CN115160340B - A small molecular compound with ACK1 inhibitory activity and its application - Google Patents

Abstract

The invention belongs to the field of organic synthetic medicines, and particularly relates to a small molecular compound with ACK1 inhibition activity, which has the following general formula:the invention synthesizes a novel compound which can effectively inhibit the activity of the ACK1 and has better antiproliferative activity on triple negative breast cancer cells MDA-MB-231, MDA-MB-453 and T47D with high expression of the ACK1, so the compound can be used as an inhibitor of the activity of the ACK1 and further used as a medicament for treating cancers caused by abnormal activation or high expression of the ACK1, has good medicinal potential and provides a new potential choice for clinical medication.

Description

A small molecule compound with ACK1 inhibitory activity and its application

Technical Field

The present invention relates to the technical field of innovative chemical drugs, and in particular to a small molecule compound with ACK1 inhibitory activity and application thereof.

Background Art

ACK1, as a subtype of non-receptor tyrosine kinase, was originally identified based on its ability to bind to activated cell division control protein 42 (Cdc42). Structurally, ACK1 contains at least eight different domains, including the tyrosine kinase core domain, SH3 domain, SAM domain, Cdc42 binding domain, PPXY domain or WW binding domain, clathrin binding domain, MIG6 domain and ubiquitin binding domain. The multiple domains of ACK1 can bind to different types of proteins, thus giving it biological functions different from other non-receptor tyrosine kinases. In terms of expression, ACK1 is a widely expressed cytoplasmic kinase, mainly expressed in the brain, spleen, thymus and bone tissues. Functionally, as the main integrator of receptor tyrosine kinase (RTKs) signals, ACK1 can interact with activated transmembrane RTKs and autophosphorylate at the Tyr284 site to transmit extracellular signals to intracellular effectors, thereby regulating biological functions such as cell survival, proliferation and migration.

In addition, a large number of clinical studies have found that abnormal expression and overactivation of ACK1 exist in a variety of human tumors such as prostate cancer, gastric cancer, lung cancer, ovarian cancer, leukemia, kidney cancer, breast cancer, pancreatic cancer and head and neck cancer, and are associated with poor prognosis and disease metastasis of patients. The latest clinical studies have found that ACK1 dysregulation is highly correlated with the occurrence, development and poor prognosis of TNBC. Overactivation of ACK1 is associated with the high proliferation, invasion and colony formation ability of TNBC. In vitro experimental studies have found that downregulating the expression of ACK1 can significantly inhibit the invasion and proliferation ability of TNBC cells in vitro and tumor formation in xenograft mouse models, and ACK1 inhibitors can lead to TNBC proliferation inhibition. Based on this, ACK1 is a new potential therapeutic target against triple-negative breast cancer (TNBC), and targeted inhibition of ACK1 is an effective means of treating TNBC.

With the deepening of the study on the biological function of ACK1, the research on specific ACK1 inhibitors has attracted the attention of scholars, and targeted ACK1 inhibitors have been reported one after another. AIM-100 is the first reported targeted ACK1 inhibitor, but its subsequent research and application are limited due to its poor pharmacokinetic properties. It is worth mentioning that although specific ACK1 inhibitors have been reported, the reported molecules cannot be used for in vivo studies due to problems such as poor pharmacokinetic properties. At present, the in vivo pharmacodynamic study of targeted inhibition of ACK1 still uses multi-target kinase inhibitors dasatinib or bosutinib as probe molecules. In short, the ACK1 inhibitors reported so far have problems such as low activity, poor selectivity and poor drugability. So far, no specific ACK1 small molecule inhibitors have entered clinical research.

Therefore, the development of inhibitors with novel skeleton structures, high ACK1 inhibitory activity and good drugability is of great significance for the targeted treatment of triple-negative breast cancer.

Summary of the invention

The purpose of the present invention is to provide a small molecule compound with novel structure and strong activity and ACK1 inhibitory activity.

Another object of the present invention is to provide a specific application of the above-mentioned small molecule compound having ACK1 inhibitory activity as an inhibitor of ACK1 activity.

Another object of the present invention is to provide a specific application of the inhibitor of ACK1 activity provided above for preparing a drug for treating cancer.

The present invention provides a small molecule compound having ACK1 inhibitory activity, and its general formula is as follows:

in,

R ₁ and R ₂ are independently methyl, ethyl, n-propyl, isopropyl, hydrogen,

R ₃ is independently isopropyl,

R ₄ is independently a methyl group, a methoxy group, or a hydrogen atom;

_R5 is independently a methyl group, a methoxy group, a halogen atom, a cyano group, or a hydrogen atom;

R ₆ is independently diethylamino, Acetylamino,

R ₇ and R ₈ are independently a halogen atom, a hydrogen atom, —CF ₃ , or a methoxy group;

R ₉ is independently a hydrogen atom, a methyl group, an ethoxy group, an isopropoxy group,

R ₁₀ is independently a hydrogen atom or a methyl group;

R ₁₁ is independently a hydrogen atom, methyl, ethyl, isopropyl or acetyl;

R ₁₂ is independently a hydrogen atom or a methyl group;

R ₁₃ is independently hydroxyl, dimethylamino,

The specific compounds it contains are as follows:

There are two synthetic routes for the above-mentioned small molecule compound with ACK1 inhibitory activity, which are as follows.

Synthetic route 1:

The specific preparation process of synthetic route 1 comprises the following steps:

(1) Demethylating the raw material under the action of boron tribromide and using dichloromethane as solvent to prepare intermediate I; the molar ratio of the raw material to boron tribromide is 1:2; the reaction temperature is 0° C.; and the reaction time is 18 hours;

(2) intermediate I reacts with methyl bromoacetate derivatives in the presence of potassium carbonate and with N,N-dimethylformamide as solvent to prepare intermediate II; the molar ratio of raw material I: methyl bromoacetate derivative: cesium carbonate is 1:2:2; the reaction temperature is from room temperature to 80°C; and the reaction time is 18 hours;

(3) Intermediate II reacts with bromoalkane R ₃ -Br in the presence of cesium carbonate and in N,N-dimethylformamide as solvent to prepare intermediate III; the molar ratio of bromoalkane R ₃ -Br:cesium carbonate is 1:2:2; the reaction temperature is room temperature; the reaction time is 18 hours;

(4) The intermediate III is subjected to a Buchwald-Hartwig coupling reaction with an aniline compound under the catalysis of Pd(OAc) ₂ , using BINAP as a ligand, cesium carbonate as a base, and 1,4-dioxane as a solvent to prepare the target compound; the molar ratio of the intermediate III: aniline derivative: Pd(OAc) ₂ : BINAP: cesium carbonate is 1:1:0.1:0.1:2; the reaction temperature is 100°C; and the reaction time is 16 hours.

Synthetic route 2:

The specific preparation process of synthetic route 2 comprises the following steps:

(1) The raw material is subjected to a nucleophilic substitution reaction with an aniline derivative in the presence of N,N-diisopropylethylamine and 1,4-dioxane as a solvent to prepare an intermediate I; the molar ratio of the raw material: aniline derivative: N,N-diisopropylethylamine is 1:1:2; the reaction temperature is 100° C.; and the reaction time is 18 hours;

(2) Demethylating intermediate I under the action of boron tribromide with dichloromethane as solvent to prepare intermediate II; the molar ratio of intermediate I to boron tribromide is 1:2; the reaction temperature is 0° C.; and the reaction time is 18 hours;

(3) intermediate II reacts with methyl bromoacetate derivatives in the presence of potassium carbonate and with N,N-dimethylformamide as solvent to prepare intermediate III; the molar ratio of intermediate II: methyl bromoacetate derivative: cesium carbonate is 1:2:2; the reaction temperature is from room temperature to 80°C; and the reaction time is 18 hours;

(4) The intermediate III is subjected to a Buchwald-Hartwig coupling reaction with an aniline compound under the catalysis of Pd(OAc) ₂ , using BINAP as a ligand, cesium carbonate as a base, and 1,4-dioxane as a solvent to prepare the target compound; the molar ratio of the intermediate III: aniline derivative: Pd(OAc) ₂ : BINAP: cesium carbonate is 1:1:0.1:0.1:2; the reaction temperature is 100°C; and the reaction time is 16 hours.

The present invention also provides an inhibitor of ACK1 activity, which is a biopharmaceutically acceptable salt, polymorph, or solvate with the above-mentioned small molecule compound having ACK1 inhibitory activity as a main active ingredient.

The present invention also provides a drug for treating cancer, which is a prodrug, a drug, and a pharmaceutical composition prepared by using the above-mentioned inhibitor of ACK1 activity as a main component and adding pharmaceutically acceptable, non-toxic and non-inert pharmaceutical carriers and/or excipient auxiliary components to humans and animals.

The pharmaceutical carrier or excipient is one or more solid, semi-solid and liquid diluents, fillers and pharmaceutical product adjuvants.

The pharmaceutical composition is prepared into various dosage forms by methods recognized in the pharmaceutical and food fields: spray, aerosol, liquid preparation or solid preparation; the liquid preparation includes injection, suspension, emulsion, solution or syrup; the solid preparation includes tablets, capsules, granules or granules.

The cancers that can be treated by the drug are cancers caused by abnormal activation or high expression of ACK1, specifically including prostate cancer, gastric cancer, lung cancer, ovarian cancer, leukemia, kidney cancer, breast cancer, pancreatic cancer, and head and neck cancer.

The administration route of the drug is oral administration, sublingual administration or mucosal dialysis; the injection includes intravenous injection, intravenous drip, intramuscular injection, intraperitoneal injection or subcutaneous injection.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

The present invention synthesizes a novel compound, which can effectively inhibit the activity of ACK1 and has good anti-proliferation activity on triple-negative breast cancer cells MDA-MB-231, MDA-MB-453 and T47D with high expression of ACK1. Therefore, the compound can be used as an inhibitor of ACK1 activity, and further used as a drug for treating cancer caused by abnormal activation or high expression of ACK1, has good medicinal potential, and provides a new potential choice for clinical drug use.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a graph showing the inhibition of different concentrations of compound I-47 on MDA-MB-453 cell clones.

DETAILED DESCRIPTION

The present invention is further described in detail below in conjunction with embodiments, but the embodiments of the present invention are not limited thereto. Without departing from the above-mentioned technical concept of the present invention, various substitutions and changes are made according to common technical knowledge and customary means in the field, which should all be included in the scope of the present invention.

In order to make the purpose, process conditions and advantages of the present invention more clearly understood, the present invention is further described in detail in conjunction with the following embodiments. The specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

Embodiment 1:

The compound disclosed in this example: 2-[(4-diethylamino)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-1)

The specific synthetic route is as follows:

The specific preparation method comprises the following steps:

(1) Weigh the raw material 2-chloro-4-amino-5-methoxypyrimidine (15.95 g, 100 mmol) into a 500 mL round-bottom flask, then add 200 mL of dichloromethane, then cool to 0°C in an ice bath, and then slowly add boron tribromide (50.10 g, 200 mmol). After the addition is complete, the reaction solution is warmed to room temperature and the reaction is continued overnight. After TLC detection of the reaction is complete, the reaction solution is cooled to 0°C, and an appropriate amount of methanol is slowly added to quench the reaction system. Then spin dry to obtain a white powder, which is intermediate I, which can be directly used in the next step without purification.

(2) Add intermediate I (7.25 g, 50 mmol) and potassium carbonate (13.80 g, 100 mmol) to a 250 mL round-bottom flask, then add 100 mL N, N-dimethylformamide as solvent and stir at room temperature. Then slowly add ethyl 2-bromo-2-methylpropionate (14.63 g, 75 mmol). After the addition is complete, the reaction solution is heated to 80°C and the reaction is continued overnight. After the reaction is complete by TLC, the reaction solution is cooled to room temperature, then filtered and dried, and purified by column chromatography to obtain a white powder, which is intermediate II (7.45 g, yield 70%). ¹ H NMR (400MHz, CDCl ₃ ) δ8.09 (s, 1H), 1.55 (s, 6H); ¹³ CNMR (101MHz, CDCl ₃ ) δ 169.53, 152.21, 149.48, 144.98, 136.28, 80.11, 24.09. MS-ESI (m/z): 214.2 [M+H ] ⁺ .

(3) Add intermediate II (6.39 g, 30 mmol) and potassium carbonate (8.28 g, 60 mmol) to a 250 mL round-bottom flask, then add 35 mL of N,N-dimethylformamide as solvent and stir at room temperature. Then slowly add bromocyclopentane (6.70 g, 45 mmol). After the addition is complete, the reaction solution is heated to 80°C and the reaction is continued overnight. After the reaction is complete as detected by TLC, the reaction solution is cooled to room temperature, then filtered and dried, and purified by column chromatography to obtain a white powder, which is intermediate III (5.66 g, yield 67%). ¹ H NMR(400MHz, CDCl ₃ )δ8.02(s,1H),5.35–5.26(m,1H),2.07–1.94(m,4H),1.91–1.78(m,2H),1.70–1.53(m,2H),1.48(s,60H); ¹³ C NMR(101MHz, CDCl ₃ )δ1 68.91,151.84,150.21,145.09,136.60,79.32,53.51,28.56,25.79,24.09.MS-ESI(m/z):282.4[M+H] ⁺ .

(4) In a 50 mL round-bottom flask, intermediate III (0.140 g, 0.5 mmol), N, N-diethyl-p-phenylenediamine (0.082 g, 0.5 mmol), palladium acetate (0.011 g, 0.05 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP) (0.062 g, 0.1 mmol) and cesium carbonate (0.325 g, 1.0 mmol) were added, and then 10 mL of anhydrous 1,4-dioxane was added as the reaction solvent, and then the reaction was carried out at 100° C. for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered off with diatomaceous earth and dried, and then purified by column chromatography to obtain a light yellow powder, which was the target compound I-1 (0.159 g, 78%).

The ¹ H NMR data of the target compound I-1 are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.91 (s, 1H), 7.99 (s, 1H), 7.36 (d, J = 9.0Hz, 2H), 6.62 (d, J = 9.0Hz, 2H) ,5.26(p,J＝8.6Hz,1H),3.27(q,J＝7.0Hz,4H),2.09–2.02(m,2H),1.86–1.75(m,4H),1.55–1.50(m,2H ), 1.40 (s, 6H), 1.05 (t, J = 7.0Hz, 6H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ170.16,155.95,149.21,145.05,143.71,129.60,122.17,112.84,78.44,52.91,44.39,28.34,25.36,23.87,12.81.HRMS(ESI-Q-TOF):C ₂₃ H ₃₂ N ₅ O ₂ ⁺ calcd :410.2551; found:410.2550.

Embodiment 2:

The compound disclosed in this example: 2-[4-(4-pyrrolidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-2)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-(1-pyrrolidinyl)aniline" to obtain the target compound I-2.

The MS (ESI) and ¹ H NMR data of the target compound I-2 are as follows:

MS (ESI): 430.2159[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.92 (s, 1H), 7.98 (s, 1H), 7.39 (d, J = 8.4Hz, 2H ),6.48(d,J＝8.6Hz,2H),5.33–5.14(m,1H),3.17(s,4H),2.08–2.01(m,2H),1.93(s,4H),1.88–1.67( m,4H),1.56–1.51(m,2H),1.40(s,6H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ169.90,156.71,148.51,146.55,144.64,133.17,128.26,112.36,79.51,78.94,52.44,48.05,27.88,25.36,25.11,24.09.

Embodiment 3:

The compound disclosed in this example: 2-[4-(acetylamino)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-3)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-aminoacetanilide" to obtain the target compound I-3.

The MS (ESI) and ¹ H NMR data of the target compound I-3 are as follows:

MS (ESI): 418.1852[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.81 (s, 1H), 9.29 (s, 1H), 8.06 (s, 1H), 7.55 (d ,J＝8.4Hz,2H),7.45(d,J＝8.5Hz,2H),5.28(q,J＝8.8Hz,1H),2.10–2.05(m,2H),2.00(s,3H),1.95 –1.74(m,4H),1.64–1.49(m,2H),1.41(s,6H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ170.04,168.41,155.18,149.31,144.96,136.46,133.60,130.22,119.89,119.47,78.58,53.09,28.42,25.43,24.25,23.88.

Embodiment 4:

The compound disclosed in this example: 2-[(4-morpholinyl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-4)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-(4-morpholinyl)aniline" to obtain the target compound I-4.

The MS (ESI) and ¹ H NMR data of the target compound I-4 are as follows:

MS (ESI): 446.2149[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.13 (s, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.9Hz, 2H ),6.87(d,J＝9.0Hz,2H),5.29(p,J＝8.5Hz,1H),3.73(t,J＝4.7Hz,4H),3.02(t,J＝4.8Hz,4H), 2.11–2.02(m,2H),1.87–1.81(m,4H),1.58–1.53(m,2H),1.41(s,6H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ170.01,155.50,149.30,146.51,144.97,133.59,129.90,120.57,116.07,78.50,66.63,52.99,49.79,28.45,25.48,23.91.

Embodiment 5:

The compound disclosed in this example: 2-[4-(4-piperazin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-5)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-piperazine-phenylamine" to obtain the target compound I-5.

The MS (ESI) and ¹ H NMR data of the target compound I-5 are as follows:

MS (ESI): 423.2509[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09 (s, 1H), 8.02 (s, 1H), 7.46 (d, J = 8.3Hz, 2H ),6.84(d,J＝8.7Hz,2H),5.28(p,J＝8.7Hz,1H),3.02–2.90(m,4H),2.84–2.80(m,4H),2.11–1.99(m, 2H),1.89–1.76(m,4H),1.54–1.53(s,2H),1.40(s,6H); ¹³ CNMR(101MHz,DMSO-d ₆ )δ170.05,155.59,149.29,147.26,145.00,133.22,129.87,120.70,116.34,78.49,53.01,50.62,46.03,28.43,25.46,23.90.

Embodiment 6:

The compound disclosed in this example: 2-[4-(4-piperidin-4-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-6)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "(4-piperidin-4-yl)aniline" to obtain the target compound I-6.

The MS (ESI) and ¹ H NMR data of the target compound I-6 are as follows:

MS (ESI): 422.2556[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.29 (s, 1H), 8.06 (s, 1H), 7.56 (d, J = 8.0Hz, 2H ),7.11(d,J＝8.2Hz,2H),5.30(p,J＝8.7Hz,1H),3.06(d,J＝10.1Hz,2H),2.73–2.56(m,1H),2.08–2.07 (m,2H),1.91–1.82(m,4H),1.71–1.68(m,2H),1.58–1.53(m,4H),1.42(s,6H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ169.96,155.21,149.34,144.91,139.27,138.99,130.27,126.91,119.36,78.40,52.64,44.96,31.98,28.40,25.39,23.85.

Embodiment 7:

The compound disclosed in this example: 2-[4-(4-methylpiperazin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-7)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "(4-methylpiperazine-1-yl)aniline" to obtain the target compound I-7.

The MS (ESI) and ¹ H NMR data of the target compound I-7 are as follows:

MS (ESI): 437.2660[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.10 (s, 1H), 8.02 (s, 1H), 7.47 (d, J = 8.5Hz, 2H ),6.86(d,J＝8.4Hz,2H),5.28(p,J＝8.7Hz,1H),3.08–3.00(m,4H),2.44–2.39(m,4H),2.21(s,3H) ,2.12–2.00(m,2H),1.92–1.74(m,4H),1.59–1.50(m,2H),1.41(s,6H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ170.01,155.53,149.28,146.53,144.99,133.25,129.85,120.59,116.29,78.49,55.18,52.97,49.38,46.27,28.44,25.48,23.90.

Embodiment 8:

The compound disclosed in this example: 2-[4-(1-methylpiperidin-4-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-8)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-(1-methylpiperidin-4-yl)aniline" to obtain the target compound I-8.

The MS (ESI) and ¹ H NMR data of the target compound I-8 are as follows:

MS (ESI): 436.2704[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.29 (s, 1H), 8.06 (s, 1H), 7.56 (d, J = 8.2Hz, 2H ),7.12(d,J＝8.1Hz,2H),5.30(p,J＝8.6Hz,1H),2.84(d,J＝11.0Hz,2H),2.41–2.33(m,1H),2.18(s ,3H),2.10–2.03(m,2H),1.97–1.77(m,6H),1.73–1.50(m,6H),1.42(s,6H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ170.19,155.23,149.31,144.93,138.89,130.26,127.09,119.53,79.37,78.61,55.91,53.12,46.08,33.06,28.39,25.39,23.81.

Embodiment 9:

The compound disclosed in this example: 2-[4-(4-ethylpiperazin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-9)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "(4-ethylpiperazine-1-yl)aniline" to obtain the target compound I-9.

The MS (ESI) and ¹ H NMR data of the target compound I-9 are as follows:

MS (ESI): 451.2818[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.10 (s, 1H), 8.02 (s, 1H), 7.47 (d, J = 8.9Hz, 2H ),6.86(d,J＝8.9Hz,2H),5.29(p,J＝8.6Hz,1H),3.04(t,J＝4.9Hz,4H),2.49–2.47(m,4H),2.36(q ,J＝7.2Hz,2H),2.09–1.98(m,2H),1.94–1.74(m,4H),1.54(d,J＝5.6Hz,2H),1.41(s,6H),1.03(t, J＝7.2Hz,3H); ¹³ C NMR (101MHz, CDCl ₃ ) δ170.33,155.39,149.58,147.36,144.61,132.42,130.50,121.32,116.94,78.51,53.41,52.86,52.35,49.91,28.39,25.48,23.8 3,11.98.

Embodiment 10:

The compound disclosed in this example: 2-[4-(4-isopropylpiperazin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-10)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-(4-isopropylpiperazine-1-yl)aniline" to obtain the target compound I-10.

The MS (ESI) and ¹ H NMR data of the target compound I-10 are as follows:

MS (ESI): 465.2977[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.09 (s, 1H), 8.02 (s, 1H), 7.46 (d, J = 8.7Hz, 2H ),6.85(d,J＝8.9Hz,2H),5.29(q,J＝8.7Hz,1H),3.03(t,J＝4.8Hz,4H),2.66(q,J＝6.5Hz,1H), 2.56(t,J＝4.9Hz,4H),2.12–2.00(m,2H),1.93–1.73(m,4H),1.64–1.50(m,2H),1.41(s,6H),1.00(d, J＝6.5Hz,6H); ¹³ C NMR (101MHz, CDCl ₃ ) δ170.33,155.40,149.57,147.43,144.60,132.39,130.47,121.33,116.95,78.50,54.51,53.41,50.24,48.75,28.38,25.47,23.8 3,18.60.

Embodiment 11:

The compound disclosed in this example: 2-[4-(4-acetylpiperazine iso-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-11)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "1-acetyl-4-(4-aminophenyl)piperazine" to obtain the target compound I-11.

The MS (ESI) and ¹ H NMR data of the target compound I-11 are as follows:

MS (ESI): 487.2426 [M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.14 (s, 1H), 8.03 (s, 1H), 7.50 (d, J = 9.0Hz, 2H ),6.90(d,J＝8.9Hz,2H),5.29(dt,J＝14.7,7.5Hz,1H),3.57(q,J＝4.8Hz,4H),3.02(dt,J＝26.8,5.0Hz ,4H),2.13–2.05(m,2H),2.04(s,3H),1.89–1.75(m,4H),1.58–1.51(m,2H),1.41(s,6H); ¹³ C NMR(101MHz ,DMSO-d ₆ )δ170.06,168.90,155.45,144.97,133.81,129.93,120.59,117.06,79.55,78.52,52.99,50.16,49.75,46.05,41.24,28.44,25.48,23.86,21.6 3.

Embodiment 12:

The compound disclosed in this example: 2-[4-(4-hydroxypiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-12)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-(4-hydroxypiperidin-1-yl)aniline" to obtain the target compound I-12.

The MS (ESI) and ¹ H NMR data of the target compound I-12 are as follows:

MS (ESI): 438.2505[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 8.02 (s, 1H), 7.45 (d, J = 9.1Hz, 2H ),6.86(d,J＝8.6Hz,2H),5.28(p,J＝8.5Hz,1H),4.66(s,1H),3.58(dq,J＝9.2,4.7Hz,1H),3.43–3.38 (m,2H),2.80–2.67(m,2H),2.13–2.01(m,2H),1.88–1.76(m,6H),1.57–1.44(m,4H),1.41(s,6H); ¹³ C NMR(101MHz,DMSO-d ₆ ) δ170.07,155.56,149.27,146.73,144.98,132.88,129.83,120.76,116.82,79.57,78.49,66.59,47.92,34.41,28.42,25.46,23.86.

Embodiment 13:

The compound disclosed in this example: 2-[4-(4-(2-hydroxyethyl)piperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-13)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-(4-(2-hydroxyethyl)piperidin-1-yl)aniline" to obtain the target compound I-13.

The MS (ESI) and ¹ H NMR data of the target compound I-13 are as follows:

MS(ESI): 467.2766[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.09(s,1H),8.02(s,1H),7.47(d,J＝8.5Hz,2H),6.85(d,J＝8.6Hz,2H),5.28(p,J＝8.8Hz, 1H),4.43(t,J＝5.3Hz,1H),3.53(q,J＝5.8Hz,2H),3.04(t,J＝4.9Hz,4H),2.54(t,J＝4.9Hz,4H) ,2.42(t,J＝6.3Hz,2H),2.14–2.00(m,2H),1.91–1.74(m,4H),1.62–1.49(m,2H),1.41(s,6H); ¹³ C NMR (101MHz,DMSO-d ₆ )δ170.40,155.83,149.57,146.93,145.28,133.43,130.16,121.06,116.59,79.82,78.80,60.91,59.18,53.91,53.28,49.69,28.72,25.75,24. 14.

Embodiment 14:

The compound disclosed in this example: 2-[4-(4-(dimethylamino)piperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-14)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-(4-(dimethylamino)piperidin-1-yl)aniline" to obtain the target compound I-14.

The MS (ESI) and ¹ H NMR data of the target compound I-14 are as follows:

MS (ESI): 465.2973[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 8.02 (s, 1H), 7.45 (d, J = 8.5Hz, 2H ),6.86(d,J＝8.6Hz,2H),5.28(p,J＝8.8Hz,1H),3.59–3.53(m,2H),2.60–2.54(m,2H),2.18(s,6H) ,2.10–1.99(m,3H),1.89–1.77(m,6H),1.54–1.44(m,4H),1.40(s,6H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ170.11,155.56,149.27,146.75,144.98,133.00,129.86,120.81,116.91,79.53,78.50,61.84,52.99,49.49,41.82,28.41,28.23,25.44,23. 85.

Embodiment 15:

The compound disclosed in this example: 2-[2-methyl-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-15)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "2-methyl-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-15.

The MS (ESI) and ¹ H NMR data of the target compound I-15 are as follows:

MS (ESI): 451.2819[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.35 (s, 1H), 7.92 (s, 1H), 7.12 (d, J = 8.6Hz, 1H ),6.79(d,J＝2.8Hz,1H),6.72(dd,J＝8.6,2.8Hz,1H),5.14(p,J＝8.8,8.1Hz,1H),3.07(t,J＝4.9Hz ,4H),2.44(t,J＝4.9Hz,4H),2.21(s,3H),2.12(s,3H),2.00–

1.91(m,2H),1.69–1.55(m,4H),1.39(s,6H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ170.22,157.34,149.10,149.02,145.27,134.51,130.55,129.53, 127.40,117.70,113.74,78.33,55.11,52.64,49.15,46.25,28.12,25.14,23.95,18.87.

Embodiment 16:

The compound disclosed in this example: 2-[3-methyl-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-16)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "3-methyl-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-16.

The MS (ESI) and ¹ H NMR data of the target compound I-16 are as follows:

MS (ESI): 451.2815[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.18 (s, 1H), 8.05 (s, 1H), 7.52 (d, J = 2.6Hz, 1H ),7.34(d,J＝8.6Hz,1H),6.94(d,J＝8.6Hz,1H),5.30(p,J＝8.8,8.1Hz,1H),,2.78(t,J＝4.7Hz, 4H),2.48–2.40(m,4H),2.22(s,3H),2.21(s,3H),2.10–2.00(m,2H),1.93–1.78(m,4H),1.60–1.50(m, 2H),1.41(s,6H); ¹³ C NMR (101MHz, CDCl ₃ ) δ170.26,155.14,149.57,146.65,144.63,135.17,133.36,130.58,122.44,119.56,117.89,78.55,55.65,53.52,51.93,46.13 ,28.45,25.55,23.83,17.92.

Embodiment 17:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-17)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-17.

The MS (ESI) and ¹ H NMR data of the target compound I-17 are as follows:

MS (ESI): 467.2768[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.98 (s, 1H), 7.82 (s, 1H), 7.53 (d, J = 8.7Hz, 1H ),6.61(d,J＝2.5Hz,1H),6.46(dd,J＝8.7,2.5Hz,1H),5.19(p,J＝8.8Hz,1H),3.77(s,3H),3.10(t ,J＝4.9Hz,4H),2.45(t,J＝5.0Hz,4H),2.22(s,3H),2.04–1.97(m,2H),1.76–1.67(m,4H),1.51–1.45( m,2H),1.40(s,6H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ170.13,156.24,152.25,149.14,148.92,145.03,129.88,123.93,121.12,107.21,100.52,78.43,55.91,55.15,52.81, 49.28,46.26,28.22,25.3.

Embodiment 18:

The compound disclosed in this example: 2-[3-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-18)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "3-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-18.

The MS (ESI) and ¹ H NMR data of the target compound I-18 are as follows:

MS (ESI): 467.2766[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.19 (s, 1H), 8.06 (s, 1H), 7.34 (d, J = 2.3Hz, 1H ),7.14(dd,J＝8.5,2.4Hz,1H),6.79(d,J＝8.6Hz,1H),5.33(p,J＝9.0Hz,1H),3.76(s,3H),2.97–2.84 (m,4H),2.47–2.37(m,4H),2.20(s,3H),2.11–2.01(m,2H),1.91–1.78(m,4H),1.59–1.52(m,2H),1.41 (s,6H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ169.95,155.31,152.37,149.26,145.11,136.35,136.01,129.99,118.34,111.51,104.46,79.48,78.51,55.62,55.30,52.9 8,50.61,46.16,28.57,25.61,23.81 .

Embodiment 19:

The compound disclosed in this example: 2-[3-fluoro-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-19)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "3-fluoro-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-19.

The MS (ESI) and ¹ H NMR data of the target compound I-19 are as follows:

MS (ESI): 455.2565[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.42 (s, 1H), 8.09 (s, 1H), 7.65 (dd, J = 15.5, 2.5Hz ,1H),7.28(dd,J＝8.7,2.4Hz,1H),6.95(t,J＝9.4Hz,1H),5.30(q,J＝8.8Hz,1H),2.95–2.92(m,4H) ,2.47–2.45(m,4H),2.22(s,3H),2.08–2.03(m,2H),1.92–1.80(m,4H),1.60–1.53(m,2H),1.42(s,6H) ; ^13C NMR (101MHz, CDCl ₃ ) δ 170.21, 155.69 (d, J _CF = 244.9Hz), 154.62, 149.64, 144.51, 135.21 (d, J _CF = 11.0Hz), 134.90 (d, J _CF = 9.5Hz), 130.91, 119.14(d,J _CF =4.2Hz),114.84,107.99(d,J _CF =25.8Hz),78.61,55.21,53.65,50.85,50.82,46.11,28.42,25.43,23.83.

Embodiment 20:

The compound disclosed in this example: 2-[3-chloro-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-20)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "3-chloro-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-20.

The MS (ESI) and ¹ H NMR data of the target compound I-20 are as follows:

MS(ESI): 471.2269[M+Na]+; ¹ H NMR (400MHz, CDCl ₃ ) δ7.96(s,1H),7.84(s,1H),7.32–7.25(m,1H),7.23–7.16 (m,1H),7.02(d,J＝8.6Hz,2H),5.40–5.19(m,1H),3.06(s,4H),2.63(s,4H),2.37(s,3H),2.20– 2.02(m,2H),1.99–1.86(m,4H),1.73–1.59(m,2H),1.49(s,6H); ¹³ C NMR (101MHz, CDCl ₃ )δ170.16,154.52,149.65,144.59,144.04,135.77,131.01,129.11,121.43,120.51,118.32,78.67,55.33,53.73,51.46,46.11,28.49,25.55,2 3.85.

Embodiment 21:

The compound disclosed in this example: 2-[3-cyano-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-21)

The synthetic route is the same as that in Example 1, except that the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced by "3-cyano-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-21.

The MS (ESI) and ¹ H NMR data of the target compound I-21 are as follows:

MS(ESI): 462.2614[M+Na]+; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.57(s,1H),8.16(s,1H),8.12(s,1H),7.70(d ,J＝8.9Hz,1H),7.14(d,J＝9.0Hz,1H),5.28(q,J＝8.9Hz,1H),3.06–3.04(m,4H),2.50–2.48(m,4H) ,2.24(s,3H),2.06–2.04(m,2H),1.87–1.84(m,4H),1.68–1.53(m,2H),1.42(s,6H); ¹³ C NMR(101MHz,DMSO- d ₆ )δ169.95,154.72,149.85,149.42,144.99,135.95,130.66,125.18,123.25,120.23,118.71,105.62,79.55,78.71,55.10,53.32,51.88,46.06, 28.50,25.50,23.88.

Embodiment 22:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-isopropyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-22)

The synthetic route is the same as in Example 1, except that the raw material "bromocyclopentane" in step (3) is replaced by "bromoisopropylane" to obtain intermediate III:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 256.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (s, 1H), 5.29–5.20 (m, 1H), 1.53 (s, 6H), 1.52 (d , J=3.0, 6H); ¹³ C NMR (101MHz, CDCl ₃ ) δ168.93,151.81,150.07,145.04,136.42,79.13,46.17,23.99,19.24.

Then, the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-22.

The MS (ESI) and ¹ H NMR data of the target compound I-22 are as follows:

MS (ESI): 441.2595[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.97 (s, 1H), 7.78 (s, 1H), 7.64 (d, J = 8.7Hz, 1H ),6.61(d,J＝2.7Hz,1H),6.46(dd,J＝8.8,2.6Hz,1H),5.10(p,J＝6.9Hz,1H),3.79(s,3H),3.11–3.09 (m,4H),2.46–2.43(m,4H),2.22(s,3H),1.39(s,6H),1.40(d,J＝2.8Hz,6H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ170.13,155.94,151.57,148.51,144.89,132.68,129.92,123.03,121.27,107.18,78.32,55.17,49.26,46.26,24.01,23.91,19.62,19.32.

Embodiment 23:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclobutyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-23)

The synthetic route is the same as in Example 1, except that the raw material "bromocyclopentane" in step (3) is replaced by "bromocyclobutane" to obtain intermediate III:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 268.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (s, 1H), 5.34–5.06 (m, 1H), 2.97–2.74 (m, 2H), 2.40 –2.32(m,2H),2.03–1.89(m,1H),1.88–1.73(m,1H),1.54(s,6H); ¹³ CNMR(101MHz, CDCl ₃ )δ169.66,151.87,150.37,145.15,136.48 ,79.49,48.26,28.00,24.14,15.25.

Then, the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-23.

The MS (ESI) and ¹ H NMR data of the target compound I-23 are as follows:

MS(ESI): 453.2599[M+Na]+; ¹ H NMR (400MHz, DMSO-d ₆ )δ7.98(s,1H),7.83(s,1H),7.58(d,J＝8.7Hz,1H),6.61(d,J＝2.7Hz,1H),6.47(dd,J＝8.7,2.6 Hz,1H),5.12(p,J＝9.0Hz,1H),3.78(s,3H),3.11(t,J＝5.1Hz,4H),2.75(dq,J＝12.2,9.7Hz,2H), 2.47(d,J=5.1Hz,4H),2.23(s,3H),2.18–2.10(m,2H),1.69–1.60(m,2H),1.39(s,6H); ¹³ C NMR(101MHz, CDCl ₃ )δ171.24,155.10,149.49,149.14,147.06,144.73,130.41,122.69,119.50,108.20,100.68,78.67,55.66,55.14,50.17,47.91,46.04,28.15,2 3.91,15.40.

Embodiment 24:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-(tetrahydrofuran-3-yl)-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-24)

The synthetic route is the same as in Example 1, except that the raw material "bromocyclopentane" in step (3) is replaced by "3-bromotetrahydrofuran" to obtain intermediate III:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 284.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.12 (s, 1H), 5.65 (dddd, J=10.7, 8.7, 7.4, 5.5Hz, 1H), 4.31 (q,J＝7.8Hz,1H),4.09–3.97(m,2H),3.94–3.87(m,1H),2.28(dddd,J＝23.4,18.5,12.6,7.6Hz,2H),1.56(s ,6H); ¹³ C NMR (101MHz, CDCl ₃ )δ168.91,151.86,149.80,145.55,136.56,79.56,68.60,68.13,51.84,28.86,24.08.

Then, the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-24.

The MS (ESI) and ¹ H NMR data of the target compound I-24 are as follows:

MS (ESI): 469.2547[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.01 (s, 1H), 7.85 (s, 1H), 7.61 (d, J = 8.6Hz, 1H ),6.61(d,J＝2.6Hz,1H),6.46(dd,J＝8.7,2.5Hz,1H),5.45(p,J＝8.9Hz Hz,1H),3.93–3.84(m,2H),3.78(s,3H),3.78–3.73(m,2H),3.11–3.09(m,4H),2.46–2.43(m,4H),2.26– 2.22(m,1H),2.22(s,3H),2.10–2.00(m,1H),1.41(d,J＝5.5Hz,6H); ¹³ CNMR(101MHz,DMSO-d ₆ )δ170.23,155.94,151.80,149.01,148.68,145.24,129.89,123.34,121.04,107.26,100.51,78.65,68.04,67.68,55.95,55.08,51.32,49.18,4 6.18,28.70,23.92,23.88.

Embodiment 25:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclohexyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-25)

The synthetic route is the same as in Example 1, except that the raw material "bromocyclopentane" in step (3) is replaced by "bromocyclohexane" to obtain intermediate III:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 296.4 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.07 (s, 1H), 4.82 (tt, J = 12.4, 3.8 Hz, 1H), 2.45 (qd, J ＝12.4,3.7Hz,2H),1.87(dt,J＝13.4,3.3Hz,2H),1.67(td,J＝15.1,12.6,7.7Hz,3H),1.52(d,J＝1.2Hz,6H) ,1.41(dtd,J＝16.2,12.8,12.0,3.0Hz,2H),1.33–1.19(m,1H); ¹³ C NMR (101MHz, CDCl ₃ )δ169.09,151.81,150.22,145.08,136.43,79.11,54.38,28.63,26.20,25.17,24.06.

Then, the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-25.

The MS (ESI) and ¹ H NMR data of the target compound I-25 are as follows:

MS(ESI): 481.2914[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ7.96(s,1H),7.88(s,1H),7.47(d,J＝8.6Hz,1H),6.61(d,J＝2.5Hz,1H),6.45(dd,J＝8.8,2.6 Hz,1H),4.61(t,J＝12.2Hz,1H),3.76(s,3H),3.10(t,J＝4.9Hz,4H),2.45(t,J＝5.0Hz,4H),2.28– 2.22(m,2H),2.22(s,3H),1.73–1.70(m,2H),1.59–1.43(m,3H),1.38(s,6H),1.23–1.20(m,3H); ¹³ CNMR (101MHz,DMSO-d ₆ )δ170.32,156.48,152.78,149.19,148.90,145.17,129.60,120.93,107.10,100.42,78.27,55.81,55.05,53.34,49.11,46.15,28.69,26.38,25 .21,23.92.

Embodiment 26:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopropylmethyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-26)

The synthetic route is the same as in Example 1, except that the raw material "bromocyclopentane" in step (3) is replaced by "bromomethylcyclopropane" to obtain intermediate III:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 268.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.05 (s, 1H), 3.92 (d, J = 7.2Hz, 2H), 1.53 (s, 6H), 1.30–1.15(m,1H),0.55–0.22(m,4H); ¹³ C NMR (101MHz, CDCl ₃ ) δ168.91,152.22,150.04,144.76,136.25,79.39,44.93,24.26,9.70,3.75.

Then, the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-26.

The MS (ESI) and ¹ H NMR data of the target compound I-26 are as follows:

MS (ESI): 453.2597[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.00 (s, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.7Hz, 1H ),6.61(d,J＝2.7Hz,1H),6.46(d,J＝9.4Hz,1H),5.15–4.90(m,1H),3.97(t,J＝7.2Hz,1H),3.80(s ,3H),3.59–3. 56(m,1H),3.14–3.10(m,1H),3.11–3.09(m,4H),2.46–2.44(m,4H),2.34(q,J＝6.9,6.5Hz,1H),2.22( s,3H),1.43(s,6H),0.41–0.37(m,1H),0.30–0.24(m,1H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ169.87,156.02,151.27,148.77,148.36,144.72,129.66,122.60,121.30,107.18,100.53,78.40,56.03,55.15,49.25, 46.23,24.11,24.04,10.19,3.89 .

Embodiment 27:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclopentylmethyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-27)

The synthetic route is the same as in Example 1, except that the raw material "bromocyclopentane" in step (3) is replaced by "bromomethylcyclopentane" to obtain intermediate III:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 296.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (s, 1H), 4.04 (d, J = 7.6Hz, 2H), 2.46–2.34 (m, 1H) ),1.75–1.63(m,4H),1.56(s,6H),1.39–1.17(m,2H); ¹³ C NMR (101MHz, CDCl ₃ )δ168.91,152.19,144.76,136.18,79.36,44.67,38.39, 30.09,24.73,24.27.

Then, the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-27.

The MS (ESI) and ¹ H NMR data of the target compound I-27 are as follows:

MS(ESI): 481.2909[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ7.99(s,1H),7.76(s,1H),7.67(d,J＝8.7Hz,1H),6.62(d,J＝2.5Hz,1H),6.44(dd,J＝8.8,2.5 Hz,1H),3.85(d,J＝7.6Hz,2H),3.80(s,3H),3.11–3.08(m,4H),2.46–2.44(m,4H),2.34(p,J＝7.5Hz ,1H),2.22(s,3H),1.56–1.54(m,4H),1.43(s,6H),1.37–1.35(m,2H),1.29–1.16(m,2H); ¹³ C NMR(101MHz ,DMSO-d ₆ )δ169.29,156.41,156.12,151.48,148.37,143.92,132.17,129.85,124.35,107.52,100.53,78.92,55.90,55.17,49.28,48.68,46.23,44.26,3 8.03,29.86,24.79,24.19.

Embodiment 28:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-cyclohexylmethyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-28)

The synthetic route is the same as in Example 1, except that the raw material "bromocyclopentane" in step (3) is replaced by "bromomethylcyclohexane" to obtain intermediate III:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 310.4 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (s, 1H), 3.93 (d, J = 7.4Hz, 2H), 1.84 (ddp, J = 11.1 ,7.2,4.2,3.6Hz,2H),1.75–1.69(m,2H),1.67–1.62(m,2H),1.61–1.58(m,1H),1.56(s,6H),1.26–1.15(m ,3H),1.11–0.98(m,2H); ¹³ C NMR (101MHz, CDCl ₃ )δ168.95,152.18,150.29,144.76,136.13,79.37,46.08,36.12,30.53,26.17,25.67,24.32.

Then, the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-28.

The MS (ESI) and ¹ H NMR data of the target compound I-28 are as follows:

MS (ESI): 517.2900 [M+Na] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.16 (d, J = 8.7Hz, 1H), 7.95 (s, 1H), 7.34 (s, 1H), 6.57(s,1H),6.53(d,J＝8.8Hz,1H),3.93(d,J＝7.3Hz,2H),3.89(s,3H),3.24–3.07(m,4H),2.67–2.55 (m,4H),2.37(s,3H),1.99–1.86(m,1H),1.77–1.59(m,4H),1.51(s,6H),1.18(t,J＝9.1Hz,2H), 1.12–1.01(m,2H); ¹³ C NMR (101MHz, CDCl ₃ ) δ170.26,155.21,148.99,148.88,146.94,144.59,130.02,122.91,119.06,108.03,100.76,78.47,55.68,55.21,50.31,46 .12,46.05,36.43,30.83,26.36,25.81 ,24.08.

Embodiment 29:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-phenyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-29)

The specific synthetic route is as follows:

The specific preparation method comprises the following steps:

(1) Add the raw material 2,4-dichloro-5-methoxypyrimidine (8.95 g, 50 mmol) and the solvent (100 mL) 1,4-dioxane into a 250 mL round-bottom flask. Then, add N,N-diisopropylethylamine (12.9 g, 100 mmol) and aniline (4.65 g, 50 mmol). Stir and heat to 100°C and react overnight. After the reaction is complete by TLC, the reaction solution is cooled to room temperature, then dried by spin drying, and purified by column chromatography to obtain a white powder, which is Intermediate I (10.25 g, yield 87%). ¹ H NMR(400MHz, CDCl ₃ )δ7.72–7.61(m,3H),7.40–7.28(m,3H),7.12–7.07(m,1H),3.91(s,3H); ¹³ C NMR(101MHz, CDCl ₃ )δ152.28,151.07,139.31,137.7,13 4.06,129.08,123.99,120.08,56.34.MS-ESI(m/z):236.4[M+H] ⁺ .

(2) Weigh intermediate I (7.07 g, 30 mmol) into a 250 mL round-bottom flask, then add 100 mL of dichloromethane, then cool to 0°C in an ice bath, and then slowly add boron tribromide (9 mL). After the addition is complete, the reaction solution is warmed to room temperature and the reaction is continued overnight. After TLC detection of the reaction is complete, the reaction solution is cooled to 0°C, and an appropriate amount of methanol is slowly added to quench the reaction system. Then spin dry to obtain a white powder, which is intermediate II, which can be directly used in the next step without purification.

(3) Add intermediate II (30 mmol) and potassium carbonate (8.28 g, 60 mmol) to a 250 mL round-bottom flask, then add 50 mL of N,N-dimethylformamide as solvent and stir at room temperature. Then slowly add ethyl 2-bromo-2-methylpropionate (8.78 g, 75 mmol). After the addition is complete, the reaction solution is heated to 80°C and the reaction is continued overnight. After TLC detection shows that the reaction is complete, the reaction solution is cooled to room temperature, then filtered and dried, and purified by column chromatography to obtain a white powder, which is intermediate III (5.63 g, yield 65%). ¹ H NMR (400MHz, CDCl ₃ ) δ8.18 (s, 1H), 7.57–7.38 (m, 3H), 7.20 (d, J = 7.3Hz, 2H), 1.66 (s, 6H); ¹³ C NMR (101MHz, CDCl ₃ ) δ 168.81, 152.51, 150.70, 145.66, 136. 13,133.42,129.55,129.17,128.52,79.93,24.21.MS-ESI(m/z):290.4[M+H] ⁺ .

(4) In a 50 mL round-bottom flask, intermediate III (0.145 g, 0.5 mmol), 2-methoxy-4-(4-methylpiperidin-1-yl)aniline (0.110 g, 0.5 mmol), palladium acetate (0.011 g, 0.05 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP) (0.062 g, 0.1 mmol) and cesium carbonate (0.325 g, 1.0 mmol) were added, and then 10 mL of anhydrous 1,4-dioxane was added as the reaction solvent, and then the reaction was carried out at 100° C. for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered off with diatomaceous earth and dried, and then purified by column chromatography to obtain a light yellow powder, which was the target compound I-29 (0.159 g, 78%).

The MS (ESI) and ¹ H NMR data of the target compound I-29 are as follows:

MS (ESI): 475.2456[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.11 (s, 1H), 7.57–7.49 (m, 3H), 7.44 (s, 1H), 7.38 –7.31(m,2H),7.29(d,J＝8.8Hz,1H),6.52(d,J＝2.5Hz,1H),6.08(d,J＝9.0Hz,1H),3.75(s,3H) ,3.02(t,J＝4.8Hz,4H),2.43(t,J＝4.9Hz,4H),2.21(s,3H),1.56(s,6H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ169.94,155.27,149.84,147.53,145.56,135.47,129.81,129.75,129.73,129.03,121.64,107.13,100.53,79.74,79.23,56.21,55.27,49.45 ,46.35,24.27.

Embodiment 30:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-o-tolyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-30)

The synthetic route is the same as in Example 29, except that the raw material "aniline" in step (1) is replaced by "o-methylaniline" to obtain intermediate I:

The MS (ESI) and ¹ H NMR data of the intermediate I are as follows:

MS (ESI): 250.4 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.05 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 7.26 (t, J = 7.6 Hz,1H),7.21(d,J＝7.4Hz,1H),7.13(s,1H),7.08(t,J＝7.4Hz,1H),3.97(s,3H),2.30(s,3H); ¹³ C NMR (101MHz, CDCl ₃ )δ152.74,151.35,139.53,135.66,133.98,130.60,128.97,126.89,124.81,122.23,56.44,17.82.

Then according to steps (2), (3) and (4), the target compound I-30 is obtained.

Wherein, the intermediate III obtained according to step (3) is:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 304.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.17 (s, 1H), 7.41–7.28 (m, 3H), 7.07 (d, J = 7.7Hz, 1H ),2.09(s,3H),1.68(s,3H),1.63(s,3H); ¹³ C NMR(101MHz,CDCl ₃ )δ168.39,152.70,150.43,145.51,136.14,136.13,132.63,131.28,129.58, 128.60,127.27,80.09,24.25,24.23,17.55.

The MS (ESI) and ¹ H NMR data of the target compound I-30 are as follows:

MS (ESI): 489.2593[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.12 (s, 1H), 7.43–7.42 (m, 3H), 7.35 (dt, J = 8.8, 4.5Hz,1H),7.25–7.22(m,2H),6.52(d,J＝2.6Hz,1H),6.10–6.00(m,1H),3.75(s,3H),3.01(t,J＝4.9 Hz, 4H), 2.43 (t, J = 4.9Hz, 4H), 2.21 (s, 3H), 2.04 (s, 3H), 1.59 (s, 3H), 1.55 (s, 3H). ¹³ C NMR (101MHz ,DMSO-d ₆ )δ169.37,155.23,149.21,147.26,145.42,136.56,134.39,131.14,129.65,129.59,129.34,127.45,121.51,106.95,100.33,79.54,79.30,56. 05,55.07,49.24,46.15,24.13,23.96,17.53.

Embodiment 31:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-(2-ethoxyphenyl)-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-31)

The synthetic route is the same as in Example 29, except that the raw material "aniline" in step (1) is replaced by "2-ethoxyaniline" to obtain intermediate I:

MS (ESI): 280.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.56 (dd, J=5.3, 2.6Hz, 1H), 8.16 (s, 1H), 7.71 (s, 1H) ),7.02(dd,J＝4.8,3.8Hz,2H),6.94–6.82(m,1H),4.15(dd,J＝13.4,6.5Hz,2H),3.99(s,3H),1.49(t, J=6.9Hz, 3H); ¹³ C NMR (101MHz, CDCl ₃ )δ151.57,150.44,147.65,139.84,133.31,127.60,123.38,120.99,119.47,111.09,64.41,56.55,14.80.

Then according to steps (2), (3) and (4), the target compound I-31 is obtained.

Wherein, the intermediate III obtained according to step (3) is:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 332.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.17 (s, 1H), 7.34 (ddd, J=8.7, 7.5, 1.8Hz, 1H), 7.18 (dd ,J＝7.8,1.8Hz,1H),7.08(td,J＝7.6,1.2Hz,1H),6.82(dd,J＝8.4,1.2Hz,1H),4.21(t,J＝7.0Hz,2H) ,1.50(s,3H),1.44(s,3H),1.21(t,J=7.1Hz,3H); ¹³ C NMR (101MHz, CDCl ₃ )δ168.45,152.43,151.29,150.83,145.14,136.18,130.28,129.90,123.87,121.64,116.61,79.96,61.59,24.25,24.22,14.00.

The MS (ESI) and ¹ H NMR data of the target compound I-31 are as follows:

MS(ESI): 519.1390[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.09(s,1H),7.48(t,J＝7.8Hz,1H),7.40(s,1H),7.28(d,J＝8.2Hz,2H),7.19(d,J＝8.4Hz, 1H),7.07(t,J＝7.6Hz,1H),6.52(s,1H),6.07(d,J＝8.8Hz,1H),3.95(dd,J＝15.5,7.7Hz,2H),3.75( s,3H),3.01(t,J＝4.8Hz,4H),2.43(t,J＝4.9Hz,4H),2.21(s,3H),1.59(s,3H),1.49(s,3H), 1.09(t,J=7.0Hz,3H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ169.53,155.17,154.74,149.56,147.22,145.12,130.70,130.58,129.52,123.92,121.54,121.04,113.67,106.92,100.32, 79.02,64.26,56.04,55.09,49.27,46.20 ,24.15,23.84,14.93.

Embodiment 32:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-(2-isopropoxyphenyl)-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-32)

The synthetic route is the same as in Example 29, except that the raw material "aniline" in step (1) is replaced by "2-isopropoxyaniline" to obtain intermediate I:

MS(ESI): 294.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.68–8.50(m,1H),8.19(s,1H),7.67(s,1H),7.05–6.83 (m,3H),4.68–4.44(m,1H),3.95(s,3H),1.39(d,J＝6.1Hz,6H); ¹³ CNMR(101MHz,CDCl ₃ )δ152.06,151.10,146.57,139.87, 133.72,128.83,123.16,121.22,119.53,113.21,71.84,56.49,22.22.

Then according to steps (2), (3) and (4), the target compound I-32 is obtained.

Wherein, the intermediate III obtained according to step (3) is:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 348.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.14 (s, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.0 Hz,1H),7.02(dd,J＝7.8,4.2Hz,2H),4.66–4.46(m,1H),1.69(s,3H),1.59(s,3H),1.17(dd,J＝14.9, 6.0Hz, 6H); ¹³ C NMR (101MHz, CDCl ₃ )δ168.70,153.26,152.46,150.85,145.05,136.13,130.52,130.04,122.88,120.54,113.79,79.88,70.25,24.21,22.11,21.70.

The MS (ESI) and ¹ H NMR data of the target compound I-32 are as follows:

MS(ESI): 533.2861[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.09(s,1H),7.47(t,J＝7.9Hz,1H),7.38(s,1H),7.28(t,J＝10.0Hz,2H),7.22(d,J＝8.4Hz, 1H),7.05(t,J＝7.6Hz,1H),6.52(s,1H),6.06(d,J＝8.9Hz,1H),4.58(p,J＝6.0Hz,1H),3.76(s, 3H),3.01(t,J＝4.8Hz,4H),2.43(t,J＝4.8Hz,4H),2.21(s,3H),1.59(s,3H),1.49(s,3H),1.12( d,J＝6.0Hz,3H),0.99(d,J＝6.0Hz,3H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ169.54,155.13,153.81,149.62,149.29,147.12,145.04,130.89,130.45,129.56,124.65,121.64,120.83,119.72,114 .72,106.95,100.32,79.03,70.47,56.07 ,55.11,49.32,46.21,24.17,23.92,22.30,22.06.

Embodiment 33:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-(2-(2,2,2-trifluoroethoxy)phenyl)-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-33)

The synthetic route is as in Example 29, except that the raw material "aniline" in step (1) is replaced by "2-(2,2,2-trifluoroethoxy)aniline", and the intermediate I is obtained:

MS (ESI): 334.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.64 (d, J=8.1Hz, 1H), 8.19 (s, 1H), 7.74 (s, 1H), 7.27(s,3H),7.16(t,J＝7.8Hz,1H),7.06(t,J＝7.7Hz,1H),6.92(d,J＝8.0Hz,1H),4.46(dd,J＝15.9 ,7.9Hz,2H),3.98(s,3H).

Then according to steps (2), (3) and (4), the target compound I-33 is obtained.

Wherein, the intermediate III obtained according to step (3) is:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS(ESI): 388.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.18(s,1H),7.51–7.46(m,1H),7.25–7.17(m,2H),7.02 (d,J＝8.2Hz,1H),4.68–4.15(m,25H),1.71(s,3H),1.58(s,3H); ¹³ CNMR(101MHz, CDCl ₃ )δ168.66,152.75,152.48,150.44, 145.39,136.13,130.90,130.50,123.16,122.90,113.28,80.11,66.03(q,J _CF =36.1Hz),24.21,23.87.

The MS (ESI) and ¹ H NMR data of the target compound I-33 are as follows:

MS(ESI): 573.2417[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.10(s,1H),7.54(t,J＝7.4Hz,1H),7.44(s,1H),7.41–7.30(m,2H),7.26–7.18(m,2H),6.51(d ,J＝2.6Hz,1H),6.10(dd,J＝8.7,2.6Hz,1H),4.74(dt,J＝11.5,8.6Hz,1H),4.61–4.46(m,1H),3.74(s, 3H),3.03(t,J＝4.9Hz,4H),2.44(t,J＝4.9Hz,4H),2.21(s,3H),1.59(s,3H),1.45(s,3H); ¹³ CNMR (101MHz,DMSO-d ₆ )δ169.50,155.32,153.17,149.78,149.31,147.41,145.22,131.14,130.78,129.47,124.06,123.97(q,J _CF =277.7Hz),122.94,121.45,120.28(q ,J _CF =4.8Hz),114.27 ,106.95,100.31,79.10,65.45(q,J _CF =36.3Hz),55.99,55.09,49.25,46.18,24.12,23.54.

Embodiment 34:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-34)

The synthetic route is the same as in Example 1, except that the raw materials "aniline" and "bromocyclopentane" in step (3) are replaced with "benzylamine" to obtain intermediate III:

The MS (ESI) and 1H NMR data of the intermediate III are as follows:

MS (ESI): 304.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.07 (s, 1H), 7.46–7.43 (m, 2H), 7.37–7.22 (m, 3H), 5.23 (s,2H),1.55(s,8H); ¹³ C NMR (101MHz, CDCl ₃ ) δ168.69,152.21,149.65,145.00,136.31,135.92,128.95,128.60,128.41,128.22,127.91,79.58,43.5 7,24.24.

Then replace the raw material "N,N-diethyl-p-phenylenediamine" in step (4) with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-34.

The MS (ESI) and ¹ H NMR data of the target compound I-34 are as follows:

MS (ESI): 489.2597[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.02 (s, 1H), 7.80 (s, 1H), 7.51 (d, J = 8.7Hz, 1H ),7.34–7.13(m,5H),6.60(s,1H),6.40(d,J＝8.8Hz,1H),5.08(s,2H),3.76(s,3H),3.09(t,J＝ 4.8Hz, 4H), 2.45 (t, J = 4.9Hz, 4H), 2.21 (s, 3H), 1.46 (s, 6H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ169.79,156.13,151.57,148.53,148.46,145.00,137.28,129.60,128.87,127.77,127.61,123.13,121.07,107.14,100.46,78.61,55.97,55. 12,49.21,46.22,43.01,24.04.

Embodiment 35:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6,6-dimethyl-8-(1-phenylethyl)-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-35)

The synthetic route is the same as in Example 1, except that the raw material "bromocyclopentane" in step (3) is replaced by "(1-bromoethyl)benzene", and the intermediate III is obtained:

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

MS (ESI): 318.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.07 (s, 1H), 7.48–7.39 (m, 2H), 7.32–7.30 (m, 2H), 7.27 –7.25(m,1H),6.39–6.28(m,1H),1.91(dd,J＝7.2,1.2Hz,3H),1.54(s,3H),1.45(s,3H); ¹³ C NMR(101MHz ,CDCl ₃ )δ168.42,151.88,149.86,145.26,139.31,136.39,128.21,127.45,127.42,127.34,127.26,79.30,51.04,24.07,23.82,16.18.

Then, the raw material "N,N-diethyl-p-phenylenediamine" in step (4) is replaced with "2-methoxy-4-(4-methylpiperidin-1-yl)aniline" to obtain the target compound I-35.

The MS (ESI) and ¹ H NMR data of the target compound I-35 are as follows:

MS (ESI): 503.2758[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.01 (s, 1H), 7.78 (s, 1H), 7.40 (d, J = 8.7Hz, 1H ),7.29–7.18(m,5H),6.59(d,J＝2.6Hz,1H),6.45–6.34(m,1H),6.18(q,J＝7.0Hz,1H),3.76(s,3H) ,3.09(t,J＝4.8Hz,4H),2.44(t,J＝4.9Hz,4H),2.21(s,3H),1.77(d,J＝7.1Hz,3H),1.44(s,3H) ,1.37(s,3H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ169.64,155.96,151.71,148.67,148.60,145.22,140.76,129.72,128.56,127.09,126.70,123.38,120.95,107.13,100.39, 78.40,55.89,55.08,49.74,49.18,46.20 ,23.91,23.62,16.72.

Embodiment 36:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-methyl-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-36)

The synthetic route is the same as in Example 29, except that the raw material "aniline" in step (1) is replaced by "benzylamine" to obtain intermediate I:

The MS (ESI) and ¹ H NMR data of the intermediate I are as follows:

MS(ESI): 250.4[M+H] ⁺ ; ¹ H NMR ((400MHz, CDCl3)δ7.51(s,1H),7.39–7.22(m,5H),5.78(s,1H),4.65(d , J=5.7Hz, 2H), 3.82 (s, 3H); ¹³ C NMR (101MHz, CDCl3) δ155.17,151.63,139.36,137.77,132.79,128.79,128.02,127.76,56.04,44.71.

Then, intermediate II is prepared according to step (2), and then the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "ethyl 2-bromopropionate" to prepare intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.06(s,1H),7.51–7.41(m,2H),7.37–7.19(m,3H),5.21(s,2H),4.91–4.70(m,1H ), 1.59 (dd, J=6.7, 1.1Hz, 3H); ¹³ C NMR (101MHz, CDCl ₃ ) δ 166.48, 152.34, 149.68, 144.68, 137.14, 135.77, 129.14, 128.60, 127.98, 74.18, 43.43, 16.95. MS -ESI(m/z):290.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-36 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-36 are as follows:

MS (ESI): 475.2443[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04 (s, 1H), 7.81 (s, 1H), 7.48 (d, J = 8.7Hz, 1H ),7.30–7.21(m,5H),6.61(d,J＝2.5Hz,1H),6.40(dd,J＝8.9,2.5Hz,1H),5.13–5.02(m,2H),4.89(q, J＝6.7Hz,1H),3.76(s,3H),3.15–3.06(m,4H),2.46–2.44(m,4H),2.22(s,3H),1.48(d,J＝6.7Hz,3H ); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ168.21,156.22,151.72,148.81,148.60,144.39,137.20,131.15,128.82,127.93,127.60,123.29,121.05,107.16,100.49, 73.71,55.97,55.10,49.17,46.18,42.86 ,16.62.

Embodiment 37:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-ethyl-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-37)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "ethyl 2-bromo-butyrate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.07 (s, 1H), 7.45 (dd, J = 8.0, 1.7Hz, 2H), 7.35–7.19 (m, 3H), 5.30–5.16 (m, 2H), 4.64 (dd, J＝7.9, 4.6Hz, 1H), 2.09–1.79 (m, 2H), 1.04 (t, J＝7.5Hz, 3H); ¹³ C NMR (101MHz, CDCl ₃ )δ166.01,152.18,149.47,144.57,137.05,135.82,129.10,128.59,127.95,78.73,43.29,24.73,9.11.MS-ESI(m/z):304.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-37 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-37 are as follows:

MS (ESI): 489.2600[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04 (s, 1H), 7.80 (s, 1H), 7.48 (d, J = 8.7Hz, 1H ),7.34–7.12(m,5H),6.61(s,1H),6.40(d,J＝8.5Hz,1H),5.08(s,2H),4.74(t,J＝6.1Hz,1H),3.76 (s,3H),3.10(t,J＝4.9Hz,4H),2.45(t,J＝4.7Hz,4H),2.22(s,3H),0.99(t,J＝7.4Hz,3H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ167.95,156.43,151.99,148.86,148.82,144.74,137.46,131.00,129.12,128.14,127.90,123.59,121.31,107.45,100.74,78.26,56.23,55. 32,49.41,46.39,42.99,24.15,9.74.

Embodiment 38:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-isopropyl-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-38)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-3-methylbutyrate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.06 (s, 1H), 7.47 (d, J = 7.0Hz, 2H), 7.27 (dt, J = 21.1, 7.2Hz, 3H), 5.30–5.13 (m, 2H), 4.51 (d, J＝5.3Hz, 1H), 2.31 (dh, J＝13.4, 6.6Hz, 1H), 1.00 (dd, J＝29.2, 6.9Hz, 6H); ¹³ C NMR (101MHz, CDCl ₃ )δ165.42,151.94,149.25,144.16,137.43,135.89,129.17,128.57,127.95,82.18,43.25,30.73,18.43,16.97.MS-ESI(m/z):318.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-38 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-38 are as follows:

MS (ESI): 503.2754[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04 (s, 1H), 7.80 (s, 1H), 7.49 (d, J = 8.7Hz, 1H ),7.30–7.19(m,5H),6.61(d,J＝2.5Hz,1H),6.41(dd,J＝8.8,2.6Hz,1H),5.08(s,2H),4.56(d,J＝ 5.6Hz,1H),3.76(s,3H),3.10(t,J＝4.9Hz,4H),2.45(t,J＝5.0Hz,4H),2.22(s,3H),0.96(dd,J＝ 15.6,6.8Hz,6H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ166.99,156.11,151.75,148.62,148.35,144.24,137.25,130.86,128.82,127.96,127.64,123.35,121.06,107.18,100.49, 81.41,55.97,55.09,49.18,46.18,42.69 ,29.59,18.65,17.41.

Embodiment 39:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-propyl-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-39)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-pentanoate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.06(s,1H),7.49–7.41(m,2H),7.34–7.19(m,3H),5.29–5.15(m,2H),4.71(ddd,J ＝8.4,4.5,1.2Hz,1H),2.00–1.75(m,2H),1.61–1.41(m,2H),0.95(td,J＝7.4,1.3Hz,3H); ¹³ C NMR (101MHz, CDCl ₃ )δ166.19,152.22,149.50,144.63,136.93,135.81,129.11,128.58,127.95,77.49,43.29,33.14,18.02,13.54.MS-ESI(m/z):318.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-39 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-39 are as follows:

MS(ESI): 503.2755[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.03(s,1H),7.80(s,1H),7.48(d,J＝8.7Hz,1H),7.32–7.16(m,5H),6.61(d,J＝2.5Hz,1H), 6.40(dd,J＝8.8,2.5Hz,1H),5.07(s,2H),4.79(dd,J＝7.3,5.4Hz,1H),3.76(s,3H),3.10(t,J＝4.9Hz ,4H),2.45(t,J＝4.9Hz,4H),2.22(s,3H),1.87–1.73(m,2H),1.47(dh,J＝13.6,6.7Hz,2H),0.91(t, J＝7.3Hz,3H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ167.79,156.18,151.72,148.61,148.55,144.52,137.21,130.61,128.82,127.90,127.61,123.31,121.03,107.14,100.46, 76.76,55.96,55.12,49.19,46.21,42.72 ,32.39,18.05,13.99.

Embodiment 40:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-cyclopropyl-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-40)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-cyclopropylpropionate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.10 (s, 1H), 7.47 (d, J = 7.1Hz, 2H), 7.28 (dt, J = 19.4, 7.0Hz, 3H), 5.36–5.10 (m, 2H), 4.15 (d, J＝8.5Hz, 1H), 1.19 (dt, J＝16.9, 6.6Hz, 1H), 0.83–0.38 (m, 4H); ¹³ C NMR (101MHz, CDCl ₃ )δ165.16,152.25,149.38,144.87,144.83,137.04,135.81,129.25,129.16,128.60,127.98,81.39,43.36,12.59,3.25,3.18.MS-ESI(m/z):316.4 [M+H] ⁺ .

Finally, according to step (4), the target compound I-40 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-40 are as follows:

MS (ESI): 501.2598[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.06 (s, 1H), 7.80 (s, 1H), 7.50 (d, J = 8.7Hz, 1H ),7.30–7.22(m,5H),6.61(s,1H),6.40(d,J＝8.7Hz,1H),5.09(s,2H),4.23(d,J＝8.7Hz,1H),3.76 (s,3H),3.10–3.09(m,4H),2.46–2.44(m,4H),2.22(s,3H),1.34–1.13(m,3H),0.65–0.56(m,2H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ166.81,156.14,151.63,148.53,148.40,144.61,137.21,130.75,128.84,127.91,127.62,123.17,121.09,107.17,100.49,80.83,55.97, 55.09,49.17,46.15,42.76,12.33,3.41,3.23.

Embodiment 41:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-phenyl-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-41)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-phenylacetate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.10 (s, 1H), 7.50–7.17 (m, 10H), 5.80 (s, 1H), 5.27 (s, 2H); ¹³ C NMR (101MHz, CDCl ₃ ) δ164.47,152.50,149.37,145.17,136.91,135.61,133.64,129.65,129.52,129.33,129.06,128.94,128.64,128.11,127.69,126.77,126.67,7 8.70,43.62.MS-ESI(m/z):352.4[M +H] ⁺ .

Finally, according to step (4), the target compound I-41 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-41 are as follows:

MS (ESI): 537.2599[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.09 (s, 1H), 7.90 (s, 1H), 7.46 (d, J = 8.7Hz, 1H ),7.41–7.32(m,5H),7.31–7.20(m,5H),6.61(d,J＝2.4Hz,1H),6.41(dd,J＝8.8,2.4Hz,1H),5.99(s, 1H),5.13(s,2H),3.76(s,3H),3.16–2.99(m,4H),2.46–2.38(m,4H),2.21(s,3H); ¹³ C NMR(101MHz,DMSO- d ₆ )δ166.70,156.34,152.22,148.96,147.67,145.74,137.97,136.66,135.62,131.43,130.01,129.16,129.11,128.63,128.19,128.03,127.66,1 27.23,125.91,124.10,120.63,107.07,100.39,85.21,55.87 ,55.08,49.12,46.19,42.90.

Embodiment 42:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-(2-fluorophenyl)-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-42)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-(2-fluorophenyl)acetate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.04 (s, 1H), 7.52 (d, J = 6.5Hz, 2H), 7.42–7.35 (m, 1H), 7.35–7.26 (m, 3H), 7.17 ( td,J＝7.5,1.8Hz,1H),7.14–7.07(m,2H),5.91(s,1H),5.37–5.25(m,2H); ¹³ C NMR (101MHz, CDCl ₃ )δ164.09,160.89( d,J _CF =250.5Hz),152.48,149.29,144.83,137.12,135.58,132.06(d,J _CF =8.5Hz),129.49,129.47,128.65,128.14,124.60(d,J _CF =3.7Hz),121.87(d,J _CF =13.8Hz),116.26(d,J _CF =21.0Hz),74.70(d, J _CF =2.5Hz),43.77.MS-ESI(m/z):370.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-42 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-42 are as follows:

MS (ESI): 555.2498[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04 (s, 1H), 7.90 (s, 1H), 7.49–7.47 (m, 3H), 7.29 –7.27(m,7H),6.62(s,1H),6.43(d,J＝7.8Hz,1H),6.10(s,1H),5.15(s,2H),3.77(s,3H),3.11( s,4H),2.46(s,4H),2.22(s,3H); ¹³ C NMR(101MHz,DMSO-d ₆ )δ166.16,160.93(d,J _CF =248.3Hz),156.35,151.99,148.80,148.41,144.44,137.05,132.25(d,J _CF =7.6Hz),131.33(d,J _CF =8.4Hz),128.82,128.06,127.68,125.07,123 .68,123.25 (d,J _CF =14.0Hz),120.91,116.33 (d,J _CF =20.3Hz),107.13,100.46,75.22,55.94,55.11,49.17,46.21,43.01.

Embodiment 43:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-(2-chlorophenyl)-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-43)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-(2-chlorophenyl)acetate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (s, 1H), 7.54 (d, J = 6.7Hz, 2H), 7.45 (d, J = 7.9Hz, 1H), 7.40–7.28 (m, 4H) ,7.24(d,J＝7.4Hz,1H),7.19(dd,J＝9.2,7.9Hz,1H),6.03(s,1H),5.33(s,2H); ¹³ C NMR (101MHz, CDCl ₃ )δ164.06,152.50,149.25,144.90,137.19,135.51,134.58,132.04,131.30,130.50,129.71,129.65,128.64,128.18,127.27,43.77.MS-ESI(m/z) :386.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-43 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-43 are as follows:

MS (ESI): 571.2205[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04 (s, 1H), 7.90 (s, 1H), 7.54 (d, J = 7.4Hz, 1H ),7.51–7.43(m,3H),7.41–7.37(m,1H),7.31–7.21(m,5H),6.62(d,J＝2.3Hz,1H),6.43(dd,J＝8.7,2.4 Hz,1H),6.16(s,1H),5.21–5.07(m,2H),3.77(s,3H),3.14–3.07(m,4H),2.48–2.42(m,4H),2.22(s, 3H); ^13C NMR (101MHz, DMSO-d ₆ ) δ166.00,156.32,148.82,148.24,144.39,137.06,133.95,133.65,131.84,131.65,131.32,130.55,128.78,128.32,127.87, 127.69,123.67,121.02,107.21,100.55,77.66 ,56.00,55.16,49.24,46.24,43.05.

Embodiment 44:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-(2-methoxyphenyl)-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-44)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-(2-methoxyphenyl)acetate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.26 (s, 1H), 7.70 (d, J = 2.4Hz, 1H), 7.60 (dd, J = 8.8, 2.4Hz, 1H), 7.47–7.24 (m, 6H), 7.03 (d, J = 8.8Hz, 1H), 6.18 (s, 1H), 5.21–5.19 (m, 2H), 3.48 (s, 3H); ¹³ C NMR (101MHz, CDCl ₃ )δ164.66,156.68,151.58,148.96,143.77,137.70,135.85,134.17,133.30,129.72,128.59,128.53,128.08,125.53,113.19,76.37,55.66,43. 44.MS-ESI(m/z):382.5[M+ H] ⁺ .

Finally, according to step (4), the target compound I-44 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-44 are as follows:

MS(ESI): 567.2700[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ7.95(d,J＝10.4Hz,1H),7.81(d,J＝13.8Hz,1H),7.61–7.47(m,3H),7.33–7.23(m,6H),7.06(dd,J ＝8.6,4.8Hz,1H),6.62(d,J＝2.5Hz,1H),6.43(d,J＝9.0Hz,1H),5.95(s,1H),5.15(d,J＝9.0Hz,2H ),3.77(s,3H),3.61(d,J＝5.4Hz,3H),3.11(t,J＝4.9Hz,4H),2.45(t,J＝4.9Hz,4H),2.22(s,3H ); ¹³ CNMR (101MHz, DMSO-d ₆ )δ166.41,157.31,155.96,151.80,148.66,148.07,143.80,137.22,133.66,131.47,131.22,128.78,128.18,127.64,126.91,124.54,123.36,1 21.10,120.75,114.66,111.88,107.19,100.52,75.88,56.42 ,56.00,55.13,49.22,46.22.

Embodiment 45:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-(2-trifluoromethylphenyl)-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-45)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-(2-trifluoromethylphenyl)acetate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.06(s,1H),7.79–7.70(m,1H),7.57–7.46(m,4H),7.38–7.21(m,4H),6.04(s,1H ),5.39–5.18(m,2H); ¹³ C NMR(101MHz, CDCl ₃ )δ164.14,152.76,149.43,145.16,137.01,135.54,132.47,132.25,132.15(q,J _CF =9.6Hz),130.13,129. 56 (q,J _CF =8.3Hz),129.53,129.45(q,J _CF ＝31.1Hz),129.39,128.69,128.21,126.94(q,J _CF ＝5.5Hz),123.89(q,J _CF ＝274.0Hz),75.92(q,J _CF ＝2.1Hz),43.88.MS-ESI( m/z):420.6[M+H] ⁺ .

Finally, according to step (4), the target compound I-45 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-45 are as follows:

MS(ESI)605.2470[M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.03(s,1H),7.96(s,1H),7.84(d,J＝7.7Hz,1H),7.76–7.70(m,1H),7.69–7.63(m,1H),7.60(d ,J＝7.6Hz,1H),7.46(d,J＝8.7Hz,1H),7.32–7.21(m,5H),6.62(d,J＝2.0Hz,1H),6.43(dd,J＝8.7, 2.0Hz,1H),6.16(s,1H),5.12(q,J＝14.9Hz,2H),3.76(s,3H),3.11(m,4H),2.49–2.43(m,4H),2.22( s,3H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ166.34,156.56,152.17,148.94,148.51,144.58,137.12,133.80,133.44,131.46,131.26,130.65,128.96,128.36,128.07(q, J _CF =30.3Hz),127.78, 127.21(q,J _CF =272.3Hz),127.17(q,J _CF =3.1Hz),123.91,121.03,107.29,100.60,76.70,56.12,55.23,49.29,46.19,43.27.

Embodiment 46:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-(2,6-difluorophenyl)-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-46)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-(2,6-difluorophenyl)acetate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.40(s,1H),7.77–7.56(m,1H),7.39–7.32(m,4H),7.30–7.24(m,3H),6.61(s ,1H),5.22(s,2H); ¹³ C NMR (101MHz, CDCl ₃ ) δ164.00,161.37(dd,J _CF =252.5,6.7Hz),152.41,149.03,144.45,137.27,135.47,132.42(t,J _CF =10.6Hz),129.28,128.61,128.05,111.99(dd,J _CF =21.7,3.4Hz),111.82(dd,J _CF =33.9,21.3Hz),69.97(t,J _CF =3.0Hz),43.73.MS-ESI(m/z):388.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-46 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-46 are as follows:

MS(ESI)573.2409[M+Na] ⁺ ; ¹ H NMR(400MHz, DMSO-d ₆ )δ8.04(s,1H),7.90(s,1H),7.64–7.57(m,1H),7.46( d,J＝8.7Hz,1H),7.31–7.20(m,6H),6.62(d,J＝2.3Hz,1H),6.43(d,J＝9.1Hz,1H),6.36(s,1H), 5.15(s,2H),3.77(s,3H),3.11(t,J＝4.9Hz,4H),2.45(t,J＝4.8Hz,4H),2.22(s,3H); ¹³ C NMR (101MHz ,DMSO-d ₆ )δ166.19,161.27(d,J _CF =250.1Hz),160.10,156.32,152.02,148.83,148.21,144.23,136.94,133.21(d,J _CF =11.6Hz),131.34,130.12,128.81,1 27.90,127.68,123.73 ,120.86,112.61(d,J _CF =18.0Hz),112.60(d,J _CF =23.9Hz)),107.16,100.45,69.94,55.94,55.08,49.15,46.18,42.92.

Embodiment 47:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-(2-fluoro-6-chlorophenyl)-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-47)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-(2-fluoro-6-chlorophenyl)acetate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.05 (s, 1H), 7.51 (d, J = 7.4Hz, 2H), 7.45–7.19 (m, 6H), 7.05 (t, J = 8.9Hz, 1H) ,6.29(s,1H),5.31(q,J=14.0Hz,2H); ¹³ C NMR(101MHz,CDCl ₃ )δ164.01,161.80(d,J _CF =253.0Hz),152.26,148.80,144.32,137.39, 135.77(d,J _CF =4.5Hz),135.43,132.07(d,J _CF =10.0Hz),129.45,128.56,128.04,126.10(d,J _CF =3.3Hz),121.54(d,J _CF =15.8Hz),114.84(d,J _CF =22.3Hz),72.63,43.67.MS- ESI(m/z):404.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-47 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-47 are as follows:

MS (ESI) 589.2112 [M+Na] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04 (s, 1H), 7.88 (s, 1H), 7.56 (q, J = 7.7Hz, 1H) ,7.51–7.42(m,2H),7.36(t,J＝9.2Hz,1H),7.29–7.23(m,5H),6.63(s,1H),6.48(s,1H),6.43(d,J ＝8.6Hz,1H),5.15(s,2H),3.77(s,3H),3.12(t,J＝4.8Hz,4H),2.47(d,J＝4.8Hz,4H),2.23(s,3H ); ¹³ C NMR (101MHz, DMSO-d ₆ )δ166.17,161.79(d,J _CF =251.0Hz),160.54,156.21,151.99,148.78,147.99,144.04,136.97,135.22(d,J _CF =4.8Hz),133.02(d,J _CF =9.3Hz), 131.43,128.74,128.13,127.63,126.61(d,J _CF =2.1Hz)),123.66,122.52(d,J _CF =16.2Hz),121.00,115.59(d,J _CF =21.9Hz),107.19,100.52,55.97,55.10,49.18,46.17,42.90.

Embodiment 48:

The compound disclosed in this example: 2-[2-methoxy-4-(4-methylpiperidin-1-yl)anilino]-6-(2,6-dichlorophenyl)-8-benzyl-6H-pyrimidin[5,4-b]oxazin-7(8H)-one (I-48)

The synthetic route is the same as in Example 36, except that the raw material "ethyl 2-bromo-2-methylpropionate" in step (3) is replaced with "methyl 2-bromo-2-(2-,6-dichlorophenyl)acetate" to obtain intermediate III;

The MS (ESI) and ¹ H NMR data of the intermediate III are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.05 (s, 1H), 7.52 (d, J = 7.3Hz, 2H), 7.43–7.19 (m, 6H), 6.53 (s, 1H), 5.30 (q, J=14.0Hz, 2H); ¹³ C NMR (101MHz, CDCl ₃ ) δ163.90,152.08,148.58,144.29,137.53,135.35,131.59,130.99,129.69,128.55,128.08,75.51,43.66.MS-ESI (m/z ):420.4[M+H] ⁺ .

Finally, according to step (4), the target compound I-48 is obtained.

The MS (ESI) and ¹ H NMR data of the target compound I-48 are as follows:

MS(ESI)605.1821[M+Na] ⁺ ; ¹ H NMR(400MHz, DMSO-d ₆ )δ8.03(s,1H),7.88(s,1H),7.63–7.44(m,4H),7.30– 7.21(m,5H),6.67(s,1H),6.63(d,J＝2.5Hz,1H),6.43(dd,J＝8.6,2.6Hz,1H),5.13(s,2H),3.78(s ,3H),3.11(t,J＝4.8Hz,4H),2.46(t,J＝4.9Hz,4H),2.22(s,3H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ166.00,156.13,152.07,148.82,147.72,143.87,136.91,132.56,132.08,131.46,128.67,128.44,127.64,123.78,120.99,107.18,100.51,7 5.38,55.96,55.11,49.19,46.20,42.93.

Embodiment 49:

This example is based on the 48 compounds provided in the above examples, and an in vitro ACK1 kinase activity test is performed on them, as follows:

In vitro kinase inhibition analysis was performed using the Kinase Profiler service provided by Eurofins. The experimental method is briefly described as follows: the small molecule compound to be tested (0.001-10 μM) or blank solvent, the ACK1 protein kinase to be tested and the corresponding peptide substrate were added to the reaction buffer for incubation, wherein the reaction buffer consisted of 8 mM propanesulfonic acid (MOPS, pH = 7.0), 0.2 mM ethylenediaminetetraacetic acid (EDTA), 10 mM magnesium acetate and Km concentration of γ- ³³ P-ATP solution. After the entire reaction was carried out at room temperature for 40 minutes, 3% phosphate solution was added to the reaction buffer to terminate the reaction. Subsequently, 10 μL of the reaction mixture was quantitatively drawn and dropped onto P30 filter paper, and washed with 75 mM phosphate three times and then washed with methanol once. The P30 filter paper was dried and then added with scintillation fluid for scintillation counting. The inhibitory activity of the compound was expressed as the half-inhibitory concentration IC ₅₀ , and the IC ₅₀ value was obtained by fitting the inhibition rate corresponding to each concentration gradient. The results are shown in Table 1. AIM-100 was used as an ACK1 positive drug (IC ₅₀ was 0.024 μM).

Table 1 IC ₅₀ values of all compounds

Compound No. ACK1(μM) Compound No. ACK1(μM) Compound No. ACK1(μM) I-1 >10 I-17 0.061 I-33 0.073 I-2 >10 I-18 0.021 I-34 0.005 I-3 0.435 I-19 0.168 I-35 0.010 I-4 0.353 I-20 0.037 I-36 0.017 I-5 0.027 I-21 0.342 I-37 0.004 I-6 0.208 I-22 0.205 I-38 0.006 I-7 0.025 I-23 0.064 I-39 0.006 I-8 0.128 I-24 0.472 I-40 0.020 I-9 0.055 I-25 0.018 I-41 0.002 I-10 0.076 I-26 0.047 I-42 0.003 I-11 0.044 I-27 0.052 I-43 0.002 I-12 0.068 I-28 0.100 I-44 0.007 I-13 0.034 I-29 0.015 I-45 0.003 I-14 0.105 I-30 0.062 I-46 0.004 I-15 0.153 I-31 0.104 I-47 0.001 I-16 0.011 I-32 0.025 I-48 0.003

According to the contents in Table 1, each compound has a certain inhibitory effect on biological activity, among which compound I-47 exhibits the best inhibitory effect on ACK1, and its IC50 is 0.001 μM.

Embodiment 50:

This example focuses on the anti-triple negative breast cancer proliferation activity test for compounds I-5, I-7, I-11, I-12, I-13, I-17, I-18, I-34, I-38, I-39, I-41, I-42, I-43, I-45, I-46, I-47, and I-48.

The specific testing process is as follows:

The MTT method was used to test the in vitro anti-TNBC activity of the compound. The test method is briefly described as follows: TNBC cells MDA-MB-453, MDA-MB-231 or T47D with high expression of ACK1 were inoculated into 96-well plates and incubated in serum-containing medium for 24 hours, followed by the addition of compounds at different concentrations for 75 hours of co-incubation. After the co-incubation, MTT was added and the absorbance was read at a wavelength of 570nm using a MultiskanMK3 ELISA photometer (Thermo Scientific). The anti-TNBC effect of the drug can be determined by comparing the differences between the drug-treated group and the control group. The test results are shown in Table 2:

Table 2 Anti-triple negative breast cancer activity of selected compounds

According to the contents of Table 2, the selected compounds have good anti-proliferative activity against triple-negative breast cancer cells MDA-MB-231, MDA-MB-453 and T47D with high expression of ACK1.

Embodiment 51:

In this example, compound I-47, which exhibits the best biological activity inhibition effect on ACK1, was subjected to an anti-triple negative breast cancer cell MDA-MB-453 clone formation test. The specific experiment is as follows:

4.1 Experimental subjects

MDA-MB-453 cells were selected for clonal form experiments.

4.2 Experimental plan

MDA-MB-453 cells were plated in 12-well plates at a density of 800 cells per well, and 1 mL of growth medium was added. Subsequently, after incubation for 24 hours, different concentrations of I-49 compounds were added. After 24 hours, the medium was replaced with drug-free medium and cultured for 14 days. The colonies were fixed with 4% paraformaldehyde and stained with crystal violet.

4.3 Experimental Conclusion

The experimental results are shown in Figure 1. Compound I-47 can effectively inhibit the clone formation of MDA-MB-453 cells in a dose-dependent manner. When the concentration of compound I-47 is 1 μM, it can show a significant inhibitory effect; when the concentration is 10 μM, complete inhibition can be achieved.

Although the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims (4)

1. A small molecule compound having ACK1 inhibitory activity, or a biologically pharmaceutically acceptable salt thereof, the small molecule compound having the specific structure:

2. a medicament for treating cancer, which is prepared by adding pharmaceutically acceptable pharmaceutical carriers and/or excipient auxiliary components into a small molecular compound with ACK1 inhibitory activity or a biologically pharmaceutically acceptable salt thereof as a main component according to claim 1.

3. The medicament for treating cancer according to claim 2, wherein the cancer is a cancer caused by abnormal activation or high expression of ACK 1.

4. A medicament for the treatment of cancer according to claim 3, characterized in that said cancer is selected from prostate cancer, gastric cancer, lung cancer, ovarian cancer, leukemia, renal cancer, breast cancer, pancreatic cancer, head and neck cancer.