition of U87MG/Luc in situ glioma by combination with TMZ

The in vivo antitumor efficacy of Example 35 and Example 36 against human glioma U87MG/Luc was evaluated on a nude mouse orthotopic brain tumor model. METHODS: Human glioma tumor cells U87MG/Luc were collected under sterile conditions, and the cell density was adjusted to 2×10 ⁸ cells/ml with sterile saline and placed on ice. After intraperitoneal injection of 50 mg/kg sodium pentobarbital in nude mice, the prone position of the animal was fixed in a mouse brain stereotaxic apparatus. After disinfecting the scalp of the nude mouse with alcohol and iodine, the scalpel cut the scalp of the nude mouse sagitally, and the incision was cleaned by 3% H ₂ O _{2 to} expose the skull. 2mm behind the anterior iliac crest, 1.5mm on the right side, and drilled in the dental drill. The No. 26 microsyringe was injected with 5 μl of U87-MG tumor solution (about 1 × 10 ⁶ cells, the needle depth was 3 mm, the needle was withdrawn 0.5 mm, and the injection time was about 5 min). After the needle was stopped for 5 minutes, the needle was slowly pulled and the incision was disinfected. Intraperitoneal injection of 50,000 units of penicillin to fight infection. The in vivo imaging test was performed 4 days after the operation to confirm the tumor formation, and the drug was administered in groups. Oral administration, temozolomide was continuously administered for 5 days, and the test compound was administered continuously for 5 days in the combined administration group, and the test compound single drug group was continuously administered for 5 days. Tumor size was determined by small animal nuclear magnetic imaging MRI. The experiment was divided into blank control group, TMZ group (30 mg/kg), TMZ group (50 mg/kg), Example 35 (50 mg/kg), and Example 35 (25 mg/kg) + TMZ (50 mg/kg) group. Example 35 (50 mg/kg) + TMZ (50 mg/kg) group, Example 36 (50 mg/kg), Example 36 (25 mg/kg) + TMZ (50 mg/kg) group, Example 36 (50 mg/kg) +TMZ (50 mg/kg) group.

On the 7th day, the blank control animals began to die due to excessive brain tumors. On the 8th day, NMR results showed that no obvious tumors were found in the TMZ group and the combined groups of Example 35 and Example 36; the NMR results on the 32nd day showed that TMZ 30 mg The tumors in the /kg and 50mg/kg dose groups showed a significant increase in tumors, and the animals in the TMZ 30mg/kg group died. Compared with the TMZ 30mg/kg group, the tumor volume of the 3525mg/kg combination group was significantly reduced. However, no obvious tumor was found in the combination group of Example 35 and Example 3650 mg/kg group (Fig. 16, Fig. 17, Table 8). The combination of Example 35 and Example 36 with temozolomide significantly prolonged the survival of nude mice (Figure 18).

Table 8. Growth inhibition of in situ glioma U87MG/Luc by Example 35 and Example 36 (Day 32)

1. The combined administration group TMZ was administered continuously for 5 days, and each inhibitor was administered continuously for 5 days.

2. NA: Not applicable

No. of CR: NMR image results showed the number of tumor-free nude mice.

Experimental Example 4: Pharmacokinetic Experiment

(1) Plasma pharmacokinetics after oral administration and intravenous administration of Example 10 in rats

experiment method:

1. Establishment of a standard curve for plasma samples

Example 10 (13 mg/mL DMSO) and AZD-2281 mother liquor (25 mg/mL DMSO) were separately diluted with acetonitrile to a concentration of 1, 2.5, 10, 50, 250, 500, 1000 ng/mL working solution.

50 μL of blank plasma was added to 50 μL of internal standard (propranolol, 10 μg/mL) and 50 μL of different concentrations of Example 10 or AZD-2281 working solution, and then centrifuged (14000 rpm×5 min) twice, and the supernatant was taken for 10 μL. LC/MS/MS analysis.

2. Plasma oral pharmacokinetic study of rats in oral and intravenous injections of Example 10 and AZD-2281

Example 10 was separately solubilized with a mixed solvent (PEG400: water = 5:1) or 0.5% CMC for 2 mg/mL for oral administration. Example 10 A 0.2 mg/mL solution was formulated with a mixed solvent (5% DMSO, 45% PEG, and 50% physiological saline) for intravenous administration. The formulation of the AZD-2281 oral and intravenous drug was the same as in Example 10.

30 SD rats were divided into 6 groups, 5 in each group. The rats in the oral group were fasted for 12 hours before administration and were given free access to water. The test used a continuous blood sampling method. Rats were orally administered with blood from the orbital venous plexus at 5, 15, 30, 1, 2, 4, 6, 8, 12, 24 h after oral administration of Example 10 or AZD-2281 (20 mg/kg); Or 2, 5, 15, 30, 1, 1.5, 2, 4, 6, 8, 12 h after AZD-2281 (1 mg/mL), blood was taken from the orbital venous plexus, and 50 μL of plasma was separated and stored frozen.

3. Plasma sample processing

50 μL of plasma sample was added with 50 μL of acetonitrile and 50 μL of internal standard. After mixing, it was centrifuged twice (14,000 rpm × 5 min), and 10 μL of the supernatant was taken for LC/MS/MS analysis.

4. LC/MS/MS conditions

Column: Zobax C18 (100 mm × 2.1 mm, 3.5 μm); column temperature: 30 ° C, mobile phase: acetonitrile / water (containing 0.1% formic acid) gradient; flow rate: 0.2 mL / min; MRM method detection m / z 465.2 → 297.0 (Example 10), m/z 435→281 (AZD-2281), m/z 260.0→183 (internal standard propranolol).

5. Data analysis

Plasma pharmacokinetic parameters were calculated using WinNonlin software.

Experimental Results: Plasma Pharmacokinetic Characteristics of Example 10

The plasma pharmacokinetic profile of Example 10 was evaluated and compared to AZD-2281 as shown in Table 9. (1) Rats were orally administered with Example 10 (20 mg/kg). The Cmax of the PEG group was significantly higher than that of the CMC group (362.7 ng/mL vs 6.7 ng/mL), and the AUC was about 4 times that of the CMC group. The bioavailability of the oral administration Example 10 (20 mg/kg) CMC group and PEG group in rats was 1.2% and 4.5%, respectively. (2) Rats were orally administered with AZD-2281 (20 mg/kg), and the Cmax and AUC of the PEG group were approximately twice that of the CMC group. The bioavailability of the oral AZD-2281 (20 mg/kg) CMC group and the PEG group in rats was 3.9% and 9.0%, respectively.

Table 9 Plasma kinetic parameters of oral administration of Example 10 and AZD (20 mg/kg) in rats

(2) Beagle dog oral administration example 10 plasma pharmacokinetics

experiment method:

1. Establishment of a standard curve for plasma samples

The mother liquor of Example 10 (DMSO preparation, 13 mg/mL) was diluted with acetonitrile to a concentration of 1, 2.5, 10, 50, 100, 250, 500, 1000 ng/mL working solution.

50 μL of blank plasma was added to 50 μL of internal standard (propranolol, 10 μg/mL) and 50 μL of working solution of Example 10 in different concentrations. After mixing, centrifuge (14000 rpm×5 min) twice, and take 10 μL of the supernatant for LC/MS/ MS analysis.

2. Oral and intravenous injection of dog Example 10 plasma pharmacokinetics study

Example 10 was ultrasonically dissolved in a mixed solvent (DMSO:PEG400:water=1:4:5) and a mixed solvent (5% DMSO, 45% PEG, and 50% physiological saline) to prepare 4 mg/mL and 0.2 mg/mL, respectively. The solution is for oral and intravenous administration.

Four Beagle dogs were orally administered with blood from the orbital venous plexus at 5, 15, 30, 1, 2, 4, 6, 8, 24 hours after oral administration of Example 10 (20 mg/5 mL/kg). After one week of washing, the lower extremity was intravenously injected with Example 10 ( Blood was taken from the upper extremity vein at 2, 5, 15, 30, 1, 1.5, 2, 4, 8, 12, 24 h after 0.4 mg / 2 mL / kg), and 50 μL of plasma was separated and stored frozen.

3. Plasma sample processing

4. LC/MS/MS conditions

Column: Zobax C18 (100 mm × 2.1 mm, 3.5 μm); column temperature: 30 ° C, mobile phase: acetonitrile / water (containing 0.1% formic acid) gradient; flow rate: 0.2 mL / min; MRM method detection m / z 465.2 → 297.0 (Example 10), m/z 260.0→183 (internal standard propranolol).

5. Data analysis

Plasma pharmacokinetic parameters were calculated using WinNonlin software.

Experimental Results: Plasma Pharmacokinetic Characteristics of Example 10

The dog peaked at 15-30 min after oral administration of Example 10 (20 mg/kg), and the mean plasma drug peak concentration was 3367.01 ng/mL, and t _1/2 was 2.65 h. The bioavailability of Oral Administration Example 10 was 18.8%, which was higher than that of rats (4.5%).

Table 10 Oral and intravenous injection of dog Example 10 plasma kinetic parameters

(3) Example 10 Determination of plasma, brain and tumor tissue in tumor-bearing mice

The tumor-bearing (MX-1) nude mice were given a single dose of 25 mg/kg in Example 10, and the tissue distribution was as shown in Table 11. The concentration of Example 10 in the tumor tissue was higher, about 60% of the plasma drug concentration. The compound can Can have better security and better PD / PK correlation.

Table 11. Tissue distribution of Example 10

(4) Plasma pharmacokinetics and brain tissue distribution after oral administration of Example 35 and Example 36 in rats:

experiment method:

1. Establishment of a standard curve for plasma samples

The mother liquor of Example 35 and Example 36 (DMSO, 10 mg/mL) was diluted with acetonitrile to a concentration of 2.5, 5, 10, 25, 50, 100, 250, 500, 1000 ng/mL working solution.

70 μL of blank plasma was added to different concentrations of Example 35 and Example 36 working solution 70 μL and internal standard (propranolol, 1 μg/mL) 70 μL, mixed and centrifuged (14,000 rpm × 5 min) twice, and the supernatant was taken 5 μL. LC/MS/MS analysis.

2. Plasma pharmacokinetic study of rats after oral administration of Example 35 and Example 36

Six rats were divided into two groups of three. Fasted for 12 hours before administration and free to drink water. The test used a continuous blood sampling method. Rats were orally administered with blood from the orbital venous plexus at 5, 15, 30, 1, 2, 4, 6, 8, 12, 24 h after oral administration of Example 35 and Example 36 (20 mg/kg, Tween 10 μL + CMC). 70 μL of plasma was frozen.

70 μL of plasma sample was added with 70 μL of acetonitrile and 70 μL of internal standard. After mixing, it was centrifuged twice (14,000 rpm × 5 min), and 5 μL of the supernatant was taken for LC/MS/MS analysis.

3. Rat oral administration of brain tissue distribution in Example 35 and Example 36

Six rats were divided into two groups of three. Fasted for 12 hours before administration and free to drink water. Rats were orally administered with blood and brain tissue at 5, 30, and 15 minutes after oral administration of Example 35 and Example 36 (20 mg/kg, Tween 10 μL). After washing the tissue with physiological saline, the filter paper was used to absorb water and weighed. A 25% tissue homogenate was prepared by adding physiological saline. 70 μL of tissue homogenate was taken, 70 μL of acetonitrile and 70 μL of internal standard were added, mixed and centrifuged (14,000 rpm×5 min) twice, and 5 μL of the supernatant was taken for LC/MS/MS analysis.

3. LC/MS/MS conditions

Column: Zobax C18 (100 mm × 2.1 mm, 3.5 μm); column temperature: 30 ° C, mobile phase: acetonitrile / water (containing 0.1% formic acid) gradient; flow rate: 0.2 mL / min; MRM method detection m / z 439.3 → 296.8 (Example 35), m/z 465.3→296.8 (Example 36).

4. Data analysis

Plasma pharmacokinetic parameters were calculated using WinNonlin software.

Experimental results:

Table 12 Plasma kinetic parameters of oral administration Example 35 and Example 36 (20 mg/kg) in rats

Table 13 Drug concentration of brain tissue after oral administration of Example 35 and Example 36 (20 mg/kg) in rats

(5) Plasma pharmacokinetic study of Beagle dogs oral Example 35 and Example 36

experiment method:

1. Establishment of a standard curve for plasma samples

The mother liquid (DMSO, 3 mg/mL) of Example 35 and Example 36 was diluted with acetonitrile to a mixed working solution having a concentration of 5, 10, 50, 200, 500, 1000, 1500, 2000 ng/mL.

60 μL of blank plasma was added to 60 μL of internal standard (propranolol, 1 μg/mL) and 60 μL of mixed test compound in different concentrations. After mixing, centrifuge (14000 rpm×5 min) twice, and take 3 μL of supernatant. LC/MS/MS analysis.

2. Plasma oral pharmacokinetic study of dogs in oral administration of Example 35 and Example 36

Example 35 and Example 36 were respectively ultrasonically prepared with a mixed solvent (DMSO:PEG400:water = 1:4:5) to prepare a 4 mg/mL suspension for oral administration.

Three of the Beagle dogs were orally administered to Example 35 for one week after oral administration of Example 36. The dog was orally administered with blood from the upper extremity at 5, 15, 30, 1, 2, 4, 6, 8, 12, 24 h after oral administration of Example 35 or Example 36 (20 mg/5 mL/kg). 60 μL of plasma was separated and frozen for 15 min. -4h plasma samples were diluted with 15 μL of 45 μL of blank plasma and frozen.

3. Plasma sample processing

60 μL of plasma sample was added with 60 μL of acetonitrile and 60 μL of internal standard. After mixing, it was centrifuged twice (14,000 rpm × 5 min), and 3 μL of the supernatant was taken for LC/MS/MS analysis.

4. LC/MS/MS conditions

Column: Zobax C18 (100 mm × 2.1 mm, 3.5 μm); column temperature: 30 ° C, mobile phase: acetonitrile / water (containing 0.1% formic acid) gradient; flow rate: 0.2 mL / min; MRM method detection m / z 439.3 → 296.8 (Example 35), m/z 465.2→297.0 (Example 36), m/z 260.0→ 183 (internal standard propranolol).

5. Data analysis

Plasma pharmacokinetic parameters were calculated using a non-compartmental model.

Experimental results:

Table 14 Plasma kinetic parameters of canine oral Example 35 and Example 36

After oral administration of Example 35 and Example 36 (20 mg/mL), the dogs peaked at 0.7 h and 2.7 h, respectively, with C _max of 6438 ng/mL and 4927 ng/mL, respectively, and t _1/2 was 3.8 h and 3.4 h, respectively. _(0-t) were 4.7 h and 4.4 h, respectively, and AUC _(0-t) was 34248 h*ng/mL and 320665*ng/mL, respectively.

Experimental Example 5: Safety Evaluation

(1) Example 10 acute toxicity test

The acute toxicity of the single dose oral and intraperitoneal administration of Example 10 was evaluated in Kunming mice. Mice were given a single oral dose of 5 g/kg and an intraperitoneal injection of 500 mg/kg, respectively, and 8 days after the administration, clinical signs and mortality of all animals were observed, and body weights were recorded at designated intervals. The mice were dissected after sacrifice and the organs were observed.

Mice did not die after oral administration of 5 g/kg for 1, 2, 4, 12, and 24 hours. After 4 and 8 days of administration, the mice showed no abnormal signs and no decrease in body weight. The animals were sacrificed and the organs were observed and observed. No abnormalities were observed.

Mice did not die after intraperitoneal injection of 500 m/kg for 1, 2, 4, 12, and 24 hours. After 4 and 8 days of administration, the mice showed no abnormal signs and no decrease in body weight. The animals were sacrificed and the organs were observed. No abnormalities were found, and no residual compounds were found in the abdominal cavity.

(2) Example 10 Mutagenicity Experiment (Ames)

The potential for the reversion mutation of the test strains TA 97, TA 98, TA 100, TA102 and TA1535 induced by Salmonella typhimurium in Example 10 was examined. The results of the study showed that Example 10 did not induce mutations in Salmonella either directly or through metabolic activation when the concentration of Example 10 reached a maximum dissolved concentration of 500 μg/plate.

(3) Example 35 acute toxicity test

The acute toxicity of a single oral dose of Example 35 was evaluated in Kunming mice. Mice were administered a single dose of each of the different doses of Example 35, observed for 10 days after administration, clinical signs and mortality of all animals were observed, and body weights were recorded at designated intervals. The mice were dissected after sacrifice and the organs were observed.

The LD _{50 of} Example 35 ranged from 3.5 to 5 g/kg.

(4) Example 36 acute toxicity test

The acute toxicity of the single dose oral administration of Example 36 was evaluated in Kunming mice. The mice were administered a single dose of different doses of Example 36, and 10 days after the administration, clinical signs and mortality of all animals were observed, and body weights were recorded at designated intervals. The mice were dissected after sacrifice and the organs were observed.

The LD _{50 of} Example 36 ranges from 1 to 3 g/kg.

Claims

a compound of the formula I and pharmaceutically acceptable salts or stereoisomers thereof,

In formula I,

A, B, C, D are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, substituted A C1-3 straight or branched alkyl group wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , R b 4 , Ra 8 , Rb 5 is independently selected from the group consisting of H, methyl, and ethyl;

The stereoisomers resulting from the substitution of A, B, C, D include the (R)-configuration and the (S)-configuration;

X is selected from the group consisting of NR A , O, S, Se, S=O, SO 2 , C=O,

When X is NR A , wherein R A is selected from the group consisting of the following atoms or groups or structural fragments:

(1) Hydrogen, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2-6 straight or branched Alkynyl, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein said Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , and Rd 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) CORe 1 , COORe 2 , CONRe 3 Rf 1 , SO 2 Re 4 , wherein the Re 1 , Re 2 , Re 3 , Re 4 , Rf 1 are independently selected from H, substituted or unsubstituted C 1 - 6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2-6 straight or branched alkynyl, substituted or unsubstituted C3-7 ring An alkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, said substituent being selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutene a group, oxetanyl, cyclopentyl, wherein said Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; 3-8 membered ring oxacycloalkyl and nitrogen heterocycle The alkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-4 straight or branched alkyl, F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclo a methylene group or a cyclobutyl group; the 3-8 membered ring oxacycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1) H, F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) a substituted or unsubstituted C1-4 straight or branched alkyl group, a substituted or unsubstituted C2-4 straight or branched alkenyl group, a substituted or unsubstituted C2-4 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, CF 3 , CH 2 CF 3 , CHF 2 , F, Cl, Br, CN, CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , ORh 5 , SRh 6 , NRh 7 Ri 3 , NRh 8 CORi 4 , NRh 9 COORi 5 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 , Rh 5 , Rh 6 , Rh 7 , Ri 3 , Rh 8 , Ri 4 , Rh 9 , Ri 5 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene , a cyclobutyl group; a 3-6 membered ring oxacycloalkyl group and a 3-6 membered ring azacycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;

(4) ORj 1 , NRj 2 Rk 1 , SRj 3 , NRj 4 CORk 2 , NRj 5 COORk 3 , NRj 6 SO 2 Rk 4 , wherein Rj 1 , Rj 2 , Rk 1 , Rj 3 , Rj 4 , Rk 2 , Rj 5 , Rk 3 , Rj 6 , Rk 4 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF 3 , CH 2 CF 3 , CHF 2 ;

R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry 2 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 , Rx 9 , Rx 10 , Ry 6 are independently selected From H, C1-3 straight or branched alkyl, halogen substituted C1-C3 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; said halogen includes F, Cl, Br, I; n 1 and n 2 are independently selected from 1, 2 , 3;

n is selected from an integer of 1, 2, and 3.
The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound is as shown in Formula IA

In Formula IA, at least one of A, B, C, and D is not hydrogen.

A, B, C, D are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, substituted A C1-3 straight or branched alkyl group wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , R b 4 , Ra 8 , Rb 5 is independently selected from the group consisting of H, methyl, and ethyl;

The stereoisomers resulting from the substitution of A, B, C, D include the (R)-configuration and the (S)-configuration;

R A is selected from the group consisting of the following atoms or groups or structural fragments:

(1) Hydrogen, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2-6 straight or branched Alkynyl, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein said Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , and Rd 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) CORe 1 , COORe 2 , CONRe 3 Rf 1 , SO 2 Re 4 , wherein the Re 1 , Re 2 , Re 3 , Re 4 , Rf 1 are independently selected from H, substituted or unsubstituted C 1 - 6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2-6 straight or branched alkynyl, substituted or unsubstituted C3-7 ring An alkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, said substituent being selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutene a group, an oxetanyl group, a cyclopentyl group, wherein said Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; 3-8 membered ring oxacycloalkyl and nitrogen heterocycle The alkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-4 straight or branched alkyl, F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclo a methylene group or a cyclobutyl group; the 3-8 membered ring oxacycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1) H, F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) a substituted or unsubstituted C1-4 straight or branched alkyl group, a substituted or unsubstituted C2-4 straight or branched alkenyl group, a substituted or unsubstituted C2-4 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein said Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, CF 3 , CH 2 CF 3 , CHF 2 , F, Cl, Br, CN, CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , ORh 5 , SRh 6 , NRh 7 Ri 3 , NRh 8 CORi 4 , NRh 9 COORi 5 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 , Rh 5 , Rh 6 , Rh 7 , Ri 3 , Rh 8 , Ri 4 , Rh 9 , Ri 5 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene , a cyclobutyl group; a 3-6 membered ring oxacycloalkyl group and a 3-6 membered ring azacycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;

(4) ORj 1 , NRj 2 Rk 1 , SRj 3 , NRj 4 CORk 2 , NRj 5 COORk 3 , NRj 6 SO 2 Rk 4 , wherein Rj 1 , Rj 2 , Rk 1 , Rj 3 , Rj 4 , Rk 2 , Rj 5 , Rk 3 , Rj 6 , Rk 4 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF 3 , CH 2 CF 3 , CHF 2 ;

R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry 2 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 , Rx 9 , Rx 10 , Ry 6 are independently selected From H, C1-3 straight or branched alkyl, halogen substituted C1-C3 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; said halogen includes F, Cl, Br, I; n 1 and n 2 are independently selected from 1, 2, and 3.
The compound according to claim 2, and pharmaceutically acceptable salts or stereoisomers thereof, wherein said compound is as shown in Formula IA-1

In Formula IA-1, at least one of A', B', C', D' is not hydrogen,

A', B', C', D' are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropene a methyl, substituted C1-3 straight or branched alkyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , wherein said Ra 1 , Ra 2 , Ra 3 and Rb 1 are independently selected from the group consisting of H, methyl and ethyl;

The stereoisomers resulting from the substitution of A', B', C', D' include the (R)-configuration and the (S)-configuration;

R' A is selected from the group consisting of the following atoms or groups or structural fragments:

(1) Hydrogen, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2-6 straight or branched Alkynyl, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, wherein Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , and Rd 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene;

(2) CORe 1 , COORe 2 , CONRe 3 Rf 1 , SO 2 Re 4 , wherein the Re 1 , Re 2 , Re 3 , Re 4 , Rf 1 are independently selected from substituted or unsubstituted C1-6 straight A chain or branched alkyl group, a substituted or unsubstituted C2-6 straight or branched alkenyl group, a substituted or unsubstituted C2-6 straight or branched alkynyl group, a substituted or unsubstituted C3-7 cycloalkyl group a substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, said substituent being selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, An oxetanyl group or a cyclopentyl group, wherein said Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene; 3-8 membered ring of oxacycloalkyl and azacycloalkyl Containing 1 hetero atom, it can also contain multiple heteroatoms at the same time;

(3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, and ring. a propyl group, a cyclopropylmethylene group, a cyclobutyl group; the 3-8 membered ring oxacycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

R' 1 , R' 2 , R' 3 and R' 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1) H, F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) a substituted or unsubstituted C1-4 straight or branched alkyl group, a substituted or unsubstituted C2-4 straight or branched alkenyl group, a substituted or unsubstituted C2-4 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, CF 3 , CH 2 CF 3 , CHF 2 , F, Cl, Br, CN, CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , ORh 5 , SRh 6 , NRh 7 Ri 3 , NRh 8 CORi 4 , NRh 9 COORi 5 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 , Rh 5 , Rh 6 , Rh 7 , Ri 3 , Rh 8 , Ri 4 , Rh 9 , Ri 5 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene , a cyclobutyl group; a 3-6 membered ring oxacycloalkyl group and a 3-6 membered ring azacycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;

(4) ORj 1 , NRj 2 Rk 1 , SRj 3 , NRj 4 CORk 2 , NRj 5 COORk 3 , NRj 6 SO 2 Rk 4 , wherein Rj 1 , Rj 2 , Rk 1 , Rj 3 , Rj 4 , Rk 2 , Rj 5 , Rk 3 , Rj 6 , Rk 4 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF 3 , CH 2 CF 3 , CHF 2 ;

R' 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , CH 2 ORx 9 , CH 2 NRx 10 Ry 6 , C1-C3 linear or branched alkyl, halogen-substituted C1-C3 straight or branched alkyl, C2-4 straight or branched Alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein said Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry 2 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 , Rx 9 , Rx 10 , Ry 6 are independently selected from H, methyl, and B. Base, propyl, CF 3 , CH 2 CF 3 , cyclopropyl, cyclopropylmethylene, cyclobutyl; the halogen includes F, Cl, Br, I.
A compound according to claim 3, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein said A', B', D' is selected from the group consisting of hydrogen.
A compound according to claim 4, and a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the stereoisomer resulting from the C' substitution is selected from the (R)-configuration.
The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound is as shown in Formula IB

In the formula IB,

R B is selected from the group consisting of the following atoms or groups or structural fragments:

(1) a substituted or unsubstituted C1-6 straight or branched alkyl group, a substituted or unsubstituted C2-6 straight or branched alkenyl group, a substituted or unsubstituted C2-6 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, an oxetanyl group, a cyclopentyl group, wherein Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) CORe 1 , COORe 2 , CONRe 3 Rf 1 , SO 2 Re 4 , wherein the Re 1 , Re 2 , Re 3 , Re 4 , Rf 1 are independently selected from substituted or unsubstituted C1-6 straight A chain or branched alkyl group, a substituted or unsubstituted C2-6 straight or branched alkenyl group, a substituted or unsubstituted C2-6 straight or branched alkynyl group, a substituted or unsubstituted C4-7 cycloalkyl group a substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, said substituent being selected from the group consisting of F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, An oxetanyl group or a cyclopentyl group, wherein said Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; 3-8 membered ring oxacycloalkyl and azacycloalkyl It may contain one hetero atom or multiple hetero atoms at the same time;

(3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-4 straight or branched alkyl, F, Cl, Br, CN, ORc 1 , SRc 2 , NRc 3 Rd 1 , COORc 4 , CONRc 5 Rd 2 , NRc 6 COORd 3 , SO 2 NRc 7 Rd 4 , NRc 8 CORd 5 , cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rc 1 , Rc 2 , Rc 3 , Rd 1 , Rc 4 , Rc 5 , Rd 2 , Rc 6 , Rd 3 , Rc 7 , Rd 4 , Rc 8 , Rd 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclo a methylene group or a cyclobutyl group; the 3-8 membered ring oxacycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1) H, F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) a substituted or unsubstituted C1-4 straight or branched alkyl group, a substituted or unsubstituted C2-4 straight or branched alkenyl group, a substituted or unsubstituted C2-4 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, CF 3 , CH 2 CF 3 , CHF 2 , F, Cl, Br, CN, CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , ORh 5 , SRh 6 , NRh 7 Ri 3 , NRh 8 CORi 4 , NRh 9 COORi 5 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 , Rh 5 , Rh 6 , Rh 7 , Ri 3 , Rh 8 , Ri 4 , Rh 9 , Ri 5 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene , a cyclobutyl group; a 3-6 membered ring oxacycloalkyl group and a 3-6 membered ring azacycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;

(4) ORj 1 , NRj 2 Rk 1 , SRj 3 , NRj 4 CORk 2 , NRj 5 COORk 3 , NRj 6 SO 2 Rk 4 , wherein Rj 1 , Rj 2 , Rk 1 , Rj 3 , Rj 4 , Rk 2 , Rj 5 , Rk 3 , Rj 6 , Rk 4 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF 3 , CH 2 CF 3 , CHF 2 ;

R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry 2 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 , Rx 9 , Rx 10 , Ry 6 are independently selected From H, C1-3 straight or branched alkyl, halogen substituted C1-C3 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; said halogen includes F, Cl, Br, I; n 1 and n 2 are independently selected from 1, 2, and 3.
The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound is as shown in the formula IC

In the formula IC, at least one of A, B, C, and D is not hydrogen.

A, B, C, D are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, substituted A C1-3 straight or branched alkyl group wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , R b 4 , Ra 8 , Rb 5 is independently selected from the group consisting of H, methyl, and ethyl;

The stereoisomers resulting from the substitution of A, B, C, D include the (R)-configuration and the (S)-configuration;

Y is selected from the group consisting of O, S, Se, S=O, SO 2 , C=O;

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1) H, F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) a substituted or unsubstituted C1-4 straight or branched alkyl group, a substituted or unsubstituted C2-4 straight or branched alkenyl group, a substituted or unsubstituted C2-4 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, CF 3 , CH 2 CF 3 , CHF 2 , F, Cl, Br, CN, CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , ORh 5 , SRh 6 , NRh 7 Ri 3 , NRh 8 CORi 4 , NRh 9 COORi 5 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 , Rh 5 , Rh 6 , Rh 7 , Ri 3 , Rh 8 , Ri 4 , Rh 9 , Ri 5 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene , a cyclobutyl group; a 3-6 membered ring oxacycloalkyl group and a 3-6 membered ring azacycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;

(4) ORj 1 , NRj 2 Rk 1 , SRj 3 , NRj 4 CORk 2 , NRj 5 COORk 3 , NRj 6 SO 2 Rk 4 , wherein Rj 1 , Rj 2 , Rk 1 , Rj 3 , Rj 4 , Rk 2 , Rj 5 , Rk 3 , Rj 6 , Rk 4 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF 3 , CH 2 CF 3 , CHF 2 ;

R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry 2 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 , Rx 9 , Rx 10 , Ry 6 are independently selected From H, C1-3 straight or branched alkyl, halogen substituted C1-C3 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; said halogen includes F, Cl, Br, I; n 1 and n 2 are independently selected from 1, 2, and 3. n is selected from an integer of 1, 2, and 3.
The compound according to claim 7 and pharmaceutically acceptable salts or stereoisomers thereof, wherein said A, B, D are selected from the group consisting of hydrogen.
A compound according to claim 8 and a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the stereoisomer resulting from the C substitution is selected from the (R)-configuration.
The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound is represented by the formula ID

In the formula ID,

Y is selected from the group consisting of O, S, Se, S=O, SO 2 , C=O;

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1) H, F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) a substituted or unsubstituted C1-4 straight or branched alkyl group, a substituted or unsubstituted C2-4 straight or branched alkenyl group, a substituted or unsubstituted C2-4 straight or branched alkynyl group Wherein the substituent is selected from the group consisting of F, Cl, Br, CN, NO 2 , CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , and Ri 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, CF 3 , CH 2 CF 3 , CHF 2 , F, Cl, Br, CN, CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , ORh 5 , SRh 6 , NRh 7 Ri 3 , NRh 8 CORi 4 , NRh 9 COORi 5 , wherein Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 , Rh 5 , Rh 6 , Rh 7 , Ri 3 , Rh 8 , Ri 4 , Rh 9 , Ri 5 are independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene , a cyclobutyl group; a 3-6 membered ring oxacycloalkyl group and a 3-6 membered ring azacycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;

(4) ORj 1 , NRj 2 Rk 1 , SRj 3 , NRj 4 CORk 2 , NRj 5 COORk 3 , NRj 6 SO 2 Rk 4 , wherein Rj 1 , Rj 2 , Rk 1 , Rj 3 , Rj 4 , Rk 2 , Rj 5 , Rk 3 , Rj 6 , Rk 4 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF 3 , CH 2 CF 3 , CHF 2 ;

R 5 is independently selected from the group consisting of H, F, Cl, Br, CN, NO 2 , ORx 1 , SRx 2 , NRx 3 Ry 1 , COORx 4 , CONRx 5 Ry 2 , NRx 6 COORy 3 , SO 2 NRx 7 Ry 4 , NRx 8 CORy 5 , (CH 2 )n 1 ORx 9 , (CH 2 )n 2 NRx 10 Ry 6 , a C1-C3 linear or branched alkyl group, a halogen-substituted C1-C3 straight or branched alkyl group, C2-4 straight or branched alkenyl, C2-4 straight or branched alkynyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl, wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Rx 5 , Ry 2 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 , Rx 9 , Rx 10 , Ry 6 are independently selected From H, C1-3 straight or branched alkyl, halogen substituted C1-C3 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; said halogen includes F, Cl, Br, I; n 1 and n 2 are independently selected from 1, 2, 3, and n is selected from integers of 1, 2, and 3.
The compound according to any one of claims 1 , 2 , 6 , 7 , 10 , and pharmaceutically acceptable salts and stereoisomers thereof, wherein said R 1 , R 2 , R 3 , R 4 , R 5 is independently selected from the group consisting of H, F, Cl, Br, and CN.
The compound according to any one of claims 1, 2, and 7 and pharmaceutically acceptable salts or stereoisomers thereof, wherein said A, D are selected from H, B, and C are independently selected from H, methyl , ethyl, propyl, CH 2 CF 3 , CHF 2 .
A compound according to claim 12, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein said B is selected from the group consisting of hydrogen.
A compound according to claim 13 and a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the stereoisomer resulting from the C substitution is selected from the (R)-configuration.
The compound and pharmaceutically acceptable salt or stereoisomer thereof as claimed in claim 3, wherein wherein said R '1, R' 2, R '3, R' 4, R '5 is independently selected from H, F, Cl, Br, CN.
A compound according to claim 3, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein said A', D' are independently selected from H, and B', C' are independently selected from H, methyl. , ethyl, propyl, CH 2 CF 3 , CHF 2 .
The compound according to claim 16 and pharmaceutically acceptable salts or stereoisomers thereof, wherein said B' is selected from the group consisting of hydrogen.
A compound according to claim 17 and a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the stereoisomer resulting from the C' substitution is selected from the (R)-configuration.
The compound according to any one of claims 1 to 18, and pharmaceutically acceptable salts or stereoisomers thereof, wherein the compound is selected from the group consisting of:

1) (S)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione 2,2, 2-trifluoroacetate

2) (R)-1-(3-(3-ethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione 2,2,2-trifluoroacetate

3) 1-(3-(morpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

4) 1-(3-(Thomamorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

5) (S)-2-Ethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluoro Benzoyl)piperazine-1-carboxylic acid tert-butyl ester

6) (R)-2-Ethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)-2-fluoro Benzoyl)piperazine-1-carboxylic acid tert-butyl ester

7) 1-(3-(4-(2,2,2-Trifluoroacetyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

8) 1-(3-(1-oxothiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

9) 1-(3-(1,1-dioxothiomorpholine-4-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

10) 1-(3-(4-(2,2,2-Trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

11) 1-(3-(4-(2,2,2-Trifluoroethyl)piperazine-1-formyl)-4-fluorobenzyl)-5-fluoroquinazoline-2,4 (1H ,3H)-dione

12) 1-(3-(4-(2,2,2-Trifluoroethyl)piperazine-1-formyl)-4-fluorobenzyl)-6-fluoroquinazoline-2,4 (1H ,3H)-dione

13) (3S,5R)-3,5-Dimethyl-4-(5-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl) )-2-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester

14) 1-(3-((3S,5R)-3,5-Dimethylpiperazine-1-formyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

15) (R)-1-(3-(3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2 ,4(1H,3H)-dione

16) (S)-1-(3-(3-methyl-4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2 ,4(1H,3H)-dione

17) (R)-1-(3-(3-Methyl-4-(isobutyryl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

18) (S)-1-(3-(3-Methyl-4-(isobutyryl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

19) (R)-1-(3-(3-methyl-4-(n-propyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

20) (S)-1-(3-(3-Methyl-4-(n-propyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

21) (R)-1-(3-(3-methyl-4-(2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H, 3H)-dione

22) (S)-1-(3-(3-methyl-4-(2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4 (1H, 3H)-dione

23) (R)-1-(3-(3-methyl-4-(cyclopropylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

24) (S)-1-(3-(3-Methyl-4-(cyclopropylmethyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H )-dione

25) (R)-1-(3-(3-Methyl-4-(isobutyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

26) (S)-1-(3-(3-Methyl-4-(isobutyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

27) (R)-1-(3-(3-methyl-4-(3-methyl-2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2 ,4(1H,3H)-dione

28) (S)-1-(3-(3-methyl-4-(3-methyl-2-butenyl)piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2 ,4(1H,3H)-dione

29) (R)-1-(3-(3-ethyl-4-methylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

30) (R)-1-(3-(3-ethyl-4-isopropylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

31) (R)-1-(3-(3-ethyl-4-cyclopropanylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

32) (R)-1-(3-(3-ethyl-4-acetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

33) (R)-1-(3-(3-ethyl-4-trifluoroacetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

34) (R)-1-(3-(3-ethyl-4-n-propylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

35) (R)-1-(3-(3-ethyl-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

36) (R)-1-(3-(3-ethyl-4-cyclopropylmethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

37) (R)-1-(3-(3-ethyl-4-propionylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

38) (R)-1-(3-(3-ethyl-4-trifluoroethylpiperazin-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

39) (S)-1-(3-(3-Ethyl-4-ethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

40) (S)-1-(3-(3-Ethyl-4-cyclopropylmethylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

41) (S)-1-(3-(3-ethyl-4-propionylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

42) (S)-1-(3-(3-ethyl-4-trifluoroethylpiperazin-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

43) (S)-1-(3-(3-ethyl-4-methylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

44) (S)-1-(3-(3-ethyl-4-isopropylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di ketone

45) (S)-1-(3-(3-ethyl-4-cyclopropanylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)- Diketone

46) (S)-1-(3-(3-ethyl-4-acetylpiperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione

47) (S)-1-(3-(3-ethyl-4-trifluoroacetyl-piperazine-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H) -dione

48) (S)-1-(3-(3-ethyl-4-n-propylpiperazin-1-carbonyl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-di Ketone

49) 1-(3-(4-Oxopiperidin-1-yl)-4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione.
A method of preparing a compound according to any one of claims 1 to 19, comprising the steps of:

The different quinazolinediones substituted with R 1 -R 4 and the 3-methoxycarbonylbenzyl bromide substituted with R 5 undergo selective alkylation reaction under the action of HMDS, and after hydrolysis, contain R 1 -R 5- substituted different 3-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzoic acid is condensed with piperazine or piperidine derivatives A partial 1-benzylquinazolinedione PARP-1 inhibitor is obtained, which can be further deprotected, alkylated, acylated, oxidized to obtain another part of 1-benzylquinazoline II. a ketone derivative obtained by direct aminolysis of methyl 3-((2,4-dioxo-3,4-dihydroquinazoline-1(2H)-yl)methyl)benzoate;

Reagents and reaction conditions: (a) urea, 140 ° C, 6 h; (b) i) lithium hexamethyldisilazide (HMDS), concentrated sulfuric acid, toluene, reflux, 2 h, ii) substituted 5-(bromo Methyl 2-fluorobenzoate, 145 ° C, 3 h, iii) methanol, hexanes, 70 ° C, 30 min; (c) LiOH, MeOH, H 2 O, THF, 55 ° C, 2 h; (d) 2 -(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBT), diisopropyl Ethylamine (DIEA), DMF (N,N-dimethylformamide), overnight definition of R 1 , R 2 , R 3 , R 4 , R 5 , A, B, C, D, X Said according to any of claims 1-19.
A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 19, and pharmaceutically acceptable salts or stereoisomers thereof, and a pharmaceutically acceptable carrier.
Use of a compound according to any one of claims 1 to 19, and a pharmaceutically acceptable salt or stereoisomer thereof, for the preparation of an antitumor drug or an antitumor drug sensitizer.
The use according to claim 22, wherein said tumor is selected from the group consisting of melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epithelial cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, Colon cancer, bladder cancer, glioma.
Use of a compound according to any one of claims 1 to 19, and pharmaceutically acceptable salts or stereoisomers thereof, for the preparation of a PARP-1 inhibitor.
Use of a compound according to any one of claims 1 to 19, and a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the prevention and/or treatment of a PARP-1 related disease.