6-arylquinazolin-4-amine and 6-arylpyridopyrimidin-4-amine derivatives, and use thereof as PI3kδ covalent inhibitors

Abstract

Disclosed in the present invention are 6-arylquinazolin-4-amine and 6-arylpyridopyrimidin-4-amine derivatives, and the use thereof as PI3Kδ covalent inhibitors. Said derivatives disclosed by the present invention are compounds capable of being used as PI3Kδ inhibitors. PI3Kδ kinase activity and PI3K selectivity tests verify that the compounds disclosed in the present invention exhibit an obvious inhibition effect on PI3Kδ kinase activity and have obvious selectivity on the activity of PI3Kδ. In-vitro cell anti-proliferative activity tests by means of using various blood tumor cell lines exhibit that the compounds disclosed in the present invention have different inhibition effects on various blood tumor cells.

Description

6-Arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives and their applications as covalent inhibitors of PI3Kδ Technical Field

[0001] This invention belongs to the field of amine derivative synthesis technology, specifically involving 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives and their application as covalent inhibitors of PI3Kδ. Background Technology

[0002] Phosphatidylinositol-3-kinase (PI3Kδ) is a PI3K isoform primarily expressed in leukocytes. It participates in B-cell receptor (BCR) signaling, regulating B-cell activation, differentiation, and autoreactivity, and controlling B-cell development and maturation. Activated PI3Kδ promotes PIP3 production. PIP3 recognizes and interacts with the N-terminal domain of BTK, mediating BTK recruitment to the membrane to activate BTK, guiding B-cell signaling, and further inducing the expression of many related genes. Additionally, PI3Kδ on the cell membrane can be recruited by phosphorylated CD19, thereby activating PI3Kδ, catalyzing the production of PIP3 from PIP2, promoting AKT activation, and regulating cell proliferation, migration, apoptosis, and other processes. Aberrant expression of PI3Kδ is closely related to the development and progression of various hematological malignancies, lymphomas, and autoimmune diseases. Developing selective PI3Kδ inhibitors is an important drug development strategy for treating hematologic malignancies (such as CLL, ALL, MCL, FL, NHL, MM, BCL, and DLBCL) and autoimmune diseases (such as rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE)). Furthermore, some other diseases, such as allergic diseases and airway diseases like asthma, also show promise for improvement with PI3Kδ inhibitors. Therefore, the development of PI3Kδ inhibitors holds great promise.

[0003] Currently, six PI3Kδ / pan-PI3Kδ inhibitors (Idelalisib, Duvelisib, Copanlisib, Umbralisib, Linperlisib, and Leniolisib) have been approved for marketing. Among them, Idelalisib and Duvelisib were given "black box warnings" due to toxicity at the time of their launch, and other drugs have also had some indications withdrawn due to toxicity. The recently approved Leniolisib is used to treat PI3Kδ hyperactivation syndrome.

[0004] The structures of Idelalisib, Duvelisib, Umbralisib, Linperlisib, and Leniolisib are as follows.

[0005] The clinical potential of PI3Kδ inhibitors has not been fully explored, and there is an urgent need to study targeted PI3Kδ therapeutics with novel structures and mechanisms.

[0006] Summary of the Invention

[0007] The purpose of this invention is to provide a class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives and their applications as covalent inhibitors of PI3Kδ.

[0008] To achieve the above objectives, the present invention employs the following technical solution:

[0009] A class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives, including compounds represented by Formula I below;

[0010] The structural formula of the compound of formula (I) is:

[0011] Where X is CH or N;

[0012] Y is either CH or N;

[0013] W is either CH or N;

[0014] V is either O or NCH3;

[0015] Z represents tetrahydropyrrole or CHCH3;

[0016] R1 is an aryloxy group, a heteroaryloxy group, or hydrogen, and the aryloxy group can be substituted by 0-3 R3 groups;

[0017] Alternatively, R1 may be directly attached to an aryl group and R1 may be chloromethyl or 2-enoylamino.

[0018] R2 is a methoxy, hydroxy, or ethynyl group;

[0019] The R3 group is selected from halogen, cyano, nitro, alkyl, haloalkyl, and alkoxy groups;

[0020] It also includes one of the compounds of formula (I) and their solvates, enantiomers, diastereomers and tautomers in any proportion;

[0021] Alternatively, it may include one of a pharmaceutically acceptable salt of the compound shown in formula (I) and its solvates, enantiomers, diastereomers and tautomers in any proportion.

[0022] The compound of formula (I) can be further defined as compounds of (I-1) and (I-2):

[0023] Where X is CH or N;

[0024] Y is either CH or N;

[0025] R1 is an aryloxy group, a heteroaryloxy group, or hydrogen, and the aryloxy group can be substituted by 0-3 R3 groups;

[0026] Alternatively, R1 may be directly attached to an aryl group and R1 may be chloromethyl or 2-enoylamino.

[0027] R2 is a methoxy, hydroxy, or ethynyl group;

[0028] The R3 group is selected from halogen, cyano, nitro, alkyl, haloalkyl, and alkoxy groups;

[0029] Preferably, R1 is phenoxy, pyridoxy, or hydrogen.

[0030] More preferably, when R1 is phenoxy, it can be replaced by 0-3 R3 groups, where R3 is selected from fluorine, chlorine, cyano, nitro, methyl, trifluoromethyl or methoxy.

[0031] Preferably, when Y is N, R2 is a methoxy group.

[0032] Preferably, when Y is CH, R2 is a hydroxyl or acetylene group.

[0033] Preferably, when R1 is directly connected to an aryl group, R1 is chloromethyl, acryloylamino, or but-2-enoylamino.

[0034] Preferably, the structural formulas of the 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives are selected from one of the following compounds:

[0035] The present invention also discloses the application of the above-mentioned 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives in the preparation of PI3Kδ inhibitors.

[0036] The present invention also discloses the use of the above-mentioned 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives in the preparation of treatments and / or preventions of diseases caused by PI3Kδ overexpression.

[0037] Preferably, the disease is rheumatoid arthritis, hematologic malignancy, lymphoma, PI3Kδ hyperactivation syndrome, Sjögren's syndrome, or asthma.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] This invention discloses a class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives, which are PI3Kδ inhibitors. Measurements of PI3Kδ kinase activity and PI3K selectivity confirm that the disclosed compounds exhibit significant inhibitory effects on PI3Kδ kinase activity and significant selectivity. In vitro antiproliferative activity assays on various hematologic malignancy cell lines show that the disclosed compounds have different inhibitory effects on various hematologic malignancy cell lines. The 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives of this invention covalently bind to PI3Kδ and exhibit long-lasting inhibitory effects. Protein mass spectrometry results confirm that the PI3Kδ binding site of the disclosed compounds is Lys779. In vivo antitumor activity of the preferred compounds was determined by constructing SU-DHL-6 cell xenografts in nude mice, demonstrating that the disclosed compounds possess potent in vivo antitumor activity. The compounds disclosed in this invention, or their pharmaceutically acceptable salts, hydrates, solvates, chemically protected forms of prodrugs, or combinations thereof, can be used as PI3Kδ inhibitors for the treatment and / or prevention of diseases including rheumatoid arthritis, hematologic malignancies, lymphoma, PI3Kδ hyperactivation syndrome, Sjögren's syndrome, and asthma. Attached Figure Description

[0040] Figure 1 shows the inhibition of AKT and p-AKT473 in SU-DHL-6 cells by 1, 13 and idelalisib;

[0041] Figure 2 shows: A. Anti-cell proliferation assay in SU-DHL-6 cells (n=3); B. AKT phosphorylation level in SU-DHL-6 cells during elution.

[0042] Figure 3 shows the antitumor effect of compound 1 in the SU-DHL-6 nude mouse xenograft model; where A represents tumor tissue from different treatment groups; and B represents the body weight curve.

[0043] Figure 4 shows the Ki67 immunohistochemical results of tumor tissues from different treatment groups (Vehicle, idelalisib, and compound 4). Detailed Implementation

[0044] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0045] It should be noted that the terms "first," "second," etc., in the specification, claims, and accompanying drawings of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of the invention described herein can be implemented in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover a non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0046] The present invention will now be described in further detail with reference to the accompanying drawings:

[0047] This invention discloses a 6-arylquinazoline-4-amine and a 6-arylpyridopyrimidine-4-amine derivative, which is one of the compounds shown in formulas (I-1) and (I-2) and their solvates, enantiomers, diastereomers, tautomers and any proportion of mixtures of enantiomers, or a pharmaceutically acceptable salt of the compounds shown in formulas (I-1) and (I-2) and its solvates, enantiomers, diastereomers, tautomers or any proportion of mixtures of enantiomers;

[0048] The structural formulas of compounds (I-1) and (I-2) are as follows:

[0049] Where X is CH or N;

[0050] Y is either CH or N;

[0051] R1 is an aryloxy group, a heteroaryloxy group, or hydrogen, and the aryloxy group may be replaced by 0-3 R3 groups;

[0052] Alternatively, R1 may be directly attached to an aryl group and R1 may be chloromethyl or 2-enoylamino.

[0053] R2 can be methoxy, hydroxy, or ethynyl.

[0054] R3 is selected from halogen, cyano, nitro, alkyl, haloalkyl, and alkoxy.

[0055] "Alkoxy" indicates -O- (unsubstituted alkyl) and -O (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, trifluoromethoxy, etc.

[0056] "2-Acryloylamino" refers to a group containing an acryloyl segment that has substituent groups at both ends of the N atom or olefin, or a group without substituent groups, including but not limited to acryloyl, but-2-acryloyl, etc.

[0057] "Aryl" refers to a monocyclic or fused polycyclic group with 6 to 10 carbon atoms, possessing a fully conjugated π-electron system. "Aryl" includes benzene, naphthalene, etc., and can be substituted or unsubstituted. "Heteroaryl" refers to a monocyclic or fused polycyclic group with 5 to 10 carbon atoms, possessing a fully conjugated π-electron system. "Heteroaryl" includes pyridine, etc.

[0058] "Aromatic oxy" refers to phenoxy compounds with and without substituent groups on the benzene ring. Representative examples include, but are not limited to, phenoxy, p-fluorophenoxy, p-chlorophenoxy, 2,4-difluorophenoxy, 2,4-dichlorophenoxy, 2,4,6-trifluorophenoxy, p-methylphenoxy, p-methoxyphenoxy, p-nitrophenoxy, p-cyanophenoxy, p-trifluoromethylphenoxy, and 3-pyridyloxy. "Heteroaryl oxy" refers to heteroaryl oxy compounds with and without substituent groups on the heteroaryl ring. Representative examples include, but are not limited to, pyridyloxy.

[0059] "Methoxy" represents -OCH3, "chloromethyl" represents -CH2Cl, "ethynyl" represents -C≡CH, "hydroxy" represents -OH, "cyano" represents -CN, "nitro" represents -NO2, and "trifluoromethyl" represents -CF3.

[0060] "Pharmaceutically acceptable salts" refer to those salts that retain the bioavailability and properties of the parent compound. These salts include: (1) salts formed by the reaction of the free base of the parent compound with inorganic or organic acids, including inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, and perchloric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, hexanoic acid, p-toluenesulfonic acid, and salicylic acid. (2) salts formed by the substitution of the acidic protons of the parent compound with metal ions or by coordination with organic bases, such as alkali metal ions, alkaline earth metal ions, or aluminum ions, and organic bases such as ethanolamine, diethanolamine, and triethanolamine.

[0061] "Pharmaceutical composition" refers to the mixing of one or more of the compounds of this invention, or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs, with other chemical components, such as a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate the administration of the drug to animals.

[0062] "Pharmaceutical carrier" refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the given compound. Examples include, but are not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymers or methacrylic polymers, gels, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.

[0063] In addition to pharmaceutically acceptable carriers, the aforementioned pharmaceutical compositions may also include pharmaceutically commonly used excipients, such as antibacterial agents, antifungal agents, antimicrobial agents, preservatives, colorants, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavorings, or combinations thereof.

[0064] The present invention also provides a method for preparing compounds having general formulas (I-1) and (I-2).

[0065] To achieve the objectives of this invention, the following technical solution is adopted (this is only for illustrative purposes and not for limiting the invention):

[0066] Synthesis Process I:

[0067] Synthesis Process II:

[0068] The specific compound in formula (I-1) was synthesized using synthetic procedure I. Starting with IA, it was reacted with methyl nicotinic acid 2-methoxy-5-pinacolborate ester under Pd catalyst (e.g., Pd(PPh3)Cl2, Pd(PPh3)4, Pd(dppf)Cl2, PdCl2, etc.) and alkaline conditions (K3PO4, K2CO3, KOH, Cs2CO3, Na2CO3, KF, CsF, Ba(OH)2, KOBU-t, NaOBu-t, KOMe, NET3, DIPEA, and t-BuNH2, etc.) and solvents (Dioxane, THF, DMF, Toluene, H2O, EtOH, DMSO, n-BuOH, etc., or combinations thereof) at 25-120°C to obtain IB. Then, after deBoc protection and reaction with tetrahydropyran-4- Formic acid condensation yields IC, which is then hydrolyzed under alkaline conditions and condensed with the corresponding aromatic phenols to obtain the target compound ID series. IA undergoes deBoc protection and condensation with tetrahydropyran-4-carboxylic acid using HATU to obtain IE. IE undergoes a Suzuki coupling reaction with 2-methoxy-5-pinacolborate-3-aminopyridine to obtain IF. IF then undergoes an acylation reaction with acryloyl chloride to obtain the target compound IG series. IE undergoes a Suzuki coupling reaction with 2-methoxy-5-pinacolborate-nicotinaldehyde to obtain the target compound IH series. IH is reduced with sodium borohydride to obtain II. The hydroxyl group in II is chlorinated with chlorinating agents (including SOC12 and POC13) to obtain the target compound IH series and IJ series. IE undergoes a Suzuki coupling reaction with the corresponding benzaldehyde pinacolborate to obtain the target compound IK series.

[0069] The specific compounds in formula (I-2) were synthesized using synthetic procedure II. Starting with Boc-alanine (II-A), it underwent a condensation reaction with 1-methylpiperazine to give II-B. II-B was deprotected from Boc to give II-C. II-C underwent a nucleophilic substitution reaction with 4,6-dichloropyridino[3,2-d]pyrimidine or 6-bromo-4-chloroquinazoline to give II-D. II-D underwent a Suzuki coupling reaction with methyl nicotinate 2-methoxy-5-pinacolborate to give II-E. II-E was hydrolyzed under alkaline conditions to give II-F. II-F then underwent a condensation reaction with the corresponding aromatic phenol to give the target compound series II-G. II-D underwent a Suzuki coupling reaction with 2-methoxy-5-pinacolborate-3-aminopyridine to give II-H. II-H then underwent an acylation reaction with 2-vinyl chloride to give the target compound series II-I.

[0070] This synthetic procedure is merely an illustrative description of the synthetic methods in this invention and is not representative of all methods, nor does it limit the synthesis of other compounds of this invention. Compounds not described in detail in formulas (I-1) and (I-2) can also be synthesized using these methods and modified in various ways. This is intended to be informative for those skilled in the art who design this disclosure. The synthesis of representative compounds of this invention is described in detail in the following examples. The starting materials and reagents used to prepare these compounds can be obtained from reagent companies or synthesized and prepared using methods known to those skilled in the art.

[0071] 1. Specific examples of the synthesis of compounds 1-54

[0072] The structural formulas of compounds 1-54 are shown in Table 1 below:

[0073] Table 1

[0074] Example 1

[0075] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid phenyl ester (1)

[0076] Weigh methyl (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid (100 mg, 0.20 mmol) and NaOH (16 mg, 0.40 mmol) into a round-bottom flask. Add methanol and water as solvents, and stir the reaction system at room temperature for 2 h. Adjust the pH to approximately 9 with hydrochloric acid, evaporate the reaction system to dryness, add phenol (30 mg, 0.30 mmol), HATU (76 mg, 0.20 mmol), DIPEA (70 μL, 0.40 mmol), and DMF (10 mL), and stir at room temperature for 6 h. Wash with water, saturated NaHCO3 solution, and saturated NaCl solution sequentially. Collect the organic phase, dry it with anhydrous Na2SO4, and separate by column chromatography to obtain 40 mg of white solid, with a yield of 36%. 1HNMR(400MHz,DMSO-d6)δ9.62(d,J=2.5Hz,1H),9.15(d,J=2.5Hz,1H),8.55 –8.46(m,3H),8.16(dd,J=8.8,3.7Hz,1H),7.52–7.43(m,2H),7.35–7.27(m, 3H),4.86(dq,J=46.3,7.1Hz,1H),4.05(s,3H),4.02–3.64(m,4H),3.67–3.3 3(m,4H),2.74–2.59(m,1H),2.37–2.06(m,2H),1.63–1.48(m,4H).HRMS(ESI + Calculated value C 30 H 31 N6O5: 555.2350 [M+H] + Measured value: 555.2358.

[0077] Example 2

[0078] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl) nicotinic acid 4-fluorophenyl ester (2)

[0079] 2 can be prepared by a similar method to 1, yielding 47 mg of a white solid in a yield of 41%. 1 H NMR (400MHz, DMSO-d6) δ9.63(dd,J=2.5,1.0Hz,1H),9.16(t,J=2.2Hz,1H),8.55–8.45(m,3H),8.17(dd,J=8.8,3.6Hz,1H),7.42–7.24(m,4H),4. 86(dq,J=47.1,7.2Hz,1H),4.05(s,3H),4.01–3.71(m,4H),3.68–3.34(m ,4H),2.70–2.63(m,1H),2.36–2.09(m,2H),1.57–1.50(m,4H).HRMS(ESI + Calculated value C 30 H 30 FN6O5: 573.2256 [M+H] + Measured value: 573.2259.

[0080] Example 3

[0081] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid 4-chlorophenyl ester (3)

[0082] 3 can be prepared by a similar method to 1, yielding 37 mg of a white solid in a yield of 31%. 1 H NMR(400MHz,DMSO-d6)δ9.67–9.61(m,1H),9.19(t,J=1.9Hz,1H),8.59–8 .49(m,3H),8.21–8.12(m,1H),7.57–7.49(m,2H),7.41–7.34(m,2H),4.85 (dq,J=47.7,6.7,6.3Hz,1H),4.04(s,3H),4.01–3.67(m,4H),3.66–3.35( m,4H),2.72–2.59(m,1H),2.34–2.10(m,2H),1.57–1.50(m,4H).HRMS(ESI + Calculated value C 30 H 30 ClN6O5:589.1961[M+H] + Measured value: 589.1985.

[0083] Example 4

[0084] 2,4-Difluorophenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (4)

[0085] Using a method similar to that used to prepare phase 1, phase 4, 27 mg of white solid, was obtained with a yield of 23%. 1 H NMR (400MHz, DMSO-d6) δ9.67(t,J=2.2Hz,1H),9.17(d,J=2.4Hz,1H),8.50(dd ,J=7.8,4.2Hz,3H),8.16(dd,J=8.8,3.7Hz,1H),7.60–7.46(m,2H),7.25–7.16 (m,1H),4.85(dq,J=46.2,7.1Hz,1H),4.05(s,3H),4.02–3.70(m,4H),3.68–3 .34(m,4H),2.75–2.60(m,1H),2.35–2.06(m,2H),1.61–1.47(m,4H).HRMS(ESI + Calculated value C 30 H 29F2N6O5: 591.2162[M+H] + Measured value: 591.2193.

[0086] Example 5

[0087] 2,4-Dichlorophenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (5)

[0088] Using a method similar to that used to prepare phase 1, 5, a white solid of 57 mg, can be obtained with a yield of 46%. 1 H NMR (400MHz, DMSO-d6) δ9.68 (d, J=2.5Hz, 1H), 9.17 (dd, J=2.5, 1.0Hz, 1H), 8. 54–8.43(m,3H),8.16(dd,J=8.8,3.6Hz,1H),7.86–7.81(m,1H),7.55(t,J=1.9 Hz,2H),4.85(dq,J=46.2,7.1Hz,1H),4.05(s,3H),4.03–3.71(m,4H),3.66–3 .33(m,4H),2.73–2.59(m,1H),2.35–2.05(m,2H),1.63–1.47(m,4H).HRMS(ESI + Calculated value C 30 H 29 Cl2N6O5: 623.1571 [M+H] + Measured value: 623.1588.

[0089] Example 6

[0090] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid p-nitrobenzene ester (6)

[0091] Using a method similar to that used to prepare phase 1, 29 mg of a pale yellow solid (6) can be obtained with a yield of 26%. 1H NMR(400MHz,DMSO-d6)δ9.66(t,J=2.2Hz,1H),9.21(t,J=2.8Hz,1H),8.57– 8.45(m,3H),8.40–8.32(m,2H),8.17(dd,J=8.8,3.9Hz,1H),7.67–7.59(m,2 H),4.85(dq,J=47.6,7.1Hz,1H),4.06(s,3H),4.02–3.72(m,4H),3.67–3.3 5(m,4H),2.76–2.57(m,1H),2.36–2.06(m,2H),1.58–1.48(m,4H).HRMS(ESI + Calculated value C 30 H 30 N7O7: 600.22O1[M+H] + Measured value: 600.2206.

[0092] Example 7

[0093] 4-(trifluoromethyl)phenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (7)

[0094] A method similar to that used to prepare phase 1 can be used to prepare phase 7, 50 mg of white solid, with a yield of 40%. 1 H NMR (400MHz, DMSO-d6) δ9.66 (dd, J=2.5, 1.5Hz, 1H), 9.22 (t, J=2.4Hz, 1H), 8.57– 8.48(m,3H),8.18(dd,J=8.8,3.6Hz,1H),7.87(dd,J=8.9,2.6Hz,2H),7.58(dd,J= 8.6,2.2Hz,2H),4.86(dq,J=48.1,7.1Hz,1H),4.05(s,3H),4.02–3.66(m,4H),3.6 5–3.34(m,4H),2.76–2.59(m,1H),2.34–2.09(m,2H),1.61–1.47(m,4H).HRMS(ESI + Calculated value C 31 H 30 F3N6O5:623.2224[M+H] + Measured value: 623.2237.

[0095] Example 8

[0096] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid 4-cyanophenyl ester (8)

[0097] Using a method similar to that used to prepare phase 1, 8, a white solid of 58 mg, can be obtained with a yield of 50%. 1 H NMR (400MHz, DMSO-d6) δ9.67–9.61 (m, 1H), 9.17 (t, J = 2.3Hz, 1H), 8.54–8. 42(m,3H),8.16(dd,J=8.8,4.0Hz,1H),8.02–7.95(m,2H),7.60–7.51(m,2H ),4.85(dq,J=47.4,7.1Hz,1H),4.05(s,3H),4.01–3.72(m,4H),3.66–3.33 (m,4H),2.74–2.59(m,1H),2.35–2.06(m,2H),1.61–1.47(m,4H).HRMS(ESI + Calculated value C 31 H 30 N7O5: 580.23O3 [M+H] + Measured value: 580.2308.

[0098] Example 9

[0099] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid p-methoxyphenyl ester (9)

[0100] A method similar to that used to prepare phase 1 can be used to prepare 9, a white solid of 29 mg, with a yield of 25%. 1 H NMR(400MHz, DMSO-d6)δ9.61(d,J=2.5Hz,1H),9.13(t,J=2.2Hz,1H),8.55–8.40(m,3H ),8.16(dd,J=8.8,3.6Hz,1H),7.22(dd,J=8.8,2.2Hz,2H),7.03–6.96(m,2H),4.86(d q,J=46.7,7.2Hz,1H),4.04(s,3H),4.01–3.78(m,4H),3.76(s,3H),3.66–3.57(m,2H) ,3.43–3.32(m,2H),2.73–2.60(m,1H),2.34–2.09(m,2H),1.59–1.50(m,4H).HRMS(ESI + Calculated value C31 H 33 N6O6: 585.2456 [M+H] + Measured value: 585.2457.

[0101] Example 10

[0102] p-Tolyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (10)

[0103] A method similar to that used to prepare phase 1 can be used to obtain 10, a white solid of 42 mg, with a yield of 37%. 1 H NMR (400MHz, DMSO-d6)δ9.61(d,J=2.5Hz,1H),9.13(d,J=2.5Hz,1H),8.57–8.48(m,3H),8.16 (dd,J=8.8,3.5Hz,1H),7.26(dd,J=8.5,1.9Hz,2H),7.17(dd,J=8.4,1.5Hz,2H), 4.86(dq,J=45.7,7.3Hz,1H),4.04(s,3H),4.00–3.71(m,4H),3.68–3.34(m,4H) ,2.71–2.59(m,1H),2.31(s,3H),2.25–2.08(m,2H),1.59–1.49(m,4H).HRMS(ESI + Calculated value C 31 H 33 N6O5: 569.2507 [M+H] + Measured value: 569.2516.

[0104] Example 11

[0105] 2,4,6-Trifluorophenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (11)

[0106] Using a method similar to that used to prepare phase 1, 11, a white solid, 60 mg, was obtained with a yield of 50%. 1H NMR (400MHz, DMSO-d6) δ9.72(dd,J=2.5,1.0Hz,1H),9.18(t,J=2.6Hz,1H),8.57–8.46(m,3H),8.16(dd,J=8.9,3.7Hz,1H),7.54–7.45(m,2H),4. 86(dq,J=44.8,7.2Hz,1H),4.06(s,3H),4.04–3.71(m,4H),3.66–3.35(m ,4H),2.73–2.60(m,1H),2.34–2.09(m,2H),1.59–1.49(m,4H).HRMS(ESI + Calculated value C 30 H 28 F3N6O5:609.2068[M+H] + Measured value: 609.2085.

[0107] Example 12

[0108] Pyridin-3-yl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (12)

[0109] A method similar to that used to prepare phase 1 can be used to prepare 12, a white solid of 39 mg, with a yield of 35%. 1 H NMR (400MHz, DMSO-d6) δ9.64 (dd, J=2.7, 1.1Hz, 1H), 9.20 (t, J=2.3Hz, 1H), 8.60 ( d,J=2.7Hz,1H),8.53–8.46(m,4H),8.17(dd,J=8.9,3.7Hz,1H),7.84–7.78(m,1H) ,7.54(ddd,J=8.3,4.7,1.6Hz,1H),4.85(dq,J=44.0,7.2Hz,1H),4.05(s,3H),4.0 2–3.41(m,8H),2.73–2.60(m,1H),2.36–2.06(m,2H),1.59–1.48(m,4H).HRMS(ESI + Calculated value C 29 H 30 N7O5: 556.23O3 [M+H] + Measured value: 556.2334.

[0110] Example 13

[0111] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinic acid phenyl ester (13)

[0112] The intermediate (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinic acid methyl ester (99 mg, 0.20 mmol) and NaOH (16 mg, 0.40 mmol) were weighed and added to a round-bottom flask. Methanol and water were added, and the reaction system was stirred at room temperature for 2 h. Hydrochloric acid was added to adjust the pH to approximately 9. The reaction system was evaporated to dryness, and phenol (30 mg, 0.30 mmol), HATU (76 mg, 0.20 mmol), DIPEA (70 μL, 0.40 mmol), and DMF (10 mL) were added as solvents. After stirring at room temperature for 6 h, water, saturated NaHCO3 solution, and saturated NaCl solution were added sequentially for washing. The organic phase was collected, dried over anhydrous Na2SO4, and separated by column chromatography to obtain 38 mg of white solid, with a yield of 35%. 1 H NMR (400MHz, DMSO-d6) δ11.06(d,J=37.7Hz,1H),9.59(dd,J=8.3,2.0Hz,1H),9.12(dd,J=5.9 ,2.6Hz,1H),8.97(dd,J=6.1,2.6Hz,1H),8.91(d,J=4.1Hz,1H),8.51–8.43(m,1H),8.02(dd,J =8.7,6.1Hz,1H),7.49–7.41(m,2H),7.34(dd,J=7.9,2.3Hz,2H),7.29(t,J=7.3Hz,1H),5.02( dq,J=45.7,6.6Hz,1H),4.02(s,3H),3.99–3.77(m,4H),3.77–3.39(m,4H),2.72–2.62(m,1H), 2.39–2.15(m,2H),1.60–1.49(m,4H).HRMS(ESI + Calculated value C 31 H 32 N5O5: 554.2398 [M+H] + Measured value: 554.3405.

[0113] Example 14

[0114] 4-Fluorophenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carboxyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinate (14)

[0115] 14, a white solid, was prepared by a similar method to that used for 13, with a yield of 38%. 1 H NMR (400MHz, DMSO-d6) δ8.93(dd,J=4.2,2.6Hz,1H),8.75(t,J=2.9Hz,2H),8.50(d,J=5.5Hz,1 H),8.41(dd,J=17.2,6.2Hz,1H),8.16(ddd,J=8.6,4.2,1.9Hz,1H),7.77(dd,J=8.7,2.8Hz,1H ),7.39–7.32(m,2H),7.32–7.25(m,2H),4.79(dq,J=53.1,6.3Hz,1H),4.01(s,3H),4.00–3.69 (m,4H),3.67–3.32(m,4H),2.74–2.57(m,1H),2.36–1.99(m,2H),1.60–1.44(m,4H).HRMS(ESI + Calculated value C 31 H 31 FN5O5: 572.23O4 [M+H] + Measured value: 572.2313.

[0116] Example 15

[0117] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinic acid 4-chlorophenyl ester (15)

[0118] Using a similar method to prepare phase 13, phase 15 can be obtained, yielding 39 mg of a white solid in a yield of 32%. 1 H NMR (400MHz, DMSO-d6) δ8.91(t,J=2.9Hz,1H),8.72(t,J=2.4Hz,1H),8.66(t,J=1.9Hz,1H),8.50( d,J=5.9Hz,1H),8.27(dd,J=8.7,6.3Hz,1H),8.16(ddd,J=8.7,4.3,1.9Hz,1H),7.77(dd,J=8.6,3 .2Hz,1H),7.56–7.48(m,2H),7.38–7.30(m,2H),4.79(dq,J=52.2,6.3Hz,1H),4.02(s,3H),4.01– 3.63(m,4H),3.62–3.32(m,4H),2.74–2.60(m,1H),2.37–1.95(m,2H),1.64–1.43(m,4H).HRMS(ESI + Calculated value C31 H 31 ClN5O5:588.2008[M+H] + Measured value: 588.2018.

[0119] Example 16

[0120] 2,4-Difluorophenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carboxyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinate (16)

[0121] 16, a white solid, was prepared by a similar method to that used for 13, with a yield of 48 mg and a recovery rate of 41%. 1 H NMR (400MHz, DMSO-d6) δ9.10–8.77(m,4H),8.48(d,J=4.5Hz,1H),8.21–8.12(m,1H ),7.78–7.71(m,1H),7.69–7.60(m,1H),7.49(td,J=9.9,3.3Hz,1H),7.18(t,J=9.0 Hz,1H),4.79(dp,J=55.1,6.4Hz,1H),4.01(s,3H),3.99–3.66(m,4H),3.63–3.37(m ,4H),2.73–2.57(m,1H),2.22(dq,J=39.2,6.6Hz,2H),1.63–1.47(m,4H).HRMS(ESI + Calculated value C 31 H 30 F2N5O5: 590.2210[M+H] + Measured value: 590.2218.

[0122] Example 17

[0123] 2,4-Dichlorophenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carboxyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinate (17)

[0124] 17, a white solid, was prepared by a similar method to that used for 13, yielding 55 mg of 17 in a yield of 45%. 1H NMR (400MHz, DMSO-d6) δ8.94(t,J=3.0Hz,1H),8.74(t,J=2.6Hz,1H),8.66(d,J=2.2Hz,1H),8.5 1(d,J=5.8Hz,1H),8.28(t,J=6.8Hz,1H),8.15(ddd,J=8.7,4.4,1.9Hz,1H),7.85–7.74(m,2H), 7.56–7.51(m,2H),4.79(dq,J=51.2,6.3Hz,1H),4.03(s,3H),4.01–3.69(m,4H),3. 66–3.36(m,4H),2.73–2.59(m,1H),2.35–1.97(m,2H),1.59–1.47(m,4H).HRMS(ESI + Calculated value C 31 H 30 Cl2N5O5: 622.1619[M+H] + Measured value: 622.1640.

[0125] Example 18

[0126] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazoline-6-yl)nicotinic acid p-nitrobenzene (18)

[0127] Using a similar method to prepare phase 13, phase 18, 28 mg of pale yellow solid, can be obtained with a yield of 25%. 1 H NMR (400MHz, DMSO-d6) δ8.98–8.92(m,1H),8.85–8.68(m,2H),8.51(d,J=5.2Hz,1H ),8.43–8.31(m,3H),8.17(d,J=8.1Hz,1H),7.78(dd,J=8.7,3.1Hz,1H),7.62(dd,J =9.5,2.9Hz,2H),4.79(dq,J=51.9,6.3Hz,1H),4.03(s,3H),4.00–3.71(m,4H),3. 69–3.34(m,4H),2.72–2.58(m,1H),2.35–2.00(m,2H),1.63–1.49(m,4H).HRMS(ESI + Calculated value C 31 H 31 N6O7: 599.2249 [M+H] + Measured value: 599.2269.

[0128] Example 19

[0129] 4-(trifluoromethyl)phenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinate (19)

[0130] Using a similar method to prepare phase 13, phase 19 can be obtained, yielding 48 mg of a white solid with a yield of 39%. 1 H NMR (400MHz, DMSO-d6) δ9.01(dd,J=5.9,2.6Hz,1H),8.95(d,J=6.0Hz,1H),8.88(dd,J=5.5,2.6Hz, 1H),8.74(d,J=32.7Hz,1H),8.49(d,J=4.8Hz,1H),8.22–8.13(m,1H),7.85(d,J=8.5Hz,2H),7.76( dd,J=8.7,2.0Hz,1H),7.60(dd,J=8.6,2.1Hz,2H),4.80(dq,J=54.6,6.4Hz,1H),4.02(s,3H),3.99 –3.69(m,4H),3.67–3.36(m,4H),2.72–2.58(m,1H),2.33–2.12(m,2H),1.61–1.46(m,4H).HRMS(ESI + Calculated value C 32 H 31 F3N5O5: 622.2272[M+H] + Measured value: 622.2281.

[0131] Example 20

[0132] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazoline-6-yl)nicotinic acid 4-cyanophenyl ester (20)

[0133] Using a similar method to prepare phase 13, 20, a white solid of 53 mg, can be obtained with a yield of 46%. 1H NMR(400MHz,DMSO-d6)δ8.92(t,J=2.9Hz,1H),8.77–8.71(m,1H),8.68(dd,J=3.6,2.0Hz,1H),8 .54(d,J=2.4Hz,1H),8.41(t,J=6.6Hz,1H),8.18(dt,J=8.7,2.1Hz,1H),8.01–7.94(m,2H),7.7 8(dd,J=8.7,2.7Hz,1H),7.58–7.49(m,2H),4.80(dq,J=49.9,6.3Hz,1H),4.02(s,3H),4.01–3. 69(m,4H),3.68–3.40(m,4H),2.74–2.59(m,1H),2.37–1.97(m,2H),1.61–1.47(m,4H).HRMS(ESI + Calculated value C 30 H 31 N6O5: 579.2350 [M+H] + Measured value: 579.2355.

[0134] Example 21

[0135] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazoline-6-yl)nicotinic acid p-methoxyphenyl ester (21)

[0136] Using a similar method to prepare phase 13, phase 21, 58 mg of white solid, can be obtained with a yield of 50%. 1 H NMR (400MHz, DMSO-d6) δ8.89(t,J=2.6Hz,1H),8.68(t,J=2.4Hz,1H),8.65(t,J=2.3Hz,1H),8.51(d,J= 5.7Hz,1H),8.25(t,J=6.6Hz,1H),8.16(ddd,J=8.8,4.2,1.9Hz,1H),7.7 8(dd,J=8.7,3.3Hz,1H),7.23–7.16(m,2H),7.02–6.95(m,2H),4.79(dq, J=52.4,6.3Hz,1H),4.02(s,3H),3.81(m,2H),3.75(s,3H),3.73–3.35(m ,6H),2.73–2.60(m,1H),2.39–1.94(m,2H),1.59–1.43(m,4H).HRMS(ESI + Calculated value C 32 H 34N5O5: 584.25O4 [M+H] + Measured value: 584.2505.

[0137] Example 22

[0138] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-formyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinic acid p-toluene ester (22)

[0139] Using a method similar to that used to prepare phase 13, phase 22, 45 mg of white solid, can be obtained with a yield of 39%. 1 H NMR (400MHz, DMSO-d6) δ8.89(t,J=2.8Hz,1H),8.68(t,J=2.4Hz,1H),8.66(t,J=2.2Hz,1H),8.50(d ,J=5.5Hz,1H),8.27(t,J=6.9Hz,1H),8.16(ddd,J=8.6,4.2,1.9Hz,1H),7.77(dd,J=8.7,3.2Hz,1H) ,7.28–7.22(m,2H),7.18–7.11(m,2H),4.79(dq,J=52.4,6.3Hz,1H),4.02(s,3H),4.00–3.61(m,4H) ,3.60–3.32(m,4H),2.70–2.60(m,1H),2.31(s,3H),2.27–1.95(m,2H),1.60–1.47(m,4H).HRMS(ESI + Calculated value C 32 H 34 N5O5: 568.2555 [M+H] + Measured value: 568.2558.

[0140] Example 23

[0141] 2,4,6-Trifluorophenyl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carboxyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)nicotinate (23)

[0142] Using a method similar to that used to prepare phase 13, phase 22, 43 mg of white solid, was obtained with a yield of 37%. 1H NMR (400MHz, DMSO-d6) δ8.96(t,J=2.8Hz,1H),8.73(t,J=2.8Hz,1H),8.64(t,J=2.4Hz,1H), 8.50(d,J=5.8Hz,1H),8.25(t,J=6.0Hz,1H),8.16(ddd,J=8.7,4.5,1.9Hz,1H),7.77(dd,J=8 .6,3.3Hz,1H),7.48(t,J=8.5Hz,2H),4.79(dq,J=52.3,6.3Hz,1H),4.04(s,3H),4.01–3.68( m,4H),3.66–3.35(m,4H),2.72–2.59(m,1H),2.36–1.96(m,2H),1.61–1.46(m,4H).HRMS(ESI + Calculated value C 31 H 29 F3N5O5:608.2115[M+H] + Measured value: 608.2123.

[0143] Example 24

[0144] Pyridin-3-yl(S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazoline-6-yl)nicotinate (24)

[0145] Using a similar method to that used to prepare phase 13, phase 24, a white solid of 38 mg, can be obtained with a yield of 35%. 1 H NMR (400MHz, DMSO-d6) δ8.93(t,J=3.0Hz,1H),8.77(t,J=2.5Hz,1H),8.68(s,1H),8.58(d,J=2.7H z,1H),8.51(dd,J=5.3,3.7Hz,2H),8.30(dd,J=9.9,6.2Hz,1H),8.16(ddd,J=8.8,4.4,1.8Hz,1H) ,7.84–7.74(m,2H),7.53(dd,J=8.4,4.7Hz,1H),4.79(dq,J=52.1,6.3Hz,1H),4.03(s,3H),4.00– 3.69(m,4H),3.66–3.33(m,4H),2.74–2.57(m,1H),2.35–1.97(m,2H),1.59–1.43(m,4H).HRMS(ESI + Calculated value C 30 H 31 N6O5: 555.2350 [M+H]+ Measured value: 555.2348.

[0146] Example 25

[0147] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinaldehyde (25)

[0148] Weigh 2-methoxy-5-bromonicoraldehyde (323 mg, 1.5 mmol), pinacol diboronic acid ester (381 mg, 1.5 mmol), KOAc (290 mg, 3.0 mmol), and Pd(dppf)Cl2 (109 mg, 0.15 mmol) into a round-bottom flask. Use dioxane (20 mL) as solvent. Stir and heat under N2 for 4 h under reflux. Cool to room temperature and add intermediate (S)-(3-((6-chloropyridino[3,2-d]pyrimidin-4-yl)amino)pyrrolidine-1-yl)(tetrahydro-2H-pyran-4-yl) methyl ketone (433 mg, 1.2 mmol), K2CO3 (414 mg, 3.0 mmol), and Pd(dppf)Cl2 (110 mg, 0.15 mmol). Add water (5 mL) as solvent. Stir and heat under reflux for about 4 h and then stop the reaction. Column chromatography yielded 460 mg of a brown solid, with a yield of 83%. 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.64(d,J=2.7Hz,1H),8.88(d,J=2.7Hz,1H),8.53–8.45(m,3H),8.15(dd,J=9.0,4.2H z,1H),5.02–4.72(m,1H),4.08(s,3H),4.01–3.40(m,8H),2.80–2.62(m,1H),2.34–2.10(m,2H),1.66–1.47(m,4H).HRMS(ESI + Calculated value C 24 H 27 N6O4: 463.2088 [M+H] + Measured value: 463.2091.

[0149] Example 26

[0150] (S)-2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazoline-6-yl)nicotinaldehyde (26)

[0151] Phase 26 can be prepared using a similar method to that used to prepare phase 25, yielding 450 mg of a brown solid with a yield of 81%. 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.96(t,J=2.6Hz,1H),8.66(t,J=2.3Hz,1H),8.54(d, J=6.0Hz,1H),8.49(t,J=2.5Hz,1H),8.34(dd,J=9.6,6.3Hz,1H),8.18(ddd,J=8.6,3.7,1.9 Hz,1H),7.79(dd,J=8.7,3.4Hz,1H),4.83(dq,J=53.9,6.3Hz,1H),4.09(s,3H),4.08–3.74( m,4H),3.72–3.37(m,4H),2.80–2.62(m,1H),2.41–2.00(m,2H),1.65–1.52(m,4H).HRMS(ESI + Calculated value C 25 H 28 N5O4: 462.2136 [M+H] + Measured value: 462.2139.

[0152] Example 27

[0153] (S)-2-ethynyl-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)benzaldehyde (27)

[0154] Weigh 140 mg (0.22 mmol) of (S)-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)-2-((triisopropylsilyl)ethynyl)benzaldehyde into a 25 mL round-bottom flask, add 5 mL of THF, and add 0.5 mL of 1.0 M TBAF. Stir the mixture at room temperature for 2 h. Extract with water and DCM, collect and combine the organic phases, dry them over anhydrous NaSO4, and separate by column chromatography to obtain 55 mg of white solid, yield 54%. 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.86–8.78(m,1H),8.66(d,J=2.0Hz,1H),8.56–8.46(m,3H),8.19(dd,J=8.8,3.6Hz,1H),7.83(dd,J= 8.2,4.1Hz,1H),4.98–4.78(m,2H),4.05–3.74(m,4H),3.69–3.35(m,4H),2.74–2.61(m,1H),2.37–2.11(m,2H),1.62–1.51(m,4H).HRMS(ESI+ Calculated value C 26 H 26 N5O3: 456.2030 [M+H] + Measured value: 456.2058.

[0155] Example 28

[0156] (S)-2-ethynyl-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)benzaldehyde (28)

[0157] Phase 28 can be prepared using a similar method to that used to prepare phase 27, yielding 45 mg of a white solid with a yield of 46%. 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.69(d,J=3.2Hz,1H),8.51(d,J=5.7Hz,1H),8.39( dd,J=8.3,6.5Hz,1H),8.23(d,J=1.8Hz,1H),8.19–8.11(m,2H),7.83(dd,J=8.1,1.8Hz,1 H),7.78(dd,J=8.7,3.5Hz,2H),4.80(dq,J=54.8,6.4Hz,1H),4.80(s,1H),4.04–3.71(m, 4H),3.67–3.36(m,4H),2.73–2.62(m,1H),2.37–1.96(m,2H),1.62–1.50(m,4H).HRMS(ESI + Calculated value C 27 H 27 N4O3: 455.2078 [M+H] + Measured value: 455.2097.

[0158] Example 29

[0159] (S)-2-hydroxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)benzaldehyde (29)

[0160] Weigh 201 mg (1.0 mmol) of 5-bromosalicylic acid aldehyde, 280 mg (1.1 mmol) of pinacol diboronate, KOAc (196 mg, 2.0 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol) into a round-bottom flask. Use dioxane (20 mL) as solvent and heat under reflux for 6 h in N2. After cooling to room temperature, add intermediate (S)-(3-((6-chloropyridino[3,2-d]pyrimidin-4-yl)amino)pyrrolidine-1-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (361 mg, 1.0 mmol), K2CO3 (138 mg, 1.0 mmol), and Pd(dppf)Cl2 (73 mg, 0.1 mmol). Add water as solvent and reflux for 12 h. Column chromatography yields 51 mg of a yellow solid, with a yield of 27%. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),10.31(s,1H),8.68(dq,J=8.9,2.0Hz,1H),8.53–8.4 6(m,2H),8.38(ddd,J=8.9,3.4,1.3Hz,1H),8.28(t,J=8.5Hz,1H),8.11(ddd,J=8.8,3.3,1. 2Hz,1H),7.15(dd,J=8.7,3.1Hz,1H),4.85(dq,J=44.9,7.2Hz,1H),4.02–3.65(m,4H),3.64 –3.32(m,4H),2.70(tt,J=14.9,6.7Hz,1H),2.36–2.07(m,2H),1.62–1.50(m,4H).HRMS(ESI + Calculated value C 24 H 26 N5O4: 448.1979 [M+H] + Measured value: 448.1980.

[0161] Example 30

[0162] (S)-2-hydroxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)benzaldehyde(30)

[0163] Using a similar method to prepare phase 29, phase 30 can be obtained, yielding 55 mg of a white solid with a yield of 29%. 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.34(s,1H),8.54(dd,J=3.3,2.1Hz,1H),8.48(d,J=5 .3Hz,1H),8.31(t,J=7.1Hz,1H),8.03(dd,J=8.6,3.0Hz,2H),7.95(dt,J=8.4,1.8Hz,1H),7.7 3(dd,J=8.6,3.2Hz,1H),7.14(dd,J=8.6,1.9Hz,1H),4.80(dq,J=53.7,6.4Hz,1H),4.05–3.70 (m,4H),3.68–3.32(m,4H),2.75–2.58(m,1H),2.35–1.96(m,2H),1.61–1.48(m,4H).HRMS(ESI + Calculated value C 25 H 27 N4O4: 447.2027 [M+H] + Measured value: 447.2030.

[0164] Example 31

[0165] (S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)nicotinic acid phenyl ester (31)

[0166] The intermediate (S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)nicotinic acid methyl ester (93 mg, 0.20 mmol) and NaOH (16 mg, 0.40 mmol) were weighed and added to a round-bottom flask. Methanol and water were added as solvents, and the reaction system was stirred at room temperature for 2 h. The pH was adjusted to approximately 9 with 1 M hydrochloric acid, and the reaction system was evaporated to dryness. Phenol (30 mg, 0.30 mmol), HATU (76 mg, 0.20 mmol), DIPEA (70 μL, 0.40 mmol), and DCM (20 mL) were added as solvents. After stirring at room temperature for 6 h, the mixture was washed successively with water, saturated NaHCO3 solution, and saturated NaCl solution. The organic phase was collected, dried over anhydrous Na2SO4, and separated by column chromatography (CH2Cl2:CH3OH = 20:1) to obtain 34 mg of white solid, with a yield of 35%. mp: 198.6~199.6℃. 1H-NMR(600MHz,DMSO-d6)δ9.21(s,4H),8.83(d,J=3.4Hz,2H),8.70(d,J=32.5Hz,4H),8.55(s,2H) ,4.84(m,1H),4.09(s,3H),3.87(m,2H),3.64(m,6H),2.28(m,3H),1.01(d,J=7.8Hz,3H).ESI-HRMS C 29 H 30 N6O4, calculated value [M+H] + : 527.24013, Measured value: 527.24029.

[0167] Example 32

[0168] 4-Fluorophenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)nicotinate (32)

[0169] Phase 32 can be prepared using a similar method to that used for phase 31, yielding 90 mg of a white solid in a yield of 65%. mp: 252.6–253.7 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.95(t,J=4.3Hz,1H),8.77(dd,J=10.6,2.0Hz,2H), 8.55(d,J=7.3Hz,1H),8.45(s,1H),8.18(dd,J=8.7,1.8Hz,1H),7.77(d,J=8.7 Hz,1H),7.35(m,4H),5.31(t,J=7.1Hz,1H),4.06(s,3H),3.58(dd,J=18.2,13. 3Hz,4H),2.33(d,J=34.1Hz,4H),2.19(s,3H),1.42(d,J=6.9Hz,3H).ESI-HRMS C 29 H 29 FN6O4, calculated value [M+H] + : 545.2307, Measured value: 545.2305

[0170] Example 33

[0171] 2,4-Difluorophenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)nicotinate (33)

[0172] Phase 37 can be prepared using a similar method to that used for phase 31, yielding 38 mg of a white solid in a yield of 21%. mp: 235.6–237.8 °C. 1 H-NMR(600MHz,DMSO-d6)δ9.58(s,2H),9.31(s,2H),8.54(dd,J=17.4,8.0Hz,4H),8.21(m,2 H),4.92(m,1H),4.10(s,3H),3.99(m,4H),3.77(m,4H),3.65(m,3H),2.27(m,3H).ESI-HRMS C 29 H 28 F2N6O4, calculated value [M+H] + : 563.22129, Measured value: 563.22165.

[0173] Example 34

[0174] 4-(trifluoromethyl)phenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)nicotinate (34)

[0175] Phase 34 can be prepared using a similar method to that used for phase 31, yielding 40 mg of a white solid in a yield of 21%. mp: 235.6–237.8 °C. 1 H-NMR(600MHz,DMSO-d6)δ9.58(s,2H),9.34(s,2H),8.55(s,4H),8.20(m,2H),4.92(ddd,J=64.8,14.4,7.2Hz,2 H),4.11(s,3H),4.06(m,2H),3.75(m,6H),2.75(d,J=17.6Hz,3H),2.24(ddd,J=14.3,12.2,5.9Hz,3H).ESI-HRMS C 30 H 29 F3N6O4, calculated value [M+H] + : 595.22571, Measured value: 595.22770.

[0176] Example 35

[0177] (S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)nicotinic acid 4-cyanophenyl ester (35)

[0178] Phase 35 can be prepared using a similar method to that used for phase 31, yielding 33 mg of a white solid in a yield of 19%. mp: 206.3–208.5 °C. 1H-NMR (600MHz, DMSO-d6) δ9.60 (s, 2H), 9.32 (d, J = 1.7Hz, 2H), 8.59 (dd, J = 44.0, 26.7Hz, 4H), 8.22 (t, J = 10.2Hz ,2H),4.60(s,1H),4.11(s,3H),4.05(dd,J=25.6,7.4Hz,2H),3.85(m,6H),2.27(m,3H),1.27(m,3H).ESI-HRMS C 30 H 29 N7O4, calculated value [M+H] + : 552.23538, Measured value: 552.23558.

[0179] Example 36

[0180] 2,4-Dichlorophenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)nicotinate (36)

[0181] Phase 36 can be prepared using a similar method to that used for phase 31, yielding 35 mg of a white solid in 18% yield. mp: 198.6–199.6 °C. 1 H-NMR(600MHz,DMSO-d6)δ8.96(d,J=5.5Hz,2H),8.51(m,8H),3.93(m,1H),3.68(m,3H),3.50(m,6H),2.83(m,2H),1.63(m,6H).ESI-HRMS C 29 H 28 Cl2N6O4, calculated value [M+H] + : 595.16219, measured value: 595.16209.

[0182] Example 37

[0183] 2,4-Difluorophenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (37)

[0184] 37 can be prepared by a similar method to that used to prepare 31, yielding 36 mg of a white solid with a yield of 20%. 1H NMR (400MHz, CDCl3) δ9.28(d,J=2.5Hz,1H),9.11(d,J=2.5Hz,1H),8.60(s,1H),8.26(d,J=7.4Hz,1H),8.23–8.10(m,2H),7.53(d,J=2.2Hz,1 H),7.37–7.30(m,2H),5.29(p,J=6.9Hz,1H),4.18(s,3H),3.92–3.58(m,4H),2.68–2.42(m,4H),2.38(s,3H),1.57(d,J=6.7Hz,3H).HRMS(ESI + Calculated value C 28 H 27 F2N7O4:564.2165[M+H + ], Measured value: 564.2166.

[0185] Example 38

[0186] 2,4-Dichlorophenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (38)

[0187] 38 can be prepared by a similar method to that used to prepare phase 31, yielding 38 mg of a white solid with a yield of 20%. 1 H NMR (400MHz, DMSO-d6) δ9.57(d,J=2.6Hz,1H),9.24(d,J=2.6Hz,1H),8.63(d ,J=7.1Hz,1H),8.58(d,J=8.8Hz,1H),8.52(s,1H),8.22(d,J=8.8Hz,1H),7. 65–7.51(m,2H),7.24(td,J=8.9,3.0Hz,1H),5.21(p,J=7.0Hz,1H),4.10(s, 3H),3.60(s,4H),3.49(m,4H),2.24(s,3H),1.46(d,J=6.9Hz,3H).HRMS(ESI + Calculated value C 28 H 27 Cl2N7O4: 596.1574 [M+H + ], Measured value: 596.1572.

[0188] Example 39

[0189] 4-(trifluoromethyl)phenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (39)

[0190] 39 can be prepared by a similar method to that used to prepare 31, yielding 25 mg of a white solid with a yield of 19%. 1 H NMR (400MHz, DMSO-d6) δ9.53(d,J=2.4Hz,1H),9.26(d,J=2.4Hz,1H),8.62(d,J =7.0Hz,1H),8.57(d,J=8.9Hz,1H),8.52(s,1H),8.22(d,J=8.8Hz,1H),7.90(d ,J=8.4Hz,2H),7.64(d,J=8.4Hz,2H),5.21(p,J=6.9Hz,1H),4.10(s,3H),3.63 –3.49(m,4H),2.45–2.28(m,4H),2.21(s,3H),1.46(d,J=6.9Hz,3H).HRMS(ESI + Calculated value C 29 H 28 F3N7O4:596.2228[M+H + ], Measured value: 596.2231.

[0191] Example 40

[0192] (S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid phenyl ester (40)

[0193] Using a similar method to prepare phase 31, phase 40 can be obtained, yielding 41 mg of a white solid with a yield of 36%. 1 H NMR (400MHz, DMSO-d6) δ9.50(d,J=2.5Hz,1H),9.21(d,J=2.5Hz,1H),8.62(d,J=7.1Hz,1H),8. 56(d,J=8.8Hz,1H),8.52(s,1H),8.21(d,J=8.8Hz,1H),7.53–7.48(m,2H),7.39–7.32(m,3H), 5.30–5.10(m,1H),4.09(s,3H),3.60–3.50(m,4H),2.42–2.28(m,4H),2.20(s,3H),1.46(d,J=6.8Hz,3H).HRMS(ESI + Calculated value C 28H 29 N7O4: 528.2354 [M+H + ], Measured value: 528.2360.

[0194] Example 41

[0195] 4-Chlorophenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (41)

[0196] 41 can be prepared by a similar method to that used to prepare 31, yielding 54 mg of a white solid with a yield of 44%. 1 H NMR (400MHz, DMSO-d6) δ9.52(d,J=2.6Hz,1H),9.22(d,J=2.5Hz,1H),8.61(d ,J=7.3Hz,1H),8.56(d,J=8.9Hz,1H),8.52(s,1H),8.21(d,J=8.8Hz,1H),7.6 0–7.53(m,2H),7.46–7.39(m,2H),5.21(t,J=6.9Hz,1H),4.09(s,3H),3.66– 3.53(m,4H),2.46–2.31(m,4H),2.24(s,3H),1.46(d,J=6.8Hz,3H).HRMS(ESI + Calculated value C 28 H 28 ClN7O4:562.1964[M+H + ], Measured value: 562.1985.

[0197] Example 42

[0198] 4-Fluorophenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (42)

[0199] 42 can be prepared by a similar method to that used to prepare phase 31, yielding 44 mg of a white solid with a yield of 37%. 1H NMR (400MHz, DMSO-d6) δ9.50(d,J=2.5Hz,1H),9.21(d,J=2.5Hz,1H),8.60(d,J=7.1 Hz,1H),8.56(d,J=8.7Hz,1H),8.51(s,1H),8.21(d,J=8.8Hz,1H),7.43(d,J=4.7Hz ,1H),7.41(d,J=4.8Hz,1H),7.36–7.30(m,2H),5.21(t,J=6.9Hz,1H),4.08(s,3H), 3.61–3.49(m,4H),2.39–2.26(m,4H),2.18(s,3H),1.46(d,J=6.7Hz,3H).HRMS(ESI + Calculated value C 28 H 28 FN7O4: 546.2260[M+H + ], Measured value: 546.2268.

[0200] Example 43

[0201] (S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid 4-cyanophenyl ester (43)

[0202] Using a similar method to prepare phase 31, phase 43 can be obtained, yielding 28 mg of a white solid with a yield of 24%. 1 H NMR (400MHz, DMSO-d6) δ9.53(d,J=2.5Hz,1H),9.24(d,J=2.5Hz,1H),8.61(d ,J=7.1Hz,1H),8.56(d,J=8.8Hz,1H),8.51(s,1H),8.21(d,J=8.8Hz,1H),8.0 7–7.97(m,2H),7.66–7.59(m,2H),5.20(p,J=7.1Hz,1H),4.08(s,3H),3.63– 3.47(m,4H),2.36–2.25(m,4H),2.18(s,3H),1.45(d,J=6.8Hz,3H).HRMS(ESI + Calculated value C 29 H 28 N8O4: 553.23O6 [M+H + ], Measured value: 553.2314.

[0203] Example 44

[0204] 2,4,6-Trifluorophenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (44)

[0205] 44 can be prepared by a similar method to that used to prepare phase 31, yielding 37 mg of a white solid with a yield of 34%. 1 H NMR (400MHz, DMSO-d6) δ9.64–9.58(m,1H),9.25(t,J=2.7Hz,1H),8.64(dd,J= 7.1,2.5Hz,1H),8.59(dd,J=8.9,2.7Hz,1H),8.52(d,J=1.8Hz,1H),8.21(dd,J =8.8,2.4Hz,1H),7.58–7.49(m,2H),5.20(p,J=6.8Hz,1H),4.10(s,3H),3.72 –3.47(m,4H),2.42–2.24(m,4H),2.18(s,3H),1.45(d,J=6.8Hz,3H).HRMS(ESI + Calculated value C 28 H 26 F3N7O4:582.2071[M+H + ], Measured value: 582.2074.

[0206] Example 45

[0207] (S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid p-toluene ester (45)

[0208] Using a similar method to prepare phase 31, phase 45 can be obtained, yielding 40 mg of a white solid with a yield of 38%. 1 H NMR (400MHz, DMSO-d6) δ9.40(d,J=2.5Hz,1H),9.10(d,J=2.5Hz,1H),8.55(d,J=7.1Hz,1H),8.48(d,J=10.1Hz,2H),8.14(d,J=8.8Hz,1H),7.25 (q,J=8.7Hz,4H),5.17(p,J=6.9Hz,1H),4.06(s,3H),3.67–3.47(m,4H),2.41–2.23(m,7H,CH2×2),2.18(s,3H),1.45(d,J=6.9Hz,3H).HRMS(ESI + Calculated value C 29 H 31N7O4: 542.2510[M+H + ], Measured value: 542.2513.

[0209] Example 46

[0210] 4-Methoxyphenyl(S)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (46)

[0211] Using a similar method to prepare phase 31, phase 46 can be obtained, yielding 45 mg of a white solid with a yield of 43%. 1 H NMR (400MHz, DMSO-d6) δ9.43–9.38(m,1H),9.13–9.08(m,1H),8.56(d,J=7 .0Hz,1H),8.52–8.43(m,2H),8.15(d,J=8.8Hz,1H),7.32–7.25(m,2H),7. 05–6.98(m,2H),5.17(p,J=6.9Hz,1H),4.06(s,3H),3.78(s,3H),3.63–3. 43(m,4H),2.43–2.25(m,4H),2.18(s,3H),1.45(d,J=6.8Hz,3H).HRMS(ESI + Calculated value C 29 H 31 N7O5: 558.2459[M+H + ], Measured value: 558.2465.

[0212] Example 47

[0213] (R)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinic acid phenyl ester (47)

[0214] 47 can be prepared by a similar method to that used to prepare phase 31, yielding 45 mg of a white solid with a yield of 47%. 1H NMR (600MHz, DMSO-d6) δ9.51(d,J=2.5Hz,1H),9.21(d,J=2.5Hz,1H),8.62(d,J=7.1Hz,1 H),8.57(d,J=8.9Hz,1H),8.52(s,1H),8.21(d,J=8.8Hz,1H),7.50(dd,J=8.5,7.3Hz,2H) ,7.40–7.36(m,2H),7.34(td,J=7.3,1.2Hz,1H),5.22(p,J=6.9Hz,1H),4.09(s,3H),3.7 0–3.46(m,4H),2.38(dt,J=3.7,1.9Hz,4H),2.25(s,3H),1.47(d,J=6.8Hz,3H).HRMS(ESI + Calculated value C 28 H 29 N7O4: 528.2354 [M+H + ], Measured value: 528.2370.

[0215] Example 48

[0216] 4-Fluorophenyl(R)-2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)nicotinate (48)

[0217] Using a similar method to prepare phase 31, phase 54 can be obtained, yielding 35 mg of a white solid with a yield of 37%. 1 H NMR (600MHz, DMSO-d6) δ9.52–9.49(m,1H),9.21(d,J=2.7Hz,1H),8.60(t,J=5.7Hz, 1H),8.56(ddt,J=8.6,3.9,1.9Hz,1H),8.52(s,1H),8.21(ddd,J=9.0,3.8,1.8Hz,1H ),7.43(dd,J=9.0,4.6Hz,2H),7.33(t,J=8.7Hz,2H),5.24–5.18(m,1H),4.09(s,3H) ,3.62–3.45(m,4H),2.40–2.26(m,4H),2.19(s,3H),1.46(d,J=6.8Hz,3H).HRMS(ESI + Calculated value C 28 H 28 FN7O4: 546.2260[M+H + ], Measured value: 546.2293.

[0218] Example 49

[0219] (S)-(3-((6-(5-(chloromethyl)-6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)pyrrolidine-1-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (49)

[0220] Weigh (S)-(3-((6-(5-(hydroxymethyl)-6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)pyrrolidine-1-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (93 mg, 0.2 mmol) into a round-bottom flask, add 5 mL of DCM as solvent, and add SOCl2 (60 μL, 1.0 mmol) dropwise. Stir the reaction at room temperature for 30 minutes, evaporate the system under reduced pressure to dryness, and separate by column chromatography to obtain 70 mg of white solid, with a yield of 72%. 1 H NMR (400MHz, DMSO-d6) δ9.32(t,J=2.7Hz,1H),8.79(d,J=2.4Hz,1H),8.50(d,J=6.6Hz,1H),8.43–8.34(m,2H),8.16(dd,J=8.8,3.9Hz,1H),4.86(dq,J =43.8,7.4Hz,1H),4.76(s,2H),4.00(s,3H),3.96–3.65(m,4H),3.65–3.32 (m,4H),2.76–2.63(m,1H),2.37–2.11(m,2H),1.61–1.50(m,4H).HRMS(ESI + Calculated value C 24 H 28 ClN6O3: 483.1906 [M+H] + Measured value: 483.1936.

[0221] Example 50

[0222] (S)-(3-((6-(5-(chloromethyl)-6-methoxypyridin-3-yl)quinazolin-4-yl)amino)pyrrolidine-1-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (50)

[0223] Using a similar method to prepare phase 49, phase 50 can be obtained, yielding 73 mg of a white solid with a yield of 76%. 1H NMR(400MHz, DMSO-d6)δ8.61(dt,J=11.8,2.3Hz,2H),8.51(d,J=4.7Hz,1H),8.29(t ,J=5.0Hz,1H),8.24(t,J=2.1Hz,1H),8.07(dt,J=8.7,2.4Hz,1H),7.76(dd,J=8.8, 3.1Hz,1H),4.89–4.70(m,3H),4.03–3.98(m,1H),3.97(s,3H),3.87–3.71(m,3H),3 .66–3.33(m,4H),2.75–2.59(m,1H),2.36–1.97(m,2H),1.60–1.49(m,4H).HRMS(ESI + Calculated value C 25 H 29 ClN5O3:482.1953[M+H] + Measured value: 482.1967.

[0224] Example 51

[0225] (S)-N-(2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)acrylamide(51)

[0226] Weigh (S)-(3-((6-(5-amino-6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)pyrrolidine-1-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (90 mg, 0.2 mmol) into a round-bottom flask, add 5 mL of DCM as solvent, then add triethylamine (55 μL, 0.4 mmol), and slowly add acryloyl chloride (33 μL, 0.4 mmol). Stir the reaction at room temperature for 30 minutes, evaporate the solvent to dryness, and separate by column chromatography to obtain 29 mg of brown solid product, with a yield of 28%. 1H NMR(400MHz, DMSO-d6)δ9.84(d,J=3.1Hz,1H),9.17–9.08(m,2H),8.54(d,J=5.4Hz,1H),8.42– 8.29(m,2H),8.19(dd,J=8.8,3.3Hz,1H),6.76(ddd,J=17.0,10.2,2.1Hz,1H),6.31(dt,J=17.0 ,2.3Hz,1H),5.81(dd,J=9.9,2.0Hz,1H),4.90(dq,J=47.2,7.1Hz,1H),4.05(s,3H),4.01–3.7 7(m,4H),3.75–3.37(m,4H),2.79–2.66(m,1H),2.38–2.13(m,2H),1.65–1.53(m,4H).HRMS(ESI + Calculated value C 26 H 30 N7O4: 504.2354 [M+H] + Measured value: 504.2365.

[0227] Example 52

[0228] (S)-N-(2-methoxy-5-(4-((1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidine-3-yl)amino)quinazolin-6-yl)pyridin-3-yl)acrylamide(52)

[0229] 52 can be prepared by a similar method to that used to prepare 51, yielding 30 mg of a brown solid with a yield of 29%. 1H NMR(400MHz, DMSO-d6)δ9.79(d,J=2.5Hz,1H),8.77(d,J=2.4Hz,1H),8.56(t,J=2.5Hz,1H),8.49(d,J=5.4Hz,1H),8.33(t,J=1 .8Hz,1H),8.26(dd,J=10.1,6.2Hz,1H),8.00(ddd,J=8.8,3.5,1.9Hz,1H),7.76(dd,J=8.7,3.4Hz,1H),6.74(dd,J =16.9,10.2Hz,1H),6.26(dd,J=17.0,2.0Hz,1H),5.76(dd,J=10.0,2.0Hz,1H),4.79(dp,J=54.6,6.2Hz,1H),3.9 9(s,3H),3.86–3.58(m,4H),3.58–3.32(m,4H),2.75–2.58(m,1H),2.35–1.96(m,2H),1.61–1.49(m,4H).HRMS(ESI + Calculated value C 27 H 31 N6O4: 503.24O1[M+H] + Measured value: 503.2410.

[0230] Example 53

[0231] (S)-N-(2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)pyridin-3-yl)acrylamide(53)

[0232] Phase 53 can be prepared using a similar method to that used for phase 51, yielding 30 mg of a white solid in 18% yield. mp: 205.6–206.8 °C. 1 H-NMR(600MHz,DMSO-d6)δ8.96(s,2H),8.65(d,J=4.6Hz,4H),8.46(d,J=36.2Hz,2H),4.77(m,2H),3 .75(dd,J=10.4,6.6Hz,2H),3.52(ddd,J=52.0,10.2,4.2Hz,4H),2.24(m,4H),0.94(m,6H).ESI-HRMS C 25 H 29 N7O3, calculated value [M+H] + : 476.24046, Measured value: 476.23971.

[0233] Example 54

[0234] (S,E)-N-(2-methoxy-5-(4-((1-(4-methylpiperazin-1-yl)-1-oxopropane-2-yl)amino)quinazolin-6-yl)pyridin-3-yl)but-2-enamide (54)

[0235] Phase 54 can be prepared using a similar method to that used for phase 51, yielding 29 mg of a white solid in a yield of 17%. mp: 241.5–242.8 °C. 1 H-NMR (600MHz, DMSO-d6) δ8.95(d,J=4.9Hz,2H),8.65(d,J=3.7Hz,2H),8.59(dd,J=20.2,5.6Hz,2H),8.48(d,J=11.7 Hz,2H),4.74(ddd,J=15.7,10.8,5.4Hz,3H),3.72(ddd,J=18.9,11.6,6.5Hz,3H),3.49(m,8H),2.11(m,9H).ESI-HRMS C 26 H 31 N7O3, calculated value [M+H] + : 490.25611, Measured value: 490.25591.

[0236] 2. Determination of the activity of the compounds of the present invention against PI3Kδ kinase

[0237] Test method: Using idelalisib as the positive control, the compound was dissolved with idelalisib in DMSO to prepare a solution of 10... -2 mol·L -1 The mother liquor was serially diluted with DMSO to obtain a concentration of 10. -5 mol·L -1 10 -6 mol·L -1 10 -7 mol·L -1 10 -8 mol·L -1 10 -9 mol·L -1 The sample solution to be tested was then diluted with water to make a DMSO solution containing 10% water, with a concentration of 10%. -6 mol·L -1 10 -7 mol·L -1 10 -8 mol·L -1 10 -9 mol·L -1 10 -10 mol·L-1 1 μL of the above-mentioned sample solutions of different concentrations and DMSO were added to 384-well plates, and then kinase, ATP, and substrate were added to form the kinase reaction system (50 mmol·L⁻¹). -1 HEPES (pH 7.5), 50 mmol·L -1 NaCl, 3 mmol·L -1 MgCl2, 0.025 mg·L -1 BSA, 0.2 μg·mL -1 PI3Kδ, 10 μmol·L -1 ATP, 0.05 mg·L -1 After PI (3PS), incubate at room temperature for 60 min. The final reaction volume is 10 μL, and the final concentration of the test samples is 10. -7 mol·L -1 10 -8 mol·L -1 10 -9 mol·L -1 10 -10 mol·L -1 10 -11 mol·L -1 Add 5μL of ADP-Glo TM Afterward, incubate at room temperature for 60 min to stop the kinase reaction and consume unreacted ATP in the system. Add 10 μL of detection reagent and continue incubation for 40 min. Then, use a multi-mode microplate reader to detect the chemiluminescent signal (Lu) in the system. The intensity of the luminescent signal is inversely proportional to the inhibitory activity of the target compound. Substitute the chemiluminescent signal (Lu) value into the formula: % activity = [(Lu)] 药物 –Lu 空白 ) / (Lu 酶 –Lu 空白 )]×100% (Lu 空白 This is the light signal from the blank control group (no enzyme, no drug added), Lu 药物 This is the light signal from the drug administration group, Lu 酶 (This is the optical signal of the solvent control group). The IC50 of the compound with respect to PI3Kδ was calculated using Graphpad Prism 5.0 software. 50 value.

[0238] The biochemical activity of the compounds of this invention was tested through the above experiments. The IC50 of the compounds of this invention against PI3Kδ was [not specified]. 50 The values ​​are shown in Table 2.

[0239] Table 2 IC50 of the compounds of this invention against PI3Kδ kinase 50 value

[0240] A represents IC 50 <1nM; B indicates IC 50 Range 1-10nM; C indicates IC 50 Range 10-100 nM.

[0241] Conclusion: The preferred compound of this invention has a significant inhibitory effect on PI3Kδ kinase, which is stronger than that of Idelalisib.

[0242] 3. Determination of the selective activity of the compounds of this invention against PI3K kinase

[0243] Using a similar method described above, the activities of the compounds of this invention against various isoforms of PI3K kinase (including PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ) were tested. The activities of some compounds of this invention against various isoforms of PI3K kinase (including PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ) are shown in Table 3.

[0244] Table 3 shows the IC50 values ​​of the compounds of this invention for various PI3K kinase isoforms. 50 value

[0245] Conclusion: The preferred compounds of this invention exhibit IC50 values ​​for PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. 50 The values ​​indicate that the compounds of this invention have a significant selective effect on the activity of PI3Kδ.

[0246] 4. Determination of the in vitro antiproliferative activity of the compounds of this invention against solid tumor cell lines and hematologic malignancy cell lines.

[0247] Test Methods: The tested solid tumor cell lines included HCT-116 cells and MCF-7 cells, and hematologic malignancy cell lines included SU-DHL-6 cells, Ramos cells, Raji cells, and Pfeiffer cells (large B-cell lymphoma). Cells were cultured in a 37°C incubator (5% CO2) until they reached 80%-90% confluence, then passaged. Cells in good growth condition and in the logarithmic growth phase were digested, resuspended, counted, and seeded at a specific cell density into clean, sterile 96-well plates. Each well contained 198 μL of culture medium. After seeding, the 96-well plates were incubated at 37°C for 24 hours. Drug administration was initiated when cells had adhered and were in good condition. Different concentrations of the test sample solution were added to each 96-well plate, 2 μL per well, resulting in a total culture medium volume of 200 μL per well (the sample solution was then diluted 100-fold to reach the final concentration). Each concentration was used in triplicate. After drug administration, the 96-well plates were incubated at 37°C for 72 hours. The cells were divided into three groups: a blank control group (no cell seeding, no DMSO); a cell control group (cell seeding, 0.1% DMSO added); and a drug-treated group (cell seeding, PBS diluted with different concentrations of the drug to achieve a final drug concentration of 10...). -2 10 -3 10 -4 3.3×10 -5 10 -5 3.3×10 -6 10 -6 mmol·L -1 After incubation for 72 hours, 20 μL of MTT solution (5 mg / mL) was added to each well under dark conditions. -1 Incubate for another 3-4 hours in a constant temperature incubator. Remove the 96-well plate and carefully aspirate the culture medium. Add 150 μL of DMSO to each well, shake for 10 min, and after the blue-purple formazan is fully dissolved, measure the OD value of each well at 490 nm using a microplate reader. Calculate the cell growth inhibition rate at different concentrations of each test compound using the formula, and calculate the GI using Graphpad Prism 5.0 software. 50 Value. Growth inhibition rate % = [1 - (OD value of drug-treated group - OD value of blank control group) / (OD value of cell control group - OD value of blank control group)] × 100%. Based on the inhibition rate, IC50 is calculated using the modified Kohl's method. 50 Values ​​were measured. Idelalisib was used as a positive control in the test. The cellular activity of the compounds of this invention was tested by this experiment, and the inhibitory activity of representative compounds against the leukemia cell line SU-DHL-6 is shown in Table 4.

[0248] Table 4. IC50 of the compounds of the present invention on SU-DHL-6 cells 50 value

[0249] In addition, the representative compounds in this invention have similar inhibitory activity against hematologic malignancy cell lines Pfeiffer, Ramos, and Raji cells as they do against SU-DHL-6 cells, and also exhibit antiproliferative activity against solid tumor cell lines HCT-116 and MCF-7 cells.

[0250] Conclusion: The preferred compounds of the present invention have different inhibitory effects on leukemia cells, indicating that the preferred compounds of the present invention have different efficacies on different cell types.

[0251] 5. Determination of the inhibition of AKT phosphorylation in SU-DHL-6 cells by the compounds of this invention.

[0252] Assay method: Western blot was used, with idelalisib as a positive control, to determine the inhibitory levels of compounds 1 and 13 of this invention on AKT phosphorylation in SU-DHL-6 cells. SU-DHL-6 cells in the logarithmic growth phase were counted at 1.2 × 10⁶ cells per well. 6 Cells were seeded into 6-well plates, with DMSO, drug administration, and positive control groups established. After incubating the 6-well plates in a 37°C, 5% CO2 incubator for 24 hours, the positive control drug idelalisib, the compound, and DMSO were added to the respective groups, with a final drug concentration of 10. -6 mol·L -1 3.3×10 -7 mol·L -1 10 -7 mol·L -1 3.3×10 -8 mol·L -1 and 10 -8 mol·L -1 After drug administration, the culture medium was incubated for another 24 hours. The medium from each well was then transferred to a centrifuge tube and centrifuged for 10 minutes at 1000 rpm. The supernatant was discarded, and the cells were washed twice with PBS. Lysis buffer (RIPA + PMSF + phosphatase inhibitor) was added to each well at 100 μL, and the cells were lysed on ice for 30 minutes, followed by high-speed centrifugation at 1.2 × 10⁻⁶ for 30 minutes. 4r / min. After completion, collect the supernatant for later use. Add standard proteins of different concentrations to 96-well plates, use a protein quantification kit, and measure the absorbance at 562 nm to plot a standard curve. Measure the absorbance of the drug-treated group and the DMSO group using the same method, and calculate the protein concentration based on the standard curve. Then add RIPA to balance the total protein concentration, add loading buffer, boil at 95℃ for 5 min to denature the protein, and set aside. Load the sample onto a precast gel and perform SDS-PAGE electrophoresis for 1 h. After electrophoresis, cut off the gel pieces corresponding to the protein locations, adhere them tightly to a PVDF membrane, and transfer using rapid transfer buffer for 30 min. After completion, block with PBST solution containing 5% skim milk powder for 2 h. After blocking, wash twice with PBST, then use the corresponding primary antibody (AKT, p-Ser). 473 AKT and β-actin were incubated at 4℃ for 13-16 h. After incubation, the membrane was washed three times with PBST, incubated with secondary antibody for 1 h, and then washed three times with PBST. After secondary antibody incubation, the membrane was removed and chemiluminescence was performed using an ECL high-sensitivity chemiluminescence kit. The effect of the compounds on AKT phosphorylation levels was evaluated. The results are shown in Figure 1. Conclusion: The preferred compounds 1 and 13 of this invention have significant inhibitory effects on phosphorylated Akt in a concentration-dependent manner, indicating that the preferred compounds of this invention have different efficacies for different cell types.

[0253] 6. Determination of the covalent binding of the compound of the present invention to PI3Kδ

[0254] Taking compound 1 as an example, in cell elution experiments, if the compound covalently binds to PI3Kδ, cell growth remains inhibited for a period of time after drug clearance, maintaining the inhibitory effect on p-AKT, and slowly recovering over time. Protein mass spectrometry was used to detect whether the compound covalently bound to PI3Kδ and the binding site.

[0255] Test methods: ① Cell elution anti-proliferation assay: 1.2 × 10⁻⁶ cells were washed off and used to treat the cell proliferation. 7 SU-DHL-6 cells were evenly distributed into 24-well plates, 1 mL of culture medium per well, and cultured at 37°C and 5% CO2 for 24 hours. The cells were then incubated with the final detection concentration at IC50. 90Incubate with the appropriate compound or DMSO for 12 hours. After incubation, for the uneluted group, divide 1 mL of cell suspension per well into 5 aliquots of 200 μL and add to each well of a 96-well plate; for the eluted group, transfer the cell suspension to a 1.5 mL Eppendorf tube and centrifuge at 1000 rpm for 3 minutes. After removing the supernatant, wash each well of a 24-well plate with PBS solution, then transfer to the corresponding Eppendorf tube, centrifuge at 1000 rpm for 3 minutes, repeat twice, remove the supernatant, resuspend the cells in 1 mL of culture medium, centrifuge, remove the supernatant again, and finally resuspend the cells in 1 mL of fresh culture medium, divide into 5 aliquots of 200 μL, and add to each well of a 96-well plate. After 60 hours of incubation, under light-protected conditions, add 20 μL of MTT solution (5 mg·mL⁻¹) to each well. -1 Incubate for another 3-4 hours in a constant temperature incubator. Remove the 96-well plate and carefully aspirate the culture medium. Add 150 μL of DMSO to each well, shake for 10 min, and after the blue-purple formazan is fully dissolved, measure the OD value of each well at 490 nm using a microplate reader. Calculate the cell growth inhibition rate using the formula and calculate the GI using Graphpad Prism 5.0 software. 50 Value. The calculation formula is the same as that used in the antiproliferative activity assay. ② Detection of p-AKT level after cell elution: 1.8 × 10 7 SU-DHL-6 cells were evenly distributed into 6-well plates, 2 mL per well, and cultured at 37°C and 5% CO2 for 24 h. The final detection concentration was then determined using IC50 assay. 90 The compound or DMSO was incubated with cells for 12 hours. For the elution group, the cell suspension was transferred to a 4 mL Eppendorf tube and centrifuged at 1000 rpm for 3 minutes. After removing the supernatant, 2 mL of PBS solution was added, the cells were resuspended, and centrifuged at 1000 rpm for 3 minutes, repeated twice. Finally, 2 mL of fresh culture medium was added, the cells were resuspended, and a new 6-well plate was added. For the non-elution group, the cells were transferred to a 4 mL Eppendorf tube, centrifuged at 1000 rpm for 3 minutes, repeated twice, without discarding the supernatant, and resuspended before adding a new 6-well plate. After culturing the elution and non-elution groups in an incubator for 12 hours, the cells were collected and lysed, and then the p-AKT level was detected by Western blot analysis. ③ Protein mass spectrometry: After incubating the compound with PI3Kδ for 12 hours, the cells were lysed with chymotrypsin, ultrafiltered, desalted, and then subjected to protein mass spectrometry to determine whether covalent binding with PI3Kδ occurred at the Lys779 site.

[0256] The results are shown in Figure 2. Conclusion: The preferred compound 1 of this invention continues to inhibit cell growth for a period of time after drug clearance, maintaining its inhibitory effect on p-AKT, which slowly recovers over time. Protein mass spectrometry analysis revealed that the preferred compound covalently binds to PI3Kδ at the Lys779 binding site.

[0257] 7. In vivo antitumor activity assay of the compounds of this invention against SU-DHL-6 cell xenografts in nude mice.

[0258] The in vivo antitumor activity of the preferred compound 1 of this invention was determined. A nude mouse xenograft model was constructed using SU-DHL-6 cells, and compound 1 was administered by gavage to observe its in vivo antitumor effect.

[0259] Test methods: ① Construction of nude mouse xenograft model: SU-DHL-6 cells were cultured in vitro. After the cells reached a sufficient quantity, they were collected, centrifuged, the supernatant was discarded, and the cells were resuspended in a solution of PBS and base gel (1:1) to make the cell suspension density 1×10⁻⁶ cells per 0.1 mL. 7 ① 0.1 mL of cell suspension was subcutaneously inoculated into the right lateral abdomen of each nude mouse. ② Grouping and administration: The average tumor volume of the nude mice to be tumor-bearing reached 100 mm. 3 Around 10:00 AM, tumor-bearing nude mice were randomly divided into 4 groups, with 6 mice in each group. The day of drug administration was designated as day 0 (d0), and the drug administration volume was 5 mL / kg. -1 The medication was administered once daily. The weight and tumor volume of the nude mice were recorded every two days. The mice were divided into a solvent group (DMSO: Tween 80: 5% glucose injection = 1:2:7) and a treatment group (positive control group, low-dose group, high-dose group). ③ Measurement and calculation of tumor volume, as well as dissection and weighing of the tumor mass: Tumor volume (V) = 1 / 2 × a × b 2 In the formula, a and b represent the length and width of the tumor, respectively. Tumor growth inhibition rate (TGI%) = [1 - (V d14， 给药组 -V d0，给药组 ) / (V d14，溶剂组 -V d0，溶剂组 [×100%] Mice were sacrificed on day 15, tumor masses were dissected, other tissues were removed, and the tumors were weighed and photographed. Finally, the data were analyzed and plotted using GraphPad Prism 5.0. ④ Immunohistochemical study of tumor tissue: Tumor tissue sections from different drug-treated groups were stained with Ki67 antibody to observe the proliferative capacity of tumor cells in different drug-treated groups; the dissected tumor tissues were lysed by low-temperature grinding and Western blot analysis to determine the level of p-AKT in the tumor tissues of different drug-treated groups.

[0260] The results are shown in Figures 3 and 4. Conclusion: The preferred compound 1 of this invention has a significant inhibitory effect on the growth of SU-DHL-6 cell xenografts in nude mice, indicating that the preferred compound of this invention has in vivo antitumor activity.

[0261] In summary, the 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives disclosed in this invention are solvates, enantiomers, diastereomers, tautomers, or mixtures thereof in any proportion, including racemic mixtures, of compounds having structures of formulas (I-1) and (I-2) or pharmaceutically acceptable salts thereof. These compounds represent a novel class of compounds capable of acting as PI3Kδ inhibitors. Measurements of PI3Kδ kinase activity and PI3K selectivity confirm that the compounds disclosed in this invention exhibit significant inhibitory activity against PI3Kδ kinase activity and significant selectivity for PI3Kδ activity. Cell elution experiments demonstrate that the compounds disclosed in this invention covalently bind to PI3Kδ and possess long-lasting inhibitory effects. Protein mass spectrometry results confirm that the binding site of the compounds disclosed in this invention for PI3Kδ is Lys779. In vitro cell proliferation assays on various hematologic malignancy cell lines showed that the compounds disclosed in this invention exhibit different inhibitory effects on hematologic malignancy cells. In vivo antitumor activity assays on SU-DHL-6 cell xenografts in nude mice showed that the compounds disclosed in this invention have significant in vivo antitumor activity. The compounds disclosed in this invention, or their pharmaceutically acceptable salts, hydrates, and solvates, can act as PI3Kδ inhibitors and play a role in the treatment and / or prevention of inflammatory diseases or tumors.

[0262] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.

Claims

1. A class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives, characterized in that, Including compounds represented by Formula I below; Where X is CH or N; Y is either CH or N; W is either CH or N; V is either O or NCH3; Z represents tetrahydropyrrole or CHCH3; R1 is an aryloxy group, a heteroaryloxy group, or hydrogen, and the aryloxy group can be substituted by 0-3 R3 groups; Alternatively, R1 may be directly attached to an aryl group and R1 may be chloromethyl or 2-enoylamino. R2 is a methoxy, hydroxy, or ethynyl group; The R3 group is selected from halogen, cyano, nitro, alkyl, haloalkyl, and alkoxy groups; It also includes one of any proportion of a solvate, enantiomer, diastereomer and tautomer of the compound shown in formula (I); Alternatively, it may include one of the following: a pharmaceutically acceptable salt of the compound represented by formula (I) and a solvate of the salt, an enantiomer, a diastereomer and a mixture of tautomers in any proportion.

2. The class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives according to claim 1, characterized in that, Including compounds represented by Formula I-1 or Formula I-2 below; The structural formulas of compounds (I-1) and (I-2) are as follows: Where X is CH or N; Y is either CH or N; R1 is an aryloxy group, a heteroaryloxy group, or hydrogen, and the aryloxy group can be substituted by 0-3 R3 groups; Alternatively, R1 may be directly attached to an aryl group and R1 may be chloromethyl or 2-enoylamino. R2 is a methoxy, hydroxy, or ethynyl group; The R3 group is selected from halogen, cyano, nitro, alkyl, haloalkyl, and alkoxy groups.

3. The class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives according to claim 2, characterized in that, R1 is phenoxy, pyridoxy, or hydrogen.

4. The class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives according to claim 2, characterized in that, When R1 is phenoxy, it can be replaced by 0-3 R3 groups, where R3 is selected from fluorine, chlorine, cyano, nitro, methyl, trifluoromethyl, or methoxy.

5. The class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives according to claim 2, characterized in that, When Y is N, R2 is methoxy; when Y is CH, R2 is hydroxy or ethynyl.

6. The class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives according to claim 2, characterized in that, When R1 is directly attached to an aryl group, R1 is chloromethyl, acryloylamino, or but-2-enoylamino.

7. A class of 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives according to any one of claims 1 to 6, characterized in that, The structural formula of the compound is selected from one of the following compounds:

8. The use of any one of the 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives as described in claims 1 to 7 in the preparation of PI3Kδ inhibitors.

9. The use of any one of the 6-arylquinazoline-4-amine and 6-arylpyridopyrimidine-4-amine derivatives as described in claims 1 to 7 in the preparation of treatments and / or preventions of diseases caused by PI3Kδ overexpression.

10. The application as described in claim 9, characterized in that, The diseases mentioned are rheumatoid arthritis, hematologic malignancies, lymphoma, PI3Kδ hyperactivation syndrome, Sjögren's syndrome, or asthma.

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