Condensed benzene ring-containing dihydropteridinone derivative and use thereof

Abstract

The invention relates to a fused benzene ring-containing dihydropteridinone derivative as shown in a general formula I, an optical isomer, a pharmaceutically acceptable salt, a solvate or a prodrug of the dihydropteridinone derivative, a preparation method of the dihydropteridinone derivative and the optical isomer, the pharmaceutically acceptable salt, the solvate or the prodrug of the dihydropteridinone derivative, and a pharmaceutical composition taking the compound as an active ingredient, wherein substituent groups R1, R2, R3, R4, m and A have meanings given in the specification. The invention further relates to application of the compound shown in the general formula I and the pharmaceutically acceptable salt, the solvate or the prodrug of the compound in preparation of drugs for treating diseases caused by abnormal expression of PLK1 / BRD4 protein, in particular to application in preparation of drugs for treating and / or preventing cancers. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, in particular to a dihydropteridone derivative containing a fused benzene ring and its use in preparing a drug for treating and / or preventing cancer. Background Art

[0002] The development of protein kinase inhibitors has great benefits for cancer patients, but drug-resistant mutations severely limit their efficacy. In recent years, more and more people have realized that targeted cancer therapy can affect the growth and survival of cancer cells in multiple ways, which can provide more lasting effects on the treatment of invasive cancers and overcome drug resistance and mutations. In other words, blocking two targets at the same time can reduce the risk of inducing drug resistance, and combined treatment may also address problems such as the limitations of a single target. Developing a dual-target inhibitor for combination therapy may reduce off-target toxicity, drug-drug interactions, and side effects.

[0003] Polo-like kinase (PLK1) is a class of serine / threonine protein kinases present in eukaryotes. It plays a key role in mitosis and is required for the establishment of mature centrosomes and bipolar spindles. According to studies, the molecular mechanism of mutual activation between PLK1 and MYC has been identified. Due to the important role of PLK1 in cell proliferation, people are highly interested in identifying and developing small molecule inhibitors of PLK1, and a series of studies have been conducted on it. Bromodomain-containing protein 4 (BRD4) belongs to the bromodomain and extra-terminal domain (BET) family of proteins. BRD4 protein is a coregulatory factor that affects MYC transcription, and inhibition of bromodomains is an effective method for targeting MYC in neuroblastoma. Studies have found that in a large number of high-risk cancer patients undergoing targeted therapy, these two key oncogenic drivers may undergo co-segregation or amplification of MYC, so designing and synthesizing dual-target inhibitors that simultaneously inhibit PLK1 and BRD4 is a potential therapeutic strategy.

[0004] At present, with the continuous development of medicinal chemistry, oncology and pharmacology, the global research on PLK1 / BRD4 targeted drugs has achieved certain results. Among them, BI 2536 is an ATP-competitive PLK1 inhibitor developed by Boehringer Ingelheim, with a half-inhibitory concentration of 0.83nM, for the treatment of acute myeloid leukemia (AML) and various solid tumors in Phase II clinical trials. BI 2536 can replace BRD4 in chromatin, thereby interfering with the function of BRD4 and effectively inhibiting the expression of BET cell marker c-MYC. BI 2536 has an inhibitor with bromodomain activity (BRD4, Kd = 37nM). BI 2536 is well tolerated when used alone or in combination with chemotherapy drugs, and its safety is acceptable, but patients show adverse drug reactions and short half-life in patients. The clinical trial of BI 2536 as a monotherapy has been terminated. In order to achieve the synergistic effect of "1+1>2", designing and synthesizing single drugs to jointly inhibit PLK1 and BET bromodomain is an effective way to develop new anti-tumor drugs. Summary of the invention

[0005] The present invention aims to provide a dihydropteridone derivative containing a fused benzene ring and its use in preparing a drug for treating and / or preventing cancer.

[0006] To achieve the above purpose, the present invention adopts the following technical solution:

[0007] A dihydropteridone derivative containing a fused benzene ring, wherein the derivative is a compound represented by general formula I and a salt, solvate or prodrug thereof,

[0008]

[0009] in,

[0010] R1 is hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl;

[0011] R2 is (C1-C6) alkyl, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 12 )spirocyclic group, 6-12 membered heterospirocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, wherein any H in the alkyl, cycloalkyl, heterocyclyl, spirocyclyl, heterospirocyclyl, aryl or heteroaryl is substituted by 1-3 identical or different R5;

[0012] R5 is hydrogen, halogen, hydroxy, cyano, amino, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy;

[0013] m is an integer from 0 to 1;

[0014] R3 is hydrogen, (C1-C3) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkoxy which is unsubstituted or substituted by at least one of the following groups; the following groups are halogen, hydroxyl or amino;

[0015] Ring A together with the benzene ring attached to it forms the following group:

[0016] R4 is H, (C1-C6) alkyl, (CO)x(CH2) n NR6R7, COR8, SO2NR6R7, SO2R8, CSNR6R7;

[0017] n is an integer from 0 to 3; x is 0 or 1;

[0018] R6 and R7 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, dimethylaminoethyl, and any H in the alkyl, cycloalkyl or heterocycloalkyl is substituted by 1-3 identical or different R9;

[0019] or R6 and R7 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds, any H in the heterocyclic group is replaced by 0-2 oxo groups, or any H in the heterocyclic group is replaced by 0-3 identical or different R 10 replace;

[0020] R9 and R 10 The same or different, each independently selected from hydrogen, hydroxy, halogen, amino substituted by 0-2 (C1-C6) alkyl groups, cyano, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted by at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C6) alkylsulfonyl, 10 )cycloalkyl-(C1-C4)alkyl; the following groups are hydroxy, amino or halogen;

[0021] R8 is (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 10 )aryl, 5-10 membered heteroaryl, (C2-C6)alkenyl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by 1-3 identical or different R 11 replace;

[0022] R 11is hydrogen, halogen, hydroxy, cyano, amino, nitro, trifluoromethyl, (C1-C6) alkyl, (C1-C6) haloalkyl, alkylacyl, (C1-C6) alkoxy;

[0023] The aryl group defined in formula I is phenyl or naphthyl; the heteroaryl group is a monocyclic or polycyclic unsaturated ring system containing one or more heteroatoms; the heterocyclic group is a monocyclic, polycyclic, bridged or spirocyclic ring system containing one or more heteroatoms; the heteroatoms may be the same or different and are selected from N, O, S.

[0024] Preferably, in the general formula I,

[0025] R1 is (C1-C4) alkyl;

[0026] R2 is (C1-C4) alkyl, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 10 ) aryl, 5-6 membered heteroaryl, wherein any H in the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is substituted by 1-3 identical or different R5;

[0027] R5 is hydrogen, halogen, hydroxy, cyano, amino, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) alkoxy;

[0028] Ring A together with the benzene ring attached to it forms the following group:

[0029] R3 is hydrogen, (C1-C3) alkyl, (C1-C3) alkoxy;

[0030] R4 is H, (C1-C6) alkyl, (CO)x(CH2) n NR6R7, COR8, SO2NR6R7, SO2R8, CSNR6R7;

[0031] n is an integer from 0 to 3; x is 0 or 1;

[0032] R6 and R7 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, dimethylaminoethyl, wherein any H in the alkyl, cycloalkyl or heterocycloalkyl is substituted by 1-3 identical or different R9;

[0033] or R6 and R7 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds, any H in the heterocyclic group is replaced by one or more oxo groups, or any H in the heterocyclic group is replaced by 0-3 identical or different R 10 replace;

[0034] R9 and R 10 The same or different, each independently selected from hydrogen, hydroxy, halogen, amino substituted by 0-2 (C1-C6) alkyl groups, cyano, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted by at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C6) alkylsulfonyl, 10 )cycloalkyl-(C1-C4)alkyl; the following groups are hydroxy, amino or halogen;

[0035] R8 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, (C2-C6) alkenyl, wherein any H in the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkylalkenyl is replaced by 1-3 identical or different R 11 replace;

[0036] R 11 It is hydrogen, halogen, hydroxy, cyano, amino, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy.

[0037] More preferably, in the general formula I,

[0038] R1 is methyl or ethyl;

[0039] R2 is (C3-C6) alkyl, (C3-C6) cycloalkyl, Phenyl, thienyl, furyl, naphthyl, wherein any H in the alkyl, cycloalkyl, heterocyclic, phenyl, thienyl, furyl, naphthyl is substituted by 1-3 identical or different R5;

[0040] R5 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl, hydroxyl, cyano;

[0041] Ring A together with the benzene ring attached to it forms the following group:

[0042] R3 is (C1-C3) alkoxy;

[0043] R4 is H, (C1-C6) alkyl, (CO)x(CH2) n NR6R7, COR8, SO2NR6R7, SO2R8, CSNR6R7;

[0044] n is an integer from 0 to 3; x is 0 or 1;

[0045] R6 and R7 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, dimethylaminoethyl, wherein any H in the alkyl, cycloalkyl or heterocycloalkyl is substituted by 1-3 identical or different R9;

[0046] or R6 and R7 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group containing at least one heteroatom; wherein the heterocyclic group contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds, the optional H in the heterocyclic group is replaced by one or more oxo groups, or the heterocyclic group is optionally replaced by 0-3 identical or different R 10 replace;

[0047] R9 and R 10 The same or different, each independently selected from hydrogen, hydroxy, halogen, amino substituted by 0-2 (C1-C4) alkyl groups, cyano, (C1-C4) alkyl acyl, (C1-C4) alkyl sulfonyl, (C1-C4) alkyl which is unsubstituted or substituted by at least one of the following groups, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C3-C 10 )cycloalkyl-(C1-C4)alkyl; the following groups are hydroxy, amino or halogen;

[0048] R8 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, (C2-C6) alkenyl, wherein any H in the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkylalkenyl is replaced by 1-3 identical or different R 11 replace;

[0049] R 11 It is hydrogen, halogen, hydroxy, cyano, amino, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy.

[0050] In further preferred embodiment, in the general formula I,

[0051] R1 is a methyl group;

[0052] R2 is (C3-C6) alkyl, (C3-C6) cycloalkyl, Phenyl, thienyl, furyl, naphthyl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl, thienyl, furyl, naphthyl is optionally substituted by 1-3 identical or different R5;

[0053] R5 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl, hydroxyl, cyano;

[0054] Ring A together with the benzene ring attached to it forms the following group:

[0055] R3 is methoxy;

[0056] R4 is H, (C1-C6) alkyl, (CO)x(CH2) n NR6R7, COR8, SO2NR6R7, SO2R8, CSNR6R7;

[0057] n is an integer from 0 to 3; x is 0 or 1;

[0058] R6 and R7 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C5) cycloalkyl, (C3-C6) heterocycloalkyl, wherein any H in the alkyl, cycloalkyl or heterocycloalkyl is replaced by 1-3 identical or different R9;

[0059] or R6 and R7 together with the nitrogen atom to which they are attached form

[0060] R9 is selected from hydrogen, hydroxy, halogen, amino substituted by 0 to 2 (C1-C6) alkyl groups, cyano, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted by at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C6) alkylsulfonyl, 10 )cycloalkyl-(C1-C4)alkyl; the following groups are hydroxy, amino or halogen;

[0061] R8 is

[0062] The above aryl group is phenyl or naphthyl; heteroaryl group is a monocyclic or polycyclic unsaturated ring system containing one or more heteroatoms; heterocyclic group is a monocyclic, polycyclic, bridged or spirocyclic ring system containing one or more heteroatoms. The heteroatoms may be the same or different and may be selected from N, O, S.

[0063] More preferably, the derivative is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

[0064] (R)-8-Cyclopentyl-7-ethyl-2-[(6-methoxy-1-oxoisoindolin-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one

[0065] (R)-8-Cyclopentyl-7-ethyl-2-[(6-methoxy-2-methyl-1-oxoisoindolin-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one

[0066] (R)-8-Cyclopentyl-7-ethyl-2-{[2-(4-morpholinyl)ethyl-6-methoxy-1-oxoisoindolin-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0067] (R)-8-Cyclopentyl-7-ethyl-2-[(2-isopropyl-6-methoxy-1-oxoisoindol-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(diglycol)-5-methoxyindol-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0068] (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]indol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0069] (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(piperidin-1-yl)acetyl]indol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0070] (R)-8-Cyclopentyl-7-ethyl-2-{1-{2-{[(R)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0071] (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0072] (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(4-methylpiperidin-1-yl)acetyl]indol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0073] (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(3-methylpiperidin-1-yl)acetyl]indol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0074] (R)-8-Cyclopentyl-7-ethyl-2-{[5-methoxy-1-(2-morpholinoacetyl)indol-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0075] (R)-8-Cyclopentyl-7-ethyl-2-{[5-methoxy-1-(2-thiomorpholinoacetyl)indol-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0076] (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(4-methylpiperazin-1-yl)acetyl]indol-6-yl}amino}5-methyl-7,8-dihydropterin-6(5H)-one

[0077] (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-ethylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0078] (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-isopropylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0079] (R)-8-Cyclopentyl-2-{{1-{2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]acetyl}-5-methoxyindol-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0080] (R)-8-Cyclopentyl-2-{{1-[2-(4-cyclopentylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0081] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0082] (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0083] (R)-8-Cyclopentyl-7-ethyl-2-{5-methoxy-1-{2-[4-(methylsulfonyl)piperazin-1-yl]acetylindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0084] (R)-2-{{[1-2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-8-(cyclopentyl)methyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0085] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-8-cyclohexyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0086] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-8-(cyclohexyl)methyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0087] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-7-ethyl-5-methyl-8-(thien-2-ylmethyl)-7,8-dihydropterin-6(5H)-one

[0088] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-7-ethyl-5-methyl-8-(3-methylthien-2-yl)methyl-7,8-dihydropterin-6(5H)-one

[0089] (R)-8-Cyclopentyl-2-{[1-(diglycol)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]indol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one

[0090] (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[(S)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-6-methoxyindol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0091] (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(piperidin-1-yl)acetyl]indol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one

[0092] (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0093] (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(2-thiomorpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-[2-(1,1-dioxidomorpholinoacetyl)acetyl]-6-methoxyindol-5-yl}amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one

[0094] (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(4-methylpiperazin-1-yl)acetyl]indol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0095] (R)-8-Cyclopentyl-2-{{1-{2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]acetyl}-6-methoxyindol-5-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0096] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0097] (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-6-methoxyindol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0098] (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-{2-[4-(methylsulfonyl)piperazin-1-yl]acetyl}indol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0099] (R)-8-Cyclopentyl-2-{[1-(cyclopropylglycinylamino)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0100] (R)-8-Cyclopentyl-2-{[1-(cyclopentylglyceryl)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-8-cyclohexyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0101] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-8-(cyclohexylmethyl)-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0102] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-7-ethyl-5-methyl-8-(thien-2-ylmethyl)-7,8-dihydropterin-6(5H)-one

[0103] (R)-8-(Cyclopentylmethyl)-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclohexyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclohexyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-8-(thien-2-ylmethyl)-7,8-dihydropterin-6(5H)-one

[0104] (R)-7-Ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropterin-6(5H)-one

[0105] (R)-8-Benzyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0106] (R)-8-Cyclopentyl-2-{[1-(cyclopropylsulfonyl)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0107] (R)-8-Cyclopentyl-2-{[1-(cyclopropanecarbonyl)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(phenylsulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{{1-[(4-acetylphenyl)sulfonyl]-6-methoxyindol-5-yl}amino}-8-Cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one

[0108] (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(methylsulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0109] (R)-8-Cyclopentyl-7-ethyl-2-{[1-(ethylsulfonyl)-6-methoxyindol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0110] (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[(2-nitrophenyl)sulfonyl]indol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{{1-[(2-bromophenyl)sulfonyl]-6-methoxyindol-5-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{{1-[(5-chloro-2,4-difluorophenyl)sulfonyl]-6-methoxyindol-5-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one

[0111] (R)-8-Cyclopentyl-7-ethyl-2-{{{6-methoxy-1-[2-(trifluoromethoxy)phenyl]sulfonyl}indol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0112] (R)-8-Cyclopentyl-7-ethyl-2-{[1-(trimethylsulfonyl)-6-methoxyindol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{{6-methoxy-1-[4-(trifluoromethyl)phenyl]sulfonyl}indol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one

[0113] (R)-2-[(1-acetyl-6-methoxyindol-5-yl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0114] (R)-8-Cyclopentyl-7-ethyl-2-[(6-methoxy-1-propionylindol-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one

[0115] (R)-2-[(1-Acryloyl-6-methoxyindol-5-yl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0116] (R)-8-Cyclopentyl-7-ethyl-2-{[1-(isobutylsulfonyl)-6-methoxyindol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0117] (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(piperidin-1-ylsulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0118] (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(piperidin-1-ylsulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0119] (R)-8-Cyclopentyl-7-ethyl-2-{[1-(isopropylsulfonyl)-6-methoxyindol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0120] (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(piperidine-1-carbonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(morpholinesulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{[1-(3-chloro-2,2-dimethylpropanoyl)-6-methoxyindol-5-yl]amino}-8-Cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one

[0121] (R)-5-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropterin-2-yl)amino]-6-methoxy-N,N-dimethylindoline-1-methylsulfamide

[0122] (R,E)-2-{[1-(But-2-enyl)-6-methoxyindol-5-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-[(6-methoxy-1-pivaloylindol-5-yl)amino]-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one

[0123] (R)-8-Cyclopentyl-2-{{1-[2-(1,1-dihydromorpholinyl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one

[0124] (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(2-thiomorpholinoacetyl)-1,2,3,4-tetrahydroquinolin-7-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0125] (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-{2-[4-(methylsulfonyl)piperazin-1-yl]acetyl}-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0126] (R)-8-Cyclopentyl-2-{[1-(diglycol)-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one

[0127] (R)-8-Cyclopentyl-7-ethyl-2-{1-{2-{[(R)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0128] (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0129] (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0130] (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)-1,2,3,4-tetrahydroquinolin-7-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0131] (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(4-methylpiperazin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0132] (R)-8-Cyclopentyl-2-{[1-(cyclopropylglycylamino)-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0133] (R)-8-Cyclopentyl-2-{[1-(cyclopentylglycine)-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0134] (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(piperidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0135] (R)-8-Cyclopentyl-2-{{1-[2-(3,5-dimethylpiperazin-1-yl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0136] (R)-8-Cyclopentyl-7-ethyl-2-{[7-methoxy-1-(2-morpholinoacetyl)-1,2,3,4-tetrahydroquinolin-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0137] (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0138] (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-1-[2-(4-methylpiperazin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0139] (R)-8-Cyclopentyl-7-ethyl-2-{{1-(2-{[(R)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0140] (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-1-[2-(piperidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0141] (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0142] (R)-8-Cyclopentyl-2-{[1-(diglycol)-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one

[0143] (R)-8-Cyclopentyl-7-ethyl-2-[(7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-[2-(1,1-dioxidodimorpholinyl)acetyl]-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one

[0144] (R)-8-Cyclopentyl-2-{{1-[2-(4,4-difluoropiperidin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0145] (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0146] (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-1-{2-[4-(methylsulfonyl)piperazin-1-yl]acetyl}-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0147] (R)-8-Cyclopentyl-7-ethyl-2-{[7-methoxy-2-(2-morpholinoacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0148] (R)-8-Cyclopentyl-7-ethyl-2-{{2-[2-(4-hydroxypiperidin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0149] (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-2-[2-(4-methylpiperazin-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0150] (R)-8-Cyclopentyl-7-ethyl-2-{{{2-[(R)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0151] (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-2-[2-(piperidin-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0152] (R)-2-{{2-[2-(4-acetylpiperazin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0153] (R)-8-Cyclopentyl-2-{{2-[2-(4,4-difluoropiperidin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0154] (R)-8-Cyclopentyl-7-ethyl-2-{{{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0155] (R)-8-Cyclopentyl-7-ethyl-2-{[7-methoxy-2-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0156] (R)-8-Cyclopentyl-2-{[2-(cyclopropanecarbonyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0157] (R)-8-Cyclopentyl-2-{{[2-(1,1-dihydromorpholinyl)acetyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one

[0158] (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-2-{2-[4-(methylsulfonyl)piperazin-1-yl]acetyl}-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0159] (R)-8-Cyclopentyl-2-{{2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one.

[0160] The compound salt is a salt formed with an acid, and the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

[0161] A pharmaceutical composition comprising a compound of general formula I and a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0162] An application of the compound, and use of the compound and its pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of drugs for preventing or treating diseases associated with PLK1 / BRD4 inhibitors.

[0163] A pharmaceutical composition comprising a compound of general formula I and a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0164] A use of a compound, wherein the compound of general formula I and a pharmaceutically acceptable salt, solvate or prodrug thereof are used in the preparation of a drug for preventing or treating a disease associated with a PLK1 / BRD4 kinase inhibitor.

[0165] Moreover, according to some common methods in the field to which the present invention belongs, the dihydropteridinone derivatives of the general formula I in the present invention can be reacted with acids to form pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and the salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

[0166] In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are dihydropteridone derivatives of general formula I, which may have weak activity or even no activity themselves, but after administration, they are converted into the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0167] In the above substituents, "halogen" refers to fluorine, chlorine or bromine; "alkyl" refers to straight-chain or branched alkyl; "cycloalkyl" refers to substituted or unsubstituted cycloalkyl; "alkoxy" refers to straight-chain or branched alkoxy; "alkenyl" refers to straight-chain or branched alkenyl; "alkynyl" refers to straight-chain or branched alkynyl; "aryl" refers to phenyl or naphthyl with or without substituents; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S, and the ring system is aromatic.

[0168] We have found that the compounds of the present invention have the activity of inhibiting tumor cell growth in vitro. Therefore, they can be used to prepare drugs for treating and / or preventing cancer, such as cancer of the breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid, esophagus and leukemia, neuroblastoma, etc.

[0169] Through in vitro inhibition of human breast cancer cells MDA-MB-231 and human myelomonocytic leukemia cells MV-4-11, the compounds of the present invention have significant inhibitory effects on breast cancer cells and leukemia cells. Through the test of PLK1 / BRD4 protein activity, it was found that the compounds of the present invention have a good inhibitory effect on PLK1 / BRD4 protein activity, and are particularly useful for preparing drugs for treating and / or preventing breast cancer and leukemia.

[0170] A pharmaceutical composition comprising a compound represented by general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs mixed with a pharmaceutically acceptable carrier.

[0171] A use of a compound and a pharmaceutical composition, wherein the compound of the general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs or a composition containing the compound of the general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs are used in the preparation of a drug for treating and / or preventing PLK1 / BRD4-mediated diseases.

[0172] The preparation for treating and / or preventing PLK1 / BRD4-mediated diseases includes but is not limited to breast cancer, glioblastoma, lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, bladder cancer, colorectal cancer, osteosarcoma, ovarian cancer, multiple myeloma, skin cancer, melanoma, leukemia or kidney cancer.

[0173] The present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of general formula (I) which may themselves have weak activity or even no activity, but after administration, are converted into the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0174] The present invention also includes a pharmaceutical composition comprising a compound of formula I and their pharmaceutically acceptable salts and / or solvates as an active ingredient and a pharmaceutically acceptable carrier; the compounds of the present invention may also be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0175] The carriers used in the pharmaceutical composition of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; pH regulators, osmotic pressure regulators, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for local preparations. The pharmaceutical preparations can be administered orally, parenterally (e.g., intravenously, subcutaneously, intraperitoneally, etc.) or topically (e.g., ocular, nasal, sublingual, skin, etc.), and if some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0176] The exact amount of the compound of the present invention for treating cancer, especially diseases caused by abnormal PLK1 / BRD4, will vary from subject to subject, depending on the type, age and general condition of the subject, the severity of the disease being treated, the specific compound used and the mode of administration, such as the route and frequency of administration, etc. A person of ordinary skill in the art can determine the appropriate effective amount using only routine experimental methods.

[0177] The dosage of the compound can be from about 0.1 to 160 mg / kg body weight per day, preferably 1 to 60 mg / kg body weight per day. It is understood that the dosage may vary depending on the patient's needs, the disease caused by the PLK1 / BRD4 abnormality being treated, and the specific compound used. Moreover, it is understood that the initial dose administered can be increased beyond the upper limit in order to quickly reach the desired blood level, or the initial dose can be less than the optimal value, and the daily dose can be gradually increased during treatment, depending on the specific situation. If necessary, the daily dose can also be divided into multiple doses, for example 2-4 times a day.

[0178] Mammal means a human or an animal.

[0179] The amount of active ingredient, i.e. the compound according to the invention, in the pharmaceutical composition and its unit dosage form may vary, depending on the specific application, the efficacy of the specific compound and the desired concentration. Generally speaking, the content of the active ingredient will be between 0.5% and 90%, based on the total weight of the composition.

[0180] In combination therapy, the compound of the present invention and other compounds may be administered simultaneously or separately. When administered simultaneously, the compound of the present invention and other compounds may be combined in a single pharmaceutical composition or in separate compositions.

[0181] The examples and preparations provided below further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations is not sufficient to limit the scope of the present invention in any way.

[0182] The following synthetic routes summarize and describe the preparation of the formula I derivatives of the present invention, all starting materials are prepared by the methods described in these routes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final derivatives of the present invention are prepared by the methods described in these routes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. All variables used in these routes are as defined below or as defined in the claims.

[0183] The derivatives of formula I according to the present invention can be prepared according to the methods of route A, route B, route C, route D, route E and route F.

[0184] Wherein, R1, R2, R3, R4, R6, R7, R8, A and m in the compound are as defined in the claims.

[0185]

[0186] In route A, compound A1 is esterified, brominated, reduced, cyclized, and reduced, and then reacted with intermediate M6 to obtain compound Ii of general formula I.

[0187]

[0188] In route B, compound B1 is reduced, acetylated, nitrated, and reduced before reacting with intermediate M6 to obtain intermediate B6, which is then deacetylated, reacted with chloroacetyl chloride, and reacted with various small molecule amines to undergo nucleophilic substitution reaction to obtain compound I-ii of general formula I.

[0189]

[0190] In route C, compound F1 is reduced, acetylated, nitrated, and reduced before reacting with intermediate M6 to synthesize intermediate C6, which is then deacetylated to obtain intermediate C7, which is then reacted with chloroacetyl chloride and subjected to nucleophilic substitution reaction with various small molecule amines to obtain compound I-iii of general formula I.

[0191] Intermediate C7 is further reacted with differently substituted acyl chlorides or sulfonyl chlorides to prepare compounds I-iv and Iv of general formula I.

[0192]

[0193] In route D, compound D1 is nitrated, reduced, acetylated, and then reduced and reacted with intermediate M6 to synthesize intermediate D6, which is then deacetylated, reacted with chloroacetyl chloride, and then reacted with various small molecule amines to undergo nucleophilic substitution reaction to obtain compound I-vi of general formula I.

[0194]

[0195] In route E, compound E1 is nitrated, reduced, acetylated, and then reduced and reacted with intermediate M6 to synthesize intermediate E6, which is then deacetylated, reacted with chloroacetyl chloride, and then reacted with various small molecule amines to undergo nucleophilic substitution reaction to obtain compound I-vii of general formula I.

[0196]

[0197] In route F, compound F1 is acylated, nitrated, cyclized, deacylated, acetylated, and reduced, and then reacted with intermediate M6 to synthesize intermediate F8, which is then deacetylated, reacted with chloroacetyl chloride, and then reacted with various small molecule amines to undergo nucleophilic substitution reactions to obtain compounds I-viii of general formula I.

[0198]

[0199] Intermediate M6 can be obtained by using M1 as the starting material according to route G, reacting with 2,4-dichloro-5-nitropyrimidine after esterification and reductive amination, then reducing and cyclizing, and finally undergoing nucleophilic substitution reaction. Wherein, R1, R2 and m in the compound are as defined in the claim. DETAILED DESCRIPTION

[0200] In the following examples, methods for preparing some of the compounds are described. It should be understood that the following methods and other methods known to those of ordinary skill in the art can be applied to the preparation of all compounds described in the present invention. The examples are intended to illustrate rather than limit the scope of the present invention. The H NMR spectra of the compounds were measured using Bruker ARX-400 or Bruker ARX-600, and the mass spectra were measured using Agilent 1100 LC / MSD; all reagents used were analytically pure or chemically pure.

[0201] Example 1: (R)-8-cyclopentyl-7-ethyl-2-[(6-methoxy-1-oxoisoindolin-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one Step A Synthesis of methyl 2-methyl-4-nitrobenzoate (A2)

[0202] Under ice bath, add 10g (55.2mmol) 2-methyl-4-nitrobenzoic acid to 100mL methanol, slowly add 7mL (126mmol) concentrated sulfuric acid, and heat the reaction solution to 55℃ for 2h. After the reaction, concentrate the reaction solution and pour it into 200mL water, adjust the pH value to 10 with NaOH aqueous solution (5%), filter, wash the filter cake with 20mL water, and dry the filter cake to obtain 10.1g yellow oil, with a yield of 93.5%. MS (ESI), m / z: 196.0 [M+H] + ,194.0[MH] - .

[0203] Step B Synthesis of methyl 2-bromomethyl-4-nitrobenzoate (A3)

[0204] At room temperature, 9.0 g (46.2 mmol) of methyl 2-methyl-4-nitrobenzoate was added to 50 mL of acetonitrile, and then 8.6 g (48.5 mmol) of NBS and 0.22 g (1 mmol) of BPO were added in batches. After the addition, the reaction solution was heated to 80 ° C and reacted for 12 hours. After the reaction, the reaction solution was concentrated and 30 mL of saturated Na2S2O3 aqueous solution was added, and DCM was extracted (30 mL × 3). The organic phases were combined and dried with Na2SO4, and the solvent was evaporated under reduced pressure. Purification by column chromatography gave 7.4 g of a light yellow solid with a yield of 58.9%. MS (ESI), m / z: 274.1 [M+H] + ,272.1[MH] - .

[0205] Step C Synthesis of 6-methoxy-5-nitroisoindol-1-one (A4)

[0206] At room temperature, add 5.0g (16.5mmol) of the intermediate methyl 2-bromomethyl-4-nitrobenzoate and 24.8mmol of the methanol solution of the amine to 30mL of methanol. After the addition, heat the reaction solution to 70°C and stir for 12h. After the reaction is completed, wait for the reaction solution to cool to room temperature, filter it with suction, wash the filter cake with 20mL of methanol, and dry the filter cake to obtain 4.3g of white solid, with a yield of 84.6%. MS (ESI), m / z: 209.0 [M+H] + .

[0207] Step D Synthesis of 5-amino-6-methoxyisoindol-1-one (A5)

[0208] At room temperature, 1.0 g (3.6 mmol) of the intermediate 6-methoxy-5-nitroisoindole-1-one and 0.1 g of Pd / C were added to 10 mL of ethanol. After the addition, the reaction solution was heated to 78°C in a hydrogen atmosphere and reacted for 6 h. After the reaction, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 10 mL of MeOH. The filtrate was collected and the solvent was evaporated under reduced pressure to obtain 0.62 g of a brown solid with a yield of 76%. MS (ESI), m / z: 179.1 [M+H] + .

[0209] Step E Synthesis of (R)-2-aminobutyric acid methyl ester hydrochloride (M2)

[0210] Under ice bath, add 200g (1.94mol) D-2-aminobutyric acid to 1000mL methanol, slowly drop 391.8g (3.49mol) SOCl2, after addition, heat the reaction solution to 70℃ and react for 10h. After reaction, evaporate the reaction solution to dryness, add methyl tert-butyl ether, stir, filter, dry the filter cake to obtain 289.0g white solid, yield 97%. MS (ESI) m / z: 118.2 [M+H] + .

[0211] Step F Synthesis of (R)-2-(cyclopentylamino)butyric acid methyl ester (M3)

[0212] At room temperature, 229.6g (1.50mol) of (R)-2-aminobutyric acid methyl ester hydrochloride was dissolved in 2500mL of DCM, and 138.7g (1.65mol) of cyclopentanone and 123.0g (1.50mol) of anhydrous sodium acetate were added. After the addition was completed, 349.7g (1.65mol) of sodium triacetoxyborohydride was added in batches and reacted at room temperature for 4h. After the reaction was completed, the solution was adjusted to weak alkalinity, extracted with DCM (1000mL×3), the organic phase was collected and dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain 249.9g of light yellow oil, with a yield of 90%. MS (ESI) m / z: 186.1 [M+H] + .

[0213] Step G Synthesis of (R)-2-[(2-chloro-5-nitro-4-pyrimidinyl)-cyclopentylamino]butyric acid methyl ester (M4)

[0214] Under ice bath, add 231.4g (1.25mol) (R)-2-(cyclopentylamino) butyric acid methyl ester, 105.0g (1.25mol) NaHCO3 and 193.9g (1.00mol) 2,4-dichloro-5-nitropyrimidine to 2000mL cyclohexane. After the addition, heat the reaction solution to 80°C and react for 10h. After the reaction, cool the reaction solution to room temperature, filter to remove the solid residue, and evaporate the solvent under reduced pressure to obtain a reddish brown crude product. After the crude product is purified by column chromatography, 239.9g of light yellow solid is obtained, with a yield of 70%, mp: 109.7–110.5°C. MS (ESI) m / z: 343.1 [M+H] + .

[0215] Step H Synthesis of (R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-6(5H)-pteridinone (M5)

[0216] At room temperature, 171.4 g (0.50 mol) of (2R)-2-[(2-chloro-5-nitro-4-pyrimidinyl)cyclopentylamino]-butyric acid methyl ester was dissolved in 2000 mL of glacial acetic acid. The reaction solution was heated to 70 °C and 156.8 g (2.80 mol) of iron powder was added in batches. After reacting for 0.5 h, diatomaceous earth was used for hot filtration. The filtrate was collected and the solvent was evaporated to dryness to obtain 130.8 g of white solid with a yield of 93.2%. mp: 171.8–172.7 °C, MS (ESI) m / z: 281.1 [M+H] + .

[0217] Step I Synthesis of (R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5-methyl-6(5H)-pteridinone (M6)

[0218] Under ice bath, 126.3g (0.45mol) (R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-6 (5H) -pteridinone was dissolved in 1000mL DMF, 10.8g (0.45mol) sodium hydride was slowly added, and 70.3g (0.495mol) iodomethane was slowly added after stirring for 1h. The reaction solution was heated to room temperature and reacted for 10h. After the reaction, the reaction solution was poured into water, filtered, and the filter cake was dried to obtain 118.9g of white solid, with a yield of 89.7%, mp: 92.1-93.5℃, MS (ESI) m / z: 295.1 [M+H] + ; 1 H NMR(600MHz, CDCl3)δ7.59(s,1H),4.30–4.24(m,1H),4.18(dd,J=7.6,3.6Hz,1H),3.25(s,3H),2.00(dtd,J=10.7,7.7,3.0Hz,1H),1.89(d t,J=7.8,5.9Hz,1H),1.86–1.74(m,4H),1.69(ddd,J=12.1,10.0,6.1Hz,1H),1.66–1.60(m,1H),1.60–1.53(m,2H),0.79(t,J=7.5Hz,3H).

[0219] Step J Synthesis of (R)-8-cyclopentyl-7-ethyl-2-[(6-methoxy-1-oxoisoindolin-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one

[0220] At room temperature, 0.1 g (0.6 mmol) of intermediate 5-amino-6-methoxyisoindol-1-one and 0.25 g (0.84 mmol) of intermediate M6 were added to 5 mL of tert-butyl alcohol, and then 0.04 g (0.08 mmol) of Xphos and 0.026 g (0.08 mmol) of Pd(dba)2 were added respectively. Under nitrogen atmosphere, the reaction solution was heated to 80°C for 7 h. After the reaction, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 10 mL of DCM. The filtrate was collected and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain 33 mg of a light yellow solid.

[0221] According to the method of Example 1, 5-methoxy-2-methyl-4-nitrobenzoic acid was used as a raw material to obtain Examples 2 to 4, and the structures and melting points, MS, 1 The H-NMR data are shown in Table 1.

[0222] Table 1 Example 1 to Example 4

[0223]

[0224] Example 5: Synthesis of (R)-8-cyclopentyl-2-{[(1-(diethylglycylamino)-5-methoxyindol-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0225] Step A Synthesis of 5-methoxyindoline (B2)

[0226] Under ice bath, 10.0g (68.0mmol) 5-methoxy-1H-indole was dissolved in 50mL acetic acid, and 17.3g (275mmol) sodium cyanoborohydride was slowly added. After the addition, the reaction solution was warmed to room temperature and reacted for 2h. After the reaction, the reaction solution was poured into 150mL water, and the pH was adjusted to 10 with saturated NaOH aqueous solution, and EA was extracted (50mL×3), the organic layers were combined and dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain 9.5g light yellow oil, with a yield of 97%. MS (ESI), m / z: 150.0 [M+H] + .

[0227] Step B1 Synthesis of (5-methoxyindol-1-yl)ethane-1-one (B3)

[0228] Under ice bath, 8g (53.7mmol) of intermediate 5-methoxyindoline was dissolved in 50mL of acetic acid, and 6.59g (64.6mmol) of acetic anhydride was slowly added. After addition, the mixture was reacted at 60°C for 30min. After the reaction, the reaction solution was poured into 50mL of water, filtered, and the filter cake was washed with water. The filter cake was dried to obtain 7.6g of yellow solid, with a yield of 74%. MS (ESI), m / z: 192.1 [M+H] + ,190.9[MH] - . 1 H NMR(600MHz, CDCl3)δ8.06(d,J=8.7Hz,1H),6.67(s,1H),6.65(d,J=8.8Hz,1H), 3.97(t,J=8.4Hz,2H), 3.72(d,J=7.4Hz,3H), 3.10(t,J=8.4Hz,2H), 2.14(s,3H).

[0229] Step C Synthesis of 1-(5-methoxy-6-nitroindol-1-yl)ethane-1-one (B4)

[0230] Under ice bath, add 6.0g (31.4mmol) of intermediate 1-(5-methoxyindol-1-yl)ethane-1-one to 50mL of acetic anhydride, add 2.18g (34.5mmol) of nitric acid dropwise, and warm the reaction solution to room temperature for 4h. Filter by suction, wash the filter cake with water, and dry the filter cake to obtain 4.8g of yellow solid, with a yield of 68%. MS (ESI), m / z: 237.1 [M+H] + .

[0231] Step D Synthesis of 1-(6-amino-5-methoxyindol-1-yl)ethane-1-one (B5)

[0232] At room temperature, 4.5g (19.0mmol) 1-(5-methoxy-6-nitroindol-1-yl)ethane-1-one was dissolved in 20mL methanol, and 0.1g Pd / C was added. After the addition was completed, the reaction solution was heated to 56°C in a hydrogen atmosphere and reacted for 6h. After the reaction was completed, the reaction solution was filtered through diatomaceous earth while hot, and the filter cake was washed with 30mL methanol. The filtrate was collected and the solvent was evaporated under reduced pressure to obtain 3.58g yellow solid, with a yield of 86%. MS (ESI), m / z: 207.1 [M+H] + ,205.1[MH] - .1H NMR (600MHz, CDCl3) δ7.66 (s, 1H), 6.56 (s, 1H), 3.94 (t, J = 11.7Hz, 2H), 3.74 (s, 3H), 3.03 (t, J = 8.3Hz, 2H), 2.12 (s, 3H).

[0233] Step E Synthesis of (R)-2-[(1-acetyl-5-methoxyindol-6-yl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (B6)

[0234] At room temperature, 3 g (14.5 mmol) of 1-(4-amino-5-methoxyisoindol-2-yl)ethane-1-one and 6 g (20.4 mmol) of the intermediate (R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (M6) were added to 15 mL of tert-butyl alcohol, and then 1.0 g (2.2 mmol) of Xphos and 0.67 g (0.7 mmol) of Pd(dba)2 were added. After the addition, the reaction solution was heated to 80°C and stirred for 7 h. After the reaction, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with DCM, the filtrate was collected and the solvent was evaporated, and the crude product was purified by column chromatography to obtain 3.6 g of a yellow solid with a yield of 53.9%. MS (ESI), m / z: 465 [M+H] + ,463[MH] - . 1 H NMR(600MHz, CDCl3)δ9.21(s,1H),7.60(s,1H),7.27(s,1H),6.64(s,1H),4.79–4.70(m,1H) ,4.11(dd,J=8.0,3.5Hz,1H),3.96(t,J=8.3Hz,2H),3.78(s,3H),3.22(s,3H),3.07(t,J=8.3 Hz,2H),2.94(t,J=8.1Hz,1H),2.42(s,1H),2.11(s,3H),2.03–1.96(m,1H),1.78–1.74(m,1H ),1.74–1.70(m,1H),1.64–1.55(m,6H),1.49(dd,J=19.1,9.0Hz,1H),0.80(t,J=7.4Hz,3H).

[0235] Step F Synthesis of (R)-8-cyclopentyl-7-ethyl-2-[(5-methoxyindol-6-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one (B7)

[0236] Under ice bath, add 3.0g (6.7mmol) (R)-2-[(1-acetyl-5-methoxyindol-6-yl) amino] -8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6 (5H) -one to 20mL methanol, slowly add 17.3g (275mmol) hydrochloric acid, after the dropwise addition, raise the temperature of the reaction solution to 60°C and stir for 12h. After the reaction is completed, after the reaction solution is cooled to room temperature, the solvent is evaporated under reduced pressure. Adjust the pH value to 10 with saturated Na2CO3 aqueous solution, filter, wash the filter cake with 10mL water, and dry to obtain 2.4g white solid, with a yield of 88%. MS (ESI), m / z: 423 [M + H] + ,421[MH] - .1H NMR(600MHz, CDCl3)δ9.20(s,1H),7.60(s,1H),7.29(s,1H),6.64(s,1H),4.81–4.6 8(m,1H),4.11(dd,J=8.0,3.4Hz,2H),3.96(t,J=8.3Hz,2H),3.78(s,3H),3.22(s,3 H),3.07(t,J=8.3Hz,2H),2.98–2.89(m,1H),2.11(s,3H),2.04–1.96(m,1H),1.73( dd,J=10.2,6.7Hz,2H),1.62–1.59(m,4H),1.53–1.47(m,1H),0.80(t,J=7.4Hz,3H).

[0237] Step G Synthesis of (R)-2-{[1-(2-chloroacetyl)-5-methoxyindol-6-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (B8)

[0238] Under ice bath, 2.4g (5.7mmol) (R)-8-cyclopentyl-7-ethyl-2-[(5-methoxyindol-6-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one and 1.43g (14.2mmol) triethylamine were added to 10mL DCM, and 1.28g (11.3mmol) chloroacetyl chloride diluted with 10mL DCM was slowly added dropwise to the reaction solution. After the addition was completed, the reaction solution was heated to room temperature and stirred for 1h. After the reaction was completed, the mixed solution was added to 20mL saturated NH4Cl aqueous solution, extracted with DCM (20mL×3), the organic phases were combined and dried with Na2SO4, and the solvent was evaporated under reduced pressure to obtain 2.7g yellow solid, with a yield of 95%. MS (ESI), m / z: 499.0 [M+H] + ,496.9[MH] - .

[0239] Step H Synthesis of (R)-8-cyclopentyl-2-{[1-(diethylglycylamino)-5-methoxyindol-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0240] At room temperature, 0.1 g (0.2 mmol) (R)-2-{[(1-(2-chloroacetyl)-5-methoxyindol-6-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one was dissolved in 5 mL DCM, and 0.07 g (0.5 mmol) K2CO3 and 0.022 g (0.3 mmol) diethylamine were added. After the addition, the reaction solution was heated to 60°C and reacted for 4 h. After the reaction, the reaction solution was concentrated, 10 mL of water was added to the reaction mixture, and it was extracted with DCM (10 mL×3). The organic phases were combined and dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain a light yellow solid. The crude product was purified by column chromatography to obtain 0.033 mg of a light yellow solid.

[0241] According to the method of Example 5, the intermediate B8 of Example 5 was used as a raw material to carry out nucleophilic substitution reaction with the corresponding small molecule amine to prepare the compounds of Examples 6 to 26. The structures, chemical names and melting points, MS, 1 The H-NMR data are shown in Table 2.

[0242] Table 2 Examples 5 to 26

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250] According to the method of Example 5, the compounds of Examples 27 to 75 can be prepared using 6-methoxy-1H-indole as a raw material. The structures, chemical names, melting points, MS, 1 The H-NMR data are shown in Table 3.

[0251] Table 3 Examples 27 to 50

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262] Example 76: Synthesis of (R)-8-cyclopentyl-2-{[1-(diethylglycylamino)-5-methoxyindol-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0263] Step A Synthesis of 6-methoxy-3,4-dihydroquinolin-2(1H)-one (K2)

[0264] Under ice bath, add 10.0g (61.3mmol) 6-hydroxy-3,4-dihydroquinolin-2(1H)-one and 25.4g (184mmol) K2CO3 to 50mL DMF, slowly add 8.7g (61.2mmol) CH3I, after the addition, warm the reaction solution to room temperature and stir for 2h. After the reaction, pour the reaction solution into 100mL water, filter, wash the filter cake with 30mL water, and dry to obtain 7.8g white solid, with a yield of 71.9%. MS (ESI), m / z: 176.1 [MH] + .

[0265] Step B Synthesis of 6-methoxy-7-nitro-3,4-dihydroquinolin-2(1H)-one (K3)

[0266] Under ice bath, add 7.5g (42.4mmol) 6-methoxy-3,4-dihydroquinolin-2(1H)-one to 20mL trifluoroacetic acid, slowly add 7.4g (107.4mmol) NaNO2, after addition, warm the reaction solution to room temperature and stir for 4h. After reaction, pour the reaction solution into 50mL water, filter, wash the filter cake with 20mL water, and dry to obtain 4.1g yellow solid, yield 43.6%. MS (ESI), m / z: 221.0 [MH]+ .

[0267] Step C Synthesis of 6-methoxy-7-nitro-1,2,3,4-tetrahydroquinoline (K4)

[0268] Under ice bath, 4g (18mmol) of 6-methoxy-7-nitro-3,4-dihydroquinolin-2(1H)-one was added to 20mL of THF, and 35mL of borane tetrahydrofuran complex was added dropwise under N2 atmosphere. After the addition, the reaction solution was heated to 60°C and reacted for 12h. After the reaction, the reaction solution was cooled, 50mL of methanol was added to the reaction solution for extraction, and the solvent was evaporated under reduced pressure to obtain 1.76g of red solid with a yield of 47%. MS (ESI), m / z: 209.2 [M+H] + ,207.2[MH] + .

[0269] Step D Synthesis of 1-(6-methoxy-7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (K5)

[0270] Under ice bath, add 1.5g (7.2mmol) 6-methoxy-7-nitro-1,2,3,4-tetrahydroquinoline to 10mL glacial acetic acid, add 0.88g (8.7mmol) acetic anhydride dropwise, and heat the reaction solution to 60℃ for 30min. After the reaction, pour the reaction solution into 10mL water, extract with EA (20mL×3) 3 times, combine the organic phases and dry with anhydrous Na2SO4, evaporate the solvent under reduced pressure to obtain 1.66g yellow solid, yield 92%. MS (ESI), m / z: 251.0 [M+H] + ,273.0[M+Na] + .

[0271] Step E Synthesis of 1-(7-amino-6-methoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (K6)

[0272] At room temperature, 1.6 g (9.4 mmol) of 1-(6-methoxy-7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethane-1-one and 0.16 g of Pd / C were added to 10 mL of methanol. The reaction solution was heated to 56°C and refluxed for 4 h under a hydrogen atmosphere. After the reaction, diatomaceous earth was placed on the filter while hot, and the filter cake was washed with 20 mL of methanol. The filtrate was collected and the solvent was evaporated under reduced pressure to obtain 1.32 g of a yellow solid with a yield of 94%. MS (ESI), m / z: 221.0 [M+H] + .

[0273] Step F Synthesis of (R)-2-[(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (K7)

[0274] At room temperature, 1.5 g (6.8 mmol) 1-(7-amino-6-methoxy-3,4-dihydroquinolin-1(2H)-yl)ethane-1-one, 2.8 g (9.5 mmol) M6, 0.31 g (0.34 mmol) Pd(dba)2, 0.49 g (1.0 mmol) XPhos and 8.88 g (27 mmol) CsCO3 were added to 10 mL tert-butyl alcohol. After the addition was completed, the mixture was reacted at 80 ° C for 7 h under a nitrogen atmosphere. After the reaction was completed, diatomaceous earth was placed on the surface of the mixture and the mixture was filtered while hot. The filter cake was washed with DCM, the filtrate was collected and the solvent was evaporated to dryness. The crude product was purified by column chromatography to obtain 0.51 g of a white solid. MS (ESI), m / z: 479.1 [M+H] + , 477.1[MH] + .

[0275] Step G Synthesis of (R)-8-cyclopentyl-7-ethyl-2-[(6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one (K8)

[0276] Under ice bath, 0.5g (1.0mmol) (R)-2-[(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one was dissolved in methanol, and 1mL (12mol / L) concentrated hydrochloric acid was added dropwise. After the addition, the reaction solution was heated to 60°C and reacted for 12h. After the reaction, the reaction solution was concentrated, 20mL of water was added, 1M NaOH aqueous solution was added to the mixture, filtered, the filter cake was washed with 10mL of water, and dried to obtain 0.38g of white solid, with a yield of 84%. MS (ESI), m / z: 437.2 [M+H] + , 435.0[MH] + .

[0277] Step H Synthesis of (R)-2-{[1-(2-chloroacetyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (K9)

[0278] Under ice bath, 0.35g (0.8mmol) (R)-8-cyclopentyl-7-ethyl-2-[(6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one was dissolved in 5mL DCM, and 0.18g (1.6mmol) chloroacetyl chloride diluted with 5mL DCM was added dropwise. After the addition, the reaction solution was warmed to room temperature and reacted for 1h. After the reaction, the reaction solution was added to 10mL saturated NH4Cl aqueous solution, extracted with DCM (10mL×3), the organic layers were combined and dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain 0.39g yellow solid, with a yield of 95%. MS (ESI), m / z: 512.0 [MH] + .

[0279] Step I Synthesis of (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one

[0280] At room temperature, 0.1 g (0.2 mmol) (R)-2-{[1-(2-chloroacetyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one, 0.053 g (0.38 mol) K2CO3 and 0.037 g (0.29 mmol) acetylpiperazine were added to 5 mL acetone. After the addition, the reaction solution was heated to 60°C for 4 h. After the reaction, the organic solvent in the reaction solution was evaporated, 5 mL of water was added, and the solution was extracted with DCM (5 mL × 3). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography to obtain 0.03 g of a light yellow solid. MS (ESI), m / z: 605.4 [M+H] + , 603.0[MH] + .

[0281] According to the method of Example 76, intermediate K9 was used as a raw material to carry out nucleophilic substitution reaction with corresponding small molecular amines to prepare compounds 77 to 90. The structures, chemical names and melting points, MS, 1 The H-NMR data are shown in Table 4.

[0282] Table 4 Examples 76 to 90

[0283]

[0284]

[0285]

[0286]

[0287] According to the method of Example 76, the compounds of Examples 91 to 103 can be prepared using 7-hydroxy-3,4-dihydroquinolin-2(1H)-one as a raw material. The structures, chemical names, melting points, MS, 1 The H-NMR data are shown in Table 5.

[0288] Table 5 Compounds 91 to 103

[0289]

[0290]

[0291]

[0292] Example 104: Synthesis of (R)-8-cyclopentyl-7-ethyl-2-{[7-methoxy-2-(2-morpholinoacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0293] Step A Synthesis of 2,2,2-trifluoro-N-(4-methoxyphenethyl)acetamide (KY2)

[0294] Under ice bath, add 10.0g (66.2mmol) 2-(4-methoxyphenyl)ethane-1-amine and 14g (132.3mmol) trifluoroacetic acid to 100mL DCM, slowly add 16.7g (79.4mmol) trifluoroacetic anhydride, and after addition, warm the reaction solution to room temperature and stir for 2h. After reaction, add 200mL water to quench, adjust pH to 2-3 with 5% citric acid aqueous solution, combine organic layers and dry with anhydrous Na2SO4, evaporate organic solvent under reduced pressure to obtain 11.2g white solid, yield 68.4%. MS (ESI), m / z: 246.2 [MH] + .

[0295] Step B Synthesis of 2,2,2-trifluoro-N-(4-methoxy-3-nitrophenylethyl)acetamide (KY3)

[0296] Under ice bath, add 10 g (40.5 mmol) of 2,2,2-trifluoro-N-(4-methoxyphenethyl)acetamide to 50 mL of TFA and slowly add dropwise

[0297] 2.6g (40.5mmol) HNO3, after the addition, the reaction solution was heated to room temperature and stirred for 2h. After the reaction, TFA was evaporated under reduced pressure, 50mL of water was added and extracted with EA (50mL×3), the organic layers were combined and dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain 11.1g of yellow oil, with a yield of 94%. MS (ESI), m / z: 290.0 [MH] + .

[0298] Step C Synthesis of 2,2,2-trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (KY4)

[0299] At room temperature, 10 g (34.2 mmol) of 2,2,2-trifluoro-N-(4-methoxy-3-nitrophenylethyl)acetamide and 4.38 g (137 mmol) of paraformaldehyde were added to a mixed solvent of 100 mL of sulfuric acid and acetic acid (3:2). After the addition, the reaction solution was heated to 50 °C and stirred for 1 h. After the reaction, 200 mL of water was added to quench the reaction, and the mixture was extracted with EA (200 mL × 3). The organic layers were combined and dried with anhydrous Na2SO4. The organic solvent was evaporated under reduced pressure to obtain 8.75 g of a yellow solid with a yield of 84%. MS (ESI), m / z: 305.2 [M+H] + ,303.2[MH] + .

[0300] Step D Synthesis of 7-methoxy-6-nitro-1,2,3,4-tetrahydroisoquinoline (KY5)

[0301] At room temperature, 8.5 g (28.0 mmol) of 2,2,2-trifluoro-1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one and 5.79 g (42.0 mmol) of K2CO3 were added to a mixed solvent of 100 mL of methanol and water (4:1). After the addition was completed, the reaction solution was heated to 65°C and stirred for 1 h. After the reaction was completed, the organic solvent was evaporated under reduced pressure, 30 mL of DCM was added, the mixture was filtered, the filter cake was washed with 10 mL of DCM, the filtrate was collected and the solvent was evaporated under reduced pressure to obtain 3.23 g of a yellow solid with a yield of 55.57%. MS (ESI), m / z: 209.2 [M+H] + ,207.2[MH] + .

[0302] Step E Synthesis of 1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (KY6)

[0303] Under ice bath, add 3.0g (14.4mmol) 7-methoxy-6-nitro-1,2,3,4-tetrahydroisoquinoline to 30mL acetic acid, slowly add 1.7g (17.3mmol) acetic anhydride, after the addition, raise the temperature of reaction solution to 60℃ and react for 1h. After the reaction, add the reaction solution to 50mL water, filter, wash the filter cake with water, and dry to obtain 3.48g yellow solid, yield 95.9%. MS (ESI), m / z: 273.1 [M+Na] + .

[0304] Step F1-Synthesis of (6-amino-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (KY7)

[0305] At room temperature, 3.0 g (12.0 mmol) of 1-(7-methoxy-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one and 0.3 g of Pd / C were added to 20 mL of methanol, and the reaction solution was heated to 56°C in a hydrogen atmosphere for 8 h. After the reaction, diatomaceous earth was placed on the filter while hot, and the filter cake was washed with methanol. The filtrate was collected and the solvent was evaporated under reduced pressure to obtain 2.48 g of yellow solid, with a yield of 94%. MS (ESI), m / z: 221.0 [M+H] + ,218.7[MH] + .

[0306] Step G Synthesis of (R)-2-((2-acetyl-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (KY8)

[0307] At room temperature, 2.0 g (9.1 mmol) 1-(6-amino-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one, 3.75 g (12.7 mmol) M6, 0.42 g (0.45 mmol) Pd(dba)2, 0.65 g (1.36 mmol) XPhos and 8.89 g (27.2 mmol) CsCO3 were added to 20 mL tert-butyl alcohol. Under nitrogen atmosphere, the reaction solution was heated to 80 ° C for 7 h. After the reaction, diatomaceous earth was placed on the filter while hot, the filter cake was washed with DCM, the filtrate was collected and the solvent was evaporated, and the crude product was purified by column chromatography to obtain 0.81 g of a white solid. MS (ESI), m / z: 479.3 [M+H] + , 477.0[MH] + .

[0308] Step H Synthesis of (R)-8-cyclopentyl-7-ethyl-2-[(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one (KY9)

[0309] At room temperature, 0.8g (1.7mmol) (R)-2-[(2-acetyl-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl) amino] -8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6 (5H) -one was dissolved in methanol, and 1mL (12mol / L) concentrated hydrochloric acid was added dropwise to the reaction solution. After the addition, the reaction solution was heated to 60°C and stirred for 12h. After the reaction, the organic solvent in the reaction solution was evaporated under reduced pressure, 10mL of water was added, and the mixed solution was poured into a 1M NaOH aqueous solution, filtered, and the filter cake was washed with 10mL of water and dried to obtain 0.39g of white solid, with a yield of 53%. MS (ESI), m / z: 437.1 [M + H] + Step I (R)-2-{[2-(2-chloroacetyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (KY 10 )

[0310] Under ice bath, 0.35g (0.8mmol) (R)-8-cyclopentyl-7-ethyl-2-[(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one was dissolved in 5mL DCM, and 0.18g (1.6mmol) chloroacetyl chloride diluted with 5mL DCM was slowly added dropwise. After the addition, the reaction solution was warmed to room temperature and reacted for 1h. After the reaction, the reaction solution was added to 10mL saturated NH4Cl aqueous solution, extracted with DCM (10mL×3), the organic layers were combined and dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain 0.37g yellow solid, with a yield of 90%. MS (ESI), m / z: 513.0 [M+H] + ,511.1[MH] + .

[0311] Step J Synthesis of (R)-8-cyclopentyl-7-ethyl-2-{[7-methoxy-2-(2-morpholinoacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one

[0312] At room temperature, 0.1 g (0.2 mmol) (R)-2-{[2-(2-chloroacetyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one, 0.054 g (0.39 mmol) K2CO3 and 0.025 g (0.29 mmol) morpholine were added to 5 mL acetone. After the addition, the reaction solution was heated to 60°C for 4 h. After the reaction, the organic solvent in the reaction solution was evaporated, 5 mL of water was added, and the solution was extracted with DCM (5 mL × 3). The organic phases were combined and dried with anhydrous Na2SO4. The organic solvent was evaporated, and the crude product was purified by column chromatography to obtain 0.03 g of a light yellow solid. MS (ESI), m / z: 564.2 [M+H] + , 562.3[MH] + .

[0313] According to the method of Example 104, intermediate KY 10 The compounds of Examples 105 to 116 were prepared by reacting the raw materials with the corresponding small molecule amines for nucleophilic substitution reaction. The structures, chemical names, melting points, MS, 1 The H-NMR data are shown in Table 6.

[0314] Table 6 Compounds 104 to 116

[0315]

[0316]

[0317]

[0318]

[0319] The compounds of the present invention were studied for PLK1 enzyme activity, and the results are as follows

[0320] The in vitro PLK1 enzyme activity test was performed on the dihydropteridone compound containing a benzobiheteroaryl group represented by the above formula I of the present invention using a fluorescence analysis method. The compounds described below are all dihydropteridone compounds containing a benzobiheteroaryl group represented by the above formula I prepared in the above examples.

[0321] Dilute PLK1 kinase to 20 ng / μL in 5x KB DTT-MgCl2 assay buffer. Add 4 μL of inhibitor solution to each test well, while adding 4 μL of the same solution without inhibitor (inhibitor buffer) to the wells labeled "Negative Control" and "Positive Control". Add 2 μL of STK Substrate-biotin to all wells. Add 2 μL of kinase to the test wells and 2 μL of 5x KB DTT-MgCl2 assay buffer to the wells labeled "Negative Control" and "Positive Control". Add 2 μL of ATP to all wells. Seal and incubate at room temperature for 1 hour.

[0322] Add 5 μL of Sa-XL665 and STK Ab-Cryptate to all wells in sequence, seal and incubate at room temperature for 1 h.

[0323] The fluorescence signal was detected using SpectraMax i3X multi-function microplate reader: Emission Ratio (ER) = 665 nm Emission signal / 615 nm Emission signal (320 nm excitation, 665 nm, 615 nm emission).

[0324] The inhibition rate was calculated according to the formula: Inhibition rate = (ER positive -ER sample ) / (ER positive -ER negative )*100%(ER positive : ER value of positive control well; ER sample : ER value of the test hole; ER negative : ER value of negative control well).

[0325] Finally, SPSS software was used to input the data and draw the inhibition rate-concentration curve to calculate the IC 50 .

[0326] Table 7 PLK1 IC of some examples 50 Activity data

[0327] Example <![CDATA[PLK1(IC 50 (nM))]]> Example 6 0.65 Example 13 1.6 Embodiment 23 0.7 Embodiment 27 0.9 Embodiment 28 0.5 Embodiment 29 0.4 Embodiment 30 0.3 Embodiment 31 0.7 Embodiment 32 0.5 Embodiment 33 1.0 Embodiment 34 0.5 Embodiment 35 0.3 Embodiment 36 0.3 Embodiment 37 0.72 Embodiment 38 0.6 Embodiment 39 0.5 Embodiment 40 0.3 Embodiment 41 0.2 Embodiment 46 0.17 Embodiment 48 1.34 Embodiment 50 10.9 Embodiment 51 0.2 Embodiment 52 0.09 Embodiment 54 0.80 Embodiment 55 0.47 Embodiment 56 0.26 Embodiment 76 0.51 Embodiment 78 0.6 Embodiment 79 0.6 Embodiment 88 0.7 Embodiment 89 0.8 Embodiment 91 0.7 Embodiment 92 0.99 Embodiment 93 0.83 Embodiment 104 0.72 Embodiment 105 0.88 Embodiment 106 0.72 Embodiment 107 0.86 Embodiment 108 0.86 BI 6727 0.82 BI 2536 0.9

[0328] The compounds of the general formula recorded in the above table all have good PLK1 inhibitory activity, and some of the compounds are equivalent to or better than the positive control drugs BI 6727 and BI 2536.

[0329] At the same time, some of the compounds in the examples also have inhibitory activity against BRD4, among which Example 1, Example 6, Example 13, Example 32, Example 35, Example 36, Example 39, Example 40, Example 41, and Example 89, respectively, have IC 50 The activity data are 61.26, 81.09, 97.3, 56.7, 61.79, 60.8, 52, 70.1, 70.6, and 83.1.

[0330] Then, the dihydropteridone derivatives containing a fused benzene ring according to the above formula I of the present invention were further subjected to an in vitro experiment to inhibit the activity of human breast cancer cells MDA-MB-231, MDA-MB-361 and human leukemia cells MV4-11.

[0331] CCK-8 assay to detect the antiproliferative activity of the compounds (MDA-MB-231, MDA-MB-361 and MV4-11 cell lines)

[0332] Cells in the logarithmic growth phase were cultured at a rate of 8 to 15 × 10 4 / mL was inoculated into a 96-well plate, and the cell solution volume was 100μL / well. 100μL of different concentrations of drug solution was added to each well, and three replicates were set for each concentration. Incubate for 48h under standard conditions. After the incubation, the 96-well plate was removed, 20μL of CCK-8 solution was added to each well, and the incubation continued for 4h before being removed and placed on a micro-oscillator for 5min. The absorbance (OD) of each well was measured at 450nm on an ELISA reader.

[0333] The inhibition rate (IR) of cell proliferation in vitro was calculated according to the formula:

[0334] IR%=(OD control -OD sample ) / (OD control -OD blank )×100%

[0335] In the formula, OD control : OD value of the well without drug addition; OD sample : OD value of the dosing hole; OD blank : In the CCK-8 method, it is the OD value of the wells with only culture medium added.

[0336] Finally, the data were input into Prism8 software and the inhibition rate-concentration curve was drawn to calculate the IC 50 .

[0337] The test results of some compounds in MDA-MB-231, MDA-MB-361 and MV4-11 cell lines are shown in Table 8.

[0338] Table 8 Cell IC of some examples 50 Activity data

[0339]

[0340] The results of the cell activity test of the compounds showed that the activities of most compounds against MDA-MB-231 and MV4-11 were comparable to or better than the positive control drugs BI 2536 and BI 6727.

[0341] At the same time, the results of in vitro kinase and cell activity tests showed that the compounds involved in the present invention have good PLK1 and BRD4 inhibitory activity and excellent cell activity, and the activity of some compounds is better than that of positive control drugs BI 2536 and BI 6727.

Claims

1. A dihydropteridone derivative containing a fused benzene ring, characterized in that: The derivatives are compounds represented by the general formula I and their salts, solvates or prodrugs. in, R1 is hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl; R2 is (C1-C6) alkyl, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 12 )spirocyclic group, 6-12 membered heterospirocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, wherein any H in the alkyl, cycloalkyl, heterocyclyl, spirocyclyl, heterospirocyclyl, aryl or heteroaryl is substituted by 1-3 identical or different R5; R5 is hydrogen, halogen, hydroxy, cyano, amino, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy; m is an integer from 0 to 1; R3 is hydrogen, (C1-C3) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkoxy which is unsubstituted or substituted by at least one of the following groups; the following groups are halogen, hydroxyl or amino; Ring A together with the benzene ring attached to it forms the following group: R4 is H, (C1-C6) alkyl, (CO)x(CH2) n NR6R7, COR8, SO2NR6R7, SO2R8, CSNR6R7; n is an integer from 0 to 3; x is 0 or 1; R6 and R7 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, dimethylaminoethyl, and any H in the alkyl, cycloalkyl or heterocycloalkyl is substituted by 1-3 identical or different R9; or R6 and R7 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds, any H in the heterocyclic group is replaced by 0-2 oxo groups, or any H in the heterocyclic group is replaced by 0-3 identical or different R 10 replace; R9 and R 10 The same or different, each independently selected from hydrogen, hydroxy, halogen, amino substituted by 0-2 (C1-C6) alkyl groups, cyano, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted by at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C6) alkylsulfonyl, 10 )cycloalkyl-(C1-C4)alkyl; the following groups are hydroxy, amino or halogen; R8 is (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 10 )aryl, 5-10 membered heteroaryl, (C2-C6)alkenyl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by 1-3 identical or different R 11 replace; R 11 is hydrogen, halogen, hydroxy, cyano, amino, nitro, trifluoromethyl, (C1-C6) alkyl, (C1-C6) haloalkyl, alkylacyl, (C1-C6) alkoxy; The aryl group defined in formula I is phenyl or naphthyl; the heteroaryl group is a monocyclic or polycyclic unsaturated ring system containing one or more heteroatoms; the heterocyclic group is a monocyclic, polycyclic, bridged or spirocyclic ring system containing one or more heteroatoms; the heteroatoms may be the same or different and are selected from N, O, S.

2. The dihydropteridone derivative containing a fused benzene ring according to claim 1, characterized in that: In the general formula I, R1 is (C1-C4) alkyl; R2 is (C1-C4) alkyl, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 10 ) aryl, 5-6 membered heteroaryl, wherein any H in the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is substituted by 1-3 identical or different R5; R5 is hydrogen, halogen, hydroxy, cyano, amino, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) alkoxy; Ring A together with the benzene ring attached to it forms the following group: R3 is hydrogen, (C1-C3) alkyl, (C1-C3) alkoxy; R4 is H, (C1-C6) alkyl, (CO)x(CH2) n NR6R7, COR8, SO2NR6R7, SO2R8, CSNR6R7; n is an integer from 0 to 3; x is 0 or 1; R6 and R7 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, dimethylaminoethyl, wherein any H in the alkyl, cycloalkyl or heterocycloalkyl is substituted by 1-3 identical or different R9; or R6 and R7 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds, any H in the heterocyclic group is replaced by one or more oxo groups, or any H in the heterocyclic group is replaced by 0-3 identical or different R 10 replace; R9 and R 10 The same or different, each independently selected from hydrogen, hydroxy, halogen, amino substituted by 0-2 (C1-C6) alkyl groups, cyano, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted by at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C6) alkylsulfonyl, 10 )cycloalkyl-(C1-C4)alkyl; the following groups are hydroxy, amino or halogen; R8 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, (C2-C6) alkenyl, wherein any H in the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkylalkenyl is replaced by 1-3 identical or different R 11 replace; R 11 It is hydrogen, halogen, hydroxy, cyano, amino, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy.

3. The dihydropteridone derivative containing a fused benzene ring according to claim 2, characterized in that: In the general formula I, R1 is methyl or ethyl; R2 is (C3-C6) alkyl, (C3-C6) cycloalkyl, Phenyl, thienyl, furyl, naphthyl, wherein any H in the alkyl, cycloalkyl, heterocyclic, phenyl, thienyl, furyl, naphthyl is substituted by 1-3 identical or different R5; R5 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl, hydroxyl, cyano; Ring A together with the benzene ring attached to it forms the following group: R3 is (C1-C3) alkoxy; R4 is H, (C1-C6) alkyl, (CO)x(CH2) n NR6R7, COR8, SO2NR6R7, SO2R8, CSNR6R7; n is an integer from 0 to 3; x is 0 or 1; R6 and R7 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, dimethylaminoethyl, wherein any H in the alkyl, cycloalkyl or heterocycloalkyl is substituted by 1-3 identical or different R9; or R6 and R7 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group containing at least one heteroatom; wherein the heterocyclic group contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds, the optional H in the heterocyclic group is replaced by one or more oxo groups, or the heterocyclic group is optionally replaced by 0-3 identical or different R 10 replace; R9 and R 10 The same or different, each independently selected from hydrogen, hydroxy, halogen, amino substituted by 0-2 (C1-C4) alkyl groups, cyano, (C1-C4) alkyl acyl, (C1-C4) alkyl sulfonyl, (C1-C4) alkyl which is unsubstituted or substituted by at least one of the following groups, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C3-C 10 )cycloalkyl-(C1-C4)alkyl; the following groups are hydroxy, amino or halogen; R8 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, 3-6 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, (C2-C6) alkenyl, wherein any H in the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkylalkenyl is replaced by 1-3 identical or different R 11 replace; R 11 It is hydrogen, halogen, hydroxy, cyano, amino, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy.

4. The dihydropteridone derivative containing a fused benzene ring according to claim 3, characterized in that: In the general formula I, R1 is a methyl group; R2 is (C3-C6) alkyl, (C3-C6) cycloalkyl, Phenyl, thienyl, furyl, naphthyl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl, thienyl, furyl, naphthyl is optionally substituted by 1-3 identical or different R5; R5 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, trifluoromethyl, hydroxyl, cyano; Ring A together with the benzene ring attached to it forms the following group: R3 is methoxy; R4 is H, (C1-C6) alkyl, (CO)x(CH2) n NR6R7, COR8, SO2NR6R7, SO2R8, CSNR6R7; n is an integer from 0 to 3; x is 0 or 1; R6 and R7 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C5) cycloalkyl, (C3-C6) heterocycloalkyl, wherein any H in the alkyl, cycloalkyl or heterocycloalkyl is replaced by 1-3 identical or different R9; or R6 and R7 together with the nitrogen atom to which they are attached form R9 is selected from hydrogen, hydroxy, halogen, amino substituted by 0 to 2 (C1-C6) alkyl groups, cyano, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted by at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C6) 10 )cycloalkyl-(C1-C4)alkyl; the following groups are hydroxy, amino or halogen; R8 is The above aryl group is phenyl or naphthyl; heteroaryl group is a monocyclic or polycyclic unsaturated ring system containing one or more heteroatoms; The heterocyclic group is a monocyclic, polycyclic, bridged or spirocyclic ring system containing one or more heteroatoms; the heteroatoms may be the same or different and are selected from N, O and S.

5. The dihydropteridone derivative containing a fused benzene ring according to claim 4, characterized in that: The derivative is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, (R)-8-Cyclopentyl-7-ethyl-2-[(6-methoxy-1-oxoisoindolin-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-[(6-methoxy-2-methyl-1-oxoisoindolin-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[2-(4-morpholinyl)ethyl-6-methoxy-1-oxoisoindolin-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-[(2-isopropyl-6-methoxy-1-oxoisoindol-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(diglycol)-5-methoxyindol-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]indol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(piperidin-1-yl)acetyl]indol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{1-{2-{[(R)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(4-methylpiperidin-1-yl)acetyl]indol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(3-methylpiperidin-1-yl)acetyl]indol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[5-methoxy-1-(2-morpholinoacetyl)indol-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[5-methoxy-1-(2-thiomorpholinoacetyl)indol-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{5-methoxy-1-[2-(4-methylpiperazin-1-yl)acetyl]indol-6-yl}amino}5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-ethylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-isopropylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-{2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]acetyl}-5-methoxyindol-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-[2-(4-cyclopentylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-5-methoxyindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{5-methoxy-1-{2-[4-(methylsulfonyl)piperazin-1-yl]acetylindol-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{[1-2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-8-(cyclopentyl)methyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-8-cyclohexyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-8-(cyclohexyl)methyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-7-ethyl-5-methyl-8-(thien-2-ylmethyl)-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-5-methoxyindol-6-yl}amino}-7-ethyl-5-methyl-8-(3-methylthien-2-yl)methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(diglycol)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]indol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[(S)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-6-methoxyindol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(piperidin-1-yl)acetyl]indol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(2-thiomorpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-[2-(1,1-dioxidomorpholinoacetyl)acetyl]-6-methoxyindol-5-yl}amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(4-methylpiperazin-1-yl)acetyl]indol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-{2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]acetyl}-6-methoxyindol-5-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-6-methoxyindol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-{2-[4-(methylsulfonyl)piperazin-1-yl]acetyl}indol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(cyclopropylglycerylamino)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(cyclopentylglyceryl)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-8-cyclohexyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-8-(cyclohexylmethyl)-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxyindol-5-yl}amino}-7-ethyl-5-methyl-8-(thien-2-ylmethyl)-7,8-dihydropterin-6(5H)-one (R)-8-(Cyclopentylmethyl)-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclohexyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclohexyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-8-(thien-2-ylmethyl)-7,8-dihydropterin-6(5H)-one (R)-7-Ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropterin-6(5H)-one (R)-8-Benzyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)indol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(cyclopropylsulfonyl)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(cyclopropanecarbonyl)-6-methoxyindol-5-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(phenylsulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[(4-acetylphenyl)sulfonyl]-6-methoxyindol-5-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(methylsulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[1-(ethylsulfonyl)-6-methoxyindol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[(2-nitrophenyl)sulfonyl]indol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{{1-[(2-bromophenyl)sulfonyl]-6-methoxyindol-5-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[(5-chloro-2,4-difluorophenyl)sulfonyl]-6-methoxyindol-5-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{{6-methoxy-1-[2-(trifluoromethoxy)phenyl]sulfonyl}indol-5-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[1-(trimethylsulfonyl)-6-methoxyindol-5-yl]amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{{6-methoxy-1-[4-(trifluoromethyl)phenyl]sulfonyl}indol-5-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-[(1-acetyl-6-methoxyindol-5-yl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-[(6-methoxy-1-propionylindol-5-yl)amino]-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-[(1-Acryloyl-6-methoxyindol-5-yl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[1-(isobutylsulfonyl)-6-methoxyindol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(piperidin-1-ylsulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(piperidin-1-ylsulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[1-(isopropylsulfonyl)-6-methoxyindol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(piperidin-1-carbonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(morpholinesulfonyl)indol-5-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{[1-(3-chloro-2,2-dimethylpropanoyl)-6-methoxyindol-5-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-5-[(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropterin-2-yl)amino]-6-methoxy-N,N-dimethylindoline-1-methylsulfamide (R,E)-2-{[1-(But-2-enyl)-6-methoxyindol-5-yl]amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-[(6-methoxy-1-pivaloylindol-5-yl)amino]-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-[2-(1,1-dihydromorpholinyl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(2-thiomorpholinoacetyl)-1,2,3,4-tetrahydroquinolin-7-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-{2-[4-(methylsulfonyl)piperazin-1-yl]acetyl}-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(diglycol)-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{1-{2-{[(R)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[6-methoxy-1-(2-morpholinoacetyl)-1,2,3,4-tetrahydroquinolin-7-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(4-methylpiperazin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(cyclopropylglycylamino)-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(cyclopentylglycine)-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{6-methoxy-1-[2-(piperidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-7-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-[2-(3,5-dimethylpiperazin-1-yl)acetyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[7-methoxy-1-(2-morpholinoacetyl)-1,2,3,4-tetrahydroquinolin-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-[2-(4-hydroxypiperidin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-1-[2-(4-methylpiperazin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-(2-{[(R)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-1-[2-(piperidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-1-[2-(pyrrolidin-1-yl)acetyl]-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[1-(diglycol)-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{1-{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-[(7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-[2-(1,1-dioxidodimorpholinyl)acetyl]-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-2-{{1-[2-(4,4-difluoropiperidin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{1-[2-(4-acetylpiperazin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-1-{2-[4-(methylsulfonyl)piperazin-1-yl]acetyl}-1,2,3,4-tetrahydroquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[7-methoxy-2-(2-morpholinoacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{2-[2-(4-hydroxypiperidin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-2-[2-(4-methylpiperazin-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{{2-[(R)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-2-[2-(piperidin-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-2-{{2-[2-(4-acetylpiperazin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{{2-[2-(4,4-difluoropiperidin-1-yl)acetyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{{2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{[7-methoxy-2-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{[2-(cyclopropanecarbonyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl]amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{{[2-(1,1-dihydromorpholinyl)acetyl]-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropteroin-6(5H)-one (R)-8-Cyclopentyl-7-ethyl-2-{{7-methoxy-2-{2-[4-(methylsulfonyl)piperazin-1-yl]acetyl}-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-5-methyl-7,8-dihydropterin-6(5H)-one (R)-8-Cyclopentyl-2-{{2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]acetyl}-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl}amino}-7-ethyl-5-methyl-7,8-dihydropterin-6(5H)-one.

6. The condensed benzene-containing compound according to any one of claims 1 to 5 A cyclic dihydropteridinone derivative characterized by: The compound salt is a salt formed with an acid, and the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

7. A pharmaceutical composition, characterized in that: The composition contains the compound of general formula I according to any one of claims 1 to 6 and a pharmaceutically acceptable salt, solvate or prodrug thereof.

8. Use of the compound according to claim 1, characterized in that: Use of the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof in the preparation of a medicament for preventing or treating a disease associated with a PLK1 / BRD4 inhibitor.

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