CN108727343A

CN108727343A - Quinazolinones PARP-1/2 inhibitor containing 3- amino nafoxidines and preparation method thereof, pharmaceutical composition and purposes

Info

Publication number: CN108727343A
Application number: CN201810313309.4A
Authority: CN
Inventors: 徐柏玲; 陈晓光; 赵海龙; 季鸣; 周洁; 王丽嫄; 姚海平; 金晶
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2017-04-21
Filing date: 2018-04-10
Publication date: 2018-11-02

Abstract

The invention discloses a new class of quinazoline -2,4 (1H, 3H)-diones PARP-1/2 inhibitor containing 3- amino nafoxidines and its preparation method and pharmaceutical composition and purposes.Specifically, the present invention relates to the quinazolines -2 containing 3- amino nafoxidines shown in general formula I, 4 (1H, 3H)-diketone derivative and its officinal salt, and preparation method thereof, composition and such compound containing such one or more compound are in preparation, prevention and/or treatment and the purposes in the relevant disease medicaments of PARP-1/2.

Description

Quinazolinones PARP-1/2 inhibitor containing 3- amino nafoxidines and its preparation Method, pharmaceutical composition and purposes

Technical field

The present invention relates to a new class of, and the quinazoline -2,4- diones PARP-1/2 containing 3- amino nafoxidines inhibits Agent, physiologically acceptable salt, and preparation method thereof, the pharmaceutical composition containing the compound and the compound are made For drug, especially as antitumor drug or as tumour medicine sensitizer and antitumor drug use in conjunction.

Background technology

Poly ADP-Ribose Polymerase (Poly ADP Ribose Polymerase, PARP) utilizes Adenosine diphosphate Glycosides ribose (ADP-ribose), with NAD⁺For substrate, posttranslational modification --- poly- ADP ribosylation is carried out to target proteins, into And the physiological function [B ü rkle, FEBS Journal 2005,272,4576-4589] of regulating cell.PARP families are altogether comprising extremely Few 17 members, wherein the research to PARP-1 is the most extensive.In the cell, PARP-1 is with NAD⁺(nicotinamide Adenine dinucleotide) it is substrate, by catalytic action by NAD⁺It is cracked into niacinamide and ADP ribose fragments, and will ADP-ribose segments are transferred on substrate protein one by one, polymer are formed, to regulate and control the function of substrate protein.This transcription It modifies afterwards in the reparation of damage dna with significant importance [Expert Rev.Anticancer Ther.10 (2010) 1125-1136].Have studies have shown that when using chemotherapeutics killing tumor cell, the increased activity of PARP-1, to generate Drug resistance.Therefore, inhibit the activity of PARP-1 that can effectively block the reparation of damage dna, it is anti-to be cooperateed with chemotherapeutics generation Function of tumor [Clin.Cancer Res.13 (2007) 2728-2737].More everybody is it is contemplated that research shows that PARP-1 There are synthetic lethal effects with breast cancer susceptibility gene (BRCA-1, BRCA-2), therefore PARP-1 inhibitor can be individually used for Treatment [Bryant, H.E.et the al.Nature 2005,434,913-7, N.Engl.J.Med.361 of BRCA mutated tumors (2009) 123-134] be in fact, tumour for other DNA repair pathways defects, PARP-1 inhibitor can generate synthesis Lethal effect, therefore PARP-1 inhibitor can be used for the treatment that a variety of DNA repair defective tumour.

In PARP families, homology highest [Kutuzov, the M.M.et al.Molecular of PARP-2 and PARP-1 Biology 48,485-495].The DNA that PARP-2 can also be damaged activates [Ame, J.C.et al.J Biol Chem 1999,274,17860-8].Pass through the observation to PARP-2 gene knockout models, it has been found that mouse is to ionising radiation, methyl The sensibility for changing reagent increases, and the unstability of genome increases.PARP-2 also plays effect in the reparation of damage dna.

There are many PARP-1 inhibitor in stage currently in clinical trials.Including ABT-888, AG-014699, AZD- [the J.Med.Chem.52 (2009) 514-523 such as 2281, MK-4827 and BMN673；J.Med.Chem.51(2008)6581– 6591；J.Med.Chem.52(2009)7170–7185；J.Med.Chem.59(2016)

335-357] wherein AZD2281, AG-014699 and MK-4827 has obtained U.S. FDA approval listing, is used for ovary The treatment of cancer.

Up to the present, there is stronger suppression to PARP-1 and PARP-2 into the PARP-1 inhibitor of clinical investigation phase System activity, and inhibitory activity is suitable.

The quinazoline diones class PARP-1/2 containing 3- amino nafoxidines that this patent design has synthesized new construction inhibits Agent, it is intended to provide completely new material base with the relevant diseases of PARP-1/2 for treatment.

Invention content

Present invention solves the technical problem that being to provide the quinazoline -2,4 containing 3- amino nafoxidines shown in Formulas I (1H, 3H)-diketone derivative and physiologically acceptable salt, preparation method, pharmaceutical composition and its preparing PARP- 1/2 inhibitor and its purposes in potential drug, the purposes in preparing antitumor drug or antitumor drug sensitizer.

To solve the technical problem of the present invention, the present invention provides following technical solutions：

There is provided the quinazoline diones containing piperazinones as shown in general formula I to spread out for the first aspect of technical solution of the present invention Biological or physiologically acceptable salt：

In Formulas I,

R₁、R₂、R₃And R₄It is independently selected from following atom or group or structure fragment, including

(1)H、F、Cl、Br、CN、NO₂、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂, wherein the Rh₁、Ri₁、 Rh₂、Rh₃、Rh₄、Ri₂Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, the third methylene of ring, cyclobutyl；

(2) substituted or non-substituted C1-4 linear or branched alkyl groups, substituted or non-substituted C2-4 linear chain or branched chains alkenyl, Substituted or non-substituted C2-4 linear chain or branched chain alkynyls, wherein substituent group are selected from F, Cl, Br, CN, NO₂、CONRh₁Ri₁、 COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂, wherein the Rh₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂Independently selected from H, methyl, ethyl, Propyl, isopropyl, cyclopropyl, the third methylene of ring, cyclobutyl；

(3) substituted or non-substituted C3-6 naphthenic base, substituted or non-substituted 3-6 membered rings oxacycloalkyl, substitution or The azacycloalkyl of non-substituted 3-6 membered rings, wherein substituent group are selected from methyl, ethyl, propyl, isopropyl, CF₃、CH₂CF₃、 CHF₂、F、Cl、Br、CN、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂、ORh₅、SRh₆、NRh₇Ri₃、NRh₈CORi₄、 NRh₉COORi₅, wherein the Rh₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂、Rh₅、Rh₆、Rh₇、Ri₃、Rh₈、Ri₄、Rh₉、Ri₅Independently Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, the third methylene of ring, cyclobutyl；The oxacycloalkyl and 3-6 of 3-6 membered rings 1 hetero atom can be contained in the azacycloalkyl of membered ring, multiple hetero atoms can also be contained simultaneously；

(4)ORj₁、NRj₂Rk₁、SRj₃、NRj₄CORk₂、NRj₅COORk₃、NRj₆SO₂Rk₄, wherein the Rj₁、Rj₂、 Rk₁、Rj₃、Rj₄、Rk₂、Rj₅、Rk₃、Rj₆、Rk₄Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, the third methylene of ring Base, cyclobutyl, CF₃, CH₂CF₃, CHF₂；

R₅Independently selected from H, F, Cl, Br, CN, NO₂、ORx₁、SRx₂、NRx3Ry1、COORx₄、CONRx₅Ry₂、 NRx₆COORy₃、SO₂NRx₇Ry₄、NRx₈CORy₅、(CH₂)n₁ORx₉、(CH₂)n₂NRx₁₀Ry₆, C1-C3 linear or branched alkyl groups, halogen The C1-C3 linear or branched alkyl groups of element substitution, C2-4 linear chain or branched chains alkenyl, C2-4 linear chain or branched chains alkynyl, cyclopropyl, ring third Methylene, cyclobutyl, oxetanylmethoxy, cyclopenta, wherein the Rx₁、Rx₂、Rx₃、Ry₁、Rx₄、Rx₅、Ry₂、Rx₆、Ry₃、 Rx₇、Ry₄、Rx₈、Ry₅、Rx₉、Rx₁₀、Ry₆Independently selected from H, C1-3 linear or branched alkyl group, halogen replace C1-C3 straight chains or Branched alkyl, cyclopropyl, the third methylene of ring, cyclobutyl；The halogen includes F, Cl, Br, I；n₁And n₂Independently selected from 1,2,3；

R₆Selected from following atom or group or structure fragment：

(1) hydrogen, substituted or non-substituted C1-8 linear or branched alkyl groups, substituted or non-substituted C2-8 linear chain or branched chain alkene Base, substituted or non-substituted C2-8 linear chain or branched chain alkynyls, wherein substituent group are selected from F, Cl, Br, CN, ORc₁、SRc₂、 NRc₃Rd₁、COORc₄、CONRc₅Rd₂、NRc₆COORd₃、SO₂NRc₇Rd₄、NRc₈CORd₅, cyclopropyl, the third methylene of ring, ring fourth Base, oxetanylmethoxy, cyclopenta, cyclohexyl, Ar, wherein the Rc₁、Rc₂、Rc₃、Rd₁、Rc₄、Rc₅、Rd₂、Rc₆、Rd₃、 Rc₇、Rd₄、Rc₈、Rd₅Independently selected from H, C1-4 linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl, wherein institute The Ar stated is independently selected from substituted or non-substituted phenyl, substituted or non-substituted nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted Five yuan of heteroaromatics, wherein substituent group be selected from C1-4 linear or branched alkyl groups, halogen replace C1-4 linear or branched alkyl groups, F, Cl、Br、NO₂, CN, methylene-dioxy, ORa '₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、 SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀, wherein the Ra '₁、Ra′₂、Ra′₃、 Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 Linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl, cyclopenta；The phenyl ring, nitrogenous hexa-atomic heteroaromatic, five yuan It can be monosubstituted in heteroaromatic, can also be polysubstituted；Hexa-atomic heteroaromatic can contain 1 N atom, can also contain multiple Nitrogen-atoms；Five yuan of heteroaromatics can contain there are one hetero atom, can also contain multiple hetero atoms, and hetero atom is selected from O, N, S；N is selected From 1,2,3；Wherein the halogen includes F, Cl, Br；

(2) substituted or non-substituted C3-7 naphthenic base, substituted or non-substituted 3-8 membered rings oxacycloalkyl, substitution or The azacycloalkyl of non-substituted 3-8 membered rings, wherein the substituent group be selected from C1-4 linear or branched alkyl groups, F, Cl, Br, CN、ORc₁、SRc₂、NRc₃Rd₁、COORc₄、CONRc₅Rd₂、NRc₆COORd₃、SO₂NRc₇Rd₄、NRc₈CORd₅, cyclopropyl, ring third Methylene, cyclobutyl, oxetanylmethoxy, cyclopenta, wherein the Rc₁、Rc₂、Rc₃、Rd₁、Rc₄、Rc₅、Rd₂、Rc₆、Rd₃、 Rc₇、Rd₄、Rc₈、Rd₅Independently selected from H, C1-4 linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl；3-8 membered rings Oxacycloalkyl and azacycloalkyl in can contain 1 hetero atom, multiple hetero atoms can also be contained simultaneously；

(3)CORe₁、COORe₂、CONRe₃Rf₁、SO₂Re₄, wherein the Re₁、Re₂、Re₃、Re₄、Rf₁Independently selected from H, substituted or non-substituted C1-6 linear or branched alkyl groups, substituted or non-substituted C2-6 linear chain or branched chains alkenyl, substitution or non- The oxa- of substituted C2-6 linear chain or branched chains alkynyl, substituted or non-substituted C3-7 naphthenic base, substituted or non-substituted 3-8 membered rings The azacycloalkyl of naphthenic base, substituted or non-substituted 3-8 membered rings, the substituent group are selected from F, Cl, Br, CN, ORc₁、SRc₂、 NRc₃Rd₁、COORc₄、CONRc₅Rd₂、NRc₆COORd₃、SO₂NRc₇Rd₄、NRc₈CORd₅, cyclopropyl, the third methylene of ring, ring fourth Base, oxetanylmethoxy, cyclopenta, wherein the Rc₁、Rc₂、Rc₃、Rd₁、Rd₄、Rc₅、Rd₂、Rc₆、Rd₃、Rc₇、Rd₄、Rc₈、 Rd₅Independently selected from H, C1-4 linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl；The oxa- cycloalkanes of 3-8 membered rings 1 hetero atom can be contained in base and azacycloalkyl, multiple hetero atoms can also be contained simultaneously；

(4) substituted or non-substituted phenyl, substituted or non-substituted nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted five yuan Heteroaromatic, wherein substituent group be selected from C1-4 linear or branched alkyl groups, halogen replace C1-4 linear or branched alkyl groups, F, Cl, Br, NO₂, CN, methylene-dioxy, ORa '₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀, wherein the Ra '₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、 Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 linear chain or branched chain Alkyl, cyclopropyl, the third methylene of ring, cyclobutyl, cyclopenta；The phenyl ring, nitrogenous hexa-atomic heteroaromatic, can in five yuan of heteroaromatics Can also be polysubstituted to be monosubstituted；Hexa-atomic heteroaromatic can contain 1 N atom, can also contain multiple nitrogen-atoms；Five First heteroaromatic can contain there are one hetero atom, can also contain multiple hetero atoms, and hetero atom is selected from O, N, S；N is selected from 1,2,3；Its Described in halogen include F, Cl, Br；

R₇Selected from following atom or group or structure fragment：

(2) substituted or non-substituted C3-7 naphthenic base, substituted or non-substituted 3-8 membered rings oxacycloalkyl, substitution or The azacycloalkyl of non-substituted 3-8 membered rings, wherein the substituent group be selected from C1-4 linear or branched alkyl groups, F, Cl, Br, CN、ORc₁、SRc₂、NRc₃Rd₁、COORc₄、CONRc₅Rd₂、NRc₆COORd₃、SO₂NRc₇Rd₄、NRc₈CORd₅, cyclopropyl, ring third Methylene, cyclobutyl, oxetanylmethoxy, cyclopenta, wherein the Rc₁、Rc₂、Rc₃、Rd₁、Rc₄、Rc₅、Rd₂、Rc₆、Rd₃、 Rc₇、Rd₄、Rc₈、Rd₅Independently selected from H, C1-4 linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl；3-8 membered rings Oxacycloalkyl and azacycloalkyl in can contain 1 hetero atom, multiple hetero atoms can also be contained simultaneously.

In general formula I, the R₁、R₂、R₃、R₄、R₅Independently it preferably is selected from H, F, Cl, Br, CN.

According to general formula I of the present invention, currently preferred compound and physiologically acceptable salt, including but not limited to general formula (IA) compound represented：

In formula (IA),

R′₁、R′₂、R′₃With R '₄It is independently selected from following atom or group or structure fragment, including

H、F、Cl、Br、CN、NO₂, methyl, ethyl, trifluoromethyl, trifluoroethyl, CHF₂、CONH₂、OH、OCH₃、OC₂H₅、 Methylene-dioxy, NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃；

R₅Independently selected from H, F, Cl, Br, CN, NO₂、ORx₁、SRx₂、NRx3Ry1、COORx₄、CONRx₅Ry₂、 NRx₆COORy₃、SO₂NRx₇Ry₄、NRx₈CORy₅、CH₂ORx₉、CH₂NRx₁₀Ry₆, C1-C3 linear or branched alkyl groups, halogen substitution C1-C3 linear or branched alkyl groups, C2-4 linear chain or branched chains alkenyl, C2-4 linear chain or branched chains alkynyl, cyclopropyl, the third methylene of ring Base, cyclobutyl, oxetanylmethoxy, cyclopenta, wherein the Rx₁、Rx₂、Rx₃、Ry₁、Rx₄、Rx₅、Ry₂、Rx₆、Ry₃、Rx₇、 Ry₄、Rx₈、Ry₅、Rx₉、Rx₁₀、Ry₆Independently selected from H, methyl, ethyl, propyl, CF₃、CH₂CF₃, cyclopropyl, the third methylene of ring, Cyclobutyl；The halogen includes F, Cl, Br, I.

R₆Selected from following atom or group or structure fragment：

(4) substituted or non-substituted phenyl, substituted or non-substituted nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted five yuan Heteroaromatic, wherein substituent group be selected from C1-4 linear or branched alkyl groups, halogen replace C1-4 linear or branched alkyl groups, F, Cl, Br, NO₂, CN, methylene-dioxy, ORa '₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀, wherein the Ra '₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、 Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 linear chain or branched chain Alkyl, cyclopropyl, the third methylene of ring, cyclobutyl, cyclopenta；The phenyl ring, nitrogenous hexa-atomic heteroaromatic, can in five yuan of heteroaromatics Can also be polysubstituted to be monosubstituted；Hexa-atomic heteroaromatic can contain 1 N atom, can also contain multiple nitrogen-atoms；Five First heteroaromatic can contain there are one hetero atom, can also contain multiple hetero atoms, and hetero atom is selected from O, N, S；N is selected from 1,2,3；Its Described in halogen include F, Cl, Br.

R₇Selected from following atom or group or structure fragment：

In general formula IA, the R '₁、R′₂、R′₃、R′₄Independently it preferably is selected from H, F, Cl, Br, CN.

According to general formula IA of the present invention, currently preferred compound and its physiologically acceptable salt, including but not limited to General formula IA-1 compounds represented：

In Formulas I A-1,

R′₅Independently selected from H, F, Cl, Br, CN, NO₂, methyl, ethyl, trifluoromethyl, trifluoroethyl, CHF₂、CONH₂、 OH、OCH₃、OC₂H₅, methylene-dioxy, NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃；R₆Selected from following atom or group or structure piece It is disconnected：

R₇Selected from following atom or group or structure fragment：

In general formula IA-1, the R '₁、R′₂、R′₃、R′₄、R′₅Independently it preferably is selected from H, F, Cl, Br, CN.

According to general formula IA-1 of the present invention, currently preferred compound and its physiologically acceptable salt, including but it is unlimited In general formula IA-1a compounds represented：

In Formulas I A-1a,

R₆Selected from following atom or group or structure fragment：

R′₇It is independently selected from following atom or group or structure fragment, including

H, CH₃, C₂H₅, CH₂CF₃, n-propyl, isopropyl, cyclopropyl, Cvclopropvlmethvl.

In general formula IA-1a, the R '₁、R′₂、R′₃、R′₄Independently it preferably is selected from H, F, Cl, Br, CN.

According to general formula IA-1a of the present invention, currently preferred compound and its physiologically acceptable salt, including but it is unlimited In general formula IA-1a-1 compounds represented：

In Formulas I A-1a-1,

R′₆Selected from following atom or group or structure fragment：

(1) hydrogen, substituted or non-substituted C1-8 linear or branched alkyl groups, substituted or non-substituted C2-8 linear chain or branched chain alkene Base, substituted or non-substituted C2-8 linear chain or branched chain alkynyls, wherein substituent group are selected from F, Cl, Br, CN, OCH3, NHCH₃, ring third Base, the third methylene of ring, cyclobutyl, Ar, wherein the Ar is independently selected from substituted or non-substituted phenyl, substituted or non-substituted Nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted five yuan of heteroaromatics, wherein substituent group be selected from C1-4 linear or branched alkyl groups, halogen The C1-4 linear or branched alkyl groups of element substitution, F, Cl, Br, NO₂, CN, methylene-dioxy, OCH₃、NHCH₃；The phenyl ring contains It can be monosubstituted in the hexa-atomic heteroaromatic of nitrogen, five yuan of heteroaromatics, can also be polysubstituted；Hexa-atomic heteroaromatic can contain 1 N original Son can also contain multiple nitrogen-atoms；Five yuan of heteroaromatics can contain there are one hetero atom, can also contain multiple hetero atoms, miscellaneous Atom is selected from O, N, S；

(2) substituted or non-substituted C3-7 naphthenic base, substituted or non-substituted 3-8 membered rings oxacycloalkyl, substitution or The azacycloalkyl of non-substituted 3-8 membered rings, wherein the substituent group be selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br；1 hetero atom can be contained in the oxacycloalkyl and azacycloalkyl of 3-8 membered rings, multiple miscellaneous originals can also be contained simultaneously Son；

(3)CORe₁、COORe₂、CONRe₃Rf₁、SO₂Re₄, wherein the Re₁、Re₂、Re₃、Re₄、Rf₁Independently selected from H, substituted or non-substituted C1-6 linear or branched alkyl groups, substituted or non-substituted C2-6 linear chain or branched chains alkenyl, substitution or non- The oxa- of substituted C2-6 linear chain or branched chains alkynyl, substituted or non-substituted C3-7 naphthenic base, substituted or non-substituted 3-8 membered rings The azacycloalkyl of naphthenic base, substituted or non-substituted 3-8 membered rings, the substituent group are selected from F, Cl, Br, CN, OCH₃, ring third Base, the third methylene of ring, cyclobutyl, oxetanylmethoxy, cyclopenta, can be in the oxacycloalkyl and azacycloalkyl of 3-8 membered rings Containing 1 hetero atom, multiple hetero atoms can also be contained simultaneously；

(4) substituted or non-substituted phenyl, substituted or non-substituted nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted five yuan Heteroaromatic, wherein substituent group be selected from C1-4 linear or branched alkyl groups, halogen replace C1-4 linear or branched alkyl groups, F, Cl, Br, NO₂, CN, methylene-dioxy, OCH₃；The phenyl ring, nitrogenous hexa-atomic heteroaromatic in five yuan of heteroaromatics can be monosubstituted, also may be used To be polysubstituted；Hexa-atomic heteroaromatic can contain 1 N atom, can also contain multiple nitrogen-atoms；Five yuan of heteroaromatics can contain One hetero atom, can also contain multiple hetero atoms, and hetero atom is selected from O, N, S；Wherein the halogen includes F, Cl, Br；

In general formula IA-1a-1, the R '₁、R′₂、R′₃、R′₄Independently it preferably is selected from H, F, Cl, Br, CN.

According to general formula IA-1 of the present invention, currently preferred compound and its physiologically acceptable salt, including but it is unlimited In general formula IA-1b compounds represented：

In Formulas I A-1b,

R₆Selected from following atom or group or structure fragment：

In general formula IA-1b, the R '₁、R′₂、R′₃、R′₄Independently it preferably is selected from H, F, Cl, Br, CN.

According to general formula IA-1b of the present invention, currently preferred compound and its physiologically acceptable salt, including but it is unlimited In general formula IA-1b-1 compounds represented：

In Formulas I A-1b-1,

R′₆Selected from following atom or group or structure fragment：

In general formula IA-1b-1, the R '₁、R′₂、R′₃、R′₄Independently it preferably is selected from H, F, Cl, Br, CN.To complete this The purpose of invention, preferred compound include but is not limited to：

1) 3- (5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoylaminos) pyrroles Alkane -1- t-butyl formates

2) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene Formamide 3) 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 5-) methyl) benzamido) Pyrrolidines -1- t-butyl formates

4) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 5-) methyl)-N- (pyrrolidines -3- Base) benzamide 2,2,2- trifluoroacetates

5) 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates

6) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide 7) 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 7-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates

8) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 7-) methyl)-N- (pyrrolidines -3- Base) benzamide 2,2,2- trifluoroacetates

9) 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 8-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates

10) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 8-) methyl)-N- (pyrrolidines - 3- yls) benzamide 2,2,2- trifluoroacetates

11) 3- (the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates

12) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines - 3- yls) benzamide

13) 3- (the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) benzamido) pyrrole Cough up alkane -1- t-butyl formates

14) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) Benzamide 15) N- (1- methylpyrrolidin- 3- yls) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzamides

16) N- (1- (the third methyl of ring) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzamides

17) N- (1- (2,2,2- trifluoroethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

18) N- (1- isopentyl pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

19) N- (1- (amyl -3- bases)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzamides

20) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

21) N- (1- normal-butyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

22) N- (1- isobutyl-pyrrolidin -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

23) N- (1- n-propyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

24) N- (1- (2,2- bis-fluoro ethyls)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

25) N- (1- (oxetanone -3- bases)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines - 1 (2H)-yl) methyl) -2- fluorobenzamides

26) N- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzene amides

27) N- (1- (cyclopropane carbonyl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzamides

28) N- (1- (2,2,2- trifluoroacetyl groups) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines - 1 (2H)-yl) methyl) -2- fluorobenzamides

29) N- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzene amides

30) N- (1- benzyls pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzene amides

31) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- methoxy benzyls Base) pyrrolidin-3-yl) benzamide

32) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- fluorobenzene first Base) pyrrolidin-3-yl) benzamide

33) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (3- methylbenzene first Base) pyrrolidin-3-yl) benzamide

34) N- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzene amides

35) N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) -5- ((2,4- dioxos -3,4- Dihydroquinazoline -1 (2H)-yl) methyl) -2- fluorobenzene amides

36) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- carbonyl hexamethylenes Base) pyrrolidin-3-yl) benzamide

37) 3- (N- methyl -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoyls Amido) pyrrolidines -1- t-butyl formates

38) N- methyl-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

39) N- (1- trifluoroacetyl groups-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) the fluoro- N-methyl-benzamides of -2-

40) N- (1- cyclopropane carbonyls-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) the fluoro- N-methyl-benzamides of -2-

41) N- (1- acetyl group-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

42) N- (1- normal-butyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

43) N- (the third methylene of 1- rings-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) the fluoro- N-methyl-benzamides of -2-

44) N- (1- isobutyl-pyrrolidin -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

45) N- (1- isopentyl-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

46) 3- (N- ethyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoyls Amido) pyrrolidines -1- t-butyl formates

47) N- ethyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

48) N- (1- trifluoroacetyl groups-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) the fluoro- N- ethyl benzamides of -2-

49) N- (1- cyclopropane carbonyls-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) the fluoro- N- ethyl benzamides of -2-

50) N- (1- acetyl group-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

51) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

52) N- (1- n-propyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

53) 3- (N- n-propyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzene first Amide groups) pyrrolidines -1- t-butyl formates

54) N- n-propyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

55) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- n-propylbenzenes formamides of -2-

56) 3- (N- phenethyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzene first Amide groups) pyrrolidines -1- t-butyl formates

57) N- phenethyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

58) 3- (N- benzyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoyls Amido) pyrrolidines -1- t-butyl formates

59) N- benzyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

60) 3- (N- isobutyl groups -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzene first Amide groups) pyrrolidines -1- t-butyl formates

61) N- isobutyl groups-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

62) N- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- of 6- two Hydrogen quinazoline -1 (2H)-yl) methyl) benzamide

63) N- (1- benzyls pyrrolidin-3-yl) fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydroquinazolines of 6- -1 (2H)-yl) methyl) benzamide

64) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- first Oxygen benzyl) pyrrolidin-3-yl) benzamide

65) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- fluorine Benzyl) pyrrolidin-3-yl) benzamide

66) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (3- first Base benzyl) pyrrolidin-3-yl) benzamide

67) N- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- of 6- two Hydrogen quinazoline -1 (2H)-yl) methyl) benzamide

68) N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) fluoro- 5- of -2- ((fluoro- 2,4- of 6- bis- - 1 (2H)-yl of oxo -3,4- dihydroquinazolines) methyl) benzamide

69) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- carbonyls Butylcyclohexyl) pyrrolidin-3-yl) benzamide

70) N- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) the fluoro- 5- of -2- ((the fluoro- 2,4- dioxos -3,4- dihydros of 6- Quinazoline -1 (2H)-yl) methyl) benzamide

71) N- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) the fluoro- 5- of -2- ((the fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

72) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- isopentyl Pyrrolidin-3-yl) benzamide

73) the chloro- N- of 2- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydro quinoline azoles Quinoline -1 (2H)-yl) methyl) benzamide

74) N- (1- benzyls pyrrolidin-3-yl) the chloro- 5- of -2- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) benzamide

75) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- methoxy benzyls Base) pyrrolidin-3-yl) benzamide

76) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- fluorobenzene first Base) pyrrolidin-3-yl) benzamide

77) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (3- methylbenzene first Base) pyrrolidin-3-yl) benzamide

78) the chloro- N- of 2- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydro quinoline azoles Quinoline -1 (2H)-yl) methyl) benzamide

79) N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) -2- chloro- 5- ((2,4- dioxos - 3,4- dihydroquinazolines -1 (2H)-yl) methyl) benzamide

80) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- carbonyl hexamethylenes Base) pyrrolidin-3-yl) benzamide

81) the chloro- N- of 2- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydro quinoline azoles Quinoline -1 (2H)-yl) methyl) benzamide

82) the chloro- N- of 2- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) benzamide

83) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- isopentyl pyrroles Alkane -3- bases) benzamide

84) the chloro- N- of 2- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((fluoro- 2,4- dioxos -3,4- of 6- two Hydrogen quinazoline -1 (2H)-yl) methyl) benzamide

85) N- (1- benzyls pyrrolidin-3-yl) chloro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydroquinazolines of 6- -1 (2H)-yl) methyl) benzamide

86) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- first Oxygen benzyl) pyrrolidin-3-yl) benzamide

87) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- fluorine Benzyl) pyrrolidin-3-yl) benzamide

88) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (3- first Base benzyl) pyrrolidin-3-yl) benzamide

89) the chloro- N- of 2- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((fluoro- 2,4- dioxos -3,4- of 6- two Hydrogen quinazoline -1 (2H)-yl) methyl) benzamide

90) N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) chloro- 5- of -2- ((fluoro- 2,4- of 6- bis- - 1 (2H)-yl of oxo -3,4- dihydroquinazolines) methyl) benzamide

91) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- carbonyls Butylcyclohexyl) pyrrolidin-3-yl) benzamide

92) the chloro- N- of 2- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((the fluoro- 2,4- dioxos -3,4- dihydros of 6- Quinazoline -1 (2H)-yl) methyl) benzamide

93) the chloro- N- of 2- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) -5- ((the fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

94) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- isopentyl Pyrrolidin-3-yl) benzamide

There is provided the preparation method of compound described in first aspect, the skills of use for the second aspect of technical solution of the present invention Art scheme includes the following steps：R₁-R₄Substituted different quinazoline diones and include R₅Substituted 3- methoxycarbonyl group bromobenzyls are in HMDS Under the action of selective alkylated reaction occurs respectively, after hydrolysis, including R₁-R₅Different 3- ((the 2,4- dioxies of substitution - 1 (2H)-yl of generation -3,4- dihydroquinazolines) methyl) benzoic acid again with include R₆And R₇3- amino pyrrolidine derivatives carry out Condensation, obtains 1- benzyl quinazoline diones class compounds；Or include R₁-R₅Different the 3- ((2,4- dioxos -3,4- of substitution Dihydroquinazoline -1 (2H)-yl) methyl) benzoic acid again with N-Boc protection R₇Substituted 3- amino pyrrolidine derivative into After row condensation, Boc protecting groups are removed, R is re-introduced into₆Structure fragment obtains 1- benzyl quinazoline diones class compounds.

Reagent and reaction condition:(a) urea, 140 DEG C, 6h；(b) i) lithium hexamethyldisilazide (HMDS), the concentrated sulfuric acid, first Benzene, reflux, 2h, ii) substitution 5- (bromomethyl) -2- fluorophenyl carbamates, 145 DEG C, 3h, iii) methanol, hexane, 70 DEG C, 30min；(c)LiOH,MeOH,H₂O,THF,55℃,2h；(d) 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylureas Hexafluorophosphoric acid ester (HATU), I-hydroxybenzotriazole (HOBT), diisopropylethylamine (DIEA), DMF (N, N- dimethyl formyls Amine), overnight (overnight)；Or 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDC), I-hydroxybenzotriazole (HOBT), diisopropylethylamine (DIEA), DMF (n,N-Dimethylformamide), overnight (overnight)；(e) trifluoroacetic acid (TFA), DCM (dichloromethane), room temperature, or trifluoroacetic acids (TFA), DCM (dichloromethane), then ammonium hydroxide, room temperature；(f) acyl chlorides Or acid anhydrides, DCM (dichloromethane), ice bath, 30min；Aldehyde or ketone, sodium acetate, DCM (dichloromethane), methanol, cyano boron cyaniding Sodium, 37 DEG C.

The wherein R₁、R₂、R₃、R₄、R₅、R₆And R₇Definition and compound described in first aspect present invention definition phase Together.

In addition, the starting material and intermediate in above-mentioned reaction are easy to get, each step reaction can be according to the document reported Or it can be easy to synthesize with the conventional method in organic synthesis to those skilled in the art.Chemical combination described in general formula I Object can exist in the form of solvate or non-solvent compound, and carrying out crystallization using different solvents is likely to be obtained different solvents Compound.Pharmaceutically acceptable salt described in general formula I includes the salt of different acid, such as the salt of following inorganic acid or organic acid：Hydrochloric acid, hydrogen Bromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, trifluoroacetic acid, matrimony vine acid, maleic acid, tartaric acid, fumaric acid, citric acid, Lactic acid.Pharmaceutically acceptable salt described in general formula I further includes different alkali metal salts (lithium, sodium, sylvite), alkali salt (calcium, magnesium Salt) and ammonium salt, and the salt of the organic base of physiologically acceptable cation can be provided, and such as methylamine, dimethylamine, trimethylamine, piperidines, The salt of morpholine and three (2- ethoxys) amine.Conventional method preparation all can be used in all these salt within the scope of the present invention.

For the third aspect of technical solution of the present invention there is provided a kind of pharmaceutical composition, described pharmaceutical composition includes conduct Compound or pharmaceutically acceptable salt thereof described in technical solution of the present invention first aspect and common carrier pharmaceutically.

The composition includes at least one of present invention compound and pharmaceutically acceptable carrier.The medicine group It closes object and is selected from tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or various particulate delivery systems.The pharmaceutical composition Object can be prepared according to method well known in the art.Can by by the compounds of this invention with it is one or more pharmaceutically acceptable solid Body or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is in its medicine Content in compositions is usually 0.1-95 weight %.

The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, Vagina, rectum etc..

Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including True solution and colloidal solution), emulsion (including o/w types, w/o types and emulsion), suspension, injection (including liquid drugs injection, powder-injection And infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), granule, dissipate Agent, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..

It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made, Particulate delivery system.

These preparations are prepared according to method well known to the skilled artisan in the art.For manufacture tablet, capsule, packet Auxiliary material used in clothing agent is auxiliary agent routinely, such as starch, gelatin, Arabic gum, silica, polyethylene glycol, liquid dosage form institute Solvent for example has water, ethyl alcohol, propylene glycol, plant oil such as corn oil, peanut oil, olive oil etc..Contain chemical combination of the present invention Can also there are other auxiliary agents, such as surfactant, lubricant, disintegrant, preservative, corrigent, pigment etc. in the preparation of object.

In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute Release agent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, breast Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..

Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double Synusia and multilayer tablet.

In order to which capsule is made in administration unit, active ingredient the compounds of this invention and diluent, glidant can be mixed It closes, mixture is placed directly in hard capsule or soft capsule.It also can active ingredient the compounds of this invention is first and diluent, bonding Particle or pellet is made in agent, disintegrant, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet Release agent, binder, wetting agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention.

For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, osmotic pressure regulator is added.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder Injection can also be added mannitol, glucose etc. and be used as proppant.

In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.

To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any Prescription method is administered.

The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization The daily Suitable dosage ranges for closing object are 0.1-1000mg/Kg weight, preferably 1-500mg/Kg weight.Above-mentioned dosage can be with One dosage unit is divided into several dosage unit administrations, this depends on the clinical experience of doctor and including using other treatments The dosage regimen of means.

The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs. When the compound of the present invention and other medicines, which exist, to act synergistically, its dosage should be adjusted according to actual conditions.

There is provided the compounds and its pharmaceutical salts described in first aspect present invention for the fourth aspect of technical solution of the present invention Application in preparing PARP-1 and/or PARP-2 inhibitor, prepare prevent and or treatment and PARP-1 and/or PARP-2 Application, application in preparation of anti-tumor drugs in the drug of related disease, in the medicine for preparing disease related with tumour Application in object, wherein the tumour be selected from melanoma, gastric cancer, lung cancer, breast cancer, kidney, liver cancer, oral cavity epidermal carcinoma, Cervical carcinoma, oophoroma, cancer of pancreas, prostate cancer, colon cancer, carcinoma of urinary bladder, glioma.

Advantageous effects：

The patent application quinazolinone PARP1/2 inhibitor has very strong inhibitory activity, to PARP1/2 inhibitory activity Reach 10^-8To 10^-9M is horizontal.Compared with PARP-2 inhibitory activity, this patent part of compounds has certain choosing to PARP-1 Selecting property.Very strong internal antitumor activity is presented in present patent application compound.

Specific implementation mode

Invention is described further below with reference to embodiment, but is not limit the scope of the invention.

The structure of compound is determined by nuclear magnetic resonance (NMR) or high resolution mass spectrum (HRMS).The measurement of NMR is With Varian mercury 300 or Varian mercury 400, measurement solvent is CDCl₃、DMSO-d₆、acetone-d₆、 CD₃OD, is inside designated as TMS, and chemical shift is provided using ppm as unit.M.p. it is with DEG C fusing point provided, temperature does not add school Just.It is carrier that silica gel column chromatography, which generally uses 200~300 mesh silica gel,.

Abbreviated list：

TLC:Thin-layer chromatography；

CDCl₃：Deuterochloroform；DIEA：Diisopropylethylamine；TFA：Trifluoroacetic acid；TEA：Triethylamine

DMF：N,N-dimethylformamide；THF：Tetrahydrofuran；PE：Petroleum ether；EA：Ethyl acetate

min：Minute；R.t. room temperature；DCM：Dichloromethane；h：Hour；Et₃N：Triethylamine

EDC or EDCI：1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate

NBS：N- bromo-succinimides；DMAP：4-dimethylaminopyridine

AIBN：Azodiisobutyronitrile；Boc：Special butoxy carbonyl

HMDS：Lithium hexamethyldisilazide

HBTU：O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester

HATU：2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters

HOBt：1- hydroxy benzo triazoles；TFA：Trifluoroacetic acid；

Et₃N：Triethylamine；HOBt：I-hydroxybenzotriazole；NaH：Sodium hydride；

CCl₄：Carbon tetrachloride；DMSO-d₆：Deuterated dimethyl sulfoxide；acetone-d₆：Deuterated acetone

CD₃OD：Deuterated methanol；TMS：Tetramethylsilane

The preparation of intermediate：

(1) preparation of quinazoline -2,4 (1H, 3H)-diketone

Ortho-aminobenzoic acid (5g, 36.46mmol) and urea (50g, 83.25mmol) are added in reaction bulb, are warming up to 150 DEG C are reacted, and after 7h, are cooled to 100 DEG C, pour into a small amount of water, and decompression filters, and filter residue is washed with a small amount of water, methanol, filter cake 1L heat Sodium hydroxide solution dissolves, and pH to 3 is adjusted with concentrated hydrochloric acid at 0 DEG C, and decompression filters, a small amount of washing of filter cake.It is solid to obtain 4.5g whites Body, yield 76.1%.

¹H NMR(400MHz,DMSO-d₆)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℃。

(2) preparation of 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorophenyl carbamates

A) the fluoro- 5- bromomethyl-benzoic acid methyl esters of 2-

By fluoro- 5 methyl toluates (100mg, 0.60mmol) of 2-, NBS (112mg, 0.63mmol), AIBN (60mg, It 0.36mmol) sequentially adds in reaction bulb, CCl is added₄(5mL), flow back under Ar atmosphere 3h, and raw material is remaining on a small quantity, removes under reduced pressure Solvent is added anhydrous ether (10mL), is filtered under diminished pressure, filtrate is spin-dried for, column chromatography, obtains 20mg white solids, yield 13.5%.

¹H NMR(300MHz,CDCl₃)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- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorophenyl carbamates

Quinazoline -2,4 (1H, 3H)-diketone (411mg, 2.54mmol) is added in reaction bulb, dry toluene is added HMDS (819mg, 5.07mmol, 2.5eq), the concentrated sulfuric acid (4 drop, 0.1eq) is then added in (6mL), is warming up to reflux, when 40min The reaction was complete, forms clear solution, and decompression is spin-dried for solvent and remaining HMDS.The fluoro- 5- bromomethyls of 2- are added into reaction residues Methyl benzoate (938mg, 3.80mmol) reacts 3h at 140 DEG C.100 DEG C are cooled to, dioxy six is added in reaction bulb successively Ring (3mL) and methanol (2mL) stir 30min at 70 DEG C, are cooled to 0 DEG C, are filtered under diminished pressure to obtain 413mg white solids, yield 49.6%.

¹H NMR(300MHz,DMSO-d₆)δ(ppm):11.47 (brs, 1H), 8.02 (d, J=5.7Hz, 1H), 7.86 (d, J=4.5Hz, 1H), 7.66 (t, J=5.7Hz, 1H), 7.58-7.61 (m, 1H), 7.23-7.34 (m, 3H), 5.34 (s, 2H), 3.83(s,3H)；m.p.212-214℃.

Following intermediate is prepared according to above-mentioned conventional method

(3) preparation of 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorophenyl carbamates (200mg, It 0.61mmol) is added in reaction bulb, sequentially adds H₂O (2mL), THF (2mL) and MeOH (4mL), addition LiOH (82mg, 1.94mmol), 55 DEG C of reactions are warming up to, stop reaction after 55min, remove organic solvent under reduced pressure, ice bath lowers pH to 2, decompression Filtering, water washing, dry 176mg solids, yield 91.9%.¹H NMR(300MHz,DMSO-d₆)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=5.7Hz, 1H), 7.55-7.57(m,1H),7.23-7.31(m,3H),5.33(s,2H).m.p.>250℃

Embodiment 1

3- (5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoylaminos) pyrroles Alkane -1- t-butyl formates

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (200mg, 0.64mmol), HATU (487mg, 1.28mmol), HOBt (173mg, 1.28mmol) are added in reaction bulb, and anhydrous DMF is added DIEA (166mg, 1.28mmol) is added dropwise in (15mL), and N-Boc-3- amino-pyrrolidines are added after 15min is stirred at room temperature (178mg, 0.96mmol) is stirred overnight under r.t., reaction solution is poured into 100mL water, extracted with DCM (100mL), organic layer It is washed, is concentrated under reduced pressure with water (100mL), saturation NaCl (100mL) and water (100mL) successively, it is light to obtain 189mg for silica gel column chromatography Yellow solid, yield 61.7%, 171-173 DEG C of fusing point.

¹H NMR(300MHz,CDCl₃)δ(ppm):9.02 (s, 1H), 8.22 (d, J=7.8Hz, 1H), 8.09 (d, J= 7.5Hz, 1H), 7.59 (t, J=7.2Hz, 1H), 7.39 (m, 1H), 7.22-7.27 (m, 1H), 7.06-7.14 (m, 2H), 6.77-6.85(m,1H),5.35(s,2H),4.65-4.78(m,1H),3.69-3.76(m,1H),3.46-3.51(m,2H), 3.33(m,1H),2.20-2.29(m,1H),1.94-1.98(m,1H),1.42-1.47(m,9H).

Embodiment 2

5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene first Amide

By 3- (5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoylaminos) pyrroles Alkane -1- t-butyl formates (500mg, 1.04mmol) are dissolved in DCM (15mL), and TFA (2mL) is added, and reaction 2.5h is stirred at room temperature, stops It only reacts, reaction solution is concentrated, DCM/MeOH (10 is added:1,33mL), through concentrated ammonia liquor tune pH to alkalinity, liquid separation, water phase passes through again DCM/MeOH(10:1,20mL × 3) it extracts, merges organic phase, magnesium sulfate drying is concentrated to give white solid 380mg, yield 96%, 170-172 DEG C of fusing point.¹H NMR(500MHz,DMSO-d₆)δ(ppm):8.30 (d, J=8.0Hz, 1H), 8.03 (dd, J₁ =7.5Hz, J₂=2.0Hz, 1H), 7.64-7.68 (m, 1H), 7.55 (dd, J₁=6.5Hz, J₂=2.5Hz, 1H), 7.39- 7.42(m,1H),7.18-7.29(m,3H),5.31(s,2H),4.23-4.27(m,1H),2.95(dd,J₁=11.5Hz, J₂= 6.5Hz,1H),2.84-2.89(m,1H),2.70-2.75(m,1H),2.61(dd,J₁=11.0Hz, J₂=4.5Hz, 1H), 1.92-1.99(m,1H),1.56-1.62(m,1H).

Embodiment 3

3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 5-) methyl) benzamido) Pyrrolidines -1- t-butyl formates

By 5- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 5-) methyl) -2- fluobenzoic acids (220mg, 0.67mmol), HATU (510mg, 1.34mmol), HOBt (182mg, 1.34mmol) are added in reaction bulb, and anhydrous DMF is added (15mL) is added dropwise DIEA (174mg, 1.34mmol) and N-Boc-3- amino-pyrrolidines (185mg, 1.00mmol) is added afterwards, Reaction is stirred at room temperature overnight, reaction solution is poured into 100mL water, is extracted with DCM (100mL), organic layer uses water successively (100mL), saturation NaCl (100mL) and water (100mL) washing, are concentrated under reduced pressure, and silica gel column chromatography obtains 217mg white solids, produces Rate 65.5%, 152-154 DEG C of fusing point.¹H NMR(300MHz,CDCl₃)δ(ppm):8.57(s,1H),8.07(dd,J₁= 7.2Hz,J₂=2.1Hz, 1H), 7.51 (dt, J₁=8.1Hz, J₂=5.4Hz, 1H), 7.35-7.40 (m, 1H), 7.10 (dd, J₁ =11.4Hz, J₂=9.0Hz, 1H), 6.76-6.95 (m, 3H), 5.33 (s, 2H), 4.65-4.68 (m, 1H), 3.69-3.76 (m,1H),3.46-3.51(m,2H),3.29-3.33(m,1H),2.16-2.32(m,1H),1.91-1.98(m,1H),1.46 (s,9H).

Embodiment 4

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 5-) methyl)-N- (pyrrolidines -3- Base) benzamide 2,2,2- trifluoroacetates

By 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 5-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates (60mg, 0.12mmol) be added reaction bulb in, sequentially add DCM (2mL) and TFA (2mL), Reaction 5h is stirred at room temperature, removes solvent and TFA under reduced pressure, a small amount of anhydrous ether is added, is filtered under diminished pressure, a small amount of anhydrous ether of filter cake Washing, dry 55mg brown solids, yield 89.2%, 62-64 DEG C of fusing point.¹H NMR(300MHz,DMSO-d₆)δ(ppm): 11.71 (s, 1H), 8.86 (brs, 2H), 8.62 (d, J=6.0Hz, 1H), 7.47-7.64 (m, 3H), 7.23-7.30 (m, 1H), 6.95-7.13(m,2H),5.30(s,2H),4.47-4.49(m,1H),3.11-3.42(m,4H),2.15-2.23(m,1H), 1.91-1.96(m,1H).

Embodiment 5

3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzamido) Pyrrolidines -1- t-butyl formates

By 5- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) -2- fluobenzoic acids (250mg, 0.76mmol), HATU (575g, 1.51mmol), HOBt (205mg, 1.51mmol) are added in reaction bulb, and dry DMF is added (15mL) is added dropwise DIEA (196mg, 1.51mmol) and N-Boc-3- amino-pyrrolidines (211mg, 1.13mmol) is added afterwards, Reaction is stirred at room temperature overnight, reaction solution is poured into 100mL water, is extracted with DCM (100mL), organic layer uses water successively (100mL), saturation NaCl (100mL) and water (100mL) washing, are concentrated under reduced pressure, and silica gel column chromatography obtains 265mg white solids, produces Rate 70.4%, 178-180 DEG C of fusing point.¹H NMR(300MHz,CDCl₃)δ(ppm):8.84 (s, 1H), 8.07 (d, J=5.7Hz, 1H),7.87-7.90(m,1H),7.26-7.37(m,2H),7.05-7.15(m,2H),6.79-6.82(m,1H),5.34(s, 2H),4.66(m,1H),3.73(dd,J₁=10.8Hz, J₂=6.0Hz, 1H), 3.49 (t, J=6.3Hz, 2H), 3.30-3.33 (m,1H),3.22-3.28(m,1H),1.94-1.98(m,1H),1.47(s,9H).

Embodiment 6

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide

By 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates (500mg, 1.00mmol) are dissolved in DCM (15mL), and TFA (1.5mL) is added, is stirred at room temperature anti- 5h is answered, stops reaction, reaction solution is concentrated, DCM/MeOH (10 is added:1,70mL), through concentrated ammonia liquor tune pH to alkalinity, liquid separation, water Mutually again through DCM/MeOH (10:1,30mL × 4) it extracts, merges organic phase, magnesium sulfate drying concentrates, then anhydrous through DCM/MeOH/ Diethyl ether recrystallization obtains white solid 360mg, yield 90%, 238-240 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):8.75 (d, J=6.0Hz, 1H), 7.73 (dd, J₁=8.0Hz, J₂ =3.0Hz, 1H), 7.65 (d, J=5.0Hz, 1H), 7.57 (td, J₁=8.5Hz, J₂=3.0Hz, 1H), 7.42-7.46 (m, 1H),7.35(dd,J₁=9.5Hz, J₂=4.0Hz, 1H), 7.25 (t, J=9.5Hz, 1H), 5.31 (s, 2H), 4.45-4.54 (m,1H),3.40(dd,J₁=12.0Hz, J₂=7.0Hz, 1H), 3.27-3.31 (m, 2H), 3.17-3.25 (m, 1H), 3.11 (dd,J₁=12.0Hz, J₂=5.0Hz, 1H), 2.14-2.22 (m, 1H), 1.89-1.97 (m, 1H)；HR-MS(ESI):m/z, calcd.for C₂₀H₁₉N₄O₃F₂[M+H]⁺401.1420,Found:401.1410.

Embodiment 7

3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 7-) methyl) benzamido) Pyrrolidines -1- t-butyl formates

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 7-) methyl) benzoic acid (220mg, 0.67mmol), HATU (510mg, 1.34mmol), HOBt (182mg, 1.34mmol) are added in reaction bulb, and dry DMF is added (15mL) is added dropwise DIEA (174mg, 1.34mmol) and the room N-Boc-3- amino-pyrrolidines (185mg, 1.00mmol) is added afterwards Temperature is stirred to react overnight, and reaction solution is poured into water (100mL), is extracted with DCM (100mL), and organic layer uses water successively (100mL), saturation NaCl (100mL) and water (100mL) washing, are concentrated under reduced pressure, and silica gel column chromatography obtains 233mg off-white powders, Yield 70.3%, 200-202 DEG C of fusing point.¹H NMR(300MHz,DMSO-d₆)δ(ppm):8.58 (d, J=6.6Hz, 1H), 8.07 (dd,J₁=8.4Hz, J₂=6.6Hz, 1H), 7.54-7.56 (m, 1H), 7.44 (m, 1H), 7.07-7.27 (m, 3H), 5.29 (s, 2H),4.35-4.38(m,1H),3.49-3.52(m,1H),3.28-3.41(m,2H),3.13-3.18(m,1H),2.05-2.08 (m,1H),1.84(m,1H),1.39(s,9H).

Embodiment 8

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 7-) methyl)-N- (pyrrolidines -3- Base) benzamide 2,2,2- trifluoroacetates

By 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 7-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates (60mg, 0.12mmol) be added reaction bulb in, sequentially add DCM (2mL) and TFA (2mL), Reaction 5h is stirred at room temperature, removes solvent and TFA under reduced pressure, a small amount of anhydrous ether is added, is filtered under diminished pressure, a small amount of anhydrous ether of filter cake Washing, dry 55mg brown solids, yield 89.2%, 105-107 DEG C of fusing point.

¹H NMR(300MHz,DMSO-d₆)δ(ppm):11.82 (s, 1H), 8.86 (brs, 2H), 8.62 (d, J=5.7Hz, 1H),8.08(dd,J₁=8.7Hz, J₂=6.6Hz, 1H), 7.57 (d, J=6.3Hz, 1H), 7.50 (m, 1H), 7.25-7.32 (m,1H),7.08-7.19(m,2H),5.30(s,2H),4.45-4.50(m,1H),3.24-3.46(m,3H),3.09-3.14 (m,1H),2.16-2.23(m,1H),1.89-1.96(m,1H).

Embodiment 9

3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 8-) methyl) benzamido) Pyrrolidines -1- t-butyl formates

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 8-) methyl) benzoic acid (180mg, 0.55mmol), HATU (419mg, 1.10mmol), HOBt (149mg, 1.10mmol) are added in reaction bulb, and dry DMF is added (15mL) is added dropwise DIEA (144mg, 1.10mmol) and the room N-Boc-3- amino-pyrrolidines (152mg, 0.82mmol) is added afterwards Temperature is stirred to react overnight, and reaction solution is poured into water (100mL), is extracted with DCM (100mL), and organic layer uses water successively (100mL), saturation NaCl (100mL) and water (100mL) washing, are concentrated under reduced pressure, and silica gel column chromatography obtains 191mg white solids, produces Rate 70.4%, 138-140 DEG C of fusing point.¹H NMR(300MHz,CDCl₃)δ(ppm):8.77 (s, 1H), 8.06 (d, J=7.8Hz, 1H), 8.01 (d, J=6.9Hz, 1H), 7.32-7.40 (m, 2H), 7.20-7.27 (m, 1H), 7.08 (dd, J₁=10.5Hz, J₂ =9.0Hz, 1H), 6.73-6.80 (m, 1H), 5.50 (s, 2H), 4.63-4.66 (m, 1H), 3.68-3.74 (m, 1H), 3.45- 3.50(m,2H),3.28-3.31(m,1H),2.20-2.28(m,1H),1.90-1.97(m,1H),1.46(s,9H)；HR-MS (ESI):m/z,calcd.For C₂₅H₂₆O₅N₄F₂Na523.1764[M+Na]⁺,Found:523.1754.

Embodiment 10

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 8-) methyl)-N- (pyrrolidines -3- Base) benzamide 2,2,2- trifluoroacetates

By 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 8-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates (77mg, 0.15mmol) be added reaction bulb in, sequentially add DCM (2mL) and TFA (2mL), Reaction 5h is stirred at room temperature, removes solvent and TFA under reduced pressure, a small amount of anhydrous ether is added, is filtered under diminished pressure, a small amount of anhydrous ether of filter cake Washing, dry 80mg pale solids, yield 101.1%, 105-106 DEG C of fusing point.

¹H NMR(300MHz,DMSO-d₆)δ(ppm):11.93 (s, 1H), 8.88 (brs, 2H), 8.61 (d, J=5.7Hz, 1H), 7.91 (d, J=7.2Hz, 1H), 7.47-7.61 (m, 2H), 7.41 (m, 1H), 7.22-7.31 (m, 2H), 5.34 (s, 2H),4.47-4.50(m,1H),3.08-3.48(m,4H),2.13-2.23(m,1H),1.90-1.97(m,1H).

Embodiment 11

3- (the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzamido) Pyrrolidines -1- t-butyl formates

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzoic acid (700mg, 2.00mmol), EDC (770mg, 4.00mmol), HOBt (540mg, 4.00mmol), DIEA (0.9mL, 5.00mmol) and change It closes object 1-Boc-3- amidos pyrrolidines (400mg, 2.08mmol) to be dissolved in anhydrous DMF (20mL), the lower ambient temperature overnight of argon gas protection Reaction.Stop reaction, reaction solution is through DCM/MeOH (10:1,60mL) it dilutes, organic phase is through saturated sodium bicarbonate (30mL), saturation Ammonium chloride (30mL), saturated salt solution (30mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=60:1--50: 1) white solid 960mg is obtained, and faint yellow solid 890mg, yield 85.6%, 150-152 DEG C of fusing point are recrystallized to obtain through DCM/PE.

¹H NMR(500MHz,CDCl₃)δ(ppm):9.06 (brs, 1H), 7.85 (d, J=7.5Hz, 1H), 7.63 (s, 1H), 7.36 (d, J=8.0Hz, 1H), 7.28-7.34 (m, 1H), 7.23 (d, J=9.0Hz, 1H), 7.03 (dd, J₁= 9.5Hz,J₂=4.0Hz, 1H), 6.55 (brs, 1H), 5.28 (brs, 2H), 4.61-4.64 (m, 1H), 3.67 (dd, J₁= 11.5Hz,J₂=6.0Hz, 1H), 3.45-3.50 (m, 2H), 3.38 (s, 1H), 2.21-2.26 (m, 1H), 2.00 (brs, 1H), 1.63(brs,1H),1.45(s,9H)；HR-MS(ESI):m/z,calcd.for C₂₅H₂₆N₄O₅FClNa[M+Na]⁺ 539.1468,Found:539.1454.

Embodiment 12

The chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide

By 3- (the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzene carbon amides Base) pyrrolidines -1- t-butyl formates (700mg, 1.35mmol) are dissolved in DCM (20mL), and TFA (2mL) is added, reaction is stirred at room temperature 5h stops reaction, reaction solution is concentrated, and DCM/MeOH (10 is added:1,70mL), through concentrated ammonia liquor tune pH to alkalinity, liquid separation, water phase Again through DCM/MeOH (10:1,30mL × 4) it extracts, merges organic phase, magnesium sulfate drying concentrates, then through the anhydrous second of DCM/MeOH/ Ether recrystallizes to obtain white solid 510mg, yield 90.4%, 199-201 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.86 (brs, 1H), 8.88 (brs, 1H), 8.80 (d, J= 6.5Hz,1H),7.74(dd,J₁=8.0Hz, J₂=3.0Hz, 1H), 7.57 (td, J₁=8.5Hz, J₂=3.0Hz, 1H), 7.47 (d, J=8.5Hz, 1H), 7.43 (s, 1H), 7.38 (d, J=8.5Hz, 1H), 7.28 (dd, J₁=9.5Hz, J₂=4.0Hz, 1H),5.32(s,2H),4.42-4.49(m,1H),3.48(dd,J₁=12.0Hz, J₂=7.5Hz, 1H), 3.21-3.31 (m, 2H),3.08(dd,J₁=12.0Hz, J₂=5.0Hz, 1H), 2.15-2.22 (m, 1H), 1.89-1.96 (m, 1H)；HR-MS (ESI):m/z,calcd.for C₂₀H₁₉N₄O₃FCl[M+H]⁺417.1124,Found:417.1112.

Embodiment 13

3- (the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) benzamido) pyrroles Alkane -1- t-butyl formates

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) benzoic acid (830mg, 2.50mmol), EDC (960mg, 5.00mmol), HOBt (680mg, 5.00mmol), DIEA (1.1mL, 6.25mmol) and change It closes object 1-Boc-3- amidos pyrrolidines (610mg, 3.25mmol) to be dissolved in anhydrous DMF (30mL), the lower room temperature reaction of argon gas protection 32h.Stop reaction, reaction solution is through DCM/MeOH (10:1,60mL) it dilutes, organic phase is through saturated sodium bicarbonate (30mL), saturation Ammonium chloride (30mL), saturated salt solution (30mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30: 1) yellow solid 1.08g is obtained, and white solid 1.06g, yield 85.5%, 197-199 DEG C of fusing point are recrystallized to obtain through DCM/PE.¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.71 (brs, 1H), 8.03 (d, J=7.0Hz, 1H), 7.66 (t, J=7.5Hz, 1H), 7.42-7.44 (m, 2H), 7.33 (d, J=8.5Hz, 1H), 7.23-7.28 (m, 2H), 5.31 (s, 2H),4.32-4.36(m,1H),3.42-3.52(m,1H),3.32-3.40(m,1H),3.28(brs,1H),3.15-3.24(m, 1H),2.01-2.11(m,1H),1.84(brs,1H),1.39(s,9H).

Embodiment 14

The chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzoyl Amine

By 3- (the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) benzamido) pyrroles Alkane -1- t-butyl formates (900mg, 1.80mmol) are dissolved in DCM (40mL), and TFA (4mL) is added, and reaction 5h is stirred at room temperature, stops Reaction, reaction solution is concentrated, and DCM/MeOH (10 is added:1,70mL), through concentrated ammonia liquor tune pH to alkalinity, liquid separation, water phase passes through again DCM/MeOH(10:1,30mL × 4) it extracts, merges organic phase, magnesium sulfate drying concentrates, then through DCM/MeOH/ anhydrous ether weights Crystallize to obtain white solid 620mg, yield 86.4%, 162-164 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.79 (brs, 1H), 8.90 (brs, 1H), 8.83 (d, J= 6.5Hz, 1H), 8.06 (d, J=7.5Hz, 1H), 7.69 (t, J=7.0Hz, 1H), 7.45-7.52 (m, 2H), 7.41 (dd, J₁ =8.5Hz, J₂=1.5Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 7.27 (d, J=8.5Hz, 1H), 5.35 (s, 2H), 4.46-4.51(m,1H),3.51(dd,J₁=12.0Hz, J₂=7.0Hz, 1H), 3.24-3.36 (m, 3H), 3.12 (dd, J₁= 12.0Hz,J₂=5.5Hz, 1H), 2.17-2.25 (m, 1H), 1.92-1.99 (m, 1H)；HR-MS(ESI):m/z,calcd.for C₂₀H₂₀N₄O₃Cl[M+H]⁺399.1218,Found:399.1212.

Embodiment 15

N- (1- methylpyrrolidin- 3- yls) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- Fluorobenzamide

A) tertiary butyl (1- methylpyrrolidin- 3- yls) carbamate

3-Boc- amino-pyrrolidines (150mg, 0.81mmol) are dissolved in MeOH (5mL), 37% formalin is sequentially added Solution (0.26mL) and sodium borohydride (92mg, 2.43mmol), are stirred overnight at room temperature, and remove solvent under reduced pressure, and gained grease is used Chloroform (40mL) dissolves, successively with salt washing (40mL), washing (40mL), anhydrous Na₂SO₄It is dry, it is solid to be concentrated to give 146mg whites Body.

¹H NMR(400MHz,CDCl₃)δ(ppm):5.02(m,1H),4.15(m,1H),2.79(m,1H),2.49-2.53 (m,2H),2.33(s,3H),2.21-2.30(m,2H),1.56-1.63(m,1H),1.43(s,9H).

B) 1- methylpyrrolidin- 3- amine hydrochlorates

Tertiary butyl (1- methylpyrrolidin- 3- yls) carbamate (140mg, 0.70mmol) is placed in a reaction flask, is added Enter the dioxane solution (2.08M, 4mL) of HCl, room temperature reaction overnight, removes solvent under reduced pressure, a small amount of anhydrous ether is added, subtracts Press filtration obtains 100mg white solids.

¹H NMR(300MHz,DMSO-d₆)δ(ppm):8.81(brs,3H),3.94(m,1H),3.34-3.58(m,4H), 2.84(s,3H),2.34(m,1H),2.12(m,1H).

C) N- (1- methylpyrrolidin- 3- yls) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzamides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (75mg, 0.24mmol), EDC (93mg, 0.48mmol), HOBt (65mg, 0.48mmol) are added in reaction bulb, and dry DMF is added (15mL), be added dropwise DIEA (63mg, 0.48mmol) be added afterwards 1- methylpyrrolidin- 3- amine hydrochlorates (40mg, 0.29mmol), be stirred at room temperature reaction overnight, reaction solution is poured into water (100mL), with DCM (100mL) extract, organic layer according to It is secondary to be washed with water (100mL), saturation NaCl (100mL) and water (100mL), it is concentrated under reduced pressure, silica gel column chromatography, it is solid to obtain 50mg whites Body, yield 47.6%, 114-116 DEG C of fusing point.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.18 (d, J=6.8Hz, 1H), 7.88 (m, 2H), 7.54 (m, 1H), 7.22(m,1H),6.92-7.09(m,3H),5.21(s,2H),4.78(m,1H),3.25(m,1H),3.06(m,1H),2.71 (m,1H),2.53(m,4H),2.38(m,1H),1.90(m,1H).

Embodiment 16

N- (1- (the third methyl of ring) pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

A) tertiary butyl (1- rings the third methylene pyrrolidine -3- bases) carbamate

3-Boc- amino-pyrrolidines (50mg, 0.27mmol) are added in reaction bulb, methanol (2mL), which is added, makes dissolving, with After sequentially add the third formaldehyde of ring (38mg, 0.54mmol), 3 drop trifluoroacetic acids and NaBH (OAc)₃(172mg, 0.81mmol), room Temperature continues to be stirred overnight, and the reaction was complete for raw material, silica gel column chromatography, obtains 30mg grease.¹H NMR(400MHz,Acetone-d₆)δ (ppm):6.11(m,1H),4.10(m,1H),2.79-2.80(m,2H),2.52-2.54(m,2H),2.35(m,2H),2.16- 2.19(m,1H),1.64-1.70(m,1H),1.40-1.41(m,9H),0.89(m,1H),0.46-0.49(m,2H),0.11- 0.12(m,2H).

B) 1- (the third methyl of ring) pyrrolidines -3- amine hydrochlorates

Tertiary butyl (1- rings the third methylene pyrrolidine -3- bases) carbamate (150mg, 0.62mmol) is placed in reaction bulb In, the dioxane solution (2.08M, 5mL) of HCl is added, is stirred overnight at room temperature, removes solvent under reduced pressure, dry grease.

C) N- (1- (the third methyl of ring) pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) -2- fluorobenzamides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (120mg, 0.39mmol), EDC (150mg, 0.78mmol), HOBt (106mg, 0.78mmol) are added in reaction bulb, and dry DMF is added (15mL), be added dropwise DIEA (79mg, 0.78mmol) be added afterwards 1- (the third methyl of ring) pyrrolidines -3- amine hydrochlorates (69mg, 0.39mmol), reaction is stirred at room temperature overnight, reaction solution is poured into 100mL water, is extracted with DCM (100mL), organic layer is successively It is washed, is concentrated under reduced pressure, silica gel column chromatography with water (100mL), saturation NaCl (100mL) and water (100mL), it is solid to obtain 40mg canescence Body, yield 24.0%, 113-115 DEG C of fusing point.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.19 (d, J=6.8Hz, 1H), 7.98 (m, 1H), 7.57 (m, 2H), 7.23 (m, 2H), 7.07 (d, J=8.0Hz, 1H), 7.00 (t, J=8.8Hz, 1H), 5.29 (s, 2H), 4.78 (m, 1H), 3.30 (m,1H),3.16(m,1H),2.84(m,1H),2.64(m,1H),2.48(m,3H),1.90(m,1H),1.00(m,1H),0.58 (m,2H),0.22(m,2H).

Embodiment 17

N- (1- (2,2,2- trifluoroethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

A) tert-butyl ester (1- trifluoroethyls pyrrolidin-3-yl) carbamic acid

3-Boc- amino-pyrrolidines (300mg, 1.62mmol) are dissolved in DMF (10mL), potassium carbonate is sequentially added (450mg, 3.24mmol) and trifluoromethanesulfonic acid trifluoroethyl ester (570mg, 2.40mmol), is stirred overnight at room temperature, by reaction solution It pouring into water (100mL), with saturated ammonium chloride tune pH to 6-7, then extracts (100mL × 3) with DCM, organic layer is concentrated under reduced pressure, Silica gel column chromatography obtains 300mg white solids, yield 62.7%.¹H NMR(400MHz,CDCl₃)δ(ppm):4.86(m,1H), 4.19(m,1H),3.03-3.11(m,3H),2.79-2.81(m,1H),2.75(m,1H),2.51-2.54(m,1H),2.23- 2.30(m,1H),1.59-1.70(m,1H),1.44(s,9H).

B) 1- (2,2,2- trifluoroethyls) pyrrolidines -3- amine hydrochlorates

(1- (2,2,2- trifluoroethyls) pyrrolidin-3-yl) t-butyl formate (150mg, 0.56mmol) is placed in reaction bulb In, the dioxane solution (2.08M, 4mL) of HCl is added, room temperature reaction overnight, removes solvent under reduced pressure, spare.

C) N- (1- (2,2,2- trifluoroethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (140mg, 0.45mmol), EDC (173mg, 0.90mmol), HOBt (122mg, 0.90mmol) are added in reaction bulb, and DIEA is added dropwise 1- (2,2,2- trifluoroethyl) pyrrolidines -3- amine hydrochlorates (113mg, 0.67mmol), room is added in (117mg, 0.90mmol) afterwards Temperature is stirred to react overnight, and reaction solution is poured into water (100mL), is extracted with DCM (100mL), and organic layer uses water successively (100mL), saturation NaCl (100mL) and water (100mL) washing, are concentrated under reduced pressure, silica gel column chromatography obtains 105mg solids, yield 50.8%, 157-158 DEG C of fusing point.

¹H NMR(400MHz,CDCl₃)δ(ppm):9.11-9.15 (m, 1H), 8.22 (d, J=7.6Hz, 1H), 8.07 (d, J=6.4Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.36 (m, 1H), 7.22-7.27 (m, 1H), 7.06-7.11 (m, 3H), 5.34(s,2H),4.69(m,1H),4.48-4.52(m,0.5H),3.58-3.61(m,0.5H),3.09-3.17(m,2.5H), 2.90-2.92(m,1.5H),2.56-2.63(m,1H),2.33-2.43(m,1H),1.80-1.83(m,1H).

Embodiment 18

N- (1- isopentyl pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzamides

A) tert-butyl ester (1- isopentyl pyrrolidin-3-yl) carbamic acid

By compound 3-Boc- amino-pyrrolidines (372mg, 2mmol), acetonitrile (15mL) is added, be added DIEA (0.52mL, 3mmol), 3- methyl-bromobutane (0.29mL, 2.4mmol) is added, is heated to 40 DEG C of reactions, stops reaction after 4h, concentration adds Enter ethyl acetate (50mL), is washed with saturation NaCl solution (20mL × 2), anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM=1: 40,MeOH:DCM=1:30) yellowish solid 420mg, yield 82%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):4.91(s,1H),4.16(s,1H),2.83(s,1H),2.58(s, 2H), 2.43 (t, J=7.2Hz, 2H), 2.20-2.30 (m, 2H), 1.52-1.65 (m, 2H), 1.44 (s, 9H), 1.30-.42 (m, 1H), 0.89 (d, J=6.4Hz, 6H)

B) 1- (isopentyl) pyrrolidines -3- amine trifluoroacetates

By tertiary butyl (1- isopentyl pyrrolidin-3-yl) carbamate (420mg, 1.65mmol), DCM is added TFA (1.2mL, 16.5mmol) is added in (10mL), and reaction is stirred at room temperature, stops reaction after 4h, concentration obtains viscous liquid 630mg, yield 100%.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):8.44(brs,2H),3.10-4.03(m,6H),1.90-2.11(m, 2H), 1.45-1.51 (m, 2H), 1.52-1.62 (m, 1H), 0.86 (d, J=6.4Hz, 6H)

C) N- (1- isopentyl pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.33mL, 1.9mmol) and 1- (isopentyl) pyrrolidines -3- amine trifluoroacetate (189mg, 0.57mmol), is stirred at room temperature Reaction, next day stop reaction, add water, use MeOH:DCM=1:10 mixed liquor extraction, organic layer saturation NaCl solution (20mL) is washed, anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM=1:40,MeOH:DCM=1:20) white solid is obtained 90mg, yield 52.6%, 175-177 DEG C of fusing point.¹H-NMR(400MHz,CDCl₃)δ(ppm):8.19 (d, J=7.6Hz, 1H), 8.00 (d, J=6.0Hz, 1H), 7.57 (t, J=7.2Hz, 1H), 7.42 (brs, 1H), 7.23 (t, J=7.6Hz, 2H), 7.06 (d, J=8.4Hz, 1H), 7.01 (t, J=10.4Hz, 1H), 5.29 (s, 2H), 4.71 (s, 1H), 3.10 (s, 1H), 2.92 (s, 1H), 2.53-2.70 (m, 2H), 1.80 (s, 1H), 1.52-1.62 (m, 1H), 1.42-1.46 (m, 2H), 0.90 (t, J= 6.4Hz,6H).

Embodiment 19

N- (1- (amyl -3- bases)-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) -2- fluorobenzamides

A) tert-butyl ester (1- (amyl -3- bases) pyrrolidin-3-yl) carbamic acid

By compound 3-Boc- amino-pyrrolidines (372mg, 2mmol), acetonitrile (15mL) is added, be added DIEA (0.52mL, 3mmol), 3- bromo pentane silanes (0.3mL, 2.4mmol), heating reflux reaction is added.Ethyl acetate (50mL) is added in concentration, with full It is washed with NaCl solution (20mL × 2), anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM=1:40,MeOH:DCM=1:30) it, obtains To yellowish solid 330mg, yield 64%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):4.33(s,1H),3.04(s,1H),2.95(s,1H),2.68(s, 1H), 2.48 (s, 1H), 2.30 (s, 1H), 1.94 (s, 1H), 1.65 (brs, 4H), 1.41 (s, 9H), 0.95 (t, J=7.2Hz, 6H)

B) 1- (amyl -3- bases) pyrrolidines -3- amine trifluoroacetates

By tertiary butyl (1- (amyl -3- bases) pyrrolidin-3-yl) carbamate (260mg, 1.01mmol), DCM is added TFA (0.73mL, 10mmol) is added in (10mL), and reaction is stirred at room temperature, stops reaction after 4h, concentration obtains viscous liquid 520mg, yield are more than 100%.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):10.41(s,0.5H),10.23(s,0.5H),8.45(s,1H), 8.39(s,0.5H),3.54-4.04(m,3H),3.17(brs,2H),1.99-2.28(m,2H),1.60-1.73(m,4H), 0.90 (t, J=7.2Hz, 6H)

C) N- (1- (amyl -3- bases)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzamides

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.33mL, 1.9mmol) and 1- (amyl -3- bases) pyrrolidines -3- amine trifluoroacetate (292mg, 0.76mmol), room temperature is stirred Reaction is mixed, next day stops reaction, adds water, use MeOH:DCM=1:10 mixed liquor extraction, organic layer saturation NaCl solution (20mL) is washed, anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM=1:40,MeOH:DCM=1:20,MeOH:DCM=1:15) Obtain white solid 50mg, yield 29.2%, 143-145 DEG C of fusing point.

¹H-NMR(400MHz,CDCl₃)δ(ppm):12.02(s,1H),8.88(s,0.4H),8.77(s,0.6H),8.18 (d, J=7.6Hz, 1H), 7.92 (d, J=6.0Hz, 1H), 7.66 (t, J=7.2Hz, 1H), 7.32 (brs, 1H), 7.23 (q, J =5.6Hz, 2H), 7.07 (t, J=9.6Hz, 1H), 5.33 (s, 2H), 5.13 (s, 1H), 3.95 (s, 1H), 3.72 (s, 1H), 3.24 (s, 1H), 2.94 (s, 2H), 2.55 (s, 1H), 2.49 (s, 1H), 1.87 (s, 4H), 1.09 (d, J=5.2Hz, 6H)

Embodiment 20

N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzamides

A) tert-butyl ester (1- ethyl pyrrolidine -3- bases) carbamic acid

By compound 3-Boc- amino-pyrrolidines (651mg, 3.5mmol), acetonitrile (20mL) is added, DIEA is added (0.92mL, 5.25mmol) is added bromoethane (0.3mL, 3.85mmol), reaction is stirred at room temperature.Stop reaction after 2h, concentrate, Column chromatography (MeOH:DCM=1:40,MeOH:DCM=1:30) yellowish solid 600mg, yield 80%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):6.16 (d, J=8.4Hz, 1H), 3.87 (s, 1H), 3.70 (s, 0.5H), 3.61 (s, 0.5H), 3.10~3.30 (m, 4H), 2.42~2.56 (m, 1H), 2.22 (brs, 1H), 1.53 (t, J= 6.0Hz,3H),1.42(s,9H)

B) 1- (ethyl) pyrrolidines -3- amine trifluoroacetates

By tertiary butyl (1- ethyl pyrrolidine -3- bases) carbamate (215mg, 1mmol), DCM (10mL) is added, is added Reaction is stirred at room temperature in TFA (0.73mL, 10mmol), stops reaction after 4h, and concentration obtains viscous liquid 400mg, and yield is super Cross 100%.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):10.53(s,0.5H),10.36(s,0.5H),8.41(s,3H), 3.45-4.02(m,3H),3.03-3.28(m,4H),2.48(brs,0.5H),2.24(brs,0.5H),2.13(brs,0.5H), 1.97 (brs, 0.5H), 1.21 (t, J=7.2Hz, 3H)

C) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), HBTU (286mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.33mL, 1.9mmol) and 1- (ethyl) pyrrolidines -3- amine trifluoroacetate (260mg, 0.76mmol) is stirred at room temperature anti- It answers, next day stops reaction, adds water, uses MeOH:DCM=1:10 mixed liquor extraction, organic layer saturation NaCl solution (20mL) It washes, anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM:Et₃N=1:60:0.3) white solid 29mg is obtained, yield 18.7%, 152-154 DEG C of fusing point.¹H-NMR(400MHz,CDCl₃)δ(ppm):8.19 (d, J=7.6Hz, 1H), 7.97 (d, J=6.8Hz, 1H), 7.70 (brs, 1H), 7.59 (t, J=8.4Hz, 1H), 7.21-7.30 (m, 2H), 7.10 (d, J=8.8Hz, 1H), 7.04 (t, J=10.4Hz, 1H), 5.30 (s, 2H), 4.83 (s, 1H), 3.37 (s, 1H), 3.20 (s, 1H), 2.73-2.85 (m, 3H), 2.60 (brs, 1H), 2.51 (brs, 1H), 2.04 (brs, 1H), 1.28 (t, J=7.2Hz, 3H)

Embodiment 21

N- (1- normal-butyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

A) tert-butyl ester (1- n-butylpyrrolioine -3- bases) carbamic acid

By compound 3-Boc- amino-pyrrolidines (558mg, 3mmol), acetonitrile (20mL) is added, be added DIEA (0.78mL, 4.5mmol), bromination of n-butane (0.38mL, 3.6mmol) is added, is heated to 40 DEG C of reactions, stops reaction after 4h, concentrate, be added Ethyl acetate (50mL) is washed with saturation NaCl solution (20mL × 2), anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM=1: 40,MeOH:DCM=1:30) yellowish solid 390mg, yield 53.7%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):5.10(s,1H),4.21(s,1H),2.96(s,1H),2.60-2.75 (m,2H),2.49(brs,2H),2.37(s,1H),2.27(s,1H),1.68(s,1H),1.48-1.55(m,2H),1.42(s, 9H), 1.31-1.36 (m, 2H), 0.91 (d, J=7.2Hz, 3H)

B) 1- (normal-butyl) pyrrolidines -3- amine trifluoroacetates

By tertiary butyl (1- n-butylpyrrolioine -3- bases) carbamate (200mg, 0.82mmol), DCM (8mL) is added, TFA (0.59mL, 8.2mmol) is added, reaction is stirred at room temperature, stops reaction after 3h, concentration obtains viscous liquid 300mg, produces Rate is more than 100%.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):10.53(s,0.5H),10.33(s,0.5H),8.41(s,3H), 3.60-4.03(m,3H),3.16-3.45(m,4H),2.47(brs,0.5H),2.23(brs,0.5H),2.11(brs,0.5H), 1.95 (brs, 0.5H), 1.50-1.62 (m, 2H), 1.20-1.31 (m, 2H), 0.88 (t, J=7.2Hz, 3H) .c) (1- is just by N- Butyl-pyrrol alkane -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), HBTU (286mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.33mL, 1.9mmol) and 1- (normal-butyl) pyrrolidines -3- amine trifluoroacetate (254mg, 0.68mmol), is stirred at room temperature Reaction, next day stop reaction, add water, use MeOH:DCM=1:10 mixed liquor extraction, organic layer saturation NaCl solution (20mL) is washed, anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM:Et3N=1:60:0.3) white solid 160mg, yield are obtained 83%, 34-136 DEG C of fusing point.¹H-NMR(400MHz,CDCl₃)δ(ppm):8.18 (d, J=7.6Hz, 1H), 7.98 (d, J= 6.8Hz, 1H), 7.58 (t, J=7.2Hz, 1H), 7.21-7.28 (m, 2H), 7.09 (d, J=8.4Hz, 1H), 7.02 (t, J= 10.4Hz, 1H), 5.29 (s, 2H), 4.76 (s, 1H), 3.28 (s, 1H), 3.10 (q, J=6.8Hz, 1H), 2.84 (brs, 1H), 2.73(brs,1H),2.64(brs,1H),2.45-2.60(m,2H),1.94(brs,1H),1.58-1.62(m,2H),1.34- 1.42 (m, 2H), 0.92 (t, J=7.2Hz, 3H)

Embodiment 22

N- (1- isobutyl-pyrrolidin -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

A) tert-butyl ester (1- isobutyl groups pyrrolidin-3-yl) carbamic acid

By compound 3-Boc- amino-pyrrolidines (651mg, 3.5mmol), acetonitrile (20mL) is added, DIEA is added Isobutane bromide (0.46mL, 4.2mmol) is added in (0.92mL, 5.25mmol), is heated to 40 DEG C of reactions, stops reaction after 3h, Concentration, column chromatography (MeOH:DCM=1:40,MeOH:DCM=1:30) yellowish solid 300mg, yield 35.4%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):4.84(s,1H),4.13(s,1H),2.76(s,1H),2.49(s, 2H), 2.16-2.30 (m, 4H), 1.66-1.73 (m, 1H), 1.52-1.58 (m, 1H), 1.43 (s, 9H), 0.89 (d, J= 6.4Hz,6H).

B) 1- (isobutyl group) pyrrolidines -3- amine trifluoroacetates

By tertiary butyl (1- isobutyl groups pyrrolidin-3-yl) carbamate (200mg, 0.82mmol), DCM (8mL) is added, TFA (0.59mL, 8.2mmol) is added, reaction is stirred at room temperature, stops reaction after 4h, concentration obtains viscous liquid 400mg, produces Rate is more than 100%.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):10.25(s,0.5H),9.95(s,0.5H),8.43(s,3H), 3.60-4.09(m,3H),3.47(brs,0.5H),3.28(brs,0.5H),3.01-3.15(m,3H),2.48(brs,0.5H), 2.26 (brs, 0.5H), 2.10 (brs, 0.5H), 0.90-1.99 (m, 1.5H), 0.92 (d, J=6.8Hz, 6H) .c) (1- is different by N- Butyl-pyrrol alkane -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), HBTU (286mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.33mL, 1.9mmol) and 1- (isobutyl group) pyrrolidines -3- amine trifluoroacetate (254mg, 0.68mmol), is stirred at room temperature Reaction, next day stop reaction, add water, use MeOH:DCM=1:10 mixed liquor extraction, organic layer saturation NaCl solution (20mL) is washed, anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM:Et3N=1:60:0.3) white solid 67mg, yield are obtained 40.3%, 174-176 DEG C of fusing point.¹H-NMR(400MHz,CDCl₃)δ(ppm):8.20 (d, J=8.0Hz, 1H), 8.03 (d, J= 6.4Hz, 1H), 7.58 (t, J=7.2Hz, 1H), 7.29 (brs, 1H), 7.23 (t, J=7.6Hz, 1H), 7.10 (d, J= 8.4Hz, 1H), 7.04 (t, J=8.8Hz, 1H), 5.32 (s, 2H), 4.73 (s, 1H), 3.09 (brs, 1H), 2.92 (brs, 1H), 2.67 (brs, 1H), 2.39 (brs, 4H), 1.83 (brs, 2H), 0.96 (d, J=6.4Hz, 6H)

Embodiment 23

N- (1- n-propyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

A) tertiary butyl (1- n-propyls pyrrolidin-3-yl) carbamate

By compound 3-Boc- amino nafoxidine (651mg, 3.5mmol), acetonitrile (20mL) is added, DIEA is added N-propyl bromide (0.38mL, 4.2mmol) is added in (0.92mL, 5.25mmol), is heated to 40 DEG C of reactions, stops reaction after 3h, Concentration, column chromatography (MeOH:DCM=1:40,MeOH:DCM=1:30) yellowish solid 650mg, yield 81%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):6.19 (d, J=8.0Hz, 1H), 4.62 (brs, 1H), 3.90 (brs, 1H), 3.64 (d, J=10.0Hz, 1H), 2.90-3.20 (m, 2.5H), 2.81-2.87 (m, 0.5H), 2.48-2.56 (m, 1H), 2.23-2.30 (m, 1H), 1.92 (brs, 2H), 1.42 (s, 9H), 1.02 (t, J=7.2Hz, 3H)

B) 1- (n-propyl) pyrrolidines -3- amine trifluoroacetates

By compound tert-butyl group (1- n-propyls pyrrolidin-3-yl) carbamate (200mg, 0.87mmol), DCM is added TFA (0.63mL, 8.7mmol) is added in (10mL), and reaction is stirred at room temperature, stops reaction after 4h, concentration obtains viscous liquid 400mg, yield are more than 100%.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):10.47(s,0.5H),10.28(s,0.5H),8.33-8.41(m, 3H),3.60-4.95(m,3H),3.46(brs,0.5H),3.30(brs,0.5H),3.05-3.20(m,3H),2.47(brs, 0.5H), 2.24 (brs, 0.5H), 2.11 (brs, 0.5H), 1.96 (brs, 0.5H), 1.57-1.67 (m, 2H), 0.89 (t, J= 7.2Hz,3H).

C) N- (1- n-propyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), HBTU (286mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.33mL, 1.9mmol) and 1- (n-propyl) pyrrolidines -3- amine trifluoroacetate (254mg, 0.68mmol), is stirred at room temperature Reaction, next day stop reaction, add water, use MeOH:DCM=1:10 mixed liquor extraction, organic layer saturation NaCl solution (20mL) is washed, anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM:Et₃N=1:60:0.3) white solid 97mg, yield are obtained 60.2%, 187-189 DEG C of fusing point.¹H-NMR(400MHz,CDCl₃)δ(ppm):8.19 (d, J=8.0Hz, 1H), 7.98 (d, J= 6.8Hz, 1H), 7.55 (t, J=7.6Hz, 1H), 7.36-7.42 (m, 1H), 7.20-7.25 (m, 2H), 7.04 (d, J= 8.8Hz, 1H), 6.98 (t, J=10.4Hz, 1H), 5.27 (s, 2H), 4.68 (s, 1H), 3.05-3.15 (m, 1H), 2.90 (d, J =9.6Hz, 1H), 2.55-2.70 (m, 2H), 2.30-2.45 (m, 3H), 1.77 (brs, 1H), 1.56 (q, J=7.6Hz, 2H), 0.93 (t, J=7.2Hz, 3H)

Embodiment 24

N- (1- (2,2- bis-fluoro ethyls)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzamides

A) tertiary butyl (1- (2,2- bis-fluoro ethyls) pyrrolidin-3-yl) carbamate

By compound 3-Boc- amino-pyrrolidines (500mg, 2.69mmol) be added DMF (20mL), be added DIEA (1.4mL, 8.07mmol) and 2,2- difluoros iodoethane (0.28mL, 3.22mmol), 70 DEG C of reactions, next day stop reaction, add water, use second Acetoacetic ester (30mL × 2) extracts, and merges organic layer and is washed with saturation NaCl (20mL × 2), anhydrous magnesium sulfate drying, concentration, column layer Analyse (MeOH:DCM=1:70) off-white powder 350mg, yield 52%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):5.98 (t, J=4.0Hz, 0.25H), 5.84 (t, J=4.0Hz, 0.5H), 5.70 (t, J=4.0Hz, 0.25H), 4.81 (brs, 1H), 4.17 (brs, 1H), 2.92 (brs, 1H), 2.83 (td, J₁=14.8Hz, J₂=4.0Hz, 2H), 2.62-2.76 (m, 2H), 2.38-2.48 (m, 1H), 2.20-2.30 (m, 1H), 1.54- 1.66(m,1H),1.44(s,9H)

B) 1- (2,2- bis-fluoro ethyls) pyrrolidines -3- amino trifluoroacetates

By compound tert-butyl group (1- (2,2- bis-fluoro ethyls) pyrrolidin-3-yl) carbamate (295mg, 1.18mmol) DCM (10mL) is added, TFA (0.87mL, 11.8mmol) is added, reaction is stirred at room temperature, stops reaction after 4h, is concentrated to dryness, directly Connect input in next step.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):5.98 (t, J=3.2Hz, 0.25H), 5.84 (t, J=3.2Hz, 0.5H), 5.70 (t, J=3.2Hz, 1H), 4.26 (brs, 5H), 3.28-3.36 (m, 1H), 2.86-3.02 (m, 4H), 2.81 (dd,J₁=12.8Hz, J₂=3.2Hz, 1H), 2.62-2.70 (m, 1H), 1.73-1.82 (m, 1H), 1.34-1.41 (m, 1H)

C) N- (1- (2,2- bis-fluoro ethyls)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (15mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.33mL, 1.9mmol) and 1- (2,2- bis-fluoro ethyls) pyrrolidines -3- amino trifluoroacetate (200mg, 0.76mmol), Reaction is stirred at room temperature, next day stops reaction, adds water, use DCM:MeOH=10:1 mixed liquor (30mL × 2) extraction, merges organic Layer is washed with saturation NaCl solution (15mL × 2), anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM=1:60,MeOH:DCM=1: 40) white solid 150mg, yield 88%, 111-113 DEG C of fusing point are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.87 (s, 1H), 8.21 (d, J=7.6Hz, 1H), 8.06 (d, J= 7.2Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.34-7.38 (m, 1H), 7.24 (t, J=7.6Hz, 1H), 7.05-7.10 (m,3H),6.03(brs,0.25H),5.90(brs,0.5H),5.76(brs,0.25H),5.33(s,2H),4.68(brs, 1H), 3.07 (brs, 0.5H), 2.83-2.95 (m, 4H), 2.51 (q, J=8.0Hz, 1H), 2.36-2.43 (m, 1H), 1.70- 1.85(m,1H)

Embodiment 25

N- (1- (oxetanone -3- bases)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

A) tertiary butyl (1- (oxetanone -3- bases)) pyrrolidin-3-yl) carbamate

DCM (5mL) is added in compound 3-Boc- amino-pyrrolidines (465mg, 2.5mmol), oxetanone is added (0.88mL, 15mmol) is added AcOH (0.2mL), reaction is stirred at room temperature, sodium triacetoxy borohydride is added after 6h (3.18g, 15mmol) continues that reaction is stirred at room temperature, and stops reaction after 2 days, and DCM (50mL) is added, with saturation NaCl solution (15mL × 2) are washed, anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM=1:70,MeOH:DCM=1:60,MEOH:DCM=1: 20) yellow oil 45mg, yield 7.5% are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):4.92 (brs, 1H), 4.69 (t, J=6.8Hz, 2H), 4.61 (q, J= 6.0Hz,2H),4.20(brs,1H),3.60-3.66(m,1H),2.82(brs,1H),2.57(brs,2H),2.25-2.30(m, 2H),1.60-1.75(m,1H),1.44(s,9H)

B) 1- (oxetanes -3- bases) pyrrolidines -3- amino trifluoroacetates

By compound tert-butyl group (1- (oxetanone -3- bases)) pyrrolidin-3-yl) carbamate (45mg, DCM (3mL) 0.18mmol) is added, TFA (0.13mL, 1.8mmol) is added, reaction is stirred at room temperature, stops reaction, concentration after 7h To doing, direct plunge into next step.

C) N- (1- (oxetanone -3- bases)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (43mg, 0.137mmol), DMF (10mL), EDC (53mg, 0.274mmol), HOBt (37mg, 0.274mmol), DIEA is added (0.12mL, 0.685mmol) and 1- (oxetanes -3- bases) pyrrolidines -3- amino trifluoroacetate (46mg, 0.18mmol), reaction is stirred at room temperature, next day stops reaction, adds water, use DCM:MeOH=10:1 mixed liquor (20mL × 2) extraction It takes, merges organic layer and washed with saturation NaCl solution (15mL × 2), anhydrous magnesium sulfate drying, column chromatography (MeOH:DCM=1:70, MeOH:DCM=1:50) white solid 25mg, yield 41.6%, 117-119 DEG C of fusing point are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):9.02 (s, 1H), 8.21 (d, J=7.6Hz, 1H), 8.05 (d, J= 7.2Hz, 1H), 7.57 (t, J=7.2Hz, 1H), 7.34-7.38 (m, 1H), 7.24 (t, J=7.6Hz, 1H), 7.03-7.10 (m,3H),5.33(s,2H),4.61-4.73(m,5H),3.65-3.72(m,1H),2.90-2.98(m,1H),2.63-2.75 (m,2H),2.32-2.43(m,2H),1.75-1,80(m,2H)

Embodiment 26

N- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzene amides

A) 4- toluenesulfonic acids (2- cyclopropylethyls) ester

2- cyclopropyl-ethanols (690mg, 9.0mmol) are dissolved in DCM (30mL), Et is added₃N (1.62g, 16.0mmol), DMAP (1.96g, 16.0mmol) is added dropwise to the DCM of paratoluensulfonyl chloride (2.3g, 12.0mmol) at room temperature (60mL) solution, drop finish the reaction was continued 2h, stop reaction, and reaction solution is washed through brine (30mL × 3), magnesium sulfate drying, concentration, Column chromatography (P:E=80:1) colorless oil 1.78g, yield 92.7% are obtained.

¹H NMR(500MHz,CDCl₃)δ(ppm):7.80 (d, J=8.0Hz, 2H), 7.35 (d, J=8.0Hz, 2H), 4.09 (t, J=7.0Hz, 2H), 2.45 (s, 3H), 1.54 (q, J=7.0Hz, 2H), 0.65-0.68 (m, 1H), 0.41 (dd, J₁ =12.5Hz, J₂=5.0Hz, 2H), 0.02 (dd, J₁=9.5Hz J₂=5.0Hz, 2H)；HR-MS(ESI):m/z, calcd.for C₁₂H₁₇O₃S[M+H]⁺241.0893,Found:241.0886.

B) (1- (2- cyclopropylethyls) pyrrolidin-3-yl) t-butyl carbamate

3- (Boc- amidos) pyrrolidines (652mg, 3.50mmol) is dissolved in acetonitrile 10mL, 4- toluenesulfonic acids are added (2- cyclopropylethyls) ester (1.01g, 4.20mmol) and DIEA (0.9mL, 5.25mmol), 40 DEG C of reaction 2d, stop reaction, will Reaction solution concentration, column chromatography (DCM:MeOH=60:1--40:1--20:1) yellow oil 470mg, yield 52.8% are obtained.

¹H NMR(500MHz,CDCl₃)δ(ppm):4.94(brs,1H),4.16(brs,1H),2.83(brs,1H),2.58 (brs,2H),2.50-2.56(m,2H),2.22-2.28(m,2H),1.60(brs,1H),1.37-1.46(m,11H),0.65- 0.69(m,1H),0.40-0.45(m,2H),0.02-0.05(m,2H)；HR-MS(ESI):m/z,calcd.forC₁₄H₂₇N₂O₂[M +H]⁺255.2067,Found:255.2060.

C) 1- (2- cyclopropylethyls) pyrrolidines -3- amine 2,2,2- trifluoroacetates

(1- (2- cyclopropylethyls) pyrrolidin-3-yl) t-butyl carbamate (650mg, 2.56mmol) is dissolved in DCM In (20mL), TFA (2mL) is added, reaction solution is concentrated, sequentially adds ethyl acetate (6mL × 2), chlorine by ambient temperature overnight reaction Imitative (6mL × 2), remove solvent and TFA under reduced pressure, obtain brown-red oil 900mg, yield 100%.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):8.17-8.40 (m, 2H), 7.54 (d, J=8.0Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 4.07 (brs, 0.5H), 3.95 (s, 1H), 3.75 (s, 0.5H), 3.64 (brs, 1H), 3.52 (brs, 0.5H),3.28(brs,3H),3.13(brs,1H),2.32(s,1.5H),2.27(brs,0.5H),2.15(brs,0.5H), 1.97 (brs, 0.5H), 1.55 (q, J=7.5Hz, 2H), 0.72 (brs, 1H), 0.44-0.50 (m, 2H), 0.11-0.16 (m, 2H).

D) N- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzene amides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (100mg, 0.318mmol), EDC (123mg, 0.64mmol), HOBt (87mg, 0.64mmol), DIEA (210mg, 1.59mmol) and 1- 2,2,2- trifluoroacetate (149mg, 0.41mmol) of (2- cyclopropylethyls) pyrrolidines -3- amine is dissolved in anhydrous DMF (15mL), The lower room temperature reaction of argon gas protection is for 24 hours.Stop reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated carbon Sour hydrogen sodium (30mL), saturated ammonium chloride (20mL × 2), saturated salt solution (20mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) faint yellow solid 130mg is obtained, and just through DCM/ Hexane recrystallizes to obtain faint yellow solid 120mg, yield 83.9%, 205-207 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.75 (s, 1H), 8.41 (d, J=6.8Hz, 1H), 8.02 (dd, J₁=8.0Hz, J₂=1.6Hz, 1H), 7.63-7.68 (m, 1H), 7.53 (dd, J₁=6.8Hz, J₂=2.4Hz, 1H), 7.38- 7.43 (m, 1H), 7.17-7.32 (m, 3H), 5.31 (s, 2H), 4.27-4.33 (m, 1H), 2.75 (t, J=8.4Hz, 1H), 2.55-2.63(m,1H),2.37-2.48(m,4H),2.06-2.16(m,1H),1.62-1.71(m,1H),1.28-1.37(m, 2H),0.63-0.7(m,1H),0.35-0.40(m,2H),-0.06-0.03(m,2H)；HR-MS(ESI):m/z,calcd.for C₂₅H₂₈N₄O₃F[M+H]⁺451.2140,Found:451.2141.

Embodiment 27

N- (1- (cyclopropane carbonyl) pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) -2- fluorobenzamides

By cyclopropanecarboxylic acid (23mg, 0.26mmol), 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluoro- N- (pyrrolidin-3-yl) benzamide 2,2,2- trifluoroacetates (83mg, 0.17mmol), HATU (130mg, 0.34mmol), reaction bulb is added in HOBt (46mg, 0.34mmol), is stirred at room temperature after DIEA (44mg, 0.34mmol) is added dropwise Overnight, reaction solution is poured into water (100mL) for reaction, is extracted with DCM (100mL), and organic layer uses water (100mL), saturation successively NaCl (100mL) and water (100mL) washing, are concentrated under reduced pressure, silica gel column chromatography, obtain 55mg faint yellow solids, and yield 73.0% melts 136-138 DEG C of point.

¹H NMR(300MHz,CDCl₃)δ(ppm):8.76 (s, 1H), 8.22 (d, J=7.8Hz, 1H), 8.08 (d, J= 5.7Hz,1H),7.56-7.62(m,1H),7.39(m,1H),7.22-7.27(m,1H),7.07-7.14(m,2H),6.84 (brs,1H),5.35(s,2H),4.72(m,1H),3.59-4.05(m,4H),2.04-2.34(m,2H),1.60(m,1H), 1.01(m,2H),0.77-0.80(m,2H).

Embodiment 28

N- (1- (2,2,2- trifluoroacetyl groups) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

A) tertiary butyl (1- (2,2,2- trifluoroacetyl groups) pyrrolidin-3-yl) carbamate

3-Boc- amino-pyrrolidines (150mg, 0.81mmol) are dissolved in DCM (2mL), pyridine is added dropwise respectively (78mg, 0.99mmol) and trifluoroacetic anhydride (192mg .0.90mmol), is stirred overnight at room temperature, and removes solvent, gained oil under reduced pressure Shape object is dissolved with ethyl acetate (100mL), is washed (100mL × 3), anhydrous Na₂SO₄It is dry, it is concentrated to give the faint yellow oilies of 177mg Object, yield 77.6%.

¹H NMR(400MHz,CDCl₃)δ(ppm):4.83(m,1H),4.26(m,1H),3.43-3.88(m,4H),2.12- 2.28(m,1H),1.96-2.05(m,0.5H),1.81-1.90(m,0.5H),1.42(s,9H).

B) 1- (3- amino-pyrrolidine -1- bases) -2,2,2- trifluoroethanone hydrochlorides

Tertiary butyl (1- (2,2,2- trifluoroacetyl groups) pyrrolidin-3-yl) carbamate (150mg, 0.53mmol) is set In reaction bulb, the ethyl acetate solution (2.16M, 4mL) of HCl is added, room temperature reaction overnight, removes solvent under reduced pressure, is added few Anhydrous ether is measured, is filtered under diminished pressure, obtains 124mg white solids, yield 107.8%.

¹H NMR(300MHz,DMSO-d₆)δ(ppm):8.46(brs,3H),3.60-3.91(m,5H),2.04-2.33(m, 2H).

C) N- (1- (2,2,2- trifluoroacetyl groups) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (75mg, 0.24mmol), EDC (93mg, 0.48mmol), HOBt (65mg, 0.48mmol) are added in reaction bulb, and DIEA is added dropwise (63mg, 0.48mmol) be raw material after be added 1- (3- amino-pyrrolidine -1- bases) -2,2,2- trifluoroethanones hydrochloride (79mg, 0.36mmol), reaction is stirred at room temperature overnight, reaction solution is poured into 100mL water, is extracted with DCM (100mL), organic layer is successively It is washed, is concentrated under reduced pressure with water (100mL), saturation NaCl (100mL) and water (100mL), silica gel column chromatography obtains 70mg pale yellow colored solids Body, yield 61.3%, 112-113 DEG C of fusing point.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.96 (brs, 1H), 8.22 (d, J=7.6Hz, 1H), 8.07 (d, J= 6.8Hz, 1H), 7.59 (t, J=7.6Hz, 1H), 7.41 (m, 1H), 7.23-7.27 (m, 1H), 7.07-7.14 (m, 2H), 6.80-6.87(m,1H),5.35(s,2H),4.72-4.79(m,1H),4.04-4.09(m,1H×0.5),3.92-3.98(m, 1H×0.5),3.58-3.84(m 3H),2.31-2.45(m,1H),2.14-2.20(m,1H×0.5),2.00-2.06(m,1H ×0.5)；HR-MS(ESI):m/z,calcd.ForC₂₂H₁₉O₄N₄F₄ 479.1337[M+H]⁺,Found:479.1335.

Embodiment 29

N- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzene amides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene Formamide (100mg, 0.40mmol), 4,4- difluoro-cyclohexanones (110mg, 0.78mmol), sodium acetate (87mg, 1.04mmol) are molten In dichloro (4mL) and methanol (1mL), 37 DEG C of reaction 2.5h are added sodium cyanoborohydride (52mg, 0.78mmol), continue anti- 2d is answered, stops reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase through saturated sodium bicarbonate solution (10mL), Saturated ammonium chloride solution (10mL), brine (20mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1) white solid 110mg is obtained, white solid 95mg, yield 72.5%, 211-213 DEG C of fusing point are recrystallized to obtain through DCM/PE.¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.42 (d, J=8.0Hz, 1H), 8.03 (dd, J₁=8.0Hz, J₂ =2.0Hz, 1H), 7.66 (td, J₁=8.0Hz, J₂=2.0Hz, 1H), 7.52 (dd, J₁=6.5Hz, J₂=2.5Hz, 1H), 7.40-7.43(m,1H),7.20-7.29(m,3H),5.31(s,2H),4.30-4.35(m,1H),2.76-2.81(m,1H), 2.65-2.71(m,1H),2.43-2.48(m,2H),1.96-2.24(m,4H),1.55-1.82(m,7H)；HR-MS(ESI):m/ z,calcd.for C₂₆H₂₈N₄O₃F₃[M+H]⁺501.2108,Found:501.2096.

Embodiment 30

N- (1- benzyls pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzene amides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene Formamide (100mg, 0.40mmol), benzaldehyde (140mg, 1.31mmol), sodium acetate (151mg, 1.83mmol) are dissolved in dichloro In (4mL) and methanol (1mL), 37 DEG C of reaction 2.5h are added sodium cyanoborohydride (120mg, 1.83mmol), the reaction was continued 2d, Stop reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated sodium bicarbonate solution (10mL), saturation Ammonium chloride solution (10mL), brine (20mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30: 1) white solid 75mg is obtained, white solid 65mg, yield 52.8%, 175-177 DEG C of fusing point are recrystallized to obtain through DCM/PE.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.75 (d, J=4.0Hz, 1H), 8.44 (d, J=7.0Hz, 1H), 8.02-8.04(m,1H),7.64-7.68(m,1H),7.51-7.53(m,1H),7.40-7.42(m,1H),7.19-7.31(m, 8H),5.30(s,2H),4.32(brs,1H),3.54-3.61(m,2H),2.76(brs,1H),2.60(brs,1H),2.45 (brs,1H),2.39(brs,1H),2.12-2.16(m,1H),1.70(brs,1H)；HR-MS(ESI):m/z,calcd.for C₂₇H₂₆N₄O₃F[M+H]⁺473.1984,Found:473.1973.

Embodiment 31

5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- methoxybenzyls) pyrroles Cough up alkane -3- bases) benzamide

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene Formamide (102mg, 0.26mmol), P-methoxybenzal-dehyde (110mg, 0.79mmol), sodium acetate (76mg, 0.92mmol) are molten In DCM (4mL) and methanol (1mL), sodium cyanoborohydride (60mg, 0.92mmol) is added, and the reaction was continued in 37 DEG C of reaction 9h 1d stops reaction, and reaction solution is through DCM/MeOH (10:1,30mL) it dilutes, organic phase is through saturated sodium bicarbonate solution (20mL), full With ammonium chloride solution (20mL), brine (20mL × 2) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) faint yellow solid 92mg is obtained, white solid is recrystallized to obtain through DCM/ n-hexanes 82mg, yield 62.1%, 171-173 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.75 (s, 1H), 8.43 (d, J=6.8Hz, 1H), 8.02 (d, J =8.0Hz, 1H), 7.65 (t, J=8.0Hz, 1H), 7.50-7.54 (m, 1H), 7.37-7.43 (m, 1H), 7.18-7.30 (m, 5H), 6.87 (d, J=8.4Hz, 2H), 5.30 (s, 2H), 4.25-4.35 (m, 1H), 3.73 (s, 3H), 3.51 (brs, 2H), 2.75(brs,1H),2.56(brs,1H),2.45(brs,1H),2.36(brs,1H),2.08-2.18(m,1H),1.67-1.71 (m,1H)；HR-MS(ESI):m/z,calcd.for C₂₈H₂₈N₄O₄F[M+H]⁺503.2089,Found:503.2080.

Embodiment 32

5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- benzyls) pyrroles Cough up alkane -3- bases) benzamide

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene Formamide (100mg, 0.26mmol), 4-Fluorobenzaldehyde (110mg, 0.79mmol), sodium acetate (76mg, 0.92mmol) are dissolved in In DCM (4mL) and methanol (1mL), 37 DEG C of reaction 9h are added sodium cyanoborohydride (60mg, 0.92mmol), the reaction was continued 1d, Stop reaction, reaction solution is through DCM/MeOH (10:1,30mL) it dilutes, organic phase is through saturated sodium bicarbonate solution (20mL), saturation Ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30: 1--DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 86mg is obtained, white solid 70mg is recrystallized to obtain through DCM/ n-hexanes, Yield 54.6%, 162-164 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.75 (s, 1H), 8.45 (d, J=6.4Hz, 1H), 8.03 (d, J =7.6Hz, 1H), 7.63-7.69 (m, 1H), 7.52 (d, J=6.4Hz, 1H), 7.38-7.44 (m, 1H), 7.31-7.37 (m, 2H), 7.18-7.30 (m, 3H), 7.13 (t, J=8.4Hz, 2H), 5.31 (s, 2H), 4.31 (brs, 1H), 3.52-3.60 (m, 2H), 2.76 (t, J=8.0Hz, 1H), 2.54-2.62 (m, 1H), 2.35-2.48 (m, 2H), 2.05-2.22 (m, 1H), 1.64- 1.79(m,1H)；HR-MS(ESI):m/z,calcd.for C₂₇H₂₅N₄O₃F₂[M+H]⁺491.1889,Found:491.1888.

Embodiment 33

5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (3- methylbenzyls) Pyrrolidin-3-yl) benzamide

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene Formamide (120mg, 0.31mmol), tolyl aldehyde (115mg, 0.93mmol), sodium acetate (90mg, 1.08mmol) are dissolved in In DCM (4mL) and methanol (1mL), 37 DEG C of reaction 1d are added sodium cyanoborohydride (70mg, 1.08mmol), the reaction was continued 1d, Stop reaction, reaction solution is through DCM/MeOH (10:1,30mL) it dilutes, organic phase is through saturated sodium bicarbonate solution (20mL), saturation Ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30: 1--DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 80mg is obtained, white solid 72mg is recrystallized to obtain through DCM/ n-hexanes, Yield 48%, 185-187 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.44 (d, J=6.8Hz, 1H), 8.02 (dd, J₁=7.6Hz, J₂=1.2Hz, 1H), 7.61-7.70 (m, 1H), 7.52 (dd, J₁=6.8Hz, J₂=2.4Hz, 1H), 7.38- 7.43(m,1H),7.17-7.30(m,4H),7.03-7.14(m,3H),5.30(s,2H),4.31(brs,1H),3.54(brs, 2H),2.76(brs,1H),2.58(brs,1H),2.47(brs,1H),2.38(brs,1H),2.29(s,3H),2.09-2.19 (m,1H),1.64-1.74(m,1H)；HR-MS(ESI):m/z,calcd.for C₂₈H₂₈N₄O₃F[M+H]⁺487.2140, Found:487.2141.

Embodiment 34

N- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzene amides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene Formamide (110mg, 0.29mmol), 4,4- dichloros cyclohexanone (150mg, 0.86mmol), sodium acetate (87mg, 1.01mmol) are molten In dichloro (6mL) and methanol (1.5mL), 37 DEG C of reaction 16h are added sodium cyanoborohydride (70mg, 1.01mmol), continue anti- Reaction should be stopped, reaction solution is through DCM/MeOH (10 for 24 hours:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated sodium bicarbonate solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH =50:1--40:1--30:1) faint yellow solid 62mg is obtained, pale solid 46mg, yield are recrystallized to obtain through DCM/ n-hexanes 29.9%, 215-217 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.42 (d, J=6.5Hz, 1H), 8.02 (d, J =7.5Hz, 1H), 7.66 (t, J=7.5Hz, 1H), 7.52 (d, J=5.0Hz, 1H), 7.41 (brs, 1H), 7.17-7.33 (m, 3H), 5.31 (s, 2H), 4.31 (brs, 1H), 2.79 (t, J=7.5Hz, 1H), 2.62-2.73 (m, 1H), 2.41-2.48 (m, 4H),2.06-2.29(m,4H),1.82(brs,2H),1.58-1.73(m,3H)；HR-MS(ESI):m/z,calcd.for C₂₆H₂₈N₄O₃Cl₂F[M+H]⁺533.1517,Found:533.1512.

Embodiment 35

N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydros Quinazoline -1 (2H)-yl) methyl) -2- fluorobenzene amides

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzene Formamide (300mg, 0.78mmol), 1,4- cyclohexanedione monoethylene acetals (370mg, 2.35mmol), sodium acetate (230mg, It 2.74mmol) is dissolved in dichloro (20mL) and methanol (5mL), 35 DEG C of reaction 12h, addition sodium cyanoborohydride (180mg, 2.74mmol), the reaction was continued for 24 hours, stops reaction, reaction solution is through DCM/MeOH (10:1,50mL) it dilutes, organic phase is through saturated carbon Sour hydrogen sodium solution (30mL), saturated ammonium chloride solution (30mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1--DCM:MeOH:Ammonium hydroxide=30:1:0.1) faint yellow solid 300mg is obtained, through DCM/ n-hexanes Recrystallize to obtain white solid 240mg, yield 58.7%, 149-151 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.73 (s, 1H), 8.40 (d, J=5.0Hz, 1H), 8.03 (d, J =7.5Hz, 1H), 7.66 (t, J=8.0Hz, 1H), 7.53 (d, J=5.5Hz, 1H), 7.41 (brs, 1H), 7.18-7.33 (m, 3H),5.31(s,2H),4.31(s,1H),3.83(s,4H),2.80(brs,1H),2.65(brs,1H),2.46(brs,2H), 2.10(brs,2H),1.64-1.79(m,5H),1.42-1.49(m,5H)；HR-MS(ESI):m/z,calcd.for C₂₈H₃₂N₄O₅F[M+H]⁺523.2351,Found:523.2335.

Embodiment 36

5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- carbonyls cyclohexyl) Pyrrolidin-3-yl) benzamide

By N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) -5- ((2,4- dioxos -3,4- two Hydrogen quinazoline -1 (2H)-yl) methyl) -2- fluorobenzene amide (100mg, 0.19mmol) is dissolved in acetone (10mL), 2N HCl are added (15mL) is reacted at room temperature for 24 hours, stops reaction, reaction solution is concentrated, and DCM/MeOH (10 is added:1,30mL), organic phase is through saturation Sodium bicarbonate solution tune pH value is to alkalinity, and liquid separation, water phase is again through DCM/MeOH (10:1,20mL × 3) it extracts, merges organic phase, Organic phase is washed through brine (20mL × 2), and magnesium sulfate drying, concentration recrystallizes to obtain faint yellow solid 52mg through DCM/ n-hexanes, Yield 57.1%, 201-203 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.79 (s, 1H), 8.49 (d, J=7.0Hz, 1H), 8.05 (d, J =7.5Hz, 1H), 7.68 (t, J=7.5Hz, 1H), 7.55 (d, J=5.0Hz, 1H), 7.44 (brs, 1H), 7.21-7.33 (m, 3H),5.34(s,2H),4.39(brs,1H),2.87(brs,1H),2.73-2.83(m,1H),2.51-2.57(m,2H), 2.37-2.49(m,3H),2.13-2.28(m,3H),1.94(br,2H),1.79-1.89(m,2H),1.69-1.78(m,1H)； HR-MS(ESI):m/z,calcd.for C₂₆H₂₈N₄O₄F[M+H]⁺479.2089,Found:479.2088.

Embodiment 37

3- (N- methyl -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

A) tertiary butyl 3- (((benzyloxy) carbonyl) amino) pyrrolidines -1- formic acid esters

N-Boc-3- amino-pyrrolidines (100mg, 0.54mmol) are added in reaction bulb, DCM (3mL) is added, at 0 DEG C by It is added dropwise to DIEA (105mg, 0.81mmol) and benzyl chloroformate (92mg, 0.54mmol), continues to stir 2h at room temperature, will react Liquid pours into 30mL water, and organic layer washes (30mL × 2), and concentration, silica gel column chromatography obtains 143mg yellow oils, yield 83.2%.

¹H NMR(300MHz,CDCl₃)δ(ppm):7.35(m,5H),5.10(s,2H),4.90(m,1H),4.24(m, 1H),3.56-3.63(m,1H),3.37-3.43(m,2H),3.16-3.22(m,1H),2.06-2.19(m,1H),1.79-1.86 (m,1H),1.45(s,9H).

B) tertiary butyl 3- (((benzyloxy) carbonyl) (methyl) amino) pyrrolidines -1- formic acid esters

Tertiary butyl 3- (((benzyloxy) carbonyl) amino) pyrrolidines -1- formic acid esters (280mg, 0.87mmol) is added and is reacted In bottle, anhydrous DMF (4mL), which is added, makes dissolving, and NaH (60%in oil, 104mg, 2.61mmol) is added, stirs at room temperature 30min is added dropwise iodomethane (230mg, 1.62mmol), is stirred at room temperature for 24 hours, then raises temperature to 50 DEG C of reactions for 24 hours, decompression is steamed Except solvent, silica gel column chromatography obtains 225mg grease, yield 76.4%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.32- 7.37(m,5H),5.14(s,2H),4.81(m,1H),3.56(m,2H),3.23-3.33(m,2H),2.86(s,3H),2.02 (m,2H),1.46(s,9H).

C) tertiary butyl 3- (methylamino) pyrrolidines -1- formic acid esters

Tertiary butyl 3- (((benzyloxy) carbonyl) (methyl) amino) pyrrolidines -1- formic acid esters (75mg, 0.23mmol) is added Enter in reaction bulb, methanol (3mL), which is added, makes dissolving, and 10%Pd-C (40mg) is added, and normal pressure hydrogenation 3h, the reaction was complete, decompression filter Except palladium carbon, filtrate concentration is spare.

D) 3- (N- methyl -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (50mg, 0.16mol), EDC (62mg, 0.32mmol), HOBt (45mg, 0.32mmol) are added in reaction bulb, and DIEA is added dropwise Tertiary butyl 3- (methylamino) pyrrolidines -1- formic acid esters (49mg, 0.24mmol) is added in (43mg, 0.32mmol) afterwards, and room temperature is stirred It mixes reaction overnight, reaction solution is poured into water (100mL), extracted with DCM (100mL), organic layer uses water (100mL), satisfies successively It washs, is concentrated under reduced pressure, silica gel column chromatography with NaCl (100mL) and water (100mL), obtain 37mg white solids, yield 46.8% melts 107-109 DEG C of point.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.76 (s, 1H), 8.23 (d, J=7.6Hz, 1H), 7.60 (t, J= 7.6Hz,1H),7.34-7.36(m,1H),7.25-7.29(m,2H),7.07-7.10(m,2H),5.32(s,2H),5.28(m, 1H×0.5),4.18(m,1H×0.5)3.18-3.71(m,4H),3.02(s,3H×0.5),2.83(s,3H×0.5),2.17 (m,1H),2.02-2.10(m,1H),1.45-1.48(m,9H).

Embodiment 38

N- methyl-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- benzamide 2,2,2- trifluoroacetates of 2-

By 3- (N- methyl -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates (45mg, 0.12mmol) be added reaction bulb in, sequentially add DCM (2mL) and TFA (2mL), Reaction 5h is stirred at room temperature, removes solvent and TFA under reduced pressure, a small amount of anhydrous ether is added, is filtered under diminished pressure, a small amount of anhydrous ether of filter cake Washing, dry 40mg pale solids, yield 86.5%, 116-118 DEG C of fusing point.

¹H NMR(300MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.80-9.18 (m, 2H), 8.03 (d, J= 7.2Hz, 1H), 7.66 (t, J=7.5Hz, 1H), 7.46 (m, 1H), 7.25-7.37 (m, 4H), 5.32 (s, 1H), 4.96 (m, 1H),4.26(m,1H),3.19-3.42(m,5H),2.91(s,3H×0.5),2.76(s,3H×0.5),2.20(m,1H), 2.05(m,1H).

Embodiment 39

N- (1- trifluoroacetyl groups-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) the fluoro- N-methyl-benzamides of -2-

By compound N-methy-N- (pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) DCM (10mL) is added in fluoro- 2,2, the 2- trifluoroacetates (70mg, 0.14mmol) of benzamide of -2-, it is added under ice bath Et₃The DCM solution of trifluoroacetic anhydride (0.02mL, 0.16mmol) is added dropwise in reaction bulb by N (0.03mL, 0.21mmol), drop Finish, be stirred to react under ice bath, stop reaction after 30min, DCM (20mL) is added, is washed with saturation NaCl solution (15mL), anhydrous sulphur Sour magnesium drying, column chromatography (D:M=70:1,D:M=60:1) white solid 40mg, yield 58.8%, fusing point 121-123 are obtained ℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.81-8.85 (m, 1H), 8.24 (d, J=7.6Hz, 1H), 7.61 (t, J=8.0Hz, 1H), 7.27-7.35 (m, 3H), 7.06-7.12 (m, 2H), 5.28-5.33 (m, 3H), 3.50-4.10 (m, 4H), 3.03(s,1.2H),2.86(s,1.8H),2.11-2.27(m,2H).

Embodiment 40

N- (1- cyclopropane carbonyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) the fluoro- N-methyl-benzamides of -2-

By compound N-methy-N- (pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) DCM (15mL) is added in fluoro- 2,2, the 2- trifluoroacetates (150mg, 0.3mmol) of benzamide of -2-, it is added under ice bath Et₃The DCM solution of the third formyl chloride of ring (0.032mL, 0.36mmol) is added dropwise in reaction bulb by N (0.17mL, 1.2mmol), drop Finish, be stirred to react under ice bath, stop reaction after 30min, DCM (30mL) is added, is washed with saturation NaCl solution (15mL), anhydrous sulphur Sour magnesium drying, column chromatography (MeOH:DCM=1:60,MeOH:DCM=1:40) white solid 100mg is obtained, yield 71.9% melts 134-136 DEG C of point.

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.92-9.08 (m, 1H), 8.23 (d, J=7.6Hz, 1H), 7.61 (t, J=6.8Hz, 1H), 7.26-7.35 (m, 3H), 7.05-7.15 (m, 2H), 5.33 (s, 2H), 3.20-4.40 (m, 5H), 3.04 (d, J=8.4Hz, 1.5H), 2.85 (d, J=15.6Hz, 1.5H), 2.05-2.40 (m, 2H), 1.50-1.67 (m, 1H), 1.00 (brs,2H),0.78(brs,2H)

Embodiment 41

N- (1- acetyl group-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

By compound N-methy-N- (pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) DCM (15mL) is added in fluoro- 2,2, the 2- trifluoroacetates (150mg, 0.3mmol) of benzamide of -2-, it is added under ice bath Et₃The DCM solution of chloroacetic chloride (0.025mL, 0.36mmol) is added dropwise in reaction bulb by N (0.17mL, 1.2mmol), and drop finishes, It is stirred to react under ice bath, stops reaction after 30min, DCM (30mL) is added, washed with saturation NaCl solution (15mL), anhydrous slufuric acid Magnesium is dried, column chromatography (MeOH:DCM=1:60,MeOH:DCM=1:50) white solid 90mg, yield 68.7%, fusing point are obtained 112-114℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.23 (d, J=8.0Hz, 1H), 7.63 (t, J=7.2Hz, 1H), 7.26-7.36(m,3H),7.08-7.14(m,2H),5.25-5.33(m,2H),4.18-4.32(m,.1H),3.20-3.90(m, 4H), 3.03 (s, 1.5H), 2.84 (d, J=11.2Hz, 1.5H), 2.68 (s, 3H)

Embodiment 42

N- (1- normal-butyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

A) tertiary butyl 3- ((benzyloxy) carbonyl) pyrrolidines -1- formic acid esters

By compound N-Boc-3- amino-pyrrolidines (2g, 10.75mmol), DCM (30mL) is added, DIEA is added The DCM solution of benzyloxy dicarbonyl chloride (1.76mL, 12.9mmol) is added dropwise to reaction bulb by (2.8mL, 16.13mmol) under ice bath In, it drips and is stirred to react under complete ice bath, stop reaction after 3h, DCM (50mL) is added, washed with saturation NaCl solution (30mL × 2), nothing Water magnesium sulfate is dried, column chromatography (E:P=1:5, E:P=1:3) colorless oil 3g, yield 87.2% are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.27-7.35(m,5H),5.09(s,2H),4.88(s,1H),4.24 (brs,1H),3.57-3.62(m,1H),3.42-3.52(m,2H),3.10-3.20(m,1H),2.10-2.20(m,1H), 1.70-1.88(m,1H),1.45(s,9H).

B) tertiary butyl 3- ((benzyloxy) carbonyl (methyl) amino) pyrrolidines -1- formic acid esters

DMF is added in compound tert-butyl group 3- ((benzyloxy) carbonyl) pyrrolidines -1- formic acid esters (250mg, 0.78mmol) (8mL) is added NaH (63mg, 1.56mmol), is stirred at room temperature 1h at room temperature under argon gas protection, be added iodomethane (0.073mL, 1.17mmol), reaction is stirred at room temperature, stops reaction after 2h, water is added, extracted with ethyl acetate (60mL), organic layer saturation NaCl solution (20mL × 2) is washed, anhydrous magnesium sulfate drying, column chromatography (E:P=1:4, E:P=1:2.5) colorless oil, is obtained 240mg, yield 92.3%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.27-7.36(m,5H),5.13(s,2H),4.72(s,1H),3.52- 3.70(m,2H),3.22-3.41(m,2H),2.77(s,3H),1.90-2.10(m,2H),1.46(s,9H)

C) benzyl (1- n-butylpyrrolioine -3- bases) (methyl) carbamate

By compound tert-butyl group 3- ((benzyloxy) carbonyl (methyl) amino) pyrrolidines -1- formic acid esters (500mg, DCM (10mL) 1.56mmol) is added, TFA (1.15mL, 15.6mmol) is added, lower reaction is stirred at room temperature, stops reaction after 3h, Addition acetonitrile (10mL) after being concentrated to dryness, addition DIEA (0.53mL, 3.44mmol), addition bromination of n-butane (0.11mL, 1.03mmol), 50 DEG C of reactions are heated to, stop reaction, concentration, column chromatography (MeOH after 4h:DCM=1:50,MeOH:DCM=1: 40) grease 280mg, yield 64.5%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.28-7.36(m,5H),5.10(s,2H),3.30(brs,3H), 2.70-2.99 (m, 6H), 2.24 (brs, 2H), 1.76 (brs, 2H), 1.37 (q, J=6.8Hz, 2H), 0.93 (t, J= 7.2Hz,3H),

D) 1- normal-butyls-N- methylpyrrolidin- 3- amine

By compound benzyl (1- n-butylpyrrolioine -3- bases) (methyl) carbamate (200mg), EtOH is added 10%pd/C (60mg) is added in (10mL), hydrogenation under normal temperature and pressure, stops reaction after 8h, filters, and concentration obtains 100mg Grease, yield 93.4%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):6.48(brs,1H),3.56(brs,1H),3.16-3.25(m,1H), 3.09-3.16(m,1H),2.87-3.09(m,2H),2.78-2.83(m,2H),2.49(s,3H),2.18-2.32(m,1H), 1.95-2.05 (m, 1H), 1.61-1.71 (m, 2H), 1.36 (q, J=7.2Hz, 2H), 0.92 (t, J=7.2Hz, 3H),

E) N- (1- normal-butyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (122mg, 0.636mmol), HOBt (86mg, 0.636mmol) is added in (100mg, 0.318mmol), DIEA (0.14mL, 0.795mmol) and 1- normal-butyl-N- methylpyrrolidin- 3- amine (99mg, 0.636mmol), are stirred at room temperature Reaction, next day stop reaction, add water, be extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous magnesium sulfate It is dry, column chromatography (MeOH:DCM:Et₃N=1:60:0.3) off-white powder 60mg, yield 41.9%, fusing point 104-, are obtained 106℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):9.05(brs,1H),8.23(s,1H),7.60(s,1H),7.27(s, 2H),5.32(s,2H),4.18(s,1H),3.08(s,2H),2.92(s,1H),2.73(brs,2H),2.00-2.50(m,4H), 1.87(brs,1H),1.61(brs,1H),1.20-1.50(m,4H),0.91(brs,3H)

Embodiment 43

N- (the third methylene of 1- rings-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) the fluoro- N-methyl-benzamides of -2-

A) benzyl (1- Cvclopropvlmethvls pyrrolidin-3-yl) (methyl) carbamate

By compound benzyl 3- ((tertbutyloxycarbonyl) (methyl) amino) pyrrolidines -1- formic acid esters (300mg, 1.56mmol) DCM (10mL) is added, TFA (1.15mL, 15.6mmol) is added, lower reaction is stirred at room temperature, stops reaction after 3h, after being concentrated to dryness Acetonitrile (10mL) is added, DIEA (0.53mL, 3.44mmol) is added, cyclopropylmethyl bromide (0.1mL, 1.03mmol) is added, adds Heat is reacted to 50 DEG C, stops reaction, concentration, column chromatography (MeOH after 4h:DCM=1:50,MeOH:DCM=1:40) oily, is obtained Object 206mg, yield 79.8%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.28-7.36(m,5H),5.07-5.15(m,2H),3.25-3.65 (m,3H),3.00(s,3H),2.87(brs,2H),2.43(brs,1H),2.24(brs,1H),0.78-0.85(m,1H),0.70 (brs,2H),0.38(brs,2H)

B) 1- Cvclopropvlmethvls-N- methylpyrrolidin- 3- amine

By compound benzyl (1- Cvclopropvlmethvls pyrrolidin-3-yl) (methyl) carbamate (195mg), EtOH is added 10%Pd/C (59mg) is added in (10mL), and hydrogenation under normal temperature and pressure, next day stops reaction, filters, and concentration obtains 100mg Grease, yield 96%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):6.48(brs,1H),3.54(brs,1H),3.20-3.25(m,1H), 3.09-3.16 (m, 1H), 2.95-3.06 (m, 2H), 2.66 (d, J=6.4Hz, 2H), 2.49 (s, 3H), 2.27-2.37 (m, 1H), 1.93-2.03 (m, 1H), 0.80-0.90 (m, 1H), 0.61 (d, J=7.2Hz, 2H), 0.27 (d, J=4.0Hz, 2H),

C) N- (1- Cyclopropylmethyl-pyrrolidine -3- bases) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) the fluoro- N-methyl-benzamides of -2-

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.17mL, 0.95mmol) and 1- Cvclopropvlmethvl-N- methylpyrrolidin- 3- amine (88mg, 0.57mmol) is stirred at room temperature anti- It answers, next day stops reaction, adds water, is extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), and anhydrous magnesium sulfate is dry It is dry, column chromatography (MeOH：DCM=1:40,MeOH:DCM:Et₃N=1:60:0.3) off-white powder 95mg, yield, are obtained 55.5%, 114-116 DEG C of fusing point.¹H-NMR(400MHz,CDCl₃)δ(ppm):8.90 (brs, 1H), 8.22 (d, J=7.6Hz, 1H), 7.60 (t, J=7.6Hz, 1H), 7.27-7.36 (m, 3H), 7.04-7.10 (m, 2H), 5.32 (s, 2H), 4.20 (brs, 1H),3.09(s,2H),2.94(s,1H),2.30-2.80(m,6H),2.21(brs,1H),1.88(brs,1H),0.80-0.90 (m, 1H), 0.60 (brs, 1H), 0.50 (d, J=5.6Hz, 1H), 0.24 (brs, 1H), 0.11 (s, 1H)

Embodiment 44

N- (1- isobutyl-pyrrolidin -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

A) benzyl (1- isobutyl groups pyrrolidin-3-yl) (methyl) carbamate

By compound benzyl 3- ((tertbutyloxycarbonyl) (methyl) amino) pyrrolidines -1- formic acid esters (330mg, 0.98mmol) DCM (10mL) is added, TFA (0.72mL, 9.8mmol) is added, lower reaction is stirred at room temperature, stops reaction after 3h, after being concentrated to dryness Acetonitrile (10mL) is added, DIEA (0.68mL, 3.9mmol) is added, isobutane bromide (0.13mL, 1.18mmol), heating is added It is reacted to 50 DEG C, stops reaction, concentration, column chromatography, (MeOH after 4h:DCM=1:50,MeOH:DCM=1:40) oily, is obtained Object 220mg, yield 76.9%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.28-7.38(m,5H),5.07-5.14(m,2H),4.70(brs, 1H),3.05-3.50(m,3H),2.98(s,3H),1.90-2.80(m,5H),1.04(brs,6H)

B) 1- isobutyl-N-methyls pyrrolidines -3- amine

By compound benzyl (1- isobutyl groups pyrrolidin-3-yl) (methyl) carbamate (200mg), EtOH is added 10%pd/C (60mg) is added in (10mL), and hydrogenation under normal temperature and pressure, next day stops reaction, filters, and concentration obtains 100mg Grease, yield 93.4%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):3.72(brs,1H),2.90-3.20(m,3H),2.80(brs,1H), 2.64 (s, 3H), 2.47 (d, J=6.4Hz, 2H), 2.30-3.40 (m, 1H), 2.10-2.20 (m, 1H), 1.75-1.90 (m, 1H), 0.97 (d, J=6.4Hz, 6H)

C) N- (1- isobutyl-pyrrolidin -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.17mL, 0.95mmol) and 1- isobutyl-N-methyl pyrrolidines -3- amine (88mg, 0.57mmol), is stirred at room temperature reaction, Next day stops reaction, adds water, is extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous magnesium sulfate drying, Column chromatography (MeOH:DCM=1:40, MeOH:DCM:Et₃N=1:60:0.03) off-white powder 67mg, yield, are obtained 39.2%, 96-98 DEG C of fusing point.

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.87 (brs, 1H), 8.23 (d, J=7.6Hz, 1H), 7.61 (t, J= 7.6Hz,1H),7.27-7.40(m,3H),7.08-7.13(m,2H),5.33(s,2H),3.40-4.20(m,3H),2.80- 3.10(m,5H),2.20-2.60(m,2H),2.10(brs,1H),1.68(brs,2H),1.12(brs,6H)

Embodiment 45

N- (1- isopentyl-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

A) benzyl (1- isopentyl pyrrolidin-3-yl) (methyl) carbamate

By compound benzyl 3- ((tertbutyloxycarbonyl) (methyl) amino) pyrrolidines -1- formic acid esters (330mg, 0.98mmol) DCM (10mL) is added, TFA (0.72mL, 9.8mmol) is added, lower reaction is stirred at room temperature, stops reaction after 3h, after being concentrated to dryness Acetonitrile (10mL) is added, DIEA (0.68mL, 3.9mmol) is added, bromo isopentane (0.13mL, 1.18mmol), heating is added It is reacted to 50 DEG C, stops reaction, concentration, column chromatography (MeOH after 4h:DCM=50:1,MeOH:DCM=40:1) grease, is obtained 286mg, yield 95.3%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.28-7.37(m,5H),5.07-5.15(m,2H),3.20-3.60 (m, 3H), 2.80-3.10 (m, 5H), 3.10-3.60 (m, 3H), 1.60-1.80 (m, 3H), 0.92 (d, J=5.6Hz, 6H)

B) 1- isopentyl-N- methylpyrrolidin- 3- amine

By compound benzyl (1- isopentyl pyrrolidin-3-yl) (methyl) carbamate (145mg), EtOH is added 10%Pd/C (44mg) is added in (10mL), and hydrogenation under normal temperature and pressure, next day stops reaction, filters, and concentration obtains 80mg Grease, yield 94.1%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):3.60-3.70(m,1H),3.31(brs,1H),3.01-3.23(m, 3H), 2.85-2.95 (m, 2H), 0.92 (d, J=6.0Hz, 6H)

C) N- (1- isopentyl-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.17mL, 0.95mmol) and 1- isopentyl-N- methylpyrrolidin- 3- amine (88mg, 0.57mmol), is stirred at room temperature reaction, Next day stops reaction, adds water, is extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous magnesium sulfate drying, Column chromatography (MeOH:DCM:Et₃N=1:60:0.03) off-white powder 45mg, yield 25.4%, 123-125 DEG C of fusing point, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.84 (brs, 1H), 8.23 (d, J=7.6Hz, 1H), 7.60 (t, J= 7.6Hz,1H),7.26-7.34(m,3H),7.04-7.11(m,2H),5.32(s,2H),4.17(brs,1H),3.08(s, 1.5H),2.93(s,1.5H),2.74(brs,2H),2.45(brs,1H),2.33(brs,2H),1.86(brs,1H),1.52- 1.70(m,2H),0.85-0.93(m,6H).

Embodiment 46

3- (N- ethyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

A) tertiary butyl 3- (((benzyloxy) carbonyl) (ethyl) amino) pyrrolidines -1- formic acid esters

Tertiary butyl 3- (((benzyloxy) carbonyl) amino) pyrrolidines -1- formic acid esters (300mg, 0.94mmol) is added and is reacted In bottle, anhydrous DMF (10mL), which is added, makes dissolving, and NaH (60%in oil, 113mg, 2.82mmol) is added, stirs at room temperature 30min is added dropwise bromoethane (308mg, 2.82mmol), is stirred at room temperature for 24 hours, then raises temperature to 50 DEG C of reactions for 24 hours, decompression is steamed Except solvent, silica gel column chromatography obtains 350mg grease, yield 92.0%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.30- 7.39(m,5H),5.15(s,2H),4.60(m,1H),3.52-3.61(m,2H),3.17-3.28(m,4H),1.93-2.08(m, 2H), 1.46 (s, 9H), 1.15 (t, J=6.8Hz, 3H)

B) tertiary butyl 3- (ethylamino) pyrrolidines -1- formic acid esters

Tertiary butyl 3- (((benzyloxy) carbonyl) (ethyl) amino) pyrrolidines -1- formic acid esters (75mg, 0.23mmol) is added Enter in reaction bulb, methanol (3mL), which is added, makes dissolving, and 10%Pd-C (40mg) is added, and normal pressure hydrogenation 3h, the reaction was complete, decompression filter Except palladium carbon, filtrate concentration is spare.

C) 3- (N- methyl -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

By 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids (50mg, 0.16mol), EDC (62mg, 0.32mmol), HOBt (45mg, 0.32mmol) are added in reaction bulb, and DIEA is added dropwise Tertiary butyl 3- (ethylamino) pyrrolidines -1- formic acid esters (49mg, 0.24mmol) is added in (43mg, 0.32mmol) afterwards, and room temperature is stirred It mixes reaction overnight, reaction solution is poured into water (100mL), extracted with DCM (100mL), organic layer uses water (100mL), satisfies successively It washs, is concentrated under reduced pressure, silica gel column chromatography with NaCl (100mL) and water (100mL), obtain 37mg faint yellow solids, yield 46.8%, 107-109 DEG C of fusing point.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.81 (s, 1H), 8.23 (d, J=8.0Hz, 1H), 7.57-7.61 (m, 1H),7.24-7.29(m,3H),7.07-7.10(m,2H),5.33(s,2H),4.82-4.86(m,1H×0.4),4.11(m,1H ×0.6),3.11-3.78(m,6H),2.17-2.19(m,1H),2.02-2.05(m,1H),1.45-1.47(m,9H),1.25- 1.32(m,3H).

Embodiment 47

N- ethyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- benzamide 2,2,2- trifluoroacetates of 2-

By 3- (N- methyl -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates (45mg, 0.09mmol) be added reaction bulb in, sequentially add DCM (2mL) and TFA (2mL), Reaction 5h is stirred at room temperature, removes solvent and TFA under reduced pressure, a small amount of anhydrous ether is added, is filtered under diminished pressure, a small amount of anhydrous ether of filter cake Washing, it is so dry that obtain 40mg pale solids, yield 86.5%, 111-112 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.74(s,1H),9.01(m,1H),8.64(m,1H),8.04(m, 1H),7.64(m,1H),7.25-7.48(m,4H),5.33(s,2H),4.20-4.34(m,1H),2.90-3.54(m,6H), 2.32(m,1H),2.16(m,1H),0.88-1.18(m,3H).

Embodiment 48

N- (1- trifluoroacetyl groups-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) the fluoro- N- ethyl benzamides of -2-

By compound N-ethyl-N- (pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) fluoro- 2,2, the 2- trifluoroacetates (120mg, 0.23mmol) of benzamide of -2- are added DCM (15mL), under ice bath plus Enter Et₃The DCM solution of trifluoroacetic anhydride (0.038mL, 0.27mmol) is added dropwise to reaction bulb by N (0.13mL, 0.92mmol) In, drop finishes, and is stirred to react under ice bath, stops reaction after 30min, and DCM (30mL) is added, and is washed with saturation NaCl solution (15mL), Anhydrous magnesium sulfate is dried, column chromatography (MeOH:DCM=1:70) white solid 80mg, yield 68.3%, fusing point 117-119 are obtained ℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.85-8.90 (m, 1H), 8.24 (d, J=7.6Hz, 1H), 7.60 (t, J=7.2Hz, 1H), 7.26-7.32 (m, 3H), 7.07-7.14 (m, 2H), 5.33 (s, 2H), 3.20-4.30 (m, 7H), 2.20- 2.50 (m, 2H), 1.26 (brs.1H), 0.96 (t, J=6.8Hz, 2H)

Embodiment 49

N- (1- cyclopropane carbonyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) the fluoro- N- ethyl benzamides of -2-

By compound N-ethyl-N- (pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) fluoro- 2,2, the 2- trifluoroacetates (120mg, 0.23mmol) of benzamide of -2- are added DCM (15mL), under ice bath plus Enter Et₃The DCM solution of the third formyl chloride of ring (0.02mL, 0.27mmol) is added dropwise in reaction bulb by N (0.13mL, 0.92mmol), Drop finishes, and is stirred to react under ice bath, stops reaction after 30min, and DCM (30mL) is added, and is washed with saturation NaCl solution (15mL), anhydrous Magnesium sulfate is dried, column chromatography (MeOH:DCM=60:1,MeOH:DCM=1:50) white solid 60mg is obtained, yield 54.5%, 120-122 DEG C of fusing point.

¹H-NMR(400MHz,CDCl₃)δ(ppm):9.00 (brs, 1H), 8.24 (d, J=7.6Hz, 1H), 7.59 (brs, 1H),7.26-7.32(m,3H),7.07-7.14(m,2H),5.33(s,2H),3.20-4.30(m,7H),2.10-2.40(m, 1H),1.50-1.70(m,2H),0.99(brs,2H),0.77(brs,2H)

Embodiment 50

N- (1- acetyl group-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

By compound N-ethyl-N- (pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) fluoro- 2,2, the 2- trifluoroacetates (120mg, 0.23mmol) of benzamide of -2- are added DCM (15mL), under ice bath plus Enter Et₃The DCM solution of chloroacetic chloride (0.02mL, 0.27mmol) is added dropwise in reaction bulb by N (0.13mL, 0.92mmol), drop Finish, be stirred to react under ice bath, stop reaction after 30min, DCM (30mL) is added, is washed with saturation NaCl solution (15mL), anhydrous sulphur Sour magnesium drying, column chromatography (MeOH:DCM=1:60, MeOH:DCM=1:50) white solid 50mg, yield 48%, fusing point are obtained 88-90℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.23 (d, J=7.2Hz, 1H), 7.60-7.70 (m, 1H), 7.26- 7.32(m,3H),7.07-7.14(m,2H),5.32(s,2H),3.20-4.20(m,6H),2.68 9s,3H),2.10-2.40 (m,2H),1.31(brs,2H),1.11(brs,1H)

Embodiment 51

N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- N- ethyl benzamides of 2-

A) tertiary butyl 3- (((benzyloxy) carbonyl) (N- ethyls) amino) pyrrolidines -1- formic acid esters

DMF is added in compound tert-butyl group 3- ((benzyloxy) carbonyl) pyrrolidines -1- formic acid esters (960mg, 3mmol) (20mL) is added NaH (180mg, 4.5mmol), is stirred at room temperature 1h at room temperature under argon gas protection, be added bromoethane (0.27mL, 3.6mmol), reaction is stirred at room temperature, stops reaction after 1h, water is added, extracted with ethyl acetate (80mL), organic layer saturation NaCl solution (30mL × 2) is washed, anhydrous magnesium sulfate drying, column chromatography (E:P=1:5) colorless oil 840mg, yield, are obtained 80.4%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.27-7.36(m,5H),5.15(s,2H),4.60(s,1H),3.45- 3.65 (m, 2H), 3.10-3.30 (m, 4H), 1.95-2.03 (m, 2H), 1.45 (s, 9H), 1.14 (t, J=6.4Hz, 3H)

B) benzyl (1- ethyl pyrrolidine -3- bases) (N- ethyls) carbamate

By compound benzyl tertiary butyl 3- (((benzyloxy) carbonyl) (N- ethyls) amino) pyrrolidines -1- formic acid esters DCM (10mL) is added in (340mg, 0.977mmol), and TFA (0.72mL, 9.77mmol) is added, lower reaction is stirred at room temperature, stops after 3h It only reacts, is concentrated to dryness.Acetonitrile (10mL) is added, DIEA (0.85mL, 4.885mmol) is added, bromic ether is added (0.09mL, 1.17mmol) is stirred at room temperature reaction, stops reaction, concentration, column chromatography (MeOH after 2h:DCM=1:50,MeOH: DCM=1:40) grease 197mg, yield 77.2%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.28-7.36(m,5H),5.06-5.15(m,2H),4.13(brs, 1H), 3.10-3.85 (m, 8H), 2.61 (brs, 1H), 2.28 (brs, 1H), 1.45 (brs, 3H), 1.11 (t, J=8.0Hz, 3H)

C) 1- ethyls-N- ethyl pyrrolidines -3- amine

By compound benzyl (1- ethyl pyrrolidine -3- bases) (N- ethyls) carbamate (190mg), EtOH is added 10%Pd/C (95mg) is added in (10mL), and hydrogenation under normal temperature and pressure, next day stops reaction, filters, and concentration obtains 95mg Grease, yield 97.2%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):3.92 (brs, 1H), 3.60 (t, J=11.2Hz, 1H), 3.38-3.44 (m,1H),3.30-3.40(m,2H),3.10-3.15(m,2H),2.89-3.00(m,2H),2.46-2.52(m,1H),2.35- 2.45 (m, 1H), 1.38 (t, J=7.2Hz, 6H)

D) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.17mL, 0.95mmol) and 1- ethyl-N- ethyl pyrrolidine -3- amine (90mg, 0.63mmol), is stirred at room temperature reaction, secondary Day stops reaction, adds water, is extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous magnesium sulfate drying, column Chromatograph (MeOH:DCM=1:40,MeOH:DCM:Et₃N=1:60:0.3) off-white powder 45mg, yield 26%, fusing point, are obtained 64-66℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.91 (brs, 1H), 8.23 (d, J=7.6Hz, 1H), 7.58 (t, J= 7.2Hz,1H),7.36(brs,1H),7.22-7.30(m,2H),7.02-7.14(m,2H),5.33(s,2H),4.17-4.40 (m,1H),3.40-3.78(m,3H),3.08-3.22(m,3H),2.36-2.76(m,4H),1.64-1.94(m,2H),1.39- 1.52 (m, 3H), 0.97 (t, J=6.8Hz, 1H), 0.66 (t, J=7.2Hz, 2H)

Embodiment 52

N- (1- n-propyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

A) benzyl (1- n-propyls pyrrolidin-3-yl) (N- ethyls) carbamate

By compound benzyl 3- ((tertbutyloxycarbonyl) (N- ethyls) amino) pyrrolidines -1- formic acid esters (340mg, DCM (10mL) 0.977mmol) is added, TFA (0.72mL, 9.77mmol) is added, lower reaction is stirred at room temperature, stops reaction after 3h, Addition acetonitrile (10mL) after being concentrated to dryness, addition DIEA (0.85mL, 4.885mmol), addition n-propyl bromide (0.09mL, 1.17mmol), reaction is stirred at room temperature, stops reaction, concentration, column chromatography (MeOH after 2h:DCM=1:50,MeOH:DCM=40: 1) grease 220mg, yield 81.7%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.28-7.37(m,5H),5.08-5.15(m,2H),4.22(brs, 1H),3.30-3.80(m,6H),3.06(brs,2H),2.60(brs,1H),2.29(brs,1H),1.88(brs,2H),1.12 (t, J=6.8Hz, 3H), 1.00 (brs, 3H)

B) 1- n-propyls-N- ethyl pyrrolidines -3- amine

By compound benzyl (1- propyl pyrrole alkane -3- bases) (N- ethyls) carbamate (190mg), EtOH is added 10%Pd/C (95mg) is added in (10mL), and hydrogenation under normal temperature and pressure, next day stops reaction, filters, and concentration obtains 100mg Grease, yield 86.9%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):3.78-3.83(m,1H),2.70-3.60(m,8H),2.40-2.48 (m,1H),2.17-2.24(m,1H),1.65-1.78(m,2H),1.23-1.29(m,3H),0.92-0.99(m,3H)

C) N- (1- n-propyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.17mL, 0.95mmol) and 1- n-propyl-N- ethyl pyrrolidine -3- amine (90mg, 0.63mmol), is stirred at room temperature reaction, Next day stops reaction, adds water, is extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous magnesium sulfate drying, Column chromatography (MeOH:DCM=1:40,MeOH:DCM:Et₃N=1:60:0.3) off-white powder 60mg, is obtained, yield 35% melts 112-114 DEG C of point.

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.98 (brs, 1H), 8.24 (d, J=7.2Hz, 1H), 7.59 (t, J= 7.6Hz,1H),7.35(brs,1H),7.22-7.30(m,2H),7.02-7.14(m,2H),5.33(s,2H),4.40(brs, 1H),3.20-4.20(m,5H),2.60-3.10(m,3H),2.20-2.50(m,2H),1.85(brs,2H),1.26-1.50(m, 3H),0.95-1.06(m,3H)

Embodiment 53

3- (N- n-propyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

A) tertiary butyl 3- (((benzyloxy) carbonyl) (N- n-propyls) amino) pyrrolidines -1- formic acid esters

DMF is added in compound tert-butyl group 3- ((benzyloxy) carbonyl) pyrrolidines -1- carboxylates (360mg, 1.125mmol) NaH (68mg, 1.69mmol) is added under argon gas protection in (10mL) at room temperature, and 1h is stirred at room temperature, and n-propyl bromide is added (0.12mL, 1.35mmol) is stirred at room temperature reaction, stops reaction after 1h, water is added, extracted with ethyl acetate (80mL), organic Layer is washed with saturation NaCl solution (30mL × 2), anhydrous magnesium sulfate drying, column chromatography (E:P=1:5) colorless oil, is obtained 300mg, yield 73.7%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.27-7.35(m,5H),5.14(s,2H),4.53(s,1H),3.50- 3.60(m,2H),3.10-3.30(m,4H),1.97-2.04(m,2H),1.53-1.61(m,2H),1.45(s,9H),0.86(t, J=7.2Hz, 3H)

B) tertiary butyl 3- (N- n-propyls amido) pyrrolidines -1- formic acid esters

By compound tert-butyl group 3- (((benzyloxy) carbonyl) (N- n-propyls) amino) pyrrolidines -1- formic acid esters (265mg), Ethyl alcohol (10mL) is added, 10%Pd/C (80mg) is added, hydrogenation under normal temperature and pressure stops reaction after 3h, filters, concentration, Obtain colorless oil 160mg, yield 95.8%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):3.25-3.60 (m, 4H), 2.95-3.15 (m, 1H), 2.56 (t, J= 6.8Hz, 2H), 1.99-2.08 (m, 1H), 1.67 (brs, 1H), 1.48 (q, J=7.2Hz, 2H), 1.44 (s, 9H), 0.91 (t, J=7.2Hz, 3H)

C) 3- (N- n-propyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoyls Amido) pyrrolidines -1- t-butyl formates

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (15mL), HBTU (364mg, 0.96mmol), HOBt (130mg, 0.96mmol), DIEA is added in (150mg, 0.48mmol) (0.25mL, 1.44mmol) and tertiary butyl 3- (N- n-propyls amido) pyrrolidines -1- formic acid esters (131mg, 0.57mmol), room Temperature is stirred to react, and next day stops reaction, adds water, is extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous Magnesium sulfate is dried, column chromatography (MeOH:DCM=1:70,MeOH:DCM=1:60) off-white powder 160mg, yield, are obtained 63.7%, 117-119 DEG C of fusing point.

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.78 (s, 1H), 8.22 (d, J=8.0Hz, 1H), 755-7.80 (m, 1H),7.23-7.28(m,3H),7.05-7.10(m,2H),5.32(s,2H),4.74-4.78(m,0.33H),4.10-4.12 (m,0.67H),3.09-3.75(m,6H),2.14-2.18(m,1H),2.00-2.05(m,1H),1.63-1.75(m,2H), 1.45 (d, J=7.2Hz, 9H), 0.96 (t, J=6.0Hz, 1H), 0.61 (t, J=7.2Hz, 2H)

Embodiment 54

N- n-propyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

By compound 3- (N- n-propyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorine Benzamido) pyrrolidines -1- t-butyl formates (90mg, 0.17mmol), addition DCM (8mL), addition TFA (0.13mL, 1.7mmol), reaction is stirred at room temperature, next day stops reaction, and ether is added, there is solid wash-off, filters, and filter cake ether is washed, obtained White solid 85mg, yield 93.4%.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):11.72(s,1H),8.98(brs,1H),8.60(brs,1H), 8.01 (d, J=7.6Hz, 1H), 7.61 (t, J=7.6Hz, 1H), 7.49 (s, 1H), 7.21-7.41 (m, 4H), 5.31 (s, 2H), 4.29 (t, J=7.2Hz, 1H), 3.50-3.65 (m, 2H), 2.97-3.25 (m, 4H), 2.25-2.35 (m, 1H), 2.10- 2.18 (m, 1H), 1.56 (brs, 0.6H), 1.29 (q, J=7.2Hz, 1.4H), 0.87 (t, J=7.2Hz, 1H), 0.47 (t, J =7.2Hz, 2H)

Embodiment 55

N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- N- n-propylbenzenes formamides of 2-

A) benzyl (ethyl pyrrolidine -3- bases) n-propyl amino formic acid esters

By compound tert-butyl group 3- (((benzyloxy) carbonyl) (N- n-propyls) amino) pyrrolidines -1- formic acid esters (308mg, DCM (10mL) 0.85mmol) is added, TFA (0.63mL, 8.5mmol) is added, lower reaction is stirred at room temperature, stops reaction after 3h, it is dense It is reduced to after doing and acetonitrile (10mL) is added, addition DIEA (0.74mL, 4.25mmol), addition bromic ether (0.078mL, 1.02mmol), reaction is stirred at room temperature, stops reaction, concentration, column chromatography (MeOH after 4h:DCM=1:50,MeOH:DCM=1: 40) grease 230mg, yield 95.8%, are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.28-7.38(m,5H),5.07-5.11(m,2H),4.14(brs, 1H),3.79(brs,1H),3.64(brs,1H),3.10-3.60(m,6H),2.63(brs,1H),2.31(brs,1H),1.40- 1.60(m,2H),0.80-0.95(m,6H).

B) -3 amine of 1- ethyls-N- n-propyls pyrrolidines

By compound benzyl (ethyl pyrrolidine -3- bases) propyl carbamate (190mg), EtOH (10mL) is added, adds Enter 10%Pd/C (95mg), hydrogenation under normal temperature and pressure, next day stops reaction, filters, and concentration obtains 100mg grease, produces Rate 86.9%.

¹H-NMR(400MHz,CDCl₃)δ(ppm):3.74-3.81(m,1H),3.44-3.52(m,1H),3.18-3.36 (m,3H),3.02-3.12(m,2H),2.66-2.74(M,2H),2.34-2.44(m,1H),2.17-2.26(m,1H),1.66- 1.76 (m, 2H), 1.33 (t, J=7.2Hz, 3H), 0.94 (t, J=7.6Hz, 3H)

C) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- propyl benzamides of -2-

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (10mL), EDC (146mg, 0.76mmol), HOBt (103mg, 0.76mmol), DIEA is added in (120mg, 0.38mmol) (0.17mL, 0.95mmol) 1- ethyl-N- n-propyl pyrrolidines -3- amine (90mg, 0.63mmol), is stirred at room temperature reaction, next day Stop reaction, add water, be extracted with ethyl acetate, organic layer is washed with saturation NaCl solution (20mL), anhydrous magnesium sulfate drying, column layer Analyse (MeOH:DCM=1:40,MeOH:DCM:Et₃N=1:60:0.3) off-white powder 45mg, yield 26%, fusing point, are obtained 105-107℃。

Embodiment 56

3- (N- phenethyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

A) tertiary butyl 3- (PhenethyIamino) pyrrolidines -1- formic acid esters

By compound 1-Boc-3- amino-pyrrolidines (558mg, 3mmol), DCM (15mL) is added, the second of catalytic amount is added Phenylacetaldehyde (540mg, 4.5mmol) is added in acid, and (1.27g, 6mmol) triacetoxy borohydride hydrogen is added after reaction 2h is stirred at room temperature Change sodium, reaction 20h is stirred at room temperature, stops reaction, NaHCO is added into reaction solution₃Saturated solution is extracted with DCM (40mL × 3) It takes, merges organic layer, washed with saturation NaCl (40mL × 2), anhydrous magnesium sulfate drying, concentration, column chromatography (E:P=1:2,MeOH: DCM=1:35) pale yellow oil 90mg, yield 10.3% are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.19-7.32(m,5H),3.30-3.65(m,5H),3.00-3.10 (m, 1H), 2.87-2.92 (m, 2H), 2.80 (t, J=6.8Hz, 2H), 2.00-2.05 (m, 1H), 1.60-1.70 (m, 1H), 1.44(s,9H)

B) 3- (N- phenethyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoyls Amido) pyrrolidines -1- t-butyl formates

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (15mL), EDC (184mg, 0.96mmol), HOBt (130mg, 0.96mmol), DIEA is added in (150mg, 0.48mmol) (0.21mL, 1.2mmol) and tertiary butyl 3- (PhenethyIamino) pyrrolidines -1- formic acid esters (210mg, 0.72mmol), room temperature It is stirred to react, next day stops reaction, adds water, is extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous sulphur Sour magnesium is dried, three times column chromatography (MeOH：DCM=1:80) off-white powder 50mg, yield 17.5%, fusing point 113-115, are obtained ℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.58-8.65(m,1H),8.19-8.25(m,1H),7.02-7.61 (m,10H),6.74(brs,1H),5.31(brs,2H),3.30-4.09(m,5H),3.05(brs,3H),2.62(brs,1H), 2.23(brs,1H),1.86(brs,1H),1.43-1.48(m,9H)

Embodiment 57

N- phenethyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

By compound 3- (N- phenethyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorine Benzamido) pyrrolidines -1- t-butyl formates (50mg, 0.085mmol), addition DCM (5mL), addition TFA (0.06mL, 0.85mmol), reaction is stirred at room temperature, next day stops reaction, and ether is added, there is solid wash-off, filters, and filter cake ether is washed, obtained White solid 35mg, yield 68.6%, 83-85 DEG C of fusing point.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):11.74(s,1H),8.93(brs,1H),8.57(brs,1H), 8.01 (t, J=11.2Hz, 1H), 7.16-7.51 (m, 10H), 6.82 (s, 1H), 5.31 (s, 2H), 4.35-4.45 (m, 1H), 3.52(brs,1H),3.25-3.40(m,3H),3.05-3.15(m,1H),2.90-2.95(m,1H),2.55-2.65(m,1H), 2.25-2.35(m,1H),2.05-2.15(m,1H)

Embodiment 58

3- (N- benzyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

A) tertiary butyl 3- (benzylamino) pyrrolidines -1- formic acid esters

By compound 1-Boc-3- amino-pyrrolidines (558mg, 3mmol), DCM (15mL) is added, the second of catalytic amount is added Benzaldehyde (0.46mL, 4.5mmol) is added in acid, and (954mg, 4.5mmol) triacetoxyl group is added after reaction 20h is stirred at room temperature Sodium borohydride is stirred at room temperature reaction 20h, stops reaction, NaHCO is added into reaction solution₃Saturated solution, with DCM (40mL × 3) Extraction merges organic layer, is washed with saturation NaCl (40mL × 2), anhydrous magnesium sulfate drying, concentration, column chromatography (E:P=1:2.5, MeOH:DCM=1:40) pale yellow oil 235mg, yield 28.4% are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):7.26-7.33(m,5H),3.78(s,2H),3.40-3.60(m,2H), 3.25-3.38(m,2H),3.05-3.20(m,1H),1.99-2.08(m,1H),1.68-1.80(m,1H),1.45(s,9H)

B) 3- (N- benzyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (15mL), EDC (184mg, 0.96mmol), HOBt (130mg, 0.96mmol), DIEA is added in (150mg, 0.48mmol) (0.21mL, 1.2mmol) and tertiary butyl 3- (benzylamino) pyrrolidines -1- formic acid esters (199mg, 0.72mmol), room temperature is stirred Reaction is mixed, next day stops reaction, adds water, be extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous slufuric acid Magnesium is dried, twice column chromatography (MeOH:DCM=80:1) off-white powder 60mg, yield 21.8%, fusing point 117-119, are obtained ℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.63-8.71(m,1H),8.18-8.25(m,1H),6.89-7.65 (m,11H),5.32(brs,1H),5.17(s,1H),4.80-4.90(m,1H),4.41(s,1H),4.28(brs,1H),3.03- 3.70(m,4H),2.11(brs,1H),1.93(brs,1H),1.42(s,9H)

Embodiment 59

N- benzyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- benzamide 2,2,2- trifluoroacetates of 2-

By compound 3- (N- benzyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzene Formamido) pyrrolidines -1- t-butyl formates (40mg, 0.07mmol), addition DCM (5mL), addition TFA (0.1mL, 1.4mmol), reaction is stirred at room temperature, next day stops reaction, and ether is added, there is solid wash-off, filters, and filter cake ether is washed, obtained White solid 25mg, yield 60.9%, 125-127 DEG C of fusing point.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):11.72-11.76(m,1H),8.89(brs,1H),8.51(brs, 1H), 8.02 (t, J=10.8Hz, 1H), 7.06-7.678 (m, 11H), 5.26-5.40 (m, 2H), 4.30~4.40 (m, 2H), 2.80-3.50(m,5H),2.03-2.13(m,1H),1.86(brs,1H)

Embodiment 60

3- (N- isobutyl groups -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

A) tertiary butyl 3- (isobutylamino) pyrrolidines -1- formic acid esters

By compound 1-Boc-3- amino-pyrrolidines (558mg, 3mmol), DCM (15mL) is added, the second of catalytic amount is added Isobutylaldehyde (0.41mL, 4.5mmol) is added in acid, and (954mg, 4.5mmol) triacetoxy borohydride is added after reaction 4h is stirred at room temperature Sodium hydride is stirred at room temperature reaction 20h, stops reaction, NaHCO is added into reaction solution₃Saturated solution is extracted with DCM (40mL × 3) It takes, merges organic layer, washed with saturation NaCl (40mL × 2), anhydrous magnesium sulfate drying, concentration, column chromatography (MeOH:DCM=1: 50,MeOH:DCM=1:40) pale yellow oil 240mg, yield 33% are obtained.

¹H-NMR(400MHz,CDCl₃)δ(ppm):3.40-3.61(m,2H),3.25-3.38(m,2H),3.04-3.15 (m, 1H), 2.40-2.50 (m, 2H), 2.00-2.10 (m, 1H), 1.62-1.80 (m, 2H), 1.45 (s, 9H), 0.91 (d, J= 6.4Hz,6H)

B) 3- (N- isobutyl groups -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoyls Amido) pyrrolidines -1- t-butyl formates

By compound 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluobenzoic acids DMF (15mL), EDC (184mg, 0.96mmol), HOBt (130mg, 0.96mmol), DIEA is added in (150mg, 0.48mmol) (0.21mL, 1.2mmol) and tertiary butyl 3- (isobutylamino) pyrrolidines -1- formic acid esters (210mg, 0.72mmol), room temperature It is stirred to react, next day stops reaction, adds water, is extracted with ethyl acetate, and organic layer is washed with saturation NaCl solution (20mL), anhydrous sulphur Sour magnesium is dried, three times column chromatography (MeOH:DCM=1:80) off-white powder 30mg, yield 11.6%, fusing point 107-109, are obtained ℃。

¹H-NMR(400MHz,CDCl₃)δ(ppm):8.77 (brs, 1H), 8.23 (d, J=7.6Hz, 1H), 7.55-7.65 (m,1H),7.24-7.38(m,3H),7.03-7.10(m,2H),5.25-5.45(m,2H),4.38(brs,0.5H),4.13 (brs,0.5H),2.90-3.80(m,6H),2.35-2.41(m,1H),2.10-2.25(m,1H),1.60-1.75(m,1H), 1.42-1.47 (m, 7H), 1.27-1.31 (m, 2H), 0.96 (d, J=4.8Hz, 3H), 0.85-0.90 (m, 1H), 0.68 (brs, 2H)

Embodiment 61

N- isobutyl groups-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- benzamide 2,2,2- trifluoroacetates of -2-

By compound 3- (N- isobutyl groups -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorine Benzamido) pyrrolidines -1- t-butyl formates (20mg, 0.05mmol), addition DCM (3mL), addition TFA (0.05mL, 0.74mmol), reaction is stirred at room temperature, next day stops reaction, and ether is added, there is solid wash-off, filters, and filter cake ether is washed, obtained White solid 8mg, yield 39.2%, 115-117 DEG C of fusing point.

¹H-NMR(400MHz,DMSO-d₆)δ(ppm):11.73(s,1H),8.97(brs,1H),8.51(brs,1H), 8.00 (d, J=7.2Hz, 1H), 7.60 (t, J=7.6Hz, 1H), 7.51 (brs, 1H), 7.19-7.31 (m, 4H), 5.31 (s, 2H),4.10-4.30(m,1H),3.54(brs,1H),3.30-3.45(m,2H),2.80-3.10(m,3H),2.31(brs, 1H), 2.18 (brs, 1H), 1.56-1.70 (m, 1H), 0.87 (d, J=6.0Hz, 1H), 0.51 (brs, 5H)

Embodiment 62

N- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) the fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (120mg, 0.24mmol), 4,4- difluoro-cyclohexanones (100mg, 0.72mmol), sodium acetate (100mg, It 1.2mmol) being dissolved in DCM (4mL) and methanol (1mL), sodium cyanoborohydride (59mg, 0.84mmol) is added in 37 DEG C of reaction 6h, The reaction was continued 2d stops reaction, and reaction solution is through DCM/MeOH (10:1,60mL) it dilutes, organic phase is through saturated sodium bicarbonate solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH =50:1--30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 105mg is obtained, through DCM/ anhydrous ethers/n-hexane Recrystallize to obtain pale solid 65mg, yield 52.4%, 253-255 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.88 (s, 1H), 8.43 (d, J=5.0Hz, 1H), 7.73 (d, J =6.0Hz, 1H), 7.51-7.60 (m, 2H), 7.41 (brs, 1H), 7.30-7.35 (m, 1H), 7.22 (t, J=9.5Hz, 1H), 5.31(s,2H),4.33(s,1H),2.79(brs,1H),2.68(brs,1H),2.42-2.48(m,2H),2.21(brs,1H), 2.12(brs,1H),2.02(brs,2H),1.64-1.86(m,5H),1.58(s,2H)；HR-MS(ESI):m/z,calcd.for C₂₆H₂₇N₄O₃F₄[M+H]⁺519.2014,Found:519.2000.

Embodiment 63

N- (1- benzyls pyrrolidin-3-yl) fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydroquinazolines of 6- -1 (2H)-yl) methyl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (110mg, 0.28mmol), benzaldehyde (90mg, 0.82mmol), sodium acetate (90mg, 1.1mmol) be dissolved in DCM In (4mL) and methanol (1mL), sodium cyanoborohydride (56mg, 0.82mmol) is added in 37 DEG C of reaction 5.5h, and the reaction was continued 2d stops It only reacts, reaction solution is through DCM/MeOH (10:1,50mL) it dilutes, organic phase is through saturated sodium bicarbonate solution (20mL), saturation chlorine Change ammonium salt solution (20mL), brine (20mL × 3) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1-- DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 102mg is obtained, recrystallizes white solid through DCM/ anhydrous ethers/n-hexane Body 70mg, yield 51.8%, 104-106 DEG C of fusing point.

¹H NMR(500MHz,CDCl₃)δ(ppm):9.16 (brs, 1H), 8.03 (d, J=6.0Hz, 1H), 7.87 (dd, J₁ =7.5Hz, J₂=2.0Hz, 1H), 7.27-7.37 (m, 6H), 7.19 (brs, 1H), 7.06-7.10 (m, 2H), 5.30 (s, 2H), 4.67 (brs, 1H), 3.73 (d, J=7.5Hz, 1H), 3.64 (d, J=12.5Hz, 1H), 2.97 (brs, 1H), 2.67- 2.73(m,2H),2.38(brs,2H),1.76(s,1H)；HR-MS(ESI):m/z,calcd.forC₂₇H₂₅N₄O₃F₂[M+H]⁺ 491.1889,Found:491.1875.

Embodiment 64

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- methoxy benzyls Base) pyrrolidin-3-yl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (90mg, 0.22mmol), P-methoxybenzal-dehyde (90mg, 0.66mmol), sodium acetate (65mg, 0.77mmol) It is dissolved in DCM (4mL) and methanol (1mL), 37 DEG C of reaction 12h are added sodium cyanoborohydride (50mg, 0.77mmol), continue anti- Reaction should be stopped, reaction solution is through DCM/MeOH (10 for 24 hours:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated sodium bicarbonate solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH =50:1--30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) faint yellow solid 92mg is obtained, is recrystallized through DCM/ n-hexanes Faint yellow solid 69mg, yield 60.5%, 182-184 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.88(s,1H),8.43(brs,1H),7.71-7.75(m,1H), 7.50-7.62(m,2H),7.40(brs,1H),7.28-7.35(m,1H),7.16-7.27(m,3H),6.85-6.89(m,2H), 5.30 (s, 2H), 4.31 (brs, 1H), 3.74 (d, J=3.2Hz, 3H), 3.51 (brs, 2H), 2.75 (brs, 1H), 2.57 (brs,1H),2.45(brs,1H),2.37(brs,1H),2.13(s,1H),1.70(s,1H)；HR-MS(ESI):m/z, calcd.for C₂₈H₂₇N₄O₄F₂[M+H]⁺521.1995,Found:521.1977.

Embodiment 65

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- fluorobenzene first Base) pyrrolidin-3-yl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (100mg, 0.25mmol), 4-Fluorobenzaldehyde (96mg, 0.75mmol), sodium acetate (72mg, 0.87mmol) be dissolved in In DCM (4mL) and methanol (1mL), 37 DEG C of reaction 12h are added sodium cyanoborohydride (59mg, 0.87mmol), the reaction was continued 1d, Stop reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated sodium bicarbonate solution (20mL), saturation Ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30: 1--DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 90mg is obtained, white solid 76mg is recrystallized to obtain through DCM/ n-hexanes, Yield 59.8%, 178-180 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.88 (s, 1H), 8.45 (d, J=7.2Hz, 1H), 7.73 (dd, J₁=8.0Hz, J₂=2.8Hz, 1H), 7.50-7.61 (m, 2H), 7.38-7.45 (m, 1H), 7.29-7.37 (m, 3H), 7.19- 7.24(m,1H),7.09-7.16(m,2H),5.30(s,2H),4.27-4.37(m,1H),3.52-3.61(m,2H),2.76(t, J=8.4Hz, 1H), 2.58-2.62 (m, 1H), 2.34-2.39 (m, 2H), 2.09-2.19 (m, 1H), 1.65-1.73 (m, 1H)； HR-MS(ESI):m/z,calcd.for C₂₇H₂₄N₄O₃F₃[M+H]⁺509.1795,Found:509.1794.

Embodiment 66

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (3- methylbenzenes Methyl) pyrrolidin-3-yl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (110mg, 0.28mmol), tolyl aldehyde (106mg, 0.83mmol), sodium acetate (70mg, 0.83mmol) It is dissolved in DCM (4mL) and methanol (1mL), 37 DEG C of reaction 12h are added sodium cyanoborohydride (66mg, 0.96mmol), continue anti- 1d is answered, stops reaction, reaction solution is through DCM/MeOH (10:1,30mL) dilute, organic phase through saturated sodium bicarbonate solution (20mL), Saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 100mg is obtained, white solid is recrystallized to obtain through DCM/ n-hexanes 89mg, yield 64.0%, 151-153 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.88 (s, 1H), 8.45 (d, J=6.8Hz, 1H), 7.73 (dd, J₁=8.4Hz, J₂=3.2Hz, 1H), 7.51-7.59 (m, 2H), 7.39-7.43 (m, 1H), 7.31 (dd, J₁=9.2Hz, J₂= 4.0Hz,1H),7.17-7.25(m,2H),7.03-7.14(m,3H),5.30(s,2H),4.32(brs,1H),3.55(brs, 2H),2.77(brs,1H),2.60(brs,1H),2.34-2.49(m,2H),2.29(s,3H),2.09-2.20(m,1H), 1.62-1.76(m,1H)；HR-MS(ESI):m/z,calcd.for C₂₈H₂₇N₄O₃F₂[M+H]⁺505.2046,Found: 505.2030.

Embodiment 67

N- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) the fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (110mg, 0.28mmol), 4,4- dichloros cyclohexanone (146mg, 0.82mmol), sodium acetate (82mg, It 0.96mmol) is dissolved in dichloro (6mL) and methanol (1.5mL), 37 DEG C of reaction 16h, addition sodium cyanoborohydride (63mg, 0.96mmol), the reaction was continued for 24 hours, stops reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated carbon Sour hydrogen sodium solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--40:1--30:1) faint yellow solid 57mg is obtained, white solid is recrystallized to obtain through DCM/ n-hexanes 42mg, yield 27.6%, 151-153 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.87 (s, 1H), 8.42 (d, J=6.5Hz, 1H), 7.73 (dd, J₁=8.0Hz, J₂=2.5Hz, 1H), 7.51-7.60 (m, 2H), 7.41 (brs, 1H), 7.32 (dd, J₁=9.0Hz, J₂= 4.0Hz, 1H), 7.21 (t, J=9.0Hz, 1H), 5.30 (s, 2H), 4.31 (brs, 1H), 2.79 (t, J=8.0Hz, 1H), 2.63-2.71(m,1H),2.43-2.49(m,4H),2.17-2.29(m,3H),2.07-2.15(m,1H),1.82(brs,2H), 1.59-1.72(m,3H)；HR-MS(ESI):m/z,calcd.for C₂₆H₂₇N₄O₃Cl₂F₂[M+H]⁺551.1423,Found: 551.1417.

Embodiment 68

N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) the fluoro- 5- of -2- ((fluoro- 2,4- dioxies of 6- - 1 (2H)-yl of generation -3,4- dihydroquinazolines) methyl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (250mg, 0.62mmol), 1,4- cyclohexanedione monoethylene acetals (296mg, 1.87mmol), sodium acetate (182mg, 2.18mmol) is dissolved in dichloro (20mL) and methanol (5mL), and sodium cyanoborohydride is added in 35 DEG C of reaction 7h (140mg, 2.18mmol), the reaction was continued 2d stop reaction, and reaction solution is through DCM/MeOH (10:1,30mL) it dilutes, organic phase warp Saturated sodium bicarbonate solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, Column chromatography (DCM:MeOH=50:1--30:1--DCM:MeOH:Ammonium hydroxide=30:1:0.1) faint yellow solid 190mg is obtained, through DCM/ N-hexane recrystallizes to obtain white solid 150mg, yield 44.5%, 143-145 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.87 (s, 1H), 8.40 (d, J=7.0Hz, 1H), 7.73 (dd, J₁=8.0Hz, J₂=2.5Hz, 1H), 7.51-7.61 (m, 2H), 7.40 (brs, 1H), 7.32 (dd, J₁=9.0Hz, J₂= 3.5Hz, 1H), 7.21 (t, J=9.5Hz, 1H), 5.31 (s, 2H), 4.30 (brs, 1H), 3.83 (s, 4H), 2.80 (t, J= 8.0Hz,1H),2.62-2.69(m,1H),2.42-2.48(m,2H),2.09(brs,2H),1.61-1.78(m,5H),1.38- 1.53(m,4H)；HR-MS(ESI):m/z,calcd.for C₂₈H₃₁N₄O₅F₂[M+H]⁺541.2257,Found:5541.2246.

Embodiment 69

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- carbonyl rings Hexyl) pyrrolidin-3-yl) benzamide

By N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) fluoro- 5- of -2- ((fluoro- 2,4- of 6- bis- Oxo -3,4- dihydroquinazoline -1 (2H)-yl) methyl) benzamide (100mg, 0.18mmol) is dissolved in acetone (10mL), it is added 2N HCl (15mL) are reacted at room temperature for 24 hours, stop reaction, reaction solution is concentrated, and DCM/MeOH (10 is added:1,30mL), organic phase Through saturated sodium bicarbonate solution tune pH value to alkalinity, liquid separation, water phase is again through DCM/MeOH (10:1,20mL × 3) it extracts, is associated with Machine phase, organic phase are washed through brine (20mL × 2), and magnesium sulfate drying, concentration recrystallizes to obtain faint yellow solid through DCM/ n-hexanes 42mg, yield 45.6%, 236-238 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.87(s,1H),8.45(s,1H),7.73(dd,J₁=8.0Hz, J₂=3.0Hz, 1H), 7.52-7.59 (m, 2H), 7.41 (brs, 1H), 7.32 (dd, J₁=9.5Hz, J₂=4.0Hz, 1H), 7.22 (t, J=9.5Hz, 1H), 5.31 (s, 2H), 4.37 (brs, 1H), 2.85 (brs, 1H), 2.76 (brs, 1H), 2.54 (brs,2H),2.35-2.47(m,3H),2.11-2.26(m,3H),1.93(brs,2H),1.76-1.86(m,2H),1.72 (brs,1H)；HR-MS(ESI):m/z,calcd.for C₂₆H₂₇N₄O₄F₂[M+H]⁺497.1995,Found:497.1986.

Embodiment 70

N- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) the fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydros quinoline azoles of 6- Quinoline -1 (2H)-yl) methyl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzoic acid (110mg, 0.33mmol), EDC (130mg, 0.67mmol), HOBt (90mg, 0.67mmol), DIEA (220mg, 1.67mmol) and 1- (2- Cyclopropylethyl) pyrrolidines -3- amine 2,2,2- trifluoroacetate (160mg, 0.43mmol) be dissolved in anhydrous DMF (15mL), argon It is reacted at room temperature for 24 hours under gas shielded.Stop reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through unsaturated carbonate Hydrogen sodium (30mL), saturated ammonium chloride (20mL × 2), saturated salt solution (20mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) faint yellow solid 116mg is obtained, and just through DCM/ Hexane recrystallizes to obtain faint yellow solid 90mg, yield 58.1%, 192-194 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.88 (brs, 1H), 8.41 (d, J=6.8Hz, 1H), 7.72 (dd,J₁=8.4Hz, J₂=3.2Hz, 1H), 7.51-7.60 (m, 2H), 7.38-7.42 (m, 1H), 7.31 (dd, J₁=9.2Hz, J₂=4.0Hz, 1H), 7.18-7.24 (m, 1H), 5.30 (s, 2H), 4.25-4.37 (m, 1H), 2.76 (brs, 1H), 2.60 (brs, 1H), 2.38-2.48 (m, 4H), 2.06-2.17 (m, 1H), 1.61-1.72 (m, 1H), 1.33 (q, J=7.2Hz, 2H), 0.63-0.76(m,1H),0.34-0.44(m,2H),0.003-0.03(m,2H)；HR-MS(ESI):m/z,calcd.for C₂₅H₂₇N₄O₃F₂[M+H]⁺469.2046,Found:469.2049.

Embodiment 71

N- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) the fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydros quinoline azoles of 6- Quinoline -1 (2H)-yl) methyl) benzamide

A) (1- (2- cyclopropylethyls) pyrrolidin-3-yl) t-butyl carbamate

3- (Boc- amidos) pyrrolidines (560mg, 3.0mmol) is dissolved in acetonitrile 10mL, addition DIEA (1mL, 6.0mmol) and bromomethyl cyclopropane (470mg, 3.4mmol), 40 DEG C of reaction 1d stop reaction, by reaction solution concentration, column chromatography (DCM:MeOH=60:1--50:1) yellow oil 510mg, yield 70.7% are obtained.¹H NMR(500MHz,CDCl₃)δ(ppm): 5.46(brs,1H),4.33(brs,1H),3.24(brs,1H),3.00(brs,1H),2.87(brs,1H),2.55(brs, 3H), 2.30-2.44 (m, 1H), 1.85 (brs, 1H), 1.44 (s, 9H), 1.01-1.04 (m, 1H), 0.61 (d, J=8.0Hz, 2H), 0.24 (d, J=5.0Hz, 2H)；HR-MS(ESI):m/z,calcd.for C₁₃H₂₅N₂O₂[M+H]⁺241.1910, Found:241.1902.

B) 1- (Cvclopropvlmethvl) pyrrolidines -3- amine 2,2,2- trifluoroacetates

(1- (2- cyclopropylethyls) pyrrolidin-3-yl) t-butyl carbamate (410mg, 1.71mmol) is dissolved in DCM In (15mL), TFA (1.5mL) is added, reaction solution is concentrated, sequentially adds ethyl acetate (6mL × 2) by ambient temperature overnight reaction, Chloroform (6mL × 2), removes solvent and TFA under reduced pressure, obtains brownish red grease 560mg, yield 98.1%.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):8.38-8.45(m,2H),4.07(brs,0.5H),3.95(brs, 1H),3.78(brs,0.5H),3.67(brs,1H),3.51(brs,0.5H),3.10-3.13(m,3H),2.28(brs, 0.5H),2.14(brs,0.5H),2.00(brs,0.5H),1.04-1.11(m,1H),0.60-0.66(m,2H),0.35-0.41 (m,2H)；HR-MS(ESI):m/z,calcd.for C₈H₁₇N₂[M+H]⁺141.1386,Found:141.1382.

C) N- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) the fluoro- 5- of -2- ((the fluoro- 2,4- dioxos -3,4- dihydros quinoline azoles of 6- Quinoline -1 (2H)-yl) methyl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzoic acid (80mg, 0.24mmol), EDC (92mg, 0.48mmol), HOBt (65mg, 0.48mmol), DIEA (160mg, 1.20mmol) and 1- (rings Hydroxypropyl methyl) pyrrolidines -3- amine 2,2,2- trifluoroacetate (100mg, 0.29mmol) be dissolved in anhydrous DMF (10mL), room temperature React 32h.Stop reaction, reaction solution is diluted through DCM (30mL), and organic phase is through saturated sodium bicarbonate (10mL), saturated ammonium chloride (10mL × 2), saturated salt solution (20mL × 4) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1-- DCM:MeOH:NH₃.H₂O=30:1:0.2) yellowish solid 70mg is obtained, and yellowish solid 62mg is recrystallized to obtain through DCM/PE, Yield 56.9%, 105-107 DEG C of fusing point.

¹H NMR(500MHz,CDCl₃)δ(ppm):7.95(dd,J₁=7.0Hz, J₂=2.5Hz, 1H), 7.85 (dd, J₁= 8.0Hz,J₂=3.0Hz, 1H), 7.54 (brs, 1H), 7.25-7.29 (m, overlapped by CDCl₃singal,1H), 7.12-7.16(m,1H),7.01(dd,J₁=9.0Hz, J₂=4.0Hz, 1H), 6.97 (dd, J₁=11.5Hz, J₂=9.0Hz, 1H), 5.28 (d, J=16.0Hz, 1H), 5.22 (d, J=16.0Hz, 1H), 4.72 (brs, 1H), 3.16 (brs, 1H), 3.04 (d, J=9.0Hz, 1H), 2.70-2.74 (m, 1H), 2.59 (dd, J₁=13.0Hz, J₂=7.0Hz, 1H), 2.32-2.46 (m, 3H),1.78(brs,1H),0.93-0.97(m,1H),0.50-0.55(m,2H),0.18-0.18(m,2H)；HR-MS(ESI): m/z,calcd.for C₂₄H₂₅N₄O₃F₂[M+H]⁺455.1889,Found:455.1878

Embodiment 72

The fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- isopentyl pyrroles Cough up alkane -3- bases) benzamide

A) (1- isopentyl pyrrolidin-3-yl) t-butyl carbamate

3- (Boc- amidos) pyrrolidines (560mg, 3.0mmol) is dissolved in acetonitrile 10mL, addition DIEA (1mL, 6.0mmol) and 1- bromos isopentane (526mg, 3.4mmol), 40 DEG C of reaction 1d stop reaction, by reaction solution concentration, column chromatography (DCM:MeOH=60:1--50:1) white solid 610mg, yield 79.3%, 167-169 DEG C of fusing point are obtained.

¹H NMR(500MHz,CDCl₃)δ(ppm):5.87(brs,1H),4.49(brs,1H),3.62(brs,1H),3.39 (brs,1H),3.20(brs,1H),2.95-3.10(m,3H),2.45-2.52(m,1H),2.16(brs,1H),1.66-1.73 (m, 3H), 1.43 (s, 9H), 0.94 (d, J=6.5Hz, 6H)；HR-MS(ESI):m/z,calcd.forC₁₄H₂₉N₂O₂[M+H]⁺ 257.2224,Found:257.2220.

B) 1- isopentyl pyrrolidines -3- amine 2,2,2- trifluoroacetates

(1- isopentyl pyrrolidin-3-yl) t-butyl carbamate (500mg, 1.95mmol) is dissolved in DCM (15mL), TFA (1.5mL) is added, reaction solution is concentrated, sequentially adds ethyl acetate (6mL × 2), chloroform (6mL by ambient temperature overnight reaction × 2) solvent and TFA, are removed under reduced pressure, obtains brownish red grease 640mg, yield 93.8%.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):8.34-8.42(m,2H),4.07(brs,1H),3.94(brs, 1H),3.75(brs,1H),3.64(brs,1H),3.48(brs,1H),3.07-3.37(m,4H),2.47(brs,0.5H), 2.26(brs,0.5H),2.15(brs,0.5H),1.98(brs,0.5H),1.59-1.65(m,1H),1.50-1.55(m,2H), 0.90 (d, J=6.5Hz, 6H)；HR-MS(ESI):m/z,calcd.for C₉H₂₁N₂[M+H]⁺157.1699,Found: 157.1694.

C) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- isopentyl Pyrrolidin-3-yl) benzamide

By the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzoic acid (100mg, 0.30mmol), EDC (120mg, 0.60mmol), HOBt (85mg, 0.60mmol), DIEA (200mg, 1.50mmol) and 1- are different 2,2,2- trifluoroacetate (130mg, 0.36mmol) of amyl pyrrolidines -3- amine is dissolved in anhydrous DMF (5mL), room temperature reaction 32h.Stop reaction, reaction solution is diluted through DCM (20mL) and MeOH (2mL), and organic phase is through saturated sodium bicarbonate (10mL), saturation Ammonium chloride (10mL), saturated salt solution (10mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30: 1--DCM:MeOH:NH₃.H₂O=30:1:0.2) yellow solid 93mg is obtained, and yellow solid 76mg is recrystallized to obtain through DCM/PE, is received Rate 53.9%, 142-144 DEG C of fusing point.

¹H NMR(500MHz,CDCl₃)δ(ppm):7.96(dd,J₁=7.0Hz, J₂=2.5Hz, 1H), 7.85 (dd, J₁= 7.5Hz,J₂=3.0Hz, 1H), 7.65 (brs, 1H), 7.30 (td, J₁=8.5Hz, J₂=3.0Hz, 1H), 7.21-7.25 (m, 1H),7.08(dd,J₁=9.5Hz, J₂=4.0Hz, 1H), 7.02 (t, J=10.0Hz, 1H), 5.30 (d, J=17.5Hz, 1H), 5.25 (d, J=17.5Hz, 1H), 4.78 (brs, 1H), 3.26 (brs, 1H), 3.09 (brs, 1H), 2.75 (brs, 2H), 2.60 (brs,1H),2.44-2.48(m,2H),1.90(brs,1H),1.61-1.66(m,1H),1.48-1.53(m,2H),0.92(d, J=6.5Hz, 6H)；HR-MS(ESI):m/z,calcd.forC₂₅H₂₉N₄O₃F₂[M+H]⁺471.2202,Found:471.2190.

Embodiment 73

The chloro- N- of 2- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines - 1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzene Amide (150mg, 0.38mmol), 4,4- difluoro-cyclohexanones (152mg, 1.13mmol), sodium acetate (110mg, 1.32mmol) are molten In DCM (4mL) and methanol (1mL), sodium cyanoborohydride (85mg, 1.32mmol) is added, and the reaction was continued in 37 DEG C of reaction 10h 1d stops reaction, and reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated sodium bicarbonate solution (10mL), full With ammonium chloride solution (10mL), brine (10mL × 3) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) faint yellow solid 130mg is obtained, is recrystallized through DCM/ methanol/anhydrous ether White solid 110mg, yield 56.7%, 164-166 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.61 (d, J=7.2Hz, 1H), 8.03 (dd, J₁=8.0Hz, J₂=1.6Hz, 1H), 7.63-7.68 (m, 1H), 7.42 (d, J=8.0Hz, 1H), 7.40 (d, J=2.0Hz, 1H),7.32(dd,J₁=8.4Hz, J₂=2.0Hz, 1H), 7.27 (d, J=5.2Hz, 1H), 7.25 (d, J=6.4Hz, 1H), 5.31(s,2H),4.29(brs,1H),2.79(brs,1H),2.68(brs,1H),2.53(brs,1H),2.45(brs,1H), 1.97-2.22(m,4H),1.65-1.87(m,5H),1.51-1.64(m,2H)；HR-MS(ESI):m/z,calcd.for C₂₆H₂₈N₄O₃ClF₂[M+H]⁺517.1812,Found:517.1803.

Embodiment 74

N- (1- benzyls pyrrolidin-3-yl) chloro- 5- of -2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzene Amide (150mg, 0.38mmol), benzaldehyde (130mg, 1.13mmol), sodium acetate (115mg, 1.32mmol) are dissolved in DCM In (4mL) and methanol (1mL), sodium cyanoborohydride (87mg, 1.32mmol) is added in 37 DEG C of reaction 10h, and the reaction was continued 1d stops It only reacts, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated sodium bicarbonate solution (10mL), saturation chlorine Change ammonium salt solution (10mL), brine (10mL × 3) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1-- DCM:MeOH:NH₃.H₂O=30:1:0.1) faint yellow solid 126mg is obtained, white solid 97mg is recrystallized to obtain through DCM/ n-hexanes, Yield 52.7%, 188-190 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.62 (d, J=6.8Hz, 1H), 8.03 (dd, J₁=8.0Hz, J₂=1.6Hz, 1H), 7.63-7.68 (m, 1H), 7.38-7.43 (m, 2H), 7.30-7.33 (m, 5H), 7.22- 7.28 (m, 3H), 5.30 (s, 2H), 4.29 (brs, 1H), 3.62 (d, J=12.4Hz, 1H), 3.54 (d, J=13.2Hz, 1H), 2.76(brs,1H),2.58(brs,1H),2.40-2.48(m,2H),2.08-2.19(m,1H),1.65-1.76(m,1H)；HR- MS(ESI):m/z,calcd.for C₂₇H₂₆N₄O₃Cl[M+H]⁺489.1688,Found:489.1692.

Embodiment 75

The chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- methoxybenzyls) pyrroles Cough up alkane -3- bases) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzene Amide (150mg, 0.38mmol), P-methoxybenzal-dehyde (160mg, 1.13mmol), sodium acetate (115mg, 1.32mmol) are molten In DCM (4mL) and methanol (1mL), sodium cyanoborohydride (84mg, 1.32mmol) is added, and the reaction was continued in 37 DEG C of reaction 3h 12h stops reaction, and reaction solution is through DCM/MeOH (10:1,30mL) dilute, organic phase through saturated sodium bicarbonate solution (20mL), Saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) faint yellow solid 156mg is obtained, recrystallizes white solid through DCM/ n-hexanes Body 130mg, yield 66.7%, 141-143 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.75 (s, 1H), 8.62 (d, J=6.0Hz, 1H), 8.02 (d, J =7.6Hz, 1H), 7.63-7.68 (m, 1H), 7.38-7.42 (m, 2H), 7.18-7.35 (m, 5H), 6.85-6.88 (m, 2H), 5.30(s,2H),4.27(brs,1H),3.72(s,3H),3.41-3.60(m,2H),2.74(brs,1H),2.54(brs,1H), 2.45(brs,1H),2.37(brs,1H),2.11(brs,1H),1.64-1.74(m,1H)；HR-MS(ESI):m/z, calcd.for C₂₈H₂₈N₄O₄Cl[M+H]⁺519.1794,Found:519.1786.

Embodiment 76

The chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- benzyls) pyrroles Cough up alkane -3- bases) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzene Amide (125mg, 0.30mmol), 4-Fluorobenzaldehyde (150mg, 1.20mmol), sodium acetate (127mg, 1.50mmol) are dissolved in DCM In (4mL) and methanol (1mL), sodium cyanoborohydride (96mg, 1.50mmol) is added in 37 DEG C of reaction 12h, and the reaction was continued 1d stops It only reacts, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated sodium bicarbonate solution (10mL), saturation chlorine Change ammonium salt solution (10mL), brine (10mL × 3) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1-- DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 106mg is obtained, white solid 86mg is recrystallized to obtain through DCM/ n-hexanes, is received Rate 56.7%, 185-187 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.62 (d, J=6.4Hz, 1H), 8.03 (d, J =8.0Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 7.37-7.44 (m, 2H), 7.29-7.36 (m, 3H), 7.23-7.28 (m, 2H), 7.13 (t, J=8.4Hz, 2H), 5.31 (s, 2H), 4.29 (brs, 1H), 3.47-3.62 (m, 2H), 2.76 (brs, 1H), 2.56(brs,1H),2.40-2.47(m,2H),2.13(brs,1H),1.68-1.72(m,1H)；HR-MS(ESI):m/z, calcd.for C₂₇H₂₅N₄O₃FCl[M+H]⁺507.1594,Found:507.1597.

Embodiment 77

The chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (3- methylbenzyls) Pyrrolidin-3-yl) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzene Amide (110mg, 0.28mmol), tolyl aldehyde (110mg, 0.83mmol), sodium acetate (82mg, 0.97mmol) are dissolved in In DCM (4mL) and methanol (1mL), 37 DEG C of reaction 1d are added sodium cyanoborohydride (63mg, 0.83mmol), the reaction was continued 1d, Stop reaction, reaction solution is through DCM/MeOH (10:1,30mL) it dilutes, organic phase is through saturated sodium bicarbonate solution (20mL), saturation Ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30: 1--DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 90mg is obtained, white solid 67mg is recrystallized to obtain through DCM/ n-hexanes, Yield 48.2%, 186-188 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.62 (d, J=6.4Hz, 1H), 8.03 (d, J =8.0Hz, 1H), 7.63-7.68 (m, 1H), 7.38-7.43 (m, 2H), 7.16-7.33 (m, 4H), 7.02-7.14 (m, 3H), 5.30(s,2H),4.29(brs,1H),3.46-3.62(m,2H),2.76(brs,1H),2.58(brs,1H),2.37-2.49 (m,2H),2.29(s,3H),2.09-2.21(m,1H),1.65-1.75(m,1H)；HR-MS(ESI):m/z,calcd.for C₂₈H₂₈N₄O₃Cl[M+H]⁺503.1844,Found:503.1848.

Embodiment 78

The chloro- N- of 2- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines - 1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzene Amide (110mg, 0.28mmol), 4,4- dichloros cyclohexanone (142mg, 0.83mmol), sodium acetate (81mg, 0.97mmol) are dissolved in In dichloro (6mL) and methanol (1.5mL), sodium cyanoborohydride (62mg, 0.97mmol) is added, and the reaction was continued in 37 DEG C of reaction 16h For 24 hours, stop reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase through saturated sodium bicarbonate solution (20mL), Saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 40:1--30:1) light red brown solid 140mg is obtained, recrystallizes to obtain white solid 92mg through DCM/ n-hexanes, yield 64.8% melts 162-164 DEG C of point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.60 (d, J=7.2Hz, 1H), 8.03 (dd, J₁=8.0Hz, J₂=1.6Hz, 1H), 7.61-7.72 (m, 1H), 7.42 (d, J=8.4Hz, 1H), 7.40 (d, J=2.0Hz, 1H),7.44–7.39(m,2H),7.31(dd,J₁=8.4Hz, J₂=2.0Hz, 1H), 7.23-7.28 (m, 2H), 5.31 (s, 2H),4.29(brs,1H),2.74-2.81(m,1H),2.62-2.71(m,1H),2.40-2.49(m,4H),2.05-2.29(m, 4H),1.81(brs,2H),1.59-1.74(m,3H).

Embodiment 79

N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) chloro- 5- of -2- ((dioxo -3 2,4-, 4- dihydroquinazolines -1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzene Amide (350mg, 0.88mmol), 1,4- cyclohexanedione monoethylene acetals (416mg, 2.64mmol), sodium acetate (253mg, It 3.08mmol) is dissolved in dichloro (20mL) and methanol (5mL), 35 DEG C of reaction 9h, addition sodium cyanoborohydride (196mg, 3.08mmol), the reaction was continued 2d stops reaction, and reaction solution is through DCM/MeOH (10:1,30mL) it dilutes, organic phase is through saturated carbon Sour hydrogen sodium solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1--DCM:MeOH:Ammonium hydroxide=30:1:0.1) white solid 400mg is obtained, through DCM/ n-hexane weights Crystallize to obtain white solid 340mg, yield 71.7%, 179-181 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.73 (s, 1H), 8.58 (d, J=7.2Hz, 1H), 8.03 (d, J =8.0Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 7.39-7.43 (m, 2H), 7.21-7.33 (m, 3H), 5.31 (s, 2H), 4.28 (brs, 1H), 3.84 (s, 4H), 2.80 (t, J=8.4Hz, 1H), 2.60-2.67 (m, 1H), 2.41-2.48 (m, 2H), 2.04-2.14(m,2H),1.63-1.77(m,5H),1.38-1.53(m,4H)；HR-MS(ESI):m/z,calcd.for C₂₈H₃₂N₄O₅Cl[M+H]⁺539.2056,Found:539.2040.

Embodiment 80

The chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- carbonyls cyclohexyl) Pyrrolidin-3-yl) benzamide

By N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) -2- chloro- 5- ((2,4- dioxos - - 1 (2H)-yl of 3,4- dihydroquinazoline) methyl) benzamide (130mg, 0.24mmol) is dissolved in acetone (10mL), 2NHCl is added (15mL) is reacted at room temperature for 24 hours, stops reaction, reaction solution is concentrated, and DCM/MeOH (10 is added:1,30mL), organic phase is through saturation Sodium bicarbonate solution tune pH value is to alkalinity, and liquid separation, water phase is again through DCM/MeOH (10:1,20mL × 3) it extracts, merges organic phase, Organic phase is washed through brine (20mL × 2), and magnesium sulfate drying, concentration recrystallizes to obtain white solid 102mg through DCM/ n-hexanes, receives Rate 85.7%, 169-171 DEG C of fusing point.¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.62 (d, J= 6.0Hz,1H),8.03(dd,J₁=8.0Hz, J₂=1.2Hz, 1H), 7.60 (td, J₁=8.0Hz, J₂=1.2Hz, 1H), 7.38-7.44 (m, 2H), 7.32 (d, J=8.0Hz, 1H), 7.23-7.29 (m, 1H), 5.31 (s, 2H), 4.34 (brs, 1H), 2.83(brs,1H),2.74(brs,1H),2.51(brs,2H),2.34-2.46(m,3H),2.09-2.25(m,3H),1.65- 1.97(m,5H)；HR-MS(ESI):m/z,calcd.for C₂₆H₂₈N₄O₄Cl[M+H]⁺495.1794,Found:495.1778.

Embodiment 81

The chloro- N- of 2- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) benzoic acid (110mg, 0.33mmol), EDC (130mg, 0.67mmol), HOBt (90mg, 0.67mmol), DIEA (220mg, 1.67mmol) and 1- (2- Cyclopropylethyl) pyrrolidines -3- amine 2,2,2- trifluoroacetate (150mg, 0.43mmol) be dissolved in anhydrous DMF (15mL), argon It is reacted at room temperature for 24 hours under gas shielded.Stop reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through unsaturated carbonate Hydrogen sodium (30mL), saturated ammonium chloride (20mL × 2), saturated salt solution (20mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) faint yellow solid 110mg is obtained, and just through DCM/ Hexane recrystallizes to obtain faint yellow solid 96mg, yield 61.9%, 226-228 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.74 (s, 1H), 8.59 (d, J=6.8Hz, 1H), 8.03 (d, J =8.0Hz, 1H), 7.63-7.69 (m, 1H), 7.39-7.42 (m, 2H), 7.31 (d, J=8.4Hz, 1H), 7.23-7.28 (m, 2H),5.31(s,2H),4.28(brs,1H),2.78(brs,1H),2.57(brs,1H),2.45(brs,4H),2.05-2.18 (m,1H),1.62-1.72(m,1H),1.27-1.36(m,2H),0.63-0.73(m,1H),0.34-0.41(m,2H),0.00- 0.04(m,2H)；HR-MS(ESI):m/z,calcd.for C₂₅H₂₈N₄O₃Cl[M+H]⁺467.1844,Found:467.1850.

Embodiment 82

The chloro- N- of 2- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((2,4- dioxo -3,4- dihydros -- quinazoline -1- (2H)-yl) methyl) benzoic acid (110mg, 0.33mmol), EDC (130mg, 0.67mmol), HOBt (90mg, 0.67mmol), DIEA (220mg, 1.67mmol) and 1- (rings Hydroxypropyl methyl) pyrrolidines -3- amine 2,2,2- trifluoroacetate (140mg, 0.40mmol) be dissolved in anhydrous DMF (6mL), argon gas protect The lower ambient temperature overnight reaction of shield.Stop reaction, reaction solution is through DCM/MeOH (10:1,60mL) it dilutes, organic phase is through unsaturated carbonate hydrogen Sodium (30mL), saturated ammonium chloride (30mL), saturated salt solution (30mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM: MeOH=50:1--20:1--DCM:MeOH:NH₃.H₂O=20:1:0.2) faint yellow solid 110mg is obtained, and is tied again through DCM/PE It is brilliant to obtain faint yellow solid 92mg, yield 61.3%, 153-155 DEG C of fusing point.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.22 (d, J=7.5Hz, 1H), 8.17 (d, J=8.0Hz, 1H), 7.54 (s, 1H), 7.51 (d, J=7.5Hz, 1H), 7.19-7.25 (m, 2H), 6.91 (d, J=8.5Hz, 1H), 6.82 (d, J= 9.0Hz, 1H), 5.19 (d, J=17.0Hz, 1H), 4.92 (d, J=16.0Hz, 1H), 4.84 (brs, 1H), 3.38-3.44 (m, 2H),2.94(dd,J₁=12.5Hz, J₂=6.5Hz, 1H), 2.68 (t, J=9.0Hz, 1H), 2.66-2.71 (m, 1H), 2.48- 2.55(m,1H),2.36-2.39(m,1H),2.29-2.33(m,1H),1.88-1.90(m,1H),0.97-1.02(m,1H), 0.84-0.88(m,1H),0.52-0.61(m,2H),0.18-0.23(m,2H)；HR-MS(ESI):m/z,calcd.for C₂₄H₂₆N₄O₃Cl[M+H]⁺453.1688,Found:453.1675.

Embodiment 83

The chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- isopentyl pyrrolidines - 3- yls) benzamide

By the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) benzoic acid (110mg, 0.33mmol), EDC (130mg, 0.67mmol), HOBt (90mg, 0.67mmol), DIEA (220mg, 1.67mmol) and 1- are different 2,2,2- trifluoroacetate (140mg, 0.40mmol) of amyl pyrrolidines -3- amine is dissolved in anhydrous DMF (6mL), under argon gas protection Ambient temperature overnight is reacted.Stop reaction, reaction solution is through DCM/MeOH (10:1,60mL) it dilutes, organic phase is through saturated sodium bicarbonate (30mL), saturated ammonium chloride (30mL), saturated salt solution (30mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH =50:1--20:1--DCM:MeOH:NH₃.H₂O=20:1:0.2) faint yellow solid 130mg is obtained, and is recrystallized through DCM/PE Faint yellow solid 95mg, yield 60.9%, 185-187 DEG C of fusing point.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.18(s,1H),8.16(s,1H),7.58-7.60(m,2H),7.25 (d, J=3.0Hz, 1H), 7.22 (d, J=7.5Hz, 1H), 7.06 (d, J=7.0Hz, 1H), 7.01 (d, J=6.0Hz, 1H), 5.23 (d, J=16.0Hz, 1H), 5.30 (d, J=16.0Hz, 1H), 4.92 (brs, 1H), 3.59 (brs, 1H), 3.44 (brs, 1H),2.96-3.04(m,1H),2.85(brs,1H),2.74(brs,1H),2.51-2.64(m,2H),2.08(brs,1H), 1.60-1.68 (m, 3H), 0.93 (d, J=6.0Hz, 6H)；HR-MS(ESI):m/z,calcd.for C₂₅H₃₀N₄O₃Cl[M+H]⁺ 469.2001,Found:469.1989.

Embodiment 84

The chloro- N- of 2- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (100mg, 0.24mmol), 4,4- difluoro-cyclohexanones (97mg, 0.72mmol), sodium acetate (86mg, 0.96mmol) It is dissolved in DCM (4mL) and methanol (1mL), sodium cyanoborohydride (49mg, 0.72mmol) is added, and the reaction was continued in 37 DEG C of reaction 4h 2d stops reaction, and reaction solution is through DCM/MeOH (10:1,60mL) it dilutes, organic phase is through saturated sodium bicarbonate solution (20mL), full With ammonium chloride solution (20mL), brine (20mL × 3) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) yellow solid 110mg is obtained, is recrystallized through DCM/ anhydrous ethers/n-hexane Pale solid 60mg, yield 46.9%, 240-241 DEG C of fusing point.

¹H NMR(500MHz,CDCl₃)δ(ppm):9.53(brs,1H),7.86(dd,J₁=7.5Hz, J₂=3.0Hz, 1H), 7.61 (s, 1H), 7.28-7.33 (m, 2H), 7.11 (d, J=10.0Hz, 1H), 7.00-7.04 (m, 1H), 5.28 (d, J =16.5Hz, 1H), 5.19 (d, J=17.0Hz, 1H), 4.70 (brs, 1H), 3.16 (brs, 1H), 2.99 (brs, 1H), 2.71 (brs,1H),2.37-2.43(m,3H),2.12(brs,2H),1.69-1.96(m,8H)；HR-MS(ESI):m/z, calcd.for C₂₆H₂₇N₄O₃F₃Cl[M+H]⁺535.1718,Found:535.1702.

Embodiment 85

N- (1- benzyls pyrrolidin-3-yl) chloro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydroquinazolines of 6- -1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (100mg, 0.24mmol), benzaldehyde (80mg, 0.72mmol), sodium acetate (82mg, 0.96mmol) be dissolved in DCM In (4mL) and methanol (1mL), sodium cyanoborohydride (47mg, 0.72mmol) is added in 37 DEG C of reaction 2.5h, and the reaction was continued 2d stops It only reacts, reaction solution is through DCM/MeOH (10:1,60mL) it dilutes, organic phase is through saturated sodium bicarbonate solution (20mL), saturation chlorine Change ammonium salt solution (20mL), brine (20mL × 3) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1-- DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 106mg is obtained, canescence is recrystallized to obtain through DCM/ anhydrous ethers/n-hexane Solid 65mg, yield 53.7%, 139-141 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.86 (s, 1H), 8.61 (d, J=6.5Hz, 1H), 7.73 (dd, J₁=8.0Hz, J₂=2.5Hz, 1H), 7.53-7.59 (m, 1H), 7.38-7.43 (m, 2H), 7.20-7.34 (m, 7H), 5.30 (s, 2H), 4.30 (brs, 1H), 3.62 (d, J=12.5Hz, 1H), 3.55 (d, J=12.5Hz, 1H), 2.77 (brs, 1H), 2.59(brs,1H),2.58(brs,1H),2.42(brs,1H),2.10-2.20(m,1H),1.68-1.75(m,1H)；HR-MS (ESI):m/z,calcd.for C₂₇H₂₅N₄O₃FCl[M+H]⁺507.1594,Found:507.1585.

Embodiment 86

The chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- methoxy benzyls Base) pyrrolidin-3-yl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (100mg, 0.24mmol), P-methoxybenzal-dehyde (100mg, 0.72mmol), sodium acetate (70mg, It 0.84mmol) is dissolved in DCM (4mL) and methanol (1mL), 37 DEG C of reaction 13h, addition sodium cyanoborohydride (54mg, 0.84mmol), the reaction was continued 6h stops reaction, and reaction solution is through DCM/MeOH (10:1,30mL) it dilutes, organic phase is through saturated carbon Sour hydrogen sodium solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1) faint yellow solid 96mg is obtained, faint yellow solid 82mg is recrystallized to obtain through DCM/ n-hexanes, is received Rate 63.6%, 197-199 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.89 (s, 1H), 8.63 (d, J=6.0Hz, 1H), 7.73 (dd, J₁=8.4Hz, J₂=3.2Hz, 1H), 7.57 (dd, J₁=9.2Hz, J₂=3.2Hz, 1H), 7.39-7.44 (m, 2H), 7.26- 7.34 (m, 2H), 7.22 (d, J=8.0Hz, 2H), 6.87 (d, J=8.4Hz, 2H), 5.30 (s, 2H), 4.28 (brs, 1H), 3.73(s,3H),3.42-3.59(m,2H),2.75(brs,1H),2.54(brs,1H),2.45(brs,1H),2.37(brs, 1H),2.07-2.18(m,1H),1.65-1.74(m,1H)；HR-MS(ESI):m/z,calcd.for C₂₈H₂₇N₄O₄ClF[M+H ]⁺537.1699,Found:537.1687.

Embodiment 87

The chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- fluorobenzene first Base) pyrrolidin-3-yl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (125mg, 0.30mmol), 4-Fluorobenzaldehyde (150mg, 1.20mmol), sodium acetate (126mg, 1.50mmol) be molten In DCM (4mL) and methanol (1mL), sodium cyanoborohydride (96mg, 1.50mmol) is added, and the reaction was continued in 37 DEG C of reaction 12h 1d stops reaction, and reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated sodium bicarbonate solution (10mL), full With ammonium chloride solution (10mL), brine (10mL × 3) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 86mg is obtained, white solid is recrystallized to obtain through DCM/ n-hexanes 74mg, yield 47.1%, 219-221 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.87 (s, 1H), 8.61 (d, J=6.8Hz, 1H), 7.73 (dd, J₁=8.4Hz, J₂=3.2Hz, 1H), 7.53-7.59 (m, 1H), 7.38-7.44 (m, 2H), 7.26-7.37 (m, 4H), 7.10- 7.15(m,2H),5.30(s,2H),4.30(brs,1H),3.45-3.67(m,2H),2.76(brs,1H),2.57(brs,1H), 2.40-2.47(m,2H),2.07-2.20(m,1H),1.64-1.76(m,1H)；HR-MS(ESI):m/z,calcd.for C₂₇H₂₄N₄O₃F₂Cl[M+H]⁺525.1500,Found:525.1501.

Embodiment 88

The chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (3- methylbenzenes Methyl) pyrrolidin-3-yl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (120mg, 0.29mmol), tolyl aldehyde (110mg, 0.86mmol), sodium acetate (86mg, 1.01mmol) It is dissolved in DCM (4mL) and methanol (1mL), 37 DEG C of reaction 12h are added sodium cyanoborohydride (67mg, 1.01mmol), continue anti- 1d is answered, stops reaction, reaction solution is through DCM/MeOH (10:1,50mL) dilute, organic phase through saturated sodium bicarbonate solution (20mL), Saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) white solid 107mg is obtained, white solid is recrystallized to obtain through DCM/ n-hexanes 94mg, yield 62.7%, 127-129 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.87(s,1H),8.61(brs,1H),7.70-7.76(m,1H), 7.53-7.60(m,1H),7.37-7.45(m,2H),7.25-7.34(m,2H),7.16-7.23(m,1H),7.02-7.15(m, 3H),5.30(s,2H),4.30(brs,1H),3.43-3.62(m,2H),2.76(brs,1H),2.58(brs,1H),2.35- 2.47(m,2H),2.29(s,3H),2.14(brs,1H),1.71(brs,1H)；HR-MS(ESI):m/z,calcd.for C₂₈H₂₇N₄O₃ClF[M+H]⁺521.1750,Found:521.1744.

Embodiment 89

The chloro- N- of 2- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (110mg, 0.26mmol), 4,4- dichloros cyclohexanone (136mg, 0.79mmol), sodium acetate (80mg, It 0.92mmol) is dissolved in dichloro (6mL) and methanol (1.5mL), 37 DEG C of reaction 16h, addition sodium cyanoborohydride (60mg, 0.92mmol), the reaction was continued for 24 hours, stops reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through saturated carbon Sour hydrogen sodium solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--40:1--30:1) faint yellow solid 62mg is obtained, white solid is recrystallized to obtain through DCM/ n-hexanes 46mg, yield 30.7%, 193-195 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.86 (s, 1H), 8.59 (d, J=7.0Hz, 1H), 7.73 (d, J =6.0Hz, 1H), 7.56 (t, J=6.5Hz, 1H), 7.37-7.44 (m, 2H), 7.26-7.34 (m, 2H), 5.30 (s, 2H), 4.29(brs,1H),2.78(brs,1H),2.67(brs,1H),2.40-2.48(m,4H),2.16-2.29(m,3H),2.06- 2.15(m,1H),1.82(brs,2H),1.67(brs,3H)；HR-MS(ESI):m/z,calcd.forC₂₆H₂₇N₄O₃Cl₃F[M+ H]⁺567.1127,Found:567.1113.

Embodiment 90

N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) the chloro- 5- of -2- ((fluoro- 2,4- dioxies of 6- - 1 (2H)-yl of generation -3,4- dihydroquinazolines) methyl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidines -3- Base) benzamide (250mg, 0.60mmol), 1,4- cyclohexanedione monoethylene acetals (286mg, 1.80mmol), sodium acetate (175mg, 2.10mmol) is dissolved in dichloro (20mL) and methanol (5mL), and sodium cyanoborohydride is added in 35 DEG C of reaction 7h (140mg, 2.10mmol), the reaction was continued 2d stop reaction, and reaction solution is through DCM/MeOH (10:1,30mL) it dilutes, organic phase warp Saturated sodium bicarbonate solution (20mL), saturated ammonium chloride solution (20mL), brine (20mL × 2) are washed, magnesium sulfate drying, concentration, Column chromatography (DCM:MeOH=50:1--30:1--DCM:MeOH:Ammonium hydroxide=30:1:0.1) faint yellow solid 200mg is obtained, through DCM/ N-hexane recrystallizes to obtain white solid 140mg, yield 41.9%, 162-164 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.86 (s, 1H), 8.57 (d, J=7.0Hz, 1H), 7.73 (dd, J₁=8.0Hz, J₂=3.0Hz, 1H), 7.57 (td, J₁=8.5Hz, J₂=3.0Hz, 1H), 7.39-7.43 (m, 2H), 7.26- 7.34 (m, 2H), 5.30 (s, 2H), 4.21-4.34 (m, 1H), 3.83 (s, 4H), 2.79 (d, J=7.5Hz, 1H), 2.61- 2.67(m,1H),2.42-2.48(m,2H),2.05-2.14(m,2H),1.61-1.80(m,5H),1.38-1.52(m,4H)； HR-MS(ESI):m/z,calcd.for C₂₈H₃₁N₄O₅ClF[M+H]⁺557.1962,Found:557.1953.

Embodiment 91

The chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- carbonyl rings Hexyl) pyrrolidin-3-yl) benzamide

By N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) chloro- 5- of -2- ((fluoro- 2,4- of 6- bis- Oxo -3,4- dihydroquinazoline -1 (2H)-yl) methyl) benzamide (100mg, 0.18mmol) is dissolved in acetone (10mL), it is added 2N HCl (15mL) are reacted at room temperature for 24 hours, stop reaction, reaction solution is concentrated, and DCM/MeOH (10 is added:1,30mL), organic phase Through saturated sodium bicarbonate solution tune pH value to alkalinity, liquid separation, water phase is again through DCM/MeOH (10:1,20mL × 3) it extracts, is associated with Machine phase, organic phase are washed through brine (20mL × 2), and magnesium sulfate drying, concentration recrystallizes to obtain faint yellow solid through DCM/ n-hexanes 46mg, yield 50%, 245-247 DEG C of fusing point.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):11.87(s,1H),8.62(s,1H),7.73(dd,J₁=8.0Hz, J₂=3.0Hz, 1H), 7.57 (td, J₁=8.5Hz, J₂=3.0Hz, 1H), 7.38-7.45 (m, 2H), 7.33 (d, J=7.5Hz, 1H),7.29(dd,J₁=9.5Hz, J₂=4.0Hz, 1H), 5.31 (s, 2H), 4.34 (brs, 1H), 2.84 (brs, 1H), 2.75 (brs,1H),2.57(brs,2H),2.34-2.47(m,3H),2.10-2.26(m,3H),1.68-1.98(m,5H)；HR-MS (ESI):m/z,calcd.for C₂₆H₂₇N₄O₄ClF[M+H]⁺513.1699,Found:513.1690.

Embodiment 92

The chloro- N- of 2- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((fluoro- 2,4- dioxos -3,4- dihydros quinoline azoles of 6- Quinoline -1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzoic acid (110mg, 0.32mmol), EDC (122mg, 0.63mmol), HOBt (87mg, 0.63mmol), DIEA (210mg, 1.58mmol) and 1- (2- Cyclopropylethyl) pyrrolidines -3- amine 2,2,2- trifluoroacetate (160mg, 0.41mmol) be dissolved in anhydrous DMF (15mL), argon It is reacted at room temperature for 24 hours under gas shielded.Stop reaction, reaction solution is through DCM/MeOH (10:Isosorbide-5-Nitrae 0mL) dilution, organic phase is through unsaturated carbonate Hydrogen sodium (30mL), saturated ammonium chloride (20mL × 2), saturated salt solution (20mL × 3) are washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1--30:1--DCM:MeOH:NH₃.H₂O=30:1:0.1) yellow solid 137mg, and through DCM/ just oneself Alkane recrystallizes to obtain yellow solid 100mg, yield 65.4%, 207-209 DEG C of fusing point.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):11.87 (brs, 1H), 8.58 (d, J=7.2Hz, 1H), 7.73 (dd,J₁=7.6Hz, J₂=3.2Hz, 1H), 7.56 (td, J₁=8.8Hz, J₂=2.8Hz, 1H), 7.39-7.43 (m, 2H), 7.26-7.33(m,2H),5.30(s,2H),4.18-4.35(m,1H),2.77(brs,1H),2.56(brs,1H),2.34- 2.48(m,4H),2.06-2.15(m,1H),1.63-1.72(m,1H),1.28-1.37(m,2H),0.64-0.72(m,1H), 0.33-0.43(m,2H),0.00-0.03(m,2H)；HR-MS(ESI):m/z,calcd.forC₂₅H₂₇N₄O₃ClF[M+H]⁺ 485.1750,Found:485.1744.

Embodiment 93

The chloro- N- of 2- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) -5- ((fluoro- 2,4- dioxos -3,4- dihydros quinoline azoles of 6- Quinoline -1 (2H)-yl) methyl) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzoic acid (100mg, 0.29mmol), EDC (110mg, 0.57mmol), HOBt (80mg, 0.57mmol), DIEA (190mg, 1.44mmol) and 1- (rings Hydroxypropyl methyl) pyrrolidines -3- amine 2,2,2- trifluoroacetate (130mg, 0.34mmol) be dissolved in anhydrous DMF (4mL), argon gas protect Shield is lower to react at room temperature 32h.Stop reaction, reaction solution is diluted through DCM (30mL), and organic phase is through saturated sodium bicarbonate (10mL), full It is washed with ammonium chloride (10mL × 2), saturated salt solution (20mL × 4), magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50: 1--20:1--DCM:MeOH:NH₃.H₂O=20:1:0.2) faint yellow solid 80mg is obtained, and recrystallizes faint yellow through DCM/PE Solid 68mg, yield 50.4%, 165-167 DEG C of fusing point.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.40(brs,1H),7.82(dd,J₁=8.0Hz, J₂=3.0Hz, 1H), 7.65 (brs, 1H), 7.35-7.40 (m, 1H), 7.29 (d, J=8.5Hz, 1H), 7.16 (brs, 1H), 7.05 (d, J= 8.0Hz, 1H), 5.24 (d, J=17.0Hz, 1H), 5.17 (d, J=17.0Hz, 1H), 4.98 (brs, 1H), 3.75 (brs, 1H),3.61(brs,1H),2.96(dd,J₁=12.5Hz, J₂=7.0Hz, 2H), 2.72 (brs, 2H), 2.57-2.60 (m, 1H),2.17(brs,1H),1.14(brs,1H),0.85-0.89(m,1H),0.72(brs,2H),0.37(brs,2H)；HR-MS (ESI):m/z,calcd.for C₂₄H₂₅N₄O₃FCl[M+H]⁺471.1594,Found:471.1581.

Embodiment 94

The chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- isopentyl pyrroles Cough up alkane -3- bases) benzamide

By the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzoic acid (100mg, 0.29mmol), EDC (110mg, 0.57mmol), HOBt (80mg, 0.57mmol), DIEA (190mg, 1.44mmol) and 1- are different 2,2,2- trifluoroacetate (126mg, 0.34mmol) of amyl pyrrolidines -3- amine is dissolved in anhydrous DMF (6mL), under argon gas protection React at room temperature 32h.Stop reaction, reaction solution is diluted through DCM (30mL), and organic phase is through saturated sodium bicarbonate (10mL), saturation chlorine Change ammonium (10mL × 2), saturated salt solution (20mL × 4) is washed, magnesium sulfate drying, concentration, column chromatography (DCM:MeOH=50:1-- 30:1--DCM:MeOH:NH₃.H₂O=30:1:0.2) faint yellow solid 106mg is obtained, and pale yellow colored solid is recrystallized to obtain through DCM/PE Body 92mg, yield 65.7%, 169-171 DEG C of fusing point.

¹H NMR(500MHz,CDCl₃)δ(ppm):8.17(brs,1H),7.83(dd,J₁=8.0Hz, J₂=3.0Hz, 1H), 7.52 (brs, 1H), 7.20-7.25 (m, 2H), 6.88 (brs, 1H), 6.81 (d, J=9.0Hz, 1H), 5.15 (d, J= 16.0Hz, 1H), 4.90 (d, J=14.0Hz, 1H), 4.83 (brs, 1H), 3.39 (brs, 1H), 3.25 (brs, 1H), 2.96- 3.03(m,1H),2.61(s,1H),2.47-2.54(m,1H),2.36(brs,1H),1.87(brs,1H),1.60-1.66(m, 1H), 1.49 (brs, 2H), 0.92 (d, J=6.5Hz, 6H)；HR-MS(ESI):m/z,calcd.for C₂₅H₂₉N₄O₃ClF[M+ H]⁺487.1907,Found:487.1894.

Pharmacological evaluation：

Experimental example 1：Zymetology level activity is evaluated

(1) compound evaluates PARP1 enzyme inhibition activities

Compound is evaluated to PARP1 enzyme inhibitions using the dual anti-ELISA sizing techniques of PAR.Specific experimental method is as follows： Using 96 orifice plates of 4 DEG C of each 100 μ l of hole of 50 μ g/mL histones coating 16h, each board-washing of the PBS and PBS of 0.1%Triton100 2 It is secondary.Then blank control wells, enzyme control wells are set and measure hole, blank control wells are added 35 μ l and measure buffer NAD⁺(5pmol), 10 μ l purification buffers, 5 μ l ShearedDNA (1 μ g/ml), enzyme control wells add 30 μ l NAD⁺ 30 μ are added in (5pmol), 10 μ l PARP1 (0.005Units), 5 μ lSheared DNA (1 μ g/ml), positive compound control wells l NAD⁺(5pmol), 5 μ l ABT-888 various concentration dilutions, 10 μ l PARP1 (0.005Units), 5ul Sheared DNA (1 μ g/ml) measures hole and 30 μ l NAD is added⁺(5pmol), 5 μ l respectively measure chemical compound diluted liquid, 10 μ l PARP1 (0.005Units), 5 μ l Sheared DNA (1 μ g/ml).50 μ l volumes are amounted to, 1h is reacted at room temperature.Using containing 0.1% Each board-washing of PBS and PBS of Triton X-100 2 times.It adds and uses PBS 1:50 μ of mouse monoclonal antibody of 500 diluted anti-PAR L is incubated at room temperature 1h, each board-washing of PBS and PBS of 0.1%Triton X-100 2 times.Then PBS1 is added:4000 diluted goats Anti- mouse IgG50 μ l are incubated at room temperature 30min, each board-washing of PBS and PBS of 0.1%Triton X-100 2 times.Add TMB reactions 50 μ l of liquid, room temperature are protected from light 15min, then terminate reaction using the 50 μ l of aqueous solution containing 20% concentrated hydrochloric acid.450nm, which is measured, to be inhaled Luminosity.Calculate inhibiting rate % of each compound various concentration dilution to PARP1.Inhibitory activity is shown in Table 1.

(2) compound evaluates PARP2 enzyme inhibition activities

Compound is evaluated to PARP2 enzyme inhibitions using the dual anti-ELISA sizing techniques of PAR.Specific experimental method is as follows： Using 96 orifice plates of 4 DEG C of each 100 μ l of hole of 50 μ g/mL histones coating 16h, each board-washing of the PBS and PBS of 0.1%Triton100 2 It is secondary.Then blank control wells, enzyme control wells, positive compound control wells are set and measure hole, 35 μ l are added in blank control wells Measure the NAD of buffer⁺(5pmol), 10 μ l purification buffers, 5 μ l Sheared DNA (1 μ g/ml), enzyme control wells Add 30 μ l NAD⁺(5pmol), 10 μ lPARP2 (0.005Units), 5 μ l Sheared DNA (1 μ g/ml), positive compound pair 30 μ l NAD are added according to hole⁺(5pmol), 5 μ l AZD-2281 various concentration dilutions, 10 μ l PARP2 (0.005Units), 5ul ShearedDNA (1 μ g/ml) measure hole and 30 μ l NAD are added⁺(5pmol), 5 μ l respectively measure chemical compound diluted liquid, 10 μ LPARP2 (0.005Units), 5 μ l Sheared DNA (1 μ g/ml).50 μ l volumes are amounted to, 1h is reacted at room temperature.Using containing Each board-washing of PBS and PBS of 0.1%Triton X-100 2 times.It adds and uses PBS 1:The murine monoclonal of 500 diluted anti-PAR is anti- 50 μ l of body are incubated at room temperature 1h, each board-washing of PBS and PBS of 0.1%Triton X-100 2 times.Then PBS 1 is added:4000 dilutions Mountain sheep anti mouse IgG50 μ l, be incubated at room temperature 30min, each board-washing of PBS and PBS of 0.1%Triton X-100 2 times.It adds 50 μ l of TMB reaction solutions, room temperature are protected from light 15min, then terminate reaction using the 50 μ l of aqueous solution containing 20% concentrated hydrochloric acid. 450nm measures absorbance.Calculate inhibiting rate % of each compound various concentration dilution to PARP2.Inhibitory activity is shown in Table 1.

1. compound of table is to PARP1/2 enzyme inhibition activities

ND, active undetermined.

Experimental example 2：Cellular level pharmacodynamic experiment

Experimental method：

Single compound is determined respectively using mtt assay to the inhibitory activity and compound of human breast cancer cell MX-1 to replacing The sensitization of Muzolimine, method are as follows：

(1) mtt assay measures single compound IC₅₀；

Cell culture and bed board：The MX-1 of DMEM cultures containing 10%FBS is cultivated to exponential phase,

Then cell is dispelled with suction pipe, after cell count, using DMEM culture mediums diluting cells to 20000/mL, so Afterwards in 96 orifice plate middle berth, 100 holes μ L/, 37 DEG C, 5%CO₂With overnight incubation under the conditions of saturated humidity.

Administration：Blank control is set, measures compound group, dilute each measurement compound with DMEM to various concentration, then 100 μ L DMEM are added in blank well, 100 μ L are added in compound group and contain each DMEM for measuring compound, until final concentration of 1, 5,10,25,50,100 μM, blank control sets 6 multiple holes, and 3 multiple holes are arranged in each concentration of dosing holes.37 DEG C of saturated humidities after administration Cultivate cell 72h.

MTT is measured：After above-mentioned cell administration culture 72h, MTT solution (50 μ g/mL) 100 μ that DMEM is prepared are added in each hole L, 37 DEG C, 5%CO₂With 4h is incubated under the conditions of saturated humidity, then 150 μ LDMSO are added in each hole, measure 570nm absorbances.Profit The IC of each compound is calculated with Graphpad₅₀.

(2) sensitization of the compound to Temozolomide

Cell culture and bed board：The MX-1 of DMEM cultures containing 10%FBS is cultivated to exponential phase, suction pipe is then used Cell is dispelled, after cell count, using DMEM culture mediums diluting cells to 20000/mL, then in 96 orifice plate middle berth, 100 μ The holes L/, 37 DEG C, 5%CO₂With overnight incubation under the conditions of saturated humidity.

Administration：Blank control is set, Temozolomide group, Temozolomide+measurement compound group, measures compound control group, Respectively with DMEM dilution Temozolomides and measurement compound.DMEM is added in blank well, DMEM dilutions are added in Temozolomide group Each concentration Temozolomide, Temozolomide+measurement compound component Jia Ru contain it is each measure compound DMEM dilutions and Each concentration Temozolomide DMEM dilutions, finally to Temozolomide it is final concentration of 1,0.5,0.25,0.1,0.05,0.025mM, survey It is 5 μM to determine final compound concentration, measures compound control and compound is added to final concentration of 5 μM, blank control sets 6 again 3 multiple holes are arranged in hole, each concentration of dosing holes.37 DEG C of saturated humidity culture cell 72h after administration.

MTT is measured：After above-mentioned cell administration culture 72h, MTT solution (50 μ g/mL) 100 μ that DMEM is prepared are added in each hole L, 37 DEG C, 5%CO₂With 4h is incubated under the conditions of saturated humidity, then 150 μ LDMSO are added in each hole, measure 570nm absorbances.Profit The IC of each group is calculated with Graphpad₅₀, and enhanced sensitivity factor PF is calculated, the calculation formula of wherein enhanced sensitivity factor PF is：PF=IC₅₀ (TMZ)/IC₅₀(TMZ+PARPi), wherein in the calculating formula of sensitizing activity, PARPi indicates PARP inhibitor, PF values be TMZ with When PARP inhibitor is administered simultaneously, the ratio with TMZ independent medications characterizes sensitizing activity.

Inhibitory activity IC of 2. compound of table to MX-1 cells₅₀Value and to the sensitization (PF) of TMZ

ND：Active undetermined.

Note：PF (5 × 10 in table 2^-6M) instruction is 5 × 10^-6Sensitizing activity under M concentration.

Experimental example 3：Pharmacodynamic experiment in animal body：

(1) it is combined with TMZ, to the inhibiting effect of human breast carcinoma MX-1

Experimental method：

(1) step：Human breast carcinoma MX-1 tumour cells are collected under aseptic condition, and cell density is adjusted with sterile saline To 1 × 10⁷A/ml takes 0.2ml to be inoculated in nude mice armpit dorsal sc, waits for tumour growth to diameter 1cm sizes, under aseptic condition It takes out, nude mice armpit dorsal sc is uniformly inoculated in after homogenate.Wait for tumour growth to 100~300mm after 7 days³Afterwards, animal is random Grouping starts that (being denoted as the 0th day) is administered.Oral medication, Temozolomide and the equal successive administration of untested compound 5 days.It weighs within every 2 days Weight simultaneously removes tumor tissues with the length and width of vernier caliper measurement tumour by nude mice dislocation execution after being administered the 9th day, It weighs and takes pictures.Tumor control rate is finally calculated, antitumor action intensity is evaluated with tumor control rate.

(2) it is grouped：Blank control group, TMZ groups (50mg/kg), embodiment 16 (50mg/kg) group, 16 (25mg/ of embodiment Kg)+TMZ (50mg/kg) group, embodiment 16 (50mg/kg)+TMZ (50mg/kg) group drugs are prepared：Temozolomide is suspended in In 0.5% carboxymethylcellulose sodium solution, after the 1mL polyethylene glycol hydrotropies of embodiment 16, it is re-dissolved in 0.5% carboxymethyl cellulose Sodium solution.

(4) computational methods：Gross tumor volume (TV)：V=1/2 × a × b², a and b indicate that knurl is long and wide respectively.Tumour inhibiting rate： Inhibition (%)=(1-T/C) × 100, T is treatment group TV or tumor weight, and C is negative control group TV or tumor weight.

Experimental result：

Temozolomide and the equal successive administration of untested compound 5 days.The 9th day after administration, animal is handled.

Administering drug combinations group successive administration 5 days, for each inhibitor successive administration after 5 days, each group has significant tumor killing effect (table 3)。

3. embodiment 16 of table to human breast carcinoma MX-1 nude mice by subcutaneous heteroplastic transplantation tumor growth inhibition effect

Note：^a%T/C_veh:% administration groups tumor weight/non-administration control group tumor weight；%TGI：With non-administered group ratio Compared with the tumour inhibiting rate of tumour growth；^b%T/C_TMZ:%TMZ inhibiting administering drug combinations groups tumor weight/TMZ administration group tumour weights Amount；%TGI：Compared with TMZ administration groups, the tumour inhibiting rate of administering drug combinations group tumour growth；^cNA:It is not applicable.

Claims

1. compound and its pharmaceutical salts as shown in general formula I

In Formulas I,

(1)H、F、Cl、Br、CN、NO₂、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂, wherein the Rh₁、Ri₁、Rh₂、 Rh₃、Rh₄、Ri₂Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, the third methylene of ring, cyclobutyl；

(2) substituted or non-substituted C1-4 linear or branched alkyl groups, substituted or non-substituted C2-4 linear chain or branched chains alkenyl, substitution Or non-substituted C2-4 linear chain or branched chain alkynyls, wherein substituent group are selected from F, Cl, Br, CN, NO₂、CONRh₁Ri₁、COORh₂、 SO₂Rh₃、SO₂NRh₄Ri₂, wherein the Rh₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂Independently selected from H, methyl, ethyl, propyl, different Propyl, cyclopropyl, the third methylene of ring, cyclobutyl；

(3) it substituted or non-substituted C3-6 naphthenic base, the oxacycloalkyl of substituted or non-substituted 3-6 membered rings, substitution or non-takes The azacycloalkyl of the 3-6 membered rings in generation, wherein substituent group are selected from methyl, ethyl, propyl, isopropyl, CF₃、CH₂CF₃、CHF₂、F、 Cl、Br、CN、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂、ORh₅、SRh₆、NRh₇Ri₃、NRh₈CORi₄、 NRh₉COORi₅, wherein the Rh₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂、Rh₅、Rh₆、Rh₇、Ri₃、Rh₈、Ri₄、Rh₉、Ri₅Independently Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, the third methylene of ring, cyclobutyl；The oxacycloalkyl and 3-6 of 3-6 membered rings 1 hetero atom can be contained in the azacycloalkyl of membered ring, multiple hetero atoms can also be contained simultaneously；

(4)ORj₁、NRj₂Rk₁、SRj₃、NRj₄CORk₂、NRj₅COORk₃、NRj₆SO₂Rk₄, wherein the Rj₁、Rj₂、Rk₁、 Rj₃、Rj₄、Rk₂、Rj₅、Rk₃、Rj₆、Rk₄Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, the third methylene of ring, Cyclobutyl, CF₃, CH₂CF₃, CHF₂；

R₅Independently selected from H, F, Cl, Br, CN, NO₂、ORx₁、SRx₂、NRx₃Ry₁、COORx₄、CONRx₅Ry₂、NRx₆COORy₃、 SO₂NRx₇Ry₄、NRx₈CORy₅、(CH₂)n₁ORx₉、(CH₂)n₂NRx₁₀Ry₆, C1-C3 linear or branched alkyl groups, halogen substitution C1-C3 linear or branched alkyl groups, C2-4 linear chain or branched chains alkenyl, C2-4 linear chain or branched chains alkynyl, cyclopropyl, the third methylene of ring, Cyclobutyl, oxetanylmethoxy, cyclopenta, wherein the Rx₁、Rx₂、Rx₃、Ry₁、Rx₄、Rx₅、Ry₂、Rx₆、Ry₃、Rx₇、Ry₄、 Rx₈、Ry₅、Rx₉、Rx₁₀、Ry₆The C1-C3 linear chain or branched chain alkane replaced independently selected from H, C1-3 linear or branched alkyl group, halogen Base, cyclopropyl, the third methylene of ring, cyclobutyl；The halogen includes F, Cl, Br, I；n₁And n₂Independently selected from 1,2,3；

R₆Selected from following atom or group or structure fragment：

(1) hydrogen, substituted or non-substituted C1-8 linear or branched alkyl groups, substituted or non-substituted C2-8 linear chain or branched chains alkenyl, Substituted or non-substituted C2-8 linear chain or branched chain alkynyls, wherein substituent group are selected from F, Cl, Br, CN, ORc₁、SRc₂、NRc₃Rd₁、 COORc₄、CONRc₅Rd₂、NRc₆COORd₃、SO₂NRc₇Rd₄、NRc₈CORd₅, cyclopropyl, the third methylene of ring, cyclobutyl, oxa- ring Butyl, cyclopenta, cyclohexyl, Ar, wherein the Rc₁、Rc₂、Rc₃、Rd₁、Rc₄、Rc₅、Rd₂、Rc₆、Rd₃、Rc₇、Rd₄、Rc₈、 Rd₅Independently selected from H, C1-4 linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl, wherein the Ar is independently Selected from substituted or non-substituted phenyl, substituted or non-substituted nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted five yuan of heteroaromatics, Wherein substituent group is selected from C1-4 linear or branched alkyl groups, the C1-4 linear or branched alkyl groups that halogen replaces, F, Cl, Br, NO₂、CN、 Methylene-dioxy, ORa '₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、 NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀, wherein the Ra '₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、 Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 linear or branched alkyl group, Cyclopropyl, the third methylene of ring, cyclobutyl, cyclopenta；The phenyl ring, nitrogenous hexa-atomic heteroaromatic can be in five yuan of heteroaromatics It is monosubstituted, can also be polysubstituted；Hexa-atomic heteroaromatic can contain 1 N atom, can also contain multiple nitrogen-atoms；Five yuan of virtues Heterocycle can contain there are one hetero atom, can also contain multiple hetero atoms, and hetero atom is selected from O, N, S；N is selected from 1,2,3；Wherein institute The halogen stated includes F, Cl, Br；

(2) it substituted or non-substituted C3-7 naphthenic base, the oxacycloalkyl of substituted or non-substituted 3-8 membered rings, substitution or non-takes The azacycloalkyl of the 3-8 membered rings in generation, wherein the substituent group be selected from C1-4 linear or branched alkyl groups, F, Cl, Br, CN, ORc₁、SRc₂、NRc₃Rd₁、COORc₄、CONRc₅Rd₂、NRc₆COORd₃、SO₂NRc₇Rd₄、NRc₈CORd₅, cyclopropyl, the third methylene of ring Base, cyclobutyl, oxetanylmethoxy, cyclopenta, wherein the Rc₁、Rc₂、Rc₃、Rd₁、Rc₄、Rc₅、Rd₂、Rc₆、Rd₃、Rc₇、 Rd₄、Rc₈、Rd₅Independently selected from H, C1-4 linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl；The oxygen of 3-8 membered rings 1 hetero atom can be contained in Heterocyclylalkyl and azacycloalkyl, multiple hetero atoms can also be contained simultaneously；

(3)CORe₁、COORe₂、CONRe₃Rf₁、SO₂Re₄, wherein the Re₁、Re₂、Re₃、Re₄、Rf₁Independently selected from H, take It is generation or non-substituted C1-6 linear or branched alkyl groups, substituted or non-substituted C2-6 linear chain or branched chains alkenyl, substituted or non-substituted C2-6 linear chain or branched chains alkynyl, substituted or non-substituted C3-7 naphthenic base, substituted or non-substituted 3-8 membered rings oxa- cycloalkanes The azacycloalkyl of base, substituted or non-substituted 3-8 membered rings, the substituent group are selected from F, Cl, Br, CN, ORc₁、SRc₂、 NRc₃Rd₁、COORc₄、CONRc₅Rd₂、NRc₆COORd₃、SO₂NRc₇Rd₄、NRc₈CORd₅, cyclopropyl, the third methylene of ring, ring fourth Base, oxetanylmethoxy, cyclopenta, wherein the Rc₁、Rc₂、Rc₃、Rd₁、Rd₄、Rc₅、Rd₂、Rc₆、Rd₃、Rc₇、Rd₄、Rc₈、 Rd₅Independently selected from H, C1-4 linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl；The oxa- cycloalkanes of 3-8 membered rings 1 hetero atom can be contained in base and azacycloalkyl, multiple hetero atoms can also be contained simultaneously；

(4) substituted or non-substituted phenyl, substituted or non-substituted nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted five yuan of virtues are miscellaneous Ring, wherein substituent group are selected from C1-4 linear or branched alkyl groups, the C1-4 linear or branched alkyl groups that halogen replaces, F, Cl, Br, NO₂、 CN, methylene-dioxy, ORa '₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb ′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀, wherein the Ra '₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、 Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 linear chain or branched chain Alkyl, cyclopropyl, the third methylene of ring, cyclobutyl, cyclopenta；The phenyl ring, nitrogenous hexa-atomic heteroaromatic, can in five yuan of heteroaromatics Can also be polysubstituted to be monosubstituted；Hexa-atomic heteroaromatic can contain 1 N atom, can also contain multiple nitrogen-atoms；Five First heteroaromatic can contain there are one hetero atom, can also contain multiple hetero atoms, and hetero atom is selected from O, N, S；N is selected from 1,2,3；Its Described in halogen include F, Cl, Br；

R₇Selected from following atom or group or structure fragment：

(2) it substituted or non-substituted C3-7 naphthenic base, the oxacycloalkyl of substituted or non-substituted 3-8 membered rings, substitution or non-takes The azacycloalkyl of the 3-8 membered rings in generation, wherein the substituent group be selected from C1-4 linear or branched alkyl groups, F, Cl, Br, CN, ORc₁、SRc₂、NRc₃Rd₁、COORc₄、CONRc₅Rd₂、NRc₆COORd₃、SO₂NRc₇Rd₄、NRc₈CORd₅, cyclopropyl, the third methylene of ring Base, cyclobutyl, oxetanylmethoxy, cyclopenta, wherein the Rc₁、Rc₂、Rc₃、Rd₁、Rc₄、Rc₅、Rd₂、Rc₆、Rd₃、Rc₇、 Rd₄、Rc₈、Rd₅Independently selected from H, C1-4 linear or branched alkyl group, cyclopropyl, the third methylene of ring, cyclobutyl；The oxygen of 3-8 membered rings 1 hetero atom can be contained in Heterocyclylalkyl and azacycloalkyl, multiple hetero atoms can also be contained simultaneously.

2. compound according to claim 1 and its pharmaceutical salts, which is characterized in that the compound is as shown in general formula IA

H、F、Cl、Br、CN、NO₂, methyl, ethyl, trifluoromethyl, trifluoroethyl, CHF₂、CONH₂、OH、OCH₃、OC₂H₅, methylene Two oxygroups, NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃；

R₅Independently selected from H, F, Cl, Br, CN, NO₂、ORx₁、SRx₂、NRx₃Ry₁、COORx₄、CONRx₅Ry₂、NRx₆COORy₃、 SO₂NRx₇Ry₄、NRx₈CORy₅、CH₂ORx₉、CH₂NRx₁₀Ry₆, C1-C3 linear or branched alkyl groups, halogen substitution C1-C3 straight chains Or branched alkyl, C2-4 linear chain or branched chains alkenyl, C2-4 linear chain or branched chains alkynyl, cyclopropyl, the third methylene of ring, cyclobutyl, oxygen Heterocycle butyl, cyclopenta, wherein the Rx₁、Rx₂、Rx₃、Ry₁、Rx₄、Rx₅、Ry₂、Rx₆、Ry₃、Rx₇、Ry₄、Rx₈、Ry₅、Rx₉、 Rx₁₀、Ry₆Independently selected from H, methyl, ethyl, propyl, CF₃、CH₂CF₃, cyclopropyl, the third methylene of ring, cyclobutyl；The halogen Including F, Cl, Br, I；

R₆Selected from following atom or group or structure fragment：

R₇Selected from following atom or group or structure fragment：

3. compound according to claim 2 and its pharmaceutical salts, which is characterized in that the compound is as shown in general formula IA-1

R′₅Independently selected from H, F, Cl, Br, CN, NO₂, methyl, ethyl, trifluoromethyl, trifluoroethyl, CHF₂、CONH₂、OH、 OCH₃、OC₂H₅, methylene-dioxy, NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃；

R₆Selected from following atom or group or structure fragment：

R₇Selected from following atom or group or structure fragment：

4. compound according to claim 3 and its pharmaceutical salts, which is characterized in that the compound is as shown in general formula IA-1a

R₆Selected from following atom or group or structure fragment：

5. compound according to claim 4 and its pharmaceutical salts, which is characterized in that the compound such as general formula IA-1a-1 institutes Show

R′₆Selected from following atom or group or structure fragment：

(1) hydrogen, substituted or non-substituted C1-8 linear or branched alkyl groups, substituted or non-substituted C2-8 linear chain or branched chains alkenyl, Substituted or non-substituted C2-8 linear chain or branched chain alkynyls, wherein substituent group are selected from F, Cl, Br, CN, OCH3, NHCH₃, cyclopropyl, The third methylene of ring, cyclobutyl, Ar, wherein the Ar is independently selected from substituted or non-substituted phenyl, substituted or non-substituted Nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted five yuan of heteroaromatics, wherein substituent group are selected from C1-4 linear or branched alkyl groups, halogen Substituted C1-4 linear or branched alkyl groups, F, Cl, Br, NO₂, CN, methylene-dioxy, OCH₃、NHCH₃；It is the phenyl ring, nitrogenous It can be monosubstituted in hexa-atomic heteroaromatic, five yuan of heteroaromatics, can also be polysubstituted；Hexa-atomic heteroaromatic can contain 1 N original Son can also contain multiple nitrogen-atoms；Five yuan of heteroaromatics can contain there are one hetero atom, can also contain multiple hetero atoms, miscellaneous Atom is selected from O, N, S；

(2) it substituted or non-substituted C3-7 naphthenic base, the oxacycloalkyl of substituted or non-substituted 3-8 membered rings, substitution or non-takes The azacycloalkyl of the 3-8 membered rings in generation, wherein the substituent group is selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br；3-8 1 hetero atom can be contained in the oxacycloalkyl and azacycloalkyl of membered ring, multiple hetero atoms can also be contained simultaneously；

(3)CORe₁、COORe₂、CONRe₃Rf₁、SO₂Re₄, wherein the Re₁、Re₂、Re₃、Re₄、Rf₁Independently selected from H, take It is generation or non-substituted C1-6 linear or branched alkyl groups, substituted or non-substituted C2-6 linear chain or branched chains alkenyl, substituted or non-substituted C2-6 linear chain or branched chains alkynyl, substituted or non-substituted C3-7 naphthenic base, substituted or non-substituted 3-8 membered rings oxa- cycloalkanes The azacycloalkyl of base, substituted or non-substituted 3-8 membered rings, the substituent group are selected from F, Cl, Br, CN, OCH₃, cyclopropyl, The third methylene of ring, cyclobutyl, oxetanylmethoxy, cyclopenta can contain in the oxacycloalkyl and azacycloalkyl of 3-8 membered rings 1 hetero atom can also contain multiple hetero atoms simultaneously；

(4) substituted or non-substituted phenyl, substituted or non-substituted nitrogenous hexa-atomic heteroaromatic, substituted or non-substituted five yuan of virtues are miscellaneous Ring, wherein substituent group are selected from C1-4 linear or branched alkyl groups, the C1-4 linear or branched alkyl groups that halogen replaces, F, Cl, Br, NO₂、 CN, methylene-dioxy, OCH₃；The phenyl ring, nitrogenous hexa-atomic heteroaromatic, can be in five yuan of heteroaromatics it is monosubstituted, can also It is polysubstituted；Hexa-atomic heteroaromatic can contain 1 N atom, can also contain multiple nitrogen-atoms；Five yuan of heteroaromatics can contain one A hetero atom, can also contain multiple hetero atoms, and hetero atom is selected from O, N, S；Wherein the halogen includes F, Cl, Br；

6. compound according to claim 3 and its pharmaceutical salts, which is characterized in that the compound is as shown in general formula IA-1b

R₆Selected from following atom or group or structure fragment：

7. compound according to claim 6 and its pharmaceutical salts, which is characterized in that the compound such as general formula IA-1b-1 institutes Show

R′₆Selected from following atom or group or structure fragment：

(2) it substituted or non-substituted C3-7 naphthenic base, the oxacycloalkyl of substituted or non-substituted 3-8 membered rings, substitution or non-takes The azacycloalkyl of the 3-8 membered rings in generation, wherein the substituent group is selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br；3-8 1 hetero atom can be contained in the oxacycloalkyl and azacycloalkyl of membered ring, multiple hetero atoms, miscellaneous original can also be contained simultaneously Son is selected from O, N, S；

(3)CORe₁、COORe₂、CONRe₃Rf₁、SO₂Re₄, wherein the Re₁、Re₂、Re₃、Re₄、Rf₁Independently selected from H, take It is generation or non-substituted C1-6 linear or branched alkyl groups, substituted or non-substituted C2-6 linear chain or branched chains alkenyl, substituted or non-substituted C2-6 linear chain or branched chains alkynyl, substituted or non-substituted C3-7 naphthenic base, substituted or non-substituted 3-8 membered rings oxa- cycloalkanes The azacycloalkyl of base, substituted or non-substituted 3-8 membered rings, the substituent group are selected from F, Cl, Br, CN, OCH₃, cyclopropyl, The third methylene of ring, cyclobutyl, oxetanylmethoxy, cyclopenta can contain in the oxacycloalkyl and azacycloalkyl of 3-8 membered rings 1 hetero atom, can also contain multiple hetero atoms simultaneously, and hetero atom is selected from O, N, S；

8. compound according to claim 1 and its pharmaceutical salts, which is characterized in that the compound is selected from following group：

1) 3- (5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzoylaminos) pyrrolidines - 1- t-butyl formates

2) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluoro- N- (pyrrolidin-3-yl) benzoyl Amine

3) 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 5-) methyl) benzamido) pyrrole Cough up alkane -1- t-butyl formates

4) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 5-) methyl)-N- (pyrrolidin-3-yl) Benzamide 2,2,2- trifluoroacetates

5) 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzamido) pyrrole Cough up alkane -1- t-butyl formates

6) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidin-3-yl) Benzamide

7) 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 7-) methyl) benzamido) pyrrole Cough up alkane -1- t-butyl formates

8) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 7-) methyl)-N- (pyrrolidin-3-yl) Benzamide 2,2,2- trifluoroacetates

9) 3- (the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 8-) methyl) benzamido) pyrrole Cough up alkane -1- t-butyl formates

10) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 8-) methyl)-N- (pyrrolidin-3-yl) Benzamide 2,2,2- trifluoroacetates

11) 3- (the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl) benzamido) pyrrole Cough up alkane -1- t-butyl formates

12) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (pyrrolidin-3-yl) Benzamide

13) 3- (the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) benzamido) pyrrolidines - 1- t-butyl formates

14) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (pyrrolidin-3-yl) benzoyl Amine

15) N- (1- methylpyrrolidin- 3- yls) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- Fluorobenzamide

16) N- (1- (the third methyl of ring) pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) -2- fluorobenzamides

17) N- (1- (2,2,2- trifluoroethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzamides

18) N- (1- isopentyl pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzamides

19) N- (1- (amyl -3- bases)-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) -2- fluorobenzamides

20) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- Fluorobenzamide

21) N- (1- normal-butyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzamides

22) N- (1- isobutyl-pyrrolidin -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzamides

23) N- (1- n-propyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzamides

24) N- (1- (2,2- bis-fluoro ethyls)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzamides

25) N- (1- (oxetanone -3- bases)-pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

26) N- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzene amides

27) N- (1- (cyclopropane carbonyl) pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) Methyl) -2- fluorobenzamides

28) N- (1- (2,2,2- trifluoroacetyl groups) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) -2- fluorobenzamides

29) N- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzene amides

30) N- (1- benzyls pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - 2- fluorobenzene amides

31) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- methoxybenzyls) pyrroles Cough up alkane -3- bases) benzamide

32) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- benzyls) pyrroles Cough up alkane -3- bases) benzamide

33) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (3- methylbenzyls) Pyrrolidin-3-yl) benzamide

34) N- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H) - Base) methyl) -2- fluorobenzene amides

35) N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydros Quinazoline -1 (2H)-yl) methyl) -2- fluorobenzene amides

36) 5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) the fluoro- N- of -2- (1- (4- carbonyls cyclohexyl) Pyrrolidin-3-yl) benzamide

38) N- methyl-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- Fluoro- benzamide 2,2,2- trifluoroacetates

39) N- (1- trifluoroacetyl groups-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

40) N- (1- cyclopropane carbonyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

41) N- (1- acetyl group-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- N-methyl-benzamides of 2-

42) N- (1- normal-butyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- N-methyl-benzamides of 2-

43) N- (the third methylene of 1- rings-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N-methyl-benzamides of -2-

44) N- (1- isobutyl-pyrrolidin -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- N-methyl-benzamides of 2-

45) N- (1- isopentyl-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- N-methyl-benzamides of 2-

47) N- ethyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- Fluoro- benzamide 2,2,2- trifluoroacetates

48) N- (1- trifluoroacetyl groups-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

49) N- (1- cyclopropane carbonyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) the fluoro- N- ethyl benzamides of -2-

50) N- (1- acetyl group-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- N- ethyl benzamides of 2-

51) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- Fluoro- N- ethyl benzamides

52) N- (1- n-propyls-pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- N- ethyl benzamides of 2-

53) 3- (N- n-propyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

54) N- n-propyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- benzamide 2,2,2- trifluoroacetates of 2-

55) N- (1- ethyl-pyrolidine -3- bases) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- Fluoro- N- n-propylbenzenes formamide

56) 3- (N- phenethyls -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

57) N- phenethyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- benzamide 2,2,2- trifluoroacetates of 2-

59) N- benzyls-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- Fluoro- benzamide 2,2,2- trifluoroacetates

60) 3- (N- isobutyl groups -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) -2- fluorobenzamides Base) pyrrolidines -1- t-butyl formates

61) N- isobutyl groups-N- (pyrrolidin-3-yl) -5- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) - The fluoro- benzamide 2,2,2- trifluoroacetates of 2-

62) N- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) the fluoro- 5- of -2- ((the fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

63) N- (1- benzyls pyrrolidin-3-yl) fluoro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydroquinazolines -1 (2H)-of 6- Base) methyl) benzamide

64) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- methoxy benzyls Base) pyrrolidin-3-yl) benzamide

65) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- fluorobenzene first Base) pyrrolidin-3-yl) benzamide

66) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (3- methylbenzenes Methyl) pyrrolidin-3-yl) benzamide

67) N- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) the fluoro- 5- of -2- ((the fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

68) N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) the fluoro- 5- of -2- ((the fluoro- 2,4- dioxies of 6- - 1 (2H)-yl of generation -3,4- dihydroquinazolines) methyl) benzamide

69) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- carbonyl rings Hexyl) pyrrolidin-3-yl) benzamide

70) N- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) the fluoro- 5- of -2- ((the fluoro- 2,4- dioxos -3,4- dihydros quinoline azoles of 6- Quinoline -1 (2H)-yl) methyl) benzamide

71) N- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) the fluoro- 5- of -2- ((the fluoro- 2,4- dioxos -3,4- dihydroquinazolines-of 6- 1 (2H)-yl) methyl) benzamide

72) the fluoro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- isopentyl pyrroles Alkane -3- bases) benzamide

73) the chloro- N- of 2- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) benzamide

74) N- (1- benzyls pyrrolidin-3-yl) chloro- 5- of -2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) first Base) benzamide

75) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- methoxybenzyls) pyrroles Cough up alkane -3- bases) benzamide

76) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- benzyls) pyrroles Cough up alkane -3- bases) benzamide

77) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (3- methylbenzyls) Pyrrolidin-3-yl) benzamide

78) the chloro- N- of 2- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) benzamide

79) N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) the chloro- 5- of -2- ((2,4- dioxos -3,4- Dihydroquinazoline -1 (2H)-yl) methyl) benzamide

80) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- (4- carbonyls cyclohexyl) Pyrrolidin-3-yl) benzamide

81) the chloro- N- of 2- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((2,4- dioxo -3,4- dihydroquinazolines -1 (2H)-yl) methyl) benzamide

83) the chloro- 5- of 2- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl)-N- (1- isopentyl pyrrolidines -3- Base) benzamide

84) the chloro- N- of 2- (1- (4,4- difiuorocyclohexyls) pyrrolidin-3-yl) -5- ((the fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

85) N- (1- benzyls pyrrolidin-3-yl) chloro- 5- of -2- ((fluoro- 2,4- dioxos -3,4- dihydroquinazolines -1 (2H)-of 6- Base) methyl) benzamide

86) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- methoxy benzyls Base) pyrrolidin-3-yl) benzamide

87) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- fluorobenzene first Base) pyrrolidin-3-yl) benzamide

88) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (3- methylbenzenes Methyl) pyrrolidin-3-yl) benzamide

89) the chloro- N- of 2- (1- (4,4- dichloros cyclohexyl) pyrrolidin-3-yl) -5- ((the fluoro- 2,4- dioxos -3,4- dihydro quinolines of 6- Oxazoline -1 (2H)-yl) methyl) benzamide

90) N- (1- (1,4- dioxo spiros [4.5] decane -8- bases) pyrrolidin-3-yl) the chloro- 5- of -2- ((the fluoro- 2,4- dioxies of 6- - 1 (2H)-yl of generation -3,4- dihydroquinazolines) methyl) benzamide

91) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- (4- carbonyl rings Hexyl) pyrrolidin-3-yl) benzamide

92) the chloro- N- of 2- (1- (2- cyclopropylethyls) pyrrolidin-3-yl) -5- ((the fluoro- 2,4- dioxos -3,4- dihydros quinoline azoles of 6- Quinoline -1 (2H)-yl) methyl) benzamide

93) the chloro- N- of 2- (1- (Cvclopropvlmethvl) pyrrolidin-3-yl) -5- ((the fluoro- 2,4- dioxos -3,4- dihydroquinazolines-of 6- 1 (2H)-yl) methyl) benzamide

94) the chloro- 5- of 2- ((fluoro- -1 (the 2H)-yls of 2,4- dioxos -3,4- dihydroquinazolines of 6-) methyl)-N- (1- isopentyl pyrroles Alkane -3- bases) benzamide.

9. the method for preparing any one of claim 1-8 compounds, which is characterized in that include the following steps：

R₁-R₄Substituted different quinazoline diones and include R₅Substituted 3- methoxycarbonyl groups bromobenzyl is sent out respectively under the action of HMDS The alkylated reaction of raw selectivity, after hydrolysis, including R₁-R₅Different the 3- ((2,4- dioxo -3,4- dihydro quinoline azoles of substitution Quinoline -1 (2H)-yl) methyl) benzoic acid again with include R₆And R₇3- amino pyrrolidine derivatives be condensed, obtain 1- benzyls Quinazoline diones class compound；

Or include R₁-R₅Different 3- ((- 1 (2H)-yl of 2,4- dioxo -3,4- dihydroquinazolines) methyl) benzene first of substitution The R that acid is protected with N-Boc again₇After substituted 3- amino pyrrolidine derivatives are condensed, Boc protecting groups are removed, R is re-introduced into₆ Structure fragment obtains 1- benzyl quinazoline diones class compounds；

Reagent and reaction condition:(a) urea, 140 DEG C, 6h；(b) i) lithium hexamethyldisilazide (HMDS), the concentrated sulfuric acid, toluene, Reflux, 2h, ii) substitution 5- (bromomethyl) -2- fluorophenyl carbamates, 145 DEG C, 3h, iii) methanol, hexane, 70 DEG C, 30min； (c)LiOH,MeOH,H₂O,THF,55℃,2h；(d) 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluoro phosphorus Acid esters (HATU), I-hydroxybenzotriazole (HOBT), diisopropylethylamine (DIEA), DMF (n,N-Dimethylformamide), Overnight (overnight), or 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDC), I-hydroxybenzotriazole (HOBT), diisopropylethylamine (DIEA), DMF (n,N-Dimethylformamide), overnight (overnight)；(e) trifluoroacetic acid (TFA), DCM (dichloromethane), room temperature, or trifluoroacetic acids (TFA), DCM (dichloromethane), then ammonium hydroxide, room temperature；(f) acyl chlorides Or acid anhydrides, DCM (dichloromethane), ice bath, 30min or aldehyde or ketone, sodium acetate, DCM (dichloromethane), methanol, cyano boron cyaniding Sodium, 37 DEG C

The wherein R₁、R₂、R₃、R₄、R₅、R₆And R₇Definition as described in claim any one of 1-8.

10. a kind of pharmaceutical composition, which is characterized in that the compound of any one of claim 1-8 comprising effective dose and Acceptable carrier in its pharmaceutical salts and pharmacodynamics.

11. the compound and its pharmaceutical salts of any one of claim 1-8 are in preparing PARP-1 and/or PARP-2 inhibitor Using.

12. the compound and its pharmaceutical salts of any one of claim 1-8 prepare prevent and or treatment PARP-1 and/or Application in the drug of the related diseases of PARP-2.

13. the compound and its pharmaceutical salts of any one of claim 1-8 are preparing antitumor drug or antitumor drug enhanced sensitivity Application in agent.

14. application according to claim 13, which is characterized in that the tumour is selected from melanoma, gastric cancer, lung cancer, mammary gland Cancer, kidney, liver cancer, oral cavity epidermal carcinoma, cervical carcinoma, oophoroma, cancer of pancreas, prostate cancer, colon cancer, carcinoma of urinary bladder, neuroglia Tumor.