CN115160340B

CN115160340B - Small molecular compound with ACK1 inhibition activity and application thereof

Info

Publication number: CN115160340B
Application number: CN202210634723.1A
Authority: CN
Inventors: 母波; 潘树雷
Original assignee: West China Hospital of Sichuan University
Current assignee: West China Hospital of Sichuan University
Priority date: 2022-06-07
Filing date: 2022-06-07
Publication date: 2023-07-21
Anticipated expiration: 2042-06-07
Also published as: CN115160340A

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

Small molecular compound with ACK1 inhibition activity and application thereof

Technical Field

The invention relates to the technical field of innovative chemical medicaments, in particular to a small molecular compound with ACK1 inhibition activity and application thereof.

Background

ACK1, a subtype of non-receptor tyrosine kinase, was originally identified based on its binding to activated cell division controlling protein 42 (Cdc 42). Structurally, ACK1 comprises at least eight distinct domains including a 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, conferring biological functions that differ from other non-receptor tyrosine kinases. In terms of expression, ACK1 is a widely expressed cytoplasmic kinase that is expressed primarily in brain, spleen, thymus and skeletal tissue. Functionally, ACK1, the major integrator of receptor tyrosine kinase (receptor tyrosine kinases, RTKs) signals, can interact with activated transmembrane RTKs and autophosphorylate at the Tyr284 site, transmitting extracellular signals to intracellular effectors, thus regulating biological functions such as cell survival, proliferation and migration.

In addition, a number of clinical studies have found that abnormal expression and over-activation of ACK1 exist in various human tumors such as prostate cancer, gastric cancer, lung cancer, ovarian cancer, leukemia, renal cancer, breast cancer, pancreatic cancer, and head and neck cancer, and are associated with poor prognosis and metastasis of the patient. Recent clinical studies have found that deregulation of ACK1 is highly correlated with the occurrence, progression, and poor prognosis of TNBC. The over-activation of ACK1 is associated with the high proliferation, invasion and colony forming capacity of TNBC. In vitro experimental studies show that down-regulating the expression of ACK1 can significantly inhibit the invasion and proliferation capacity of TNBC cells in vitro and the formation of tumors in xenograft mouse models, and ACK1 inhibitors can lead to inhibition of TNBC proliferation. 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 deep research of the biological functions of the ACK1, the research of specific ACK1 inhibitors attracts attention of students, and the targeted ACK1 inhibitors are reported successively. AIM-100 was the first reported targeted ACK1 inhibitor, but its pharmacokinetic properties were poor limiting its subsequent research and use. It is worth mentioning that although specific ACK1 inhibitors have been reported, the reported molecules cannot be used for in vivo studies due to the problems of poor pharmacokinetic properties. Currently, targeted inhibition ACK1 in vivo pharmacodynamics studies still select the multi-target kinase inhibitors dasatinib or bosutinib as probe molecules. In summary, the ACK1 inhibitors reported at present have the problems of low activity, poor selectivity, poor drug formation and the like, and no specific ACK1 small molecule inhibitors have been put into clinical study until now.

Therefore, the development of the inhibitor with a brand-new framework structure, high ACK1 inhibition activity and good drug formation has great significance for the targeted treatment of triple negative breast cancer.

Disclosure of Invention

The invention aims to provide a small molecular compound with novel structure and strong activity and ACK1 inhibition activity.

It is another object of the present invention to provide a specific use of the above small molecule compound having ACK1 inhibitory activity as an inhibitor of ACK1 activity.

It is also an object of the present invention to provide a specific use of an inhibitor of ACK1 activity based on the above for the preparation of a medicament for the treatment of cancer.

The invention provides a small molecule compound with ACK1 inhibition activity, which has the following general formula:

wherein, the liquid crystal display device comprises a liquid crystal display device,

R ₁ 、R ₂ is an independent methyl, ethyl, n-propyl, isopropyl, hydrogen atom,

R ₃ Is independently isopropyl,

R ₄ Is an independent methyl, methoxy and hydrogen atom;

R ₅ is an independent methyl group, methoxy group, halogen atom, cyano group, hydrogen atom;

R ₆ is independently diethylamino,Acetamido group,

R ₇ 、R ₈ Is an independent halogen atom, hydrogen atom, -CF ₃ Methoxy;

R ₉ is independently hydrogen atom, methyl, ethoxy or isopropoxyA base group,

R ₁₀ Is an independent hydrogen atom or methyl;

R ₁₁ is an independent hydrogen atom, methyl, ethyl, isopropyl and acetyl;

R ₁₂ is an independent hydrogen atom or methyl;

R ₁₃ is independently hydroxy, dimethylamino,

The specific compounds contained are as follows:

the synthetic route of the above small molecule compound having ACK1 inhibitory activity is two, and is specifically as follows.

Synthetic route 1:

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

(1) Under the action of boron tribromide, the raw materials are demethylated by taking methylene dichloride as a solvent, and an intermediate I is prepared; the raw materials are as follows: the molar ratio of the boron tribromide is 1:2; the reaction temperature is 0 ℃; the reaction time was 18 hours;

(2) Under the action of potassium carbonate, the intermediate I reacts with bromoacetic acid methyl ester derivatives by taking N, N-dimethylformamide as a solvent to prepare an intermediate II; the raw material I: methyl bromoacetate derivatives: the molar ratio of cesium carbonate is 1:2:2; the reaction temperature is between room temperature and 80 ℃; the reaction time was 18 hours;

(3) The intermediate II reacts with bromoalkane R under the action of cesium carbonate by taking N, N-dimethylformamide as a solvent ₃ -Br, preparing intermediate III; the bromoalkane reaction R ₃ -Br: the molar ratio of cesium carbonate is 1:2:2; the reaction temperature is room temperature; the reaction time was 18 hours;

(4) Intermediate III in Pd (OAc) ₂ Under the catalytic action of (1), using BINAP as a ligand, cesium carbonate as alkali, and 1, 4-dioxane as a solvent, and carrying out Buchwald-Hartwig coupling reaction with an aniline compound to prepare a target compound; the intermediate III: aniline derivatives: pd (OAc) ₂ : BINAP: the molar ratio of cesium carbonate is 1:1:0.1:0.1:2; the reaction temperature is 100 ℃; the reaction time was 16 hours.

Synthetic route 2:

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

(1) Under the action of N, N-diisopropylethylamine, carrying out nucleophilic substitution reaction on the raw materials and aniline derivatives by taking 1, 4-dioxane as a solvent to prepare an intermediate I; the raw materials are as follows: aniline derivatives: the molar ratio of N, N-diisopropylethylamine is 1:1:2; the reaction temperature is 100 ℃; the reaction time was 18 hours;

(2) Under the action of boron tribromide, the intermediate I is subjected to demethylation by taking methylene dichloride as a solvent, so as to prepare an intermediate II; the intermediate I: the molar ratio of the boron tribromide is 1:2; the reaction temperature is 0 ℃; the reaction time was 18 hours;

(3) Under the action of potassium carbonate, the intermediate II reacts with bromoacetic acid methyl ester derivatives by taking N, N-dimethylformamide as a solvent to prepare an intermediate III; the intermediate II: methyl bromoacetate derivatives: the molar ratio of cesium carbonate is 1:2:2; the reaction temperature is between room temperature and 80 ℃; the reaction time was 18 hours;

The invention also provides an inhibitor of the activity of ACK1, and a biological pharmaceutically acceptable salt, a polymorph and a solvate which take the small molecular compound with the activity of the ACK1 as a main active ingredient.

The invention also provides a medicine for treating cancers, which is prepared by taking the inhibitor of the ACK1 activity as a main component and adding pharmaceutically acceptable medicinal carriers and/or excipient auxiliary components which are nontoxic and inert to human and animals.

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

The pharmaceutical composition is prepared into various dosage forms by adopting a method accepted in the pharmaceutical and food fields: spray, aerosol, liquid formulation or solid formulation; the liquid preparation comprises injection, suspension, emulsion, solution or syrup; the solid preparation comprises tablets, capsules, granules or medicinal granules.

The cancers which can be treated by the medicine are cancers caused by abnormal activation or high expression of ACK1, and specifically comprise prostate cancer, gastric cancer, lung cancer, ovarian cancer, leukemia, renal cancer, breast cancer, pancreatic cancer and head and neck cancer.

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

Compared with the prior art, the invention has the following advantages:

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.

Drawings

FIG. 1 is a graph showing the inhibition of MDA-MB-453 cell clones by compound I-47 at various concentrations in the present invention.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto, and various substitutions and modifications can be made by those skilled in the art without departing from the technical spirit of the present invention, and are intended to be included in the scope of the present invention.

The invention will now be further described in detail with reference to the following examples, which are provided to illustrate the invention and are not intended to limit the invention, in any way, for the purpose of making the objects, process conditions and advantages of the invention more apparent.

Example 1:

the present example discloses compounds: 2- [ (4-diethylamino) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-1)

The specific synthetic route is as follows:

the preparation method comprises the following steps:

(1) The starting material 2-chloro-4-amino-5-methoxypyrimidine (15.95 g,100 mmol) was weighed into a 500mL round bottom flask, 200mL of dichloromethane was then added, and then cooled to 0deg.C in an ice bath, followed by slow dropwise addition of boron tribromide (50.10 g,200 mmol). After the completion of the dropwise addition, the reaction solution was warmed to room temperature, and the reaction was continued overnight. After completion of the TLC detection reaction, the reaction solution was cooled to 0℃and the reaction system was quenched by slowly adding an appropriate amount of methanol. And then spin-drying to obtain white powder, namely the intermediate I, which can be directly used for the next reaction without purification.

(2) In a 250mL round bottom flask was added intermediate I (7.25 g,50 mmol) and potassium carbonate (13.80 g,100 mmol), followed by 100mLN, N-dimethylformamide as solvent and stirred at room temperature. Ethyl 2-bromo-2-methylpropionate (14.63 g,75 mmol) was then slowly added dropwise. After the completion of the dropwise addition, the reaction mixture was warmed to 80℃and the reaction was continued overnight. After the TLC detection reaction was completed, the reaction solution was cooled to room temperature, followed by suction filtration and spin-drying, and column chromatography separation and purification to give a white powder, 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 )δ169.53,152.21,149.48,144.98,136.28,80.11,24.09.MS-ESI(m/z):214.2[M+H] ⁺ .

(3) In a 250mL round bottom flask was added intermediate II (6.39 g,30 mmol) and potassium carbonate (8.28 g,60 mmol), then 35mLN, N-dimethylformamide was added as solvent and stirred at room temperature. Then, bromopentane (6.70 g,45 mmol) was slowly added dropwise. After the completion of the dropwise addition, the reaction mixture was warmed to 80℃and the reaction was continued overnight. After the TLC detection reaction was completed, the reaction solution was cooled to room temperature, followed by suction filtration and spin-drying, and column chromatography separation and purification to give a white powder, 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 )δ168.91,151.84,150.21,145.09,136.60,79.32,53.51,28.56,25.79,24.09.MS-ESI(m/z):282.4[M+H] ⁺ .

(4) In a 50mL round bottom flask, intermediate III (0.140 g,0.5 mmol), N-diethyl-p-phenylenediamine (0.082 g,0.5 mmol), palladium acetate (0.0111 g,0.05 mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (BINAP) (0.062 g,0.1 mmol) and cesium carbonate (0.325 g,1.0 mmol) were added followed by 10mL of anhydrous 1, 4-dioxane as the reaction solvent followed by a reaction at 100℃for 16 hours under nitrogen. After the reaction, the diatomite is filtered by suction and dried by spin, and the light yellow powder is obtained after column chromatography separation and purification, namely the target compound I-1 (0.1599 g, 78%).

The object compound I-1 ¹ The H NMR data 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.

example 2:

the present example discloses compounds: 2- [4- (4-pyrrolidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-2)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "4- (1-pyrrolidinyl) aniline" to prepare the target compound I-2.

MS (ESI) and MS (ESI) of the object Compound I-2 ¹ The H NMR data 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.

example 3:

the present example discloses compounds: 2- [4- (acetylamino) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-3)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-aminoacetoanilide" to prepare the target compound I-3.

MS (ESI) and MS (ESI) of the object Compound I-3 ¹ The H NMR data 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.

example 4:

the present example discloses compounds: 2- [ (4-morpholinyl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-4)

The synthesis route is as in example 1, substituting "4- (4-morpholinyl) aniline" for "N, N-diethyl-p-phenylenediamine" as starting material in step (4) to produce the desired compound I-4.

MS (ESI) and MS (ESI) of the object Compound I-4 ¹ The H NMR data 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.

example 5:

the present example discloses compounds: 2- [4- (4-piperazin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-5)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "4-piperazinylaniline" to prepare the target compound I-5.

MS (ESI) and MS (ESI) of the objective Compound I-5 ¹ The H NMR data 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 C NMR(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.

example 6:

the present example discloses compounds: 2- [4- (4-piperidin-4-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-6)

The synthesis route is as in example 1, and the starting material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "(4-piperidin-4-yl) -aniline" to give the desired compound I-6.

MS (ESI) and MS (ESI) of the object Compound I-6 ¹ The H NMR data 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.

example 7:

the present example discloses compounds: 2- [4- (4-methylpiperazin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-7)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "(4-methylpiperazin-1-yl) aniline" to prepare the target compound I-7.

MS (ESI) and MS (ESI) of the objective Compound I-7 ¹ The H NMR data 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.

example 8:

the present example discloses compounds: 2- [4- (1-methylpiperidin-4-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-8)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "4- (1-methylpiperidin-4-yl) aniline" to prepare the target compound I-8.

MS (ESI) and MS (ESI) of the objective Compound I-8 ¹ The H NMR data 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.

example 9:

the present example discloses compounds: 2- [4- (4-ethylpiperazin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-9)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "(4-ethylpiperazin-1-yl) aniline" to prepare the target compound I-9.

MS (ESI) and MS (ESI) of the objective Compound I-9 ¹ The H NMR data 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 )δ170.33,155.39,149.58,147.36,144.61,132.42,130.50,121.32,116.94,78.51,53.41,52.86,52.35,49.91,28.39,25.48,23.83,11.98.

example 10:

the present example discloses compounds: 2- [4- (4-isopropylpiperazin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-10)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "4- (4-isopropylpiperazin-1-yl) aniline" to prepare the target compound I-10.

MS (ESI) and MS (ESI) of the object Compound I-10 ¹ The H NMR data 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 )δ170.33,155.40,149.57,147.43,144.60,132.39,130.47,121.33,116.95,78.50,54.51,53.41,50.24,48.75,28.38,25.47,23.83,18.60.

example 11:

the present example discloses compounds: 2- [4- (4-Acetylpiperazin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-11)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "1-acetyl-4- (4-aminophenyl) piperazine" to prepare the target compound I-11.

MS (ESI) and MS (ESI) of the objective Compound I-11 ¹ The H NMR data 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 )δ170.06,168.90,155.45,144.97,133.81,129.93,120.59,117.06,79.55,78.52,52.99,50.16,49.75,46.05,41.24,28.44,25.48,23.86,21.63.

example 12:

the present example discloses compounds: 2- [4- (4-hydroxy-piperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-12)

The synthesis route is as in example 1, and the raw material "N, N-diethyl-p-phenylenediamine" in step (4) is replaced by "4- (4-hydroxypiperidin-1-yl) aniline" to prepare the target compound I-12.

MS (ESI) and MS (ESI) of the object Compound I-12 ¹ The H NMR data 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.

example 13:

the present example discloses compounds: 2- [4- (4- (2-hydroxyethyl) piperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-13)

The synthesis route is as in example 1, substituting "4- (4- (2-hydroxyethyl) piperidin-1-yl) aniline" for the starting material "N, N-diethyl-p-phenylenediamine" in step (4) to give the desired compound I-13.

MS (ESI) and MS (ESI) of the object Compound I-13 ¹ The H NMR data 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.

example 14:

the present example discloses compounds: 2- [4- (4- (dimethylamino) piperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-14)

The synthesis route is as in example 1, substituting "4- (4- (dimethylamino) piperidin-1-yl) aniline" for the starting material "N, N-diethyl-p-phenylenediamine" in step (4) to give the desired compound I-14.

MS (ESI) and MS (ESI) of the object Compound I-14 ¹ The H NMR data 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.

example 15:

the present example discloses compounds: 2- [ 2-methyl-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-15)

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The synthesis route is as in example 1, substituting "N, N-diethyl-p-phenylenediamine" as starting material in step (4) with "2-methyl-4- (4-methylpiperidin-1-yl) aniline" to give the desired compound I-15.

MS (ESI) and MS (ESI) of the objective Compound I-15 ¹ The H NMR data 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.

example 16:

the present example discloses compounds: 2- [ 3-methyl-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-16)

The synthesis route is as in example 1, substituting the starting material "N, N-diethyl-p-phenylenediamine" in step (4) with "3-methyl-4- (4-methylpiperidin-1-yl) aniline" to give the desired compound I-16.

MS (ESI) and MS (ESI) of the object Compound I-16 ¹ The H NMR data 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.

example 17:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-17)

The synthesis route is as in example 1, substituting "N, N-diethyl-p-phenylenediamine" as starting material in step (4) with "2-methoxy-4- (4-methylpiperidin-1-yl) aniline" to give the desired compound I-17.

MS (ESI) and MS (ESI) of the target Compound I-17 ¹ The H NMR data 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.

example 18:

the present example discloses compounds: 2- [ 3-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-18)

The synthesis route is as in example 1, substituting the starting material "N, N-diethyl-p-phenylenediamine" in step (4) with "3-methoxy-4- (4-methylpiperidin-1-yl) aniline" to give the desired compound I-18.

MS (ESI) and MS (ESI) of the object Compound I-18 ¹ The H NMR data 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 )δ169.95,155.31,152.37,149.26,145.11,136.35,136.01,129.99,118.34,111.51,104.46,79.48,78.51,55.62,55.30,52.98,50.61,46.16,28.57,25.61,23.81.

example 19:

the present example discloses compounds: 2- [ 3-fluoro-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-19)

The synthesis route is as in example 1, substituting the starting material "N, N-diethyl-p-phenylenediamine" in step (4) with "3-fluoro-4- (4-methylpiperidin-1-yl) aniline" to give the desired compound I-19.

MS (ESI) and MS (ESI) of the object Compound I-19 ¹ The H NMR data 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)； ¹³ C NMR(101MHz,CDCl ₃ )δ170.21,155.69(d,J _C-F ＝244.9Hz),154.62,149.64,144.51,135.21(d,J _C-F ＝11.0Hz),134.90(d,J _C-F ＝9.5Hz),130.91,119.14(d,J _C-F ＝4.2Hz),114.84,107.99(d,J _C-F ＝25.8Hz),78.61,55.21,53.65,50.85,50.82,46.11,28.42,25.43,23.83.

example 20:

the present example discloses compounds: 2- [ 3-chloro-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-20)

The synthesis route is as in example 1, substituting "N, N-diethyl-p-phenylenediamine" as the starting material in step (4) with "3-chloro-4- (4-methylpiperidin-1-yl) aniline" to give the desired compound I-20.

MS (ESI) and MS (ESI) of the objective Compound I-20 ¹ The H NMR data 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 )δ170.16,154.52,149.65,144.59,144.04,135.77,131.01,129.11,121.43,120.51,118.32,78.67,55.33,53.73,51.46,46.11,28.49,25.55,23.85.

example 21:

the present example discloses compounds: 2- [ 3-cyano-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-21)

The synthesis route is as in example 1, substituting the starting material "N, N-diethyl-p-phenylenediamine" in step (4) with "3-cyano-4- (4-methylpiperidin-1-yl) aniline" to give the desired compound I-21.

MS (ESI) and MS (ESI) of the object Compound I-21 ¹ The H NMR data 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.

example 22:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-isopropyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-22)

The synthetic route is as in example 1, substituting "bromocyclopentane" as the starting material in step (3) with "bromoisopropane" to give intermediate III:

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MS (ESI) and intermediate III ¹ The H NMR data 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.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-22.

MS (ESI) and MS (ESI) of the object Compound I-22 ¹ The H NMR data 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.

example 23:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclobutyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-23)

The synthetic route is as in example 1, substituting "bromocyclopentane" as the starting material in step (3) with "bromocyclobutane" to give intermediate III:

MS (ESI) and intermediate III ¹ The H NMR data 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 C NMR(101MHz,CDCl ₃ )δ169.66,151.87,150.37,145.15,136.48,79.49,48.26,28.00,24.14,15.25.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-23.

MS (ESI) and MS (ESI) of the objective Compound I-23 ¹ The H NMR data 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＝8.7,2.6Hz,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 )δ171.24,155.10,149.49,149.14,147.06,144.73,130.41,122.69,119.50,108.20,100.68,78.67,55.66,55.14,50.17,47.91,46.04,28.15,23.91,15.40.

example 24:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8- (tetrahydrofuran-3-yl) -6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-24)

The synthetic route is as in example 1, substituting the starting material "bromopentane" in step (3) with "3-bromotetrahydrofuran" to give intermediate III:

MS (ESI) and intermediate III ¹ The H NMR data 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.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-24.

MS (ESI) and MS (ESI) of the object Compound I-24 ¹ The H NMR data 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 )δ170.23,155.94,151.80,149.01,148.68,145.24,129.89,123.34,121.04,107.26,100.51,78.65,68.04,67.68,55.95,55.08,51.32,49.18,46.18,28.70,23.92,23.88.

example 25:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclohexyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-25)

The synthetic route is as in example 1, substituting "bromocyclopentane" as the starting material in step (3) with "bromocyclohexane", the intermediate III prepared:

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

MS(ESI)：296.4[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ8.07(s,1H),4.82(tt,J＝12.4,3.8Hz,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.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-25.

MS (ESI) and MS (ESI) of the objective Compound I-25 ¹ The H NMR data 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＝8.8,2.6Hz,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 C NMR(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.

example 26:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopropylmethyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-26)

The synthetic route is as in example 1, substituting "bromocyclopentane" as the starting material in step (3) with "bromomethylcyclopropane", the intermediate III prepared:

MS (ESI) and intermediate III ¹ The H NMR data 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.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-26.

MS (ESI) and MS (ESI) of the object Compound I-26 ¹ The H NMR data 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.

example 27:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclopentylmethyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-27)

The synthetic route is as in example 1, substituting "bromocyclopentane" as the starting material in step (3) with "bromomethylcyclopentane" to give intermediate III:

MS (ESI) and intermediate III ¹ The H NMR data 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.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-27.

MS (ESI) and MS (ESI) of the target Compound I-27 ¹ The H NMR data 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＝8.8,2.5Hz,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 )δ169.29,156.41,156.12,151.48,148.37,143.92,132.17,129.85,124.35,107.52,100.53,78.92,55.90,55.17,49.28,48.68,46.23,44.26,38.03,29.86,24.79,24.19.

example 28:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-cyclohexylmethyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-28)

The synthetic route is as in example 1, substituting "bromocyclopentane" as the starting material in step (3) with "bromomethylcyclohexane" to give intermediate III:

MS (ESI) and intermediate III ¹ The H NMR data 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.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-28.

MS (ESI) and MS (ESI) of the object Compound I-28 ¹ The H NMR data 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.

example 29:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-phenyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-29)

The specific synthetic route is as follows:

the preparation method comprises the following steps:

(1) A250 mL round bottom flask was charged with starting 2, 4-dichloro-5-methoxypyrimidine (8.95 g,50 mmol) and solvent (100 mL) 1, 4-dioxane. Subsequently, N-diisopropylethylamine (12.9 g,100 mmol) and were addedAniline (4.65 g,50 mmol). And stirred to 100℃and allowed to react overnight. After the completion of the TLC detection reaction, the reaction solution was cooled to room temperature, followed by spin-drying, and column chromatography separation and purification to give a white powder, 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 )δ152.28,151.07,139.31,137.7,134.06,129.08,123.99,120.08,56.34.MS-ESI(m/z):236.4[M+H] ⁺ .

(2) Intermediate I (7.07 g,30 mmol) was weighed into a 250mL round bottom flask, 100mL of methylene chloride was added, then cooled to 0deg.C in an ice bath, followed by slow dropwise addition of boron tribromide (9 mL). After the completion of the dropwise addition, the reaction solution was warmed to room temperature, and the reaction was continued overnight. After completion of the TLC detection reaction, the reaction solution was cooled to 0℃and the reaction system was quenched by slowly adding an appropriate amount of methanol. And then spin-drying to obtain white powder, namely an intermediate II, which can be directly used for the next reaction without purification.

(3) In a 250mL round bottom flask was added intermediate II (30 mmol) and potassium carbonate (8.28 g,60 mmol), then 50mLN, N-dimethylformamide was added as solvent and stirred at room temperature. Ethyl 2-bromo-2-methylpropionate (8.78 g,75 mmol) was then slowly added dropwise. After the completion of the dropwise addition, the reaction mixture was warmed to 80℃and the reaction was continued overnight. After the TLC detection reaction was completed, the reaction solution was cooled to room temperature, followed by suction filtration and spin-drying, and column chromatography separation and purification to give a white powder, 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 )δ168.81,152.51,150.70,145.66,136.13,133.42,129.55,129.17,128.52,79.93,24.21.MS-ESI(m/z):290.4[M+H] ⁺ .

(4) In a 50mL 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 (0.01 g,0.05 mmol), 1 '-binaphthyl-2, 2' -Bisdiphenylphosphine (BINAP) (0.062 g,0.1 mmol) and cesium carbonate (0.325 g,1.0 mmol) were added followed by 10mL of anhydrous 1, 4-dioxane as the reaction solvent followed by a reaction at 100℃for 16 hours under nitrogen protection. After the reaction, the diatomite is filtered by suction and dried by spin, and the light yellow powder is obtained after column chromatography separation and purification, namely the target compound I-29 (0.1599 g, 78%).

MS (ESI) and MS (ESI) of the object Compound I-29 ¹ The H NMR data 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.

example 30:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-o-tolyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-30)

The synthetic route is as in example 29, substituting "o-methylaniline" for the starting material "aniline" in step (1), intermediate I prepared:

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

MS(ESI)：250.4[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ8.05(d,J＝8.1Hz,1H),7.69(s,1H),7.26(t,J＝7.6Hz,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.

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

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

MS (ESI) and intermediate III ¹ The H NMR data 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.

MS (ESI) and MS (ESI) of the objective Compound I-30 ¹ The H NMR data 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＝4.9Hz,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.

example 31:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8- (2-ethoxyphenyl) -6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-31)

The synthetic route is as in example 29, substituting "2-ethoxyaniline" for "aniline" as starting material in step (1) to give 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.

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

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

MS (ESI) and intermediate III ¹ The H NMR data 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.

MS (ESI) and MS (ESI) of the object Compound I-31 ¹ The H NMR data 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.

example 32:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8- (2-isopropoxyphenyl) -6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-32)

The synthetic route is as in example 29, substituting "2-isopropoxy aniline" for the starting material "aniline" in step (1), intermediate I is prepared:

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.

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

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

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

MS(ESI)：348.4[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ8.14(s,1H),7.39(t,J＝7.9Hz,1H),7.16(d,J＝7.0Hz,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.

MS (ESI) and MS (ESI) of the object Compound I-32 ¹ The H NMR data 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.

example 33:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8- (2, 2-trifluoroethoxy) phenyl) -6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-33)

The synthetic route is as in example 29, substituting "2- (2, 2-trifluoroethoxy) aniline" as starting material "aniline" in step (1) to give intermediate I:

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 the steps (2), (3) and (4), the target compound I-33 is prepared.

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

MS (ESI) and intermediate III ¹ The H NMR data 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 _C-F ＝36.1Hz),24.21,23.87.

MS (ESI) and MS (ESI) of the objective Compound I-33 ¹ The H NMR data 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 C NMR(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 _C-F ＝277.7Hz),122.94,121.45,120.28(q,J _C-F ＝4.8Hz),114.27,106.95,100.31,79.10,65.45(q,J _C-F ＝36.3Hz),55.99,55.09,49.25,46.18,24.12,23.54.

example 34:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-34)

The synthetic route is as in example 1, substituting "benzylamine" for the starting material "aniline", "bromopentane" in step (3) to give intermediate III:

MS (ESI) and 1H NMR data for this 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 )δ168.69,152.21,149.65,145.00,136.31,135.92,128.95,128.60,128.41,128.22,127.91,79.58,43.57,24.24.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-34.

MS (ESI) and MS (ESI) of the object Compound I-34 ¹ The H NMR data 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.

example 35:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6, 6-dimethyl-8- (1-phenethyl) -6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-35)

The synthetic route is as in example 1, substituting starting material "bromocyclopentane" in step (3) with "(1-bromoethyl) benzene", intermediate III prepared:

MS (ESI) and intermediate III ¹ The H NMR data 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.

and (3) replacing the raw material N, N-diethyl p-phenylenediamine in the step (4) with 2-methoxy-4- (4-methylpiperidin-1-yl) aniline to prepare the target compound I-35.

MS (ESI) and MS (ESI) of the object Compound I-35 ¹ The H NMR data 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.

example 36:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6-methyl-8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-36)

The synthetic route is as in example 29, substituting "benzylamine" for the starting material "aniline" in step (1) to give intermediate I:

MS (ESI) and intermediate I ¹ The H NMR data 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 preparing an intermediate II according to the step (2), and replacing the raw material of the ethyl 2-bromo-2-methylpropionate in the step (3) with the ethyl 2-bromo-propionate to prepare an intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 )δ166.48,152.34,149.68,144.68,137.14,135.77,129.14,128.60,127.98,74.18,43.43,16.95.MS-ESI(m/z):290.4[M+H] ⁺ .

finally, according to the step (4), the objective compound I-36 is obtained.

MS (ESI) and MS (ESI) of the object Compound I-36 ¹ The H NMR data 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.

example 37:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6-ethyl-8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-37)

The synthesis route was as in example 36, substituting the starting material "ethyl 2-bromo-2-methylpropionate" in step (3) with "ethyl 2-bromo-butyrate" to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 the step (4), the target compound I-37 is prepared.

MS (ESI) and MS (ESI) of the target Compound I-37 ¹ The H NMR data 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.

example 38:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6-isopropyl-8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-38)

The synthesis route was as in example 36, substituting the starting material "ethyl 2-bromo-2-methylpropionate" in step (3) with "methyl 2-bromo-3-methylbutyrate" to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 the step (4), the objective compound I-38 is obtained.

MS (ESI) and MS (ESI) of the object Compound I-38 ¹ The H NMR data 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.

example 39:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6-propyl-8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-39)

The synthesis route was as in example 36, substituting the starting material "ethyl 2-bromo-2-methylpropionate" in step (3) with "methyl 2-bromo-valerate" to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 the step (4), the objective compound I-39 is obtained.

MS (ESI) and MS (ESI) of the object Compound I-39 ¹ The H NMR data 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.

example 40:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6-cyclopropyl-8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-40)

The synthesis route was as in example 36, substituting the starting material "ethyl 2-bromo-2-methylpropionate" in step (3) with "methyl 2-bromo-2-cyclopropylpropionate" to produce intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 the step (4), the target compound I-40 is prepared.

MS (ESI) and MS (ESI) of the object Compound I-40 ¹ The H NMR data 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.

example 41:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6-phenyl-8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-41)

The procedure is as in example 36, substituting ethyl 2-bromo-2-methylpropionate for methyl 2-bromo-2-phenylacetate, the starting material in step (3), to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 )δ164.47,152.50,149.37,145.17,136.91,135.61,133.64,129.65,129.52,129.33,129.06,128.94,128.64,128.11,127.69,126.77,126.67,78.70,43.62.MS-ESI(m/z):352.4[M+H] ⁺ .

finally, according to the step (4), the objective compound I-41 is obtained.

MS (ESI) and MS (ESI) of the objective Compound I-41 ¹ The H NMR data 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 )δ166.70,156.34,152.22,148.96,147.67,145.74,137.97,136.66,135.62,131.43,130.01,129.16,129.11,128.63,128.19,128.03,127.66,127.23,125.91,124.10,120.63,107.07,100.39,85.21,55.87,55.08,49.12,46.19,42.90.

example 42:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6- (2-fluorophenyl) -8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-42)

The procedure is as in example 36, substituting ethyl 2-bromo-2-methylpropionate for methyl 2-bromo-2- (2-fluorophenyl) acetate to give intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 _C-F ＝250.5Hz),152.48,149.29,144.83,137.12,135.58,132.06(d,J _C-F ＝8.5Hz),129.49,129.47,128.65,128.14,124.60(d,J _C-F ＝3.7Hz),121.87(d,J _C-F ＝13.8Hz),116.26(d,J _C-F ＝21.0Hz),74.70(d,J _C-F ＝2.5Hz),43.77.MS-ESI(m/z):370.4[M+H] ⁺ .

finally, according to the step (4), the target compound I-42 is prepared.

MS (ESI) and MS (ESI) of the object Compound I-42 ¹ The H NMR data 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 _C-F ＝248.3Hz),156.35,151.99,148.80,148.41,144.44,137.05,132.25(d,J _C-F ＝7.6Hz),131.33(d,J _C-F ＝8.4Hz),128.82,128.06,127.68,125.07,123.68,123.25(d,J _C-F ＝14.0Hz),120.91,116.33(d,J _C-F ＝20.3Hz),107.13,100.46,75.22,55.94,55.11,49.17,46.21,43.01.

example 43:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6- (2-chlorophenyl) -8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-43)

The procedure is as in example 36, substituting ethyl 2-bromo-2-methylpropionate, starting material in step (3), with methyl 2-bromo-2- (2-chlorophenyl) acetate to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 the step (4), the objective compound I-43 is obtained.

MS (ESI) and MS (ESI) of the object Compound I-43 ¹ The H NMR data 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＝8.7,2.4Hz,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)； ¹³ C 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.

example 44:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6- (2-methoxyphenyl) -8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-44)

The procedure is as in example 36, substituting ethyl 2-bromo-2-methylpropionate, starting material in step (3), with methyl 2-bromo-2- (2-methoxyphenyl) acetate to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 the step (4), the target compound I-44 is prepared.

MS (ESI) and MS (ESI) of the object Compound I-44 ¹ The H NMR data 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 )δ166.41,157.31,155.96,151.80,148.66,148.07,143.80,137.22,133.66,131.47,131.22,128.78,128.18,127.64,126.91,124.54,123.36,121.10,120.75,114.66,111.88,107.19,100.52,75.88,56.42,56.00,55.13,49.22,46.22.

example 45:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6- (2-trifluoromethylphenyl) -8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-45)

The synthetic route was as in example 36, substituting the starting material "ethyl 2-bromo-2-methylpropionate" in step (3) with "methyl 2-bromo-2- (2-trifluoromethylphenyl) acetate" to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 _C-F ＝9.6Hz),130.13,129.56(q,J _C-F ＝8.3Hz),129.53,129.45(q,J _C-F ＝31.1Hz),129.39,128.69,128.21,126.94(q,J _C-F ＝5.5Hz),123.89(q,J _C-F ＝274.0Hz),75.92(q,J _C-F ＝2.1Hz),43.88.MS-ESI(m/z):420.6[M+H] ⁺ .

finally, according to the step (4), the target compound I-45 is prepared.

MS (ESI) and MS (ESI) of the object Compound I-45 ¹ The H NMR data 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 _C-F ＝30.3Hz),127.78,127.21(q,J _C-F ＝272.3Hz),127.17(q,J _C-F ＝3.1Hz),123.91,121.03,107.29,100.60,76.70,56.12,55.23,49.29,46.19,43.27.

example 46:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6- (2, 6-difluorophenyl) -8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-46)

The procedure is as in example 36, substituting ethyl 2-bromo-2-methylpropionate, starting material in step (3), with methyl 2-bromo-2- (2, 6-difluorophenyl) acetate to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 _C-F ＝252.5,6.7Hz),152.41,149.03,144.45,137.27,135.47,132.42(t,J _C-F ＝10.6Hz),129.28,128.61,128.05,111.99(dd,J _C-F ＝21.7,3.4Hz),111.82(dd,J _C-F ＝33.9,21.3Hz),69.97(t,J _C-F ＝3.0Hz),43.73.MS-ESI(m/z):388.4[M+H] ⁺ .

finally, according to the step (4), the objective compound I-46 is obtained.

MS (ESI) and MS (ESI) of the object Compound I-46 ¹ The H NMR data 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 _C-F ＝250.1Hz),160.10,156.32,152.02,148.83,148.21,144.23,136.94,133.21(d,J _C-F ＝11.6Hz),131.34,130.12,128.81,127.90,127.68,123.73,120.86,112.61(d,J _C-F ＝18.0Hz),112.60(d,J _C-F ＝23.9Hz)),107.16,100.45,69.94,55.94,55.08,49.15,46.18,42.92.

example 47:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6- (2-fluoro-6-chlorophenyl) -8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-47)

The synthesis route was as in example 36, substituting the starting material "ethyl 2-bromo-2-methylpropionate" in step (3) with "methyl 2-bromo-2- (2-fluoro-6-chlorophenyl) acetate" to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 _C-F ＝253.0Hz),152.26,148.80,144.32,137.39,135.77(d,J _C-F ＝4.5Hz),135.43,132.07(d,J _C-F ＝10.0Hz),129.45,128.56,128.04,126.10(d,J _C-F ＝3.3Hz),121.54(d,J _C-F ＝15.8Hz),114.84(d,J _C-F ＝22.3Hz),72.63,43.67.MS-ESI(m/z):404.4[M+H] ⁺ .

finally, according to the step (4), the objective compound I-47 is obtained.

MS (ESI) and MS (ESI) of the objective Compound I-47 ¹ The H NMR data 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 _C-F ＝251.0Hz),160.54,156.21,151.99,148.78,147.99,144.04,136.97,135.22(d,J _C-F ＝4.8Hz),133.02(d,J _C-F ＝9.3Hz),131.43,128.74,128.13,127.63,126.61(d,J _C-F ＝2.1Hz)),123.66,122.52(d,J _C-F ＝16.2Hz),121.00,115.59(d,J _C-F ＝21.9Hz),107.19,100.52,55.97,55.10,49.18,46.17,42.90.

example 48:

the present example discloses compounds: 2- [ 2-methoxy-4- (4-methylpiperidin-1-yl) anilino ] -6- (2, 6-dichlorophenyl) -8-benzyl-6H-pyrimidine [5,4-b ] oxazin-7 (8H) -one (I-48)

The synthesis route was as in example 36, substituting the starting material "ethyl 2-bromo-2-methylpropionate" in step (3) with "methyl 2-bromo-2- (2-, 6-dichlorophenyl) acetate" to afford intermediate III;

MS (ESI) and intermediate III ¹ The H NMR data 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 the step (4), the objective compound I-48 is obtained.

MS (ESI) and MS (ESI) of the object Compound I-48 ¹ The H NMR data 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 )δ166.00,156.13,152.07,148.82,147.72,143.87,136.91,132.56,132.08,131.46,128.67,128.44,127.64,123.78,120.99,107.18,100.51,75.38,55.96,55.11,49.19,46.20,42.93.

example 49:

this example was based on 48 compounds provided in the above example, and was subjected to an ACK1 in vitro kinase activity assay as follows:

in vitro Kinase inhibition assays were performed using the Kinase Profiler service provided by Eurofins Inc. The experimental procedure is briefly described as follows: adding a small molecular compound (0.001-10 mu M) or blank solvent to be detected and ACK1 protein kinase to be detected and a corresponding polypeptide substrate into a reaction buffer solution for incubation, wherein the reaction buffer solution comprises 8mM propane sulfonic acid (MOPS, PH=7.0), 0.2mM ethylenediamine tetraacetic acid (EDTA), 10mM magnesium acetate and gamma-17 of Km concentration ³³ P-ATP solution composition. After the whole reaction was carried out at room temperature for 40min, a 3% phosphate solution was added to the reaction buffer to terminate the reaction. Subsequently, 10. Mu.L of the reaction mixture was quantitatively pipetted onto a P30 filter paper and washed 3 times with 75mM phosphate and once with methanol, and the P30 filter paper was air-dried and then added to scintillation liquid for scintillation counting. Semi-inhibitory concentration IC for inhibitory activity of Compounds ₅₀ To express, IC ₅₀ Values were obtained by fitting the inhibition ratios corresponding to the respective concentration gradients, and the results are shown in table 1. ACK1 positive drug (IC) using AIM-100 ₅₀ 0.024 μm).

TABLE I all Compounds IC ₅₀ Value of

Numbering of compounds	ACK1(μM)	Numbering of compounds	ACK1(μM)	Numbering of compounds	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

As is clear from Table 1, each of the compounds had a certain biological activity inhibitory effect, and among them, compound I-47 exhibited the best biological activity inhibitory effect on ACK1, and the IC50 thereof was 0.001. Mu.M, respectively.

Example 50:

this example focused on anti-triple negative breast cancer proliferation activity tests 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, I-48.

The specific test process is as follows:

compounds were tested for anti-TNBC activity in vitro using the MTT method. The test method is briefly described below, and TNBC cells MDA-MB-453, MDA-MB-231 or T47D with high expression of ACK1 are inoculated into 96-well plates and incubated in a serum-containing medium for 24 hours, followed by addition of compounds at different concentrations for co-incubation for 75 hours. MTT was added after the end of co-incubation and absorbance was read at 570nm using a multispan MK3 ELISA photometer (Thermo Scientific). The anti-TNBC effect of the drug can be judged by comparing the differences between the drug-treated group and the control group. The test results are shown in Table II:

triple negative breast cancer resistance activity of selected compounds of Table II

/>

As can be seen from Table II, the selected compounds have good antiproliferative activity on triple negative breast cancer cells MDA-MB-231, MDA-MB-453 and T47D with high ACK1 expression.

Example 51:

in this example, the compound I-47 exhibiting the best biological activity inhibition effect on ACK1 was subjected to a triple negative breast cancer cell MDA-MB-453 clone formation test, which is specifically described as follows:

4.1 subjects

MDA-MB-453 cells were selected for cloning format experiments.

4.2 Experimental protocol

MDA-MB-453 cells were plated in 12-well plates at a density of 800 cells per well, and 1mL of growth medium was added. Subsequently, incubation was carried out for 24 hours, and different concentrations of the I-49 compound were added. After 24 hours, the medium was changed to a medium containing no drug and cultured for 14 days. Colonies were fixed with 4% paraformaldehyde and stained with crystal violet.

4.3 conclusion of experiments

As shown in FIG. 1, the compound I-47 can effectively inhibit MDA-MB-453 cell clone formation and show a dose-dependent relationship, and when the concentration of the compound I-47 is 1 mu M, the compound I-47 can show an obvious inhibition effect; when the concentration is 10. Mu.M, the total inhibition can be achieved.

While embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that: many changes, modifications, substitutions and variations may be made to the embodiments without departing from the spirit and principles of the invention, the scope of which is defined by the claims and their equivalents.

Claims

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.